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ANALISA ARTIKEL “TANAMAN PARE SEBAGAI TERAPI UNTUK DIABETES”
Disusun untuk memenuhi tugas mata kuliah Farmakologi dalam Keperawatan
Dosen Pembimbing: Ns. Nur Widayati, S.Kep., MN
Disusun oleh : Dhea Cristina Damaiyanti Saragih
(172310101071)
Della Kharisma Putri
(172310101100)
PROGRAM STUDI ILMU KEPERAWATAN UNIVERSITAS JEMBER 2017
ANALISA ARTIKEL “TANAMAN PARE SEBAGAI TERAPI UNTUK DIABETES”
Disusun untuk memenuhi tugas mata kuliah Farmakologi dalam Keperawatan
Dosen Pembimbing: Ns. Nur Widayati, S.Kep., MN
Disusun oleh : Dhea Cristina Damaiyanti Saragih
(172310101071)
Della Kharisma Putri
(172310101100)
PROGRAM STUDI ILMU KEPERAWATAN UNIVERSITAS JEMBER 2017
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HALAMAN PENGESAHAN
Tugas Analisa Pemanfaatan Hasil-hasil Pertanian dalam Pengobatan dengan Judul “TANAMAN ALPUKAT SEBAGAI TERAPI UNTUK DIABETES” yang disusun oleh: Dhea Cristina Damaiyanti Della Kharisma Putri
172310101071 17231010101100
telah disetujui untuk diseminarkan dan dikumpulkan pada: hari/tanggal:……………….
Makalah ini disusun dengan pemikiran sendiri, bukan hasil jiplakan atau reproduksi ulang makalah yang telah ada.
Ketua,
Dhea Cristina Damaiyanti NIM 172310101071
Mengetahui, Penanggung jawab mata kuliah
Dosen Pembimbing
Ns. Nur Widayati, S.Kep., MN
Ns. Wantiyah, S.Kep., M.kep NIP 198107122006042001
NIP 198106102006042001
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PRAKATA Puji syukur ke hadirat Allah SWT, atas segala rahmat dan karunia-Nya sehingga penulis dapat menyelesaikan makalah yang berjudul “Tanaman Pare Sebagai Terapi Untuk Diabetes” Makalah ini disusun untuk memenuhi tugas mata kuliah Farmakologi dalam Keperawatan pada Program Studi Ilmu Keperwatan Universitas Jember. Penulis menyusun makalah ini dengan judul “Analisa Artikel Pemanfaatan buah pare (Momordica charantia L.) untuk Terapi Diabetes”. Makalah ini disusun dengan tujuan untuk memenuhi tugas mata kuliah Farmakologi dan juga untuk menjadi salah satu sumber bacaan mahasiswa dalam mempelajari obat dan pengobatan tradisional. Penyusunan makalah ini tidak lepas dari bantuan berbagai pihak. Oleh karena itu, penulis menyampaikan terima kasih kepada: 1. Ns. Wantiyah, M.Kep., selaku dosen pengampuh dan penanggung jawab mata kuliah Farmakologi dalam Keperawatan; 2. Ns. Nur Widayati, S.Kep., MN selaku dosen pembimbing umum; 3. Semua pihak yang telah membantu dalam menyelesaikan makalah ini. Penulis juga menerima segala kritik dan saran dari semua pihak demi kesempurnaan makalah ini. Akhirnya penulis berharap semoga makalah ini dapat bermanfaat.
Jember, 09 April 2018
Penulis
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DAFTAR ISI
Halaman HALAMAN SAMPUL ........................................................................................
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HALAMAN JUDUL ..........................................................................................
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HALAMAN PENGESAHAN ...........................................................................
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PRAKATA ........................................................................................................
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DAFTAR ISI ......................................................................................................
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BAB 1. PENDAHULUAN ..................................................................................
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1.1 Latar Belakang ...............................................................................
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1.2 Tujuan Pembuatan Makalah .........................................................
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BAB 2. KONSEP DASAR OBAT TRADISIONAL ..........................................
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2.1 Obat Tradisional .............................................................................
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2.1.1 Definisi............................................................................. 2.1.2 Macam-macam Obat Tradisional..................................... 2.1.3 Ciri-Ciri Obat Tradisional................................................
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2.2 Tingkatan obat tradisional ............................................................
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2.3 Syarat-Syarat Obat Tradisional (Safety Drug) ............................
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2.4 Peraturan terkait obat dan pengobatan tradisional .....................
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BAB 3. ANALISA ARTIKEL...............................................................................
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3.1 Jenis Tanaman Obat ......................................................................
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3.1.1 Nama Ilmiah Tanaman........................................................
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3.2.2 Ciri-Ciri...............................................................................
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3.1.3 Nama Produk yang Sudah Dibuat Obat............................
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3.2 Kandungan Dalam Obat Tradisional ........................................
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3.3 Farmasetika ................................................................................
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3.4 Farmakokinetik ..........................................................................
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3.5 Farmakodinamik .........................................................................
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3.6 Dosis......................................................................................................................15 3.7 Indikasi dan Kontraindikasi.......................................................................16 3.8 Efek Samping Obat
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3.9 Hal-hal yang harus diperhatikan.............................................................17 3.10 Implikasi Keperawatan
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BAB 4. PENUTUP...................................................................................................................19 4.1 Kesimpulan........................................................................................................19 4.2 Saran....................................................................................................................19 DAFTAR PUSTAKA..............................................................................................................21 LAMPIRAN...............................................................................................................................23
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BAB 1. PENDAHULUAN
1.1 Latar Belakang Penyakit Diabetes Melitus saat ini hampir merambah seluruh dunia, Menurut data Organisasi Kesehatan Dunia (WHO), Indonesia menempati urutan keenam dunia sebagai negara dengan jumlah penderita DM terbanyak setelah India, China, Uni Soviyet, Jepang dan Brazil. Tercatat pada tahun 1995, jumlah penderita DM di Indonesia mencapai 5 juta. Pada tahun 2000 yang lalu saja, terdapat sekitar 5,6 juta penduduk Indonesia yang mengidap diabetes. Namun, pada tahun 2006 diperkirakan jumlah penderita diabetes di Indonesia meningkat tajam menjadi 14 juta orang, jika peningkatan penderita Diabetes Mellitus pertahunnya 230.000 orang, maka bisa kita bayangkan berapa banyak jumlah penderita Diabetes Mellitus pada tahun 2017 (Hady, 2011). Penyakit diabetes adalah penyakit gangguan metabolisme yang merupakan suatu kumpulan gejala yang timbul pada seseorang karena adanya peningkatan kadar glukosa darah di atas nilai normal. Berbagai peneitian epidemologi yang dilakukan, penderita diabetes selalu meningkat dari tahun 1980-an. Data hasil riskesdas tahun 2013 menunjukkan peningkatan dari data hasil riskesdas tahun 2007, yaitu dengan proporsi dari 5,7% menjadi 6,9% pada penduduk usia 15 tahun ke atas (Riskesdas, 2013). Sedangkan menurut IDM (International Diabetes Federation) tahun 2015 jumlah penderita diabetes di dunia mencapai 415 juta orang yang tersebar di setiap benua. Diabetes yang tidak terkontrol dapat menyebabkan komplikasi akut dan kronis, yaitu seperti hipoglikemia, sering terjadi pada penderita diabetes tipe 1 karena lupa atau sengaja meninggalkan makan, atau karena olahraga terlalu berat. Selain itu, penderita diabetes juga berpotensi terkena komplikasi lain seperti hiperglikemia, makrovaskular dan mikrovakular (Dirjen Bina Farmasi Komunitas dan Klinik, 2005). Diabetes juga dapat menyebabkan meningkatnya risiko penyakit jantung dan stroke, neuropati, dan menjadi penyebab utama terjadinya gagal ginjal bahkan kematian (Kemenkes, 2014). Pengobatan tradisional merupakan upaya kesehatan yang dilakukan secara turun temurun yang dipercaya masyarakat untuk dapat menangani berbagai penyakit. Hal ini menjadi familier kembali di kalangan masyarakat modern dikarenakan banyaknya penelitian ilmiah untuk menunjukkan potensi berbagai tumbuhan alami dalam mengatasi permasalahan kesehatan manusia. Oleh karenanya muncullah berbagai bentuk sediaan obat dari tanaman obat sehingga mempermudah masyarakat dalam mengonsumsinya 1
(Suprapto, 1992). Kelebihan dari tanaman obat seperti mudah didapat, murah dan rendahnya efek samping membuatnya lebih menarik dari obat kimia. Namun, terdapat juga kelemahan dari obat tradisional yaitu efek farmakologisnya masih relative lemah, belum teruji klinik dan masih mudah tercemar mikroorganisme (Katno, 2004) Berdasarkan penelitian secara in –vitro , pare (Momorcadia charantia) memiliki aktivitas menghambat enzim a-glukosidase dan a- amylase (Zuraini Ahmad,2012). Terdapat beberapa zat aktif utama yang terkandung dalam buah pare yaitu phyto-nutrient, polypeptide-p, dan charantine. Senyawa ini secara structural mirip dengan insulin hewan (Antinio Miguel dkk, 2006). Sementara zat yang memiliki potensi antidiabetes yaitu alkaloid, saponin, flavonoid, polifenol dan glikosida cucurbitacin, zat – zat inilah yang membuat buah pare memiliki aktivitas antiglikasi (Fernandes, 2007) Dari hasil penelitian menunjukkan beberapa data yang signifikan terkait potensi dan efek samping dari penggunaan Pare sebagai antidiabetes diantaranya peningkatan alkaline-phospatase dan gamma glutamyl transferase di tikus (Tennekon KH dkk, 1994), hipotensi pada anjing (Feng PC, 1962), sterilitas pada tikus betina, perdarahan uterus pada tikus hamil dan kelinci (Dixit, 1996), dan peningkatan kolesterol serum dan nonesterifikasi asam lemak pada anjing (Dixit, 1996). Dalam uji coba manusia, yang paling umum efek samping yang dilaporkan adalah sakit perut dan diare (Sharma VN,1960). Efek hipoglikemik yang berpotensi fatal sering terjadi pada anak-anak setelah pemberian sediaan teh daun sebelum sarapan (Hulin A,1988). Selain itu, individu dengan kekurangan glukosa-6-fosfat beresiko terkena defisiensi G6PD (Basch E, 2003). Dari penjelasan diatas maka dapat ditarik kesimpulan bahwa Momordica charantia berpotensi dalam aktivitas antidiabetes. 1.2 Tujuan 1.2.1 Mengetahui pengaruh pemberian ekstrak pare terhadap penderita Diabetes Melitus 1.2.2 Mengetahui manfaat pengobatan non-farmakologi menggunakan bahan alami buah pare 1.2.3 Mengetahui farmasetika, farmakokinetik, farmakodinamik, dosis, indikasi dan kontraindikasi, serta efek samping obat pada obat tradisional pare
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BAB 2. KONSEP DASAR OBAT TRADISIONAL 2.1 Obat Tradisional 2.1.1 Pengertian Obat tradisional adalah obat yang didapat dari bahan alam (mineral, tumbuhan atau hewan), terolah secara sederhana atau dasar pengalaman yang digunakan dalam pengobatan tradisional (Syamsuni, 2006). Obat tradisional adalah bahan atau ramuan bahan yang berupa bahan tumbuhan, bahan hewan, bahan mineral, sediaan sarian (galenik) atau campuran dari bahan tersebut yang secara turun temurun telah digunakan untuk pengobatan, dan dapat diterapkan sesuai dengan norma yang berlaku di masyarakat (Peraturan Kepala BPOM No. 12 Th. 2014). Obat tradisional merupakan obat-obatan yang dibuat dari bahan alami secara tradisional dan merupakan resep yang berdasarkan nenek moyang atau sudah ada sejak jaman dahulu (Redaksi Kesehatan, 2015). 2.1.2 Macam – Macam Obat Tradisional Menurut Peraturan Kepala BPOM RI No. 12 Tahun 2014 Tentang Persyaratan Mutu Obat Tradisional, macam – macam obat tradisional adalah sebagai berikut : 1. Sediaan Galenik yang selanjutnya disebut ekstrak adalah sediaan kering, kental atau cair dibuat dengan menyari Simplisia nabati atau hewani menurut cara yang cocok, di luar pengaruh cahaya matahari langsung. 2. Simplisia adalah bahan alam yang telah dikeringkan yang digunakan untuk pengobatan dan belum mengalami pengolahan, kecuali dinyatakan lain suhu pengeringan tidak lebih dari 60oC. 3. Rajangan adalah sediaan Obat Tradisional berupa satu jenis Simplisia atau campuran beberapa jenis Simplisia, yang cara penggunaannya dilakukan dengan pendidihan atau penyeduhan dengan air panas. 4. Serbuk Simplisia adalah sediaan Obat Tradisional berupa butiran homogen dengan derajat halus yang sesuai, terbuat dari simplisia atau campuran dengan Ekstrak yang cara penggunaannya diseduh dengan air panas.
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5. Serbuk Instan adalah sediaan Obat Tradisional berupa butiran homogen dengan derajat halus yang sesuai, terbuat dari Ekstrak yang cara penggunaannya diseduh dengan air panas atau dilarutkan dalam air dingin. 6. Kapsul adalah sediaan Obat Tradisional yang terbungkus cangkang keras. 7. Kapsul Lunak adalah sediaan Obat Tradisional yang terbungkus cangkang lunak. 8. Tablet adalah sediaan Obat Tradisional padat kompak, dibuat secara kempa cetak, dalam bentuk tabung pipih, silindris, atau bentuk lain, kedua permukaannya rata atau cembung, terbuat dari Ekstrak kering atau campuran Ekstrak kental dengan bahan pengering dengan bahan tambahan yang sesuai. 9. Efervesen adalah sediaan padat Obat Tradisional, terbuat dari Ekstrak, mengandung natrium bikarbonat dan asam organik yang menghasilkan gelembung gas (karbondioksida) saat dimasukkan ke dalam air. 10. Pil adalah sediaan padat Obat Tradisional berupa masa bulat, terbuat dari serbuk Simplisia dan/atau Ekstrak. 11. Dodol/Jenang adalah sediaan padat Obat Tradisional dengan konsistensi lunak tetapi liat, terbuat dari Serbuk Simplisia dan/atau Ekstrak. 12. Pastiles adalah sediaan padat Obat Tradisional berupa lempengan pipih, umumnya berbentuk segi empat, terbuat dari Serbuk Simplisia dan/atau Ekstrak. 13. Cairan Obat Dalam adalah sediaan Obat Tradisional berupa minyak, larutan, suspensi atau emulsi, terbuat dari Serbuk Simplisia dan/atau Ekstrak dan digunakan sebagai obat dalam. 14. Cairan Obat Luar adalah sediaan Obat Tradisional berupa minyak, larutan, suspensi atau emulsi, terbuat dari Simplisia dan/atau Ekstrak dan digunakan sebagai obat luar. 15. Salep dan Krim adalah sediaan Obat Tradisional setengah padat terbuat dari Ekstrak yang larut atau terdispersi homogen dalam dasar Salep/Krim yang sesuai dan digunakan sebagai obat luar. 16. Parem adalah sediaan padat atau cair Obat Tradisional, terbuat dari Serbuk Simplisia dan/atau Ekstrak dan digunakan sebagai obat luar. 4
17. Pilis dan Tapel adalah sediaan padat Obat Tradisional, terbuat dari Serbuk Simplisia dan/atau Ekstrak dan digunakan sebagai obat luar. 18. Koyo/Plester adalah sediaan Obat tradisional terbuat dari bahan yang dapat melekat pada kulit dan tahan air yang dapat berisi Serbuk Simplisia dan/atau Ekstrak, digunakan sebagai obat luar dan cara penggunaannya ditempelkan pada kulit. 19. Supositoria untuk wasir adalah sediaan padat Obat Tradisional, terbuat dari Ekstrak yang larut atau terdispersi homogen dalam dasar supositoria yang sesuai, umumnya meleleh, melunak atau melarut pada suhu tubuh dan cara penggunaannya melalui rektal. 20. Film Strip adalah sediaan padat Obat Tradisional berbentuk lembaran tipis yang digunakan secara oral. 2.1.3 Ciri – Ciri Obat Tradisional Menurut Eraherbs, 2016, obat tradisional memiliki ciri – ciri yang berbeda dengan obat modern, yaitu : 1. Obat tradisional terbuat dari bahan – bahan tradisional dan alami yaitu tanaman obat atau dikenal dengan apotek hidup. 2. Dalam meracik obat tradisional, tumbuhan obat yang digunakan tidak perlu dilakukan pengujian laboratorium terlebih dahulu. 3. Resep obat tradisional yang digunakan untuk menyembuhkan penyait biasanya diperoleh dari resep nenek moyang. Dengan kata lain, resep racikan obat tradisional diperoleh secara turun-temurun. 4. Obat tradisional umumnya memiliki efek samping yang lebih kecil dibanding obat modern. Karena dosis yang digunakan langsung memilki efek positif pada orang yang mengkonsumsi. Meskipun ukuran dosis obat tradisional tidak ditentukan secara kuantitatif, namun biasanya dosis obat tradisional tidak terlalu tinggi. 5. Dalam mengkonsumsi obat tradisional diperlukan dalam waktu lama, karena obat tradisional memiliki dosis yang rendah dibanding obat modern. Jadi obat tradisional harus dikonsumsi secara teratur.
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6. Obat tradisional biasanya tidak hanya dapat menyembuhkan satu penyakit. Misalnya satu tanaman dapat digunakan sebagai obat antikanker dan hipertensi juga dapat untuk mengontrol diabetes. 7. Obat tradisional umumnya memiliki harga lebih murah karena mudah dijumpai. 2.2 Tingkatan Obat Tradisional Berdasarkan Keputusan Kepala Badan Pengawas Obat dan Makanan Republik Indonesia Nomor HK.00.05.4.2411 Tahun 2004 Tentang Ketentuan Pokok Pengelompokan dan Penandaan Obat Bahan Alam Indonesia, obat tradisional di Indonesia dikelompokkan menjadi Jamu, Obat Herbal Terstandar dan Fitofarmaka. 1. Jamu (Empirical Based Herbalmedicine) Jamu merupakan bagian dari obat tradisional yang digunakan secara turun temurun dan baru memiliki klaim penggunaan sesuai dengan jenis pembuktian tradisional (secara empiris/turun temurun) dan telah melewati 3 generasi. Artinya jika satu generasi rata – rata umur adalah 60 tahun, maka ramuan tersebut sudah bertahan 180 tahun. Sebagai contoh, masyarakat telah menggunakan rimpang temulawak untuk mengatasi hepatitis selama ratusan tahun. Pembuktian khasiat tersebut baru sebatas pengalaman, selama belum ada penelitian ilmiah yang membuktikan bahwa temulawak sebagai antihepatitis. Jadi Curcuma xanthorriza itu tetaplah jamu. Jadi, ketika dikemas dan dipasarkan, produsen dilarang mengklaim produk tersebut sebagai obat dan harus tertera logo berupa ranting daun berwarna hijau dalam lingkaran. Sediaan jamu dapat berupa simplisia sederhana, seperti rimpang, daun atau akar kering (Azrim, 2013).
Gambar 2.1 Logo jamu. (Azrim, 2015) 2. Obat Herbal Standar (Scientificbased Herbal Medicine) OHT adalah sediaan obat bahan alam yang sediaannya berupa ekstrak yang telah dibuktikan keamanan dan khasiatnya secara ilmiah dengan uji praklinik dan bahan bakunya telah distandarisasi. Disamping itu herbal terstandar harus melewati uji pra klinis seperti uji toksisitas (keamanan), kisaran dosis, farmakodinamik (kemanfaatan) dan teratogenik (keamanan terhadap janin). Uji praklinis 6
meliputi uji in vivo dan in vitro. Uji in vivo dilakukan terhadap mencit, sedangkan uji in vitro dilakukan terhadap sebagian organ yang teriolasi, kultur sel atau mikroba (Azrim, 2013).
Gambar 2.2 Logo Obat Herbal Terstandar (OHT). (Azrim, 2015) 3. Fitofarmaka (Clinical Basedherbal Medicine) Adalah sediaan obat bahan alam yang telah dibuktikan kemanan dan khasiatnya secara ilmiah dengan uji praklinik dan uji klinik, bahan baku dan produk jadinya telah distandarisasi. Fitofarmaka merupakan tingkatan tertinggi dari bahan alami sebagai “obat”. Uji klinik sudah dilakukan terhadap manusia dengan dosis yang disesuaikan. Setelah lulus uji fitofarmaka, produk dapat dikatakan sebagai obat dengan syarat tidak menyimpang dari materi uji klinis sebelumnya. Artinya, jika uji klinis hanya sebagai antikanker, maka produk tidak boleh diklaim sebagai antikanker dan antidiabetes (Azrim, 2013).
Gambar 2.3 Logo Fitofarmaka. (Azrim, 2015) 2.3 Syarat-Syarat Obat Tradisional Menurut Badan Pengawas Obat dan Makanan (BPOM) tahun 2012 menyebutkan persyaratan yang harus dipenuhi dalam memproduksi obat tradisional yaitu : a.
Personalia Personalia hendaklah mempunyai pengetahuan, pengalaman, ketrampilan dan kemampuan yang sesuai dengan tugas dan fungsinya, dan tersedia dalam jumlah yang cukup.
b.
Bangunan Bangunan industri obat tradisional hendaklah menjamin aktifitas industri dapat berlangsung dengan aman, syarat bangunan industri obat itu sendiri yaitu:
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1) Bangunan industri obat tradisional hendaklah berada di lokasi yang terhindar dari pencemaran, dan tidak mencemari lingkungan. 2) Bangunan industri obat tradisional hendaklah memenuhi persyaratan hygiene. 3) Bangunan untuk pembuatan obat tradisional hendaklah memiliki rancangan, konstruksi, dan pekerja yang memadai. c.
Peralatan Peralatan yang digunakan dalam pembuatan produk hendaklah memiliki rancang bangun konstruksi yang tepat, ukuran yang memadai serta ditempatkan dengan tepat, sehingga mutu yang dirancang bagi tiap produk terjamin secara seragam, serta untuk memudahkan pembersihan dan perawatannya. Sarana pengolahan produk hendaklah dilengkapi dengan peralatan sesuai dengan proses pembuatan dan bentuk sediaan yang akan dibuat.
d. Sanitasi dan Hygiene Dalam pembuatan produk hendaklah diterapkan tindakan sanitasi dan hygiene yang meliputi bangunan, peralatan dan perlengkapan, personalia, bahan dan wadah serta faktor lain sebagai sumber pencemaran produk. e. Penyiapan Bahan Baku Setiap bahan baku yang digunakan untuk pembuatan hendaklah memenuhi persyaratan yang berlaku. f. Pengolahan dan Pengemasan Pengolahan dan pengemasan hendaklah dilaksanakan dengan mengikuti cara yang telah ditetapkan oleh industri sehingga dapat menjamin produk yang dihasilkan senantiasa memenuhi persyaratan yang berlaku: 1. Menjalankan verifikasi 2. Tidak menimbulkan pencemaran 3. Melakukan system penomeran kode produksi 4. Penimbangan dan penyerahan 5. Waktu pengolahan dan pengemasan. 2.4 Peraturan Terkait Obat dan Pengobatan Tradisional Peraturan terkait obat dan pengobatan tradisional tercantum dalam : 1. Keputusan Menteri Kesehatan Republik Indonesia Nomor 1076/Menkes/SK/VII/2003 Tentang Penyelenggaraan Pengobatan Tradisional Menteri Kesehatan Republik Indonesia 8
2. Peraturan Pemerintah Republik Indonesia Nomor 103 Tahun 2014 Tentang Pelayanan Kesehatan Tradisional 3. Peraturan Menteri Kesehatan Republik Indonesia Nomor 007 Tahun 2012 Tentang Registrasi Obat Tradisional 4. Peraturan Kepala Badan Pengawas Obat Dan Makanan Republik Indonesia Nomor 12 Tahun 2014 Tentang Persyaratan Mutu Obat Tradisional 5. Keputusan Menteri Kesehatan RI No. 661/Menkes/SK/VII/1994 tentang Persyaratan Obat Tradisional BAB 3. ANALISA ARTIKEL 3.1 Jenis Tanaman Obat 3.1.1 Nama Ilmiah Tanaman Menurut Krisnakai, 2017 tanaman buah pare (Momordica charantia) memiliki klasifikasi ilmiah sebagai berikut: Kingdom: Plantae Devisio: Spermatophyta Sub-Devisio: Angiospermae Classis: Dicotyledoneae Ordo: Cucurbitales Familia: Cucurbitaceae Genus: Momordica Spesies: Momordica Charantia L. 3.1.2 Ciri-ciri Menurut Santoso (2008), Pare adalah tanaman yang rasanya pahit namun memiliki khasiat yang berbuah manis. Nama ilmiahnya adalah Momordica charantia. Adapun ciri-ciri dari tanaman obat ini ialah : a. Termasuk tanaman herbal dari famili Cucurbitaceae b. Tanaman semak semusim yang hidup menjalar dengan sulur berbentuk spiral
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c. Batang tidak bulat sempurna, berusuk lima, berambut saat muda dan gundul setelah tua, dan warnanya hijau d. Daun tunggal, berbentuk lekuk tangan, berbulu, panjang tangkai 7-13 cm, dan warnanya hijau e. Bunga tunggal, berkelamin satu, kelopak berbentuk lonceng, berusuk banyak, panjang 5-15 cm, mahkota berbentuk bulat telur dan warnanya kuning muda f. Buah buni, berbentuk bulat memanjang, berusuk, berwarna hijau saat muda dan berwarna jingga setelah tua, rasanya pahit, renyah serta teksturnya berair g. Biji berada di dalam buah, berbentuk pipih, keras, warna coklat kekuningan h. Akar tunggang, warna putih kotor
Gambar 3.1 Momordica charantia 3.1.3 Nama Produk yang Sudah Dibuat Obat (Jika Ada) Salah satu produk obat tradisional yang memanfaatkan buah pare yaitu karela tablet yang dikonsumsi dalam bentuk tablet. Telah banyak produk kapsul maupun tablet yang berasal dari buah pare yang memang mampu sebagai obat tradisional untuk diabetes. Teh daun tin juga dapat diproduksi sendiri di rumah apabila memiliki tanaman buah tin ini.
Gambar 3.2 Produk Tablet buah Pare
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3.2 Kandungan dalam Obat Tradisional Analisis gizi buah pare menunjukkan bahwa buah ini kaya akan karbohidrat, protein, vitamin dan serat. Buah pare memegang nilai gizi tertinggi di antara semua famili Cucurbitaceae (Kwarta, et. all, 2016). Memanfaatkan pare untuk diabetes dikenal sebagai bantuan pengobatan yang sangat efektif karena memiliki kandungan zat yang berperan aktif sebagai penurun gula darah dalam tubuh, diantaranya adalah sebagai Antiradang, sifatnya dingin. Charantin dan polypeptide-P di dalam pare merangsang sel beta pankreas untuk mengeluarkan insulin dan juga meningkatkan cadangan glikogen di hati.. (Febryan, 2016) Pare juga tinggi zat besi, dan dua kali lipat kalium dari pisang dan dua kali kalsium dari bayam. Untuk membantu diabetes tipe 2, pare bisa dimakan mentah setiap hari. Hal ini akan membantu memberikan nutrisi yang anda butuhkan untuk mengalahkan resistensi insulin atau diabetes tipe 2. Anda juga bisa menggunakan pare untuk mengatasi diabetes tipe 1, karena pare dianggap melawan proses penghancuran sel oleh sistem kekebalan tubuh menjadi bagian dari gangguan autoimun. (Anah, 2015) Berikut ini Kandungan Buah Pare tiap 100 gramnya :
Gambar 3.3 Kandungan Buah Pare tiap 100 gram
3.3 Farmasetika Buah pare (Momordica charantia L.) apabila dikonsumsi secara langsung dalam bentuk segar kemungkinan kurang disukai oleh masyarakat karena rasa pahit dari buah pare tidak bisa dihindari. Sehingga untuk meningkatkan kepraktisan dalam penggunaannya serta 11
meningkatkan nilai ekonomisnya perlu dikembangkan dalam bentuk sediaan lain yaitu tablet ekstrak buah pare. Bentuk sediaan tablet sangat menguntungkan karena mudah untuk dikonsumsi, praktis, takarannya tepat, dikemas secara baik, praktis transportasi dan penyimpanannya (stabilitasnya terjaga dalam sediaannya) serta mudah ditelan, sehingga diharapkan masyarakat dapat tertarik untuk mengkonsumsi sediaan tablet ekstrak buah pare. Buah pare telah banyak dimanfaatkan sebagai obat tradisional karena kandungannya yang banyak memberikan manfaat bagi kesehatan. Saat ini ada beberapa bentuk sediaan buah pare yang dapat dikonsumsi sebagai obat, yaitu dalam bentuk kapsul ataupun tablet. Sedangkan dalam penelitian yang dilakukan oleh Fitri Arum, Sunyoto, Nurul Hidayati, 2015 bentuk sediaan yang digunakan adalah berbentuk ekstrak yang dicampur dengan aspartam. Tujuan penelitian ini adalah untuk membuat tablet ekstrak buah pare (Momordica carantia L.) dengan bahan pemanis aspartam dengan berbagai konsentrasi yang dapat menutupi rasa pahit dan memenuhi persyaratan mutu fisik tablet. Formula tablet ekstrak buah pare ( Momordica charantia L.) dengan bahan pemanis aspartam pada konsentrasi 0,5% dan 0,625% mampu menghasilkan tablet yang memenuhi persyaratan. Sedangkan pada konsentrasi 0,75% belum mampu menghasilkan tablet yang memenuhi persyaratan. Konsentrasi pemanis aspartam memberi pengaruh terhadap sifat fisik granul dan sifat fisik tablet yaitu pada kekerasan dan waktu hancur tablet. Konsentrasi pemanis aspartam yang paling baik sebagai bahan pemanis tablet ekstrak buah pare (Momordica charantia L.) adalah formula I yaitu dengan konsentrasi bahan pengikat 0,5%. Untuk mendapatkan zat aktif yang terdapat dalam pare (Momordica charantia L.) tersebut dilakukan penyarian zat aktif dengan metode maserasi. Metode ini sangat sesuai dengan zat berkhasiat yang tidak tahan terhadap pemanasan tinggi, mudah dilakukan dan sederhana. Pelarut yang digunakan adalah pelarut etanol 70%, hal ini dikarenakan kandungan senyawa yang akan diambil dari buah pare (Momordica charantia L.) adalah senyawa triterpenoid dan polisakarida yang pada umumnya larut dalam etanol. Kandungan zat aktif ekstrak pare tidak tahan panas, tidak tahan terhadap tekanan tinggi, sifat alir jelek apabila menggunakan granulasi kering. Berdasarkan sifat-sifat tersebut maka metode pembuatan tablet ini dapat menggunakan metode granulasi basah. Metode granulasi basah dapat memperbaiki sifat alir dan kompaktibilitas bahan sehingga menjadi lebih mudah di tablet. Bahan tambahan pemanis yang digunakan pada penelitian ini adalah aspartam dengan konsentrasi 0,5% - 0,75% yang diharapkan dapat menutupi rasa pahit dari 12
buah pare (Momordica charantia L.) dan kita dapat mengetahui tablet dengan konsentrasi pemanis aspartam yang sesuai dengan standar sifat fisik. Proses pembuatan Tablet ekstrak buah pare : 1. Pengambilan Sampel Bahan utama yang akan digunakan dalam penelitian ini adalah buah pare (Momordica charantia L.) jenis pare pare gajih. Pare gajih berdaging tebal, warnanya hijau muda, bentuknya besar, panjang dan rasanya tidak begitu pahit yang diambil dari perkebunan di daerah Jatinom, Klaten Utara dengan umur 2 bulan sejak berbuah. 2. Determinasi Sampel Dilakukan untuk menetapkan kebenaran sampel tanaman pare (Momordica charantia L.) dan dibuktikan di Laboratorium Biologi Universitas Ahmad Dahlan. 3. Pembuatan Simplisia dan Serbuk Buah pare segar dicuci bersih, Dipotong-potong tipis dengan diameter 2-3 mm, Simplisia diletakkan dalam loyang yang terbuat dari alumunium dan dikeringkan dalam oven pada suhu 40o C sampai kering selama 48 jam (2 hari) hingga memenuhi kadar air kurang dari 10%. Diserbukkan, kemudian diayak dengan ayakan ukuran 40 mesh. 4. Pembuatan Ekstrak Pare Serbuk buah pare kering sebanyak 300 gram dimaserasi dengan cairan penyari 2000 ml etanol 70%. Maserasi dilakukan selama 5 hari sambil digojok sekalikali, kemudian disaring menggunakan kain flannel dengan tujuan untuk memisahkan sari dengan ampas buah pare. Selanjutnya disaring menggunakan kain flanel. Sari yang didapat dicampur dengan sari yang pertama agar homogen. Sari dipekatkan menggunakan rotary evaporator dengan tekanan rendah dan suhu 50°C sehingga didapatkan ekstrak kental buah pare (Momordica charantia L.). 5. Pembuatan Tablet Ekstrak kental pare ditambah Aerosil 5% diaduk hingga kering kemudian ditambah Avicel PH 101 dan Eksplotab diaduk sampai homogen. Tambahkan gelatin sebagai bahan pengikat. Adonan diayak dengan ayakan no.16 membentuk granul basah. Dikeringkan dalam oven pada suhu 60˚ C. Granul kering diayak dengan ayakan no.18 kemudian dilakukan pengujian granul kering. Granul + Aspartam + Mg stearat dicampur hingga homogen. Tablet dikempa dengan berat 600 mg. Pengujian sifat fisik tablet. Tabel 1. Formulasi Tablet Ekstrak Pare
13
Formula 1 (mg)
Formula 2 (mg)
Formula 3 (mg)
Komposisi
Aspartam 0,5%
Aspartam 0,625%
Aspartam 0,75%
Zat aktif
400
400
400
Avicel PH
111
110,25
109,5
Eksplotab
30
30
30
Gelatin
30
30
30
Aspartam
3
3,75
4,5
Mg stearat
6
6
6
Aerosil
20
20
20
Bobot Tablet
600
600
600
3.4 Farmakokinetik Farmakokinetik merupakan fase yang meliputi waktu selama obat diangkut menuju organ sasaran, yaitu setelah obat dilepas dari bentuk sediaan kemudian diabsorpsi ke dalam darah dan segera didistribusikan ke semua jaringan tubuh (Syamsuni, 2006). Pare dalam sediaan tablet diberikan melalui oral seperti kebanyakan obat pada umumnya. Obat oral akan diabsorbsi melalui saluran cerna karena merupakan cara yang paling mudah, ekonomis dan aman. Obat per oral absorbsinya terjadi di usus halus. Setelah itu di distribusikan ke seluruh tubuh melalui sirkulasi darah. Karena bentuk sediaan obat dalam bentuk tablet maka distribusinya akan melintasi membran sel dan langsung terdistribusi ke dalam otak sebab kapsul ini sifatnya mudah larut. Setelah di distribusikan, maka lanjut ke proses metabolisme yaitu proses perubahan struktur kimia obat yang terjadi di dalam tubuh dan di katalis oleh enzim khususnya CYT 45. Pada proses ini molekul obat diubah menjadi lebih polar, artinya lebih mudah larut dalam air dan kurang larut dalam lemak sehingga lebih mudah disekresi melalui ginjal. Kemudian, obat dikeluarkan dari tubuh melalui berbagai organ ekskresi dalam bentuk metabolis hasil biotransformasi atau dalam bentuk asalnya. Eksresi obat dapat terjadi melalui keringat, dan air liur (Tripathi, 2003). Gejala-gejala reaksi metabolisme setelah mengonsumsi ekstrak daun pare, diantaranya adalah bau nafas tidak sedap, diare, kepala sakit ringan, dan sering buang angin. Charantin yang ada di dalam daun pare yang memiliki aktivitas mirip insulin dapat menurunkan kadar glukosa darah dengan 14
menghambat terjadinya aborbsi glukosa oleh usus. Dan obat diekskresi melalui urine/ginjal karena bentuk sediaan obat ini (kapsul) dapat larut dalam air. (Doble dan Prabhakar, 2008) 3.5 Farmakodinamik Charantin dan polypeptide-p yang terkandung dalam daun pare dapat meningkatkan sensitivitas insulin dengan mempengaruhi aktivitas postreseptornya, yaitu pada fosforilasi tyrosine IRS-1. Perbaikan dari fosforilasi tyrosine IRS-1 ini sangat penting karena berpotensi dalam menyebabkan resistensi insulin. Hal ini akan menyebabkan terjadinya transport glukosa pada sel otot dan adiposa, sehingga kadar glukosa pada darah dapat kembali turun mendekati normal. Penurunan kadar glukosa ini akan menekan mekanisme kompensasi tubuh untuk memproduksi insulin dalam jumlah yang tinggi sehingga hal tersebut akan menghalangi terjadinya kondisi hyperinsulinemia dan kadar insulin akan kembali normal. (Zahirah, 2015). Penurunan kadar glukosa dimulai setelah 30 menit, mencapai maksimum 4 jam dan berakhir dalam 12 jam. (Peraturan Menteri Kesehatan Republik Indonesia (PERMENKES RI) no 6 tahun 2016) 3.6 Dosis Terdapat berbagai pendapat tentang ketentuan dosis pare untuk diabetes milletus. Menurut departemen kesehatan Filipina, dosis normal penggunaan Pare sebanyak 100mg/kgBB setara dengan 2,5mg/kg dari obat antidiabet glibenklamid (Charantia product information. Las Pinas City, Philippines; Herbcare Corporation. April
2002).
Menurut
Peraturan
Menteri
Kesehatan
Republik
Indonesia
(PERMENKES RI) no 6 tahun 2016 tentang Formulasi Obat Herbal Asli Indonesia, dosis lazim obat pare ini 2 x 2 kapsul (100-200 mg ekstrak)/hari. Dosis toksik senilai 2000mg/kgBB dapat menyebabkan pusing dan depresi dalam 30 menit pertama. Hal ini terjadi karena jumlah sel darah merah mengalami penurunan secara signifikan terutama hemoglobin pada hati. Selain itu penggunaan dalam dosis ini juga memprovokasi efek racun pada darah, jaringan dan organ vital lainnya. (Nurul Husna, dkk, 2013). Penggunaan dalam dosis diatas 2000g/kgBB dapat bersifat letal. 3.7 Indikasi dan Kontraindikasi 3.7.1 Indikasi Diabetes Mellitus
15
3.7.2 Kontraindikasi 1. Ibu Hamil Mengkonsumsi momordica charantia dapat menyebabkan keguguran karena kandungan momorcharin pada tanaman ini memiliki efek antifertilitas. Selain itu dampak lain juga dapat terjadi seperti pendarahan vagina, aborsi dan kontraksi prematur. (Rae Uddin, 2017) 2. Defisiensi G6PD G6PD merukapakan kondisi dimana seseorang mengalami masalah herediter terkait
aktivitas
eritrosit
dimana
kekurangan enzim
glukosa-6-fosfat
dehydrogenase. Kandungan vicine yag terdapat pada tanaman ini tidak dapat dicerna oleh penderita defisiensi G6PD sehingga tidak dianjurkan untuk menggunakan terapi obat dari momordica charantia. (Rae Uddin,2017) 3. Menyusui 4. Anak – anak 3.8 Efek Samping 1. Sakit perut Iritasi saluran pencernaan seperti diare dapat terjadi apabila penggunaan ekstrak Momordica charantia (pare) dikonsumsi secara berlebihan terutama pada anak – anak. Kandungan yang menyebabkan efek samping ini adalah arils merah atau panutup pada biji pare.Hal ini dapat menyebabkan seseorang mengalami dehidrasi akibat kekurangan elektrolit. 2. Hipoglikemia Kandungan charantin dari Momordica charantia berpotensi untuk penderita diabetes. Jika dikonsumsi oleh seseorang dengan kadar gula darah normal maka akan mengakibatkan penurunan kadar gula darah secara drastis sehingga menyebabkan hipoglikemia. Hal ini ditandai dengan rasa sakit kepala, lapar, berkeringat, lemas dan rasa cemas. 3. Keguguran Kandungan momorcharin pada tanaman ini telah terbukti memiliki efek antifertilitas. 4. Hepatotoksisitas Seseorang yang mengonsumsi obat ini juga berdampak terkena toksisitas hati dikarenakan keracunan. Gelaja dari kasus ini yaitu demam dan koma.
16
5. Konvulsi pada anak (Peraturan Menteri Kesehatan Republik Indonesia (PERMENKES RI) no 6 tahun 2016) 6. Peningkatan kadar glutamil transferase dan fosfatase alkali (Peraturan Menteri Kesehatan Republik Indonesia (PERMENKES RI) no 6 tahun 2016). 7. Sakit kepala (Peraturan Menteri Kesehatan Republik Indonesia (PERMENKES RI) no 6 tahun 2016) 3.9
Hal – hal yang perlu diperhatikan
Pare memiliki efek toksisitas yang tinggi pada anak – anak jika arils merah disekitar biji pare tercampur dalam formula obat. Namun pada orang dewasa efek toksisitas pare masih dapat ditoleransi dengan baik. Hanya beberapa efek samping pare yang perlu diwaspadai seperti diare dan perut kembung yang sering terjadi. Berdasarkan uji klinis terkait pengaruh pare pada gula darah, tanaman ini tidak dianjurkan sebagai pengganti maupun dikombinasi dengan obat –obat antidiabetik lain yang diresepkan dokter karena memiliki efek aditif yang menyebabkan terjadinya hipoglikemia (Rae Uddin, 2017). Efek penurunan fertilitas pada perempuan maupun laki-laki juga perlu diperhatikan (Peraturan Menteri Kesehatan Republik Indonesia (PERMENKES RI) no 6 tahun 2016) 3.10
Implikasi Keperawatan
Ada beberapa implikasi keperawatan yang dapat diterapkan seorang perawat dalam menanggapi manfaat Momorcadia charantia sebagai obat herbal ini, yakni : 1. Sebagai pendidik Seorang perawat diharapkan mampu mendorong masyarakat untuk menjaga kesehatannya dengan mengonsumsi obat – obatan herbal melalui edukasi sehingga pemakaiannya tepat aturan. Perawat dapat menjelaskan berbagai manfaat dari pare terutama untuk penderita diabetes. Hal ini dilakukan agar masyarakat dapat meminimalisir penggunaan obat kimia yang cenderung berakibat buruk bagi tubuh jika dikonsumsi terus menerus. Selain itu, perawat merupakan pemantau ketika klien sudah menggunakan obat herbal terkait prosedur penggunaan, efek samping dan hal – hal lain yang perlu diperhatikan dalam terapi obat herbal tersebut. 2. Sebagai Advokat Dalam hal ini perawat diharapkan dapat melakukan pembelaan apabila terjadi kesalahan pemberian obat dalam kolaborasi dengan tenaga kesehatan lain. Pengetahuan tentang efek samping, indikasi dan kontraindikasi tentang
17
pengggunaan obat herbal dapat menjadi landasan seorang perawat dalam memberi perlindungan kepada pasiennya terkait penggunaan obat – obatan. 3. Sebagai peneliti Perawat dapat melakukan penelitian lebih lanjut terkait manfaat pare sehingga dapat berfikir kritis menangani segala permasalahan klien dari segi keperawatan. Inovasi baru tentang manfaat obat – obatan herbal akan semakin membantu perawat dalam menyelesaikan permasalahan klien. 4. Sebagai konsultan Perawat memberikan solusi kepada setiap permasalahan klien mengenai penggunaan obat – obatan herbal tanpa mengesampingkan kebutuhan akan obat – obatan kimia. Memberi pandangan tentang dampak positif dan negative tentang penggunaan obat herbal juga sangat penting dilakukan.
18
BAB 4. PENUTUP 4.1 Kesimpulan Pare adalah salah satu jenis sayuran yang memiliki rasa yang khas, yaitu rasa pahit adalah salah satu sifat yang dimiliki pare. Nama ilmiahnya adalah Momordica charantia. Tanaman pare (Momordica charantia L.) berasal dari kawasan Asia Tropis. Pare dapat dikemas menjadi tablet agar dapat ditelan secara mudah dan absorbsinya lancar ke usus. Mula-mula obat diabsorbsi melalui oral kemudian masuk ke dalam pembuluh darah lalu melalui tahap pendistribusian. Charantin yang merupakan saponin steroid yang diisolasi dari biji pare yang memiliki aktivitas mirip insulin dengan menstimulasi pengeluaran insulin di pancreas dan menekan gluconeogenesis di hati dan polipeptida-p yang merupakan polipeptida yang kerjanya mirip insulin yang dapat menstimulasi pengeluaran insulin dari sel beta pancreas serta glikosida asam oleanol yang dapat menurunkan kadar glukosa darah dengan menghambat terjadinya aborbsi glukosa oleh usus. Dan obat diekskresi melalui urine/ginjal karena bentuk sediaan obat ini (kapsul) dapat larut dalam air. Charantin dan polypeptide-p yang terkandung dalam daun pare dapat meningkatkan sensitivitas insulin dengan mempengaruhi aktivitas postreseptornya. Perbaikan dari fosforilasi tyrosine IRS-1 ini sangat penting karena berpotensi dalam menyebabkan resistensi insulin. Hal ini akan menyebabkan terjadinya transport glukosa pada sel otot dan adiposa, sehingga kadar glukosa pada darah dapat kembali turun mendekati normal. Penurunan kadar glukosa dimulai setelah 30 menit, mencapai maksimum 4 jam dan berakhir dalam 12 jam. 4.2 Saran Menurut WHO obat tradisional memiliki sedikit efek samping dan bahkan tidak ada. Maka dari itu, akan baik jika lebih banyak tanaman obat yang dikembangkan dalam pemanfaatannya untuk kesehatan. Selain sediaannya banyak, secara tidak langsung akan menjadi alasan seseorang melestarikan tanaman tersebut. Untuk perawat juga tidak hanya dapat menjalankan pengobatan dengan hasil yang sudah ada, tetapi dapat juga melakukan penelitian terhadap tanaman obat lain.
19
DAFTAR PUSTAKA
Anah, Yuli. (2015). Kandungan Nutrisi Khasiat Pare. Dapat diakses pada: https://www.google.co.id/amp/resepcaramemasak.org/kandungan-nutrisi-khasiatpare/amp. (Diakses pada tanggal 25 Maret 2018) Arum, F., Sunyoto, dan Hidayati, N. 2015. Uji Sifat Fisik Formulasi Tablet Anti Diabetes Ekstrak Pare (Momordica Charantia L.) Dengan Variasi Konsentrasi Pemanis Aspartam Secara Granulasi Basah. CERATA Journal Of Pharmacy Science. 57-63 Badan Pengawas Obat dan Makanan (BPOM). (2012). Cara pembuatan Obat Tradisional yang baik (CPOTB). Dapat diakses pada: http://jdih.pom.go.id/showpdf.php?u=QSE %2BdU4fTSsiCZkrMdUDWgjfvC7qrLkX 0jUHn9AnEuc%3D. (Diakses tanggal 22 Maret 2018) Badan Pengawas Obat dan Makanan. 2012. http://jdih.pom.go.id/ (Diakses tanggal 23 Maret 2018) Dans, A.M.L., Villaruz, M.V.C., Jimeno, C.A., Javelosa, A.U., Chua, J., Bautista, R., Vellez, G.B. 2007. The effect of Momordica charantia capsule preparation on glycemic control in Type 2 Diabetes Mellitus needs further studies. Journal of Clinical Epidemiology. 60: 554-559 Deshmukh, N.S. 2016. Safety assessment of McB-E60 (extract of a Momordica sp.):Subchronic toxicity study in rats. Toxicology Reports. 3: 481-489 Dewanti, A. 2017. Pengaruh Pemberian Buah Pare (Momordica Charantia L.) Dalam Bentuk Fruit Pulp Terhadap Parameter Farmakokinetika Obat Diabetes Pioglitazone. Skripsi. Surabaya. : Fakultas Farmasi Universitas Katolik Widya Mandala Surabaya. Dianita, P.S., dan Kusuma, T.M. 2016. Formulasi Tablet Ekstrak Buah Pare Dengan Variasi Konsentrasi Avicel Sebagai Bahan Pengikat. Jurnal Farmasi Sains dan Praktis. 2(1): 1-6. Doble M., Prabhakar K.P., 2008. A Target Based Therapeutic Approach Towards Diabetes Melitus
Using
Medicinal
Plants.
4:291-308
(Dapat
diakses
pada
:
https://www.researchgate.net/publication/23458791_A_Target_Based_Therapeutic_A pproach_Towards_Diabetes_Mellitus_Using_Medicinal_Plants)
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Hady. (2011). Buah Pare untuk Obat Diabetes Melitus. Dapat diakses pada: https://hadyherbs.wordpress.com/category/obat-alami-2/buah-pare-untuk-obat-dm/ (Diakses pada tanggal 20 Maret 2018) Husna, R.N., Noriham, A., Nooraain, H., Azizah, A.H., dan Amna, O.F. 2013. Acute Oral Toxicity Effects of Momordica Charantia in Sprague Dawley Rats. International Journal of Bioscience, Biochemistry and Bioinformatics. 3(4): 1-3. Joseph, B., dkk. (2013). Antidiabetic effect of Momordica Charantia (bitter melon) and its medicinal
potency.
Asian
Pac
J
Trop
Dis
(Dapat
diakses
pada
:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027280/) Kemenkes. 2014. Pusat Data dan Informasi (Infodatin) Kemenkes RI. Jakarta : Kemenkes. http://www.depkes.go.id/resources/download/pusdatin/infodatin/ infodatin-diabetes.pdf [diakses pada tanggal 22 Maret 2018] Kepala BPOM RI. 2014. Peraturan Kepala Badan Pengawas Obat Dan Makanan Republik Indonesia No. 12 Tahun 2014 Tentang Persyaratan Mutu Obat Tradisional. Jakarta
: BPOM RI. http://asrot.pom.go.id/img/Peraturan /Peraturan%20Kepala %20BPOM%20No.%2012%20Tahun%202014%20tentan g%20Persyaratan %20Mutu%20Obat%20Tradisional.pdf [diakses pada tanggal 20 Maret 2018]. Kepala BPOM RI. 2005. Peraturan Kepala Badan Pengawas Obat Dan Makanan Republik Indonesia Nomor : HK.00.05.41.1384 Tentang Kriteria Dan Tata Laksana Pendaftaran Obat Tradisional, Obat Herbal Terstandar Dan Fitofarmaka. Jakarta : BPOM RI. http://sireka.pom.go.id/requirement/HK.00. 05.41.13842005.pdf[diakses pada tanggal 23 Maret 2018]. Keputusan Menteri Kesehatan RI. 2003. Keputusan Menteri Kesehatan No. 1076/Menkes/SK/VII/2003 Tentang Penyelenggaraan Pengobatan Tradisional Menteri Kesehatan Republik Indonesia. Jakarta : Menkes RI. http://pelayan an.jakarta.go.id/download/regulasi/keputusan-menteri-kesehatan-republikindo nesia-no-1076-menkes-sk-vii-2003-tentang-penyelenggaraanpengobatan-tradi sional.pdf[diakses pada tanggal 20 Maret 2018]. Kwarta, D., dkk. (2016). Bitter Melon as a Therapy for Diabetes, Inflammation and Cancer: a
Panacea.
Topical
Collection 21
(Dapat
diakses
pada
:
https://www.semanticscholar.org/paper/Bitter-Melon-as-a-Therapy-for-DiabetesKwatra-Dandawate/ab1b856d65d05b06d7e11dad4f5f4dd27172dde0/abstract)
Lim, S.T., Cecilia, M.D., Gonzales-Razon, E.B., dan Velasquez, M.E.N. 2010. The MOCHA DM study: The Effect Of MOmordica CHArantia Tablets on Glucose and Insulin Levels During the Postprandial State Among Patients with Type 2 Diabetes Mellitus. Philippine journal of international medicine. 48(2): 1-7. Peraturan Menteri Kesehatan Republik Indonesia (PERMENKES RI). (2016). Formularium Obat Herbal Asli Indonesia no 6 tahun 2016. PP RI. 2014. Peraturan Pemerintah Republik Indonesia Nomor 103 Tahun 2014 Tentang Pelayanan Kesehatan Tradisional. Jakarta : Kemenkes. http://tradkom.depkes.go.id/wp-content/uploads/2015/1-PP%20No.%20103% 20Th%202014%20ttg%20Kesehatan%20Tradisional.pdf [diakses pada tanggal 20 Maret 2018]. Peraturan Menteri Kesehatan RI. 2012. Peraturan Menteri Kesehatan Republik Indonesia Nomor 007 Tahun 2012 Tentang Registrasi Obat Tradisional. Jakarta : Menkes. http://sireka.pom.go.id/requirement/PMK-7-2012-Registrasi ObatTradisional.pdf [diakses pada tanggal 25 Maret 2018]. Sayoeti, A.Z. 2015. Effect Of Decocta In Bitter Melon Fruit (Momordicacharantial.) For Decrease Blood Glucose Levels. J Majority. 4(4): 1-5. Syamsuni. 2006. Ilmu Resep. Jakarta : EGC. Tripathi. 2003. Essentials of Medical Pharmacology. 5th Edition. New Delhi : Jaypee Zahirah, Azatu. (2015). Effect of Deccota in Bitter Melon Fruit (Momordica charantia L.) For Descrease Blood Glucose Levels. J Majority (Dapat diakses pada : http://juke.kedokteran.unila.ac.id/index.php/majority/article/view/573)
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A Target Based Therapeutic Approach Towards Diabetes Mellitus Using Medicinal Plants Pranav K. Prabhakar and Mukesh Doble* Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai-600 036, India Abstract: Diabetes mellitus (DM) is not one disease but is a heterogonous group of syndromes. Contrary to the popular belief DM is a metabolic disorder characterized by increased blood glucose level (hyperglycemia) and this is because of insufficient or inefficient insulin secretary response. Glucose is the main energy source for the body, and in the case of DM, management of glucose becomes irregular. There are around 410 experimentally proven medicinal plants having antidiabetic properties but the complete mechanism of action is available only for about 109. There are several medicinal plants whose extract modulate glycolysis, Krebs cycle, gluconeogenesis, HMP shunt pathway, glycogen synthesis and their degradation, cholesterol synthesis, metabolism and absorption of carbohydrates, and synthesis and release of insulin. This paper provides a comprehensive review of the mode of action of medicinal plants that exhibit anti-diabetic properties.
Keywords: Diabetes mellitus, Hyperglycemia, Ayurveda, Anti-diabetic, Insulin. 1. INTRODUCTION Diabetes mellitus (DM) is the most common endocrine disorder, which is characterized by a defective or deficient insulin secretary process, glucose underutilization, and increased blood sugar (hyperglycemia). It is a congenital or acquired inability to transport sugar from the bloodstream into the cells. DM is a major health problem, affecting 5% of the total population in the US and 3% of the population worldwide [1]. It causes about 5% of all deaths globally each year. DM can be divided into two major categories- Insulin dependent diabetes mellitus (IDDM) or type 1 (an autoimmune disease of younger patients with a lack of insulin production causing hyperglycemia and a tendency towards ketosis) and noninsulin-dependent diabetes mellitus (NIDDM) or type 2 (a metabolic disorder resulting from the body’s inability to produce enough or properly utilize insulin hence patients have hyperglycemia but are ketosis resistant). Over 90% of patients with diabetes have type 2 and the remainder has type 1 diabetes [2]. The complications associated with diabetes are neuropathy, nephropathy, retinopathy, diabetic foot, and ketoacidosis. All tissues have energy requirement that is usually met by metabolizing glucose. The entry of glucose from the blood into the cells, liver, skeletal muscle, and adipose tissue is promoted by insulin. In the case of diabetics, these tissues cannot normally assimilate glucose, and hence it accumulates within the blood. As the blood glucose concentrations increases, osmotic forces come into play that tends to increase the blood volume and urine output (polyuria). As the blood glucose level exceeds its renal threshold (i.e., 180
*Address correspondence to this author at the Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai-600 036, India; Tel: +914422574107; Fax: +914422574102; E-mail: [email protected] 1573-3998/08 $55.00+.00
mg/dL), glucose appears in the urine (glucouria). This causes an increased loss of water from the body and triggers a compensatory adjustment that leads to an increase in thirst (polydipsia) [3]. The inability of glucose to enter some tissues increases the need for alternate sources of energy, such as ketone bodies (acetoacetate, acetone and 3-betahydroxybutyrate) [4]. Humankind has a long history in the use of herbal medicines. Well-known Ayurvedic physicians Maharshi Charaka (600 BC) and Sushruta (400 BC) correctly described almost all the symptoms of this disease [5]. The present review discusses the mechanism of action of medicinal plants to combating diabetes. World ethnobotanical information about medicinal plants reports that about 800 plants are used in the control of diabetes mellitus [6, 7]. There are around 410 experimentally proven medicinal plants having antidiabetic properties but complete mechanism of action is available only for about 109 plants. 2. THERAPEUTIC STRATEGIES The management of diabetes without any side effect is still a challenge to the medical system. Herbal drugs are prescribed widely because of their effectiveness, fewer side effects and relatively low cost. Wide array of plant derived active principles have demonstrated antidiabetic activity. The main active constituents of these plants include alkaloids, glycosides, galactomannan gum, polysaccharides, peptidoglycan, hypoglycans, guanidine, steroids, carbohydrates, glycopeptides, terpenoids, amino acids and inorganic ions. These affect various metabolic cascades, which directly or indirectly affect the level of glucose in the human body [8]. Previous work, which has been published in non-indexed and obscure journals, may have been missed out in this re-view as citations for the present article were predominantly taken from Diabetes Medicinal Plant Database “DiaMed-Base” (http://www.progenebio.in/DMP/DMP.htm) [9]. © 2008 Bentham Science Publishers Ltd.
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Table 1. Medicinal Plants that Regulate Glycolysis and Krebs Cycle S. No.
Plant
Constituent
Activity
References
1.
Aegle marmelose L. Correa exRoxb(Rutaceae)
Aegelin, & -Sitosterol, Marmelosin, Marmesin.
1 gm/kg/day
[11, 43]
2.
Allium cepa L. (Liliaceae)
100-200 mg/kg
[27, 28]
3.
Allium sativum L. (Alliaceae)
Allicin, Apigenin, Alliin, S-allyl cysteine sulfoxide.
200 mg/kg
[25, 26]
4.
Casearia esculenta Roxb. (Flacourtaceae)
Leucopelargonidin, Dulcitol, Beta sitosterole.
[19]
5.
Coscinium fenestratum Colebr(Menispermaceae)
Berberine, saponin.
[29]
6.
Curcuma longa L. (Zingiberaceae)
Curcumin, Turmerone, -Sitosterol, Zingiberene.
7.
Eclipta alba L. (Asteraceae)
Wedelolactone, Demethyl wedelolactone, Eclipticine.
8.
Eugenia jambolana Lam. (Myrtaceae)
Mallic acid, Gallic acid, Oxalic acid, Tannins.
9.
Eucommia ulmoides Oliv. (Eucommiaceae)
Isoquercitrin, Quercetin3-O- -larabinopyrano syl -(1, 2)- -dglucopyranoside, Astragalin.
10.
Gongronema latifolium Benth (Asclepiadaceae)
11.
Momordica charantia L. (Cucurbitaceae)
12.
Mucuna pruriens L. (Fabaceae)
13.
Murraya koenigii L. Speng (Rutaceae)
14.
Ocimum sanctum L. (Lamiaceae)
Eugenol, Carvacrol, Linalool, Caryophylline, -Sitosterol.
[11, 62, 78]
15.
Panax quinquefolius L. (Araliaceae)
Quinquenoside L3 & L9, Vina-Ginsenoside R3.
[79]
16.
Piper betleL. (Piperaceae)
-phenol, Chavicol, Cadinene.
17.
Plumbago zeylanica Linn. (Plumbaginaceae)
18.
Pterocarpus marsupium Roxb. (Fabaceae)
Pterostilbene, Liquiritigerin, Isoliquiritigerin, Epicatechin.
19.
Tinospora cordifolia Hook. f. & Thomson (Meninspermaceae)
Berberine.
20.
Trigonella foenumgraecum L. (Leguminosae)
Trigonelline, Choline, Galactomannan.
S-methyl cysteine sulfoxide, S-allyl cysteine sulfoxide.
0.08 g/kg body Wt.
[30, 37, 48, 66] [20]
100 mg/kg
[24, 30, 76]
[14]
100 mg/Kg
[15]
Charantin, Momordicoside.
200 mg/kg /day
[24, 30, 44, 53, 63, 77]
Mucunine, Mucunadine, -Sitosterol, Mucuadinine.
200 mg/kg /day
[77]
80 mg/kg /day
[11, 31]
75 mg/kg
[21] [80]
3. BIOCHEMICAL PATHWAYS, MEDICINAL PLANTS AND THEIR TARGET SITES Most of the tissues metabolize glucose for their energy requirement and other purposes such as glucosylation of protein. In mammals, glucose is the only fuel that the brain uses under nonstarvation conditions and the fuel that red blood cells use [10]. In the following sections the important biochemical pathways where glucose is involved, either as a
1g/kg
[8, 30] [30, 32, 60, 76]
1g/kg
[22, 81]
substrate or liberated as a product and the medicinal plants that inhibit or activate one of these regulatory steps in the pathways are listed. 3.1. Glycolysis and Krebs Cycle Glycolysis is the most important metabolic pathway in all the cells of the human body through which the 6-carbon glucose molecule is oxidized to two molecules of pyruvic acid.
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Fig. (1). Medicinal plants which regulate the glycolysis and Krebs cycle (see Table 1). {Plant No. 95 = Panax ginseng C. Meyer [13]}.
Glycolysis is the main energy producing pathway in some specific tissues which lack mitochondria such as mature RBC and cells under low oxygen conditions such as heavilyexercising muscle. In glycolysis, the reactions catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase are irreversible, and hence, these enzymes would be expected to have regulatory as well as catalytic roles [10]. Krebs cycle is the central pathway for energy production in which pyruvate is oxidized to CO 2 and H2O via acetyl CoA with the synthesis of energy equivalent, NADH. The latter gets oxidized and produces ATP through the electron transport chain. There are seven enzymes involved in this cycle, of which only two enzymes, succinate dehydrogenase and malate synthase are regulated by plants and their respective constituents [10]. Several medicinal plants control the glycolysis and the Krebs cycle (Fig. 1). The activity and the principal constitu-
ents of medicinal plants which regulate the enzyme hexokinase/ glucokinase are listed in Table 1 (Plants No.120). Plants No: 9-12, 15 and 17-22 activate phosphofructokinase (Table 1, Fig. 1). However, last regulatory step of the glycolytic pathway which is catalysed by pyruvate kinase is not regulated by any medicinal plant. In the case of anaerobic respiration and in tissues which lack mitochondria, pyruvate is converted to lactic acid by the enzyme lactic acid dehydrogenase. The plants that regulate the conversion of pyruvate to lactate by inhibiting lactate dehydrogenase (LDH) in the anaerobic glycolysis step are plants No: 1, 3, 5, 13-14, 17, 19 and 20 respectively (Table 1, Fig. 1). Plants such as Aegle marmelose L. Correa ex Roxb [11], Catharanthus roseus (L.) G. Don. [12] and Panax ginseng C. Meyer [13] (Plant No: 1, 27 and 95 respectively) activate succinate dehydrogenase, while Catharanthus roseus (L.) G. Don. [12] and Panax ginseng C. Meyer [13], activate malate dehydrogenase (Plant No: 27 and 95 respectively) (Table 1, Fig. 1).
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Fig. (2). Medicinal plant that modulate gluconeogenesis pathway (see Table 3). Table 2. Medicinal Plants (in Addition to Plant No. 1-5, 7, 9, 11, 13-14, 16, 19-20) that Inhibit Gluconeogenesis (Glucose-6phosphatase) S. No.
Plant
Constituent
21.
Aconitum carmichaeli Debeaux(Renunculaceae)
Songoramine, Hypaconitine, Karakanine, Songorine
22.
Coccinia indica Weigh & Arn (Cucurbitaceae)
Taraxerone, Taraxerol
23.
Enicostemma littorale Blume (Gentianaceae)
24.
Syzygium aromaticum (L.) Merr. & Perry (Myrtaceae)
3.2. Gluconeogenesis Gluconeogenesis is the pathway that generates glucose from non-sugar carbon substrates like pyruvate, lactate, glycerol, and glucogenic amino acids (primarily alanine and glutamine). Gluconeogenesis cannot be considered to be simply a reverse process of glycolysis, as the three irreversible steps in glycolysis are bypassed here with four irreversible and regulatory steps which are catalyzed by pyruvate carboxylase; PEP carboxykinase; Fructose-1, 6-bisphosphatase and glucose-6-phosphatase. The medicinal plants Eucommia ulmoides Oliv [14], Gongronema latifolium Benth. [15], Panax quinofolium L. [16], Syzygium aromaticum (L.) Merr. & Perry [17] and Camellia sinensis (L.) Kuntze. [16, 18] inhibit phosphoenol pyruvate carboxykinase (Plant No: 9-10, 14-15, 24 and 93 respectively); and Aegle marmelose L. Correa ex Roxb [11], Casearia esculenta Roxb. [19], Eclipta alba L. [20], Murraya koenigii (L.) [11], Ocimum sanctum L. [11], Piper betle L. [21], Trigonella foenum-graecum L. [22] and Coccinia indica Weigh & Arn [23, 24] inhibit fructose-1, 6-bisphosphatase (Plant No: 1, 4, 7, 13-14, 16, 20 and 22 respectively). Green tea flavonoid epigallocatechin gallate (I) has glucose lowering effect by
Isoflavones
Activity
References [33]
2 gm/kg
[23, 24]
2 gm/kg
[30, 34]
50 mg/kg
[17, 46, 47]
decreasing the expression of phosphoenol pyruvate carboxykinase gene (Fig. 2) [18]. The last regulatory enzyme in this pathway is glucose-6phosphatase, which is inhibited by Aegle marmelose L. Correa ex Roxb [11], Allium sativum L. [25, 26], Allium cepa L. [27, 28], Casearia esculenta Roxb. [19], Coscinium fenestra-tum Colebr. [29], Eclipta alba L [20], Eugenia jambolana L. [24, 30], Eucommia ulmoides Oliv [14], Momordica charan-tia L. [24, 30], Murraya koenigii (L.) [11,31], Ocimum sanc-tum L. [11], Piper betle L. [21], Pterocarpus marsupium Roxb. [8], Tinospora cordifolia (Willd.) Hook. f. & Thom-son [32], Aconitum carmichaeli Debeaux. [33], Coccinia indica Weigh & Arn [23, 24], Enicostemma littorale Blume [34] and Syzygium aromaticum (L.) Merr. & Perry [17] (Plant No: 1-5, 7-9, 11, 13-14, 16, 18-19 and 21-24 respectively) (Table 2, Fig. 2). 3.3. Hexose Monophosphate (HMP) Shunt HMP Shunt is an alternative pathway to glycolysis and Krebs cycle for the oxidation of glucose. It generates two important products namely pentoses (ribose-5-phosphate) and NADPH. It is an anabolic pathway that utilizes the six
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Fig. (3). Medicinal plants affecting HMP shunt. Table 3. Medicinal Plants (in Addition to Plant No. 1, 5, 10-11, 13-14, 21-22, 24) that Regulate HMP Shunt (Glucose-6-phosphate dehydrogenase) S. No.
Plant
Constituent
Activity
References
25.
Balanites roxburghii (Balanitaceae)
Sapogenin, Diosgenin, Yamogenin, -sitosterol.
1.5 g/kg
[82]
26.
Casearia esculenta Roxb. (Flacourtaceae)
Resin, Sterol, Flavonoid.
300 mg/kg
[19]
27.
Catharanthus roseus (L.) G.Don (Apocynaceae)
Vinblastine, Vineristine, Vinine, Vincamine, Alstonine.
500 mg/kg
[12, 61]
28.
Dioscorea cayenensis Lam. (Dioscoreaceae)
[35, 36]
Fig. (4). Glycogen synthesis and medicinal plants involved in its regulation. Plant No. 96 = Brassica juncea (L.) Czem. [31].
carbons of glucose to generate five carbon sugars (Fig. 3). The regulatory and irreversible step in HMP shunt pathway is catalyzed by enzyme glucose-6-phosphate dehydrogenase. Hence, regulation of enzyme glucose-6-phosphate dehydrogenase in the case of diabetes is a very important issue. There are several plants which regulates this enzyme. Aegle marmelose L. [11], Coscinium fenestratum Colebr. [29], Gongronema latifolium Benth [15], Momordica charantia L. [24, 30], Murraya koenigii (L.) [11, 31], Ocimum sanctum L. [11], Aconitum carmichaeli Debeaux. [33], Coccinia indica Weigh & Arn [23, 24], Colocassia esculenta (L.) Schott [35], Catharanthus roseus (L.) G.Don [12] and Dioscorea cayenensis Lam. [36], affect the enzyme glucose-6phosphate dehydrogenase in the HMP shunt pathway (Plant No: 1, 5, 10-11, 13-14, 21-22 and 24-28 respectively) (Table 3, Fig. 3).
3.4. Glycogen Synthesis Synthesis of glycogen from unused glucose is a multistep process carried out by the enzyme glycogen synthase in the liver. This enzyme utilizes UDP-glucose and the nonreducing end of glycogen as another substrate and progressively lengthens the glycogen chain. The activation of glucose to be used for glycogen synthesis is carried out by the enzyme UDP-glucose pyrophosphorylase (Fig. 4). In the case of diabetes the glucose is not properly converted to glycogen and as a result of which blood glucose level increases. Several plants affect the enzyme glycogen synthase action and they are Aegle marmelose L. [11], Curcuma longa L.[30, 37], Dioscorea esculenta (Lour.) Burk. [37], Momordica charantia L [24, 30], Murraya koenigii (L.) [11, 31] Ocimum sanctum L. [11], Piper betle L. [21], Coccinia indica Weigh
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Fig. (5). Medicinal plants which repress the glycogenolysis process.
Fig. (6). Mechanism of action of medicinal plant in the digestion and absorption of carbohydrate (see Table 4).
& Arn [23, 24], Catharanthus roseus (L.) G. Don [12] and Brassica juncea (L.) Czem [31] (Plant No: 1, 6, 11, 13-14, 16, 22, 27 and 96 respectively) (Fig. 4). 3.5. Glycogenolysis Glycogenolysis is the degradation of glycogen to glucose which leads to increase in glucose level in the blood. Glycogen phosphorylase (GP) is the primary enzyme involved in the glycogen breakdown. Plants like Aegle marmelose L [11], Murraya koenigii (L.) [11, 31], Ocimum sanctum L. [11] and Brassica juncea (L.) Czem [31], inhibit the enzyme GP, thereby regulating the gluconeogenolysis pathway and hence decrease the glucose level in the blood (Plant No: 1, 13-14 and 96 respectively) (Fig. 5). It is reported that leaf extract of Azadirachta indica is able to block the reduction in the peripheral utilization of glucose and glycogenolysis in diabetic rabbits [38]. 3.6. Digestion and Absorption of Carbohydrates Carbohydrates are the major energy producing components of the normal diet, supplying more than 80% of the quick requirement of the body. The main constituents of carbohydrates are starch and sucrose. Starch is first decomposed into oligosaccharides by the enzyme -amylase present in saliva and various pancreatic juices. -Glucisidase (EC 3.2.1.20), which is a membrane-bound enzyme located at the epithelium of the small intestine, catalyzes the cleavage of glucose from disaccharides and oligosaccharides. Digestion
of starch and sugar produces glucose, which is absorbed in the blood stream through the walls of the intestine, and fi-nally carried to the liver (Fig. 6). This process maintains the glucose level in the blood. Several enzymes take part during the carbohydrate digestion process, which primarily include -Glucosidase, maltase, sucrase, amylase, lactase, isomaltase etc of which -glucosidase is the most important. Hence, inhibition of -glucosidase can be the effective treatments of DM. There are a number of medicinal plants known to sup-press this activity (Plant No: 18 and 29-48 respectively) (Ta-ble 4) and some of the plants decrease the absorption of car-bohydrates via the brush border cell of the intestine. The two active components, (-)-3-O-galloylepicatechin and (-)-3-Ogalloylcatechin, from Bergenia ciliata Haw have demon-strated inhibition of inhibit rat intestinal -glucosidase and porcine pancreatic -amylase [39]. Alstonia scholaris (L.) R. Br. containing quercetin 3-O-b-D-xylopyranosyl (1’’’ 2’’)-b-Dgalactopyranoside and (-)-lyoniresinol 3O-b-Dglucopyranoside [40], also inhibits -glucosidase. These inhibitors are known as "diabetes pills" however they are not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or its sensitivity, but they slow the digestion of starch in the small intestine. The glucose comesfrom the starch present in daily intake food enter the bloodstream slowly and can be matched to an impaired insulin response or low production. Miglitol and Acarbose are two commercially available synthetic drugs which inhibits the activity of -glucosidase.
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Table 4. Medicinal Plants (in Addition to Plant No. 18) that Inhibit -Glucosidase Activity and Glucose Absorption S. No.
Plant
Constituent
29.
Anemarrhena asphodeloides Bunge. (Asphodelaceae)
Sarsasapogenin, mangiferin, neomangifrin.
[83]
30.
Alstonia scholaris (Apocynaceae)
Chlorogenic Acid.
[40]
31.
Angylocalyx pynaertii de Wild (Leguminosae)
1,4-dideoxy-1,4-imino-D-ribitol, 2,5-dideoxy2, 5-imino-D-fucitol.
[84]
32.
Artemisia pallens Wall ex. DC. (Compositae)
T-Cadinol, -urunene, -Eudesmol, -Ubebene.
33.
Bauhinia candicans Link. (Leguminosae)
Astragalin, Kaempferitrin, Astragalin, Bauhinoside.
[86, 87]
34.
Bergenia ciliata Haw (Saxifragaceae)
( )-3-O-galloylepicatechin, ( )-3-Ogalloylcatechin.
[12]
35.
Cassia auriculata L. (Leguminoceae)
Di-(2-ethyl) hexyl phthalate.
36.
Hydnocarpus wightiana Blume. (Flacourtaceae)
Hydnowightin, Hydnocarpin, Neohydnocarpin.
[89]
37.
Morus insignis Bur. (Moraceae)
-Sitosterol, Ursolic acid, Moracin M,MulberrofuranU.
[90]
38.
Myrtus communis L. (Myrtaceae)
Mulberrofuran U, Moracin M3-O--Dglucopyranoside.
[91]
39.
Morus alba L. (Moraceae)
Isoquercitrin, Astragalin, Scopolin, Roseoside II.
200 mg/kg
[92]
40.
Morus bombycis Koide. (Moraceae)
3-Epifagomine, Fagomine, Castanospermine.
IC50 = 0.1 mg/ml
[92]
41.
Myrcia multiflora DC. (Myrtaceae)
Myrciaphenones A & B, Myrciacitrins I-V, Kotalanol.
[93]
42.
Phylanthus embelica L. (Euphorbiaceae)
Pterostilbene, Epicatechin, Liquiritigerin.
[88]
43.
Salacia reticulata Wight. (Celastraceae)
Mangiferin, Salacinol, Kotalanol, Epigallocatechin.
1 ml/day/rat
[94]
44.
Salacia oblonga (Celastraceae)
Mangiferin, Salacinol, Kotalanol, Epigallocatechin.
250 mg/kg
[94]
45.
Taraxacum officinale Weber. (Compositae)
Taraxacin, Acrystalline, Inulin,Taraxacerin, Laevulin.
IC50 = 38 g/mL
[91, 90]
46.
Urtica dioica L. (Urticaceae)
Quercetin, Kaempferol, Glucoquinone.
[91]
47.
Viscum album L. (Loranthaceae)
Lectins, Misteloe lectin I, II, III, Viscotoxins, Cyclitols.
[91]
4. INSULIN MIMETIC NATURAL DRUGS Insulin is the most important peptide hormone in the human body. It not only regulates the carbohydrate metabolism, but also stimulates lipogenesis, diminishes lipolysis, and increases amino acid transport into the cells. This is secreted from the -cells of the islets of Langerhans in re-sponse to hyperglycemia. Presently, all focus is targeted to increase the expression of insulin genes, increase secretion of insulin from secretary granules, and inhibit their degrada-tion.
Activity
100 mg/kg
IC50 =0.023 mg/mL
References
[85]
[30, 88]
The mechanism of insulin release from -cells in re-sponse to changes in blood glucose concentration is a com-plex process (Fig. 7). The release of insulin from insulin stored granules involves closure of ATP-gated potassium channels and activation of voltage-gated calcium channels [41]. Many medicinal plants modulate this expression, synthesis and degradation of insulin (Table 5a). There are a few plants which act on the Sulfonylurea binding site 1 (SUR1) and close the ATP-sensitive potassium channel (KATP), due
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Fig. (7). Mechanism of action of exocytosis of insulin and of sulfonylurea (Table 5a).
to which the cell membrane gets depolarized leading to the influx of Ca2+ [41]. Plants which directly act on the Ca 2+ channels affecting insulin secretion are listed in Table 5a (Plant No: 12, 14-15, 18, 40 and 49-89) and those which increase the activity of insulin and decrease their degradation by inhibiting insulinase are listed in Table 5b (Plant No: 14, 51 and 90-92). Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor transcription factors that induce the proliferation of peroxisomes in the cells, which are also involved in the cellular metabolism of carbohydrates, protein and lipids [41]. There are three types of PPAR, namely, alpha, delta/ beta and gamma. Among these, alpha participates in the metabolism of lipids and peroxisome proliferation, beta has been implicated to be involved in some disorder such as cancer, infertility and dislipidemis whereas gamma participates in the insulin resistance [42]. Medicinal plants such as Aegle marmelose (L.) Correa ex Roxb (Rutaceae) [43], Momordica charantia L. [44], Helicteres isora L. (Sterculiaceae) [45], and Syzyzium cumini (L.) Skeel [43], increase the expression of PPAR gamma and decrease the insulin resistance (Plant No: 1, 11, 72 and 94 respectively). Thiazolidinedione class of drugs which include roziglitazone, troglitazone and piaglitazome also target PPAR gamma. DehydroglyasperinC (II), dehydroglyasperinD (III), glyasperinB (IV), glycycoumarine (V), glycyrin (VI), and glyasperinD (VII), isolated from Glycyrrhiza uralensis and neolgnan dehydroeugenol (VIII) isolated from Syzygium aromaticum exhibit significant PPAR-
gamma ligand-binding activity [46, 47]. PPAR gamma is one of the most important targets for Curcumin (IX), extracted from curcuma longa and 6-gingerol (X), a natural analog of curcumin derived from the root of ginger (Zingiber officinale Roscoe.). The latter compound exhibits biological activity profile similar to that of curcumin [48]. Cyclic AMP is one of the second messengers that mediate intracellular signaling networks triggered by membrane receptor stimulation, eventually leading to alteration of cell functions including metabolic activities. The synthesis of cAMP is catalyzed by adenylate cyclase, which has a short half life as the enzyme cAMP phosphodiesterase cleaves it. This eventually leads to a decrease in the intensity of insulin [49]. Several medicinal plants which include Orthosiphon aristatus Blume.[50], Passiflora edulis Sims. f [51], Hylocereus undatus (Haworth) Britton & Rose [52], Luffa cylindrical (L.) Roem [53], Momordica charantia L. [53] and Panax ginseng L. [13] possess cAMP phosphodiesterase inhibitory activity, as a result of which the action of insulin is retained. Glucose transporters (GLUT) which are present on the vesicles in the cytoplasm help in transporting glucose in and out of the cells. On excitation by glucose, GLUT comes to the membrane and performs its required function. In the case of DM the transportation of GLUT to the plasma membrane does not takes place (Fig. 8). A group of medicinal plants, such as Aegle marmelose (L.) Correa ex Roxb [11, 43], Allium sativum L. [25, 26], Canna indica L. [54], Lagerstro-
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Current Diabetes Reviews, 2008, Vol. 4, No. 4 299
Table 5a. Medicinal Plants (in Addition to Plant No. 12, 14-15, 18, 40) that Increase Insulin Secretion and Potentiates its Action S. No.
Plant
Constituent
Activity
References
48.
Abelmoschus moschatus L. (Malvaceae)
-Sitosterol, Ambrettelide, Myricetin-3glucoside.
1.0 mg/kg
[95]
49.
Abies pindrow Royle. (Pinaceae)
-Sitosteral, Terpenoids, Flavonoids.
10 μg/ml
[96]
50.
Acacia arabica (Lam.) Muhl. ex Willd. (Mimosaceae)
m-Digallic acid, Chlorogenic acid, (+)Catechin.
4 gm/kg
[97, 98]
51.
Achyranthes aspera L. (Amaranthaceae)
Betaine, Achyranthine, Aschyranthes aponins (B3).
4 mg/kg
[99]
52.
Agaricus campestris L.. (Agaricaceae)
-Terpineol, Hexanol, Furfural, Captylic acid.
1 mg/mL
[100]
53.
Artemisia roxburghiana Besser. (Compositae)
1,8-Cineole, Camphor, -Thujone.
1 g/mL
[66, 85, 96]
54.
Aloe barbadensis L. (Aloaceae)
Isobarbalin, Aloe-emodin, Aloetic acid, Barbaloin.
500 mg/kg
[62]
55.
Asparagus adscendens Roxb.(Asparagaceae)
3-Hepatadecanone, Steroidal glycosides.
[101]
56.
Azorella compacta Lam. (Umbelliferae)
Mulinol, Azorellanol, Mulinolic acid.
[102]
57.
Bauhinia forficata Link. (Leguminosae)
58.
Biophytum sensitivum auct. (Oxalidaceae)
Shamimin (flavonol glucoside).
59.
Bauhinia variegata L. (Caesalpiniaceae)
Quercetin, Quercetrin, Apigenin, Rutin.
20 g/ml
[105]
60.
Bergenia himalaica Boriss. (Saxifloriaceae)
Bergenin.
20 g/ml
[96]
61.
Caesalpinia bonducella L. Roxb. (Cesalpinaceae)
Bargenin, Caeselpinine A, & -Amyrin, Lupeol.
30 mg/kg
[106]
62.
Centaurea iberica Trev. ex Spreng (Asteraceae)
10 g/mL
[96]
63.
Cinnamomum cassia Lour. (Lauraceae)
Melilotic acid, Cinnamaldehyde
0.1 mg/ml
[107]
64.
Cinnamomum zeylanicum Blume. (Lauraceae)
L-arabino-D-xylan, D-glucan, Cinnzeylanin, Cinnzeylanol,
[107]
65.
Citrullus colocynthis L. Schrad. (Cucurbitaceae)
Citrullol, Elaterin, Elatericin B, Colosynthetin.
[108]
66.
Coriandrum sativum L. (Umbelliferae)
Linalool, Geraniol, -Pinene, p-Cymene, Limonene.
[109]
67.
Eugenia uniflora Lam. (Myrtaceae)
68.
Euphorbia helioscopiaL. (Euphorbiaceae)
69.
Ficus religiosa L.(Moraceae)
70.
Gynostemma pentaphyllum Thumb. (Cucurbitaceae)
71.
Gymnema sylvestre Retz. (Asclepiadaceae)
Gymnemosides, Gymnemic acid I-IV.
72.
Helicteres isora L. (Sterculiaceae)
Cucurbitacin B, Isocucurbitacin B.
73.
Hylocereus undatus Britton & Rose. (Cactaceae)
-Sitosterol, Vit-B1, B2, B3, C, Stigmasterol, Ca, P, Fe.
Astragalin, Kaempferitrin, Bauhinoside,
25.9%
-sitosterol.
decrease
[103] [104]
[110] 10 g/mL Leucopelargonidin, Pelargonidine.
[96] [111] [112] [30, 65]
100 mg/kg
[45] [52]
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Prabhakar and Doble
Table 5a. contd… S. No.
Plant
Constituent
Activity
References
74.
Luffa cylindrica (L.) Roem (Cucurbitaceae)
Momordin-a, Luffin-a.
75.
Musa sapientum L. (Musaceae)
2-heptyl acetate, 2-methylbutyl acetate.
76.
Marrubium vulgare L. (Lamiaceae)
77.
Monstera deliciosa Liebm. (Areceae)
78.
Orthosiphon aristatus Blume. (Lamiaceae)
Neoorthosiphols A & B, 3-hydroxy-2methyl-4-pyrone
[50]
79.
Panax notoginseng (Burk.) F.H.Chem (Araliaceae)
Saponin, Dencichine, Flavonoid, Polysaccharide.
[115]
80.
Panax quinquefolium L. (Araliaceae)
Quinquenoside L3 & L9, Vina-Ginsenoside R3.
[79, 116]
81.
Salvia coccinia Salmon & Red. (Lamiaceae)
82.
Scoparia dulcis L. (Scrophulariaceae)
83.
Swertia chirayita Roxb. ex Fleming.(Gentinaceae)
Amarogentin, Swerchirin, Chirantin, Gentiopicrin.
84.
Stevia rebaudiana Bertoni (Compositae)
Sstevioside.
85.
Teucrium polium L. Labiaceae)
86.
Tinospora crispa L. (Menispermaceae)
Cordifole, Cordifolide, -Sitosterol, Tinosporine.
87.
Vinca rosea (L.) G. Don (Apocyanaceae)
Vinblastine, Vincristine, Reserpine, Vinceine.
88.
Viburnum foetens Decne (Caprifoliaceae)
89.
Xanthocercis zambesiaca (Baker) Harms (Leguminoceae)
[53] 150 mg/kg
[113] [114]
1 g/mL
1 g/mL
[96]
[96] [117]
100 mg/kg
[118] [119] [120]
Castanospermine, Fagomine, Epifagomine, Homono jirimycin, Deoxynojirimycin.
[121] 500 mg/kg
[12, 61]
40 g/mL
[96]
50 mg/ml
[122]
Table 5b. Medicinal Plants (in Addition to Plant No. 14 and 51) that Potentiates Insulin Action by Inactivating Insulinase Enzyme S. No.
Plant
Constituent
Activity
References
90.
Arctostaphylos uva-ursi (L.) Spreng.(Ericaceae)
Arbutin, Ericolin, Ellagic acid, Myricetin, Ursone.
6.25% by weight
[123]
91.
Ocimum canum L. (Lamiaceae)
Camphor, Eugenol, Juvocimene I & II, Transß-ocimene, Linalool.
0.03 mg/ml
[124]
emia speciosa (L.) Pers. [55], Syzyzium cumini (L.) Skeel. [43], and Cornus officinalis Siebold. & Zucc. [56] help in the effective transportation of GLUT to the plasma membrane, as a result of which glucose gets transported into the cells and its concentration in the blood decreases. Insulin modulates several metabolic pathways through a cascade of steps by activating PI3 Kinase (Fig. 8) [57]. However, when its action is insufficient then these steps do not take place. Plants, such as Aegle marmelose (L.) Correa ex Roxb [11, 43], Helicteres isora L. [45], catharanthus roseus (L.) G. Don [12], Camellia sinensis (L.) Kuntze. [16, 18] and Hericium erinaceus Persoon. (Fungi) [58] have PI3 kinase activating capacity thereby affecting all the metabolic pathways inspite of inefiicient insulin (Table 5c, and Plant No: 1, 72, 86-87 and 92-94 respectively). Epigallocatechin
gallate (I), a green tea flavonoid, mimics insulin by increasing the PI3 Kinase activity [18]. 5. PHYTOCOSTITUENTS HAVING HYPOGLYCEMIC POTENTIAL Several phytochemicals including alkaloids, flavonoids, glycosides, glycolipid, polysaccharides, peptidoglycans, carbohydrates, amino acids and saponin obtained from plant sources have been reported to posses hypoglycemic activity (Fig. 9) [8]. Many of them may be found in a single plant and their combined synergistic action may be giving the observed behaviors. First three groups of phytochemical, which are explained below, can be considered as insulin mimetic natural drugs. They either increase the serum insulin level or increase the activity of insulin. The remaining groups either suppress glucose production or enhance glucose metabolism.
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301
Fig. (8). Mechanism of action of insulin (Tables 5b and 5c). Table 5c. Medicinal Plants (in Addition to Plant 1, 72, 86-87) that Activate PI3K S. No.
Plant
Constituent
92.
Camellia sinensis (L.) Kuntze. (Theaceae)
Epicatechin Epigallocatechin gallate, Epigallocatechin.
93.
Hericium erinaceus Persoon. (Fungi)(Hericiaceae)
94.
Syzyzium cumini (L.) Skeel.
5.1. Alkaloids Alkaloids are naturally occurring amines and they have pharmacological effects on human and animals. Resveratrol is a phytoalexin, a class of antibiotic compounds produced as part of a plant's defense system against disease. It increases glucose uptake in STZ-induced type 1 diabetic rat mediated through nitric oxide [59]. Berberine (XI) is known to have potent hypoglycemic activity and it is found in Tinospora cordifolia (Willd.) Hook. f. & Thomson [60]. Alkaloids such as Catharanthine (XII.), vindoline (XIII) and vindolinine (XIV) isolated from Catharanthus roseus (L.) G. Don have been reported to lower blood sugar level [61]. 5.2. Polysaccharides Medicinal plants which include Aloe vera L., Ocimum sanctum L., and Alpinia galanga (L.) Willd. contain polysachharides which increases the insulin level and showing hypoglycemic properties [62]. A protein-bound polysaccharide isolated from pumpkin is shown to increase the levels of
Activity
References [16, 18] [58]
200 mg/kg
[43]
serum insulin, reduce blood glucose level and improve tolerance of glucose [62]. 5.3. Saponins Saponins are glycosides of steroids, steroid alkaloids (steroids with a nitrogen function) or triterpinoids found in plants. Charantin (XV), a steroidal saponin, isolated from Momordica charantia L. is reported to posses an insulin-like activity [63], by enhancing the release of insulin and slowing down the glucogenesis. -Sitosterol (XVI), a steroid found in Azadirachta indica A.Juss. andrographolide (XVII), a diterpenoid lactone, isolated from Andrographis paniculata Nees. [64] and saponin gymnemic acid IV (XVIII) isolated from Gymnema sylvestre R, exhibit potent hypoglycemic activity in animal models [65]. 5.4. Ferulic Acids Ferulic acid (4-hydroxy-3-methoxycinnamic acid) (XIX) is a flavonoid which is a highly abundant phenolic photochemical present in cell walls of many plants that include
302 Current Diabetes Reviews, 2008, Vol. 4, No. 4
Prabhakar and Doble
OH OH HO
O
HO
OH
O
HO
O
OH
Me2C HC H2C OH
O
OMe
OH
Dehydroglyasperin C [II]
OH OH Epigallocatechin gallate [I]
MeO MeO Me2C
O
Me2C
C H2C
H
OMe
HC
H2C
Me2C
O
O
HO
O
MeO
OH Me2C
OMe
OH
O
O
OH
C H2C
H
OMe
OH
Glycyrin [VI]
Glycycoumarin [V]
MeO
OH
Glyasperin B[IV]
C H2C
H
OH
OH
Dehydroglyasperin D [III]
HO
O
OH
O OH
Me2C
HC
H2C OMe
O
Dihydroeugenol [VIII]
Glyasperin D [VII] O
O
OH
HO
O CH3 (CH2)4
HO
OH OMe
OMe
6-Gingerol [X]
Curcumin [IX]
O O
N
N+
H OCH3 OCH3
Berberine [XI]
Fig (9). Hypoglycemic phytochemicals. (Contd…)
N H
MeO O Catharanthine [XII]
Et
A Target Based Therapeutic Approach Towards Diabetes
Current Diabetes Reviews, 2008, Vol. 4, No. 4
Fig (9). Contd…. N
N
H3CO
CH3
H
N CH3
N
COCH3 HO
COOCH3
H
COOCH3
Vindolinine [XIV]
Vindoline [XIII]
CH3 H
CH(CH3)2
CH3
H3C
H CH3
H3C
H H
H
Glucose Beta O
HO
Charantin [XV]
B-Sitosterol[XVI]
O
H3C
CH3
O
O-Toqloyl
HO H3C
H3C CH2
HOOC O
HO
H CH
HOH2C
H3C
OH
CH3 O
HC
HO
3
OH CH2OH
H
3
CH OH 2
OH
Andrographolide [XVII]
Gymnemic acid [XVIII] OH
H3CO
OH HO
OH
O
COOH Ferulic acid [XIX]
OH
OH O
Quercetin [XX] O OH
O
H3CO
OH
O
HO O
O HO
O
O
O
CH3 HO
HO
O CH3
OH OH
HO
Hespiridin [XXI]
Fig (9). Hypoglycemic phytochemicals. (Contd…)
OH
HO
O
O O OH OH HO
OH
Naringin [XXII]
303
304 Current Diabetes Reviews, 2008, Vol. 4, No. 4
Prabhakar and Doble
Fig (9). Contd…. OH HO
O
OH
HO
O
OH
O
OH
OH
Genistein [XXIII]
O
HO
OH
(-) Epicatechin [XXIV]
+
O+
HO
OH
OH OH
OH OH
OH
.Cl
OH
-
OH
-
Delphinidin [XXVI]
Pelargonidin [XXV]
H 3C
.Cl
O O H 3C
N
N
N
N
H
N H
N
CH3
H Norharmane [XXVIII]
Harmane [XXVII]
O
H
HC 2
CH
CH
S
S
2
C
C
C
O
2
H2 N S-allyl cysteine sulfoxide [XXX]
O H2C
H
Pinoline [XIX]
CH
CH2
S
S
H2 C
C
CH2
OH H Allicin(Diallyl thiosulfinate) [XXXI]
Fig (9). Hypoglycemic phytochemicals.
Curcuma longa L, Artemisia arborescens L (Compositeae), A. herba habla L (Compositeae) and it may have significant health benefits through its antioxidant, anti-cancer properties and blood glucose lowering activity [66]. 5.5. Flavonoids Flavonoides is a group of naturally occurring compounds which possess hypoglycemic as well as antioxidant properties. They are also a class of plant secondary metabolites. Flavonoids can be widely classified into flavanols, flavones, catechins, flavanones, etc. Some flavonoids have hypoglycemic properties because they improve altered glucose and oxidative metabolisms of the diabetic states [67]. Quercetin (XX) is an important flavonoid known to increase hepatic glucokinase activity, probably by enhancing the insulin release from pancreatic islets [68]. It also exerts stimulatory effect on insulin secretion by changing Ca2+ concentration [69]. Supplimentation of (0.2 g/kg) citrus bioflavonoids, namely hesperidin (XXI) and naringin (XXII), in the diet of the male C57BL7KsJ-db/db mice (Type II diabetes model) lead to reduction in the blood glucose levels, increase in hepatic glucokinase activity and glycogen concentration. Naringin lowers the activity of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase and the plasma insulin, C-peptide. Genistein (XXIII) and soy isoflavonoids
when tested on obese Zucker rats (type II diabetes model) significantly improved lipid and glucose metabolism by acting as a hypoglycemic on PPAR [70]. Green tea flavonoid, epigallocatechin gallate (I) has a glucose-lowering effect in animals [18]. It is reported to decrease hepatic glucose production and increase tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), similar to insulin. It also reduces phosphoenolpyruvate carboxykinase gene expression in a phosphoinositide 3-kinase-dependent manner and mimics insulin by increasing PI3K, MAP kinase [18]. Another flavonoid, ( )-epicatechin (XXIV), has been reported to possess insulin-like activity [71] which acts on erythrocyte membrane-bound acetylcholinesterase in Type II diabetic patients [72]. Pelargonidin (XXV) and delphinidin (XXVI) have also shown good hypoglycemic activity [73]. 5.6. Imidazoline Compounds Pancreatic beta cells have imidazoline-I binding sites on them and imizoline derivatives found in some of the plants have stimulatory action on insulin secretion by activating this binding site [74]. -carbolines which include harmane (XXVII), norharmane (XXVIII) and pinoline (XXIX), obtained from Tribulus terrestris L. have found to increase insulin secretion two- to three-folds in isolated human islets of Langerhans [75].
A Target Based Therapeutic Approach Towards Diabetes
5.7. Sulfur Containing Compounds Administration of sulfur containing amino acids namely S-methyl cysteine sulfoxide (XXX) and Diallyl thiosulfinate isolated from the plants Allium sativum L. [25, 26] and Allium cepa L. [27, 28], to alloxan induced diabetic rats activate the enzymes hexokinase, glucose-6-phosphatase, HMG Co-A reductase, and LCAT. 6. CONCLUSION Traditionally herbal treatments for diabetes have been used in patients with insulin-dependent and non-insulindependant diabetes, diabetic retinopathy, diabetic peripheral neuropathy, etc. There are a number of plants which have the capacity to reduce the glucose production, induce the utilization of glucose and combat with secondary complications. Out of an estimated 250 000 plants, less than 1% have been screened pharmacologically and only a fraction of these for DM [8]. The most commonly used drugs of modern medicine such as aspirin, anti-malarials, anti-cancers, digitalis etc. have originated from plant sources. Therefore, it is prudent to look for options in herbal medicine for diabetes. Hence it is proven that medicinal plants have potential effectiveness against diabetes and the photochemical play a major role in the management of diabetes, which needs further exploration for necessary development of drugs and nutraceuticals from natural plant resources. This aspect also gains importance in the light of the fact that many herbal therapies have not undergone proper scientific assessment for their potential to cause serious toxic effects and major drug-to-drug interaction. Continued research is necessary to elucidate the pharmacological activities of herbal remedies being used to treat diabetes mellitus.
Current Diabetes Reviews, 2008, Vol. 4, No. 4
PPAR
=
Peroxisome proliferator-activated receptors
SUR
=
Sulfonylurea binding site 1
REFERENCES [1] [2] [3] [4] [5] [6]
[7] [8] [9] [10] [11]
[12]
ABBREVIATIONS [13]
ADP
=
Adenosine diphosphate
ATP
=
Adenosine triphosphate
cAMP
=
Cyclic AMP
DM
=
Diabetes mellitus
GLUT
=
Glucose transporter
HMP
=
Hexose monophosphate
IRS
=
Insulin receptor substrate
IDDM
=
Insulin dependent diabetes mellitus
[17]
NIDDM
=
Non-Insulin dependent diabetes mellitus
[18]
KATP
=
ATP dependent K channel
LDH
=
Lactate dehydrogenase
[19]
NADH
=
Reduced nicotinamide adenosine dinucleotide
[20]
Reduced nicotinamide adenosine dinucleotide phosphate
[21]
NADPH
=
PI3K
=
Phosphatidylinositol-3-kinase
PKC
=
Protein kinase C
RNA
=
Ribose nucleic acid
TZD
=
Thiazolidinedione
305
[14]
[15]
[16]
[22] [23]
WHO, Traditional medicine strategy (2002–2005). WHO Publications 2002; 1–6. ADA, Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2004, 27: S5-S10. International Diabetes Federation: What are the warning signs of diabetes. Available from www.idf.org/home/index.cfm?node=11. Accessed 9 March 2007. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999; 15(6): 412-26. Grover JK, Vats V. Shifting Paradigm “from conventional to alternate medicine.” An introduction on traditional Indian medicine. Asia Pacific Biotechnol News 2001; 51: 28–32. Alarcon-Aguilara FJ, Roman-Ramos R, Perez-Gutierrez S, Aguilar-Contreras A, Contreras-Weber C, Flores-Saenz JL. Study of the anti-hypoglycemic effect of plants used as anti-diabetics. J Ethnopharmacol 1998; 61 (2): 101-10. Prabhakar PK, Doble M. Recent trends in medicinal plants volume 22, Mechanism of action of medicinal plants towards diabetes mellitus-A review. Studium press LLC, USA 2008; 181-204. Grover JK, Vats V, Yadav S. Medicinal plants of India with antidiabetic properties. J Ethnopharmacol 2002; 81: 81-100. Arulrayan N, Rangasamy S, James E, Pitchai D. A database for medicinal plants used in the treatment of diabetes and its secondary complications. Bioinformation 2007; 2(1): 22-3. Berg JM, Tymoczko JL, Stryer L. Biochemistry, 5th ed. WH Freeman and Co. pp. 644-89. Narendhirakannan RT, Subramanian S, Kandaswamy M. Biochemical evaluation of antidiabetogenic properties of some commonly used Indian plants on streptozotocin-induced diabetes in experimental rats. Clin Exp Pharmacol Physiol 2006; 33(12): 1150-7. Singh SN, Vats P, Suri S. Effect of an antidiabetic extract of Catharanthus roseus on enzymic activities in streptozotocin induced diabetic rats. J Ethnopharmacol 2001; 76: 269-77. Yeung HW, Ng TB. Hypoglycemic constituents of Panax ginseng. Gen Pharmacol 1985; 16(6): 549-52. Park SA, Myung-Sook C, Myung-Joo K, et al. Hypoglycemic and hypolipidemic action of Du-zhong (Eucommia ulmoides Oliver) leaves water extract in C57BL/KsJ-db/db mice. J Ethnopharmacol 2006; 107(3): 412-7. Ugochukwu NH, Babady NE. Antihyperglycemic effect of aqueous and ethanolic extracts of Gongronema latifolium leaves on glucose and glycogen metabolism in livers of normal and streptozotocininduced diabetic rats. Life Sci 2003; 73(15): 1925-38. Broadhurst CL, Polansky MM, Anderson RA. Insulin-like biological activity of culinary and medicinal plant aqueous extracts invitro. J Agric Food Chem 2000; 48(3): 849-52. Prasad RC, Herzog B, Boone B, Sims L, Waltner-Law M. An extract of Syzygium aromaticum represses genes encoding hepatic gluconeogenic enzymes. J Ethnopharmacol 2005; 96: 295-01. Waltner-Law ME, Wang XL, Law BK, et al. A Constituent of Green Tea, Represses Hepatic Glucose Production. J Biol Chem 2002; 277(38): 34933-40. Prakasam A, Sethupathy S, Pugalendi KV. Influence of Casearia esculenta root extract on glycoprotein components in streptozotocin diabetic rats. Pharmazie 2005; 60(3): 229-32. Ananthi J, Prakasam A, Pugalendi KV. Antihyperglycemic activity of Eclipta alba leaf on alloxan-induced diabetic rats. Yale J Biol Med 2003; 76(3): 97-102. Santhakumari P, Prakasam A, Pugalendi KV. Antihyperglycemic activity of Piper betle leaf on streptozotocin-induced diabetic rats. J Med Food 2006; 9(1): 108-12. Gupta D, Raju J, Baquer NJ. Modulation of some gluconeogenic enzyme activities in diabetic rat liver and kidney: effect of antidiabetic compounds. Indian J Exp Biol 1999; 37(2): 196-9. Mukherjee K, Ghosh NC, Datta T. Coccinia indica Linn. as potential hypoglycemic agent. Indian J Exp Biol 1972; 10(5): 347-9.
306 Current Diabetes Reviews, 2008, Vol. 4, No. 4 [24] [25] [26] [27] [28] [29]
[30]
[31]
[32] [33] [34] [35]
[36]
[37]
[38] [39]
[40] [41] [42]
[43]
[44]
Kar A, Choudhary BK, Bandyopadhyay NG. Comparative evaluation of hypoglycaemic activity of some Indian medicinal plants in alloxan diabetic rats. J Ethnopharmacol 2003; 84(1): 105-8. Sheela CG, Augusti KT. Antidiabetic effects of S-allyl cysteine sulphoxide isolated from garlic Allium sativum Linn. Indian J Exp Biol 1992; 30: 523-6. Sheela CG, Kumud K, Augusti KT. Anti-diabetic effects of onion and garlic sulfoxide amino acids in rats. Planta Med 1995; 61(4): 356-7. Mathew PT, Augusti KT. Hypoglycaemic effects of onion, Allium cepa Linn. on diabetes mellitus - a preliminary report. Indian J Physiol Pharmacol 1975; 19(4): 213-7. Kumari K, Mathew BC, Augusti KT. Hypoglycemic and hypolipidemic effects of S-methyl cysteine sulfoxide isolated from Allium cepa Linn. Indian J Biochem Biophys 1995; 32: 49-54. Punitha ISR, Rajendran K, Shirwaikar A, Shirwaikar A. Alcoholic stem extract of Coscinium fenestratum regulates carbohydrate metabolism and improves antioxidant status in streptozotocinnicotinamide induced diabetic rats. Evid Based Complement Alternat Med 2005; 2(3): 375-81. Babu PS, Stanely Mainzen Prince P. Antihyperglycaemic and antioxidant effect of hyponidd, an ayurvedic herbomineral formulation in streptozotocin-induced diabetic rats. J Pharm Pharmacol 2004; 56(11): 1435-42. Khan BA, Abraham A, Leelamma S. Hypoglycemic action of Murraya koenigii (curry leaf) and Brassica juncea (mustard): mechanism of action. Indian J Biochem Biophys 1995; 32(2): 1068. Stanely P, Prince M, Menon VP. Hypoglycaemic and other related actions of Tinospora cordifolia roots in alloxan-induced diabetic rats. J Ethnopharmacol 2000; 70(1): 9-15. Hikino H, Kobayashi M, Suzuki Y, Konno C. Mechanisms of hypoglycemic activity of aconitan A, a glycan from Aconitum carmichaeli roots. J Ethnopharmacol 1989; 25(3): 295-04. Maroo J, Vasu VT, Gupta S. Dose dependent hypoglycemic effect of aqueous extract of Enicostemma littorale Blume in alloxan induced diabetic rats. Phytomedicine 2003; 10(2-3): 196-9. Omoruyi FO, Grindley PB, Asemota HN, Morrison EY. Increased plasma and liver lipids in streptozotocin-induced diabetic rats: Effects of yam (Dioscorea cayenensis) or dasheen (Colocassia esculenta) extract supplements. Diabetol Croat 2001; 30(3): 87-92. Dansi A, Mignouna HD, Zoundjihékpon J, Sangare A, Asiedu R, Ahoussou N. Using isozyme polymorphism to assess genetic variation within cultivated yams (Dioscorea cayenensis/Dioscorea rotundata complex) of the Republic of Benin. Genetic Resour Crop Evol 2000; 47(4): 371-83. Panneerselvam R, Jaleel CA, Somasundaram R, Sridharan R, Gomathinayagam M. Carbohydrate metabolism in Dioscorea esculenta (Lour.) Burk. tubers and Curcuma longa L. rhizomes during two phases of dormancy. Colloids Surf B Biointerf 2007; 59: 59-66. Chattopadhyay RR. Possible mechanism of antihyperglycemic effect of Azadirachta indica leaf extract, Part IV. Gen Pharmacol 1996; 27(3): 431-4. Bhandari MR, Jong-Anurakkun N, Hong G, Kawabata J. -Glucosidase and -amylase inhibitory activities of Nepalese medicinal herb Pakhanbhed (Bergenia ciliata, Haw.). Food Chem 2008; 106(1): 247-52. Anurakkun NJ, Bhandari MR, Kawabata J. -Glucosidase inhibitors from Devil tree (Alstonia scholaris). Food Chem 2007; 103: 1319-23. Jones PM, Persaud SJ. Protein Kinases, Protein Phosphorylation, and the Regulation of Insulin Secretion from Pancreatic -Cells. Endocr Rev 1998; 19(4): 429-61. Fernyhough ME, Okine E, Hausman G, Vierck JL, Dodson MV. PPAR and GLUT-4 expression as developmental regulators/markers for preadipocyte differentiation into an adipocyte. Domest Anim Endocrinol 2007; 33(4): 367-78. Anandharajan R, Jaiganesh S, Shankernarayanan NP, Viswakarma RA, Balakrishnan A. In vitro glucose uptake activity of Aegles marmelos and Syzygium cumini by activation of Glut-4, PI3 kinase and PPARgamma in L6 myotubes. Phytomedicine 2006; 13(6): 434-41. Che-Yi C, Ching-Jang H. Bitter Gourd (Momordica charantia) Extract Activates Peroxisome Proliferator-Activated Receptors and upregulates the expression of the acyl CoA oxidase gene in H4IIEC3 hepatoma cells. J Biomed Sci 2003; 10: 782-91.
Prabhakar and Doble [45] [46]
[47] [48] [49]
[50] [51]
[52] [53]
[54]
[55] [56]
[57] [58] [59]
[60] [61] [62] [63] [64] [65]
[66] [67]
Chakrabarti R, Vikramadithyanm RK, Mullangi R, et al. Antidiabetic and hypolipidemic activity of Helicteres isora in animal models. J Ethnopharmacol 2002; 81(3): 343-9. Mae T, Tsukagawa M, Kitahara M, et al. Peroxisome proliferator activated receptor ligands containing prenyl flavonoid, related substances, or plant extracts containing the same, and process for producing the same. PCT Int Appl 2003; 74. Mimaki Y. New biologically active compounds from natural sources. J Jpn Cosmetic Sci Soc 2006; 30(4): 256-60. Shishodia S, Sethi G, Aggarwal BB. Curcumin: getting back to the roots. Ann NY Acad Sci 2005; 1056: 206-17. Kitamura T, Kitamura Y, Kuroda S, et al. Insulin-Induced Phosphorylation and Activation of Cyclic Nucleotide Phosphodiesterase 3B by the Serine-Threonine Kinase Akt. Mol Cell Biol 1999; 19(9): 6286-96. Ngamrojanavanich N, Manakit S, Pornpakakul S, Petsom A. Inhibitory effects of selected Thai medicinal plants on Na +-K+ATPase. Fitoterapia 2006; 77(6): 481-3. Dhanabal SP, Edwin JE, Kumar EP, Suresh EP. Hypoglycemic effects of Alcoholic extract of various species of Passiflora on alloxan induced diabetes mellitus in albino Rats. Nig J Nat Prod Med 2004; 8: 19-21. Perez GR, Vargas SYD, Ortiz H. Wound healing properties of Hylocereus undatus on diabetic rats. Phytother Res 2005; 19(8): 665-8. Minami Y. Chemical modifications of momordin- and luffin- , ribosome-inactivating proteins from the seeds of Momordica charantia and Luffa cylindrica: involvement of His140, Tyr165, and Lys231 in the protein-synthesis inhibitory activity. Biosci Biotechnol Biochem 1998; 62(5): 959-64. Purintrapiban J, Suttajit M, Forsberg NE. Differential activation of glucose transport in cultured muscle cells by polyphenolic compounds from Canna indica L. root. Biol Pharm Bull 2006; 29(10): 1995-8. Klein G, Kim J, Himmeldirk K, Cao Y, Chen X. Antidiabetes and Anti-obesity Activity of Lagerstroemia speciosa. Evid Based Complement Altern Med 2007; doi: 10.1093/ecam/nem013. Xu HQ, Hao HP. Effects of iridoid total glycoside from Cornus officinalis on prevention of glomerular overexpression of transforming growth factor beta 1 and matrixes in an experimental diabetes model. Biol Pharm Bull 2004; 27(7): 1014-8. Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular Actions of Insulin. Endocr Rev 2007; 28 (5): 463-91 Wang JC, Hu SH, Wang JT, Chen KS, Chia YC. Hypoglycemic effect of extract of Hericium erinaceus. J Sci Food Agric 2004; 85(4): 641-6. Penumathsa SV, Thirunavukkarasu M, Zhan L, et al. Resveratrol enhances GLUT-4 translocation to the caveolar lipid raft fractions through AMPK/AKT/eNOS signaling pathway in diabetic myocardium. J Cell Mol Med. doi:10.1111/j.1582-4934.2008.00251.x. Singh SS, Pandey SC, Srivastava S, Gupta VS, Patro B, Ghosh AC. Chemistry and medicinal properties of Tinospora cordifolia (Guduchi). Ind J Pharmacol 2003; 35: 83-91. Chattopadhyay RR. A comparative evaluation of some blood sugar lowering agents of plant origin. J Ethnopharmacol 1999; 67: 36772. Mukherjee PK, Maiti K, Mukherjee K, Houghton PJ. Leads from Indian medicinal plants with hypoglycemic potentials. J Ethnopharmacol 2006; 106: 1-28. Ng TB, Wong CM, Li WW, Yeung HW. Insulin-like molecules in Momordica charantia seeds. J Ethnopharmacol 1986; 15: 107-17. Yu BC, Hung CR, Chen WC, Cheng JT. Antihyperglycemic effect of andrographolide in streptozotocin-induced diabetic rats. Planta Med 2003; 69: 1075-9. Sugihara Y, Nojima H, Matsuda H, Murakami T, Yoshikawa M, Kimura I. Antihyperglycemic effects of gymnemic acid IV, a compound derived from Gymnema sylvestre leaves in streptozotocindiabetic mice. J Asian Nat Prod Res 2000; 2: 321-7. Ohnishi M, Matuo T, Tsuno T, et al. Antioxidant activity and hypoglycemic effect of ferulic acid in STZ-induced diabetic mice and KK-Ay mice. Biofactors 2004; 21: 315-9. Song Y, Manson JE, Buring JE, Howard D, Simin Liu S. Associations of Dietary Flavonoids with Risk of Type 2 Diabetes, and Markers of Insulin Resistance and Systemic Inflammation in Women: A Prospective Study and Cross-Sectional Analysis. J Am Coll Nutr 2005; 24(5): 376-84.
A Target Based Therapeutic Approach Towards Diabetes [68] [69] [70]
[71] [72] [73] [74]
[75]
[76]
[77]
[78]
[79]
[80]
[81] [82] [83]
[84] [85]
[86] [87] [88]
Vessal M, Hemmati M, Vasei M. Hypoglycemic effects of quercetin in streptozocin-induced diabetic rats. Comp Biochem Physiol C Toxicol Pharmacol 2003; 135C: 357-64. Hii CS, Howell SL. Effects of flavonoids on insulin secretion and 45Ca2+ handling in rat islets of Langerhans. J Endocrinol 1985; 107: 1-8. Mezei O, Banz WJ, Steger RW, Peluso MR, Winters TA, Shay N. Soy isoflavones exert hypoglycemic and hypolipidemic effects through the PPAR pathways in obese Zucker rats and murine RAW 264.7 cells. J Nutr 2003; 133: 1238-43. Chakravarthy BK, Gupta S, Gambhir SS, Gode KD. The prophylactic action of ( )epicatechin against alloxan induced diabetes in rats. Life Sci 1981; 29: 2043-7. Rizvi SI, Zaid MA. Insulin-like effect of ( )-epicatechin on erythrocyte membrane acetylcholinesterase activity in type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2001; 28: 776-8. Cherian S, Augusti KT. Antidiabetic effects of a glycoside of leucopelargonidin isolated from Ficus bengalensis Linn. Indian J Exp Biol 1993; 31(1): 26-9. Hongwei G, Mirna M, Noel GM. Effects of the Imidazoline binding Site Ligands, Idazoxan and Efaroxan, on the Viability of Insulin-Secreting BRIN-BD11 cells. J Pancreas (Online) 2003; 4(3): 117-24. Cooper EJ, Hudson AL, Parker CA, Morgan NG. Effects of the beta-carbolines, harmane and pinoline, on insulin secretion from isolated human islets of Langerhans. Eur J Pharmacol 2003; 482: 189-96. Grover JK, Vats V, Rathi SS. Anti-hyperglycemic effect of Eugenia jambolana and Tinospora cordifolia in experimental dia-betes and their effects on key metabolic enzymes involved in car-bohydrate metabolism. J Ethnopharmacol 2000; 73(3): 461-70. Rathi Ss, Grover JK, Vats V. The effect of Momordica charantia and Mucuna pruriens in experimental diabetes and their effect on key metabolic enzymes involved in carbohydrate metabolism. Phytother Res 2002; 16(3): 236-43 Hannan JM, Marenah L, Ali L, Rokeya B, Flatt PR, Abdel-Wahab YH. Ocimum sanctum leaf extracts stimulate insulin secretion from perfused pancreas, isolated islets and clonal pancreatic -cells. J Endocrinol 2006; 89(1): 127-136. Vuksan V, Sievenpiper JL, Koo VY, et al. American ginseng (Panax quinquefolius L) reduces postprandial glycemia in nondiabetic subjects and subjects with type2 diabetes mellitus. Arch Intern Med 2000; 160(7): 1009-13. Olagunju JA, Jobi AA, Oyedapo OO. An investigation into the biochemical basis of the observed hyperglycaemia in rats treated with ethanol root extract of Plumbago zeylanica. Phytother Res 1999; 13(4): 346-8. Vats V, Yadav SP, Grover JK. Effect of T. foenumgraecum on glycogen content of tissues and the key enzymes of carbohydrate metabolism. J Ethnopharmacol 2003; 85(2-3): 237-42. Gad MZ, El-Sawalhi MM, Ismail MF, El-Tanbouly ND. Biochemical study of the anti-diabetic action of the Egyptian plants Fenugreek and Balanites. Mol Cell Biochem 2006; 281(1&2): 173-83. Ichiki H, Takeda O, Sakakibara I, Terabayashi S, Takeda S, Sasaki H. Inhibitory effects of compounds from Anemarrhenae Rhizoma on -glucosidase and aldose reductase and its contents by drying conditions. J Nat Med 2007; 61(2): 146-53. Yasuda K, Kizu H, Yamashita T, et al. New sugar-mimic alkaloids from the pods of Angylocalyx pynaertii. J Nat Prod 2002; 65(2): 198-02. Subramanian A, Pushpagandan P, Ragasekharan S, Evans DA, Latha PG, Valsaraj R. Effects of Artemisia pallens Wall on Blood Glucose Levels in Nomal and Alloxan-induced Diabetic Rats. J Ethnopharmacol 1996; 50: 13-7. Lemus I, García R, Delvillar E, Knop G. Hypoglycemic activity of four plants used in Chilean popular medicine. Phytother Res 1999; 13(2): 91-4. Fuentes O, Arancibia-Avila P, Alarcón J. Hypoglycemic activity of Bauhinia candicans in diabetic induced rabbits. Fitoterapia 2004; 75: 527-32. Abesundara KJM, Mastui T, Matsumoto K. Glucosidase inhibitory activity of some Sri Lanka plant extracts, one of which, Cassia auriculata, exerts a strong antihyperglycemic effect in rats comparable to the therapeutic drug acarbose. J Agric Food Chem 2004; 52: 2541-5.
Current Diabetes Reviews, 2008, Vol. 4, No. 4 [89] [90]
[91] [92] [93]
[94]
[95]
[96] [97] [98]
[99] [100] [101] [102] [103] [104] [105] [106]
[107] [108] [109] [110] [111]
307
Sharma DK, Hall IH. Hypolipidemic, anti-inflammatory and antineoplastic activity and cytotoxicity of flavonolignans isolated from Hydnocarpus wightiana seeds. J Nat Prod 1991; 54(5): 1298-02. Basnet P, Kadota S, Terashima S, Shimizu M, Namba T. Two new 2-arylbenzofuran derivatives from hypoglycemic activity-bearing fractions of Morus insignis. Chem Pharm Bull (Tokyo) 1993; 41(7): 1238-43. Onal S, Timur S, Okutucu B, Zihnioglu F. Inhibition of alphaglucosidase by aqueous extracts of some potent antidiabetic medicinal herbs. Prep Biochem Biotechnol 2005; 35(1): 29-36. Kimura T, Nakagawa K, Saito Y, et al. Simple and rapid determination of 1-deoxynojirimycin in mulberry leaves. BioFactors 2004; 22(1-4): 341-5. Yoshikawa M, Shimoda H, Nishida N, et al. Antidiabetic principles of natural medicines. II. Aldose reductase and alpha-glucosidase inhibitors from Brazilian natural medicine, the leaves of Myrcia multiflora DC. (Myrtaceae): structures of myrciacitrins I and II and myrciaphenones A and B. Chem Pharm Bull 1998; 46(1): 113-9. Yoshikawa M, Nishida N, Shimoda H, Takada M, Kawahara Y, Matsuda H. Polyphenol constituents from Salacia species: quantitative analysis of mangiferin with alpha-glucosidase and aldose reductase inhibitory activities. Yakugaku Zasshi 2001; 121(5): 371-8. Liu I-M, Shorong-Shii L, Ting-Wei L, Feng-Lin H, Juei-Tang C. Myricetin as the active principle of Abelmoschus moschatus to lower plasma glucose in streptozotocin-induced diabetic rats. Planta Med 2005; 71(7): 617-21. Hussain Z, Waheed A, Qureshi RA, et al. The effect of medicinal plants of Islamabad and Murree region of Pakistan on insulin secretion from INS-1 cells. Phytother Res 2004; 18(1): 73-7. Wadood A, Wadood N, Shah SA. Effects of Acacia arabica and Caralluma edulis on blood glucose levels of normal and alloxan diabetic rabbits. J Pak Med Assoc 1989; 39: 208-12. Singh KN, Chandra V, Barthwal KC. Hypoglycemic activity of Acacia arabica, Acacia benthami and Acacia modesta leguminous seed diets in normal young albino rats. Indian J Physiol Pharmacol 1975; 19: 167-8. Akhtar MS, Iqbal J. Evaluation of the hypoglycaemic effect of Achyranthes aspera in normal and alloxan-diabetic rabbits. J Ethnopharmacol 1991; 31(1): 49-57. Gray AM, Flatt PM. Insulin-releasing and insulin-like activity of Agaricus campestris (mushroom). J Endocrinol 1998; 157: 259-66. Mathews JN, Flatt PR, Abdel-Wahab YH. Asparagus adscendens (Shweta musali) stimulates insulin secretion, insulin action and inhibits starch digestion. Br J Nutr 2006; 95(3): 576-81. Fuentes NL, Sagua H, Morales G, et al. Experimental antihyperglycemic effect of diterpenoids of llareta Azorella compacta (Umbelliferae) Phil in rats. Phytother Res 2005; 19(8): 713-6. de Sousa E, Zanatta L, Seifriz I, et al. Hypoglycemic effect and antioxidant potential of kaempferol-3,7-O-(alpha)-dirhamnoside from Bauhinia forficata leaves. J Nat Prod 2004; 67(5): 829-32. Puri D, Baral N. Hypoglycemic effect of Biophytum sensitivum in the alloxan diabetic rabbits. Indian J Physiol Pharmacol 1998; 42(3): 401-6. Azevedo CR, Maciel FM, Silva LB, et al. Isolation and intracellular localization of insulin/like proteins from leaves of Bauhinia variegata. Braz J Med Biol Res 2006; 39(11): 1435-44. Chakrabarti S, Biswas TK, Seal T, et al. Antidiabetic activity of Caesalpinia bonducella F. in chronic type 2 diabetic model in Long-Evans rats and evaluation of insulin secretagogue property of its fractions on isolated islets. J Ethnopharmacol 2005; 97(1): 11722. Verspohl EJ, Bauer K, Neddermann E. Antidiabetic effect of Cinnamomum cassia and Cinnamomum zeylanicum in vivo and in vitro. Phytother Res 2005; 19(3): 203-6. Nmila R, Gross R, Rchid H, et al. Insulinotropic effect of Citrullus colocynthis fruit extracts. Planta Med 2000; 66(5): 418-23. Gray AM, Flatt PM. Insulin-releasing and insulin-like activity of the traditional anti-diabetic plant Coriandrum sativum (coriander). Br J Nutr 1999; 81: 203-9. Consolini AE, Baldini OAN, Amat AG. Pharmacological basis for the empirical use of Eugenia uniflora L. (Myrtaceae) as antihypertensive. J Ethnopharmacol 1999; 66: 33-9. Wang HX, Ng TB. Natural products with hypoglycemic, hypotensive, hypocholesterolemic, antiatherosclerotic and antithrombotic activities. Life Sci 1999; 65(25): 2663-77.
308 Current Diabetes Reviews, 2008, Vol. 4, No. 4 [112] [113] [114]
[115]
[116]
[117]
Prabhakar and Doble
Norberg A, Khanh N, Liepinsh HE, et al. A Novel Insulin-releasing Substance, Phanoside, from the Plant Gynostemma pentaphyllum. J Biol. Chem 2004; 279 (40): 41361-7. Pari L, Maheswari JU. Hypoglycaemic effect of Musa sapientum L. in alloxan-induced diabetic rats. J Ethnopharmacol 1999; 68 (1-3): 321-5. Herrera-Arellano A, Aguilar-Santamar L, Garc´ a-Herna´ nuez B, Nicasio-Torresa P, Tortorielloa J. Clinical trial of Cecropia obtusifolia and Marrubium vulgare leaf extracts on blood glucose and serum lipids in type 2 diabetics. Phytomedicine 2004; 11: 561–6. Liu KZ, Li JB, Lu HL, Wen JK, Han M. Effects of Astragalus and saponins of Panax notoginseng on MMP-9 in patients with type 2 diabetic macroangiopathy. Zhongguo Zhong Yao Za Zhi 2004; 29(3): 264-6. Kimura M, Waki I, Chujo T, et al. Effects of hypoglycemic components in ginseng radix on blood insulin level in alloxan diabetic mice and on insulin release from perfused rat pancreas. J Pharmacobiodyn 1981; 4(6): 410-7. Lathaa M, Paria L, Sitasawadb S, Bhondeb R. Insulin-secretagogue activity and cytoprotective role of the traditional antidiabetic plant Scoparia dulcis (Sweet Broom weed). Life Sci 2004; 75: 2003-14.
Received: 22 January, 2008
[118] [119] [120] [121] [122]
[123]
[124]
Joshi P, Dhawan V. Swertia chirayita–an overview. Curr Sci 2005; 89(4): 635-40. Chen TH, Chen SC, Chan P, Chu YL, Yang HY, Cheng JT. Mechanism of the hypoglycemic effect of stevioside, a glycoside of Stevia rebaudiana. Planta Med 2005; 71(2): 108-13. Gharaibeh MN, Elayan HH, Salhab AS. Hypoglycemic effects of Teucrium polium. J Ethnopharmacol 1988; 24(1): 93-9. Noor H, Ashcroft SJH. Pharmacological characterisation of the antihyperglycaemic properties of Tinospora crispa extract. J Ethnopharmacol 1998; 62(1): 7-13. Nojima H, Kimura I, Chen FJ, et al. Antihyperglycemic effects of N-containing sugars from Xanthocercis zambesiaca, Morus bombycis, Aglaonema treubii, and Castanospermum australe in streptozotocin-diabetic mice. J Nat Prod 1998; 61(3): 397-00. Swanston-Flatt SK, Day C, Flatt PR, Gould BJ, Bailey CJ. Glycaemic effects of traditional European plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice. Diabetes Res 1989; 10(2): 69-73. Nyarko AK, Asare-Anane H, Ofosuhene M, Addy ME. Extract of Ocimum canum lowers blood glucose and facilitates insulin release by isolated pancreatic -islet cells. Phytomedicine 2002; 9(4): 34651.
Revised: 17 March, 2008
Accepted: 15 May, 2008
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Curr Pharmacol Rep (2016) 2:34–44 DOI 10.1007/s40495-016-0045-2
CANCER CHEMOPREVENTION (R AGARWAL, SECTION EDITOR)
Bitter Melon as a Therapy for Diabetes, Inflammation, and Cancer: a Panacea? Deep Kwatra
1,2
&
Prasad Dandawate
1
&
3
Subhash Padhye
&
Shrikant Anant
1,2
Published online: 21 January 2016 # Springer International Publishing AG 2016
Abstract Natural products have been used for centuries for cures prevention, treatment, and cure of multiple diseases. Some dietary agents are present in multiple systems of medi-cines as proposed treatments for chronic and difficult to treat diseases. Once such natural product is Momordica charantia or bitter melon. Bitter melon is cultivated in multiple regions across the world, and various parts of the plant, such as fruit, leaves seed, etc. have been shown to possess medicinal prop-erties in ancient literature. Over the last few decades, multiple well-structured scientific studies have been performed to study the effects of bitter melon in various diseases. Some of the properties for which bitter melon has been studied include: antioxidant, antidiabetic, anticancer, anti-inflammatory, anti-bacterial, antifungal, antiviral, anti-HIV, anthelmintic, hypo-tensive, anti-obesity, immunomodulatory, antihyperlipidemic, hepato-protective, and neuroprotective activities. This review attempts to summarize the various literature findings regarding medicinal properties of bitter melon. With such strong scien-tific support on so many medicinal claims, bitter melon comes close to being considered a panacea.
This article is part of the Topical Collection on Cancer Chemoprevention
*
Shrikant Anant [email protected]
1
Department of Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
2
The University of Kansas Cancer Center, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
3
Interdisciplinary Science and Technology Research Academy, Abeda Inamdar College, University of Pune, Pune 411001, India
.
.
.
Keywords Herbal remedy Anticancer Antidiabetic Anti-
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inflammatory Drug resistance Dietary agent Obesity
Introduction Nature is full of deadly poisons as well as life-saving entities. In natural products such as medicinal plants, their extracts have been used for thousands of years in traditional medicine throughout the world. In the past century, new drug development is mainly being carried out using combinatorial chemistry and targeted drug design. However, phytochemicals and their analogs have also started to garner a lot of attention in drug discovery because of their relatively better safety profile, possible multi-targeted activities, and potential to treat wide range of diseases. A report from the World Health Organization (WHO) had reported that about 80 % of the world’s population utilizes traditional system of medicine as their first line of therapy [1]. Multiple countries in Asia, Africa, and the Middle East have long-standing and still prevailing systems of traditional medicines, most containing within them large compilations of therapeutic plants and related products [2]. Some of the medicinal plants described in Ayurveda (the traditional Indian system of medicine), viz. bitter melon (BM) [3–5], turmeric [6, 7], and stone apple [8, 9], have demonstrat-ed their importance in recent years for treatment of various diseases including diabetes and cancer. With advancement in science and technology, it is now a lot more feasible to dis-cover the active constituents present in these plants and estab-lish their pharmacology for developing them into safer and more efficient therapeutics. The current review discusses and summarizes the potential biological activities of BM or Momordica charantia (MC).
BM, though a medicinal plant in Ayurveda and Chinese sys-tems of medicine, is often consumed as a cooked vegetable in
Curr Pharmacol Rep (2016) 2:34–44
both these countries as well as other parts of Southeast Asia. It is known as bitter melon, bitter gourd, balsam pear, bitter cucumber, and Karela [10]. All parts of the plant, including the fruit, taste bitter. The shoot and leaves of bitter melon are used as vegetables for cooking, while fruit extracts are also utilized in tea preparations [11, 12]. Since the bitterness of the vegetable is considered desirable, hence, the bitter flavor has been preferentially selected during domestication [13]. In Ayurveda, MC is claimed to possess antidiabetic, abortifacient, anthelmintic, antimalarial, and laxative properties. Additional indications include dysmenorrhea, emmenagogue, eczema, gout, galactagogue, kidney (stone), jaundice, leucorrhea, leprosy, pneumonia, piles, rheuma-tism, and psoriasis [14]. In recent years, MC and its various extracts have been studied for biological activities including antioxidant [15], antidiabetic [16], anticancer [3, 4], antiinflammatory [17], antibacterial [18], antifungal [19], anti-v i ral[20],anti-HIV[21],anthelmintic[22], antimycobacterial [23], hypotensive [24], anti-obesity [25], Immuno-modulatory [26], antihyperlipidemic [27], hepatoprotective [28], and neuro-protective activities [29]. Numerous chemical constituents such as curcubitane-type triterpenoids, curcubitane-type glycosides, triterpene saponins, phenolic and flavonoid compounds, and protein components [30] have been identified and studied for various therapeutic activities. In the present review, we are summarizing some of the important reports dealing with antioxi-dant, anti-inflammatory, anticancer, and antidiabetic activi-ties of MC. With so many health and therapeutic benefits, one can consider bitter melon to be as close to panacea as possible that exists in nature.
M. charantia The genus Momordica occurs to subtribe Thladianthinae, tribe Joliffieae, subfamily Cucurbitoideae, of the Cucurbitaceae family [31]. The genus Momordica includes 45 plant species domesticated in Asia and Africa [32]. The plant grows in tropical areas of Asia, Amazon, east Africa, and the Caribbean. The core of MC domestication is mainly in eastern Asia, with greater proportion in India and southern China [33]. Other countries of prominent cultivation include Brazil, Colombia, Cuba, Ghana, Haiti, Mexico, Malaya, New Zealand, Nicaragua, Panama, and Peru [34, 35]. MC has been mentioned in Ayurvedic books from 2000 to 200 BCE [32], providing reference of early cultivation of MC in India. The Chinese written reference to MC was documented in 1370 [33]. Both the domesticated and putative wild progenitors of MC are recorded in floras of India, tropical Africa, and Asia as well as Brazil, where it first came and then spread into Central America [13].
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Morphological Characteristics MC is an herbaceous plant with tendril-bearing vines that grows up to 5 m in length. It has simple and al-ternate leaves, which are 4–12 cm across. These leaves bear 3–7 deeply separated lobes. The plant has two different kinds of flowers separated based on sex. MC has easily differentiable male and female, yellow-colored flowers, owing to its monecious qualities. The male flowers grow at the end of thin, long stems, whereas the female flowers have a small fruit at the base of flower stem. The fruit is oblong in shape with a distinct warty on exterior. The cross-sections of the fruit show hollow interior with thin layer of flesh cov-ering a central seed cavity filled with large, flat seeds as well as pith. Often, fruit is eaten when it is green or just starts turning yellow in color. At this stage, the fruit is crunchy as well as watery in texture. As the fruit progress to ripening, the rind becomes tough and with sometimes increased bitterness, while pith becomes sweet in taste and red in color. After full ripening, fruit turns orange in color, mushy, and often splits into seg-ments, that curl back to expose seeds covered in bright red pulp (Fig. 1). MC is available commercially in a variety of shapes and sizes. The Chinese variety is 20–30 cm long, ob-long with bluntly tapering ends, and pale green colored with a gently undulating, warty surface, whereas the Indian variety has a narrower shape with pointed ends and a surface covered with jagged, triangular Bteeth^ and ridges. Indian MC is available in two varieties based on size, shape, color, and surface texture of the fruit. The first variety is M. charantia var. charantia having large fusiform of fruits that are not tapered at both ends and possesses numerous triangular tubercles looking like a Bcrocodile’s back.^ The second variety is M. charantia var. muricato (Wild), which produces small and round fruits with tubercles, and more or less tapering at both ends [36].
Nutritional Values The nutritional analysis of MC fruits shows that it is a rich in carbohydrates, proteins, vitamins, fibers, and min-erals (Table 1). MC holds the highest nutritive value among all cucurbits [37]. Vitamin C content of Chinese MC differs significantly (440–780 mg/kg edible portion). Considerable variation in nutrients, including protein, carbohydrates, iron, zinc, calcium, magnesium, phosphorous, and ascorbic acid, has been observed in MC [37, 38]. The pulp around the seeds of the mature ripe fruit is a major source of the carotenoid lycopene.
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Fig. 1 Raw and ripened fruit of bitter melon
Biological Activities of Bitter Melon Antioxidant Activity and Antidiabetic Activity Oxidant production as normal metabolic by-products or their exposure from environment often leads to effects such as aging or other degenerative disorders. Consumption of antioxidant-rich foods can help alleviate such issues. Multiple reports using different extracts of BM have shown potential antioxidant properties of the fruit. Lu and group have studied the protective effects of the ethanolic extracts of MC fruit, against chronic alcohol-induced hepatic injury in C57BL/6 mice. It is believed that the protective effects are facilitated by improving levels of liver antioxidant enzymes (GSH, GPx, GRd, CAT, and SOD), decreasing lipid peroxidation (MDA), and lowering expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) [28]. Similarly, antioxidant potential of MC extract was studied in ammonium chlorideinduced (AC) hyperammonemic rats. Treatment with MC extract normalized the abovementioned chang-es by reversing the oxidant–antioxidant imbalance dur-ing AC-induced hyperammonemia [39]. The antioxidant activity of MC extracts may vary, depending on the method of extraction. Wei and coworkers have shown that the free radical scavenging activity of MC extract was significantly increased by using heat drying process for extraction. The extract was found to exert higher proliferation activity on NIT-1 beta cells, thus resulting in possibly better antidiabetic activity of the fruit [15]. Liu et al. developed sulfated polysaccharide from MC with variable degrees of
sulfation. There results showed that polysaccharides with high degree of sulfation exhibited better antioxidant activities as compared to native polysaccharides from MC in vitro [28]. Different ingredients in MC have found to be responsible for its potential antioxidant and antidiabetic properties. Lin et al. in 2011 isolated a number of new compounds including a novel cucurbitane-type triterpene glycoside, taiwacin A, taiwacin B, a known cucurbitane-type triterpene glycoside, and a known steroid glycoside from the stems and fruits of MC. They further proposed the structure of the new compounds by utilizing spectroscopic methods. All four compounds were shown to exhibit ABTS radical cation scavenging activity with IC50 values of 119.1 ± 4.3, 204.5 ± 1.2, 159.7 ± 11.0, and 98.1 ± 2.4 μM respectively [40]. In a study comparing the antioxidant activities of various herbal agents, the highest free radical scavenging activity was observed with the extracts of MC and Eugenia jambolana [41]. Kumar et al. also carried out the evaluation of the antioxidant activity of the total aqueous extract (TAE) and total phenolic extract (TPE) of MC fruits. The antioxidant activities were measured by using radical-scavenging methods. Further, the cytoprotective effects of the extracts on hydrogen peroxide (H2O2)- and hypoxanthin-xanthin oxidase (HX-XO)-induced damage to various cell types were also measured. At 200 and 300 μg/ mL, TPE showed dose-dependent cytoprotection against the used oxidants [42]. Dhar et al. have studied the in vitro anti-oxidant activity of MC seed oil containing conjugated octadecatrienoic fatty acid and alpha-eleostearic acid. Alpha-eleostearic acid also decreased the lipid peroxidation level in a dose-dependent manner [43 ].
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Table 1 Nutritional values of Momordica charantia raw leafy tips, raw pods, and their cooked forms Nutrients Proximates
Minerals
Vitamins
Lipids
Leafy tips, raw
Leafy tips, cooked, boiled, drained, no salt
Pods, raw
Pods, cooked, boiled, drained, no salt
Water (g) Energy (Kcal) Proteins (g) Total lipids (fats) (g) Carbohydrate, by difference (g) Fiber, total dietary (g) Sugars, total Calcium, Ca (mg) Iron, Fe (mg) Magnesium, Mg (mg) Phosphorus, P (mg) Potassium, K (mg) Sodium, Na (mg) Zinc, Zn (mg) Vitamin C, total ascorbic acid (mg) Thiamin (mg) Riboflavin (mg) Niacin (mg) Vitamin B-6 (mg)
89.25 30 5.30 0.69 3.29 –
94.03 17 1 0.17 3.70 2.8
84 2.04 85 99 608 11 0.30 88 0.181 0.362 1.110 0.803
88.69 34 3.60 0.20 6.68 1.9 1.04 42 1.02 94 77 602 13 0.30 55.6 0.147 0.282 0.995 0.760
19 0.43 17 31 296 5 0.80 84.0 0.040 0.040 0.040 0.043
93.95 19 0.84 0.18 4.32 2.0 1.95 9 0.38 16 36 319 6 0.77 33.0 0.051 0.053 0.280 0.041
Folate, DFE (μg) Vitamin A, RAE (μg) Vitamin A, IU (IU)
128 87 1734
88 121 2416
72 24 471
51 6 113
Vitamin E (mg)
1.45
0.14
Vitamin K (μg) Fatty acids, total saturated (g) Fatty acids, total monounsaturated (g) Fatty acids, total polyunsaturated (g)
163.1 0.032 0.005 0.083
4.8 0.014 0.033 0.078
The detailed nutritional information can be found from the United States Department of Agriculture, Agricultural research services websites at the following weblinks. For leafy tips, raw: http://ndb.nal.usda.gov/ndb/foods/show/2867; for pods, raw: http://ndb.nal.usda.gov/ndb/foods/show/2869; for pods, cooked, boiled, drained, without salt: http://ndb.nal.usda.gov/ndb/foods/show/2870
The antioxidant and α-glucosidase inhibitory activity of the methanolic and ethyl acetate extracts of MC was studied by Sulaiman et al. The reducing power was found to be 692.56 ± 43.38 and 221.97 ± 17.20 mM AscAE/g extract re-spectively, and the α-glucosidase inhibitory activities were 18.04 ± 0.47 and 66.64 ± 2.94 %, respectively [44]. Ching et al. evaluated the effects of maternal high-fructose intake on the offspring and if metabolic control in the offspring could improve from supplementing bioactive food components to the maternal diet. Their results showed that MC supplementa-tion to dams could offset the adverse effects arising from the maternal high-fructose intake in adult offspring [45]. Tripathi and Chandra further studied the antihyperglycemic and antioxidative activities of MC aqueous extracts and found that it improved fasting blood glucose levels in rats. In addition, antioxidant activities such as the levels of superoxide dismutase, catalase, glutathione, and glutathione-s-transferase within
the heart, kidney, and liver tissues and TBARS levels were also improved [46]. These authors also studied the effect of MC on antioxidant levels and lipid peroxidation in heart tissue of non-diabetic and alloxan-induced diabetic rats. They found that MC treatment reduced the elevated levels of fasting blood glucose, decreased lipid peroxida-tion and increased antioxidant enzyme activity in heart tissue of diabetic rats [47]. These results all suggest that some portion of the antidiabetic benefits of MC also come from its antioxidative properties, which supplement the hypoglycemic effects with the reversal of oxidant-induced damage. Further studies in diabetic animal models showed that MC extracts possess not only the hypoglycemic properties but can also alleviate diabetes-related adverse effects. A study by Chaturvedi and George in alloxan-induced diabetic rats subjected to a sucrose load showed that MC maintained the
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normal glucose levels in all experimental groups. It also re-duced triglyceride and low-density lipoprotein levels and in-creased high-density lipoprotein levels. It further improved the antioxidant status by lowering the levels of thiobarbituric acidreactive substances and normalizing the levels of reduced glutathione [48]. Teoh et al. studied the nephro protective effect of MC extract in streptozotocin-induced diabetes in rats. The MC extract was found to reverse streptozotocin-induced thickening of the basement membrane of the Bowman’s cap-sule, edema, and hypercellularity of the proximal tubules, ne-crosis, and hyaline deposits. The MC extract also exerted nephro-protective activity by preventing the oxidative damage involved in the diabetic kidney [49]. In a separate study, the livers of the diabetic rats had hepatocytes showing features of inflammation. These signs of liver damage were found to re-verse with administration of the MC extract [50]. Another important study was to determine the potential cell reparative effects of MC boiling water extract (MCE) on the HITT15 Hamster Pancreatic beta cells by Xiang and col-leagues. The high molecular weight fraction of MCE (MHMF, MW > 3 kDa) exhibited better repairing in alloxan-damaged cells than the low molecular weight fraction (MLMF, MW < or =3 kDa). Contrary to the cell proliferation improve-ments, it was observed that MLMF showed higher overall activity through the increase in insulin secretion of both nor-mal and damaged cells. Their results indicated MCE has sig-nificant repairing activity against superoxide anion radicals. Further, their data shows that different components of the extracts may elicit different aspects of response when it comes to its antidiabetic properties [51]. Antioxidant activities of the aqueous extract of seeds of two varieties of MC (MCSEt1 and MCSEt2) were studied in streptozotocin-induced diabetes in rats. The extracts were shown to possess protective effects against lipid peroxidation by scavenging of free radicals, thus reducing the risk of diabetic complications. The effect was more pronounced in MCSEt1 compared to MCSEt2 [52].
Kavitha and colleagues evaluated the effects of ethanolic fruit extract of MC on stress-induced changes in Wister albino rats. MC pretreatment significantly coun-tered acute stressinduced changes in plasma corticosterone levels and brain monoamine levels (5-hydroxy tryptamine, norepinephrine, epinephrine, and dopamine) [53]. Nerurkar et al. have also investigated the neuroprotective effects of MC on high-fat diet (HFD)-associated changes in C57BL/ 6 female mice. MC treatment ameliorated HFD-associated changes in BBB permeability. The treatment also normal-ized HFD-induced glial cells activation and expression of neuroinflammatory markers such as NF-κB1, IL-16, IL-22 as well as IL-17R in brains of MC-dosed mice. Brain oxidative stress was significantly reduced by MC along with reduction in FoxO, normalization of Sirt1 protein expression, and upregulation of Sirt3 mRNA expression [54].
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The protective effects of MC extract on lipid peroxidation induced by immobilization stress in rats were studied. Here too, MC inhibited stress-induced lipid peroxidation in rats, which was in part due to increasing levels of reduced glutathione and increased catalase activity [55]. The anti-oxygenic activity of MC pulp and seed powders as well as their various solvent extracts were evaluated. Overall, the MC pulp and seed powders exhibited stronger anti-oxygenic activity than other solvent extracts. However, MC pulp and its extracts showed little higher activity when compared to MC seeds and its extracts [56]. De et al. determined the effects of fresh juices of MC and tomato separately as well as together in repairing DNA damage. They found that the combination could protect from DNA damage, but not as effectively as either agent alone [57].
Anti-inflammatory Activity Immune cells are involved in inflammation-based responses. Bitter melon is known to interact with immune cells. Multiple studies have shown that various extracts of MC can act as immunomodulators and, hence, can also act as antiinflammatory agents. Bao et al. looked at the effects of MC treatment in C57BL/6 mice administered with HFD. Once again, MC-containing diets reduced the HFD-induced obesity as well as insulin resistance. MC was also shown to decrease macrophage infiltration into epididymal adipose tis-sues (EAT) and brown adipose tissues (BAT). MC further reduced IL-6 and TNF-α expression in EAT and normalized serum levels of cytokines, suggesting the potential anti-inflammatory role of MC in obese rats [58]. Further, Xu et al. studied the effects of MC on mitochondrial function during the development of obesity-linked fatty liver in C57BL/6 mice. The mouse model involved feeding with high fat diet (HFD) supplemented with two doses of MC powder {0.5 (HFD + 0.5MC) and 5 (HFD + 5MC) g/kg}. The mice in HFD + 5MC group showed less body and tissue weight gain and less hyperglycemia and hyperlipidemia compared to con-trol HFD group. In both treatment groups, serum interleukin-6 concentration was lower than that in HFD group, though the serum C-reactive protein concentration was lower only in HFD + 5MC group [59].
Hsieh et al. suggested that the anti-adiposity effects of MC seed oil is linked to white adipose tissue delipidation, inflam-mation, and browning [60]. The triterpene, EMCD extracted from wild variant of MC WB24 have been shown to suppress TNFα-induced expres-sion of inflammatory markers including inducible nitric oxide synthase (iNOS), NF-κB, protein-tyrosine phosphatase-1B, and interleukin-1β in FL83B cells. Moreover, EMCD exerted more pronounced antiinflammatory activity in combination with EGCG [61].
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The protective effect of MC in tibial and sural nerve transection (TST)-induced neuropathic pain were studied in rats. TST induce significant development of cold allodynia, me-chanical and heat hyperalgesia, dynamic mechanical allodynia, and functional deficit in walking along with increase in TBARS and TNF-α levels. Administration of MC at vari-ous doses significantly reduced TST-induced behavioral and biochemical changes [62]. Hsu et al. showed that ethyl acetate extract of MC fruit and its saponofiable as well as nonsapon-ifiable fractions reduced pro-inflammatory cytokine and ma-trix metalloproteinase (MMP)-9 levels in Propionibacterium acnesstimulated THP-1 cells. The intradermal injection of MC extract in mice effectively attenuated P. acnes-induced ear swelling and granulomatous inflammation [63].
In further studies, Lii and group have shown that the etha-nol extracts of MC exerted the greatest decrease of lipopoly-saccharide treatment (LPS)-induced production of nitric oxide and prostaglandin E2 as well as iNOS and prointerleukin-1beta expression in RAW264.7 macrophages [64]. Similarly, Kobori et al. also showed that the butanolsoluble fraction of MC extract decreased LPS-induced TNF-α production in RAW 264.7 cells [65]. Anticancer Activities In the previous three decades, the research with MC was focused on its antidiabetic, anti-inflammatory, and antioxidative properties. Over the last 10 years, the interest in studying MC in the prevention or treatment of cancer has increased. The Warburg effect, which deals with the shift in metabolic profile of tumor cells by increasing their dependence on glycolysis and lactic acid fermentation, also regained prominence during this time. MC was found to be effective in multiple cancers by affecting multiple pathways including metabolic pathways. In the following section, we have sum-marized the potential activities of MC and its chemical con-stituents against numerous cancers including breast, colon, pancreatic, liver, prostate, and skin cancers.
Breast Cancer Weng et al. have studied a cucurbitane-type triterpene DMC isolated from wild MC. DMC was found to activate PPAR-γ. The pharmacological inhibition of PPAR-γ protected cells from DMC’s anti-proliferative effect, further confirming its mechanism of action. DMC suppressed the expression of PPAR-γ targets, such as cyclin D1, CDK6, Bcl-2, XIAP, cyclooxygenase-2, NF-κB, and estrogen receptor-α. It induced ER stress, as manifested by GADD153 and GRP78 induction. DMC also inhibited mTOR-p70S6K signaling by downregulating Akt and activating AMPK. The study suggested involvement of PPAR-γ signaling in the antitumor activity of MC [66].
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Fang et al. have isolated and characterized a 14-kDa ribonuclease (RNase MC2) from MC seeds. RNase MC2 showed both cytostatic and cytotoxic properties against MCF-7 breast cancer (BC) cells causing nuclear damage, leading to either early or late apoptosis. Additionally, RNase MC2 induced activation of MAPKs such as p38, JNK, and ERK as well as Akt, caspases 8, 9, and 7, enhanced Bax and cleaved PARP levels, further contributing to apoptosis [67]. In another study, the anticancer activity of MC extract was studied in MCF-7 and MDA-MB-231 human BC cells as well as in primary human mammary epithelial cells. MC treatment reduced cell proliferation and induced apoptosis in BC cells tested, which was accompanied by increased levels of cleaved poly (ADP-ribose) polymerase and caspase activation. The treatment also inhibited the expression of survivin and claspin. MC-treated MCF-7 cells accumulated during the G2M phase of the cell cycle. MC treatment enhanced p53, p21, and pChk1/2 expression and inhibited cyclin B1 and cyclin D1 expression, suggesting a further mechanism involving cell cycle regulation [68]. Nagasawa et al. have shown that SHN virgin mice supplimented with free access to hot water extract of MC (0.5 %) in drinking water developed significantly less breast tumors. The treatment also inhibited uterine adenomyosis. Moreover, there were no adverse effects observed with MC treatment [69]. Eleostearic acid (α-ESA) is a conjugated form of linolenic acid (CLN) that constitutes up to 60 % of MC seed oil. Grossmann and group have studied the effects of α-ESA on estrogen receptor (ER)-negative MDA-MB-231 (MDA-wt) and ER-positive MDA-ERalpha7 human BC cells. Their studies found that α-ESA inhibited proliferation of MDA-wt and MDA-ERalpha7 cells. α-ESA treatment also induced apoptosis in both cell lines (70 %–90 %), whereas CLN resulted in only 5 to 10 % apoptosis. Moreover, the addition of α-ESA also caused loss of mitochondrial membrane potential and translocation of apoptosis-inducing factor as well as endonuclease G from the mitochondria to the nucleus. α-ESA treatment also caused a G(2)-M arrest in the cell cycle [70]. Lee-Huang et al. have studied the efficacy of a peptide MAP30 found in MC on estrogen-independent and highly metastatic human breast tumor MDA-MB-231. The treatment resulted in inhibition of cancer cell proliferation and inhibition of HER2 gene expression in vitro. When MDA-MB-231 cells were transferred into SCID mice, they developed extensive metastases and all mice succumbed to tumor by day 46. Treat-ment of the BC-bearing mice with MAP30 injections resulted in significant increases in survival, with 20–25 % of the mice remaining tumor free for 96 days [71].
Colon Cancer The utilization of multiple food agents with potential cancer preventive properties in the daily diet has been attributed to
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relatively lower incidence rate of colon cancer in South and East Asian countries. MC is one such food, and hence, it has also been studied for its potential role in preventing/treating colon cancer. We have evaluated the potential of methanolic extracts of MC (whole fruit and skin) on colon cancer stem and progenitor cells. Both the whole fruit and the skin extracts significantly inhibited cell proliferation and colony formation, where the whole fruit extract showed greater efficacy. In these studies, the cells were arrested at the S-phase of cell cycle. The extracts induced the cleavage of LC3B, but not caspase 3/7, indicating that the cells were undergoing autophagy and not apoptosis. Autophagy was further confirmed by reduced Bcl-2 and increased Beclin-1, Atg 7, and 12 expression after MC treatment. The treatment also led to reduced cellular ATP levels and activation of AMPK. Exogenous additions of ATP led to revival of cell proliferation even in the presence of MC. Treatment with MC resulted in decrease in the num-ber, and size of colonospheres coupled with decreased expres-sion of DCLK1 and Lgr5 suggested the activity of extracts on colon cancer stem cells [3]. The effects of the same MC extract on anticancer activity and bioavailability of doxorubicin (DOX) was also studied. MC extract enhanced the effect of DOX on proliferation and sensitized the cancer cells toward DOX upon pretreatment. This synergism was attributed to both an increase in drug uptake and reduction in drug efflux. Reduced expression of multidrug resistance conferring pro-teins (MDRCP) P-glycoprotein, MRP-2, and BCRP was also observed. Suppression of DOX efflux in MDCK cells overexpressing the three MDRCP individually suggests that MC extract is a potent inhibitor of MDR function. MC extract also suppressed PXR (a xenobiotic sensing nuclear receptor that controls the expression of MDRCP) promoter activity. These results suggested that MC can enhance efficacy of convention-al cancer chemotherapy [4]. Li et al. also showed that the methanolic extracts of MC exerted cytotoxic activity on Hone-1 (nasopharyngeal carcinoma), AGS (gastric adenocarcinoma), HCT-116 (colorectal carcinoma), and CL1-0 lung adenocarcinoma in a timedependent manner. MC treatment induced apoptosis by activation of caspase-3, enhanced cleavage of downstream DFF45 and PARP, resulting in DNA fragmentation and nucle-ar condensation. Bax expression was increased, whereas Bcl-2 was decreased in all treated cells, indicating the involvement of mitochondrial pathway in MC activity [72]. Another study identified a resistance-like protein P-B from MC by using high-speed counter-current chromatography (HSCCC) coupled with a reverse micelle solvent system. Fractions I and III were identified as resistance-like protein P-B and pentatricopeptide repeat-containing protein, respectively. However, fraction II, which is thought to be a new protein, has not yet been identified. The fraction II had excellent anticancer activity (IC50 value 0.116 mg/ml for 48 h treatment) on human gastric cancer cell line SGC-7901 [73].
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Kupradinun et al. examined effect of MC against clastogens, cyclophosphamide (CYP), and DMBA using in vivo erythrocyte micronucleus assay in mice and azoxymethane (AOM)-induced colon carcinogenesis in rats. The study demonstrated that mice fed with MC containing diets showed potential anticancer activity against clastogens. Surprisingly, the MC extracts did not show any preventive effects in AOM model with treatment resulting in increased incidence and multiplicities of colon tumors than control [74]. Fan et al. showed that proliferation of LoVo cells was suppressed by MAP30 in both time- and dose-dependent manner. MAP30-induced the apoptotic nuclei observed in LoVo cells. Additionally, genomic degradation was detected in treated cells by using single-cell gel electrophoresis (comet assay). Upregulation of Bax and downregulation of Bcl-2 were also observed [75]. Yasui et al. investigated the effects of free fatty acids prepared from the MC seed oil in Caco-2 cells. The expression of Bcl-2 was found to be decreased by the treatment. Apoptosis regulators GADD45 and p53 were also remarkably upregulated by the treatment [76]. Konishi et al. observed that MC fraction extracted with 40 % methanol showed the greatest increase of rhodamine-123 accumulation in Caco-2 cells. Inhibitory compound in the MC fraction was identified as 1-monopalmitin. They hypothesized that that certain types of monoglyceride might modulate the bioavailability of drugs by inhibiting efflux mediated by P-gp, which matched the MDR-based claims of Kwatra et al. [77]. The inhibitory activity of 1-monopalmitin and related compounds suggested that the P-gp inhibition activity was independent of degree of unsaturation of fatty acid instead depending on chain length, with the monoglyceride structure deciding the ultimate inhibition of P-gp efflux. Monoglycer-ides could therefore alter drug pharmacokinetics by inhibiting efflux [78]. Deep et al. tested MC fruit extract (2.5 % and 5 % of standard mice feed) against 3,4 benzo(a)pyrene [B(a)P]-induced forestomach papillomagenesis in Swiss albino mice. A significant decrease in tumor burden was observed after MC treatment. Also, total tumor incidence reduced by 80 % to 90 % in short-term treatment and close to 75 % in long-term treatment [79]. Kohno et al. studied the effects of MC containing diet in AOM-induced colonic neoplasms in male F344 rats. The treatment reduced both the incidence and the multiplicity of colonic adenocarcinoma. The inhibition was associated with increased content of CLN in colonic mucosa and liver [80]. In another study, Kohno et al. had studied the dietary effects of CLN isolated from the seeds of MC against AOM - induced colonic aberrant crypt foci (ACF) in male F344. Dietary administration of CLN caused a significant reduction in the frequency of ACF, lowered the PCNA index, and induced apoptosis in ACF. The possible mechanism of chemo-preventive activity was hypothesized to be modulation of cryptal cell proliferation activity and/or apoptosis [81].
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Pancreatic Cancer The efficacy of MC juice against pancreatic carcinoma cells both in culture and MiaPaCa-2 tumors in nude mice was investigated. Their results showed that MC (2–5 % v/v) decreased cell viability in all tested cell lines by inducing strong apoptotic cell death caused by activation of caspases. It was also found to activate AMPK, alter expression of Bcl-2 family members, and release cytochrome-c into the cytosol. Additionally, the treatment with MC juice resulted in reduced survivin and XIAP expression but increased p21, CHOP, and phosphorylated MAP kinases levels. Oral administration of lyophilized MC juice inhibited MiaPaCa-2 tumor xenograft growth by 60 % without noticeable toxicity in nude mice. IHC analyses of xenografts suggested that MC also inhibits proliferation, induces apoptosis, and activates AMPK in mouse model [82].
Liver Cancer Fang et al. have shown that RNase MC2 restricted cell proliferation and induced apoptosis in HepG2 cells. RNase MC2 caused S-phase cell cycle arrest, induced phosphorylation of ERK and JNK as well as caused activation of both caspase-8 and caspase-9 mediated apoptosis. RNase MC2 treatment also reduced Bcl-2 and enhanced Bak expression. RNase MC2 suppressed tumor growth by inducing apoptosis in the HepG2 xenograft-bearing nude mice. RNase MC2 mediated apoptosis was confirmed by enhanced number of caspase-3-, PARP-, and TUNEL-positive cells in the tumor tissues of HepG2 xenograft-bearing nude mice [83]. Further studies have been performed to establish the efficacy of MAP30 against human hepatocellular carcinoma HepG2 cells and HepG2-bearing mice. The mechanistic studies showed the involvement of both extrinsically (caspase-8) as well as intrin-sically (caspase-9) induced apoptosis in MAP30-treated cells. The peptide was also found to be effective in HepG2 tumorbearing nude mice [84].
Prostate Cancer Ru et al. have evaluated the of MC against human prostate cancer (PC3 and LNCaP) cells. The cancer cells treated with MC extract got arrested during the S-phase of the cell cycle. MC treatment also modulated cyclin D1, cyclin E, and p21 expression within the cells. The treatment also increased Bax expression and induced PARP cleavage. Oral gavage of MC extract in TRAMP mice delayed the progression to high-grade prostatic intraepithelial neoplasia by 31 %. Prostate tissue from MC extract-fed mice displayed approximately 51 % reduction in the expression of proliferating cell nuclear antigen (PCNA) [85].
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Pitchakarn et al. have shown that MC leaf extract and Kuguacin J (KuJ) exerted growth inhibition through a G1arrest of cell cycle and induced apoptosis in androgendependent LNCaP cells. MC leaf extract and KuJ also reduced the expression levels of prostate-specific antigen (PSA) and androgen receptor (AR). These two together induced P53 protein level upon treatment. Additionally, the inhibition of p53 by RNAi confirmed the mechanism partially to be p53-dependent. MC leaf extract and KuJ were less toxic in normal prostate cells (PNT1A); hence, these effects were prostate cancer specific [86]. In another study, the same group studied the anti-invasive effects of MC on a rat prostate cancer cell line (PLS10) and found that MC leaf extract significantly reduced the migration and invasion ability of cells in vitro. The MC extract successfully inhibited MMP-2, MMP-9, and uPA secretion from PLS10. It also markedly increased the mRNA expression of TIMP-2. The collagenase type IV activity was also partially inhibited by MC leaf extract. Intravenous inoculation of PLS10 to nude mice resulted in 20 % deaths, but a 100 % survival rate in the mice given MC leaf extract. The treatment did not affect the incidence rate of lung metastasis but reduced the percentage of lung area occupied by metastatic lesions [87]. Xiong et al. also isolated a protein from MC seeds, which they called MCP30. MCP30 - induced apoptosis in PIN and PCa cells in vitro and also suppressed the PC-3 growth in vivo with minimal effects on normal prostate cells. MCP30 inhibited HDAC-1 activity and promoted histone-3 and histone-4 protein acetylation. The treatment also induced PTEN expression in both cell lines, resulting in inhibition of Akt phosphorylation. MCP30 inhibited Wnt signaling by reduced nuclear accumulation of β-catenin and decreased the levels of c-Myc and Cyclin-D1 [88].
Skin Cancer Agrawal and Beohar have shown that the treatment with MC fruit and leaf extract in Swiss albino mice resulted in reduced tumor incidence, tumor burden, and cumulative number of papillomas when compared to untreated controls. In a melanoma model, the mice receiving either fruit or leaf extracts showed improved life spans and reduced tumor volumes [89]. Further, Ganguly et al. have also evaluated the anticarcinogenic effect of aqueous extract of MC fruit in skin carcinogenesis mouse model. Though high doses of extract had an adverse effect on the health of the animals, but on reducing the dose by half, the extract reduced the development of skin tumors and increased life expectancy. Hence, this study showed both the potential positive effects and potential toxic effects upon overdosing [90]. Singh et al. have studied the potential of different MC plant parts (peel, pulp, seed, and whole fruit) extracts on mouse model of skin papillomagenesis. Topical use of MC against
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DMBA resulted in reduced incident rate, tumor burden, and cumulative number of papillomas. The results suggested that the most effective extract was the MC peel, indicating that biotransformation system enzymes may be the reason for these effects [91].
5. 6. 7.
Miscellaneous Cancers 8.
MC has been evaluated in other cancers including cervical cancer [92, 93], leukemia [94–97], adrenocortical can-cer [98], adenocarcinoma of rat prostate [99], human lung adenocarcinoma cells with different metastatic ability [100], human nasopharyngeal carcinoma CNE2 and HONE1 cells [101], and head and neck squamous cell carcinoma cells [102].
Nkambo W, Anyama NG, Onegi B. In vivo hypoglycemic effect of methanolic fruit extract of Momordica charantia L. Afr Health Sci. 2013;13(4):933–9. Vyas A et al. Perspectives on new synthetic curcumin analogs and their potential anticancer properties. Curr Pharm Des. 2013;19(11):2047. Zhang D-W. Curcumin and diabetes: A systematic review. evidence-based complementary and alternative medicine, 2013. 2013. Panaskar SN et al. Aegle marmelos Correa leaf extract prevents secondary complications in streptozotocin‐induced diabetic rats and demonstration of limonene as a potent antiglycating agent. J Pharm Pharmacol. 2013;65(6):884–94.
9.
Subramaniam D et al. Activation of apoptosis by 1-hydroxy-5, 7dimethoxy-2-naphthalene-carboxaldehyde, a novel compound from Aegle marmelos. Cancer Res. 2008;68(20):8573–81. 10. Heiser CB. The gourd book. 1993: University of Oklahoma Press. 11. Tindall HD. Vegetables in the tropics. Macmillan Press Ltd, 1983.
12.
Reyes M, Gildemacher B, Jansen G. Momordica L. Wageningon. Netherland: Pudoc Scientific Publishers; 1994.
Conclusions
13.
MC, also called as bitter melon, an edible fruit, is traditionally used in alternative system of medicines as a remedy for treatment of diabetes, laxative, antiulcer, anthelmintic, and antimalarial activity. MC contains numerous important chemical constituents that thought to be involved in therapeutic activity of MC. Several studies have been conducted to establish therapeutic activities of MC for various disorders. MC has exhibited multiple targeting ability against several cancers in vitro and animal models, but systematic clinical studies are needed to establish its efficacy in patients. More studies are also need-ed to establish its detailed pharmacological and toxicological profile.
Marr KL, Mei XY, Bhattarai NK. Allozyme, morphological and nutritional analysis bearing on the domestication of Momordica charantia L. (Cucurbitaceae). Econ Bot. 2004;58(3):435–55.
14.
Grover J, Yadav S. Pharmacological actions and potential uses of Momordica charantia: a review. J Ethnopharmacol. 2004;93(1): 123–32. Wei L et al. Increase in the free radical scavenging capability of bitter gourd by a heat-drying process. Food Funct. 2013;4(12): 1850–5.
15. 16.
Zhu Y et al. Effect of superfine grinding on antidiabetic activity of bitter melon powder. Int J Mol Sci. 2012;13(11):14203–18.
17.
Chao C-Yet al. Anti-inflammatory effect of Momordica Charantia in sepsis mice. Molecules. 2014;19(8):12777–88. Costa JGM et al. Antibacterial activity of Momordica charantia (Curcubitaceae) extracts and fractions. J Basic Clin Pharma. 2010;2(1):45.
18. 19.
Santos KK et al. Trypanocide, cytotoxic, and antifungal activities of Momordica charantia. Pharm Biol. 2012;50(2):162–6.
20.
Pongthanapisith V et al. Antiviral protein of Momordica charantia L. inhibits different subtypes of Influenza A. Evid Based Complement Alternat Med. 2013;2013:729081.
Conflict of Interest Deep Kwatra, Prasad Dandawate, Subhash Padhye, and Shrikant Anant declare that they have no conflict of interest.
21.
Fang FE, Ng TB. Bitter gourd (Momordica charantia) is a cornucopia of health: a review of its credited antidiabetic, anti-HIV, and antitumor properties. Curr Molec Med. 2011;11(5):417–36.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
22.
Lal J et al. In vitro anthelmintic action of some indigenous medic-inal plants on Ascardia galli worms. Indian J Physiol Pharmacol. 1975;20(2):64–8.
23.
Frame AD et al. Plants from Puerto Rico with anti-Mycobacterium tuberculosis properties. P R Health Sci J. 1998;17(3):243–52.
24.
Ojewole J, Adewole SO, Olayiwola G. Hypoglycaemic and hy-potensive effects of Momordica charantia Linn (Cucurbitaceae) whole-plant aqueous extract in rats. Cardiovasc J South Africa: Off J Southern Africa Cardiac Soc South African Soc Cardiac Practitioners. 2005;17(5):227–32. Shih C-C, Lin C-H, Lin W-L. Effects of Momordica charantia on insulin resistance and visceral obesity in mice on high-fat diet. Diabetes Res Clin Pract. 2008;81(2):134–43.
Compliance with Ethical Standards
References 1. 2.
3.
4.
Organization WH. WHO traditional medicine strategy 2002– 2005. 2002. Patwardhan B et al. Ayurveda and traditional Chinese medicine: a comparative overview. Evidence-Based Complement Alternat Med. 2005;2(4):465–73. Kwatra D et al. Methanolic extracts of bitter melon inhibit colon cancer stem cells by affecting energy homeostasis and autophagy. Evidence-Based Complementary and Alternative Medicine, 2013. 2013. Kwatra D et al. Bitter melon extracts enhance the activity of che-motherapeutic agents through the modulation of multiple drug resistance. J Pharm Sci. 2013;102(12):4444–54.
25. 26.
Deng Y-Y et al. Immunomodulatory activity and partial characterisation of polysaccharides from Momordica charantia. Molecules.
2014;19(9):13432–47. 2 7 . M a n i k S , G a u t t a m V, K a l i a A . A n t i - d i a b e t i c a n d antihyperlipidemic effect of allopolyherbal formulation in OGTT and STZ-induced diabetic rat model. 2013. 28. Lu KH et al. Wild bitter gourd protects against alcoholic fatty liver in mice by attenuating oxidative stress and inflammatory re-sponses. Food Funct. 2014;5(5):1027–37.
Curr Pharmacol Rep (2016) 2:34–44 29. Malik ZA, Singh M, Sharma P. Neuroprotective effect of Momordica charantia in global cerebral ischemia and reperfusion induced neuronal damage in diabetic mice. J Ethnopharmacol. 2011;133(2):729–34. 30. Haque ME, Alam MB, Hossain MS. The efficacy of cucurbitane
43 49.
Teoh S, Latiff AA, Das S. Histological changes in the kidneys of experimental diabetic rats fed with Momordica charantia (bitter gourd) extract. Rom J Morphol Embryol. 2010;51(1):91–5.
50.
Teoh S, Latiff A, Das S. A histological study of the structural changes in the liver of streptozotocin-induced diabetic rats treated with or without Momordica charantia (bitter gourd). La Clinica Terapeutica. 2008;160(4):283–6. Xiang L et al. The reparative effects of Momordica Charantia Linn. extract on HIT-T15 pancreatic beta-cells. Asia Pac J Clin Nutr. 2007;16(1):249–52.
type triterpenoids, glycosides and phenolic compounds isolated from Momordica charantia: a review. IJPSR. 2011;2(5):1135–46.
31. Pitrat M, Chauvet M, Foury C. Diversity, history and production of cultivated cucurbits. in I International Symposium on Cucurbits 492, 1997. 32. Decker-Walters DS. Cucurbits, sanskrit, and the Indo-Aryas 1. Econ Bot. 1999;53(1):98–112. 33. Behera T et al. Morphological and molecular analyses define the genetic diversity of Asian bitter gourd (‘Momordica charantia’L.). 2012. 34. Satyavati G, Raina M, Sharma M. Medicinal plants of India. vol. 1. New Delhi: Indian council of medical research; 1976. 35. Yeşilada E, Gürbüz II, Sh H. Screening of Turkish antiulcerogenic folk remedies for anti-Helicobacter pylori activity. J Ethnopharmacol. 1999;66(3):289–93. 36. Chakravarty H. Cucurbits of India and their role in the development of vegetable crops. Biology and utilization of the cucurbitaceae. Ithaca: Comstock, Cornell University Press; 1990.
37. Behera T et al. Minor cucurbits. genetics, genomics and breeding of cucurbits, 2011: p. 17. 38. Behera TK et al. 2 bitter gourd: botany, horticulture, breeding. Hortic Rev. 2010;37:101. 39. Thenmozhi AJ, Subramanian P. Antioxidant potential of Momordica charantia in ammonium chloride-induced hyperammonemic rats. Evidence-Based Complement Alternat Med, 2011. 2011. 40. Lin K-W, Yang S-C, Lin C-N. Antioxidant constituents from the stems and fruits of Momordica charantia. Food Chem. 2011;127(2):609–14. 41. Santos AK et al. Antioxidant activity of five Brazilian plants used as traditional medicines and food in Brazil. Pharmacogn Mag. 2010;6(24):335. 42. Kumar R et al. In vitro evaluation of antioxidants of fruit extract of Momordica charantia L. on fibroblasts and keratinocytes. J Agric Food Chem. 2010;58(3):1518–22. 43. Dhar P et al. Antioxidative effect of conjugated linolenic acid in diabetic and non-diabetic blood: an in vitro study. J Oleo Sci. 2007;56(1):19–24. 44. Sulaiman SF, Ooi KL. Antioxidant and α-glucosidase inhibitory activities of cucurbit fruit vegetables and identification of active and major constituents from phenolicrich extracts of Lagenaria siceraria and Sechium edule. J Agric Food Chem. 2013;61(42): 10080–90. 45. Ching R et al. Supplementation of bitter melon to rats fed a high-fructose diet during gestation and lactation ameliorates fructose-induced dyslipidemia and hepatic oxidative stress in male off-spring. J Nutr. 2011;141:1664–72. 46. Tripathi UN, Chandra D. Anti-hyperglycemic and antioxidative effect of aqueous extract of Momordica charantia pulp and Trigonella foenum graecum seed in alloxan-induced diabetic rats. 2010. 47. Tripathi UN, Chandra D. The plant extracts of Momordica charantia and Trigonella foenum graecum have antioxidant and anti-hyperglycemic properties for cardiac tissue during diabetes mellitus. Oxidative Med Cell Longev. 2009;2(5):
51.
52.
Sathishsekar D, Subramanian S. Antioxidant properties of Momordica Charantia (bitter gourd) seeds on Streptozotocin induced diabetic rats. Asia Pac J Clin Nutr. 2005;14(2):153–8.
53.
Kavitha CN, Babu SM, Rao MB. Influence of Momordica charantia on oxidative stress-induced perturbations in brain mono-amines and plasma corticosterone in albino rats. Indian J Pharmacol. 2011;43(4):424.
54.
Nerurkar PV et al. Momordica charantia (bitter melon) attenuates high-fat diet-associated oxidative stress and neuroinflammation. J Neuroinflammation. 2011;8(64):2094–8.
55.
Chaturvedi P. Bitter melon protects against lipid peroxidation caused by immobilization stress in albino rats. Int J Vitam Nutr Res. 2009;79(1):48–56. Padmashree A et al. Studies on the antioxygenic activity of bitter gourd (Momordica charantia) and its fractions using various in vitro models. J Sci Food Agric. 2011;91(4):776–82. De S, Ganguly C, Das S. Natural dietary agents can protect against DMBA genotoxicity in lymphocytes as revealed by single cell gel electrophoresis assay. Teratog Carcinog Mutagen. 2003;23(S1): 71–8. Bao B et al. Momordica charantia (Bitter Melon) reduces obesity-associated macrophage and mast cell infiltration as well as inflam-matory cytokine expression in adipose tissues. PLoS One. 2013;8(12):e84075. Xu J et al. Bitter gourd inhibits the development of obesityassociated fatty liver in C57BL/6 mice fed a high-fat diet. J Nutrit. 2014;144(4):475–83. Hsieh C-H et al. Altered white adipose tissue protein profile in C57BL/6J mice displaying delipidative, inflammatory, and brow-ning characteristics after bitter melon seed oil treatment. PLoS One. 2013;8(9):e72917.
56.
57.
58.
59.
60.
61.
Cheng H-L et al. EMCD, a hypoglycemic triterpene isolated from Momordica charantia wild variant, attenuates TNF-α-induced inflammation in FL83B cells in an AMP-activated protein kinaseindependent manner. Eur J Pharmacol. 2012;689(1):241–8.
62.
Jain V et al. Antinociceptive and antiallodynic effects of Momordica charantia L. in tibial and sural nerve transectioninduced neuropathic pain in rats. Nutr Neurosci. 2014;17(2):88– 96. Hsu C et al. Wild bitter melon (Momordica charantia Linn. var. abbreviata Ser.) extract and its bioactive components suppress Propionibacterium acnes-induced inflammation. Food Chem. 2012;135(3):976–84. Lii CK et al. Suppressive effects of wild bitter gourd (Momordica charantia Linn. var. abbreviata ser.) fruit extracts on inflammatory responses in RAW264.7 macrophages. J Ethnopharmacol. 2009;122(2):227–33. Kobori M et al. Bitter gourd suppresses lipopolysaccharideinduced inflammatory responses. J Agric Food Chem. 2008;56(11):4004–11.
63.
64.
65.
66.
290–6.
48. Chaturvedi P, George S. Momordica charantia maintains normal glucose levels and lipid profiles and prevents oxidative stress in diabetic rats subjected to chronic sucrose load. J Med Food. 2010;13(3):520–7.
67.
Weng J et al. Cucurbitane triterpenoid from Momordica charantia induces apoptosis and autophagy in breast cancer cells, in Part, through peroxisome proliferator-activated receptor gamma activation. Evid Based Complement Alternat Med. 2013. Fang EF et al. RNase MC2: a new Momordica charantia ribonuclease that induces apoptosis in breast cancer cells associated with
44
Curr Pharmacol Rep (2016) 2:34–44
activation of MAPKs and induction of caspase pathways. Apoptosis. 2012;17(4):377–87. 68.
Ray RB et al. Bitter melon (Momordica charantia) extract inhibits breast cancer cell proliferation by modulating cell cycle regulatory genes and promotes apoptosis. Cancer Res. 2010;70(5):1925–31.
69.
Nagasawa H, Watanabe K, Inatomi H. Effects of bitter melon (Momordica charantia l.) or ginger rhizome (Zingiber offifinale rosc) on spontaneous mammary tumorigenesis in SHN mice. Am J Chin Med. 2002;30(02n03):195–205. Grossmann ME et al. Eleostearic acid inhibits breast cancer pro-liferation by means of an oxidation-dependent mechanism. Cancer Prevent Res. 2009;2(10):879–86. Lee-Huang S et al. Inhibition of MDA-MB-231 human breast tumor xenografts and HER2 expression by anti-tumor agents GAP31 and MAP30. Anticancer Res. 1999;20(2A):653–9. Li C-J et al. Momordica charantia extract induces apoptosis in human cancer cells through caspase-and mitochondriadependent pathways. Evidence-Based Complement Alternat Med. 2012;2012.
70.
71.
72.
73.
Li S, Tse IM, Li ET. Maternal green tea extract supplementation to rats fed a high-fat diet ameliorates insulin resistance in adult male offspring. J Nutr Biochem. 2012;23(12):1655–60.
74.
Kupradinun P et al. Anticlastogenic and anticarcinogenic potential of Thai bitter: gourd fruits. Asian Pacific J Cancer Prevent. 2011;12(5):1299–305. Fan J-M et al. Effects of recombinant MAP30 on cell proliferation and apoptosis of human colorectal carcinoma LoVo cells. Mol Biotechnol. 2008;39(1):79–86.
75.
76.
Yasui Y et al. Bitter gourd seed fatty acid rich in 9c11t13t-conjugated linolenic acid induces apoptosis and up-regulates the GADD45, p53 and PPARγ in human colon cancer Caco-2 cells. Prostaglandins Leukot Essent Fat Acids. 2005;73(2):113–9.
77.
Konishi T et al. A bitter melon extract inhibits the Pglycoprotein activity in intestinal Caco-2 cells: monoglyceride as an active compound. Biofactors. 2004;22(1):71–4. Konishi T et al. Inhibitory effect of a bitter melon extract on the P‐ glycoprotein activity in intestinal Caco‐2 cells. Br J Pharmacol. 2004;143(3):379–87.
78.
79.
Deep G et al. Cancer preventive potential of Momordica charantia L. against benzo (a) pyrene induced forestomach tumourigenesis in murine model system. Indian J Exp Biol. 2004;42(3):319–22.
80.
Kohno H et al. Dietary seed oil rich in conjugated linolenic acid from bitter melon inhibits azoxymethane‐induced rat colon carci-nogenesis through elevation of colonic PPARγ expression and alteration of lipid composition. Int J Cancer. 2004;110(6): 896–901. Kohno H et al. Dietary conjugated linolenic acid inhibits azoxymethane‐induced colonic aberrant crypt foci in rats. Cancer Sci. 2002;93(2):133–42.
81.
82.
83.
Kaur M et al. Bitter melon juice activates cellular energy sensor AMP-activated protein kinase causing apoptotic death of human pancreatic carcinoma cells. Carcinogenesis, 2013;bgt081.
Fang EF et al. In vitro and in vivo anticarcinogenic effects of RNase MC2, a ribonuclease isolated from dietary bitter gourd, toward human liver cancer cells. Int J Biochem Cell Biol. 2012;44(8):1351–1360.
84.
Fang EF et al. The MAP30 protein from bitter gourd (Momordica charantia) seeds promotes apoptosis in liver cancer cells in vitro and in vivo. Cancer Lett. 2012;324(1):66–74.
85.
Ru P et al. Bitter melon extract impairs prostate cancer cellcycle progression and delays prostatic intraepithelial neoplasia in TRAMP model. Cancer Prevent Res. 2011;4(12):2122–30.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
Pitchakarn P et al. Induction of G1 arrest and apoptosis in androgen-dependent human prostate cancer by Kuguacin J, a triterpenoid from Momordica charantia leaf. Cancer Lett. 2011;306(2):142–50. Pitchakarn P et al. Momordica charantia leaf extract suppresses rat prostate cancer progression in vitro and in vivo. Cancer Sci. 2010;101(10):2234–40. Xiong SD et al. Ribosome‐inactivating proteins isolated from di-etary bitter melon induce apoptosis and inhibit histone deacetylase‐1 selectively in premalignant and malignant prostate cancer cells. Int J Cancer. 2009;125(4):774–82. Agrawal R, Beohar T. Chemopreventive and anticarcinogenic ef-fects of Momordica charantia extract. Asian Pacific J Cancer Prevent. 2010;11(2):371–5. Ganguly C, De S, Das S. Prevention of carcinogen-induced mouse skin papilloma by whole fruit aqueous extract of Momordica charantia. Eur J Cancer Prev. 2000;9(4):283–8. Singh A, Singh SP, Bamezai R. Momordica charantia (Bitter Gourd) peel, pulp, seed and whole fruit extract inhibits mouse skin papillomagenesis. Toxicol Lett. 1998;94(1):37–46. Limtrakul P et al. Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug re-sistance. 2012. Limtrakul P, Khantamat O, Pintha K. Inhibition of Pglycoprotein activity and reversal of cancer multidrug resistance by Momordica charantia extract. Cancer Chemother Pharmacol. 2004;54(6):525– 30. Kai H et al. Inhibition of proliferation by agricultural plant extracts in seven human adult T-cell leukaemia (ATL)-related cell lines. J Nat Med. 2011;65(3–4):651–5. Kobori M et al. Alpha-eleostearic acid and its dihydroxy deriva-tive are major apoptosis-inducing components of bitter gourd. J Agric Food Chem. 2008;56(22):10515–20. Takemoto D et al. Guanylate cyclase activity in human leukemic and normal lymphocytes. enzyme inhibition and cytotoxicity of plant extracts. Enzyme. 1981;27(3):179–88. Porro G et al. In vitro and in vivo properties of an anti-CD5— momordin immunotoxin on normal and neoplastic T lymphocytes. Cancer Immunol Immunother. 1993;36(5):346–50. Brennan VC, Wang C-M, Yang W-H. Bitter melon (Momordica charantia) extract suppresses adrenocortical cancer cell prolifera-tion through modulation of the apoptotic pathway, steroidogene-sis, and insulin-like growth factor type 1 receptor/RAC-α serine/ threonine-protein kinase signaling. J Med Food. 2012;15(4):325– 34. Claflin AJ et al. Inhibition of growth and guanylate cyclase activ-ity of an undifferentiated prostate adenocarcinoma by an extract of the balsam pear (Momordica charantia abbreviata). Proc Natl Acad Sci. 1978;75(2):989–93. Hsu H-Y et al. Antimigratory effects of the methanol extract from Momordica charantia on human lung adenocarcinoma CL1 cells. Evidence-Based Complement Alternat Med. 2012;2012. Pan WL et al. Preferential cytotoxicity of the type I ribosome inactivating protein alpha-momorcharin on human nasopharyn-geal carcinoma cells under normoxia and hypoxia. Biochem Pharmacol. 2014;89(3):329–39. Rajamoorthi A et al. Bitter melon reduces head and neck squamous cell carcinoma growth by targeting c-met signaling. PLoS One. 2013;8(10):e78006.
Philippine Journal of Internal Medicine
Original Article
The MOCHA DM study: The Effect Of MOmordica CHArantia Tablets on Glucose and Insulin Levels During the Postprandial State Among Patients with Type 2 Diabetes Mellitus* Sheila T. Lim, M.D.1 Cecilia A. Jimeno, M.D.2 Elvie B. Razon-Gonzales, M.D.3 and Marie Ellaine N. Velasquez, M.D.4
Abstract Background: The worldwide prevalence of diabetes is rising both in developed and developing countries like the Philippines where 4.6% of the population has the disease. Because of the high cost of medications, the use of dietary supplements has also increased. Momordica charantia (ampalaya), is a well known plant with glucose-lowering properties which have been demonstrated by previous clinical studies. Its mechanism of action and pharmacologic properties are not yet well understood, and hence continues to be used as a supplement rather than as a standard drug for the treatment of Type 2 diabetes.
tablets, and d) placebo. Subjects were fasted for 8 hours and given standardized meal after taking assigned drug. Fasting blood sugar and plasma insulin were determined at 0 minute, 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours after the given dose. Statistical analysis was done using analysis of variance (ANOVA), Kruskal-Wallis, Bonferroni and Ranksum pairwise comparison tests.
Results: 40 participants completed the study with no adverse events. There is significantly higher insulin levels (p value = 0.0756) and significantly lower plasma glucose levels (p value = 0.024) for the 100 mg/kg/day ampalaya group (but not with the other dose groups) versus placebo after 15 minutes.
Objective: To compare the effect of Momordica charantia (MC) and placebo on insulin and glucose among type 2 diabetic patients using different doses Methodology: A double-blind, placebo-controlled, randomized trial was conducted on 40 diabetic subjects who randomly received single oral doses of either: a) 60 mg/kg/day, b) 80 mg/kg/day, c) 100 mg/kg/day MC
Introduction Diabetes mellitus is the new epidemic. The prevalence of diabetes for all age groups worldwide was estimated to be 2.8% in 2000, and to rise to 4.4% by the year 2030. 1 The total number of people with diabetes is projected to increase from 171 million in 2000 to 366 million in 2030, with the Philippines ranking 9 th among the top most countries with the greatest number of diabetic patients.1 According to local data, the prevalence rate of diabetes in the Philippines is 4.6%, based on fasting blood sugar (FBS) > 125 mg/dL or a previous history of diabetes.2 Manypatientsdevelopmicrovascularand macrovascular complications that can cause significant morbidity and mortality.3,4 The prevention or slowing down *Presented at the 15th Congress of the ASEAN Federation of Endocrine Societies November 2009 at Bangkok, Thailand; Best Poster in Clinical Science, National Institute of Health, February 2009 1Fellow, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, UP-Philippine General Hospital 2Consultant, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, UP-Philippine General Hospital
Resident, Department of Medicine, UP-Philippine General Hospital
3
Resident, Department of Medicine, UP-Philippine General Hospital
4
Conclusion: In this single dose study in type 2 diabetic patients, 100 mg/kg/day of ampalaya showed incremental dose effect and provided more rapid and shorter-lived stimulation of insulin secretion than placebo, resulting in lower meal-related glucose excursions.
of these complications are possible by adequate control of blood glucose using different pharmacologic agents. There are currently many classes of pharmacological agents for type 2 diabetes mellitus such as sulfonylureas, biguanides, thiazolidinediones and alpha glucosidase inhibitors. However, these drugs have also shown adverse effects, including hypoglycemia, lactic acidosis, and diarrhea.5 Studies of functional food components with blood glucose-controlling effects are in progress, and many useful components have been discovered in plants.6-7 In the Philippines, and other Asian and developing countries, the uses of natural drugs, such as plants and herbal remedies to treat diseases is very common. These populations are linked with the use of traditional medicines, due to their efficacy or due to the high cost of pharmaceutical production.5-7 The annual prevalence of dietary supplement use increased from 14.2% in 1998 – 1999 to 18.8% in 2002 based on data from the United States.8 In a local study done by Tanchoco et al., it was estimated that 23% use nutraceutical products,9 and ampalaya supplements are among the top five of the most commonly used herbal medication.10,11,12,13,14 Momordica charantia, is a well known plant for its glucoselowering properties.15,16 However, the sample sizes of the investigations were small, with vaguely described
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Lim S T, et al
charantia tablets has not been determined, especially as it relates to blood glucose and insulin levels at different doses. It has only been shown that Momordica charantia has insulin-like properties without the documentation of the actual levels of insulin. It is the purpose of this study to provide physicians with significant data on the comparative efficacy of Momordica charantia tablets and placebo as glucose lowering agents among subjects, emphasizing its effect on blood glucose and insulin levels. This research seeks to integrate the existing data on Momordica charantia and offer additional inputs to fill in the gaps in knowledge, thereby improving its clinical use.
Objectives The objective of this study was to compare the effect of Momordica charantia tablets and placebo on insulin secretion and glucose excursions among type 2 diabetic patients using different doses. Specifically, this study aimed
18-19
statistical analysis. Some of the researches did not even have control groups. There were no randomized trials that were included. Subsequently, no conclusions on effectiveness were made. The mechanism of action of the hypoglycemic effect brought about by Momordica charantia has been variedly described. According to experimental evidence, whole plant-aqueous extract contains a hypoglycemic principle, which is an insulin-like peptide (polypeptide p-insulin) or an alkaloid, variously called foetidin, momordicin, or charantin.17 It is hypothesized that this plant extract mimics or improves insulin action at the cellular level, and may even have an extra-pancreatic mode of action. 17 Theoretical mechanisms have also been proposed. These include increased insulin secretion, tissue glucose uptake, liver muscle glycogen synthesis, glucose oxidation, and decreased hepatic gluconeogenesis.15
The leaves of Momordica charantia, particularly of the Makiling variety, produced the most consistent hypoglycemic properties with acceptable safety profiles compared to other parts of the plant. It has undergone
several clinical trials.18, 20, 21 Based on these studies, it was determined that the mean difference in fasting blood sugar of 40.8% from baseline compared to 36.8% for the glibenclamide group at 12 weeks using a dose of 100mg/ kg/day of ampalaya tablets. Mean HbAic also showed a 4.8% decrease from baseline using Momordica charantia, compared to 4.2% for the glibenclamide group.21
Clinical Significance Despite these clinical trials however, the joint position statement of the Philippine Society of Endocrinology and Metabolism, Philippine Diabetes Association, Institute for Studies on Diabetes Foundation, and Philippine Center for Diabetes Education Foundation still does not consider ampalaya-derived products as part of the standard care for diabetes in the absence of more research data. The pharmacodynamics of the Momordica
The MOCHA DM study
to: a) indirectly demonstrate the mechanism of action of Momordica charantia by determining its effect in insulin levels since theoretically, ampalaya extracts have been shown to improve insulin levels; and b) determine the time of peak effect and onset of efficacy of Momordica charantia tablets versus placebo using different doses of 60 mg/kg/ day, 80 mg/kg/day and 100 mg/kg/day among patients with type 2 diabetes mellitus during the postprandial state. This will be significant in establishing the dosage intervals of Momordica charantia tablets in maximizing its medical use.
Methodolgy Research Design This study was a double-blind, placebo-controlled, randomized trial conducted in the Philippine General Hospital, from June to December 2008. Study population Subjects were recruited from the outpatient clinics of the University of the Philippines-Philippine General Hospital and were enrolled to the study after fulfilling the following inclusion criteria:
2.
Newly diagnosed diabetes mellitus AND is drug naïve OR is NOT on anti-diabetic agents for the past 3 months
3.
4.
Glycemic criteria: Glycosylated hemoglobin (HbA1c) ≥ 6.5% and ≤ 9.0% and fasting blood glucose of ≥126 mg/dL but ≤ 205 mg/dL Patient is ≥ 21 years old but ≤ 65 years old
Exclusion criteria included: 1. Unstable co-morbidities 2. Significant acute illness in the previous 2 weeks before the start of the study 3. History of diabetic emergency 4. History of corticosteroid use, herbal medications or any other drugs that may affect glucose metabolism within the preceding 6 months 5. Hypersensitivity to the drug 6. Presence of conditions affecting compliance, e.g., drug or alcohol abuse or psychiatric illness 7. Recipient of another investigational drug during and preceding 6 months 8. Pregnancy 9. Unwillingness to participate in the study Materials and Methods 1. Data collection
1.
Type 2 diabetes mellitus based on the American Diabetes Association (ADA) Criteria for Diabetes Mellitus, 2007 (APPENDIX B)
20 Volume 48 Number 2 July-September, 2010
a. Determination of clinical data. Volunteers were asked to sign a written consent after explaining the objectives and procedures involved in the study. They were then interviewed upon entry to the study for demographic data, risk factors
Lim S T, et al
The MOCHA DM study for coronary artery diseases such as smoking, family history of diabetes, presence or absence of sedentary lifestyle (being on his/her feet for
