Journal of Clinical Epidemiology 60 (2007) 554e559

The effect of Momordica charantia capsule preparation on glycemic control in Type 2 Diabetes Mellitus needs further studies
Antonio Miguel Limcaco Dansa,*, Maria Vanessa C. Villarruzb, Cecilia A. Jimenoa, Mark Anthony U. Javelosab, Joel Chuaa, Rhida Bautistaa, Gwyneth Giselle B. Veleza
a

Department of Medicine, Philippine General Hospital Medicine, Taft Avenue, Manila, Philippines b Adult Medicine Research Unit, Section of Adult Medicine, Taft Avenue, Manila, Philippines Accepted 3 July 2006

Abstract Background and Objectives: Momordica charantia, locally known as Ampalaya, is being widely used and advertised for its hypoglycemic effects. However, to date, no large clinical trial has been published on the efcacy of any type of preparation. The main objective of this study is to determine if addition of M. charantia capsules to standard therapy can decrease glycosylated hemoglobin (hemoglobin A1c or HbA1c) levels in diabetic patients with poor sugar control. Study Design and Setting: A randomized, double-blind, placebo-controlled trial was conducted between April and September 2004 at the outpatient clinics of the Philippine General Hospital. The trial included 40 patients, 18 years old and above, who were either newly diagnosed or poorly controlled type 2 diabetics with A1c levels between 7% and 9%. On top of the standard therapy, the patients were randomized to either M. charantia capsules or placebo. The treatment group received two capsules of M. charantia three times a day after meals, for 3 months. The control group received placebo at the same dose. The primary efcacy endpoint was change in the A1c level in the two groups. The secondary efcacy endpoints included its effect on fasting blood sugar, serum cholesterol, and weight. Safety endpoints included effects on serum creatinine, hepatic transaminases (Alanine aminotransferase/ALT and Aspartate aminotransferase/AST), sodium, potassium, and adverse events. Results: Baseline characteristics between the treatment and control groups were similar. The difference in mean change in A1c between the two groups was 0.22% in favor of M. charantia (95% CI: 0.40 to 0.84) with P 5 0.4825.There was no signicant effect on mean fasting blood sugar, total cholesterol, and weight or on serum creatinine, ALT, AST, sodium, and potassium. There were few adverse events and these were generally mild. Conclusion: This is the rst randomized controlled trial to shed light on the issue concerning the hypoglycemic effects of M. charantia. The investigators targeted a 1% decline in A1c at the outset with an estimated power of 88%. With the observed decline of 0.24%, the achieved power was only 11%. For this reason, we are unable to make a denite conclusion about the effectiveness of M. charantia. However, the results of this study can be used estimate the sample size for bigger studies. 2007 Elsevier Inc. All rights reserved.

1. Introduction Momordica charantia, locally known as Ampalaya, has been used traditionally as an antidiabetic agent. Locally available preparations of this plant are widely used and advertised. It is approved by the Department of Health as one of the 10 scientically proven medicinal plants [1]. Animal and human studies suggest that the fruits, seeds, and leaf extracts of this plant possess hypoglycemic effects. The active components of M. charantia are thought to be charantin, vicine, and polypeptide pdwhich is structurally similar to animal insulin [2,3]. Theoretical mechanisms of

* Corresponding author. Tel./fax: 6325239740. E-mail address: tdans@zpdee.net (A.M.L. Dans). 0895-4356/07/$ e see front matter 2007 Elsevier Inc. All rights reserved. doi: 10.1016/j.jclinepi.2006.07.009

action include increased insulin-like effects [4], stimulation of pancreatic secretion [5] leading to decreased hepatic gluconeogenesis, increased hepatic glycogen synthesis, and increased peripheral glucose oxidation [6,7]. We conducted a systematic review of studies on the effectiveness of M. charantia in diabetic patients by searching the following sources: 1) MEDLINE, 2) literature from manufacturers, 3) local journals, and 4) cross-references of any articles that we retrieved. Eight studies were found and these are summarized in Table 1. Although the results seem promising, all the studies had serious methodologic aws. Sample sizes were consistently small, statistical analyses were vaguely described, and most did not even have a control group. None of these studies were randomized trials. For these reasons, rm conclusions on effectiveness could not be drawn.

A.M.L. Dans et al. / Journal of Clinical Epidemiology 60 (2007) 554e559 Table 1 Studies on Momordica charantia Study Baldwa et al., 1977 [4] Khanna et al., 1981 [8] Leatherdale et al., [9] Preparation Puried protein extract subcutaneously Subcutaneous polypeptide p 50 mL of fruit juice Dried fruit for 8e11 weeks 50 mL of fruit juice Aqueous extract of 100 g of chopped fruit OD 21 days 5 g of dried fruit three times daily 21 days Bitter melon seeds Aqueous suspension of the vegetable pulp Ampalaya tea 12 weeks Sample size 9 19 9 Design Controlled clinical trial Controlled clinical trial Case series Results

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Welhinda et al., 1986 [10] Srivasatva et al., 1993 [11]

18 7 5 20 100 27

Case series Case series

Decrease in serum glucose levels Decrease in serum glucose levels Decrease in glucose levels in glucose tolerance test Decrease in HbA1c levels Improvements in glucose tolerance tests Reduction in mean blood glucose decrease in Hba1c level Reduction in mean blood glucose level Reduction in postprandial blood glucose Reduction of fasting and postprandial serum glucose levels Signicant decrease in A1c non signicant decrease in FBS

Grover et al., 1990 [12] Ahmad et al., 1999 [13] Rosales and Fernando 1990 [14]

Case series Case series Open label cross over trial

There is also little data regarding the safety of M. charantia [3]. Animal trials have shown 1) signicant increases in alkaline phosphatase and gamma glutamyl transferase in rats [15], 2) hypotension in dogs [16], 3) sterility in female mice, 4) uterine bleeding in pregnant mice and rabbits [17e20], and 5) elevated serum cholesterol and nonesteried fatty acids in dogs [17] (the opposite of cholesterol drops seen in mice) [21]. In human trials, the most commonly reported side effects are abdominal pain and diarrhea [22]. A potentially fatal hypoglycemic coma was reported in two children after administration of a tea preparation of the leaves before breakfast, but causation was difcult to establish [23]. In addition, individuals with glucose-6-phosphate deciency are at risk of developing favism [3]. The Philippine Institute of Traditional and Alternative Health Care recommends that the leaves and fruits be prepared as a decoction, eaten as a salad, or steamed with rice [1]. Locally, preparations of M. charantia have come in the form of capsules and a tea like drink. Charantia is the registered brand name of Herbcare Corporation for its line of Herbal Food supplement products made from the fruits and seeds of the Ampalaya plant. The active ingredients of these preparations were extracted from the plant. It is promoted solely as a food supplement for diabetics and not as a substitute for the medications prescribed by physicians. The recommended dose of Charantia is 3 grams per day [24]. However, the optimum dose has also not been established at this time. This study was conducted to guide sample size estimates for trials in the future since there were no good estimates of efcacy prior to this study. The main objective was to determine the efcacy and safety of Charantia Ampalaya Capsules compared to placebo, as an adjunct to standard therapy of newly diagnosed or suboptimally controlled type 2 diabetes. The primary efcacy endpoint was a decrease in A1c level, while the secondary endpoints included effect on

fasting blood sugar, total cholesterol, and weight. Aside from adverse events, other safety endpoints monitored were effect on serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), sodium, and potassium.

2. Methodology 2.1. Study design and patients This study was a randomized, double-blind, placebocontrolled trial conducted between April and September of 2004. Patients were considered eligible if they satised all of the following criteria: 1) at least 18 years old 2) diagnosed by a physician to have type 2 diabetes mellitus (DM), and 3) suboptimal glycemic controlddened as HbA1c of 7%e9% despite pharmacologic or dietary therapy or before initiation of therapy in newly diagnosed DM. Exclusion criteria included any of the following: 1) evidence of hepatic dysfunction (ALT or AST greater than 3 times the upper limit of normal), 2) known allergy to any part of the plant, 3) presence of severe chronic illness, 4) presence of acute illness, 5) presence of illness limiting life expectancy, 6) presence of conditions affecting compliance (i.e., drug or alcohol abuse or psychiatric problems), 7) inability to attend follow-up clinic, 8) recipient of another investigational product during and 3 months preceding, and 9) pregnancy or lactation. The protocol was approved by the institutional review board and the ethics review board of the institution. Each patient screened gave written informed consent for the study. 2.2. Randomization Random allocation was done using a computer-generated sequence (Stata version 6.0). To conceal allocation, medications were prepared by a third party. The treatment

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A.M.L. Dans et al. / Journal of Clinical Epidemiology 60 (2007) 554e559 Table 2 Baseline characteristics of patients included in the study Demographics Charantia (N 5 20) Placebo (N 5 20) P-value 0.7906 1.000 0.7906 0.8910 0.7217 0.4853 0.7310 0.6842 0.5186 0.3902

and placebo capsules were matched in appearance and packaged in unmarked blisters. 2.3. Study procedure Eligible patients were asked to undergo baseline laboratory examination, which included HbA1c, fasting blood glucose, creatinine, total cholesterol, sodium, potassium, and ALT/AST levels. They were then randomized to either a treatment or placebo group. The patients, investigators, and statistician were unaware of the treatments received until the end of analysis. Patients were advised to take two capsules of the assigned treatment three times daily after meals for a period of 3 months (the generally accepted period necessary to make meaningful changes in HbA1c). Monthly follow-up was scheduled during these 3 months and a termination visit was scheduled a month thereafter. During each visit, vital signs were recorded and capillary blood sugar levels were taken. The patients were interviewed regarding compliance and adverse events. Diet and concomitant medication intake were also reinforced. Laboratory examinations including HbA1c, fasting blood sugar, creatinine, total cholesterol, sodium, potassium, ALT, and AST levels were repeated at the end of the treatment period. 2.4. Outcome measures The primary efcacy measure was the change in HbA1c level after treatment. Secondary efcacy measures included change in fasting blood sugar, serum cholesterol, and weight. The following safety measures were also analyzed: change in serum creatinine, AST, ALT, sodium, potassium, and incidence of adverse events. 2.5. Statistical analysis The intention-to-treat principle was used in all statistical analyses. The t-test was used to compare the two groups in terms of the mean change in HbA1c levels, as well as weight, fasting blood sugar, total cholesterol, creatinine, AST, ALT, sodium, and potassium. Ninety-ve percent condence intervals for the group differences were also computed to supplement the result of the t-test. The sample size estimate was based on an arbitrary targetdan absolute difference of 1% in HbA1c change between the two groups, with a standard deviation of 1%. Using these targets, a xed sample size of 20 per group would yield a power of 88.54%.

Age in years 58.70 (9.81) 59.76 (10.04) Number of males 7 8 Mean body 26.37 (4.75) 26.00 (3.94) mass index in Kg/m2 (SD) Mean systolic BP in mmHg 132.5 (11.18) 133.0 (11.74) (SD) Mean diastolic BP in mmHg 80.5 (9.44) 77.8 (18.75) (SD) Mean HbA1c level in % (SD) 7.92 (0.59) 8.07 (0.77) Mean fasting plasma 8.40 (2.24) 8.14 (2.36) glucose in mmol/L (SD) Mean total cholesterol 5.25 (1.46) 5.08 (1.09) in mmol/L (SD) Mean creatinine 111.56 (65.11) 100.95 (32.58) in mmol/L (SD) Mean ALT in IU/L (SD) 29.87 (21.42) 37.12 (26.26) Abbreviation: BP, blood pressure.

3. Results All 40 patients enrolled had similar baseline characteristics (Table 2). All were on oral hypoglycemic agents but no dose adjustments were made during the study. One patient from the Charantia group withdrew from the study because

of diarrhea. There were no dropouts. All patients were included in the analysis. The efcacy results are summarized in Table 3. Changes were computed by subtracting the posttreatment value from the pretreatment value. A positive difference indicated lower posttreatment values. The HbA1c in both the Charantia group and the control group showed a statistically insignicant rise with a mean change of 0.28% and 0.50%, respectively. The mean difference of 0.217 (95% CI: 0.40 to 0.84) in favor of Charantia was not statistically signicant (P 5 0.483). There were no signicant differences in BMI and fasting blood sugar (Table 3). Safety results are summarized in Table 4. There was a decrease in the mean creatinine, ALT, AST, and sodium levels in both groups, and a rise in mean potassium level in the Charantia group compared to placebo. None of these changes were statistically signicant. Gastrointestinal complaints were the most common reported adverse events. One patient in the Charantia group refused further participation after 1 month because of diarrhea and epigastric pain. Two other patients also reported bouts of diarrhea after 2 months of intake of Charantia. These patients resumed medications after resolution of symptoms. A patient in the Charantia group was admitted for 10 days for gastroenteritis. Another patient in the treatment arm was admitted for cholecystolithiasis, but this did not seem causally related to drug intake. This patient refused surgery and was sent home improved. Other reported adverse events from the treatment group were chest pain (one patient), urinary incontinence (one patient), and fever (one patient). One patient from the placebo group reported diarrhea after 1 month of medications. This patient later resumed medications.

Table 3 Primary and secondary efcacy measures Charantia n 5 20 Pretreatment (SD) HbA1c hemoglobin levels (%) Fasting plasma glucose (in mmol/L) Total cholesterol (in umol/L) Body mass index (in kg/m2) 7.92% (0.59%) 8.4 (2.24 mmol/L) 5.25 (1.46 umol/L) 26.37 (4.75 kg/m2) Posttreatment (SD) 8.2% (1.25%) 7.99 (0.77 mmol/L) 5.08 (1.39 umol/L) 26.33 (4.87 kg/m2) Mean change (SD) 0.28% (0.88%) 0.41 (3.18 mmol/L) 0.17 (0.86 umol/L) 0.04 (0.96g/m2) Placebo n 5 20 Pretreatment (SD) 8.07% (0.77%) 8.14 (2.36 mmol/L) 5.08 (1.09 umol/L) 26.00 (3.94 kg/m2) Posttreatment (SD) 8.57% (0.30%) 8.40 (4.01 mmol/L) 5.21 (1.08 umol/L) 26.04 (3.55 kg/m2) Mean change (SD) 0.50% (0.99%) .25 (4.32 mmol/L) .13 (1.27 umol/L) 0.03 (1.21 kg/m2) Treatment mean difference (95%CI) 0.22% (0.40%e0.84%) 0.66 (1.77e3.08 mmol/L) 0.30 (0.39e0.99 umol/L) 0.08 (0.62e0.76 kg/m2)

P-value 0.4825 0.5862 0.3876 0.8266 A.M.L. Dans et al. / Journal of Clinical Epidemiology 60 (2007) 554e559

Table 4 Laboratory proles used for safety evaluation Charantia (N 5 20) Proles mean (SD) Creatinine (umol/L) AST (IU/L) ALT (IU/L) Na (mmol/L) K (mmol/L) Pretreatment 111.56 (umol/L (65 umol/L) 29.58 IU/L (17.72 IU/L) 29.87 IU/L (21.42 IU/L) 142.28 mmol/L (2.30 mmol/L) 4.03 mmol/L (0.58 mmol/L) Posttreatment 105.28 umol/L (54.83 (umol/L) 23.12 IU/L (7.44 IU/L) 26.03 IU/L (9.50 IU/L) 140.97 mmol/L (2.42 mmol/L) 4.22 mmol/L (0.45 mmol/L) Mean change (SD) 6.28 umol/L (24.56 umol/L) 6.45 IU/L (16.94 IU/L) 3.85 IU/L (19.36 IU/L) 1.31 mmol/L (2.36 mmol/L) 0.19 mmol/L (0.41 mmol/L) Placebo (N 5 20) Pretreatment 100.95 umol/L (32.58 umol/L) 32.57 IU/L (17.96 IU/L) 37.12 IU/L (30.48 IU/L) 141.36 mmol/L (2.21 mmol/L) 4.09 mmol/L (0.58 mmol/L) Posttreatment 92.33 umol/L (22.53 (umol/L) 24.18 IU/L (9.71 IU/L) 28.43 IU/L (15.33 IU/L) 141.35 mmol/L (2.16 mmol/L) 4.07 mmol/L (0.39 mmol/L) Mean change (SD) 8.62 umol/L (23.91 umol/L) 8.39 IU/L (15.97 IU/L) 8.68 IU/L (28.65 IU/L) 0.002 mmol/L (2.67 mmol/L) 0.02 mmol/L (0.35 mmol/L) Treatment mean difference (95% CI) 2.34 umol/L (17.86 umol/L to 13.17 umol/L) 1.94 IU/L (12.98 IU/L to 8.61 IU/L) 4.83 IU/L (20.49 IU/L to 10.82 IU/L) 1.31 mmol/L (0.31 mmol/L to 2.92 mmol/L) 0.22 mmol/L (0.46 mmol/L to 0.03 mmol/L) P-value 0.7614 0.585 0.535 0.141 0.076

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4. Discussion The hypoglycemic effect documented from previous nonrandomized trials was not demonstrated in our study. The estimated power of this study was based on an anticipated 1% difference in the change in HbA1c level. The value of 1% was arbitrary, but there were no prior studies on which to base an expected change. This estimate was used to calculate the sample size of 20 per group. The power to detect the difference was estimated at 88.54%. The actual difference seen in this pilot was only 0.24%; therefore, the observed power in this study was only 11%. Based on our results which showed a mean drop in HbA1c(%) of 0.217 (95% CI: 0.40 to 0.84) we are unable to exclude a clinically important effect of M. charantia on glycemic control. Information from this pilot study may be used for sample size computations in the future. Generally, Charantia capsule preparations were well tolerated. The most common adverse events seen were gastrointestinal symptoms such as abdominal discomfort or pain and diarrhea, occurring in two and three patients, respectively. No serious adverse event was noted during the 3-month follow-up period, though one patient dropped out due to persistent abdominal pain. Animal trials have shown signicant increases in alkaline phosphatase and gamma glutamyl transferase in rats after oral administration of fruit juice and seed extract [15]. In the study done by Rosales and Fernando, there were no signicant changes in the AST and ALT levels. Likewise, surrogate laboratory parameters monitored for adverse events such as creatinine, sodium, and potassium levels were not different between groups.

Acknowledgment The assistance of Jemimah Joy Gambito-Esguerra is gratefully acknowledged for overseeing management and patient follow-up. We also thank the patients who participated in this study.

References
[1] Philippine Institute of Traditional and Alternative Health Care (PITAHC). Ampalaya (Momordica charantia). Available at www.doh. gov.ph/pitahc/Ampalaya.html. Accessed September 10, 2004. [2] Torres, W. Momordica Charantia Linn (Family CucurbitaeeChemistry and Pharmacology. Available at http://www.charanteausa.com/ ampalaya_archive/studies/1.doc. [3] Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efcacy and safety. Am J Health Syst Pharm 2003;60:356e9. [4] Baldwa VS, Bhandari CM, Pangaria A, Goyal RK. Clinical trials in patients with diabetes mellitus of an insulin-like compound obtained from a plant source. Ups J Med Sci 1977;82:39e41. [5] Welihinda J, Karunanayake EH, Sheriff MH, Jayasinghe KS. Effect of Momordica charantia on the glucose tolerance in maturity onset diabetes. J Ethnopharmacol 1986;17:277e82. In: Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efcacy and safety. Am J Health Syst Pharm 2003;60:356e359. [6] Shibib BA, Khan LA, Rahman R. Hypoglycaemic activity of Coccinia indica and Momordica charantia in diabetic rats: depression of the hepatic gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase and elevation of both liver and red-cell shunt enzyme glucose-6-phosphate dehydrogenase. Biochem J 1993;292(Pt 1):267e70. In: Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efcacy and safety. Am J Health Syst Pharm 2003;60:356e359. [7] Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care 2003;26:1277e94. Review. [8] Khanna P, Jain SC, Panagariya A, Dixit VP. Hypoglycemic activity of polypeptide-p from a plant source. J Nat Prod 1981;44:648e55. [9] Leatherdale BA, Panesar RK, Singh G, Atkins TW, Bailey CJ, Bignell AH. Improvement in glucose tolerance due to Momordica charantia (karela). BMJ (Clin Res Ed) 1981;282:1823e4. [10] Welihinda J, Karunanayake EH, Sheriff MH, Jayasinghe KS. Effect of Momordica charantia on the Glucose tolerance in maturity onset diabetes. J Ethnopharmacol 1986;17:277e82. In: Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efcacy and safety. Am J Health Syst Pharm 2003;60:356e359. [11] Srivastava Y, Venkatakrishna-Bhatt H, Verma Y, Venkaiah Y, Raval BH. Antidiabetic and adaptogenic properties of Momordica charantia extract: an experimental and clinical evaluation. Phytother Res 1993;7:285e9. In: Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efcacy and safety. Am J Health Syst Pharm 2003;60:356e359. [12] Grover JK, Gupta SR. Hypoglycemic activity of seeds of Momordica charantia. Eur J Pharmacol 1990;183:1026e7. [13] Ahmad N, Hassan MR, Halder H, Bennoor KS. Effect of Momordica charantia (Karolla) extracts on fasting and postprandial serum glucose levels in NIDDM patients. Bangladesh Med Res Counc Bull 1999;25(1):11e3. [14] Rosales R, Fernando R. An inquiry to the hypoglycemic action of Momordica charantia among type 2 diabetic patients. Phil J Inter Med 2001;39:213e6. [15] Tennekoon KH, Jeevathayaparan S, Angunawala P, Karunanayake EH, Jayasinghe KS. Effect of Momordica charantia

5. Conclusion This is the rst randomized controlled trial of Charantia compared to placebo in diabetic patients. This study had a power of 11% to detect a 0.22% difference in A1c level. There appears to be a modest, albeit not statistically significant, decline in A1c levels among patients taking Charantia compared to those taking placebo but we are unable to make a denite conclusion at this time. The results of this trial can be used to estimate the sample size for a bigger study of similar design.

6. Declaration The trial was commissioned by Herbcare Corp. specically to investigate the efcacy of their product. The investigation was conducted under the supervision of the Medical Research Unit of the Philippine General Hospital. The sponsors were involved in planning the study but not in data collection and analysis.

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