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THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 15, Number 5, 2009, pp. 1–6 ª Mary Ann Liebert, Inc. DOI: 10.1089=acm.2008.0367
ACM-2008-0367-Qidwai Type: research-article
Original Papers
Effectiveness, Safety, and Tolerability of Powdered Nigella sativa (Kalonji) Seed in Capsules on Serum Lipid Levels, Blood Sugar, Blood Pressure, and Body Weight in Adults: Results of a Randomized Double-Blind Controlled Trial Waris Qidwai, M.C.P.S., F.C.P.S.,1 Hasan Bin Hamza, M.Sc.,2 Riaz Qureshi, F.R.C.G.P. (UK),3 and Anwar Gilani, Ph.D.4
Abstract
Objective: The seed extracts from Nigella sativa is used by Unani physicians of traditional medicine (Hakims or Tabibs) and Ayurvedic practitioners (Vaids) in the treatment of several medical disorders including dyslipidemia, obesity, and hypertension. It is, therefore, important to prove or disprove the effectiveness, safety, and tolerability of powdered N. sativa (Kalonji) seed in capsules on serum lipid levels, blood sugar, blood pressure, and body weight in adults. Design: The study design was a randomized, double-blind trial. Settings=location: Conducted at Aga Khan University Hospital, Karachi, from February 2006 to January 2007. Subjects: Half of the respondents received powdered N. sativa (Kalonji) seed in capsule and the rest received a placebo. Intervention=outcome: Baseline and after-intervention variables recorded were the following: body–mass index, waist–hip ratio, blood pressure, fasting blood sugar, serum lipids, serum alanine aminotransferase, and serum creatinine. Results: One hundred and twenty-three (123) patients were recruited. Sixty-four (64) and 59 patients were randomized to the intervention and the control arms, respectively. Thirty-nine (39) patients in the intervention group and 34 in the control group completed the study. Favorable impact of powdered N. sativa (Kalonji) seed in capsule was noted on almost all variable but results were not statistically significant, because of small sample size. Conclusions: Favorable impact of powdered N. sativa (Kalonji) seed in capsule was noted on almost all variables, but results were not statistically significant. A larger study with adequate sample size is recommended.
analgesic, anti-inflammatory and immunopotentiating properties.4,5 The seed extracts from this plant are used by Unani Physicians of Traditional Medicine (Hakims or Tabibs) and Ayurvedic Practitioners (Vaids) in the treatment of several medical disorders including dyslipidemia, obesity, and hypertension. Several studies have demonstrated the favorable impact of Nigella sativa seed extract on dyslipidemia in rats.6 Evidence exists regarding cultivation and use of N. sativa seeds in Pakistan for its medicinal properties.7
Introduction
P
akistan is a developing country with limited resources and a high burden of diseases such as dyslipidemia, diabetes mellitus, hypertension, and obesity.1–3 Nigella sativa (black cumin) is a small plant originating in the Middle East and is found abundantly, growing wild in Egypt, Asiatic Turkey, and the Balkan states. N. sativa seeds are claimed to have bronchodilatory, hypotensive, antibacterial, antifungal, 1–3
Department of Family Medicine, Aga Khan University, Karachi, Pakistan. Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan.
4
1
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2 Scientifically sound studies on human subjects have not been carried out to prove or disprove the effectiveness of Nigella sativa extract on dyslipidemia, blood sugar, or obesity. Human studies with small sample size, methodological shortcomings, and conflict of interest have been reported from Sri Lanka. Despite their limitations, these studies show favorable results in favor of N. sativa extract in lowering serum cholesterol and blood sugar.8,9 The use of simple remedies such as N. sativa seeds for the control of dyslipidemia and blood sugar in diabetics can be a cost-effective and safe solution to treat complex and expensive-to-treat problems. The use of N. sativa seeds is claimed to be free from major side-effects including hepatic or renal toxicity, but cases of contact dermatitis have been reported with local applications.10 Complimentary and alternative therapies are reported to be very popular and accepted forms of treatment in Pakistan.11,12 In Pakistan, kalonji seed is considered to be a traditional medicine (under national systems of medicine: Unani and Ayurveda) and is still not considered to be a complementary and alternative medicine. It is, therefore, important to prove or disprove the effectiveness, safety, and tolerability of powdered N. sativa (Kalonji) seed in capsule on lipid levels, blood sugar, blood pressure, and body weight in adults. This study was carried out after this need was identified. Materials and Methods A randomized double-blind trial in the form of a pilot study was conducted at Aga Khan University Hospital, Karachi, from February 2006 to January 2007. This period included the enrollment, intervention, and postintervention follow-up periods. Outpatients visiting family physicians were recruited into the study and followed up in the same settings. Inclusion criteria We included adult men and women of Pakistani origin, 18 years or older and available to participate in the study for 6 weeks. Their inclusion in the trial required serum total cholesterol level between >180 to 250 mg=dL, or serum total cholesterol level 250 mg=dL and taking statins for at least 1 month. Those on statins were recruited only if they were on them for a minimum of 4 weeks, so that the impact of powdered N. sativa (Kalonji) seed in capsule could be studied. The reasons for taking statins were not documented. Exclusion criteria We excluded those who had diabetes, hypothyroidism, renal disease or malignancy or were on thiazide diuretics, b-blockers or corticosteroids; had admission to hospital with a severe illness within the previous 3 months; or were pregnant or breast feeding within the previous 12 months. Those with a known cardiovascular condition (ischemic heart disease, peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease) were excluded including those with fasting triglyceride concentration 236 mg=dL. Outcome measures The primary endpoint for the trial was serum total cholesterol concentration measured at 6 weeks after interven-
QIDWAI ET AL. tion. The secondary endpoint was serum concentrations of low density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and serum triglyceride concentrations measured at 6 weeks after intervention. The samples were taken by a phlebotomist and tested in the laboratory by the Research Officer hired for the purpose. Every tenth sample was cross-checked with the main laboratory to check for reliability of the testing. The entire testing was done at the university hospital, where the study was conducted. Due to double blinding, the investigators were unaware of the status of the patients. The assessment of patients, recruitment, informed consent form filling, allotment of patients to either groups A or B (blinded), storage and dispensing of capsules, and follow-up were done by a research officer, a qualified and licensed medical practitioner, hired for this work. Authors of the study were not involved. Trial groups The intervention group was recommended dietary changes, lifestyle changes, and powdered N. sativa seed in capsule as intervention. The seeds were crushed and were filled in the capsule. Excipients were not used. Patients were administered two capsules twice daily after meals; each capsule contained 500 mg crushed powdered N. sativa seed for 6 weeks. Volunteers took the medication home and were self-administered. Five hundred (500) mg of crushed powdered N. sativa seeds was in the capsule. A dose of 1 g twice daily was agreed upon after literature review. The dose we have used is based on the recommendations of the Unani Pharmacopoeia of India (1–2 g), Ayurvedic Pharmacopoeia of India (1–3 g) and Siddha Pharmacopoeia of India (0.5–4 g). The control group was recommended dietary changes and lifestyle changes the same as the intervention group and calcium lactate powder as placebo. Controls were administered two capsules twice daily after meals, each capsule containing 500 mg of calcium lactate for 6 weeks. The capsules were similar to those that contained powdered N. sativa seed extract and one could not guess the capsule contents by looking at the blister packs. The rationale for using calcium lactate as placebo was based on its inert quality with regard to study outcomes, and easy availability of the powder. The study participants received individual dietary advice from a study assistant and a standard diet history was taken. Subjects in both groups were advised to take a brisk 30minute walk for 5 days in a week on empty stomach or 1 hour after having a meal. The laboratory investigations included total serum cholesterol, LDL cholesterol, HDL cholesterol, serum triglycerides, fasting blood sugar, serum creatinine, and serum glutamic pyruvic transaminase. A randomization plan with a block size of four was used to assign subjects to the intervention and control groups. Double-blinding was employed and both the patient as well as the investigators were unaware of the treatment group they were assigned. The laboratory was kept unaware of intervention or control group allocation. To achieve blinding, powdered crushed seeds were packed in capsules which were then blister packed. After the packing of the powder in capsules that were later blister packed, it was not possible for the investigators or the study participants to distinguish
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ROLE OF POWDERED NIGELLA SATIVA SEED IN CAPSULES IN METABOLIC SYNDROME between the two. An independent epidemiologist assigned a code to the intervention in collaboration with the in-charge at the site of packing. The code assigned by the epidemiologist was engraved on each blister pack. A similar process was followed for packing calcium lactate powder, and a separate code assigned by the epidemiologist was allocated to blister packs containing capsules with calcium lactate. Ethical considerations Subjects in both groups of the study were given standard dietary advice, which is recommended by the National Cholesterol Education Program, in cases fitting the inclusion criteria of this proposed study. In studies conducted previously, N. sativa seed has been shown to demonstrate protective effect against nephrotoxicity and hepatotoxicity induced by either disease or chemicals. However, in case adverse events were observed, the intervention with N. sativa was planned to be stopped for that particular individual. Quality of seeds was ensured by way of direct observation. A study team representative purchased the seeds from a known quality vendor personally. Written informed consent was obtained from all study participants. Ethical approval was obtained from the Ethical Review Committee. The N. sativa seeds used in this study were of food-grade quality and were purchased from the open market. The raw material was not tested for determination of conformance to any pharmacopoeial quality standard, which is a limitation of this study. Sample size considerations This was a pilot study, and we planned to include 40 participants each in the intervention and control group.
3
Total recruited 123
Randomization
Intervention 64
Control 59
(Kalonji) Ineligible Loss to follow up Completed follow up
(Placebo) Ineligible Loss to follow up Completed follow up
04 21 39
02 23 34
Included in analysis 34
Included in analysis 39
FIG. 1. An overview of the trial. were checked against the quantity dispensed. The overall compliance was in excess of 90%. Table 1 show that patients in both the intervention and the b T1 control groups were similar in sociodemographic parameters such as age, gender, education, marital status, and occupation. Table 2 lists the means of the baseline characteristics of the b T2 study participants. It show that patients in both the intervention and the control groups were similar in age, total cholesterol, LDL cholesterol, HDL cholesterol, serum triglycerides, fasting blood sugar, serum creatinine, serum alanine aminotransferase (ALT), body–mass index (BMI), waist and hip measurement, diastolic and systolic blood pressure, and average daily exercise. A statistically significant difference ( p 0.01) was observed in calorie intake, with the
Statistical analysis The analysis was based on intention to treat. In descriptive statistics, comparison of the two treatment groups was done on variables such as age and gender. To detect a significant difference in the primary outcome between the two groups, t-test was applied. Mean caloric intake was measured using food intake recorded in the food diary. Differences if any in the intervention and control groups regarding mean caloric intake were measured using the t-test as a test of significance. For multivariate analysis, linear regression analysis was used to identify variables associated with the primary outcome, and to control for confounding factors. A similar process was adopted for secondary outcome variables. Results One hundred and twenty-three (123) patients were recruited in the trial. Sixty-four (64) and 59 patients were randomized to the intervention and the control arms, respectively. Thirty-nine (39) patients in the intervention group F1 c and 34 in the control group completed the study (Fig. 1). A high dropout rate was present in the study. The reasons were several and not available in several instances. The main reason was concern about possible side-effects from the interventional product. The compliance of patients with regard to intake of interventional product was ensured by the research officer who re-enforced it by following up with patients over the phone. Unused capsules were returned and
Table 1. Sociodemographic Characteristics of Study Participants (n ¼ 123) Intervention (n ¼ 60) Characteristics Age (in years) mean (SD) Gender Male Female Education Illiterate Matric Inter Graduate Postgraduate Marital status Single Married Occupation Service Business persons Bankers Housewife
Control (n ¼ 57)
n
%
n
%
p-value*
45.58
10.86
46.86
11.00
0.53
54 6
90.0 10.0
49 8
86.0 14.0
0.50
1 4 7 30 18
1.7 6.7 11.7 50.0 30.0
1 6 6 24 20
1.8 10.5 10.5 42.1 35.1
1.00 0.46 0.84 0.39 0.56
1 59
1.7 98.3
1 56
1.8 98.2
1.00
46 7 4 3
76.7 11.7 6.7 5.0
33 11 9 4
57.9 19.3 15.8 7.0
0.03 0.25 0.12 0.65
*Fischer’s exact test (cell count 5). SD, standard deviation.
b AU1
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QIDWAI ET AL. Table 2. Baseline Characteristics of Study Participants (n ¼ 117) Intervention (n ¼ 60)
Characteristics Age (in years) Total cholesterol (mg=dL) LDL (mg=dL) HDL (mg=dL) Triglycerides (mg=dL) Fasting blood sugar (mg=dL) Serum creatinine (mg=dL) ALT (mg=L) BMI Waist (cm) Hip circumference (cm) Diastolic blood pressure (mm Hg) Systolic blood pressure (mm Hg) Calorie intake Average daily exercise (in minutes)
Control (n ¼ 57)
Mean
SD
Mean
SD
p-value
45.58 209.07 145.76 40.53 163.14 95.76 1.15 32.10 27.13 95.12 118.15 81.82 128.90 1636.29 15.56
10.86 28.63 23.30 8.52 71.43 16.79 1.05 15.18 3.88 8.44 111.31 11.24 18.37 578.31 31.86
46.86 217.11 144.43 41.74 157.12 98.37 1.15 32.66 28.26 96.18 103.57 80.45 122.30 1338.10 14.25
11.00 27.72 24.00 10.63 84.53 12.37 1.08 26.03 6.75 8.81 7.66 11.48 17.76 527.21 25.03
0.53 0.13 0.77 0.50 0.68 0.35 0.98 0.89 0.27 0.51 0.33 0.52 0.05 0.01 0.81
SD, standard deviation; LDL, low density lipoprotein; HDL, high density lipoprotein; ALT, alanine aminotransferase; BMI, body–mass index.
intervention group consuming 1636.29 calories per day in comparison to 1338.10 calories daily in the control group. T3 c Table 3 compares the means of the baseline characteristics of the study participants who completed the trial with those who were lost to follow-up. It show that patients in both the groups were similar in age, total cholesterol, LDL cholesterol, HDL cholesterol, serum triglycerides, fasting blood sugar, serum creatinine, serum ALT, BMI, waist and hip measurement, diastolic and systolic blood pressure, calorie intake, and average daily exercise. T4 c Table 4 shows the differences in lipid levels and other indicators of study participants by treatment group, at the end of follow-up. The total serum cholesterol was 188.95 and 199.64 mg=dL in the intervention and control arms, respectively. The LDL cholesterol was 128.03 and 133.21 mg=dL in the intervention and control arms, respectively. The HDL cholesterol was 35.87 and 36.07 mg=dL in the intervention and control arms, respectively. The serum triglycerides were
140.24 and 157.76 mg=dL in the intervention and control arms, respectively. The fasting blood sugar was 86.01 and 90.27 mg=dL in the intervention and control arms, respectively. The serum creatinine was 1.04 and 1.08 mg=dL in the intervention and control arms, respectively. Serum ALT was 43.82 and 40.43 mg=dL in the intervention and control arms, respectively. BMI was 27.13 and 28.08 kg=m2 in the intervention and control arms, respectively. Waist measurements were 93.11 and 92.92 cm in the intervention and control arms, respectively. Hip measurements were 101.22 and 100.41 cm in the intervention and control arms, respectively. Diastolic BP was 80.87 and 79.12 mm Hg in the intervention and control arms, respectively. Systolic BP was 115.39 and 116.97 mm Hg in the intervention and control arms, respectively. The calorie intake was 1316.02 and 1482.24 calories daily in the intervention and control arms, respectively.
Table 3. Comparison of Baseline Characteristics of Study Participants by Loss to Follow-up and Completed Follow-up (n ¼ 117) Completed follow-up n ¼ 73 Characteristics Age (in years) Total cholesterol (mg=dL) LDL (mg=dL) HDL (mg=dL) Triglycerides (mg=dL) Fasting blood sugar (mg=dL) Serum creatinine (mg=dL) BMI Diastolic BP (mm Hg) Systolic BP (mm Hg) Calorie intake Average daily exercise (in minutes)
Loss to follow-up n ¼ 44
Mean
SD
Mean
SD
p-value
45.58 211.52 143.17 41.31 162.61 97.00 1.01 28.01 79.63 123.74 1500.15 17.17
10.61 29.65 24.52 9.76 89.38 15.19 0.16 4.47 10.30 16.28 545.15 31.73
47.25 215.41 148.37 40.81 156.23 97.11 1.39 27.15 83.74 129.07 1475.86 11.19
11.42 26.23 21.72 9.44 54.13 14.25 1.73 6.85 12.59 21.08 619.12 22.40
0.42 0.48 0.26 0.79 0.67 0.97 0.07 0.41 0.06 0.13 0.83 0.28
SD, standard deviation; LDL, low density lipoprotein; HDL, high density lipoprotein; BMI, body–mass index; BP, blood pressure.
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Table 4. Differences in Lipid Levels and Other Indicators of Study Participants by Treatment Group (n ¼ 73) Intervention (n ¼ 39) Characteristics Total cholesterol (mg=dL) LDL (mg=dL) HDL (mg=dL) Triglycerides (mg=dL) Fasting blood sugar (mg=dL) Serum creatinine (mg=dL) ALT (mg=L) BMI Waist (cm) Hip circumference (cm) Diastolic BP (mm Hg) Systolic BP (mm Hg) Caloric intake Average daily exercise (in minutes)
Control (n ¼ 34)
Mean
SD
Mean
SD
p value
188.95 128.03 35.87 140.24 86.01 1.04 43.82 27.13 93.11 101.22 80.87 115.39 1316.02 24.67
20.37 18.02 8.48 58.09 18.36 0.17 32.82 3.50 7.23 6.43 11.39 12.65 452.77 39.15
199.64 133.21 36.07 157.76 90.27 1.08 40.43 28.08 92.92 100.41 79.12 116.97 1482.24 15.50
27.30 20.90 9.13 90.71 23.78 0.18 23.43 5.59 11.42 10.22 8.57 13.58 693.06 14.45
0.06 0.27 0.92 0.33 0.39 0.35 0.63 0.39 0.93 0.69 0.47 0.61 0.23 0.20
SD, standard deviation; LDL, low density lipoprotein; HDL, high density lipoprotein; ALT, alanine aminotransferase; BMI, body–mass index; BP, blood pressure.
Average daily exercise was 24.67 and 15.50 minutes daily in the intervention and control arms, respectively. Discussion This was a pilot study. A robust and strong study design was selected to establish causal relationship between an intervention and its effect. The sample size was restricted to a small number, because it was realized that a pilot study on a small group of patients should be undertaken before subjecting a larger group of patients to the interventional product. Since prior data on safety and tolerability of the drug was limited, it was decided to first undertake a pilot study. We had decided to recruit 40 patients in each group and recruitment was carried out keeping this point in mind. It was decided that we would go for a full study with larger sample size if the results of this pilot study were encouraging. Loss to follow-up was considerable in both the interventional and control groups, but the baseline characteristics of patients who completed the study and those who were lost to follow-up were similar. Despite such limitations, very useful data were collected to form the basis for a larger trial in future. It is important to note that the baseline sociodemographic characteristics of patients in interventional and control groups were similar. Statistically significant difference ( p 0.01) was observed in calorie intake, with the intervention group consuming 1636.29 calories per day in comparison to 1338.10 calories daily in the control group. This difference was removed during follow-up, with 1316.02 and 1482.24 calories being consumed daily by the interventional and control groups, respectively. It is important to note that at the end of follow-up, a favorable impact on total cholesterol, LDL cholesterol, serum triglycerides, and fasting blood sugar was observed in the intervention group in comparison to the control group. The difference was not statistically significant because of small sample size. No adverse effect on liver and kidney was observed as evidenced by normal liver and renal function tests.
No significant effect of interventional product was observed on both systolic and diastolic blood pressure. This could be because of small sample size as well as short duration of intervention. BMI showed a favorable result in the interventional group in comparison to the control group, but both waist and hip measurements were slightly higher in the interventional group, a finding difficult to explain. Since the interventional product is claimed to cause reduce appetite, a reduction in BMI is expected. Average daily exercise was 24.67 and 15.50 minutes daily in the intervention and control arms, respectively. This difference in exercise may explain the favorable results observed on blood sugar, lipid profile, and BMI. The results of the study do not prove effectiveness of powdered N. sativa seed in capsule on serum lips, blood sugar, and BMI due to small sample size and loss to followup of a large number of study subjects. It demonstrates the safety and tolerability of the interventional product, opening opportunity for a larger trial on similar lines. Conclusions Favorable impact of powdered N. sativa (Kalonji) seed in capsule was noted on almost all variable, but results were not statistically significant. A full study with adequate sample size is recommended. Acknowledgments The authors acknowledge with thanks a grant of US $7,500 given by University Research Council (URC), Aga Khan University for conduct of the trial. We acknowledge with thanks, the time given and information provided by the study participants. The ClinicalTrials.gov Identifier for this study is NCT00327054. Author Disclosure Statement No competing financial interests exist.
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Authors’ contributions The research project was conceived, developed, and its conduct supervised by the Principal Investigator. The Co-Investigators collected the data and entered into the computer software programs for analysis. The Principal Investigator took the lead in manuscript writing with input from Co-Investigators. The fourth co-author provided statistical support. References 1. Dennis B, Aziz K, She L, et al. High rates of obesity and cardiovascular disease risk factors in lower middle class community in Pakistan: The Metroville Health Study. J Pak Med Assoc 2006;56:267–272. 2. Razak F, Anand SS, Shannon H, et al. Defining obesity cut points in a multiethnic population. Circulation 2007;115: 2111–2118. 3. Jafar TH, Jafary FH, Jessani S, Chaturvedi N. Heart disease epidemic in Pakistan: Women and men at equal risk. Am Heart J 2005;150:221–226. 4. Khan MA. Chemical composition and medicinal properties of Nigella sativa Linn. Inflammopharmacology 1999;7:15–35. 5. Schmall R. The secret of the black seed: An ancient healing remedy for the modern healer. Beginnings 2007;27:14–15. 6. Le PM, Benhaddou-Andaloussi A, Elimadi A, et al. The petroleum ether extract of Nigella sativa exerts lipid-lowering and insulin-sensitizing actions in the rat. J Ethnopharmacol 2004;94:251–259. 7. Aslam M. Guidelines for cultivation, collection, conversation and propagation of medicinal herbs. Online document
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at: www.pakistan.gov.pk=divisions=food-division=media= Guidlines%20book.pdf Accessed November 21, 2008. Tissera MHA. Effective reduction of serum cholesterol by baraka oil (oil of Nigella sativa). (Accessed: December 13, 2007). Online document at: http:==barakaoil.org=reduction cholesterol.php Tissera MHA. Effect of baraka oil (oil of Nigella sativa) on Blood sugar in persons with hyperglycemia. Online document at: http:==barakaoil.org=persons_hyperglycemia.php Accessed December 13, 2007. Ali BH, Blunden G. Pharmacological and toxicological properties of Nigella sativa. Phytother Res 2003;17:299–305. Qidwai W, Azam SI, Ali SS, Ayub S. The utilization of services of health care providers among patients presenting to family physicians at a teaching hospital in Karachi, Pakistan. J Pak Med Assoc 2002;52:269–272. Malik IA, Gopalan S. Use of CAM results in delay in seeking medical advice for breast cancer. Eur J Epidemiol 2003;18: 817–822.
Address reprint requests to: Waris Qidwai, M.C.P.S., F.C.P.S. Department of Family Medicine The Aga Khan University Stadium Road P.O. Box 3500 Karachi 74800 Pakistan E-mail:
[email protected]
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AUTHOR QUERY FOR ACM-2008-0367-QIDWAI AU1: In Table 1, spell out ‘‘Matric’’ and ‘‘Inter’’
