|Year : 2012 | Volume
| Issue : 2 | Page : 73-80
Effect of Nigella sativa on hemodynamics, hemoglobin, and blood coagulation in patients with type 2 diabetes
Fatma M. Lebda1, Abdullah O. Bamosa1, Huda Kaatabi1, Abdulmohsen Al Elq2, Ali Al-Sultan2
1 Department of Physiology, College of Medicine, Dammam University, Dammam, Saudi Arabia
2 Department of Internal Medicine, College of Medicine, Dammam University, Dammam, Saudi Arabia
|Date of Submission||29-Nov-2011|
|Date of Acceptance||10-Jan-2012|
|Date of Web Publication||23-Jun-2014|
Abdullah O. Bamosa
Department of Physiology, College of Medicine, Dammam University, PO Box 2114, Dammam 31451
Source of Support: None, Conflict of Interest: None
This study aimed to determine the efficacy of a Nigella sativa (NS) seed supplement on hemodynamics, hemoglobin (Hb) levels, and blood coagulation in patients with type 2 diabetes mellitus.
This study included 94 patients who were divided randomly into three dose groups. Capsules containing NS seeds were administered orally at a dose of 1, 2, and 3 g/day for 12 weeks. In all patients, the hemodynamic markers [systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate (HR), and rate pressure product (RPP)], Hb levels, and coagulation markers (prothrombin time, partial thromboplastin time, fibrinogen levels, and platelet count) were determined before treatment and after 4, 8, and 12 weeks.
Patients receiving 1 g/day NS for 12 weeks (group 1) showed nonsignificant changes in the hemodynamic parameters, whereas patients who received a supplement of 2 g/day NS (group 2) showed a significant reduction in the systolic blood pressure, diastolic blood pressure, mean arterial pressure, HR, and rate pressure product, compared with the baseline values. An increase in the NS dose to 3 g/day exerted less effect on the blood pressure and reversed the effect on HR. The Hb levels decreased slightly, but significantly in the three groups. Partial thromboplastin time showed a significant increase in group 2 at the end of the treatment period and a nonsignificant increase in groups 1 and 3 throughout the treatment period. However, the fibrinogen levels increased significantly in groups 2 and 3 compared with the baseline values.
Ingestion of 2 g/day NS seeds for 12 weeks exerted a favorable impact on the hemodynamic parameters. However, NS should be administered with caution in diabetic patients with anemia.
Keywords: blood coagulation, blood pressure, heart rate, hemodynamic, hemoglobin content, Nigella sativa, type 2 diabetes mellitus
|How to cite this article:|
Lebda FM, Bamosa AO, Kaatabi H, Al Elq A, Al-Sultan A. Effect of Nigella sativa on hemodynamics, hemoglobin, and blood coagulation in patients with type 2 diabetes. Egypt J Haematol 2012;37:73-80
|How to cite this URL:|
Lebda FM, Bamosa AO, Kaatabi H, Al Elq A, Al-Sultan A. Effect of Nigella sativa on hemodynamics, hemoglobin, and blood coagulation in patients with type 2 diabetes. Egypt J Haematol [serial online] 2012 [cited 2022 Dec 6];37:73-80. Available from: http://www.ehj.eg.net/text.asp?2012/37/2/73/135058
| Introduction|| |
Hypertension 1 and a prothrombotic state 2 are associated with higher incidences of cardiovascular diseases (CVDs) in patients with type 2 diabetes mellitus (T2 DM). Hypertension affects 20–60% of patients with diabetes 3. T2 DM, and primarily increased systolic blood pressure (SBP), significantly worsens patient prognosis with respect to microvascular and macrovascular complications 4. Conversely, control of blood pressure may decrease diabetes-related death and cardiovascular events 5.
It is noteworthy that up to 75% of CVD in patients with diabetes may be attributed to hypertension, leading to recommendations for more aggressive control of blood pressure in patients with coexistent diabetes and hypertension 6. Although many efforts have been made to reduce blood pressure in diabetic patients, the results are still unsatisfactory. In contrast, an increase in prothrombotic risk 7 and adverse effects on the coagulation cascade and platelet function 8 have been observed in patients with T2 DM.
Nigella sativa (NS) seeds have been used as a natural remedy for a variety of illnesses, including hypertension and diabetes 9, and no complications caused by NS have been observed 10. The few studies available have indicated that NS seed extract have blood pressure-lowering effects in spontaneously hypertensive rats 11 and in patients with mild hypertension 10, whereas powdered NS seeds have shown a nonsignificant favorable impact on blood pressure, fasting blood sugar level, and serum lipids in adults 12.
NS treatment decreased the elevated heart rate (HR) and glucose concentration of alloxan-induced diabetic rabbits 13 and also reduced the HR and contractility of isolated guinea-pig heart 14, in contrast to increased HR and enhanced cardiac inotropy in isolated perfused hearts of NS-treated rats 15.
The effect of NS on blood coagulability is controversial. Some investigators have reported a reduction in both bleeding and clotting times and inhibition of fibrinolytic activity induced by NS treatment in rats 16. Other studies, also in rats, have reported transient anticoagulant and coagulant effects 17. However, an in-vitro study observed inhibitory effects on platelet aggregation and blood coagulation 18. It was suggested that NS oil modulates the balance of fibrinolysis/thrombus formation by altering the fibrinolytic potential of endothelial cells 19.
In view of the above data, this study was carried out to determine the efficacy of an NS seed supplement on hemodynamics, hemoglobin (Hb) level, and blood coagulation in patients with T2 DM.
| Patients and methods|| |
This study was carried out on 94 patients (43 men and 51 women) with uncontrolled T2 DM. Patients were enrolled from the King Fahad University Hospital and the Al-Agharabia Primary Health Care Center, Al-Khobar, Saudi Arabia. Diabetes was diagnosed according to the latest criteria of the American Diabetes Association for the diagnosis of diabetes mellitus 20. The diagnosis of uncontrolled diabetes was made on the basis of two successive readings of HbA1c of more than 7%, taken 3 months apart. The patients included were 18–60 years of age, treated only with oral hypoglycemic drugs (sulfonylurea, biguanide, and/or thiazolidinedione), who agreed to regular follow-up, and had HbA1c more than 7%. Patients were excluded if they had chronic cardiac illness (ischemic heart disease, heart failure, and cardiac arrhythmias), chronic liver disease (active hepatitis and liver cirrhosis), renal complications, and any other chronic depleting illness. Patients were also excluded if they showed less than 90% compliance with NS medication and if their standard medications were changed during the 12 weeks of the study. All patients were fully informed about the purpose and the duration of the study and they were free to leave the study at any time. Written informed consent was obtained from all the participants. The study was approved by the research ethics committee of King Faisal University (Dammam, reference number KFU-LEC-132).
NS seeds (Bioextract Pvt Ltd, Colombo, Sri Lanka) were provided in the form of capsules. Each capsule contained 500 mg of grounded NS. Recruited T2 DM patients who fulfilled the above criteria were randomly divided into three groups and were administered three different oral doses of NS (1, 2, and 3 g/day for 12 weeks). These doses were selected on the basis of a previous study carried out on healthy human volunteers, in which a daily ingestion of 2 g NS was effective in reducing blood glucose following 1 week of administration 21.
All patients in the three groups were subjected to history taking, physical examination, laboratory investigations, and self-monitoring of blood glucose. Hemodynamic markers [SBP, diastolic blood pressure (DBP), mean arterial pressure (MAP), HR, and rate pressure product (RPP)], Hb levels, and coagulation markers [prothrombin time (PT), partial thromboplastin time (PTT), platelet count, and fibrinogen levels] were assessed for all patients before the initiation of treatment (baseline) and after 4, 8, and 12 weeks. During the first 2 weeks of administration of NS, patients were contacted daily by telephone and it was enquired whether they had any new symptoms and were asked about compliance with medications. They were also asked to report any change in their medication or lifestyle throughout the study. Patients were asked not to smoke or engage in physical activity for 30 min before the above measurements and drawing of blood.
Determination of hemodynamic markers
Blood pressure levels were measured in the sitting position with the arm supported at the level of the heart, after 10 min of rest, with a mercury sphygmomanometer by the auscultatory method. Blood pressure readings were based on the average of two independent measurements. HR at rest was determined by counting the radial pulse for 1 min. The mean arterial pressure (the diastolic pressure+1/3 pulse pressure) and RPP (the product of HR and SBP divided by 100) were calculated.
Blood samples were collected, after a 12-h overnight fasting, into EDTA tubes to prevent clotting. One blood sample was used immediately for the automatic determination of the platelet count and Hb levels using the coulter system (Beckman Coulter Company, Miami, Florida, USA). The other blood sample was centrifuged at 3000 rpm for 8 min to separate plasma, and then the plasma was kept on melting ice, until used within 2 h for the determination of PT, PTT, and fibrinogen levels, manually, using the kits provided by the Dade Behring Company, Siemens Healthcare Diagnostics Inc., Benedict, Germany. All assays were carried out according to the manufacturer’s instructions.
Statistical analysis was performed using the statistical package of social science (SPSS) version 11 (SPSS Inc., Chicago, Illinois, USA). Data were presented as mean±SEM. All experimental results were compared with their own baseline values using a paired Student’s t-test. The corresponding parameters in the three groups (presented as mean±SEM of the values as percentages of the baseline values, considering the baseline values equal to 100) were compared using a one-way analysis of variance (ANOVA) test, followed by the least significant difference multiple range test to determine the intergroup significance. A P value of less than 0.05 was considered significant.
| Results|| |
Among the 94 patients recruited, 13 were excluded because of less than 90% compliance with the treatment, seven were excluded because of a change in the antidiabetic medications, and nine were lost to follow-up. None of the studied individuals had side effects that necessitated the discontinuation of NS treatment. [Table 1] presents the baseline characteristics of the study population. Age and duration of diabetes were nonsignificantly different between the three groups, except for age, which was significantly lower in group 3 compared with group 2, using ANOVA.
|Table 1: Number of patients, age, duration of diabetes, dose of Nigella sativa, and duration of supplementation in three groups of patients with type 2 diabetes mellitus|
Click here to view
Effect of Nigella sativa seeds on the hemodynamic parameters and hemoglobin content in patients with type 2 diabetes mellitus
Patients supplied with 1 g/day NS for 12 weeks (group 1) showed no significant change in the hemodynamic parameters studied. However, 2 g/day NS supplementation in group 2 patients resulted in a significant reduction in SBP, MAP, and RPP throughout the 12-week treatment period. SBP decreased by 6.9, 3.6, and 6.5%, whereas MAP decreased by 6.4, 3.8, and 5.8% after 4, 8, and 12 weeks, respectively, compared with the baseline values. Meanwhile, DBP reduced significantly by 4.9 and 3.9% after 4 and 12 weeks, respectively. HR decreased during the treatment duration; yet, the decrease (3.4%) was significant only after 4 weeks, as compared with the corresponding baseline values [Table 2].
|Table 2: Mean±SEM of systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, heart rate, rate pressure product, and hemoglobin levels, in type 2 diabetes mellitus patients, treated with Nigella sativa, 1 g/day (group 1), 2 g/day (group 2), and 3 g/day (group 3), for 12 weeks, compared with the corresponding baseline values|
Click here to view
However, it was found that supplementation of NS at a dose of 3 g/day (group 3) reduced SBP, DBP, MAP, and RPP throughout the treatment duration, decreasing SBP significantly by 5.3% and MAP by 4.0% after 12 weeks, decreasing nonsignificantly otherwise. In contrast, there was a significant increase in HR by 3.4 and 4.8% after 4 and 8 weeks of treatment, respectively, compared with the corresponding baseline data [Table 2].
On comparing the corresponding data among the three groups by ANOVA, it was found that MAP decreased significantly in group 2 compared with group 1 after 8 and 12 weeks of treatment, whereas HR decreased significantly in group 2 after 4 weeks when compared with group 1 and throughout the treatment period when compared with group 3. Meanwhile, the Hb levels declined in the three treatment groups, being statistically significant after 12 weeks in group 1 and after 8 and 12 weeks in group 2, and after 4 and 12 weeks in group 3, compared with the baseline values. Also, Hb decreased nonsignificantly in the three groups, except in group 3, in which Hb decreased significantly after 4 weeks, compared with group 1, indicating a dose-dependent effect [Table 2] and [Figure 1].
|Figure 1: Changes in the mean arterial pressure (MAP), heart rate (HR), and hemoglobin (Hb) content in patients with type 2 diabetes who received 1 g/day (group 1), 2 g/day (group 2), and 3 g/day (group 3) of Nigella sativa for 12 weeks. The corresponding parameters in the three groups were compared using analysis of variance. Data are mean±SEM of the values as percentages of the corresponding baseline values, considering that baseline values equal 100. aSignificance of difference between groups 2 and 1 (P<0.05), bsignificance of difference between groups 3 and 1 (P<0.05), csignificance of difference between groups 2 and 3 (P<0.05).|
Click here to view
Effect of Nigella sativa seeds on blood coagulation in patients with type 2 diabetes mellitus
PT and the platelet count did not change significantly in the three groups, whereas PTT was increased significantly by 2.99% after 12 weeks in group 2 patients and increased nonsignificantly during the entire treatment period in patients of groups 1 and 3 compared with the baseline data. However, fibrinogen levels increased significantly in group 2 by 14.15 and 14.8%, after 8 and 12 weeks, respectively, and in group 3 by 15.2% after 12 weeks of treatment, and were nonsignificantly changed otherwise, compared with the baseline data [Table 3]. In addition, the coagulation parameters were nonsignificantly changed among the three groups, except in group 2, in which PTT had reduced significantly after 8 weeks and fibrinogen increased significantly after 12 weeks of treatment, compared with group 1 [Figure 2].
|Table 3: Mean±SEM of prothrombin time, partial thromboplastin time, platelet count, and fibrinogen levels, in type 2 diabetes mellitus patients, treated with Nigella sativa, 1 g/day (group 1), 2 g/day (group 2), and 3 g/day (group 3), for 12 weeks, compared with the corresponding baseline values|
Click here to view
|Figure 2: Changes in the partial thromboplastin time (PTT), prothrombin time (PT), platelet count, and fibrinogen level, in patients with type 2 diabetes who received 1 g/day (group 1), 2 g/day (group 2), and 3 g/day (group 3) of Nigella sativa for 12 weeks. The corresponding parameters in the three groups were compared using analysis of variance. Data are mean±SEM of the values as percentages of the corresponding baseline values, considering that baseline values equal 100. aSignificance in difference between groups 2 and 1 (P<0.05), bsignificance in difference between groups 3 and 1 (P<0.05), csignificance in difference between groups 2 and 3 (P<0.05).|
Click here to view
| Discussion|| |
Effects of Nigella sativa seeds on hemodynamics and hemoglobin content in patients with type 2 diabetes mellitus
In the current study, patients with diabetes who received 1 g/day NS for 12 weeks showed nonsignificant changes in the hemodynamic parameters, whereas patients who received NS at a dose of 2 g/day showed a significant decrease in SBP, DBP, MAP, HR, and RPP, compared with the corresponding baseline values, in addition to a significant decrease in MAP and HR, compared with group 1. Supplementation of NS at a dose of 3 g/day led to improved SBP, DBP, MAP, and RPP throughout the treatment duration, despite the prominent increase in HR, compared with the baseline data.
It is noteworthy that despite the dose-dependent significant decrease in the Hb level following NS treatment with the three doses, the Hb level was still within the normal range for adults. Therefore, NS seeds should be administered with caution in diabetic patients with anemia. This finding, however, is in contrast to the previously reported increase in the red blood cell count to the control level in NS-treated alloxan-induced diabetic rabbits 13.
The clear, persistent hypotensive effect of 2 g/day NS seeds relative to the baseline level and to that induced by 1 g/day NS is seemingly in agreement with earlier studies that showed a reduction in blood pressure in normal 22 or spontaneously hypertensive 11 rats.
An analysis of the United Kingdom Prospective Diabetes Study showed that any reduction in SBP is likely to reduce the risk of complications in patients with T2 DM 23,24. A 10 mmHg (6.5%) reduction in SBP was associated with an 11% reduction in any diabetes-related endpoint, including stroke and myocardial infarction 24. Accordingly, the moderate but significant decreases in SBP by 6.9 and 6.5% after 4 and 12 weeks of 2 g/day NS supplementation, observed in the current study, may also have clinical significance.
As MAP is determined by the cardiac output and the total peripheral resistance, the observed decline in MAP, might be, at least partly, because of the cardiac inhibitory effect of NS, evidenced by the decreased HR and SBP (index of stroke volume) in the present study with 2 g/day NS. In agreement with this, a potent inhibitory effect of NS on both HR and contractility was shown in isolated guinea-pig heart 14.
Meanwhile, the decreased HR observed with 2 g/day NS supplementation indicates a favorable cardiovascular outcome, as HR is mainly considered a secondary result of sympathetic stimulation reflecting the severity of pre-existing CVD, which was reversible after interventional lowering of the HR 25. Similar to our results, previous studies have found a decreased HR; one study indicated that the HR-reducing effect of NS oil occurred through the activation of cholinergic mechanisms 22, whereas another study attributed the decreased HR to a normalized red blood cell count in NS-treated rabbits, thus inhibiting the increased sympathetic output produced by diabetes-induced anemia 13.
It is known that the product of HR and SBP is used as an index for the level of oxygen consumption by a cardiac muscle 26. The decrease in RPP observed herein implies a reduction in the myocardial oxygen demand under basal conditions in T2 DM patients receiving 2 g/day NS. This decrease in oxygen consumption might be because of the expected decline in the cardiac workload in response to the reduced after-load resistance, induced by the observed decrease in SBP and MAP. These findings reflect economic cardiac mechanics under basal conditions as a consequence of NS seed treatment.
Effects of Nigella sativa seeds on blood coagulation in patients with type 2 diabetes mellitus
In the current study, PT and platelet count were nonsignificantly changed in the three groups, whereas there was a significant increase in PTT in group 2 at the end of the treatment period and a nonsignificant increase in groups 1 and 2 throughout the treatment period compared with the baseline values. In addition, PTT was significantly reduced after 8 weeks of treatment in group 2, compared with group 1, indicating that the increased PTT with the three doses of NS was not dose dependent. However, the fibrinogen level increased significantly following 2 and 3 g/day NS supplementation compared with the baseline values.
An earlier report had shown a significant increase in factors VIII, IX, and XII (markers of the intrinsic pathway of the clotting cascades) and not factor VII in T2 DM patients 7. Besides, the increase in PTT and not PT, observed herein, on administration of NS seeds, suggests a trend toward an antithrombotic effect related to inhibition of the intrinsic pathway of the clotting mechanism.
It has been suggested that improvements in glycemic control 27 and reduction in insulin resistance 28 in patients with diabetes may reduce their tendency to develop thrombosis. In addition, high-density lipoprotein cholesterol levels have been inversely correlated with thrombosis and have been shown to mediate various antithrombotic effects 29. On the basis of the above data, the trend toward a favorable impact on blood coagulability observed in the current study may be attributed to improved hyperglycemia and insulin resistance 30, and/or increased high-density lipoprotein cholesterol 31, mediated by the antioxidant effects of the supplemented NS seeds.
The majority of studies have reported plasma fibrinogen levels to be increased in T2 DM 32,33. A correlation exists between plasma fibrinogen levels and glycemic control 34, although intensive treatment to improve glycemic control does not consistently result in a reduction in fibrinogen levels 35. Accordingly, despite the significant reduction in the blood glucose level and insulin resistance following NS treatment in T2 DM patients 30, the apparent increase in the fibrinogen levels following 2 and 3 g/day NS supplementation in the current study may be attributed to the direct stimulation of fibrinogen synthesis by the liver exceeding the reduction in the fibrinogen levels because of an improvement in glycemic control. The administration of NS has been shown to prevent liver damage and to increase the antioxidant defense system activity in experimentally induced diabetic rabbits 36. Besides, fibrinogen and albumin are important indicators of the synthetic function of the liver 37. Therefore, the increased fibrinogen level in the present study may also be attributed to the suppression of liver damage with an improvement in liver synthetic function through the antioxidant activity of NS seeds. However, this increase in the fibrinogen level may increase the risk of thrombosis. This is an interesting area that should be further investigated to determine the overall effect of NS on the coagulation process.
In conclusion, ingestion of 2 g/day NS seeds for 12 weeks showed a favorable impact on the hemodynamic parameters. However, NS should be administered with caution in diabetic patients with anemia. Further placebo-controlled clinical trials are required to confirm the results of this study.
This study was supported by a grant from King Abdul-Aziz City for Science and Technology, Ryiadh, Saudi Arabia.
| References|| |
|1.||Anderson RJ, Bahn GD, Moritz TE, Kaufman D, Abraira C, Duckworth W. Blood pressure and cardiovascular disease risk in the Veterans Affairs Diabetes Trial. Diabetes Care. 2011;34:34–38 |
|2.||Jax TW, Peters AJ, Plehn G, Schoebel FC. Relevance of hemostatic risk factors on coronary morphology in patients with diabetes mellitus type 2. Cardiovasc Diabetol. 2009;8:24–31 |
|3.||Arauz Pacheo C, Parrott MA, Raskin P. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26(Suppl. 1):S80–S82 |
|4.||Souček M. Hypertension in patients with diabetes mellitus. Vnitr Lek. 2010;56:995–999 |
|5.||Turner R, Holman R, Stratton I, Cull C, Frighi V, Manley S, et al. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J. 1998;317:703–713 |
|6.||Sowers JR, Frohlich ED. Insulin and insulin resistance: impact on blood pressure and cardiovascular disease. Med Clin North Am. 2004;88:63–82 |
|7.||Barillari G, Fabbro E, Pasca S, Bigotto E. Coagulation and oxidative stress plasmatic levels in a type 2 diabetes population. Blood Coagul Fibrinolysis. 2009;20:290–296 |
|8.||Mafrici A, Proietti R. Atherothrombosis in patients with type 2 diabetes mellitus: an overview of pathophysiology. G Ital Cardiol. 2010;11:467–477 |
|9.||Ali BH, Blunden G. Pharmacological and toxicological properties of Nigella sativa. Phytother Res. 2003;17:299–305 |
|10.||Dehkordi FR, Kamkhah AF. Antihypertensive effect of Nigella sativa seed extract in patients with mild hypertension. Fundam Clin Pharmacol. 2008;22:447–452 |
|11.||Zaoui A, Cherrah Y, Lacaille Dubois MA, Settaf A, Amarouch H, Hassar M. Diuretic and hypotensive effects of Nigella sativa on the spontaneously hypertensive rat. Therapie. 2000;55:379–382 |
|12.||Qidwai W, Hamza HB, Qureshi R, Gilani A. 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. J Altern Complement Med. 2009;15:639–644 |
|13.||Meral I, Donmez N, Baydas B, Belge F, Kanter M. Effect of Nigella sativa L. on heart rate and some haematological values of alloxan-induced diabetic rabbits. Scand J Lab Anim Sci. 2004;31:49–53 |
|14.||Boskabady MH, Shafei MN, Parsaee H. Effects of aqueous and macerated extracts from Nigella sativa on Guinea pig isolated heart activity. Pharmazie. 2005;60:943–948 |
|15.||El Bahai MN, Al Hariri MT, Yar T, Bamosa AO. Cardiac inotropic and hypertrophic effects of Nigella sativa supplementation in rats. Int J Cardiol. 2009;131:e115–e117 |
|16.||Ghoneim MT, El Gindy AR, El Alami R, Shoukry E, Yaseen S Possible effect of some extracts of Nigella sativa L. seeds on blood coagulation system and fibrinolytic activity. Proceedings of the Second International Conference on Islamic Medicine, November 1982; Kuwait; 1982: 528–535 |
|17.||Al Jishi SA, Abuo Hozaifa B. Effect of Nigella sativa on blood hemostatic function in rats. J Ethnopharmacol. 2003;85:7–14 |
|18.||Enomoto S, Asano R, Iwahori Y, Narui T, Okada Y, Singab ANB, et al. Hematological studies on black cumin oil from the seeds of Nigella sativa L. Biol Pharm Bull. 2001;24:307–310 |
|19.||Awad EM, Binder BR. In vitro induction of endothelial cell fibrinolytic alterations by Nigella sativa. Phytomedicine. 2005;12:194–202 |
|20.||Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26:3160–3167 |
|21.||Bamosa AO, Ali BA, Sowayan SA. Effect of oral ingestion of Nigella sativa seeds on some blood parameters. Saudi Pharm J. 1997;5:126–129 |
|22.||El Tahir KEH, Ashour MMS, Al Harbi MM. The cardiovascular actions of the volatile oil of the black seed (Nigella sativa) in rats: elucidation of the mechanism of action. Gen Pharmacol. 1993;24:1123–1131 |
|23.||Adler AI, Stratton IM, Neil HAW, Yudkin JS, Matthews DR, Cull CA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. Br Med J. 2000;321:412–419 |
|24.||Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HAW, Holman RR. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia. 2006;49:1761–1769 |
|25.||Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science. 1984;226:180–182 |
|26.||Baller D, Bretschneider HJ, Hellige G. A critical look at currently used indirect indices of myocardial oxygen consumption. Basic Res Cardiol. 1981;76:163–181 |
|27.||Osende JI, Badimon JJ, Fuster V, Herson P, Rabito P, Vidhun R, et al. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control. J Am Coll Cardiol. 2001;38:1307–1312 |
|28.||Wannamethee SG, Lowe GDO, Shaper AG, Rumley A, Lennon L, Whincup PH. Insulin resistance, haemostatic and inflammatory markers and coronary heart disease risk factors in type 2 diabetic men with and without coronary heart disease. Diabetologia. 2004;47:1557–1565 |
|29.||Doggen CJM, Smith NL, Lemaitre RN, Heckbert SR, Rosendaal FR, Psaty BM. Serum lipid levels and the risk of venous thrombosis. Arteriosc Thromb Vasc Biol. 2004;24:1970–1975 |
|30.||Bamosa AO, Kaatabi H, Lebda FM, Al Elq AM, Al Sultan A. Effect of Nigella sativa seeds on the glycemic control of patients with type 2 diabetes mellitus. Indian J Physiol Pharmacol. 2010;54:344–354 |
|31.||Kocyigit Y, Atamer Y, Uysal E. The effect of dietary supplementation of Nigella sativa L. on serum lipid profile in rats. Saudi Med J. 2009;30:893–896 |
|32.||Asakawa H, Tokunaga K, Kawakami F. Elevation of fibrinogen and thrombin-antithrombin III complex levels of type 2 diabetes mellitus patients with retinopathy and nephropathy. J Diabetes Complications. 2000;14:121–126 |
|33.||Barazzoni R, Zanetti M, Davanzo G, Kiwanuka E, Carraro P, Tiengo A, et al. Increased fibrinogen production in type 2 diabetic patients without detectable vascular complications: correlation with plasma glucagon concentrations. J Clin Endocrinol Metab. 2000;85:3121–3125 |
|34.||Jain A, Gupta HL, Narayan S. Hyperfibrinogenemia in patients of diabetes mellitus in relation to glycemic control and urinary albumin excretion rate. J Assoc Physicians India. 2001;49:227–230 |
|35.||Becker A, van der Does FEE, van Hinsbergh VWM, Heine RJ, Bouter LM, Stehouwer CDA. Improvement of glycaemic control in type 2 diabetes: favourable changes in blood pressure, total cholesterol and triglycerides, but not in HDL cholesterol, fibrinogen, von Willebrand factor and (pro)insulin. Neth J Med. 2003;61:129–136 |
|36.||Meral I, Yener Z, Kahraman T, Mert N. Effect of Nigella sativa on glucose concentration, lipid peroxidation, anti-oxidant defense system and liver damage in experimentally-induced diabetic rabbits. J Vet Med A Physiol Pathol Clin Med. 2001;48:593–599 |
|37.||Chang EB, Sitrin MD, Black DD Gastrointestinal, hepatobiliary and nutritional physiology. 1996 Philadelphia Lippincott-Raven:223–227 |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]