|Year : 2020 | Volume
| Issue : 3 | Page : 259-265
Fenofibrate and Crataegus oxyacantha is an effectual combo for mixed dyslipidemia
Huda A Rasheed, Nawar R Hussien, Marwa S Al-Naimi, Hayder M Al-Kuraishy, Ali I Al-Gareeb
Department of Pharmacology, Toxicology and Medicine, College of Medicine Almustansiriya University, Baghdad, Iraq
|Date of Submission||03-Feb-2020|
|Date of Acceptance||05-Feb-2020|
|Date of Web Publication||12-Sep-2020|
Dr. Hayder M Al-Kuraishy
Department of Pharmacology, Toxicology and Medicine, College of Medicine Almustansiriya University, P.O. Box: 14132, Baghdad
Source of Support: None, Conflict of Interest: None
Background: Dyslipidemia (DL) is a blood lipid disorder characterized by high cholesterol, triglyceride and low density lipoprotein with reduction of high density lipoprotein. Crataegus Oxyacantha hawthorn (COH) is used in treatment of hyperlipidemia , hypertension , angina pectoris and arrhythmia as alternative medicine . The aim of the present study was to evaluate the effect of fenofibrate alone or in combination with Crataegus Oxyacantha on lipid profile in patients with mixed dyslipidemia. Methods: A total number of 64 patients with MD on fenofibrate therapy compared to 24 healthy controls were recruited and randomized into three groups: Group A: (control, n = 24) not received any lipid-lowering agents, Group B: (fenofibrate, n = 30) received fenofibrate 200 mg/day for 10 weeks, and Group C: (combination, n = 34) received fenofibrate 200 mg/day plus C. oxycantha for 10 weeks. The estimation of lipid profile and blood pressure changes were done at baseline and following 10 weeks of therapy. Results: Following 10 weeks of C. oxycantha add on fenofibrate therapy, there was a significant reduction on total cholesterol, triglyceride, non-high-density lipoprotein-cholesterol AI, and low-density lipoprotein plasma levels compared with fenofibrate-treated patients (P < 0.05). Blood pressure profile showed more significant reduction in patients with dyslipidemia (DL) treated with C. oxycantha compared with baseline data and with patients with DL treated with fenofibrate alone (P < 0.05). Fenofibrate plus C. oxycantha showed more significant reduction on high-sensitive C-reactive protein serum levels from 5.28 ± 1.61 mg/dL to 2.74 ± 1.99 mg/dL, P < 0.0001. Conclusion: C. oxycantha synergized the effect of fenofibrate therapy in patients with MD through the improvement of lipid profile and attenuation of endothelial inflammation.
Keywords: Crataegus oxyacantha hawthorns, dyslipidemias, fenofibrates
|How to cite this article:|
Rasheed HA, Hussien NR, Al-Naimi MS, Al-Kuraishy HM, Al-Gareeb AI. Fenofibrate and Crataegus oxyacantha is an effectual combo for mixed dyslipidemia. Biomed Biotechnol Res J 2020;4:259-65
|How to cite this URL:|
Rasheed HA, Hussien NR, Al-Naimi MS, Al-Kuraishy HM, Al-Gareeb AI. Fenofibrate and Crataegus oxyacantha is an effectual combo for mixed dyslipidemia. Biomed Biotechnol Res J [serial online] 2020 [cited 2021 Nov 30];4:259-65. Available from: https://www.bmbtrj.org/text.asp?2020/4/3/259/294852
| Introduction|| |
Dyslipidemia (DL) is a blood lipid disorder characterized by high cholesterol, triglyceride (TG), and low-density lipoprotein (LDL) with reduction of high-density lipoprotein (HDL). DL is commonly linked with cardiovascular complications and oxidative stress. Hyperlipidemia (HL) is the most common form of DL, in which one or more of blood lipid or lipoprotein is elevated. Blood lipid disorder is due to primary causes such as receptor mutations or secondary causes as in obesity and diabetes mellitus. Increase in cholesterol level leads to atherosclerosis, increase risk of hypertension, and ischemic heart disease (IHD), whereas high TG levels could increase the risk of acute pancreatitis. Mixed dyslipidemia (MD), which is also called atherogenic dyslipidemia, is a blood lipid disorder characterized by high TG plasma levels and low HDL plasma levels. MD increases the risk of IHD and major cardiovascular events independently of LDL plasma levels.
Fenofibrate is a clofibrate derivative which activates peroxisome proliferator-activator receptor α (PPARα) used in the treatment of hypertriglyceridemia and MD through the elimination of TG-rich particles from plasma through activation of lipoprotein lipase, catabolism of TG, inhibition secretion of very LDL (VLDL), and elevation of HDL. In addition, fenofibrate modulates LDL and VLDL containing apolipoprotein. In addition, fenofibrate is effective in the management of diabetic retinopathy and reduction of cardiovascular complications.
In clinical practice, various therapeutic options including herbs are used in the management of DL. One of these herbal medicines is Crataegus oxyacantha which belongs to Rosaceae family of spiny shrubs hawthorn which is used for a long time in folk medicine for the treatment of different diseases including asthma, insomnia, and diarrhea.C. oxycantha hawthorn (COH) is also used in the treatment of HL, hypertension, angina pectoris, and arrhythmia as alternative medicine.
COH contains different active constituents including flavonoids, triterpenic acids, and phenol carboxylic acids. Vitexin and rutin are the most active flavonoid constituents which are investigated extensively in animal and human trial studies.
COH has a significant hypolipidemic effect through the reduction of ApoB synthesis, total cholesterol (TC), and LDL with significant elevation of HDL. Recently, Yang et al.'s study confirmed that COH improves lipid profile and enhances immune function and rheological blood flow in patients with atherosclerosis.
Therefore, the aim of the present study was to evaluate the effect of fenofibrate alone or in combination with C. oxycantha on lipid profile in patients with MD.
| Methods|| |
Ethical approval and informed consent
This study was permitted by the Ethical Committee and Review Board in College of Medicine in conduction with guide of the Declaration of Helsinki according to the ethical No.53YR In 2019. All enrolled controlled participants and recruited patients gave informed consent for their participation in this study regarding human care procedure.
This randomized population-based controlled prospective study was done in the Department of Clinical Pharmacology and Therapeutics in cooperation with the Department of Internal Medicine, College of Medicine, Al-Mustansiriya University, from January to July 2017, Baghdad, Iraq. A total number of 64 patients (23 females and 41 males) with MD with age range between 50 and 68 years were recruited and selected according to the Guideline of American College of Cardiology and American Heart Association, compared with 24 healthy controlled participants that recruited from medical staff members. Direct interview, full history, and physical examination were done by senior and junior doctors. Full routine investigations were recommended for each patient regarding previous investigations, dietary habits, and lifestyle modifications.
- Inclusion criteria: Patients with MD on fenofibrate therapy were included in the study
- Exclusion criteria: Any patients with severe or morbid obesity, end-stage kidney disease, liver failure, psychiatric disorders, severe anemia, connective tissue diseases, statin therapy, and malignancy were excluded from the present study.
The selected patients and healthy controlled participants were randomized into three groups
- Group A: (control, n = 24) not received any lipid-lowering agents
- Group B: (fenofibrate, n = 30) received fenofibrate 200 mg/day for 10 weeks
- Group C: (combination, n = 34) received fenofibrate (fenacore Taj, India) 200 mg/day plus C. Oxyacantha (Rucardin capsule, Ghaem Darou, Iran) 500 mg/day for 10 weeks.
Baseline data were estimated before and after 10 weeks of therapy with strict recommendations concerning dietary habits.
Biochemical and anthropometric measurements
Estimation of lipid profile: TC, TG, and HDL were measured by the auto-analyzer (ERBA diagnostic Manheim, Germany). LDL was estimated by the Friedewald equation. VLDL = TG/5, atherogenic index (AI) = log (TG/HDL), atherogenic coefficient (AC) = (TC-HDL)/HDL, cardiac risk ratio CRR = TC/HDL. High-sensitive C-reactive protein (Hs-CRP) was measured by enzyme-linked immunosorbent assay kit method (Cat. ABIN1115432, Wuhan, USCN Business, Co. Ltd, China).
Estimation of blood pressure changes: Blood pressure of each recruited patient was measured at supine position from the left arm by digital automated blood pressure monitoring 2 h apart. Pulse pressure = systolic blood pressure (SBP) − diastolic blood pressure (DBP) and mean arterial pressure (MAP),
Estimation of anthropometric variables: Body mass index (BMI) = body weight (kg)/height (m2).
The data were presented as mean ± standard deviation, and paired Student's t-test was used to determine the differences before and after therapeutic intervention. Continuous variables were evaluated by one-way analysis of variance test. Data analysis was done using the Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows version 20.0, 2014 Armonk, NY, IBM, Corp., USA). The level of significance was regarded when P < 0.05.
| Results|| |
Consort flow diagram of the present study illustrated that out of a total number of ninety enrollments, two were excluded due to noncompliance, and one patient with hypothyroidism. Therefore, only 88 participants were continued the study, as illustrated in [Figure 1].
In the present study, there was 72.72% patients with MD compared to 27, 27% healthy control. About 64.06% of the patients were male and 35.93% were female. The duration of DL was 5.87 ± 2.98 years. All patients were on fenofibrate therapy and other pharmacotherapy regarding associated diseases [Table 1]. Baseline values characterized by high lipid profile, atherogenicity, BMI, and blood pressure profile in patients with MD on fenofibrate or fenofibrate with C. oxycantha were compared with control healthy participants (P < 0.05), except on DBP which was not significantly differed in patients with MD compared with control (P > 0.05) [Table 2].
|Table 2: Baseline lipid profile and atherogenicity in patients with mixed dyslipidemia compared with controls|
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Following 10 weeks of C. oxycantha add on fenofibrate therapy, there was insignificant effect on BMI in patients and controls. C. oxycantha add on fenofibrate therapy illustrated more significant reduction on TC, TG, non-HDL-C AI, and LDL plasma levels compared with fenofibrate-treated patients and also to the baseline data (P < 0.05). However, C. oxycantha adds on fenofibrate therapy produced insignificant effect on AC and Cardiac risk ratio (CRR). Blood pressure profile showed more significant reduction in patients with MD treated with C. oxycantha compared with baseline data and with patients with MD treated with fenofibrate alone (P < 0.05), [Table 3].
|Table 3: Effect of fenofibrate and/or Crataegus oxyacantha on lipid profile and atherogenicity|
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Moreover, fenofibrate reduced Hs-CRP serum levels from 5.15 ± 2.87 mg/dL to 3.90 ± 1.85 mg/dL significantly, P = 0.04, whereas fenofibrate plus C. oxycantha showed more significant reduction on Hs-CRP serum levels from 5.28 ± 1.61 mg/dL to 2.74 ± 1.99 mg/dL, P < 0.0001, [Figure 2].
|Figure 2: Effect of fenofibrate and/or Crataegus oxycantha on high-sensitive C-reactive protein in patients with mixed dyslipidemia|
Click here to view
| Discussion|| |
It has been reported that DL is a major cause of cardiovascular disorders and complications. Different classes of hypolipidemic agents are used effectively in the treatment of DL but are associated with wide spectrum of adverse effects. In the present study, fenofibrate was effective in amelioration of DL within 10 weeks of therapy through improvement of lipid profile as reported by Tarantino et al. study that confirmed fenofibrate provides a reliable support against residual metabolic and cardiovascular risk. However, C. oxycantha adds on fenofibrate illustrated more significant effect on reduction of TC, TG, LDL, non-HDL, and AI with significant elevation of HDL-c levels due to potential hypolipidemic effects of C. oxycantha as demonstrated by a recent study. Animal model study revealed that C. oxycantha is effective in improving of lipid profile in mice fed on atherogenic diet.
Moreover, C. oxycantha reduces TC, TG, LDL-c, and LDL-c/TC ratio significantly due to potentiating the binding of LDL-c to the hepatic LDL-c receptors and inhibition of hepatic de novo cholesterol synthesis which results in the reduction of cholesterol plasma levels and risk of atherogenicity.
Beside, C. oxycantha inhibits intestinal absorption of cholesterol through downregulation of intestinal acyl CoA transferase which results in a significant reduction of TC and non-HDL-c with elevation in HDL-c. These studies certainly confirmed findings of the present study, since C. oxycantha illustrated a significant reduction on TC levels with reduction of AI.
Indeed, coadministration of C. oxycantha with fenofibrate led to significant reduction on TG levels compared with fenofibrate alone as supported by Othman et al.'s study that demonstrated a significant effect of C. oxycantha on hypertriglyceridemia in rat with MD.
It has been shown that flavonoid fraction of C. oxycantha inhibits intestinal absorption of TG and peripheral accumulation of free fatty acids and TG in adipose tissue. As well, C. oxycantha reduces TG through antioxidant effect and attenuation of oxidative stress.
Interestingly, PPARα is an important target for lipid-lowering drugs, since it concerns with hypertriglyceridemia and regulation of fatty acid β-oxidation. C. oxycantha activates and upregulates PPARα and induces β-oxidation-related enzymes which eventually lead to reduction of hypertriglyceridemia.
Therefore, the combination of fenofibrate and C. oxycantha leads to synergistic effect on the reduction of hypertriglyceridemia, since both fenofibrate and C. oxycantha activate PPARα that leads to activation of acyl-CoA oxidase-1 and carnitine palmitoyltransferase which involved in plasma lipid degradation.
Thus, findings of the present study confirmed that C. oxycantha is an alternative herbal medicine in the treatment of DL which illustrated insignificant adverse effect compared with fenofibrate alone.
It was well reported that C. oxycantha produced mild side effects without significant drug–drug interactions. These findings might explain insignificant side effect of C. oxycantha in the present study.
In addition, the present study demonstrated a significant effect of C. oxycantha in the reduction of SBP, DBP, and MAP compared with baseline and with fenofibrate alone as revealed by Kashyap et al.'s study that demonstrated the hypotensive effect of C. oxycantha which is due to attenuation of atherogenicity, hypolipidemic effect, and vasodilator effect with significant angiotensin-converting enzyme inhibition.
Entertainingly, C. oxycantha produced dose-dependent effect in the reduction of SBP, MAP, and heart rate due to activation of vascular endothelial nitric oxide and stimulation of cardiac muscarinic 2 receptor (M2), respectively.
Furthermore, findings of the present study illustrated that both fenofibrate and C. oxycantha led to a significant reduction of vascular endothelial inflammation through reduction of Hs-CRP serum levels. This effect might due to significant reduction of endothelial dysfunction in patients with DL.
Kim et al. study showed that C. oxycantha improves endothelial function through activation of adenosine triphosphate (ATP) and Ca2+-dependent K+ channels in vascular smooth muscle cells which lead to vasodilatation. In addition, procyanidins of C. oxycantha activate K+ channel in the isolated aorta in rats. Besides, long-term therapy with C. oxycantha leads to inhibition of endoplasmic and sarcoplasmic Ca2+ ATPase and inositol triphosphate-dependent endothelial vascular permeability. In addition, different active constituents of C. oxycantha have ability to inhibit prostanoid-mediated oxidative stress and endothelial dysfunction.
Much evidence proposed that DL is linked with endothelial injury and induction of endothelial inflammation through induction of different cytokines and mediators including Hs-CRP, E-selectin, tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM).
C. oxycantha attenuates endothelial inflammation through significant reduction of Hs-CRP, E-selectin, TNF-α, ICAM-1, and VCAM. This effect is occurring due to the stabilization of endothelial collagen and prevention of its degradation by leukocyte mediators. These studies may in part explain the attenuating effect of C. oxycantha on vascular endothelial inflammation.
The present study illustrated various limitations including small sample size, short duration of the prospective study, and shortage in the evaluation of endothelial function. In spite of these limitations, this study is regarded as preliminary study for future large-scale study involving dose-dependent effect. In conclusion, C. oxycantha synergized the effect of fenofibrate therapy in patients with MD through improvement of lipid profile and attenuation of endothelial inflammation.
| Conclusion|| |
C. oxycantha synergized the effect of fenofibrate therapy in patients with MD through the improvement of lipid profile and attenuation of endothelial inflammation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Le Master E, Levitan I. Endothelial stiffening in dyslipidemia. Aging (Albany NY) 2019;11:299-300.
Al-Kuraishy HM, Al-Gareeb AI. Effects of rosuvastatin on metabolic profile: Versatility of dose-dependent effect. J Adv Pharm Technol Res 2019;10:33-8.
] [Full text]
Al-Kuraishy HM, Al-Gareeb AI, Al-Buhadilly AK. Rosuvastatin improves vaspin serum levels in obese patients with acute coronary syndrome. Diseases 2018;6:9-17.
Al-Naimi MS, Rasheed HA, Al-Kuraishy HM, Al-Gareeb AI. Berberine attenuates olanzapine induced-metabolic syndrome. JPMA 2019;69:S88-92.
Xu N, Wang Q, Jiang S, Wang Q, Hu W, Zhou S, et al
. Fenofibrate improves vascular endothelial function and contractility in diabetic mice. Redox Biol 2019;20:87-97.
Benabderrahmane W, Lores M, Benaissa O, Lamas JP, de Miguel T, Amrani A, et al
. Polyphenolic content and bioactivities of Crataegus oxyacantha
L. (Rosaceae). Nat Prod Res 2019;23:1-6.
Orhan IE. Phytochemical and pharmacological activity profile of Crataegus oxyacantha
L. (Hawthorn)-A cardiotonic herb. Curr Med Chem 2018;25:4854-65.
Venskutonis PR. Phytochemical composition and bioactivities of hawthorn (Crataegus
spp.): Review of recent research advances. J Food Bioactives 2018:69-87.
Martinez-Rodriguez JL, Reyes-Estrada CA, Gutierrez-Hernandez R, Lopez JA. Antioxidant, hypolipidemic and preventive effect of Hawthorn (Crataegus oxyacantha
) on alcoholic liver damage in rats. J Pharmacognosy Phytother 2016;30;8:193-202.
Yang T, Zhang X, Pan S, Zhang X, Dang Z. Effect of hawthorn Jiangzhi powder on blood lipids in patients with hyperlipidemia: A pathological analysis of 484 cases. Chin J Integ Tradit Western Med Intensive Critical Care 2017;24:166-9.
Stone NJ, Robinson JG, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, et al
. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
Al-Kuraishy HM, Al-Gareeb AI, Waheed HJ, Al-Maiahy TJ. Differential effect of metformin and/or glyburide on apelin serum levels in patients with type 2 diabetes mellitus: Concepts and clinical practice. J Adv Pharm Technol Res 2018;9:80-6.
] [Full text]
Al-Kuraishy HM, Al-Gareeb AI. Effects of rosuvastatin alone or in combination with omega-3 fatty acid on adiponectin levels and cardiometabolic profile. J Basic Clin Pharm 2016;8:8-14.
Al-Kuraishy HM, Al-Gareeb AI, Shams HA, Al-Mamorri F. Endothelial dysfunction and inflammatory biomarkers as a response factor of concurrent coenzyme Q10 add-on metformin in patients with type 2 diabetes mellitus. J Lab Physicians 2019;11:317-22.
] [Full text]
Gazzola K, Vigna GB. Hypolipidemic drugs in elderly subjects: Indications and limits. Nutr Metab Cardiovasc Dis 2016;26:1064-70.
Tarantino N, Santoro F, Correale M, De Gennaro L, Romano S, Di Biase M, et al
. Fenofibrate and dyslipidemia: Still a place in therapy? Drugs 2018;78:1289-96.
Diane A, Borthwick F, Wu S, Lee J, Brown PN, Dickinson TA, et al
. Hypolipidemic and cardioprotective benefits of a novel fireberry hawthorn fruit extract in the JCR: LA-cp rodent model of dyslipidemia and cardiac dysfunction. Food Funct 2016;7:3943-52.
Xu H. Use of Biomarkes in Toxic Risk Assessment for Rare Earth Element in “the Progress of Resource, Environment and Health in China”(SCOPE China 3). Vol. 4. Beijing: Peking University Medical Press; 2004. p. 20.
Zhang Z, Ho WK, Huang Y, James AE, Lam LW, Chen ZY. Hawthorn fruit is hypolipidemic in rabbits fed a high cholesterol diet. J Nutr 2002;132:5-10.
Othman GQ, Mustafa TA. The liver protective role of hawthorn (Crataegus
sp.) in hypertriglycerdimic induced rats. Polytechnic J 2017;7:111-8.
Akila M, Devaraj H. Synergistic effect of tincture of Crataegus and Mangifera indica L
. Extract on hyperlipidemic and antioxidant status in atherogenic rats. Vascul Pharmacol 2008;49:173-7.
Niu C, Chen C, Chen L, Cheng K, Yeh C, Cheng J. Decrease of blood lipids induced by Shan-Zha (fruit of Crataegus pinnatifida
) is mainly related to an increase of PPARα in liver of mice fed high-fat diet. Horm Metab Res 2011;43:625-30.
Akbiyik F, Cinar K, Demirpence E, Ozsullu T, Tunca R, Haziroglu R, et al
. Ligand-induced expression of peroxisome proliferator-activated receptor α and activation of fatty acid oxidation enzymes in fatty liver. Europ J Clin Investigat 2004;34:429-35.
Lans C. Do recent research studies validate the medicinal plants used in British Columbia, Canada for immune-mediated and other problems in pets? J Ethnopharmacol 2019;236:366-92.
Kashyap CP, Arya V, Thakur N. Ethnomedicinal and phytopharmacological potential of Crataegus oxyacantha
Linn – A review. Asian Pacific J Trop Biomed 2012;2:S1194-9.
Wang J, Xiong X, Feng B. Effect of crataegus usage in cardiovascular disease prevention: An evidence-based approach. Evid Based Complement Alternat Med 2013;2013:149363.
Cuevas-Durán RE, Medrano-Rodríguez JC, Sánchez-Aguilar M, Soria-Castro E, Rubio-Ruíz ME, Del Valle-Mondragón L, et al
. Extracts of Crataegus oxyacantha
and Rosmarinus officinalis
attenuate ischemic myocardial damage by decreasing oxidative stress and regulating the production of cardiac vasoactive agents. Int J Mol Sci 2017;18:23-9.
Kim SH, Kang KW, Kim KW, Kim ND. Procyanidins in crataegus extract evoke endothelium-dependent vasorelaxation in rat aorta. Life Sci 2000;67:121-31.
Idris-Khodja N, Auger C, Koch E, Schini-Kerth VB. Crataegus special extract WS(®) 1442 prevents aging-related endothelial dysfunction. Phytomedicine 2012;19:699-706.
Rech A, Botton CE, Lopez P, Quincozes-Santos A, Umpierre D, Pinto RS. Effects of short-term resistance training on endothelial function and inflammation markers in elderly patients with type 2 diabetes: A randomized controlled trial. Exp Gerontol 2019;118:19-25.
Chen ZY, Peng C, Jiao R, Wong YM, Yang N, Huang Y. Anti-hypertensive nutraceuticals and functional foods. J Agric Food Chem 2009;57:4485-99.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]