HYPERLIPIDEMIA: ITS MANAGEMENT AND INDUCTIONHTML Full Text
Received on 19 February, 2014; received in revised form, 21 June, 2014; accepted, 15 July, 2014; published 01 August, 2014
HYPERLIPIDEMIA: ITS MANAGEMENT AND INDUCTION
Vichitra Kaushik*1, Shivali 2 and Vipin Saini 1
MM College of Pharmacy, Maharishi Markandeshwar University 1, Mullana, Ambala, Punjab, India
Rayat and Bahra Institute of Pharmacy 2, Mohali, Punjab, India
ABSTRACT: In the present review an attempt has been made to explore and study the various in vitro animal models used for the evaluation of hypolipidemic and antihyperlipidemic drugs. Hyperlipidemia has been ranked as one of the greatest risk factors contributing to the prevalence and severity of coronary heart disease. The main aim of treatment in patients with hyperlipidemia is to reduce the risk of the occurrence of cardiovascular or cerebrovascular disease. The present review throws a light on the various herbal drugs used as potential hypolipidemics and antihyperlipidemics. Emphasis has been laid on the study of animal models used in the evaluation and screening of antihyperlipidemic drugs. The review also encompasses the various treatments used for the management of hyperlipidemia.
Hyperlipidemia, Herbal drugs, Animal models
INTRODUCTION:Human health is one of the most important issues that have been addressed in the past and present. Currently, modern medicine, chemistry, biochemistry and pharmacology are trying to prevent, diagnose, treat and understand the reasons, mechanisms and pathways of disorders in the normal function of human body. Herbal medicine is still the mainstay of about 75-80% of the world population, mainly in the developing countries, for primary health care because of better cultural acceptability, better compatibility with the human body and lesser side effects 1. There are several areas wherein plant derived drugs are used. Some of them have antiprotozoal activity like quinine from Cinchona, berberine from Berberis, harmaline from Peganum, artemisin from Artemesia.
Allicin from garlic is antifingal, ricin from castor is specific immunotoxin against protozoa and liquorice is used in cleansing inflammed stomach. Oleanolic acid, sericic acid, quillia saponins and nimbidine from the seed oil of Azadirchta indica, catechin from Acacia catechu and lapachol from common teak have antiulcer activity. Colenol from Coleus forskohli is a hypotensive drug 2.
Plant products are frequently considered to be less toxic and freer from side effects than synthetic ones. Plants play a major role in the introduction of new therapeutic agents and have received much attention as sources of biologically active substances including antioxidants, hypoglycemics and hypolipidemics. Lipids play an important, but not an exclusive role in development and progression of atherosclerosis. In some persons, lipids will be a major factor, and in some, lipids play a minor role 3.
Hyperlipidemia has been ranked as one of the greatest risk factors contributing to the prevalence and severity of coronary heart disease 4.
The main aim of treatment in patients with hyperlipidemia is to reduce the risk of developing ischemic heart disease or the occurrence of further cardiovascular or cerebrovascular disease. Currently available hypolipidemic drugs have been associated with a number of side effects. The consumption of synthetic drugs leads to hyperuricemia, diarrhoea, nausea, myositis, gastric irritation, flushing, dry skin and abnormal liver function. Many investigators have demonstrated a correlation between raised serum lipids and the incidence of coronary heart disease (CHD) and atherosclerosis. Coronary heart disease (CHD) is the major cause of death in most developed countries and in many developing countries. The clinical complications of CHD lead to substantial disability and are a main source of the rising cost of health 5-8 Age, sex, and personal and family history of cardiovascular disease are nonmodifiable risk factors for CHD. Hypercholesterolemia, hyper-tension and cigarette smoking are the major modifiable risk factors 9-11. They powerfully influence risk are common in populations and are widely amenable to prevention and treatment. It is well known that atherosclerosis is associated with elevated circulating cholesterol levels 12.
Recently, several herbal drugs have been advocated for their hypolipidaemic action. A list of medicinal plants possessing hypolipidaemic and anti-hyperlipidaemic activity is given in Table 1.
Management of hyperlipidemia: Hyperlipidemia, also known as hyperlipoproteinemia or high cholesterol, is a disorder characterized by abnormally high concentrations of lipids (fats) in the blood that are correlated with the development of atherosclerosis, the underlying cause of coronary heart disease (CHD) and stroke. Hyperlipidemia is caused by abnormal lipid and lipoprotein metabolism. Lipids are a group of naturally occurring fatty substances that are present in the blood and tissues of the body. They include cholesterol, cholesterol esters, triglycerides and phospholipids. Lipids are essential dietary constituents because of their important functions 13.
Treatment of hyperlipidemia involves non pharmacological options which includes, diet control, exercise and the pharmacological options which include, the use of lipid-lowering diets and drugs. However, some patients cannot tolerate the adverse effects from these oral drugs. Therefore, improvement in human diet is highly recommended for disease prevention. As a consequence, there continues to be a high demand for new oral antihyperlipidemic drugs. Management of hyper lipidemia without any side effects is still a challenge to the medical system 14.
Drug treatment should be reserved for at risk patients with diet resistant hyperlipidaemia. Commonly used drugs include statins (simvastatin, pravastatin), resins (cholecystyramine) and fibrates (gemfibrozil). Less commonly used drugs include nicotinic acid, probucol, clofibrate and colestipol. Fish oils have been advocated for the treatment of increased triglycerides (TG) but were found to raise low density lipoproteins (LDL). The statins have been used for almost a decade and have not produced untoward effects. Furthermore they are more efficacious than existing therapies and have a higher degree of patient acceptability 15.
Therapy should be selected on the basis of the predominant lipoprotein abnormality. Total cholesterol is the most easily measured lipid and reflects LDL. Triglycerides should be measured only following an overnight 14 hour fast and is rarely treated in isolation except at very high levels (> 10mmol/L). Patients with low (< 1mmol/L) HDL cholesterol levels are at increased risk of CHD. Diabetics with elevated TG and cholesterol with reduced HDL are best treated with gemfibrozil. Opinions vary with regard to the threshold for commencing drug therapy. Cholesterol greater than 5.5mmol/L in those with established CHD and greater than 6.5mmol/L in high risk middle-aged men can be justified 16.
Hence, to reduce the amount of side effects caused by these drugs, newer drugs have to be screened. To evaluate the drugs various in vitro and in vivo methods are used. Evaluation of antihyperlipdemic drugs requires induction of hyperlipdemia in various animals like rats, mice, rabbits etc. induction of hyperlipidemia is done using various animal models which are discussed in this review. Experimental hyperlipdemia can be successfully induced using models discussed below.
TABLE 1: PLANTS WITH HYPOLIPIDAEMIC AND ANTIHYPERLIPDAEMIC ACTIVITY
|Sl. No.||Name of Plant||Family||Common/ Indian vernacular names||Plant parts|
|1||Aegle marmelos||Rutaceae||Beal fruit, bilwa||Fruits|
|2||Agave veracruz||Amaryllidaceae||American aloe, barakhawar||Roots, leaves, gum|
|3||Allium cepa||Lilliaceae||Onion, piyaj, palandu||Bulbs|
|4||Aloe barbadensis||Lilliaceae||Ghee kumar, gwarpatha||Leaves|
|5||Bambusa arundunacea||Graminae||Bamboo vamsha||Leaves|
|6||Bosswellia serrata||Burserraceae||Salai guggal||Gum|
|8||Cajanus cajan||Fabaceae||Red gram||Seeds|
|9||Capparis decidua||Capparaceae||Karli, tint||Leaves, fruits and stems|
|11||Carum capaticum||Umbelliferae||Jowan, ajowan||Fruits, roots|
|12||Celastrus paniculatus||Celastraceae||Khunjri, kusur||Seed oil, barks, roots and fruits|
|13||Curcuma amada||Zingiberaceae||Mango ginger, haridra||Rhizomes|
|14||Cyamopsis tetragonoloba||Leguminosae||Guar, gwar||Seeds|
|15||Emblica officinalis||Euphorbiaceae||Amla, amlki||Dried fruits, Seeds, leaves|
|18||Juglans regia||Juglandaceae||Walnut, akhrot||Kernel, oil|
|21||Musa saspientum||Musaceae||Banana, kela||Roots, Stems, Flowers, Fruits|
|22||Nepeta hindostana||Labiatae||Billiola, badranj boya||Whole plant|
|23||Phaseolus aureus||Fabaceae||Green gram||Seeds|
|24||Phaseolus mungo||Fabaceae||Black gram||Seeds|
|25||Picrohiza kurroa||Scrophulariaceae||Kulki, kataki||Roots|
|26||Piper nigrum||Piperaceae||Golmirch, kalimich||Leaves|
|27||Pisum sativum||Papilionaceae||Gardenpea, matar||Seeds|
|28||Pterocarpus marsupium||Papilionaceae||Indian malabarkino||Gum and leaves|
|29||Saussuraea lappa||Asteraceae||Kustha, Kut||Roots|
TABLE 2: DRUGS USED IN DIFFERENT TYPES OF HYPERLIPDEMIA
|Hypercholesterolaemia: The statins, pravastatin (Lipostat) and simvastatin (Zocor) are first choice. Alternatives are bile acid resins such as cholecystyramine (Questran).|
|Mixed hyperlipidaemia: The statins or alternatively fibrates such as (elevated cholesterol and TG) gemfibrozil (Lopid) may be used.|
|Hypertriglyceridaemia: Use fibrates such as gemfibrozil as first line therapy, (elevated TG) alternatively use the statins.|
Cholesterol-diet induced atherosclerosis in rabbits and other species: Rabbitsare known to be susceptible to hypercholesterolemia and arteriosclerosis after excessive cholesterol feeding. Therefore, this approach has been chosen by many authors to study the effect of potential anti-arteriosclerotic drugs.
Several modifications of the method have also been done in which different experimental animals are used like Cockerels, turkeys, pigeons, Japanese sea quails, rats, mice, hamster, guinea pigs, chimpanzee, the baboon and the rhesus macacus.
Hereditary hypercholesterolemia in rats: A strain of genetically hypercholesterolemic rats (RICO) is used to induce experimental hyper-lipidemia. In contrast to Zucker-rats, these animals are normotriglyceridemic and non-obese. The hypercholesterolemia of the RICO rat is related to a decreased rate of catabolism of chylomicrons and LDL, but more specifically to an excessive production of these two types of lipoproteins. This strain has been proposed to study hypolipidemic drugs, particularly those designed to decrease the plasma concentrations of chylomicrons and LDL.
Hereditary hyperlipemia in rabbits: A strain of rabbits with hereditary hyperlipemia (WHHL rabbit) has been used by several scientists to study development of atherosclerosis, as well as for histological and functional changes of the aorta.
At the age of 10–14 months homozygous animals exhibit an atheromatous plaque, distributed heterogeneously over the luminal surface of the aorta. Serum cholesterol is increased up to 400–600 mg/dl. The increased levels of LDL have been studied in detail using this model.
Transgenic animals: Several transgenic animals as disease model were created during the last decade, mice, rats and rabbits. The widely used model is the Apo E knockout mouse originally created by Nubuyo Maeda, University of North Carolina, Chapell Hill, NC. These Apo E knockout mice have spontaneously elevated plasma cholesterol levels, and develop atherosclerosis even on regular chow within 3–4 months.
The time dependent progression of atherosclerosis leads to lesions similar in histopathology to those observed in humans. This animal model is used as background for atherosclerosis research and target validation.
Triton-induced hyperlipidemia: The systemic administration of the surfactant Triton WR 1 339 (isooctyl-polyoxyethylene phenol) to mice or rats results in a biphasic elevation of plasma cholesterol and triglycerides. In this method, Male Sprague Dawley or Wistar rats weighing 200–350 g are starved for 18 h and then injected intravenously with 200 mg/kg. Serum cholesterol levels increase sharply 2–3 times after 24 h.
Fructose induced hypertriglyceridemia in rats: In this method the rats are switched from a diet low in carbohydrates and high in protein to a high intake of fructose and develop an acute hypertriglyceridemia. Compounds are tested for inhibition of this phenomenon 17.
Cyclosporin A-induced Hyperlipidemia: Cyclosporin A (CsA) is an immunosuppressant drug widely used in organ transplant recipients and patients with auto-immune disorders.
Long-term treatment with CsA is associated with hyperlipidemia and an increased risk of atherosclerosis 18.
TABLE 3: ANIMAL MODELS FOR HYPERLIPIDEMIA
|Animal model||Type of animal used|
|Cholesterol-diet induced atherosclerosis in rabbits and other species||Rabbits, Cockerels, turkeys, pigeons, Japanese sea quails, rats, mice, hamster, guinea pigs, chimpanzee, the baboon and the rhesus macacus.|
|Hereditary hypercholesterolemia in rats||Rats|
|Hereditary hyperlipemia in rabbits||Rabbits|
|Fructose induced hypertriglyceridemia in rats||Rats|
|Cyclosporin A-Induced Hyperlipidemia||Rats and mice|
CONCLUSION: This review gives an insight of the frequently used animal models used for the evaluation of hypolipidemic and antihyperlipidemic drugs. Most of the herbal drugs lack scientific and pharmacological data in relation with the animal activity. Therefore, more emphasis should be given on the evaluation of the drugs for their safe use. This article focuses on the in vitro methods of evaluation. Out of the methods explored, the high fat diet induced model is most frequently used.
ACKNOWLEDGEMENT: The authors are thankful to MMU, Mullana for their unflinching support throughout the writing of this paper. We deeply acknowledge timely support and valuable suggestions from the Rayat and Bahra College of Pharmacy, Kharar.
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Vichitra Kaushik*, Shivali and Vipin Saini
MM College of Pharmacy, Maharishi Markandeshwar University, Mullana, Ambala, Punjab, India
19 February, 2014
21 June, 2014
15 July, 2014
01 August, 2014