New Considerations in Therapeutics

Introduction

The association between various lipid measurements and secondary risk of CAD deserves more attention due to limited and inconsistent results of previous studies. Atherosclerotic problems are encountered with enhancement of LDL uptake by monocytes and macrophages [1-2]. In the liver, uptake of plasma LDL is mediated via specific LDL receptors, but a scavenger receptor system is employed by macrophages. Plasma LDL must be modified prior to uptake by macrophages. Analysis of the lipid content in the oxidatively modified LDL from hyper lipidemic patients revealed that the level of lysophosphatidylcholine was greatly elevated, and the high level of the lysolipid was shown to impair the endothelium-dependent relaxation of the blood vessels [3-7]. In allopathy blood lipid levels are normalized by statins, fibrates, niacin and bile acid binding resins (BABRs). All of these allopathy related drugs have low compliance ranges from mild compliance due to metallic taste of BABRs to severe side effects like rhabdomyolysis by fibrates and statins [8]. Due to low compliance and adverse effects of conventionally used hypolipidemic agents, herbal medicines are going to be famous among Physicians, and Cardiologists [9]. Medicinal herbs like Curcuma Longa, Fenugreek, and Lemon contents are being used as mild to moderate hypolipidemic agents. Curcuma Longa commonly known as Haldi in India and Pakistan is used to lower plasma lipids, in view of their contents. It contains Curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin), turmerone, atlantone, zingiberene, proteins, and resins [10]. Curcumin reduces both the oxidation and circulation of oxidized levels of LDL cholesterol which leads to reduction in the occurrence or treatment of already present atherosclerosis in the subjects [11]. Research has revealed that curcumin from turmeric is an extremely efficient agent in increasing cholesterol uptake by the liver cells [12]. Several independent studies have shown that curcumin increases the expression of cholesterol and lipoprotein receptors on the liver cells [13]. Curcumin also increases cholesterol and bile acids excretion in feces [14]. Additionally, curcumin also increases the amount of ABC (ATP-binding cassette ) transporters. These transporters are basically involved in flushing out excess cholesterol from the inside of the macrophages. When the numbers of ABC transporters are increased on the surface of a macrophage, the deposited cholesterol is effluxes out through these channels again into the blood. Through the blood, it reaches liver where it is metabolized efficiently [15].

The composition of fenugreek includes a large number of chemical components. They include proteins and amino acids, flavonoids, saponins and steroidal saponins, coumarin, lipids, vitamins, minerals, galactomannan fiber and alkaloids, such as trigonelline. Extracts are available standardized to contain 50 percent saponins or 20 percent of the amino acid 4-hydroxyisoleucine [16]. Treatment with fenugreek. Seed powder normalized the enhanced lipid peroxidation and increased susceptibility to oxidative stress associated with depletion of antioxidants [17]. The steroidal saponins (diosgenin, yamogenin, tigogenin and neotigogenin) are thought to inhibit cholesterol absorption and synthesis and hence its potential role in arteriosclerosis [18]. Phenolics in Curcuma Longa have potential health benefits mainly due to their antioxidant properties such as reactive oxygen species (ROS) scavenging and inhibition, electrophile scavenging and metal chelation [19-21].

Patients and Methods

PLACE AND PERIOD OF RESEARCH WORK: The research work was conducted at Jinnah Hospital, Lahore from January 2018 to May 2018 with approval of Research ethics committee of the Hospital. SAMPLE SIZE: Ninety hyperlipidemic patients were selected for research work. CONSENT: Written consent was taken from all patients. Specific Performa was designed for the research work. Hyperlipidemic patients were selected with age range from 19 to 70 years. EXCLUSION CRITERIA: Exclusion criteria were hypertension, hypothyroidism, diabetes mellitus, alcohol addictive patients, peptic ulcer, any gastrointestinal upset, renal impairment, and any hepatic or cardiac problem. GRPOUPING: All patients were divided in three groups (group-I, group-II, group-III), 30 patients in each group.

Their baseline lipid profile data were taken and filed in specifically designed Performa, at start of taking medicine, like lipid profile, blood pressure and pulse rate. LIPID PROFILE: Serum lipid profile (total cholesterol, HDL-cholesterol, triglyceride) parameters were determined after a 12 hour overnight fast by standard methods. LDL-cholesterol level was calculated according to the Friedewald’s formula. Thirty patients of group-I were advised to take 500 mg of Curcuma longa (haldi) mixed in fresh milk without cream, thrice daily for two months. Group-II patients were advised to take 100 grams of Fenugreek leaves mixed with salad in each meal (thrice daily) for the period of two months. Group-III patients were advised to take 40 ml of fresh lemon juice mixed with 40 ml mineral water thrice daily for two months. They all were advised not to take heavy meal rich with any type of fat like junk food etc. One hour daily brisk walk was advised to all participants. 15 days follow up visit was scheduled for them. After two months their lipid profile was re-determined. STATISTICAL ANALYSIS: Mean values of the day-0 and day-60 of tested parameters (total cholesterol, LDL cholesterol, triglycerides, and HDL cholesterol) ± SD were taken to be analyzed statistically. SPSS 10 version 2.00.01.10 was used to analyze pretreatment and post treatment values of all parameters. Paired ‘t’ test was applied to determine changes in pre and post treatment values. P-value >0.05 was considered as non significant changes in tested parameters, and p-values <0.01 were considered as significant changes.

Results

When results were compiled and statistically analyzed by using SPSS 10 version 02.00.01.10, it revealed that curcuma longa decreased triglycerides (TG), total cholesterol (TC), and LDL cholesterol of 29 hyperlipidemic patients 20.01, 16.10, and 17.59 mg/dl respectively. Raise in HDL cholesterol in this group was 03.70 mg/dl. Fenugreek leaves reduced TG, TC, LDL cholesterol of 28 hyperlipidemic patients 17.33, 14.70, and 17.06 mg/dl respectively. Lemon juice reduced TC, TG, and LDL cholesterol 15.45, 10.13, and 11.97 mg/dl respectively. HDL raised 03.55 mg/dl in this group. Changes in all tested parameters, and their statistical significance are shown in following table.

Table 1: Showing Parameters Values Before and After Treatment with their Statistical Significance in Group-1(n = 29) (Curcuma Longa or Haldi)

Table 2: Showing Parameters Values Before and After Treatment with their Statistical Significance in Group-2 (n = 28) (Fenugreek or Methi)

Table 3: Showing Parameters Values Before and After Treatment with their Statistical Significance in Group-3 (n = 29) (Lemon water)

Key: All values are written in mean and ± stands for standard error of mean. T-C= serum total cholesterol, TG= serum triglycerides, LDL-C= low density lipoprotein cholesterol, HDL-C= high density lipoprotein cholesterol. All parameters pre and post-treatment are measured in mg/d. n = sample size. P-value <0.01 stands for significant change, P-value >0.05 stands for non-significant change.

Discussion

Fenugreek (Trigonella foenum-graecum) seeds, used as a condiment, are documented for health benefits including amelioration of abnormalities in lipid homeostasis due to its hypolipidemic properties. However, molecular mechanisms underlying the hypolipidemic effect of fenugreek seeds remain obscure. In our results lemon, curcula longa, and Fenugreek proved that significant reduction occurs in TC, TG, LDL cholesterol by using these herbal preparation/mixture. But all of these three herbs have no significant influence on HDL cholesterol. Same results did prove in the study conducted by Wiseman SA et al who described that pectin present in these three herbs inhibit enterohepatic circulation of bile acids and excrete cholesterol in feces [22]. Flavenoids present in Fenugreek are responsible for inhibition of cholesterol synthesis [23].

Gidez LI et al stated that herbal medications have more than one or two mechanism to balance plasma lipids in hyperlipidemic patients [24]. Bingham SA et al stated that the major reasons for hypercholesterolemia in today’s world are obesity, consuming high fat food, diabetes and having a family history of high cholesterol [25]. This disorder is reported to affect a large number of people all across the world and is one of the leading causes of death as well. Cholesterol is reduced in the body by managing weight and diet. Regular exercise, lesser consumption of fatty foods, more consumption of fruits and vegetables help in ameliorating the symptoms of hypercholesterolemia. However, in most cases, medications also known as anti hypertensive and anti cholesterol drugs are also required, especially in chronic cases. There are several problems associated with medications though and people are now switching towards newer and less toxic therapies to control and reduce cholesterol levels in the body.

Several natural herbs, supplements and food products are known to maintain healthy cholesterol levels and reduce cholesterol in mild hypercholesterolemia. These therapies, if opted for, help in preventing the disorder but are less helpful in chronic cases of this disease. In an experiment, controlled dosing of turmeric was used to feed hypercholesterolemic rabbits and the effects on LDL oxidation was analyzed [26]. It was found that turmeric extracts efficiently and quickly reduced the levels of cholesterol in the blood along with the incidences of atherosclerosis with time. The reason for these therapeutic effects, when analyzed, was found to be the preventive action of turmeric on the oxidation of LDL cholesterol. Mattern T et al have also explained same important mechanism of action of Turmeric that oil of these seeds inhibits enterohepatic circulation causing biosynthesis of bile acids instead of cholesterol by hepatocytes [27]. The results obtained from research work conducted by Geleijnse JMet al revealed that all extracts of the fenugreek exhibit antioxidant activity [28]. These findings suggest that the fenugreek extracts could act as potent source of antioxidants. Magee E et al mentioned that many herbs and their constituents have potential to reduce total plasma cholesterol LDL cholesterol, and triglycerides but they do not raise HDL cholesterol because it needs special plasma proteins as lipoproteins responsible for structural and functional integrity of HDL particles [29].

High levels of LDL can cause arcus corneae and tendinous xanthomas at the Achilles, elbow, and knee tendons and over metacarpophalangeal joints. Other clinical findings seen in patients with high LDL (eg, in familial hypercholesterolemia) include xanthelasma (lipid rich yellow plaques on the medial eyelids). Xanthelasma can also occur in patients with primary biliary cirrhosis and normal lipid levels [30-33]. Patients with premature atherosclerotic cardiovascular disease, cardiovascular disease with normal or near-normal lipid levels, or high LDL levels refractory to drug therapy should have Lp(a) levels measured. Lp(a) levels may also be directly measured in patients with borderline high LDL cholesterol levels to determine whether drug therapy is warranted [34]. According to the United States Department of Agriculture , the juice of one lemon provides about 18.6 milligrams of vitamin C. The recommended daily amount for adults is 65 to 90 milligrams [35-37].

Acknowledgment

We all researchers acknowledge management and laboratory staff and faculty of Jinnah Hospital Lahore Pakistan for their support and help in this research work.

Conflict of Interest: N/A

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