Study Of The Introduction To Herbal Medicine Biology Essay

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Plant based products, as an evidence of efficacy, have great promising role and is gratifying to note that World Health Organization (WHO) have shown an abiding interest in plant derived product. According to the WHO, because of poverty and poor accessibility to modern medicine, approx 65 - 80% of the world's population, which lives in developed countries, still depends on plants based therapies for primary health care.1 Humans are dependent on plant based therapies for management of health, for example the ancient system of medicines Ayurveda, Yoga, Unani, Sridhar, Homeopathy and Naturopathy.

The major drawbacks of modern medicines is due to its variety side effects endangers the safety of patient quiet often. Moreover medicines used in chronic diseases are seldom curative and needs to be taken lifelong. Although herbal therapies are no match compare to modern herbal therapies are medicines but still they are popular due to the fact that they are mild and do not cause injuries as synthetic drugs.2 It was estimated last year $ 60 billion of herbal medicines are consumed worldwide.3

Due to increase in plant based product being introduced in market, the regulatory agencies have become alert and are asking for registration of the product, which should accompany the evaluation of safety and evaluation data. They should also submit the rational along with ethical practices followed in product development. It is grossly estimated, currently 25000 plant based products are available in the market belonging the folklore and traditional medicines.

Clinical trials of plant based products are required to evaluate the safety and efficacy of plant based formulations in human subject, before releasing in the market, and they are evaluated according to scientific and ethical norms. Research and development of new plant based medicines are done under strict government regulations such as drug control general of India(DCGI), Food and drug Administration (FDA) and committee for the purpose of control and supervision of experiments of animals (CPCSEA) which have become very systematic and stringent over the past couple of decades.4

Table 1: List of few biologically active plants


Plant Medicine

Therapeutic potential


Aloe Vera

Heals burns and wounds


Canada carunculous

Reduce cholesterol levels


Boo phone distichal

Treatment of mental illness


Calendula officinal is

Treatment of abdominal cramps and constipation


Chrysanthemum parthenium

To treat migraine headaches


Alliums sativa

Reduce Cholesterol levels.


Zingier officinal

Effectively decreases nausea and vomiting of pregnancy


Camellia saneness

Inhibit growth of breast cancer cells and may heal scar faster.


Punic granite

Ellagitannins inhibit cancer cell growth in mice.


Lentinus eddoes

Antimicrobial and cytotoxic effect.

Clinical development on safety and efficacy of plant based products.

Patient safety is a serious global public health issue. Clinical trials in India being poorly organized and there is no systematic documentation of clinical practice. Medicinal plants are much more economic to use, than those of synthetic modern medicines. Due to this reason and also due easy availability many poor patients of developing countries are attracted to these, even in developed countries like Germany, USA etc. interest of peoples are growing. People believe that these herbal medicines are always safe. But unfortunately this is not the case. There are number of cases reported in the scientific reports around the globe, about the toxicity of plant medicinal products. Consistency in composition and biological activity are essential requirements for the safe and effective use of therapeutic agents.

Quality is a critical determinant of safety and efficacy of plant based medicines; however plant preparations rarely meet the standards of quality, which refers to the procedures and markers for accessing and verifying the strength of plant raw materials or extracts or formulation thereof. Production of quality plant based medicines has become challenge to the regulatory authorities, scientific organization and manufactures. WHO, USFDA, ESCOP have published standard sets of guidelines.5,6

Although clinical trials with plant based medicinal products are feasible, a survey of the specialized literature reveals that few well controlled double blind (Placebo controlled) trials have been carried out with plant based medicinal products. There are several factors which might contribute to the explanation of such discrepancies, for example lack of standardization, and quality control of herbal drugs used in clinical trials; inadequate randomization in most studies, and patients not poorly selected; number of patients in most trials are insufficient for the attainment of statistically significance, etc; wide variations in duration of treatments using plant based products. According to Good Clinical practice (GCP) clinical trials of plant products should be conducted in accordance with the ethical principles and should be described in a clear and detailed protocol. GCP in clinical studies with herbal remedies has only recently started and routinely used by the few pharmaceutical companies.4

Recently conducted clinical trials on plant based products.

Liver cancer is the common malignancy with a high mortality rate. Given the poor prognosis associated with this cancer, many patients seek additional therapies that may improve quality of life or survival. Several traditional Chinese Medicines (TCM) have been evaluated in clinical trials. Products containing ginseng, astragalus, and mylabris were studied and had a large treatment effect.7

Among herbal medicines, those containing extracts of Asteraceae (compositae) such as Echinaceae spp., Arnica montana, Matricaria recutita, Calendula officinal is, are especially popular in primary care setting. The study indicated that treatment with Asteraceae - containing remedies is not associated with high risk of adverse drug reactions.8

Antifungal activity of tea tree oil from Melaleuca alternifolia against Trichophyton equine was conducted on animals like breeding horses affected by equine ringworm. The animals were randomly divided into 2 groups of 30 subjects. Data analysis was performed by Chi square test. All the treated animals showed complete clinical and etiological healing.9

Menstrual irregularity is a considerable nuisance for women because it leads to an unpredictable menstrual flow. The pharmacotherapy consists of herbs which alleviate vita, which is primarily responsible of causation of such irregularity Egg. Asoka, Triphala, Hingu, Trivit. etc. A polyhedral formulations been designed on the basis of available literature. The effects of polyhedral preparation Dabber Mensa were studied on 50 women in mean age group of 25 - 30 in an open prospective clinical study.10

A review conducted those natural products such as cur cumin (from turmeric, reseveratol (red grapes, cran berries and peanuts) tea polyphenol, genistein (Soy) silymirin, boswellicacid and withonilides can suppress the cell signaling intermediates in inducing arthritis.11

Natural products against hyperlipidemia in HIV infected individuals.

HIV- associated lipodystropy and dyslipidemia is a syndrome that occurs in HIV - infected patients under antiretroviral therapy. Lipodystrophy in HIV infected patients is associated with metabolic complications such as impaired glucose tolerance, high levels of cholesterol and triglyceride.12,13,14 This may significantly increase the cardiovascular complications in these individuals.15


Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia. It involves abnormally elevated levels of any or all lipids and/or lipoproteins in the blood.

Hyperlipidemias may basically be classified as either familial (also called primary) caused by specific genetic abnormalities, or acquired (also called secondary) when resulting from another underlying disorder that leads to alterations in plasma lipid and lipoprotein metabolism.32 Also, hyperlipidemia may be idiopathic, that is, without known cause.

Table 2: The Phenotypic classification of hyperlipidemia



Major elevation of plasma lipid

Type I

Chylomicron ++

TG+++, Cholesterol+

Type Imia

LDL ++

Cholesterol ++, TG+

Type Ibis

LDL ++, VLDL ++

Cholesterol +, TG++

Type III

Remnants +, LDL ++,

TG++, Cholesterol ++

Type IV


TG++, Cholesterol +

Type V

VLDL ++, Chylomicron ++

Cholesterol +, TG ++

Frequently both triglycerides and cholesterol are increased which may be due to either by increase in Chylomicron or VLDL and LDL. The Table 1.2 shows the various phenotypes based on the WHO classification of hyperlipoproteinemia.



Normal human serum cholesterol level ranges between 140-200 mg/100ml. The presence of excess cholesterol in the blood is known as hypercholesterolemia. The relationship between serum cholesterol, triglycerides, LDL and HDL levels with incidence of coronary artery diseases are given in the table 1.2

Table 3: Classification of Total Cholesterol, LDL Cholesterol, HDL Cholesterol and Triglycerides from premature cardiovascular disease. (National Cholesterol Education Programmed Summary 1993)


Total cholesterol mg/dl

Triglycerides mg/dl

LDL Cholesterol mg/dl

HDL Cholesterol mg/dl











High risk






Atherosclerosis is one of the top killers both in the developed and developing countries.33 World Health Organization (WHO) has predicted that by 2000 AD as many as 34% of death in underdeveloped nations will be related to Coronary Heart Disease (CHD) whereas the developed world holding at about 50%. The majority of risk factors involved in the causation of atherosclerosis are directly or indirectly due to disturbances in the lipid and lipoprotein metabolism. 34

Atherosclerosis is a disease of the large and intermediate sized arteries in which fatty lesions called atherosclerotic plaques develop on the inner surface of the arterial wall due to deposition of cholesteryl esters and cholesterol rich lipoprotein like LDL cholesterol.35


Atherosclerosis is a slowly progressive condition which is asymptomatic for most of its course and which only comes to the attention of clinicians when it causes a marked narrowing of an artery or is complicated by a superimposed thrombosis. Early atheromatous lesions can be found at autopsy in the arteries of young adults.

Atherosclerosis is a focal condition with a propensity to affect certain sites in the vascular system. There are many factors which contribute to its formation, including lipoproteins, mutagenic agents which cause smooth muscle cell proliferation, cytotoxic factors that damage endothelial cells or cause death to macrophages and factors that stimulate secretion of connective tissue matrix components. These factors all interact and are likely to contribute to a variable extent in different patients and in different lesions.

When atherosclerosis affecting the coronary arteries is sufficiently severe to compromise blood flow it may cause chest pain (angina pectoris), or if the conducting system of the heart is involved, disturbances of the heart's rhythm (dysarrhythmias) occur. A blood clot may form over an atheromatous lesion leading to total occlusion of the artery and hence ischaemia of the heart muscle served by that artery leading to myocardial infarction.

In epidemiological studies, three major risk factors for coronary heart disease (atherosclerosis) have been identified: hypertension, cigarette smoking and total plasma cholesterol concentration and minor factors like diabetes mellitus, obesity & stress, physical inactivity, family history and increased triglyceride levels.


The initial step in atheroma development is infiltration of the arterial wall by lipoprotein particles and their subsequent entrapment in the intima. Entrapment may occur by interaction of the protein component of LDL (apoB) with substances such as glycosaminoglycans within the intima, or the lipoprotein may be chemically modified by oxidation or glycation or by the attachment of malondialdehyde.

These modified lipoproteins are taken up by macrophages by a receptor dependent mechanism which does not involve the LDL receptor. This 'scavenger receptor' is not down regulated by the presence of excess intracellular cholesterol (unlike the LDL receptor) and therefore continued uptake of modified LDL occurs, giving rise to intracellular cholesterol droplets.

The mature atherosclerotic lesion is termed the fibrous plaque; this results from proliferation of smooth muscle cells and their stimulation to produce collagen. Growth factors responsible for smooth muscle cell proliferation are produced by macrophages, endothelial cells and platelets. Whilest the endothelium over the plaque remains intact, circulating platelets do not come in to contact with the subendothelial layer but occasionally the plaque ruptures.

The consequence of plaque rupture is that the sub-endothelium comes in contact with the blood and the clotting cascade is activated. The resultant thrombosis may lead to total occlusion of the vessel. Another consequence of plaque rupture is the dispersal of its contents into the circulation (embolization), which may produce effects distant from the plaque but in the territory supplied by the affect vessel.


A number of biochemical, physiological and environment risk factors have been identified that modify atherogenesis.

I Modifiable risk factors

Elevated serum lipid levels

Cigarette smoking and exposure to tobacco smoke

High blood pressure

Diabetes mellitus


Diet rich in saturated fats, cholesterol and calories

II Non modifiable risk factors

Male gender


Family history of premature atherosclerosis

Genetic abnormalities.

III Other risk factors (genetically determined)


Lipoprotein (a)





The main form in which cholesterol transported in blood is LDL cholesterol. LDL cholesterol is absorbed into cells by binding to the LDL-receptor, which uses Apo Lipoprotein - B 100, or Apd-E as its Ligands. LDL is absorbed, internalized and the cholesterol liberated in the lysosomes used for steroid synthesis and for the membrane formation.

LDL is oxidative modified in the arterial wall by monocytes and smooth muscle cells. The modification of LDL involves oxidation of the unsaturated fatty acids in the LDL particles, with the appearance of lipid peroxidation products including reactive aldehyde.36

These aldehydes form covalent bonds with the lysine amino group of apolipoprotein B-100. The oxidized LDL acts as chemoattractant for monocytes.37 It also inhibits macrophage motility and thus allowing the lesion to develop. Oxidized LDL is a cytotoxic agent that induces release of lysosomal enzymes and lipids which develop atherosclerotic lesion.38

Oxidized LDL is shown to alter gene expression in the arterial wall. It also prevents the vascular endothelium from releasing nitric oxide through interrupting the stimulation of nitric oxide release and direct inhibition of nitric oxide by lipid peroxidation products.39,40


ApoA-I is the major HDL apoprotein. ApoA-I synthesis is required for the production of HDL. Mutation in the apoA-I gene that causes HDL deficiency is variable in their clinical expression and often are associated with accelerated atherosclerosis. 41

Discoidal pre-B-I HDL can then acquire free cholesterol from the cell membrane of the tissues, such as arterial wall macrophages, by an interaction with the class B, type I scavenger receptor. SR-BI facilitates the movement of excess free cholesterol from cells with excess cholesterol e.g. arterial wall foam cells.42

In the liver SR-BI facilitates the uptake of cholesteryl esters from the HDL without internalizing and degrading the lipoproteins. In mice elimination of SR-BI significantly increases the atherosclerosis.43


Lipid peroxidation is a free radical mediated process. It is defined as the oxidative deterioration of polyunsaturated fatty acids to form free radical intermediates and peroxides which damage cellular constituents.44

Role of Lipid peroxidation in atherosclerosis

Native LDL can become oxidized in the arterial subendothelial space, thus stimulating the synthesis of chemotactic and growth factors. Increased monocyte infiltration into the subendothelial space and further peroxidation of the lipoprotein generating a highly oxidized LDL, which becomes proatherogenic and exerts significant cytotoxicity. These effects are associated with the increased formation of lipid hydroperoxides, aldehydes and cholesterol oxides, resulting in endothelial dysfunction and accelerated atherogenesis.45


A free radical is one or more unpaired electrons in atomic or molecular orbital. Free radicals are generally unstable, highly reactive and energized molecules. Free radical often damage DNA, protein molecules, enzymes and cells leading to alterations in genetic materials and cell proliferation.46 The family of free radicals generated from the oxygen is called ROS which cause damage to other molecules by extracting electrons from them in order to attain stability. When these attacked molecule loses its electron, it becomes free radical itself beginning a chain reaction, finally results in destruction of living cell.47 The free radical may be either oxygen derived (ROS, Reactive oxygen species) or Nitrogen derived (RNS, Reactive nitrogen species).

Reactive oxygen species

Reactive nitrogen species

Oxygen cantered radical

Superoxide anion

Hydroxyl radical

Alkoxyl radical

Peroxyl radical

Oxygen cantered non-radical

Superoxide anion

Hydroxyl radical

Alkoxyl radical

Peroxyl radical

Nitric oxide

Nitric dioxide

Peroxyl nitrite

Reactive Species

Free radicals are generated while our body metabolizes foods for energy and for storage. They are also generated when body is exposed to tobacco smoke, radiation, and environmental contaminants and antigens and allergens. In normal cell, there are appropriate oxidants: antioxidant balance. However this balance can be shifted, when the production of species is increased or when the levels of antioxidants are diminished. This stage is called oxidative stress. Oxidative stress results in a damage of biopolymers including nucleic acid. Proteins, polyunsaturated fatty acids and carbohydrate oxidative stress causes serious cell damage leading to variety of human diseases like Atherosclerosis, Cancer, Alzheimer's disease, Parkinsons disease, arthritis, immunological incompetence and neurogenerative disorders.48


i) Superoxide anion (O2€­)

It is a reduced form of molecular oxygen created by receiving one electron. Superoxide anion is an initial free radical formed from mitochondrial electron transport systems.

The superoxide anion plays an important role in the formation of other reactive oxygen species such as hydrogen peroxide, hydroxyl radical or singlet oxygen. The superoxide anion can react with nitric oxide (NO) and form peroxynitrite (ONOO) which can generate toxic compounds such as hydroxyl radical and nitric dioxide (ONOO€­ + H+ ® OH + NO2).

2. Hydroxyl radical (OH-)

Hydroxyl radical is the most reactive free radical and can be formed from superoxide anion and hydrogen peroxide in the presence of metal ions such as copper or iron.

O2€­ + H2O2 ® OH + OH€­ + O2

In general, aromatic compounds or compounds with carbon-carbon multiple bonds undergo addition reaction with hydroxyl radicals resulting in the hydroxylated free radicals. In saturated compounds, a hydroxyl radical abstracts a hydrogen atom from the weakest C-H bond to yield a free radical. The resulting radicals can react with oxygen and generate other free radicals.

Clinical studies reported that reactive oxygen species are associated with many age related degenerative diseases, including atherosclerosis, cancers, trauma, stroke, asthma, hyperoxia, arthritis, heart attack, dermatitis, retinal damage, hepatitis and liver injury.

Hydroxyl radicals react with lipid, polypeptides, proteins and DNA, especially thiamine and guanosine. Hydroxyl radicals also add readily to double bonds. When a hydroxyl radical reacts with aromatic compounds, it can add on across a double bond, resulting in hydroxycyclohexadienyl radical. The resulting radical can undergo further reactions, such as reaction with oxygen, to give peroxyl radical or decompose to phenoxyl-type radicals by water elimination.

Hydrogen peroxide (H2O2)

Hydrogen peroxide can be generated through a dismutation reaction from superoxide anion by superoxide dismutase. Enzymes such as amino acid oxidase and xanthine oxidase also produce hydrogen peroxide from superoxide anion.

It is the least reactive molecule among reactive oxygen species and is stable under physiological pH and temperature in the absence of metal ions. It can generate the hydroxyl radical in the presence of metal ions and superoxide anion

O2€­ + H2O2 OH + OH€­ + O2


Singlet oxygen is a non - radical and excited status. Oxygen can be formed from hydrogen peroxide, which reacts with superoxide anion or with HOCI or chloramines in cells and tissues. Compared with other reactive oxygen species, singlet oxygen is rather mild and non-toxic for mammalian tissue. However, singlet oxygen has been known to be involved in cholesterol oxidation.

Peroxyl and alkoxyl radicals

Peroxyl radicals (ROO€­) are formed by a direct reaction of oxygen with alkyl radical (R), for example the reaction between lipid radicals and oxygen. Decomposition of alkyl peroxide (ROOH) also results in peroxyl (ROO€­) and alkoxyl (RO€­) radicals. Irradiation of UV light or the presence of transition metal ions can cause homolysis of peroxides to produce peroxyl and alkoxyl radicals.


ROOH+Fe3+ ROO€­ + Fe2+ + H+


1. Nitric oxide (NO€­)

Nitric Oxide (NO€­) is a free radical with a single unpaired electron. Nitric oxide is formed from L-arginine by nitric oxide synthase. Nitric oxide itself is not a very reactive free radical, but the overproduction of nitric oxide is involved in ischemia reperfusion and neurodegenerative and chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Nitric oxide exposed in human blood plasma, can deplete the concentration of ascorbic acid, uric acid and initiate lipid peroxidation.

2. Nitric dioxide (NO2)

Nitric dioxide (NO2) is formed from the reaction of peroxyl radical and nitric oxide, polluted air and smoking. Nitric dioxide adds to double bonds and abstract liable hydrogen atoms initiating lipid peroxidation and production of free radicals.

3. Peroxynitrite

Reaction of NO and superoxide anion can generate peroxynitrite.

O2€­ + NO OONO€­

Peroxynitrite is a cytotoxic species and cause tissue injury and oxidizes low-density lipoprotein (LDL). Peroxynitrite appears to be an important tissue-damaging species generated at the sites of inflammation and is involved in various neurodegenerative disorders and several kidney diseases.


Non - enzymatic

Superoxide dismutase (SOD)



Glutathione peroxidase

Glutathione S- transferase


Vitamin C

Vitamin E

¢ - Carotene




Dihydro epiandrosterone (DHEA)



Antioxidants are compounds which act as inhibitors of the oxidative process. Antioxidants at relatively small concentration have the potential to inhibit the oxidants chain reactions. Antioxidants are also of paramount importance in pharmaceutical preparation because there are innumerate medical products possessing diverse chemical functions and are known to undergo oxidative decomposition.46

The toxicity of LDL cholesterol may be reduced by the use of antioxidants. Vitamin E inhibits the oxidation of LDL in vitro. In earlier studies vitamin E consumption appeared to be strongly and inversely correlated with CHD risk.49,50

Vitamin A, may affect atherogenesis by scavenging oxidizing free radicals. Vitamin C may also enhance the transformation of cholesterol into bile acids.51

Antioxidants in foods and their supplements are considered safe, antioxidant supplements have not shown any adverse effects. However,

Beta carotene supplements in smokers may increase the risk of lung cancer.

Supplements of Vitamin E can increase the risk of bleeding in certain individuals. Hence one should not use antioxidant supplements as a replacement of healthy diet or medicines prescribed by your doctor.


1 Superoxide Dismutase (SOD): Superoxide dismutase is widely distributed enzyme in a variety of forms. This copper and zinc containing enzyme is found in the cytosol and in the mitochondrial intermembrane space. SOD catalyses the dismutation of superoxide anion, which leads to the formation of H2O2 and O2


2O2 + 2H H2O2 + O2

2 Catalase

Catalase is present in all mammalian cell types. The enzyme is largely located in subcellular organelles such as the peroxisomes (microbodies) of liver and kidney. Catalase consists of four protein subunits, each of which contains a haem (Fe (III) - protoporphyrin) group bound to its active site. Catalase catalyses conversion of hydrogen peroxide to water.


2H2O2 2H2O + O2

3 Peroxidases

Peroxidases remove the hydrogen peroxide by the following reaction in the presence of a hydrogen donor.


SH2 + H2O2 S + 2H2O (SH2 - Hydrogen donor)

4 Glutathione Peroxidase (GPx)

This enzyme is found in abundance in liver and erythrocytes. It is made up of four protein subunits, each of which contains one atom of selenium at its active site. It catalyzes the conversion of lipid hydroperoxide (ROOH) to alcohol (ROH) in the presence of reduced glutathione (GSH). During the process of catalyses GSH gets oxidised to GSSG.

Glutathione peroxidase


Glutathione S-transferase (GST)

Many xenobiotics supplied to living organisms are metabolized by conjugation with GSH catalysed by glutathione-S-transferase enzyme.52



These enzymes transfer thiol group from reduced glutathione. Glutathione S-transferase present abundantly in the liver can metabolise cytotoxic aldehyde such as 4-hydroxy nonenal produced lipid peroxidation.


1 Glutathione (GSH)

Free glutathione is present at GSH rather than GSSG Glutathione is a tripeptide. The structure of glutathione is

Glu - Cys _ Gly

S - S - R

GSH acts as substrate for H2O2 removing enzymes such as glutathione perioxidase and dehydroascorbate reductase. It reacts with hydroxyl radical and single oxygen. GSH is also a co-factor for several enzymes like glyoxlase, prostaglandin endoperoxide isomerase etc.

2 Vitamin C (Ascorbic acid)

Vitamin C is a water-soluble molecule. In vivo, vitamin C functions as a co-factor for various enzymes such as proline hydroxylase, lysine hydroxylase and ¢ dopamine hydroxylase. Ascorbate reacts rapidly with O2 and more rapidly with OH and forms semihydroascorbate. It also scavenges singlet oxygen and protects the cell from oxygen derived species.


The dietary changes should take place to initiate cholesterol concentration lowering.

Decrease in food consumption to lower total calories in obese patients.

Reduction in the consumption of cholesterol containing foods

Decrease in saturated food intake and increase polyunsaturated fats.

Many research works say that the possible mechanism by which the unsaturated fats (as in corn oil) lower serum cholesterol level is by inducing the excretion of cholesterol, cholesteryl esters and bile acids. Also some studies say the effect of corn oil may also be due to the presence of plant sterols like ¢-sitosterol.

Unsaturated fatty acids occupy greater area than saturated fatty acids thereby altering the spatial configuration of the lipoprotein into which they are incorporated as a result fewer unsaturated lipid molecules can be accommodated by the protein portion of the lipoprotein and hypolipidemic effect is observed. The cholesterol lowering effect of unsaturated fatty acids is associated with decrease in both LDL and HDL cholesterol, also a reduction in HDL2 to HDL3 ratio, which might be undesirable.

Some forms of hyperlipidemia can be controlled by carbohydrate restriction. In early 1939, Burger observed an increase in serum cholesteryl esters following glucose, starch, sucrose and fructose ingestion. When carbohydrate is substituted for dietary fat, marked increase of triglyceride levels is observed. A disturbance in carbohydrate metabolism can be responsible for atherosclerosis and thus carbohydrate be included in the list of primary risk factors.

Non-drug therapy is done by bringing about a change in the life style of the persons who are likely to suffer from this disease or those who are been diagnosed as patients.

The development of atherosclerosis may be due to diabetes mellitus, hypothyroidism, hypertension, which should be treated to reduce the risk of hypercholesterolemia.

Drug therapy

There are five classes of drugs which reduce the lipid levels in the blood. Based on the types of drug and their main modes of action they have been broadly classified in to seven sections for convenience and these are given below.53,54

Cholesterol biosynthesis inhibitors (HMG-CoA reductase inhibitors)


Bile acid sequestrant resins

Cholesterol absorption inhibitors

LDL oxidation inhibitors

Unique hypolipidemic drugs with multiple modes of action

Recent approaches

(a) Cholesterol biosynthesis inhibitors (HMG-CoA reductase inhibitors).55

Examples: Compaction, Lovostatin, Mevastatin, Simvastatin, Pravastatin, and Fluvastin. These all products derived from fungal metabolites. Compactin, lovastatin and mevastatin are fungal metabolize of Penicillium berivicompactum, Aspergillus tereus and Penicillium citrinum respectively. Simvastain and pravastatin are slightly modified molecules of lovostatin.

Potent competitive inhibitors of HMG-CoA reductase, the rate controlling enzyme in the biosynthesis of cholesterol increase LDL receptor in the liver. These drugs reduce serum cholesterol and LDL level to remarkable extents. These drugs lower LDL levels 25% to 45% in a dose dependant manner, the dosage of 10 to 80mg/day.

(b) Fibric acid derivatives

Examples: Clofibrate, Gemfibrozil, Fenofibrate, Ciprofibrate. These compounds act by increasing the activity of lipoprotein lipase, an enzyme which promotes the catabolism of VLDL and LDL, clofibrate inhibits the hepatic synthesis of triglycerides leading to lower output of triglycerides by increasing the rate of synthesis of Hepatic mitochondrial ¡-glycerol phosphate dehydrogenase resulting in reduced availability of precursor ¡-glycerophosphate for the synthesis of triglycerides in the liver. It also inhibits cholesterol biosynthesis by competitive inhibition of HMG-COA reductase.56

(c) Bile acid binding resins

Examples: Cholestyramine and colestipol (Dorr et al 1978).57 These resins are not absorbed when given orally. They bind bile acid in the intestine and increase the faecal excretion of bile acids which necessitates liver to synthesis more and more bile acids. This results in the increased utilization of cholesterol for bile acids synthesis and its elimination.

(d) Cholesterol absorption inhibitors

An approach that has received intensive research attention in recent years is inhibition of Acyl Coenzyme A Cholesterol Acyl Transferase (ACAT) is an enzyme that esterifies cholesterol in the body by a process believed to be a key step for cholesterol absorption.

ACAT inhibitors also have potential actions beyond inhibition of cholesterol absorption. Inhibition of hepatic ACAT could reduce the production of cholesteryl esters for packaging in lipoprotins, whole inhibition of ACAT at the artery wall could reduce the deposition of cholesteryl esters in atherosclerotic lesions. Several potent ACAT inhibitors have been reported in recent years.

e) LDL oxidation inhibitors

Probucol is a synthetic lipophilic antioxidant. It acts by preventing the oxidation of LDL. It is believed that LDL has to undergo oxidation before depositing its cholesterol content in the artery wall.

(f) Unique hypolipidemic drug with multiple modes of action

In this group there are four drug groups which warrant special mention; (i) Nicotinic acid (ii) Gugulipid, (iii) Compound 80/574, (iv) Natural sources and phytochemical.

(i) Nicotinic acid (Coronary Drug Project, 1975)

It reduce lipolysis in adipose tissues, direct inhibition of the synthesis and secretion apoB containing particles by the liver, a reduction in the synthesis of lipoprotein (a) [LP(a)] and changes in the metabolism of the HDL particles with a resultant shift in HDL subtype distribution. Triglycerides, cholesterol are decreased, VLDL, LDL production falls and HDL increases.

(ii) Gugulipid

Gugulipid is a plant sterol and steroid derived from Commiphora mukul. Gugulipid exerts hypolipidemic effects by inhibition of cholesterol biosynthesis, enhancing the rate of excretion of cholesterol, promoting rapid degradation of cholesterol, thyroid stimulation, alterations in biogenic amines.

(iii) CDRI Compound 80/574

This compound inhibits biosynthesis of cholesterol and reduces the cholesterol turnover rate. It also stimulates the receptor binding activity and thereby increasing catabolism of LDL cholesterol and produces significant reduction of lipid peroxidation. There was also definite platelet aggregation inhibition activity in animal models which was further confirmed in human platelet rich plasma ex-vivo in adenosine diphosphate, serotonin and collagen induced aggregation.

iv) Natural Sources and Phytochemicals

Costal Eskimos eat a traditional diet rich in fish and seeds are known to have a low incidence of cardiovascular diseases. This is believed to be due to consumption of fish rich in the ·-3 fatty acids namely eicospentanoic acid and docosahexanoic acid. ·-3 fatty acid rich fish oil also reduces blood cholesterol.

Plant sterols

The mixture of sterols from plant origin including soyabean sterols & ¢ sitosterol, whose structure is related to cholesterol ester ethyl group on C-24 of its side chain, are absorbed to a limited extent form the gastrointestinal tract. It competes with cholesterol for absorption sites in the intestine and triglycerides levels perhaps by lowering blood lipids and improving the blood flow.

Need of herbal drugs

A large number of indigenous plants and mineral compounds mentioned have valuable hypocholesterolaemic remedy in Ayurvedic, Unani and other systems of medicine. Today many Indian medicinal plants are used in the treatment of hypercholesterolemia.

Many indigenous plants have been studied recently and found to posses good hypocholesterolaemic activity which is comparable to synthetic drugs without any side effects.


Cytotoxicity is the quality of being toxic to cells. Treating cells with the cytotoxic compound can result in a variety of cell fates. The cells may undergo necrosis, so that they lose membrane integrity and also die rapidly as a result of cell lysis. The cell growth and multiplication can be arrested or the cells may undergo a genetic program of controlled cell death (apoptosis).

Cells undergoing necrosis typically exhibit rapid swelling and lose membrane integrity and shut down the metabolism and release their contents into the environment.42 Apoptosis is characterized by cytological and molecular events including a change in refractive index of the cell and cytoplasmic shrinkage and cleavage of DNA into fragments.43

Assessing cell membrane integrity is one of the common ways to measure cell viability and cytotoxic effects. Compounds that have cytotoxic effects often compromise cell membrane integrity. Vital dyes, such as trypan blue or propidium iodide are normally excluded from the inside of healthy cells; however, if the cell membrane has been compromised, they freely cross the membrane and stain intracellular components.44

Alternatively, membrane integrity can be assessed by monitoring the passage of substances that are normally sequestered inside cells to the outside. One commonly measured molecule is lactate dehydrogenase (LDH).45 Protease biomarkers have been identified and that allowed researchers to measure relative numbers of live and dead cells within the same cell population. The live-cell protease is only active in cells that have a healthy cell membrane, and loses activity once the cell is compromised and also when the protease is exposed to the external environment. The dead-cell protease cannot cross the cell membrane, and can only be measured in culture media after cells have lost their membrane integrity.46

Cytotoxicity can also be monitored using the MTT or MTS assay. This assay measures the reducing potential of the cell using a colorimetric reaction. Viable cells will reduce the MTS reagent to a colored formazan product. Redox-based assay has also been developed by using the fluorescent dye, resazurin. In addition in using dyes to indicate the redox potential of cells to monitor their viability, researchers have developed assays that use ATP content as a marker of viability 42. Such ATP-based assays include bioluminescent assays in which ATP is the limiting reagent for the luciferase reaction.47

Cytotoxicity can also be measured by the sulforhodamine B (SRB) assay, WST assay and clonogenic assay.


Cancer (malignant tumour) is an abnormal growth and proliferation of cells. It is a frightful disease because the patient suffers pain, disfigurement and loss of many physiological processes. Cancer may be uncontrollable and incurable, and may occur at any time at any age in any part of the body. It is caused by a complex, poorly understood interplay of genetic and environmental factors.48,49 It continues to represent the largest cause of mortality in the world and claims over 6 millions. Cancer kills annually about 3500 per million population around the world. A large number of chemopreventive agents are used to cure various cancers, but they produce side effects that prevent their extensive usage. Hence there is an urgent need of much effective and less toxic drugs.50 It has been also reported that more than 50% of all modern drugs in clinical use are of natural products, many of which have been recognized to have the ability to include apoptosis in various cancer cells of human origin.51

Causes of cancer 52,53

There are many causes of cancers, including:

Benzene and other chemicals,

Alcohol drinking,

Toxins from environment like poisonous mushrooms and aflotoxins, a type of poison which grow on peanut plants.

Excessive sunlight exposure, Genetic problems, radiation and viruses were some the causes of cancer.

phytochemicals and Cancer

Phytochemicals are a fascinating group of thousands of chemicals found in plant foods. It is known that many phytochemicals, when kept in their natural food forms, can protect us from cancer as they interact with other phytochemicals and the cells in our bodies.

The most extensively researched phytochemicals are phytoestrogens which include isoflavones (high amounts of which are found in soy foods), coumestans and lignans. These chemicals may protect against breast cancer by protecting cells from estrogen. Because of their similar structure to estrogen hence the name phytoestrogen

Other powerful phytochemicals are the isothiocyanates present in cruciferous vegetables (such as broccoli, cauliflower, and Brussels sprouts), which have been shown to prevent lung cancer and other types of cancer among non-smokers.54, 55

Another important phytochemical is the compound allicin which is found abundantly in fresh garlic and in smaller amounts in onions, chives, and leeks. This chemical acts as an antioxidant like vitamin A, C, and E, and may protect the body from free radicals. It is also possible that allicin fights cancer by reacting with carcinogens by changing their structure so that they no longer initiate tumors or by speeding the death of cancer cells that have already formed.56, 57, 58

The group of phytochemicals called catechins found in black and green teas, wine and some fruits such as apples, function similarly to allicin.59,60 These antioxidants prevent cancer and kill cancer cells that have already formed. Recent studies have shown that catechins may prevent the stomach and prostate cancer.61,62

Other phytochemicals include phytic acid found in wheat bran, which may prevent colon cancer, and quercetin (a flavonoid), apigenin, and hexaphosphate, all are found in a variety of fruits and vegetables and thought to prevent many types of cancer.63



Antibiotics is a group of drugs or substance or compounds which inhibits or completely stops growth or kills bacteria, fungi, yeast and protozoa, when present in minute concentration, these are mostly metabolites produced by microorganisms which antagonizes the microbial growth itself if present in very low concentration.

Antibiotic resistance

Antibiotics possess very complex stereo chemical structures which are highly susceptible for degradation or alteration by numerous factors like enzymatic actions or effluxing out or removing out absorbed antibiotic from microbial cell, resulting in to nullification of microbicidal or microbistatic actions of these antibiotics. Enzymes or efflux pumps which brings about degradation or alteration or exclusion or removal of an antibiotic are mostly induced in to microbial or bacterial metabolic systems once these microbes some in contact with these antibiotic substances, this is one of the protective mechanism of microorganisms. These microorganisms then develop a resistance for a particular antibiotic with which these microorganism were in contact, thus an antibiotic become little, or less or inactive microorganisms.84

Plants as a source of new antimicrobials and resistance modifying agents.

Plants have traditionally provided a source of hope for novel drug compounds, as plant herbal mixtures have made large contributions to human health and well - being.85 Owing to their popular use as remedies for many infectious diseases, searches for substances with antimicrobial activity in plants are frequent.86,87 Plants are rich in wide variety of secondary metabolites, such as tannins, terpenoids, alkaloids and flavonoids which have been in vitro to have antimicrobial properties.88,89