Review Article Inti. Chem. Pharm. Med. J. Vol. I, pp 1-26 (2004)

METHODS IN CLINICAL EV ALUA TION AND V ALIDA TION OF HERBAL DRUGSIMEDICINEIPREP ARA TIONS

Mansoor Ahmad Research Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Faculty of Pharmacy, University of Karachi, Karachi-75270, Pakistan

ABSTRACT: This review article is written with the objective to introduce the recent techniques used in evaluation of herbal drugs/medicine/preparations and adopts the methods prescribed by WHO in their monographs and are in use of evaluation of allopathic medicines.

INTRODUCTION

KEY WORDS: Evaluation of herbal Remedies, Clinical Evaluation, Validation of Herbal Remedies, Validation Process

From time immemorial man has had a wide range of natural products, which were obtained from herbal, animal or mineral sources, and were used as medicine or pharmaceuticals for prevention or cure of disease(s). Some of them were very effective but majority of them were found toxic. The maximum use of natural remedies (mostly herbal preparations) was reported to be in its highest peak in the seventeenth century and disappeared between the eighteenth and the twentieth century. This happened due to the gaining of the popularity of synthetic drugs during this period (Dobelis, 1990). Once again the same story had been repeated here for herbal remedies. But this time scientists, physicians, clinicians were more careful in the usage of natural remedies from every point of view. In this regard World Health Organization (WHO) is providing health related scientific information all over the world. Different groups of scientists are working on different aspects of herbal remedies such as cultivation, collection, standardization, and chemical composition, biological, microbiological, pharmacological, toxicological and pharmaceutical preparations. Clinicians are looking at these herbal remedies from pharmacokinetic and pharmacodynamic point of view. But in fact clinical evaluation of herbal remedies requires investigation in other aspects too, which are going to be discussed below.

Clinical Evaluation Clinical evaluation of a drug is a broad term and it consists of many folds that start from oral administration into human volunteers (usually healthy) through studies in special patient groups and formal clinical trials to post marketing surveys of adverse effects. All these steps require standard clinical

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measurement methods but usually clinical evaluation is based on specific pharmacological and therapeutic action (Nimmo & Tucker, 1991; Rashid et al., 2000; Evan, 1997).

The measurement of therapeutic and adverse effects involves dosage, concentration, effects and time. Another important factor in this matter is reliability, accurate sensitivity, specificity and reproducibility of effects. Apart from it, is the acceptability of it by a patient, physicians/clinicians and scientists because therapeutic and adverse effects are very important for human life. Therefore, the study of duration of stay of drug, related to function time, has required critical evaluation and reproducibility. The evidences of such evaluation in herbal remedies are rare and need to be carried out. Before starting of clinical evaluation of an herbal remedy needs pre-qualification test for the fulfillment of eligibility criteria. Now the question arises what are the pre-requisites? These are general identification tests e.g. physical tests, chemical tests, purity tests, chromatographic analysis, chemical assay, anti-microbial tests, antiviral test, pharmacological tests, toxicity tests, chemotherapeutic index, therapeutic index etc. If an herbal remedy on repetition of experiments always fulfills the requirement then it should be selected for clinical evaluation.

Class and Types of Herbal Remedy As we know herbal drugs exist in different forms (liquid, solid and semi-solid) and each form is a mixture of chemical compounds. It may be a combination of alkaloid, tannin, flavonoid, fixed oil, steroid, volatile oil, carbohydrate, saponin, resin, glycoside, hormone, phenol & phenol-glycoside, vitamin, coumarin, cynogenic glycoside, protein, amino acid etc (Evan, 1997).

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An herbal remedy may be a single herb preparation or a combination of different herbs. It may be a water based preparation (infusion or decoction), alcohol based tincture, vinegar based tincture, glycerin based tincture, syrup, oxymal, inhalant, baths, douche, ointment, suppository, compressor, poultice, liniment, oil, lotion, cream etc. These preparations are broadly divided into two groups i.e. internal remedies (taken through oral route) and external remedies (for skin only). Here we will discuss the clinical evaluation of internal remedies only.

Different scientists of the world carried out intensive research work on a number of medicinal plants. If we look into the results of these researches then will reach on this conclusion that for one kind of disease a number of drugs are present for cure (Tyler, 1993; 1994; Malik, 2001; Lust 1974; Bisset, 1994; Newall, 1996; Kapoor, 1996; Kammarata, 1999) for example:

Circulatory System:

Heart Tonics: Broom, Bugleweed, Figwort, Hawthorn, Lily qf the Valley, Motherwort, Night Blooming Cereus etc. Broom, Buckwheat, Cayenne, Dandelion, Ginger, Hawthorn, Horse chestnut, Lime Blossom, Mistletoe, Yarrow etc. Broom, Dandelion, Lily qf the Valley, Yarrow etc. Balm, Hops, Lime Flowers, Motherwort, Pasque Flower, skullcap, Valerian etc. Lily qf the Valley, Hawthorn Berries, Motherwort, Balm, and Lime Blossom etc. Motherwort, Broom, Bugleweed, Mistletoe, Passion Flowers, Valerian etc. Hawthorn Berries, Motherwort, Lime Blossom, Lily qf the Valley, and Mistletoe etc. Mistletoe, Yarrow, Blossom, Hawthorn, Cramp Bark, skullcap, Wood Betony ete. Broom, Hawthorn Berries, Kola etc. Lime Blossom, Berries, Garlic, Yarrow etc.

Herbs for Circulation:

Diuretics:

Nervines:

Heart weakness:

Palpitations:

Angina pectoris:

High Blood Pressure: Lime Garlic,

Valerian,

Low Blood Pressure:

Arteriosclerosis: Hawthorn Mistletoe,

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Thrombosis & phlebitis:

Varicose veins:

Varicose ulcer:

Lymphatic System:

Respiratory System

Respiratory Stimulants:

Respiratory Relaxants:

Amphoteric Remedies:

Demulcents:

Congestion: Coughs:

Bronchitis:

Pleurisy:

Whooping cough:

Asthma:

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Hawthorn Berries, Comf'rey, Marigold etc. Cayenne, Ginger, Prickly Ash Bark or Berries, Buckwheat, Hawthorn Berries, Horse chestnut, Dandelion, Yarrow, Witch Hazel, Marigold. Comfrey etc. Marigold, Marshmallow, Echinacea etc. Cleaver, Echinacea, Marigold, Golden Seal, Poke root etc.

Arnica,

Bittersweet, Cowslip, Daisy, Senega, Soapwort, Squill, Thuja ete. Coltsfoot, Elecampane, Ehedra, Flaxseed, Grindelia, Hyssop, Plantain, Pill-bearing Spruge, Sundew, Thyme, Wild Cherry Bark, Wild Lettuce etc. Blood Root, Lobelia, Mullein, Pleurisy Root, White Horehound etc. Comfrey Roots, Coltsfoot, Flaxseed, Liquorice, Lungwort Moss, Marshmallow leaf; Mullein etc.

Marshmallow Flowers, Mallow Flowers, Colt.\foot Flowers, Violet Flowers, Mullein Flowers, Red Poppy Flowers, White Horehound, Motherwort etc. Aniseed,. Angelica Root, Blood Root, Colt~foot, Com/rey Root, Elecampane Roots, Flaxseed, Hyssop, Lobelia, Lungwort, Mouse Ear, Mullein, Senega, Thyme, White Horehound, Garlic, Echinacea, Eucalyptus, Cleavers, Poke Root etc. Boneset, Cayenne, Con1frey Root, Hyssop, Garlic, Pleurisy Root, Mullein, Flaxseed, Mustard etc. Mouse Ear, Sundew, Colt.\f()()t, Thyme, White Horehound, Liquorice, Aniseed, Flaxseed, Com.frey Root, Elecampane etc. Ephedra, Grindelia, Lohelia, Mouse Ear, Pill Bearing Spruge, Sundew, Wild Cherry, Aniseed, Blood Root, Colt.\foot, COl11frey

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Nervous System:

Nervine relaxant:

Nervine stimulant:

Stress: Anxiety:

Hyperactivity:

Depression:

Root, Liquorice, Senega, Motherwort, Hawthorn, Lime Blossom, Hops, Skullcap, Valerian etc.

Black Cohosh, Black Haw, Cal!fornia Poppy, Chamomile, Cramp Bark, Hops, Hyssop, Jamaican Dogwood, Lady's Slipper, Lavender, Lime Blossom, Mistletoe, Motherwort, Pasque Flower, Passion Flower, Rosemary, St. John's Wort, Skullcap, Valerian etc. Kola Nut, C(~ffee Mate', Black Tea, Peppermint ete.

Skullcap, Ginseng etc. Lady's Slipper, Lime Blossom, Mistletoe, Skullcap, Valerian etc. Red Clover, Oats, Valerian, Dandelion, Centauryetc. Damiana, Ginseng, Kola, Lady's Slipper, Lavender, Lime Blossom, Oats, Rosemary, Skullcap, Valerian, Vervain etc.

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Insomnia: California Poppy, Hops, Jamaican Dogwood, Valerian, Passion Flower etc. Balm, Lavender, Meadowsweet, skullcap, Valerian etc. Jamaican Dogwood, Valerian, Passion Flower, Black Willow, Wood Betony, Black Horehound, Chamomile, Golden Seal, Meadowsweet, Balmony, Wormwood ete. Hops, Jamaican Dogwood, Pasque Flower, Passion Flower, Ginseng, St. John's Wort, Valerian etc. Evening Primrose ete. Thuja, Dandelion, Podophyllum, Taxus, Colchicum, Catharanthus, Caster oil, Conium etc.

Headaches:

Migraine:

Neuralgia:

Multiple sclerosis: Cancer:

Clinical evaluation is usually carried out on a drug that alters the present diseased situation with restoration of normal functions of the body. This is known as DrugApproach-System (DAS). This means approach of drug in the body system for curative purpose e.g. Digitalis, a drug of cardiovascular system, Ephedra, a

Figure 1. Herbal Drug Development Scheme for Drug Regulatory Bodies

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drug of respiratory system and Panax ginseng, a drug of general weakness of body system (Dobelis, 1990; Evan, 1997; Soldati, 2000). Some medicinal plants of DAS are given above.

Clinical Trials Clinical trials for different problem are different therefore few protocols will be discussed here for understanding the methods of evaluation, significance of tests and adverse effects recognition. According to drug regulatory bodies following are the requirements for drug development. A scheme for drug development, based on current guidelines, involves a pre-clinic toxicology, the manner in which the drug is absorbed, metabolized and excreted after administration into animals (Nimmo & Tucker, 1991).

Phase-I (Pharmacokinetics Studies)

When Pre-clinical toxicology in model experiments is successfully completed then the next Phase-I starts with pharmacokinetic studies, which is the requirement of regulatory bodies. In these studies of drug trial emphasis is given on assessment of human tolerance, as well as on the absorption, distribution, metabolism and excretion of drugs (Nimmo & Tucker, 1991) .

Phase-II & III (Pharmacodynamics Studies)

When a drug is reported as a safe drug in pre-clinical and phase-I then it can be subjected to Phase-II & ill that is Pharmacodynamic phase. Pharmacodynamics

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deals with the results of interaction of drug and body at the receptor level. In other words it defined as the efficacy of the drug i.e. when the stereo-electronic configuration of the drug is complementary with the stereo-electronic structure of the active site or receptor (Nimmo & Tucker, 1991).

Phase-IV (Post Marketing Survey Reports)

After approval of drug for marketing, phase-IV trial or post marketing surveillance is done to delineate additional information about the drug's risks, benefits and optimal use. It is an important aspect of drug trial on the long-term effects of the drugs (Nimmo & Tucker, 1991).

WHO recommendations for Model protocols of Good Clinical Practices, for trials on pharmaceutical products and for Good Clinical Trial Regulations must be considered during evaluation.

Absorption

Absorption is the entrance of herbal remedy from its route of administration (eternal) into the plasma. This process involves different mechanism of the entrance of drug through selective membrane. There are few herbal remedies (single isolated molecule) like morphine, steroids and cardiac glycosides having parenteral administration, where entrance through membrane is not involved. The absorption process has direct relation with solubility, dosage form, excepients, and particle size (Nimmo & Tucker, 1991; Thomas, 2000).

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Distribution

Distribution of drug involves the transportation of drug from its route of administration or absorption to site of action. Mainly blood stream is involved in distribution but in some cases distribution take place through lymphatic system. In the blood stream drug moves either in free form or bound with plasma proteins (serum proteins) which is reversible. Reaching of the drug to the site of action is usually influenced by solubility and stability into the biological environment of the blood (Nimmo & Tucker, 1991; Thomas, 2000).

Metabolism

Metabolism of drug is referred to biotransformation of drug into its components (metabolites). They are usually water-soluble therefore excrete out through urine. Mostly biotransformations take place in liver but it can occur in blood and other organ of the body like kidney, lungs and brain. This action is more beneficial because it reduces the concentration of the drug in the circulatory system and lowers or completely suppresses the pharmacological and toxic effects (Nimmo & Tucker, 1991; Thomas, 2000).

Excretion

In this process elimination or removal of active form as well as degradative forms (metabolites) of drug occur through body excretions. A slow removal of drug & its metabolites result in a build-up of drug concentration in the body and it keeps the patient from the development of side effects. The main route of excretion of drug and its metabolite is through kidney in the form of solution i.e. urine, but in case of herb(s) taken in original form intestinal waste must be considered other includes lungs for exhaled gases (Nimmo & Tucker, 1991; Thomas, 2000).

All such processes and testing require proper dosing, concentration and duration for the development of correct pharmacological action.

Dose Range

In herbal remedy if it is a new herbal entity (NHE) for human and it needs to acquire desired pharmacodynamic response then a balance in dosage is required from the safety point of view. This can be achieved on the results of animal studies. The desired

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pharmacological actions can be obtained by the adjustment of minimum and maximum' therapeutic dose from the early studies of pharmacokinetics and dynamics. During studies, in healthy human volunteers, assessment of the intensity and duration of pharmacodynamic effects as a function of dose are of great importance in the development of dose regime (Nimmo & Tucker, 1991; Thomas, 2000).

This study, dose-response, should be carried out in different groups with fixed doses and the results obtained must be taken in mean parameter.

Time Effect

The effect of drug after administration of proper dose is totally related to concentration stay of drug in plasma and tolerance i.e. time effect. Time effect reflects the pharmacological action for a period of time but it is totally dependent on concentration of the drug in plasma (Nimmo & Tucker, 1991; Thomas, 2000).

Concentration

The concentration of drug in plasma can be maintained by maintaining the dose regime and it can be monitored by bioavailability tests (Nimmo & Tucker, 1991; Thomas, 2000).

Prolonged treatment may change the effect expected from the first dose due to the formation of metabolites with agonistic or anti-agonistic activity or the development of tolerance. Concentration and effect relationship, after single and multiple dosing, must remain the same in order to exclude the development of tolerance.

Interaction

The co-administration of two drugs having different mechanism of action may produce an additive or synergistic-effect due to pharmacodynamic or pharmacokinetic interactions. The concentration-effect relationship may be more complicated than that of each individual drug, with additive or synergistic effect at lower concentrations, while higher concentration may impair the effectiveness of combination (Nimmo & Tucker, 1991; Thomas, 2000).

Relationship of concentration-effect may be influenced by metabolites formed during the first phase.

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Administration through veins may produce a different relationship between concentration and effect than an oral administration. Usually metabolites are formed and accumulated during multiple administrations and some time they produce different drug-effect relationships from those seen after single doses (Nimmo & Tucker, 1991; Thomas, 2000).

Drug stability

For understanding the drug action and the maintenance of concentration in plasma drug stability can be divided into stability after administration and shelf life. Shelf life is a time bar of active ingredient to remain pharmacologically active in this period. This period varies from drug to drug and cannot be specified universally. A 10% degradation of the drug is considered as an acceptable limit unless the degraded products are toxic. The reasons of degradation are many (fungi, bacteria, heat light, humidity, oxidation-reduction, racemisation etc.) but usually microbial and chemical degradation are common.

Drug stability in situ is essential if therapeutic dose is going to reach the receptor. Drug stability is usually influenced by water solubility, acid nature of gastric fluid, enzymes' action and the stereo-electronic configurations of drug molecules (Nimmo & Tucker, 1991; Thomas, 2000).

The Methods of Clinical Evaluation of Herbal Remedies The measurement of the response to an herbal remedy involves the same parameters as considered in clinical evaluation of synthetic medicine such as dose, concentration, effect and time, because subject's condition and its physiological functions remain the same. The fast and slow responses of a remedy can be monitored on the following:

1. Arterial Pressure 2. Psychometric Screening 3. Pain Models 4. Analgesic Effects 5. Clinical Pathology Measurements 6. Dose Taking versus Dose Timing 7. Gastrointestinal Methodology 8. Markers of Drug Allergy

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1. Monitoring of Arterial Pressure The basic reason of monitoring arterial pressure during evaluation of any remedy is i) safety, ii) efficacy, iii) use of arterial pressure as a pharmacological model in human and iv) part of the assessment in studies of haemodynamics of a remedy affecting cardiovascular system (CVS). Safety is an important issue for a potent remedy because if remedy produces any change in arterial pressure that needs to be known. If these changes are of sufficient or high magnitude, the remedy may be with drawn from its developments. In this respect the use of ambulatory monitoring has great value. If during evaluation of remedy it is reported that the remedy is producing side effects, which might be attributed to postural hypotension, and this can be checked/confirmed by ambulatory monitoring of the blood pressure.

The herbal remedy act on the heart/CVS may require haemodynamic assessments. It is usually monitored by invasive techniques, where antiarrythmic or inotropic agents are used for this purpose (Dupont, 1987; Floras, 1982; Gould, 1981; Korotkoff, 1905; 0' Brien, 1985; 1989; Petrie, 1986; Raftery, 1978; Rose, 1980). These are having direct effects on arterial pressure. By using invasive haemodynamic technique it is also possible to assess the mechanism of change in arterial pressure.

The change in blood pressure if induced by isoprenaline can be used as LJ -adenocepter blocking agent of cardio-selective in man. The decrease in diastolic pressure, induced by isoprenaline, can be attenuated by Lh-selective blocking agent while the increase in systolic pressure cannot. Furthermore, the rise in systolic pressure induced by exercise cannot attenuate by [h-selective blocking agent. The conclusion drawn from these results is that the fall in diastolic pressure induced by isoprenaline is essentially dependent upon stimulation of LJr adenoreceptors, while changes in systolic pressure by isoprenaline and exercise are IJ I effects. With this knowledge a putative [J I-selective agent can be tested for differential effects on these 0,- and [Ir dependent changes in arterial pressure (Harry, 1989). Arterial pressure can be monitored to a great extent when a new antihypertensive agent is under evaluation. Initial studies can be performed in volunteers using standard sphygmomanometry technique; care in measurements can be taken as suggested by Petrie et at. (1986). These results may provide some idea of efficacy and

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safety, in particular indicating a dose with which to proceed into Phase II studies in patients with hypertension. Efficacy should be shown in the clinic, in the home and also in ambulatory states. From these studies should come evidence of the effect of the drug in lying, standing, work, exercise and sleep conditions. The ideal method for these studies should be direct invasive ambulatory for at least 24 hours. A smooth study can be carried out on different days especially if comparison with placebo and/or another active agent is considered (Littler & Komsuoghu, 1989). The confirmatory evidence could be obtained from noninvasive assessments.

It is only with ambulatory techniques that the duration of action of a remedy can be assessed accurately and from which sensible dose regime can be determined (0' Brien, 1985; 1989).

2. Psychometric Screening There are many drugs that cause impairment of skills of the body due to their effects on the central nervous system (Altmann, 1989; Donelson, 1980; Mortimer & Howat, 1986) and, therefore, this leads to the use of psychological tests to investigate the effects of drugs on CNS. The principles usually used in selecting tests for a screening are:

Measurement of Attention: The most commonly used tests are vigilance, concentrated attention and divided attention.

Vigilance Test of vigilance is related to the detection of signals, which are usually small and close to the threshold detection. Most commonly used method is Wilkinson Auditory Vigilance Task (Wilkinson, 1968). In this test, the subject listens through headphones to a series of tones against a background of white noise. Most of the tones are 500 msec long, but occasional tone is 400 msec. The subject's task is to press a button each time a short tone is heard. The test typically lasts one hour.

The test is simple but difficult because the average performance is dependent on the approximately 50% of correct detections. The test is also very sensitive and able to detect the very low dose of sedatives and mild stimulants e.g. caffeine & theophyline (Clubley, 1979; Fagan, 1988; Hart, 1976; Tiplady, 1990). The test is time consuming; therefore, its usefulness is limited.

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Concentrated Attention The commonly used test is the Continuous Performance Test (Rosvold, 1956). During test a series of different letters are flashed on a screen and the subject has to respond each time an X (easy condition) or an X preceded by an A (hard condition) is seen. The duration between the letters is 0.92 sec and the test is of either 5 or 10 minutes. The test is capable of detecting the effects of brain damage; sleep deprivation and drugs such as barbiturates (Mirsky & Kornetsky, 1964).

Another test of same kind is the Continuous Attention Task (Tiplady, 1990). In this test geometric pattern are used as stimuli and subject is asked to respond how many times consecutively seen the same shapes. The duration between the stimuli are 1.5-2.5 sec and the test lasts about 8 minutes. Test is sensitive to the effects of a number of drugs such as caffeine (Swift, 1988; 1988).

Divided Attention This test is useful in sensitive drugs and alcohol. The common paradigm used in it is tracking, coupled with a peripheral signal detection task (Moskowitz, 1984; Moskowitz & Sharma, 1974).

Psychomotor Tests: A variety and number of tests are available. Few of them are given below.

Pencil-and-Paper Tests There are two common test methods, Gibson Spiral Maze and Digit-Symbol Substitution, are used in it. In Gibson Spiral Maze method (Gibson, 1978) usually subject follows a spiral path marked on a sheet of paper while attempting to avoid the sides of the path and series of obstacles. The time taken and the number of errors are recorded.

In Digit-Symbol Substitution test (Stone, 1984; Mirsky& Kornetsky, 1964) a key is provided to the subject, in which the number 1-9 are matched to a symbol. Whereas, a series of random numbers is printed on a grid on the sheet and the subject writes the corresponding symbol under each digit as quickly as possible (written time is fixed and is 90 sec). The number of correct and incorrect symbols is recorded.

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Psychomotor Speed The most commonly used method in this test is the Choice Reaction Time (Frewer & Hindmarch, 1988; Hindmarch, 1980), where Leeds Psychomotor Tester is incorporated in it. The apparatus has six button arranged in a semicircular way, by each of which is a light. There is also seventh button in the middle. The subject places the index finger on the middle button. With different timing one or other of lights comes on and subject moves his finger to touch the corresponding button as soon as possible. The time to move the finger from the start button and total reaction time are recorded. The movement time is calculated by subtraction. This test is capable of detecting the effects of wide range of CNS depressant drugs.

Saccadic Eye Movements Eye movement is very important because its movement shows the activeness of brain. The eye movement is of two types, slow pursuit movements and rapid saccadic movements. Their movements require special kind of apparatus. The peak velocity and accuracy of saccades are lower-downed by several CNS depressant drugs (Bittencourt, 1981; Griffiths, 1984) .

Body Sway This method is used to measure psychomotor coordination instead of speed. This apparatus consists of one simple box with a string. The box is placed at a height of 1 01 above the ground, and the string is attached to the standing subject at the same height. The apparatus sums the movements in the anteriorposterior plane over one minute period, giving a measure of the body sway. It can demonstrate the effects of a variety of sedative drugs (Swift, 1984; Wright, 1971).

Tracking It is simple method usually used in car driving test or controlling of joystick/mouse in computer games. The subject is allowed to keep himself on the said track. The deviation from the path is recorded (Hindmarch, 1983; O'Hanlon, 1984; Volkerts & 0' Hanlon, 1986).

Test of Memory: The testing of memory can be divided into verbal and non-verbal, and short-term an~ long-term.

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Selective Reminding This is a verbal memory test. It belongs to long-term and short-term assessment (Buschke & Fuld, 1974). In this method a list of word is read to the subject at 2 sec intervals. The subject tries to recall the words in any order. The subject is then reminded only of those words that were not recalled correctly, and then attempts again to recall all the words in the list. This procedure repeated until the list is completed recalled. This test has been used in a number of studies where memory has been of interest, particularly where drugs are having anticholinergic effects.

Paired Word Learning In this method the subject is presented with three word pairs, following' which the first word of the pair is given as a cue. The subject responds by saying the second word. This repeated until each cue word has been represented three times. The procedure is then repeated with two further sets of three word pair. The test shows memory impairments with other sedative drugs (Isaacs & Walkey, 1964; Fagan & Swift, 1988; 1989).

Spatial Learning A test analogous to the Verbal Selective Reminding Test has been developed which uses pairs of rectangles from an irregular grid instead of words. This has been shown to detect the effects of scopolamine like drugs (Preston, 1988).

Cognitive Tests: This test covers slightly elaborated tests of attention to deep explore processing. It consists of Rapid Information Processing, Arithmetic, Semantic Processing and Subjective Measures.

Rapid Information Processing The subject is presented with a sequence of digits rate typically of 100/min. Presentation may aural (Talland, 1966) or on a monitor screen (Wesnes & Warburton, 1983). The task is to respond either to three successive even digits or to three successive odd digits. The test has been shown to detect impairments due to the alkaloid of Atropa belladonna, as well as improvements with tobacco alkaloid.

Arithmetic Many studies have used some kind of arithmetic (Ekman, 1963; Evans, 1973). A test as simple as

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(0' Hanlon, 1984). The most realistic is of course actual driving. A laboratory-based test is a more sensitive indicator than a real life-driving test. This test is more important for drug-induced impairments causing accidents. This again indicates the importance of assessing a broad range of abilities rather than just a single aspect of behaviour (Moskowitz, 1984). It is precisely the function of a validation study to determine this.

Magnitude of Effects:

Even if our tests are valid, appropriate and reliable, there still remains the question of how to interpret an effect a particular size. If criterion validation data were available in sufficient detail, it would be possible to establish a direct numerical relation between the various types of impairment and increased risk. This may be illustrated by a comparison of two recent studies carried out by a group on drugs with quite different actions. One sedative/hypnotic (chlormethiazole), the second is dopamine-2 receptor antagonist, antipsychotic (remoxipride). The results are shown in the table given below.

3. Pain Models for Natural Medicine

The International Association for the study of Pain has defined Pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage". It involves a stimulus, nociception and sensation and also components of suffering and behaviour. Any attempt to measure pain under laboratory conditions must inevitably eliminate much of the reactive component and the element of surprise, which is important in many traumatic conditions.

Criteria for Pain Model: A pain model experiment must have following characteristics: 1. The stimulus must not cause significant tissue damage. 2. The stimulus must be quantifiable so that it can be administered on repeated occasions in a highly reproducible manner. 3. The stimulus must cause a sensation that is unequivocally

identified by the subject as painful, and it should be possible to adjust the stimulus strength to produce a perceptible range of pain intensity ranging from slight to severe.

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4. The pain response must be quantifiable and it must be specifically suppressed by analgesics, i.e. sedatives and other drugs, which do not exhibit analgesic properties in the clinical situation, should not be effective.

5. The model should be sufficiently sensitive for the effect of analgesics to be demonstrable using normal therapeutic doses in small groups of volunteers who may be considered representative of the general population.

Some experimental pain stimuli are Radiant heat to skin, Laser heat to skin, Cold immersion of limb, Electrical shocks to fingers, ear lobe, tooth pulp, Electrical shock to nerve fibers, Hyper/hypo tonic saline injected into muscle, Chemical s on catharidin blister base, Pressure to bony prominences, Pressure to skin folds and Ischaemic limb.

Pain rating can be recorded as subjective assessment (e.g. amplitude of certain potentials) and objective assessment (e.g. verbal rating) (Beecher, 1956; Campbell & Lahuerta, 1983; Carmon, 1978; Chapman, 1985; Chatrian, 1975; Foster, 1986).

4. Measurement of Analgesic Effects

The correct measurement of analgesics is usually dependent on the ability of measurement in clinical situation and the methods. These methods may overlap with those used in pain models. There are many types of pain varying with different patients' populations, diseases and settings. Pain is a complex and multidimensional perception, which involves sensory, affecting and cognitive aspects, therefore, its measurement classified into objective or observational and subjective or self-report methods.

Objective or Observational:

In it clinician assigns numbers to scale a patient on one or more aspect of pain. This type of measurements consist of observation of physiological variables and behaviour patterns for example changes in heart rate, arterial pressure, cardiac out put, changes in respiration, changes in blood cortisol or catecholamines, changes in beta endorphins, changes in skin temperature, nerve conduction velocity, evoked potentials, sighing, groaning, grunting and demanding analgesics (Gracely, 1978; Huskisson, 1973; Keats, 1950).

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Subjective or Self-Reported Methods: All these measurements involve the patient making assessment and assigning the numbers. They include single dimension (e.g. category scales i.e. SDS, VRS; numerical rating scale i.e. 0 to 10 or 0 to 100; visual analogue scale etc.) and multi-dimension methods (e.g. McGill pain questionnaire, Dartmouth pain questionnaire, pain inventory, behavioural observational techniques, pain diaries, sickness impact profile).

There are also three main sources of error in pain measurement that are investigator bias, patient bias and data collection and scoring. Subjective or Self Reported Methods: All these measurements involve the patient making assessment and assigning the

Type

Oassification oflaboratol;l abnoffilalities

Criteria

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numbers. They include single dimension (e.g. category scales i.e. SDS, VRS; numerical rating scale i.e. 0 to 10 or 0 to 100; visual analogue scale etc.) and multidimension methods (e.g. McGill pain questionnaire, Dartmouth pain questionnaire, pain inventory, behavioural observational techniques, pain diaries, sickness impact profile).

There are also three main sources of error in pain measurement that are investigator bias, patient bias and data collection and scoring. Poor methodology or analysis of data should be avoided (Morton & Dobson, 1990). Clinical trial of analgesics can be carried out only if patient understand the instructions, subject of a suitable age and appropriate educational ability. Clinical trials guidelines include population, goal of

Sp ontaneous change s/vari ati on

Laboratory or recording error

Abnonnalitypresem for am aximum of 1-2 visits i.e. tern por ary change, abnorm ali ty over 3-4 visit never be considered as spontaneous change/variation. No relevam unwanted effects i.e. otherlaboratory abnorm aliti e s or concom itam di se ase. No relevam concomitantm edication. No c omm ents or action by inve sti gator .

U sual1 Y a sin~ e aberram value or, if more than one, evi dence of center effe ct. No relevam unwanted effects i.e. other laboratory abnorm aliti e s or concom itant. di se ase. Nor el evam c oncomi tant medic ati on. No c omm ents or action by inve sti gator .

Minimum change of no clinical im portance

Sli ght deviati on from the norm, but not im p ortam. No relevamunwanted effects i.e. otherlaboratory abnorm aliti e s or concom itam di se ase.

No relevam concomitantm edication. No c omm ents or action by inve sti gator .

Re1 l'V'"aflt c onc omi tant dise ase or operation

Possible dt.ug effect

eN 0 relevant, concomitantm edic ati on Relevant concomitant m edication taken)

Relevant c onc omi tant di sease or operati on pre sent at tim e of abnorm ality Any unwante d effe cts or lab oratory abnorm ali ti e s pr e sent must confinn thi s im pre ssion. Nor el evam c oncomi tant medic ati on. No comments or action by investigator.

Abnonnalityprogressive1yincreased during trial. Re1 evant unwanted effe cts and other 1 abor atcry abnorm aliti e s pr esem. C onfirm atory comm ems or acti ons by investi gator . Abnonnality, other than minimal, present at the last visit only.

Probable drug effect Abnonnalityprogressive1yincreases during trial. Re1 evant unwanted effe cts and other 1 abor atcry abnorm aliti e s pr esem. No relevam concomitantm edic ati on taken or disease present. Confirmatory commems or action byinvestigator.

11

Mansoor Ahmad

measurement, assess different options and know the limits of the tests used (Gracely, 1978; Huskisson, 1973; Keats, 1950; Keefe & Block, 1982; Melzack, 1975).

There are also three main sources of error in pain measurement that are investigator bias, patient bias and data collection and scoring. Poor methodology or analysis of data should be avoided (Morton & Dobson, 1990). Clinical trial of analgesics can be carried out only if patient understand the instructions, subject of a suitable age and appropriate educational ability. Clinical trials guidelines include population, goal of measurement, assess different options and know the limits of the tests used (Gracely, 1978; Huskisson, 1973; Keats, 1950; Keefe & Block, 1982; Melzack, 1975).

5. Clinical Pathology Measurements

In assessment of new drugs laboratory tests are carried out for many reasons. In practice, laboratory tests are performed for two reasons i.e. analysis of pharmacodynamic effects and screening for adverse effects. But some time regulatory authorities also require these two during the development of a drug.

The range of tests, which can be performed along with new technologies, includes platelet count/volume, mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), aspartate transaminase (Ast), alanine transaminase (Alt), alkaline phosphate (AP), bilirubin, GGT, SGPT, urea, creatinin, uric acid, blood sugar RIF, cholesterol, LDL, HDL, BUN etc. In clinical trials there are guidelines that recommend not only the test to be performed, but also the frequency with which it should be performed (Chuen & Hallsworth, 1990). Criteria for interpretation and classification of results are also available which may allow comparisons to be made between studies. Determination of the normality of laboratory data relies largely on clinical interpretation in all stages of clinical trials.

6. Dose Taking versus Dose Timing

Assessment of drug effects in clinical trials is controversial due to variable drug response, which involves pharmacokinetic, and patient compliance (Harter & Peck, 1990). Pharmacokinetic variability can be minimized by measuring drug concentration in plasma at a defined time after a defined dose on

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several occasions, thereby identifying those patients who arepharmacokinetic outliers and who, therefore, need adjustment of their dose regimen. The recent digital methods for monitoring the time of dosage now form the basis of reliable estimation of compliance. In particular, they also make it possible to measure dose timing in outpatient clinical trials, turning variable compliance from disadvantage into new source of information about response to drugs. It is relevant in this context to consider the extent of poor and partial compliance in clinical trials, its clinical pharmacological correlates, and finally its implications for statistical analysis of trial results.

"Dose Taking" Compliance

Recent methods, chemical marker and digital monitoring, both show a wide range of compliance among patients prescribed various kinds of chronic therapy. The over all average of prescribed doses taken is approximately 70%, with a range from 0% to approximately 120%. A more informative view shows that when patients are classified with respect to the fraction of prescribed doses taken during a month or more of observation, 50-60% take more than four-fifths, 30-40% take between two- and four-fifths, and the rest are more or less equally divided between those who take less than two-fifths of prescribed doses and those who take more doses than prescribed (Cheung, 1988; Cramer, 1989; Jeiven & Anderson, 1989; Kass, 1986; 1987; 1986; Kruse, 1990; Kruse & Wiber, 1990; Pullar, 1989). One of the striking aspects of reliable

Figure 3: shows the similar distribution of compliance (as a percentage of prescribed doses taken) in the treatment of epilepsy and glaucoma.

Review Article

findings across different types of chronic drug therapy. For example, fig. 3 shows the similar distribution of compliance (as a percentage of prescribed doses taken) in the treatment of epilepsy and glaucoma.

'Dose Timinf{' Compliance It is noted that many patients who take most or all of their prescribed doses do so at intervals that are substantially different from those directed. For example, Rudd et al. (Rudd, 1990) observed that only a small minority of patients took more than two-thirds of their doses within 9-15 hours of one another, despite taking more than 80% of prescribed doses in a ten-week trial or two anti-hypertensive agents. Instead, most dosed themselves at intervals that alternate between 16-18 hours and 6-8 hours. If a drug product intended to be dosed twice-daily has duration of action of only 12-13 hours, drug action will cease during the later part of 16-18 hours dose intervals. Whether such recurring gaps in drug action h"ave an adverse influence on the course of therapy depends on the clinical condition and the drug. Such interpretations in dosing may also cause rebound effects.

Clearly gaps in therapy will be much longer when patients omit doses, particularly when skipping several doses in sequence. In this event, not only do patients fail to receive the benefits of treatment, but the risk from rebound phenomena is much greater. A prominent example is the risk of myocardial infarction and other manifestations of coronary heart disease in patients who abruptly discontinue beta-blockers, in case beta-blocker is prescribed for hypertension.

Wide variations in compliance, due mainly to extensive negligence, are often the single greatest source of variance in drug response. Reliable, realtime measurements of compliance can not only account for appreciable proportion of the variance in drug response, but can also be used to improve the understanding of how drug effects-both beneficial and undesirable-depend on both dose quantity and dose timing.

7. Gastrointestinal Methodology

To prove the efficacy and safety of a drug in the treatment of a disease requires adequate and wellcontrolled studies. It is necessary, however, not only to show that the drug works, but also to determine the optimal dose and dose interval in which the drug

IntI. Chern. Pharm. Med. J.

should be used, as well as the optimal duration of therapy.

For the evaluation of new drugs, new indications or new dosage regimens of known compounds in gastrointestinal therapy, a number of methods are available which yield accurate and reproducible data. These methods include, oesophageal manometry, endoscopy, pH-metry, gastric secretion measurement, long term monitoring of gastric pH, ulcer studies (endoscopy), gastric potential difference, faecal occult blood-loss measurement, methods for analyzing gastric emptying, gallbladder sonography, sphincter of Oddi endoscopic manomery, small bowel and large bowel endoscopy ~Lanza, 1980; Prichard, 1985; Weihrauch, 1988; Weihrauch & Demol, 1988; Wiener,

1988).

8. Drug Allergy/Drug Reaction

In drug evaluation Type I hypersensitivity is one of the most important part among all types of hypersensitivity (Type I-IV) because it is the immediate response of the body. Those reactions whose clinical features mimic are classified as "pseudo-allergic" or "anaphylactoid". True anaphylactic hypersensitivity is often mediated through IgE. Anaphylaxis is a relatively uncommon form of drug hypersensitivity, but the serious consequences of failing to recognize it or to follow up survivors with appropriate investigation and advice.

Type I Hypersensitivity

This type includes acute generalized reactions, occasionally fatal, to bee or wasp venom, or more commonly, to inhalant or ingestant allergens such as dust mite, pollen of animal proteins, or, more rarely, food protein or other macromolecules. The classic type allergy, for example bee venom allergy, follows:

Induction of sensitivity: following one or more stings, which involve up to 50 f..lg of foreign protein, mainly enzymes, being injected to the skin. Some individuals respond by producing high titers of IgE specifically directed towards one or more of the protein antigens in the venom. The IgE become attached to high and low affinity receptor sites on mast cells, blood basophiles, platelets and possibly other cells/tissues. If specific IgE is still present on these potentially mediators-releasing cells at the time of a

13

It fulfills the criteria laid down by WHO for herbal medicine i.e. macro & microscopic tests, physical tests, chemical tests, purity tests, chromatographic analysis, chemical assay, anti-microbial tests, antiviral tests, pharmacological tests and toxicity tests etc.

Mansoor Ahmad

subsequent sting, venom antigens can trigger massive release of potent mixture of pre-formed and newly synthesized inflammatory mediators, including histamine, prostaglandins and leukotrienes.

The released mediators, by interaction with receptors on target tissues, including vascular, bronchial or intestinal smooth muscle, the heart, etc., produce local and/or generalized effects. The exact outcome of these depends, not only on the types and amounts of mediators released, but also on the target organ sensitivity of the victim at the time of the sting.

There are other (non-lgE) mechanisms, which can lead to an identical result, including direct effects on mediators-releasing cells e.g. by codeine phosphate, or by other immunological pathways, e.g. by antigen/IgG reaction, activating the complement pathway to produce anaphylatoxins,. with direct and/or indirect (via mast cell activation) effects.

In case of drugs which are themselves protein, it is not surprising that IgE-mediated hypersensitivity can occur.

Recognition of allergy

It is difficult to recognize anaphylactic or anaphylactoid reaction and differentiate from other acute reactions such as vasovagal attacks, hypoglycemia, epilepsy etc. In it most helpful factor is the history, either from patient, a witness or a doctor. Clinical features for anaphylaxis are itch, flush, weal and angioedema, voice change, stridor, wheeze and dyspnoea. Other features often present such as tachycardia and other arrhythmias, hypotension, sudden loss of consciousness and feeling of doom. Rarely, gastrointestinal or genito-urinary manifestations can be prominent features of anaphylaxis.

Investigation

This includes the measurement of plasma or urine inflammatory mediators or their metabolites. Schwartz (Schwartz, 1987) identified a specific mast cell derived tryptase, which can be assayed in secretions or in plasma, which remains detectable for some hours after reactions. An assay for this mast cell activation marker is now commercially available and it is useful in differentiation of anaphylactic-anaphylactoid reactions from other reactions than in histamine or

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Inti. Chem. Phw7Il. Med. J.

methyl histamine assays (Adkinson, 1984; Mathison & Stevenson, 1979; Schwartz, 1987).

Clinical Evaluation Researches on Herbal Remedies

Single Herbal Remedies

Researches on single herbal remedies are reported from different part of the world but on collection of data it is found that very less number of clinical trials are reported though the drugs are in use since a long time. Here we are quoting some example having more or less complete data such as:

Hypericum perforatum L. (Clusiaceae or Guttiferae or Hypericaceae)

Other names (synonyms) of S1. John's Wort are Hypericum officinarum Crantz, Hypericum officinale Gater ex, Steud, Hypericum vulgare Lam. It is a drug of anti-depression frequently used in systematic treatment of mild and moderate depressive episode. In International statistical classification of diseases and related health problem it is classified as F32.0 and 32.1. Its other uses are in the treatment of minor cuts, burns and skin ulcer and it is also valuable in topical viral infections, inflammation of bronchi, urogenital tract, billary disorders, bladder irritation, common cold, diabetes mellitus, dyspepsia, haemorrhoids, neuralgia, migraine, headache, sciatica and ulcers. It also has diuretic action and is also used as emmenagogue and antimalarial agent (Tyler, 1994; 1993, Malik, 2001; Lust, 1974; Newall, 1996).

WHO monographs on selected medicinal plants describes two types of clinical trials on the antidepressant activity of Hypericum perforatum (i.e. clinical trails without control and clinical trails with control) along photodynamics effects, pharmacokinetics, drug interaction, contraindications etc. or in

other words this an example of clinical evaluation of herbal remedy. In this monograph clinical trials of H. perforatum are described as (WHO monograph, 2002; Ernst, 2002).

Review Article

Clinical trials without control

"The safety and efficacy of oral administration of Herba Hyperici has been assessed in more than 5000 patients in numerous case reports and studies. In a drug monitoring study involving 3250 patients, 49% were assessed as being mildly depressed, 46% as moderately depressed and 3% as severely depressed at the beginning of the trail. The patients were treated with 300 mg of a dried 80% methanol extract of the herb three times daily, and evaluated after 2 and 4 weeks of therapy. After treatment, 80% of patients had improved or were symptom-free, while 13-16% remained unchanged or were worse. Minor adverse reactions were reported in 2.4% of patients. A post marketing trial was performed with 2404 patients with symptoms of mild to moderate depression who were treated with 2-4 capsules of an ethanol extract of the herb (equivalent to 0.6-1.8 mg total hypericin) daily for 4-6 weeks. Symptomatic improvement was evaluated as good to very good in 77% of patients and satisfactory in 15%".

"The effects on an ethanol extract of the herb on the electroencephalogram (EEG) of 40 patients with depression were determined following administration of the extract (equivalent to 0.5 mg total hypericin or 1.4 crude drug) daily for 4 weeks. An increase in theta-activity, a decrease in alpha-activity and no change in beta-activity were observed, indicating the induction of relaxation. A significant increase in nocturnal melatonin plasma was observed in 13 healthy subjects treated with a hydroethanolic extract of the herb (equivalent to 0.53 mg total hypericin) daily for 3 weeks. A significant increase in the concentration of neurotransmitters in the urine was observed 2 hours after administration of a standardized ethanol extract of the crude drug to six women with symptoms of depression" (WHO monograph, 2002).

Clinical trials with control

'The results from 28 controlled clinical trials involving oral administration of Herba Hyperici have been published. Twelve of the trials, involving 950 patients, were conducted using an ethanol extract 0 the herb, while other 16 trials of

1170 patients used dried 80% methanol extract. A

systematic review and meta-analysis of 23 of the'

randomized clinical trials involving 1757 patients assessed the efficacy of the herb in the symptomatic treatment of mild to moderate depression. Twenty trials were doubleblind, one was single-blind and two were open studies. Fifteen of the trials involving 1008 patients were placebocontrolled and eight studies of 749 patients were comparison trials with other antidepressant drugs. With the exception of two trials, all studies had treatment period of 48 weeks. Daily dosage ranged from 0.4 to 2.7 mg hypericin in 300-1000 mg standardized extract of the herb. Seventeen trials used the Hamilton Rating Scale for Depression, which

Inti. Chem. Pharm. Med. J.

focuses primarily on somatic symptom, to measure effectiveness, while 12 trials used the Clinical Global Impression Scale. The latter involves observed-rated analysis of severity of illness, global improvement and efficacy. The meta-analysis concluded that the herb was significantly superior to the placebo and was as effective as standard antidepressants such as maprotiline or imipramine (75 mg three times daily). Few side effects were seen in the herb-treated patients (19.8%) than in those receiving standard antidepressants (WHO monograph, 2002).

Some other examples of single remedy which are clinically evaluated according to WHO guidelines or the criteria mentioned above (figure 1 & 2) are Urtica dioica L. (synonyms U. gracillis Ait, U. major Kanitz, U. urens maxima Blackw), U. urens (synonyms U. minor Fuch, U. minor Moench., U. urens minima Dod.); roots of these species are used in symptomatic treatment of nocturia, polyurea, urinary retention due to benign prostratic hyperplasias (BPH) stages I and II, and/or where prostrate cancer declared negative; Prunus africana (Hook. F.) Kalkman (synonyms Pygeum africanum Hook. f.) dried bark of the trunk is used in the treatment of urinary tract symptoms of BPH stages I & II (nocturia, polyurea, urinary retention) or where prostrate cancer diagnosed negative; the fruits of saw palmetto, Serenoa repens (Bartr.) Small. (synonyms Brachea serrulata (Michx.) H. Wendl., Chamaerops serrulata Michx., Corypha repens Bartr., Sabal serrulata (Michx.) Nichols, S. serrulata (Michx.) Nuttall. ex Schult, Serenoa serrulata Hook, S. serrulata Roem. et Schult., S. serrulatum (Michx.) Benth et Hook, S. serrulatum Schult), are used in the treatment of urinary tract symptoms of BPH stages I & II (nocturia, polyurea, urinary retention) or where prostrate cancer diagnosed negative; the dried flower branches of Crataegus monogyna Jacq. (Lindm) (synonyms C. appiifolia Medik. Non Moichx., C. oxyacantha L. ssp monogyna Lev., Mespilus elegans Poir., M. monogyna All., M. monogyna Ehrh.), C. laevigata (Poir.) DC (synonyms C. oxyacantha L., C. oxyacantha L. ssp. polygala Lev., C. oxyacanthoides Thuill, Mespilus oxyacantha (Gartn.,) Crantz.) and other species are useful in the treatment of chronic congestive heart failure stage II (as reported by New York Heart Association). Dried ripe seeds of Aesculus hippocastanum L. (synonyms A. procera Salisb., A. castanea Gilib., Castanea equina,

Hippocastanum vulgare Gaertner), not to interchange with common chestnut, are useful, internally, for the treatment of chronic venous insufficiency (including pain, feeling of heaviness in leg, nocturnal calf-muscle

15

Mansoor Ahmad

spasm, itching and oedema), externally, venous insufficiency, sprains and bruises; dried leaves of Melisssa o.tficinalis L. (synonyms Calamintha officinalis Moench., Melissa graveolens Host, Thymus melissa E.H.L. Krause) are used externally in the treatment of herpes labialis; fresh or dried leaves of Ocimum sanctum L., (synonyms Moschosma tenuiflorum (L.) Heynhold, Ocimum album Blanco, O. anisodorum Muell., O. brachiatum Hasskarl, O.

flexuosum Blanco, O. frutescens Burm., O. gratissimum Lour., O. inodorum Burm., O. monachorum L. O. nelsonii Zipp ex Span., O. tenuiflorum L., O. virgatum Blanco) are useful in diabetes (but more clinical data is required for support); Fixed oil of the seed of Evening Primrose i.e. Oenothera biennis L. (synonyms O. communis Leveille, O. graveolens Gilib., Onagra biennis Scop., Onagra vulgaris Spach.) is used internally in the treatment of eczema, diabetes, neuropathy and mastalgia; dried rhizomes of Piper methysticum G. Forst. (synonyms Macropiper latifolium Miq., M.

methystiscum (G. Forst.) Hook. et Arnott, Piper inebrians Soland) are useful in short-term treatment of insomnia, anxiety due to nervousness, stress or tension; Dried ripe fruits of Silybum marianum (L.) Gaertn. (synonyms Carduus marianus L., Carthamus maculatum Lam., Cirsium maculatum Scop., Mariana mariana (L.) Hill., Silybum maculatum Moench.) are used in the treatment of acute and chronic hepatitis and cirrhosis; Dried aerial parts of Andrgraphis paniculata (Burm. F.) Nees (synonyms lusticia latebrosa Russ., 1. paniculata Burm. f., J. stricta Lam. Ex steud) are

used in prophylaxis, uncomplicated sinusitis, bronchitis, pharyngotonsillitis, urinary tract infections and acute diarrhoea; essential oil of leaves and terminal branches of Melaleuca alternifolia (Maiden

and Betche) Cheel is used topically in the treatment of acne, tinea pedis, bromidrosis, furunculosis, mycotic onchyia (in chomycosis only) and vaginitis due to Trichomonas vagina lis or Candida albicans, cystitis and cervicitis (Dobelis, 1990; Rashid, 2000; Kammarata, 1999; WHO monograph, 2002).

Compound Herbal Remedies

Different herbal pharmaceutical industries (HPI) in Asia especially in the Indo-Pak subcontine~t are exporting compound remedies to USA, Europe and Russian States. The standard of quality and efficacy of compound herbal remedies of China, Japan, Singapore and Malaysia are up to the standard mark but the

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Inti. Chem. Pharm. Med. J.

standard of herbal remedies of both the countries, India and Pakistan, is doubtful. Major problem is of GMP and validation. Another problem is of the availability of clinical data. No HPI likes to publish and provide clinical data of its product(s). Therefore, incomplete information is available on products, which is not enough to quote here.

The regulatory bodies should have to order herbal pharmaceutical industries to comply the protocol designed by WHO for herbal remedies or follow the same pattern designed for allopathic drugs.

Usually compound herbal remedies are prepared by mixing a major herb of particular curative property with supporting herbs to avoid or minimize side effects or some time two herbs of same property with the aim to enhance curative property in a shorter period. This is an art and science and it requires clinical evaluation and validation. Now the question arises what is validation? Why should it follow in herbal remedies?

Validation of Herbal Remedies at Industrial Level

Validation is an essential part of herbal drug manufacturing and it starts with the establishment of product specifications. Through validation manufacturer and regulatory bodies control the manufacturing process, specification and consistency of the product. Another aspect of validation is documentation of the process. This documentation helps in demonstration and presentation of manufacturing process, which are under control (Colton, 1994).

It can also be defined like this, "Validation is a tool with which we provide documented evidence that the

,Jacilities we build, the equipment we operate, and the standard operating procedures (SOPs) and manufacturing formulae we follow will consistently produce products that meet their predetermined specifications and quality attributes" (Colton, 1994). There are some terminologies used in validation of herbal remedies, biochemical and pharmaceutical procedures:

Calibration A measuring device procedure where produced

results are compared directly with reference standard devices with in specified limits or in an appropriate range of measurements.

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Cell Seed: A quantity of cells/seeds/tissues/part of herb/whole herb store in aliquots at -70°C or below.

Certification: It is an administrative procedure where the review and approval process is accomplished as a final step in the validation program.

Concurrent Validation: It is a term used for establishing documented evidence that a process does its activity with in the frame works or the data gathered followed the actual process implemented.

Drug Product: An end product i.e. a finished dosage form

for example capsule tablet, solution. HVAC: Heating, ventilation and air conditioning system. Intermediate: Any substance, which is produced by

chemical, physical, or biological action at some stage of bulk production of drug but it is used at another stage of bulk production.

Installation Qualification (IQ): It is a documental proof that a system has been installed with all key designed specifications.

Master Working Cell Bank (MWCB): A quantity of cells/seeds/tissues/part of herb/herb of uniform composition, derive from stored ampoules, stored at -70°C.

Operational Qualification (OQ): It is a documental proof that a system performs its activities as designed through out all anticipated operating ranges.

Pet:formance Qualification (PQ): It an approved plan, which

will be performed to validate a system or process.

Population Doubling Level (PDL): The number of

population doublings that a cell culture has

undergone.

Process validation: It is a documental proof that provides a high degree of assurance of the process, means it has been performed consistently and produced a product meeting its predetermined specifications and quality attributes.

Prospective validation: It is a documental proof prior to process implementation and that a process does what it is supposed to do.

Qualification: It is a part of validation program where physical parameters control the manufacturing system and is evaluated to demonstrate its suitability to carry out the designed process, as separate from validation of the process itself.

Regulatory Authorities FDA is the official regulatory authority in USA and in other countries Ministry of Health is responsible for that. All countries of world are having more or less the same type of law as FDA has postulated for US manufacturers. The drug manufacturers are bound to

IntI. Chem. Pharm. Med. 1.

comply GMP's rules and provide drugs with assurance of safety and efficacy to public. According to FD&CA (Federal Food, Drug and Cosmetic Act), a drug "meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that is purports or is represented to possess". Production of herbal remedies can be regulated with the training of inspectors in unique production technologies and the investors must follow the government regulations toward drug production (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Process Development

The basic requirement of process development is planning, foresight and follows up of assured process, which is ready for implementation into manufacturing use. Process development works together with validation, QC, QA, manufacturing, and engineering staff. The end product is successful development, validation and implementation of the process into routine manufacturing (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Change Control and Revalidation

Change control and revalidation are linked together whenever there is a need to change control policy, it

. gives insurance to the integrity of validation status of system and procedures. If changes are made or new procedures are adopted, the change control program is required to evaluate the needs and scope of revalidation testing. Revalidation consists of changes in production system, product formulation, manufacturing process, equipment, control software, packaging, and the manufacturing facility. Up to this point various departments are involved with this validation i.e. SOPs, periodic audit, routine training of personnel, QC testing, preventive maintenance of equipment, periodic calibration of critical process instrumentation and periodic review of SOPs (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Validation of Utilities System

For validation of utilities of system proofs are prepared in the form of documents, which confirm that system has been installed properly, meeting process

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Mansoor Ahmad

design requirements, manufacture's recommendations and all applicable code. The product of the utility should be measured to provide assurance that it meets both the utility specifications and the entire process requirements for example compressed air should be tested for humidity, microbes, particulate and hydrocarbon levels, nitrogen, oxygen, and other gases (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

EnvironmentaI ConroI Validauon

The basic purpose of it is to provide assurance that the facilities designed and environmental control procedures are enough to maintain the environment within the defined limits. In this system microbial monitoring, temperature levels, humidity, airborne microbial and particulate quality must be monitored on daily basis. This monitoring comes under QC and maintenance department (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Cleaning methods and product changeover

Cleaning method validation is carried out to evaluate residual detergent and product levels on washed equipment and having use in manufacturing operation. It also includes endotoxin testing. The effectiveness of these methods can be assessed on final rinse water and by surface testing (swabs). Selection of specific test

method is depending upon the equipment. configuration, chemical nature of product, cleaning agents and stages in the production process.

The most common methods for cleaning procedure validation are visual examination, Lowry assay for total residual protein level determination, limulus amebocyte lysate (LAL) assay for endotoxin level determination etc. (Colton, 1994; Guideline on general principles of process validation, 1987;. Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Bio-inactivation Validation

According to the National Institutes of Health (NIH), organisms should be inactivated prior to removal from a closed system and waste solutions and waste materials should be inactivated, with respect to their biohazard potential, thus bio-inactivation should be validated through different methods such as heat kill, steam sterilization and chemical treatment by monitoring variables that is time, temperature, pH etc.

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(Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Sterilization Validation

The aim of sterilization validation is to achieve the highest degree of desired sterility. The basic methods of sterilization are filtration, autoclaving, freeze dryer etc. Validation of sterilization process is either based upon bio-burden approach (lethality calculation) or the over kill approach described by Parenteral Drug Association (PDA) technical Monograph No. I(Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Media hold challenge Validation

Sterilized liquid products require an adequate handling to maintain the sterility, therefore the vessel in which it is kept and time interval should be validate to inhibit microbiological contamination. For that purpose microbiological growth media such as trypticase soy broth is sterile filtered into or steam sterilized within the vessel then inspected for evidence of microbial contamination. Some time manipulation of the medium should be performed during holding period (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

De-pyrogenation validation

Validation process of depyrogenation is more or less same as process of sterilization. The only difference is the use of endotoxin challenge in place of biological indicator challenge because the desired effect of a depyrogenation process is endotoxin destruction. Validation of depyrogenation equipment and process are carried out by both empty chamber heat distribution and load~d chamber heat penetration studies (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Validation of Filtration

Filtration is used in various steps of manufacturing process e.g. in filter medium, removal of debris, or diafiltration of the intermediate drug product etc. and a complete validation of filtration process is incomplete without evaluation of the product. Therefore, documentation of each step is essential to protect

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validation process (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Programmable Logic Controllers (PLCs) Validation

Computers, computerized systems and robotic systems are now essential part of various operations of herbal pharmaceutical industry. For this purpose FDA has published a guideline for investigators and pharmaceutical industry. This facility becomes the part of sensitive computerized programs and production equipment therefore needs validation (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Validation of Bulk Drug Manufacturing

This validation indicates that process controls are valid and up to standard. It also assures consistent product quality with characterization of the MWCB, testing of product recovery and purification steps and development of in-process tests.

Characterization of the MWCB

This is carried out to provide information about the integrity, purity, consistency of herbal material and cells used during production as well as to document the purity of the MWCB. Herbs and cell line characterization depends on general information i.e. history, morphology, methods used in storage, maintenance, propagation of herb and cell line, determination of cell marker relevant to final product purity & cell line identity, tumerogenecity, karyology, retroviruses, examination of cells and organs of herb, testing of MWCB for virus, fungi, bacteria or mycoplasma. In case of bacterial production system characterization consist of carbohydrate utilization, antibiotic resistance, prototrophy, auxotrophy, contamination, for plasmid; sequence and restriction map, and for the transformed host; growth rate, production expression, plasmid form, plasmid restriction map and sequence, and SDS-P AGE gel product profile. On top of it testing should be performed to document stability of herbal material, cell and the genetic materials encoding the product (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Recovery and Purification

Objective of it is to separate the drug material from impurities, contamination, and process waste. The

Inti. Chem. Pharlll. Met/. J.

main purpose of this recovery and purification is to produce a good quality drug product, which meets its all pre-determined specifications. In case of herbal remedy chromatography procedure, column and regeneration of column, extraction with solvents, recycling of solvents validation must be documented (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Validation of Pharmaceutical Manufacturing

Pharmaceutical process of validation is performed to provide documented evidence of manufacturing process, which is reproducible and constantly performs for which it is designed. This validation also covers other documented - evidences of the process

performance like aseptic conditions & processing, lyophilization, packaging etc.

Aseptic Processing

This validation demonstrates the environment, equipment and procedures performed in aseptic condition and the product is free from induced contamination. Environment monitoring, HV AC validation, personnel training & monitoring and the aseptic filling of solutionslMedia preparation usually perform validation of aseptic processing (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Freeze Drying (Lyophilization)

This is performed to stop enzyme activity, chemical reactions, interaction, degradation in fresh plant material, mixing of chemical, cell activity, and to increase shelf life and stability of products. During this process a protein-containing solution is first frozen and then subjected to lower level of vacuum and temperature, this evaporates the frozen moisture from the material. During validation of pharmaceutical manufacturing lyophilization takes place multiple times (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Container/Closure Integrity

Container/Closure System has basic importance in pharmaceutical industries and it is a combination of different components, which includes method of sealing, proper container material and color for light protection in case of light sensitive drugs. Variation in

19

Mansoor Ahmad

container and closure are not permitted from safety & efficacy point of view.

Two test methods are available in USP for verification of the integrity of containers and closures seal. These are USP bacterial challenge test and dye leak test (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

Packaging and Labeling

Before disbursement of products from warehouse there should be an assurance that the product meets the predetermined quality and proper labeling. Because it has been observed that 26-32% of the product recalls are due to wrong labelling. Froin safety point of view packaging and labelling material should be specified, use different colors to avoid mislabelling and handling. Validation of labelling is a matter of choice of right labels, equipment, operator training and process flow & control. A label must contain batch number, manufacturing and expiry date (Colton, 1994; Guideline on general principles of process validation, 1987; Loftus & Nash, 1984; Carleton & Agalloco, 1986).

General Equipment Validation

All kinds of equipment require frequent checking of gauges, sensors, switches and sensitive equipment used in process control or production like balances, analyzers, particle specific instruments need calibration and proper validation.

General Ethical Principles

Clinical study (for the measurement of therapeutic and adverse effects) involving human subject should be conducted with basic ethical principles i.e. volunteer (subject), beneficence and justice (http:// www. ayurveda-herbal-remedy.com/).

The investigator must obtain the informed consent of the subject or, in the case of an individual who is not capable of giving informed consent, the consent of a legal guardian. Informed consent is based on the principle that competent individuals are entitled to choose freely whether to participate in clinical study or not. Informed consent protects the individual's freedom of choice and respect for individual's autonomy.

20

Inti. Chern. Pharm. Mal. J.

The investigator is advised to provide the individual with the following information in the language he or she is able to understand:

the objectives and methods of the clinical study, the calculated duration of the subject participation, the benefits expected as an outcome of this study, any risk to the subject, related with study, maintenance of confidentiality of records, responsibility of investigators,

provision of free treatment for study related injury, compensation of subjects for disability or death resulting from such injury, and

freedom of individual to participate and to withdraw from study any time without penalty or loss of benefits to which the subject would otherwise be entitled.

Subjects may be paid for the inconvenience and time spent, and should be reimbursed for expenses incurred, in connection with their participation in research. They may also receive free medical services. However, payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in research against their better

judgment (inducement). All payments, reimbursement and medical services provided to research subjects, should be approved by the Ethical Committee to which all clinicians, herbalists are signatories.

When a guardian is asked to give consent on behalf of an incompetent person, no remuneration should be offered except a refund of out of pocket expenses.

When a subject is withdrawn from research for medical reasons related to the study the subject should get the benefit for full participation. When a subject withdraws for any other reasons, he/she should be paid in proportion to the amount of partici pati on.

The investigator should safeguard the confidentiality of research data, which might lead to the identification of individual subjects. Data of individual subjects can be disclosed only in a court of law under the orders of the presiding judge or in some cases may be required to communicate to drug registration authority or industrial sponsor of research or in cases of certain communicable diseases to health authority. Therefore, the

Review Article

limitations in maintaining the confidentiality of data should be anticipated and assessed.

All trials involving human subjects must be submitted for scientific review and approval of ethical review committee before starting such study.

Conclusion

Still there are many things that need discussion and explanation for example the adverse effects of those drugs, which are present in the market on sale and the people are having complaints against or complaining about their side effects. On the Internet search a number of reports were found against some herbal remedies, which were not recommended/prescribed by any authentic physicians. This is an alarming situation for herbal remedies regulatory bodies, manufacturers and consumers. Here I am presenting some examples of adverse effects derived from the Internet:

l. Herbal medicinals: selected clinical considerations focusing on unknown or potential drug-herb interaction (Miller, 1998; Webb, 1995); Miller 1998 reported that if Echinacea (E. angust!folia, E. purpurea) used for a longer period than 8 weeks, it may cause hepatotoxicity. Therefore it is also advised that it should not be taken along with other drug of hepatotoxicity producer/promoter, such as amiodarone, methotrexate, and Ketoconazole. lmmunosutimulants, e.g. Echinacea and zinc, are not recommended with immuno-supressants e.g. corticosteroids and cyclosporine.

Non-steroidal anti-inflammatory drugs may act as antidote the usefulness of Feverfew (Tanacetum parthenium) in the treatment of migraine headache (Miller, 1998; Webb 1995; Knight, 1995; Maries & Kaminski, 1992; Guin & Skisdmore, 1987).

The use of Ginseng (Panax ginseng) may cause headache, tremulousness, and manic episodes in patients having phenelzine sulfate in their treatment (Miller, 1998). For expected additive effects Ginseng is not recommended with estrogen or corticosteriods.

Kava (Piper methysticum) should not be used with alprazolam because it becomes a cause of coma (Miller,

1998; Ernst, 2002; Wheatly, 2001; Volz, 2001).

Valerian (Valeriana officinalis) has sedative effect, therefore, is not recommended to use with barbiturates (Miller, 1998; Houghton, 1988; Willey, 1995).

Feverfew (Tanacetum parthenium), Ginseng (Panax ginseng), Garlic (Allium sativum), Ginger (Zingibar officinale) and Ginkgo (Ginkgo biloba) are blood purifier, therefore, they may alter bleeding time concomitantly with warfarin sodium. It may interfere with anticogulant and antiplatelet agent (Miller, 1998;

')

3.

4.

5.

6.

lnt/. Chem. Pharm. Med. J.

Webb 1995; Knight, 1995; MarIes & Kaminski, 1992; Guin & Skisdmore, 1987; Gaby, 1996; Knight, 1995).

7. Kyushin, Liquorice (Glycyrrhiza glabra), Plantain (Plantago major), Uzara root, Hawthorn (Crataegus monogyna) and Ginseng are not advisable to take with digoxine. They interfere with digoxine pharmacodynamically or with digoxine monitoring (Miller, 1998).

8. Evening primrose oil (Oenothera biennis) and Borage (Borago officinalis) are not advised to take with anticonvulsant because they lower the seizer threshold (Miller, 1998).

9. Kelp (Fucus vesiculosus) is a source of iodine. If it is taken with thyroid replacement therapies, it may interfere in therapies (Miller, 1998).

10. Garlic (Allium sativum), when taken with paracetamol, changes the pharmacokinetic. It decreases the warfarin concentration in bl<2°d and produce hypoglycemia when taken with chlorpropamide (lzzo & Ernst, 200 I).

11. St. John Wort (Hypericum perj"oratum) is used for the treatment of depression, its action is monoamine oxidase-inhibiting, therefore, some time it increases the level of serotonin, dopamine and norepinephrine. It is not recommended to take with antidepressant (lzzo & Ernst, 200 I; D' Epiro 1997; Crigliano, 1998).

12. Herbal drugs containing Ephedrin or Ephedra plant may effect adversely on cardiac problem, rise in blood pressure and increased heart rate. It may cause nerve and muscles destruction, memory loss, strokes, psychcosis and even death (V ann & Cleve, 1998).

13. Ginkgo (Ginkgo biloba) interactions involve in bleeding time especially when combined with warfarin (anticogulant). It raises the blood pressure when taken with thiazide diuretic and a state of coma when combined with trazodone (Gaby, 1996; Kleijnen & Knipschild, 1992; Le Bars, 1997; Kleijnen & Knipschild, 1992; Hoglers, 1994; Rowin & Lewis,

1996; Morris, 1995; Bordia, 1998; Johnson, 1985, Knight, 1995).

14. The concomitant uses of opium alkaloids as analgesic

with sedative herbal remedies e.g. valerian, kava and chamomile (Blumenthal, 1998) may become the cause of CNS depression. The use of Ginseng may inhibit the analgesic effect of opium alkaloids.

15. Chamomile (Matricaria chamomilla) is used for reducing the side effects of cancer treatment but research has failed to show effectiveness in it for example chamomile did not decrease stomatitis caused by the cancer drug 5-fluorouracil in random clinical trial. In another study, radiation-induced skin reaction was not found effective in area treated with chamomile. Its use in sedation, inflammation and intestinal cramps has not been proven in human clinical trials. Some time its use may cause many allergic reactions (Fidler,

1996). 21

without overt aluminium toxicity. Lancet, ii: 7-12 ( 1989).

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Blumenthal, M. (1998). The Complete German COli/mission E Monographs: TherapeuticGuide to Herbal Medicine, American Botanical Council, Austin, Tx.

Bond, A. & Lader, M. The use of analogue scales in rating subjective feelings. Br. J. Med. Psycho/., 47, 211-18 (1974).

Bordia, A., Verma, S.K., Srivastava, K.C. Effect of garlic (Allium sativum) on blood lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with coronary artery disease. Prostaglandins Leukot E.\'sent Fatty Acids, 58, 257 (1998).

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Carleton, F.J. & Agalloco, J.P.(I986). Validation of Aseptic

Pharmaceutical Processes, Marcel Dekker: New York.

Carmon, A., Dotan, Y., Same, Y. Correlation of subjective pain experience with cerebral evoked responses to noxious thermal stimulations. Exp. Brain. Res., 33, 44553 (1978).

Chapman, C.R., Casey, K.L., Dubner, R., Foley, K.M., Gracely, R.H., Reading, A.E. Pain measurement:

an overview. Pain, 22, 1-31 (1985).

Chatrian, G. E., Canfield, R. c., Knauss, T. A., Lettich, E. Cerebral responses to electrical tooth pulp

stimulation in man. An objective correlate to acute experimental pain. Neurology, 25, 745-57 (1975).

Cheung, R., Dickins, J., Nicholson, P.W., Thomas, A.S.C., Smith, H.H., Larson, RE., Deshmukh, A.A., Dobbs, R. J., Dobbs, S.M. Compliance with antituberculous therapy: a field trial of a pill-box with a

concealed recording device. Eur. 1. Clin. Pharmacol., 35,401-7 (1988).

Chuen, L. P. & Hallsworth, P. Rapid viral diagnosis in

perspective. Brit. Med. J:, 300, 1413-18 (1990).

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lntf. Chem. Pharm. Mal. J.

Mansoor Ahmad

Certain frequently used drugs require proper clinical evaluation due to their reported side and adverse effects in two directions i) drug (herbal)-drug (herbal) and ii) drug (herbal)-drug (allopathic) interaction. There remain some serious questions about safety and efficacy of several herbal remedies. But there are four major concerns, which need to be solved that is:

quality research in standardization of herbal remedies

clinical trials need more intensive investigations quality and quantity wise,

compulsory validation process of herbal remedies, common international regulatory rules for herbal remedies control.

Some other aspects also need evaluation and validation and these are medical devices, diagnostic agents like sonograph, radioactive materials, X-rays, MR!, CT scan, and vaccines.

This is CBS News on herbal remedies (Hong Kong, March 11, 2003)~ "In 2001, the Singapore-listed company invested $2.6 million in a high-tech, dust free plant in Hong Kong that executives say is comparable to those operated by Western drug makers".

In Germany, Switzerland and in some other European countries, herbal medicines are approved by the government and physicians are allowed to prescribe under strict guidelines, but these herbal remedieslherbal preparations are not well regulated in other countries of the world.

Now it is for the clinicians and herbalists who use these natural products to derive a conclusion from the above provided information.

Acknowledgement:

Author is very much thankful to Ms. Mehjabeen and Noor Jahan for their cooperation and assistance in typing this review article.

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