Need for Phyto-Pharmacological Evaluation

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Chapter: Pharmacognosy and Phytochemistry : Biological Screening of Herbal Drugs

To demonstrate a pharmacological effect, nothing can replace observation of animal models; but as they are expensive and often difficult to interpret, simpler tests are used. These tests require less effort and also make possible a better understanding of the mechanisms of action of substances being tested. Nonanimal models are becoming smaller and smaller while still remaining representative of a living organism.


NEED FOR PHYTO-PHARMACOLOGICAL EVALUATION

 

 

To demonstrate a pharmacological effect, nothing can replace observation of animal models; but as they are expensive and often difficult to interpret, simpler tests are used. These tests require less effort and also make possible a better understanding of the mechanisms of action of substances being tested. Nonanimal models are becoming smaller and smaller while still remaining representative of a living organism.

 

By means of finely adjusted multidisciplinary efforts and of a choice of tests that accurately represent future thera-peutic applications, research centres, such as the National Cancer Institute in the United States, have been able to select active substances with some success. Thus, the combination of several selective, sensitive, and specific tests (such as the model of P-338 leukaemia in vivo versus astrocytoma in vitro) has made it possible to detect directly up to 90% of clinically active antitumour compounds. These methods have also helped to eliminate substances that give false positive results, such as cardenolides, saponosides, flavonoids, and terpenic lactones. At the cost of a huge effort applied to more than 100,000 plant extracts, only about 10 particularly promising antileukaemic substances were selected, Among these were: indicine N-oxide, may-tansine, homoharringtonine, taxol and its derivatives, and 4-beta-hydroxywithanolide E (whose 17-alpha side chain removes all its cardioactivity).

 

Of course, most pharmaco-chemical researches are performed with more limited means, but the scientific literature flows with interesting results. These may be cat-egorized into two groups according to the possible methods of approach. One approach is to demonstrate new phar-macological activities, or even future clinical applications, from raw materials or natural substances already known. For example; hypericin inhibits monoamine oxidases A and B from rat brain, which may explain its antidepressive properties; 5 to 6 g of pectin ingested daily significantly decrease cholesterol levels by inhibiting the reabsorption of bile; trigoneiline, from fenugreek, displays a hypogly-caemic effect in animals with experimental alloxan-induced diabetes; sulphur compounds from garlic and onions, and phenylpropane derivatives from the essential oil of nutmeg, have displayed good properties against platelet aggregation; gossypol, obtained from raw cottonseed oil, is well-known as a male contraceptive agent, acting after 4 to 5 weeks of treatment, without affecting the testosterone level—its molecular mechanism of action towards lipid membranes has been elucidated.

 

The second type of approach is the discovery of new natural substances displaying pharmacological or even new therapeutic effects. This is the royal road par excellence that most often leads to patents being taken out. Publications in this field are numerous, which can be further explained by the following examples.


1. Withanolide F has an antiinflammatory action, dem-onstrated by the classical plantar oedema test in rats, which is five times that of phenylbutazone and com-parable to that of hydrocortisone (a substance with no effect on the central nervous system).

 

2.Certain tetracylic sesquiterpenes isolated from sponges of the genus phyllospongia have comparable antiin-flammatory effects in vivo, and

 

3. New triterpenic saponosides, such as dianosides A and B isolated from Dianthus superbus L. var longica-lycinus (Carycphyilaceae) have analgesic properties at subcutaneous doses of 10–30 mg/kg as measured by the acetic acid test in mice.

 

These few results, taken as examples, demonstrate—if such a demonstration is necessary—that this approach to research leads along an extremely interesting trail. It is a technique permitting innovation of the type currently much sought. The accumulation of scientific knowledge also leads to the development of a rigorous pharmacologi-cal vigilance, particularly with regard to natural substances that are considered a priority to be of secondary therapeu-tic value. Examples that come to mind are: glycyrrhizin, whose not inconsiderable mineralocorticoid activity induces iatrogenic hypertension with hypokalaemic and metabolic alkalosis; the pyrrolizidine alkaloids present in the Bor-aginaceae and Astgeraceae (particularly the genera Senecic and Eupatorium), which induce fatty degeneration of liver cells and eventually necrosis and fibrosis, caused by certain bifunctional alkylating pyurrole metabolites that bind to DNA; diterpene esters of the phorbol and ingenol types, present in the Euphorbiaceae and Thymeliaceae, which are in fact cocarcinogenic substances.

 

The terpenes, as with the flavonoids, certain molecules in the environment, though considered inactive in their normal state, may nevertheless show some activity when combined with an appropriate vector. Such is the case of epoxylathyrol, a diterpene present in the latex and seeds of Euphorbia lathysis L. This plant contains natural esters that have no activity on cultures of hepatic tumour cells. However, Schroeder et al. (1979) have synthesized a series of aliphatic esters with chain lengths ranging from 2 to 20 carbon atoms and have performed tests in vitro. The cytotoxicity curves demonstrate that the dibutyrate ester represents the optimal chain length, revealing an activity that the nonesterified epoxylathyrol does not possess. All this shows how greatly the interaction between the human body and molecules in our environment may be modifiable, and how research on substances thought to be devoid of interest may lead to surprises.

 

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