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.
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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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