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Roots of Modern Drugs in Reverse Pharmacology

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Roots of Modern Drugs in Reverse Pharmacology 20 : 1 Roots OF MODERN DRUGS IN REVERSE Pharmacology “That medicines and cures were first found out, and then after the reasons and causes were discoursed; and not the causes Ashok B Vaidya, Rama A Vaidya, Mumbai first found out, and by light from them the medicines and cures discovered.” term Reverse Pharmacology, currently coined and systematized, bear any relevance to the discovery of modern drugs? These are Aulus Cornelius Celsus (ca 25BC-ca 50) the questions which may provide answers to assist the shift in paradigm for the new drug discovery process. INTRODUCTION In these days of huge but fallible investments by drug companies in POISONS AND EXPERIMENTAL PHARMACOLOGY the discovery of new drugs, we tend to forget that several major The word ‘pharmacon’ means a medicine or drug; also a poison.6 drugs were first discovered, at the bedside, by astute physicians. In The etymology is in new Latin, later in Italian farmaco, from Greek the Oxford Textbook of Clinical Pharmacology and Drug Therapy øά μαĸον, a drug, whether healing or noxious, a potion spell, charm, it is stated “Historically modern drug therapy has developed from a deadly drug, poison, dye, colour etc.7 It is surprising that the term the herbal and folklore medicine of the past with its mixture of pharmacon also meant poison in Greek. That indeed was quite magic, empirical pharmacology and faith of the patient in the an example of Greek “wisdom”! The word ‘poison’ dates to circa 1 doctor.” The recent rational route to drug discovery, adopted 1230, from old French puison “a drink”, later “a potion, poisonous by major multinational pharmaceutical companies, costs for a drink” from Latin potionem; Potare meant to drink from the base single new chemical/biotechnological product around $1.7 billion. po/pi-to drink.8 The closeness to Sanskrit ipba to drink is obvious. The drug development process takes around 8 to 12 years and However, in Sanskrit the terms for medicine and poison were 2 the synthesis and screening of more than 25,000 molecules. distinct – AaOYaiQa (Aushadhi) and ivaYa/Agad (Visha/Agaga) Rigorous attention is given to preclinical safety, activity and respectively.9 The roots of the Western therapeutics lie in Graeco- kinetics of the molecules. Despite this humongous endeavour, Roman medicine. As a consequence poisons and strong drugs have the post-marketing failures and withdrawal of blockbuster drugs always interested scientists and early pharmacologists. Swain, had have become fairly common; the withdrawal of Vioxx ® is one traced the origin of some of the adverse effects of modern drugs 3 such major example. The pipeline for new drugs appears to be to these roots.10 Table 1 lists some of the poisons investigated for relatively dry when compared to the 1960’s golden era of new their mechanisms. That led to a new understanding in physiology drugs despite the major mergers of big R&D of companies and and pharmacology. The quest for safer chemical derivatives of 4 academia-industry collaborative research. Is there a need for these “poisons” led to the burgeoning field of medicinal chemistry a paradigm shift for new drug discovery? Could we pay more for synthetic modern drugs. Later, the further development of the attention to the unplanned and serendipitous bedside therapeutic structure-activity relationship led to innumerable “new drugs” of a or adverse effects to convert such observed hits into drug leads? “me too” nature, Ivan Illich, a social critic, calls this situation of too For any attempt at shift in a dominant paradigm, we need to first many prescription drugs as “paradoxical counterproductivity.”11 look at the history of that knowledge domain. That is one reason The book - African Ethnobotany-Poisons and Drugs - by Hans why Celsus has been cited (vide supra) in relation to medicines Dieter Neuwinger has covered more than 240 poisonous plants. In and cures preceding their mechanisms of action. Fleming, who an interdisciplinary manner he has dealt with the poisonous plants pioneered antibiotics, said, “It is the lone worker who makes the used for hunting as well as for medical treatment in traditional first advance in a subject: the detail may be worked out by a team, African medicine.12 The relationship of Asian, African and South but the prime idea is due to the enterprise, thought and perception American poisons to the development of modern drugs has been of an individual.”5 It is worthwhile to assess this statement in a relatively less stressed. Hence roots of several modern drugs relation to the evolution of several drugs. We can then explore activities in Ayurvedic therapeutics often go unrecognized. the clinical roots of modern drugs. How much role have also Rauwolfia serpentina to Modern Drugs field medicine and observational therapeutics played also in the development of the basic physiology and pharmacology? Does the Rauwolfia serpentina, Benth, the snake root of India, was widely used Medicine Update 2010 Vol. 20 Table 1 : Poisons as roots of modern drugs Table 2 : Spin-off Rauwolfia serpentina for modern drugs Poison Source Human/animal Mechanism/ Modern drugs R. serpentina Mechanisms Modern Drugs effect Agonist Antihypertension effect Noradrenaline (NA) Reserpine, guanethidine, Curare tomento- Conscious paraly- Neuromuscular Tubocurarine, Inhibition of reuptake of α-methyldopa, clonidine sum sis Death block pancuronium, catecholamines gallamine, suxam- Depression Depletion of NA, 5-HT Imipramine Amit- ethonium ryptiline fluoxetine, Physostigma Ordeal poison Anticholines- Neostigmine, sertraline, bupropion venenosum terase Pyridostigmine, Gynecomartia/ Dopamine Depletion Bromocriptine, cavergo- Edrophonium, Galactorrhea Increase in prolactin line pergolide, dostinex Pilocarpine Parkinsonism Syndrome Dopamine depletion in L-dopa, carbidopa Strychnos nux- Convulsive death Glycinergic recep- corpus striation pramipexole vomica tor Hyperacidity & peptic Release of histamine Cimetidine, ranitidine, Atropa belladonna Fatal poisoning Cholinergic Scopolamine, ulcer brocresine, famotidine blockage Cyclopentolate, Nasal congestion Depletion of noradrena- Oxymetazoline, xylom- Iratropium line etazoline Meliotus alba Bleeding disease Anti Vitamin K Dicumarol war- farin ADVERSE EFFECTS OF α METHYLDOPA AND Claviceps purpurea St.Anthonys f Vasoconstrictor 1. Noradren PROLACTIN agonists 2. and β antago- In 1969, a young hypertensive girl was observed to have nists galactorrhoea-amenorrhoea with Parkinsonism.17 The syndrome Erythroxylon coca Central Stimulant Local anaesthetic Procaine l- was abscribed to hypothalamic depletion of caricholamines with utacaine dibucaine special reference to dopamine, due to α methyldopa therapy. lidocaine At that time assays for human prolactin were not available. This Bothrops jaraca Viper poison ACE inhibitor Captopril, Enal- clinical observation led to the proposal of dopaminergic inhibitory april control of prolactin secretion. 18 In 1981, eleven years later, α before scientific studies showed its efficacy in hypertension and there were two cases reported with - methyldopa with dose- mental disorders. Gananath Sen and Kartik Bose were the first response relationship with a prolactin increase and amenorrhoea- 19 to show, in 1931, the antihypertensive effects of the plant.13 Later galactorrhoea due to dopamine-depletion. While studying the Rustom Jal Vakil, published his clinical studies with R. serpentina effects of bromocriptine in a patient with hyperprolactinemia with in hypertension in the British Heart Journal, after 18 years.14 visual field defects, a serendipitous finding emerged. The reduction Isolation of the active principle of the plant - reserpine – and its of prolactin levels was accompanied by normalization of visual pharmacology by Bein and colleagues led to the first major globally fields. This was the first demonstration of medical management 20 - used antihypertensive drug – Serpasil ® (CIBA).15 But this major of prolactinoma, later confirmed and accepted globally. These drug discovery on giviating, from India was not recognized by the events suggest the need for meticulous recording and documenting Nobel Foundation. Gananath Sen deserved the prize even more of unusual bedside adverse or beneficial effects with an eye to because of his astute clinical documentation of the side effects the potential of new drug development. Later Mucuna pruriens of the plant viz depression, Parkinson’s syndrome, gynecomastia, Bak was investigated for reducing chlorpromazine- included peptic ulcer etc besides its antihypertensive and tranquillising hyperprolactinemia in psychiatric patients and for therapeutic 21,22 effects. The spin-offs of these pioneering observations led to a effects in Parkinson’s disease. Zandopa HP-200) was evolved 23 watershed in the pharmacology of catecholamines and new drugs as an anti-Parkinson drug from Mucuna pruriens. A double modulating biogenic amines, their synthetic/degradative enzymes, blind clinical and pharmacological study with Mucuna pruriens in and their diverse receptors. Table 2 lists the clinical effects of Parkinson’s disease suggested advantage of L-Dopa in long term 24 Rauwolfia serpentina and subsequent spin-offs of a spate of modern arrangement of Parkinson’s disease. drugs. This revolution in new drugs ushered in by reserpine as an experimental tool coupled with clinical observations has escaped ANTIMALARIAL DRUGS OF NATURAL ORIGIN the attention in many scholarly reviews. Even those scientists Cinchona-the Peruvian bark - story illustrates the tale of centuries
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