PHARMACOLOGY

the rapid growth of the science of pharmacology has been one of the most striking features of the development of the science of medicine (g¢.v.) during the present century. a knowledge of the functions of the body in health and disease is obviously a necessary preliminary to the study of the changes produced by drugs upon these functions, and hence the development of pharmacology has been depend- ent upon the development of the sciences of physiology, pathology and_ bacteriology. organic chemistry.—the only substances available for medi- cal use a century ago were certain inorganic salts and crude pharmacology vegetable extracts. the development of organic chemistry provided therapeutics with purified active principles of the crude vegetable extracts, and thus the use of crude preparations of unknown strength was replaced to a large extent by the use of chemical substances of known composition. organic chemis- try rendered a still more important service to pharmacology with the synthesis of organic compounds by which the number of substances available for use in therapeutics was increased indefinitely. the anaesthetics, ether (1846) and chloroform (1847), were the first synthetic organic compounds to be used extensively in medicine. twenty years later the first synthctic hypnotic, chloral hydrate, was introduced, and about 1885 the coal tar antipyretics, acetanilide and antipyrin, were discovered. since then hundreds of new synthetic drugs have been discovered, and most of the important recent advances in pharmacology have been dependent upon the production of new synthetic drugs. | salvarsan.—the discovery by ehrlich in 1910 of salvarsan, a very potent remedy for syphilis, established a new method of research which has since yielded other results of great impor- tance and promises to produce even greater successes in the future. in his search for a substance which would kill the infectious organism of syphilis (¢.v.), the treponema pallidum, without in- juring the patient, ehrlich started with the knowledge that allied organisms, the trypanosomes, were killed by certain dyes and organic arsenic compounds. not content with a random examination of the known compounds, he determined quanti- tatively which types of compounds were the most satisfactory for his purpose and then got new compounds prepared according to a definite plan. he made a systematic examination of a long series of organic arsenic compounds, determining in each case the minimal dose of the drug which would cure an animal in- fected with trypanosomes (minimal curative dose) and the maximal dose which the animal could tolerate (maximal toler- ated dose). he termed the ratio:— (maximal tolerated dose) (minimal curative dose) - the therapeutic index, and sought for a drug with the highest possible therapeutic index. the compound salvarsan or arseno- benzole was the 606th arsenic preparation investigated, and in 1910 it was introduced as a remedy for syphilis. two years later, ehrlich introduced neosalvarsan or novarsenobenzole, which has to a large extent replaced salvarsan in the treatment of syphilis (see venereal diseases). ehrlich’s brilliant suc- cess stimulated an intensive investigation of the action of or- ganic metallic compounds upon diseases due to infections by animal parasites. new afethods—a number of important new methods of treatment have been discovered. intramuscular injections of bismuth salts have been found to be of value in the treatment of cases of syphilis which are refractory to the organic arsenicals. salts of antimony also have been found to have important new therapeutic actions. a century ago the production of subacute antimony poisoning by large doses of tartar emetic was a routine treatment for a very large number of diseases, but the revolt against the ‘‘ heroic” methods of treatment of disease, in the middle of last century led to tartar emetic being almost aban- doned as a therapeutic agent. the drug was discovered to pos- sess the new and important therapeutic action of acting like arsenic as a specific disinfectant for animal parasites (see hookworm). intravenous injections of antimony salts have been found of great value in treating various diseases due to trypanosomal infection, and also have been found to cure the disease bilharziasis (q.v.). perhaps the most important internal disinfectant to be dis- covered is the compound ‘ bayer 205,” a derivative of the dye trypan blue. this substance has a powerful action both in preventing and relieving the trypanosomal disease sleeping sickness (g.v.), the worst scourge of tropical africa. pharmacology sanocrystn.—the search for internal disinfectants with which to combat bacterial diseases has not achieved any very out- standing triumphs. mollgaard has shown recently that an organic compound of gold, sodium aurithiosulphate, named “‘ sanocrysin ” can produce very remarkable curative effects, in acertain proportion of cases of tuberculosis (g.v.), but is equally capable of producing deleterious effects, and therefore great care is needed in its administration. auntisepiics.—the special conditions of world war surgery made the discovery of powerful wound disinfectants an urgent problem, and a number of new disinfectant compounds of great activity were discovered, for example the dye “ acriflavine,”’ and the quinine derivatives “ vuzin’”’ and “ optochin ” (see antiseptics). although the synthesis of the alkaloid quinine has not yet been cffected, nevertheless its chemical structure is known, and it is possible to modify the structure of the alka- loid and thus produce new compounds. vuzin and optochin are two quinine derivatives which differ from quinine in having a far more potent disinfectant action on bacteria. another im- portant new wound disinfectant is chloramine-t, an organic chlorine compound which acts by slowly liberating chlorine. the disinfection of the kidney and the bladder is another impor- tant problem in which advances recently have been made. a new organic compound termed hexyl resorcinol appears to be a more powerful urinary disinfectant than any previously known. use of active principles—most of the advances mentioned hitherto have depended upon the discovery of new synthetic organic compounds of greater potency than any known hitherto, but cures for other diseases have been discovered by substituting purified active principles for crude vegetable extracts. ipecacuanha has been known for more than a century to benefit amoebic dysentery, but the administration of the drug by mouth was limited by its action as an emetic. sir leonard rogers showed in 1912 that subcutaneous injections of the alka- loid emetine, the chief active principle present in ipecacuanha, usually produced a rapid cure in cases of amoebic dysentery (see dysentery). similarly, it has been known for many years that leprosy (q.v.) 1s often benefited by administration of chaulmoogra. oil, but it was found impossible to administer large doses of this oil by mouth on account of its irritant properties. organic chemists isolated from chaulmoogra oil certain complex fatty acids named hydnocarpic and chaulmoogric acids, which were believed to be the chief active principles present in the oil. sir leonard rogers in india and heiser in the philippines intro- duced the method of injecting preparations of these purified fatty acids intravenously or intramuscularly and = obtained remarkable curative effects even in the cases of leprosy of many years’ duration (see leprosy). the most striking recent suc- cesses of pharmacology have been achieved in the cure of in- fectious diseases, because in most other serious diseases some vital organ has received irreparable damage, which drugs may alleviate but cannot cure. anaesthetics important progress has, however, been made in the discovery of drugs needed to produce certain temporary alterations in the functions of the body. general anaesthetics are perhaps the most important group of drugs of this class. in 1924 and 1925 acetylene and ethylene were tried as substi- tutes for nitrous oxide, but at present it is doubtful whether the new gases will prove to have any marked superiority over nitrous oxice. many drugs produce some very useful action but have in addition some highly undesirable side action. cocaine, for example, is an excellent local anaesthetic, with the grave dis- advantage of sometimes producing dangerous effects on the brain. of the large number of local anaesthetics, which have been synthesised in the hope of producing some complete sub- stitute for cocaine, novocaine is one of the best known and can replace cocaine completely for many but not for all purposes. since 1910 a number of new compounds of great potency as local anaesthetics have been discovered, and probably it will soon be possible to avoid the use of cocaine almost completely. 105 hypnotics—similarly, a host of new and very potent hyp- notics have been synthesised in the hope of finding a reliable hypnotic which will not produce a habit, and is perfectly safe. unfortunately, not much advance has been made in this field. in a few cases important new uses have been discovered for drugs which have been known for many years, such as the dis- covery in 1918 that quinidine, one of the alkaloids present in cinchona bark or jesuit’s bark, can cure the important disorder of the heart known as auricular fibrillation. physiological features —the accurate analysis of the mode of action of drugs of well-established reputation has in certain cases greatly increased their value, making it possible to increase their dosage with safety and thus ensuring that sufficient of the drug is given to produce the physiological effect desired. the administration of digitalis in heart disease is a case where considerable improvements in technique of this character have been effected in recent years. the study of the actions of extracts of the glands of internal secretion (see endocrinology) is a field common to physiology and pharmacology. in 1886 it was shown that the two diseases myxoedema and cretinism, due to deficiency of the thyroid secre- tion, and previously considered completely incurable, could be cured by the simple remedy of administering dried thyroid gland by the mouth. in 1922 banting obtained an extract from the pancreas, which he termed insulin (g.v.), and which he proved would relieve the disease of diabetes mellitus (q.v.). internal secretions.—there are peculiar difficulties attending the study of the secretions of the endocrine glands. active principles have been obtained from the parathyroid glands and the ovaries which also promise to be of value as agents for sub- stitution therapy, where the normal secretions of these organs are deficient. substances have been obtained from other endo- crine organs which have no certain value as agents for substitu- tion therapy but are drugs with powerful and interesting phar- macological actions. one such substance, adrenalin, was dis- covered in 1896, and has been found of great value in producing constriction of small arteries and thus acting as a haemostatic. extracts of the posterior lobe of the pituitary gland produce a rise of blood pressure and constriction of plain muscle and since 1916 thts extract has been brought into therapeutic use, and is now very extensively tised to cause contraction of the utcrus, and thus to accelerate childbirth and to prevent the dis- astrous complication known as post-partum haemorrhage. vitantins.—the vitamins (q.v.) are biological products which have important pharmacological actions. they are unstable bodies of unknown chemical composition which are present in minute amounts in a large variety of fresh foods, but usually are absent in preserved foods. several vitamins exist, and a regular supply of all of them is essential to normal development and health. scurvy and rickets are two examples of diseases caused by vitamin lack. lemon juice has been known for more than a century to be a specific cure for scurvy, and biochemists have now succeeded in concentrating the vitamins of lemon juice so that a child suffering from infantile scurvy can be given the vitamin equivalent of 20 lemons in a single day. similarly, cod liver oil has long been recognised as a cure for rickets, and the vitamin of cod liver oil has also been prepared in concentrated form. the practical need for such preparation will, one hopes, be small in the future, for the knowledge gained regarding vita- mins ought to result in the disappearance of these deficiency diseases. the most striking recent advances have been made along two lines, firstly in the synthesis of drugs which will kill parasites that produce disease, and secondly in the isolation of biological products with important pharmacological actions. parasttology —the disease-producing parasites are of two classes, firstly the animal parasites such as the trypanosomes, and secondly the vegetable parasites, the bacteria. very re- markable successes have attended the preparation of internal disinfectants for the animal parasites, and cures have been found for a number of the worst diseases that afflict mankind; in particular, cures have been discovered for a number of very serious tropical diseases (g.v.). less striking success has attended 106 the endeavour to find disinfectants that will kill bacteria infect- ing the body, but a certain amount of progress has been made, and any advance in this field is of the greatest importance to the inhabitants of temperate climates, because most of the worst infectious diseases of the temperate zone are bacterial in origin. bibliography.—the most important work for general reference is a. heffter, handbuch der experimentelle pharmakologie, 3 vol. (1920); see also a. r. cushny, pharmacology and therapeutics, 8th ed. (1924); w. e. dixon, manual of pharmacology, 6th ed. (1925); a. j. clark, applied pharmacology, 2nd ed. (1926). (a. tc)