BOOK REVIEWS

Drugs--Development and Use. September 1970. British Medical Bulletin. Volume 26, No. 3. The rapid proliferation of new drugs on the market over the past 20 years makes it

difficult for anyone in any way concerned with medical therapeutics to keep abreast not only of the data dealing with particular drugs but of the procedures and investigations required both before and after the drug is marketed. The edition of the British Medical Bulletin, September 1970 offers, in a concise form, a series of papers dealing with various facets of the development and use of drugs at this particular stage of time and it is well to pause and assess the present position.

A consideration of the whole subject can most simply be separated into a discussion on the procedures undertaken to investigate and assess a drug prior to marketing, a demonstration of the advances achieved and the problems encountered in the use of new drugs in therapeutics and an assessment of the monitoring methods used to detect side- effects arising from the use of those drugs in practice.

Pharmaceutical companies are required to provide, for each new drug, complete details of pharmacology, indicating the presence and absence of activity in various systems, toxi- cology, and teratology in at least two animal species, the results of human pharmacody- namic data, and finally the results of carefully conducted clinical trials in human patients, In addition, they must supply information on methods of manufacture, specifications and standards of the drug and the formulation. All the data so provided are now submitted to a government-appointed agency, the members of which are specialists in appropriate fields, who can act as independent assessors. As Mansel-Jones notes in his discussion of the role of the Committee on Safety of Drugs in the United Kingdom, such an agency, concerned as it is with the safety of a product, can serve as a most useful "second opinion" for manufacturers whilst yet maintaining vigilance for the protection of the ultimate consumers.

Hanley et al, and Baker et al present a review of the procedures undertaken by drug manufacturers to meet the requirements of such agencies. At the same time we are re- minded of a series of as yet unanswerable problems. Not the least of these is the inability to predict the toxicity in man from the results obtained in animals. Some help is possible from a demonstration of comparable metabolism between certain animal species and man, but it is only relatively recently that investigators have realised the importance of the study of drug metabolism in predicting the presence or absence of hazards in man. Three par- ticular problems are highlighted--that of carcinogenesis, which =nay appear in animals and not in man or vice versa, damage to sensory organs in man, and not detectable in animals, and finally teratogenesis, the animal tests for which are so inadequate now because of unfamiliarity with the precise mechanisms whereby organogenesis and functions are triggered and developed. As Robson points out it is essential that more study be devoted to the cellular mechanisms by which drugs act, in order that one can predict binding states, for instance, in which a drug may act as a teratogen or carcinogen. The emerging subjects of pharmacogenesis and drug interaction are unfortunately not discussed, but it is in these fields also that current drug study is poor and in need of amplification. Some reassurance with regard to drug metabolism is obtained in the initial clinical trials (Dollery) provided these are meticulously conducted with a study of all the parameters offered by blochemistry.

The in-built pharmaceutical quality control of drugs as practised by manufacturers is well outlined by Johnson and offers a readily understandable ~ummary for doctors.

The papers by Brander and Crampton serve to remind us that drugs used in animals, and chemical additives may be consumed by man in considerable quantities through food. It is increasingly important that the same careful assessment should be made of these chemicals before their use is permitted in food material for human consumption.

Two of the fields in which the greatest advances have been made in drug research are the antibiotics and the psycho-pharmacologic drugs. Garrod's review of the achieve- ments of modern antibiotics is cheering, despite the warnings concerning uncontrolled virus diseases, the development of resistant bacterial strains and the escalation of infec- tions due to bacteria such as proteus which are not, so far, amenable to antibiotic therapy. Roth and Schapira ascribe the improvement in mental health care not only to the liberaliza- tion of mental hospitals, with a policy of early discharge and to public education, but to the availability of various drugs which can restore many patients suffering from schizophrenia, depression or severe anxieties to a useful, social integration in which they can function normally despite the necessity of continued medication.

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BOOK REVIEWS 93

The analyses of statistical trends in various diseases serve, however, to remind us that nature as well as drugs is playing a part in the decreased mortality from some illnesses.

A programme for the monitoring of adverse reactions to drugs, such as that set up in the United Kingdom is dependent to a large extent upon the co-operation of practitioners in notifying the unit of various side-effects. Unfortunately, as Waoe points out, and as is noted also in the subsequent articles, reports received generally amount to less than 10 per cent of those actually occurring, the sort of reports which all too often follow the expected pattern of recognized reactions. Even of this some use can be made and profiles of drugs can be compared with salutory results. For instance phenylbutazone and oxy- phenbutazone present similar patterns, as expected from metabolic identity, while Ibufenac, which should have followed a not too dissimilar pattern, showed a high proportion of hepatic reactions, for which reason it was withdrawn from the market. Special forms of monitoring may, to some extent, counterbalance this lack of intergst and Wade's experiences with intensive hospital monitoring is of use. It is important, however, to remember that not all side-effects are expected, and it is from suspicions that the monitoring system gains its greatest help, by indicating a particular direction for intensive study. Two such sus- picions led to the discovery that misuse of sympathomimetics in aerosols was causing an increase in the mortality rate in patients with asthma (Heaf) and, to the suggest{on that oestrogens increase the relative risk of thromboembolism in women taking oral contracep- tives. Although the results obtained in the U.K. from the latter iqvestigation are open to considerable variation in interpretation, the exercise at least has demonstrated a hazard and a method of investigation.

At the end of all the investigations, assessments and monitoring of drugs, one still must return to the responsibility of the doctor for the proper use of these potent agents, and Dunlop's survey of drug abuse serves to remind us of the sometimes dire consequences of ignorance and lack of thought on the part of doctors and patients.

A. SCOTT.

Clinical Gastroscopy: A Manual and Atlas by W. Bruhl and K. Krentz. Translated by H. Lamm. Stuttgart. George Thieme Verlag. DM. 74.00.

This book was originally published in German in 1969 and since then has been trans- lated into Italian, Spanish and English. The English edition by Dr. Heinrich Lamm of Harlingen, Texas, USA, has a rather stilted style so common to this type of translation. The text at times does not flow easily and the emphasis in many cases on germanic ideas and methods may, to some readers appear rather overdone. Harmon-Taylor's instrument, well loved by many English gastroscopists is dismissed in one ,ine.

These, however, are a few minor criticisms of an excellent review both past and present of the whole subject of clinical gastroscopy. The evolution of the technique through the years and a survey of the modern gastroscopic armamentaritlm are very good. Yet the book already is dated as with the introduction of the long ACMI panendoscope, not de. scribed in the text, one can in one procedure examine the whole oesophagus, stomach and in many cases the first part of the duodenum. Gastroscopy as such has died and we are now entering an era of upper intestinal endoscopy. The Japanese have alredy described an endoscopic technique for cannulation of the ampulla of Vater.

This book is essential reading for any embryonic endoscopists and also for people of experience. It emphasises the importance of routine and the development of gentle technique. It describes how the instruments should be handled thus prolonging the life of these expensive objects.

The chapters on orientation in the stomach and the appearance of the normal stomach are of a high standard. More attention could have been given tc the emergency use of endoscopy in upper intestinal haemorrhage and certainly the appearance after pyloroplasty warranted more than one paragraph.

However, the photographs, particularly those in colour, are the crowning glory of the book. The colour and reproduct!on are excellent and this, of course, explains the relatively high cost of the small volume.

When the authors remind us that endoscopy is the only method presently available to improve the mortality rate from gastric carcinoma and that 45 pro cent of deaths from cancer arise from the stomach, we realise the importance of endoscopy and hope that this book in some small way will encourage the further expansion of this essential diagnostic technique.

J. STEPHEN DOYLE.

94 IRISH JOURNAL OF MEDICAL SCIENCE

Splrochetes in Late Seronegative Syphilis, Penicillin Notwithstanding by J. L. Smith. Spring- field, Illinois. Chas C. Thomas. $36.

This book I class as Great. It sounds a warning which should make the medical world "Stop and Think". It shows that syphilis is neither easy to diagnose, nor easy to treat. Very clear evidence is presented to demonstrate that syphilis is not always cured (not even by the administration of 177,800,000 units of Penicillin) and that it is a frequently missed diagnosis in progressive ocular and neurological diseases.

The author has not spared any effort in preparing this magnificent work. All that he has set out to prove has been very clearly substantiated. The book is very easy to read, is laid out in clear order and interest is not lost at any time.

In the first section the book presents its prima facie case that seronegative active syphilis does exist. Indeed, doubt is cast upon the presence of a genuine B.F.P. test (Bio- logical False Positive). It is suggested that it stand for "Barely Findable Pallidum". In this section the author also managed to fit in an excellent resum6 of ocular and neuro-syphilis.

The following sections discuss the laboratory investigations, animal studies, research and clinical aspects of seronegative active syphilis, and very clearly show : - -

1. That clinical manifestations of ocular and neuro-syphilis are not rare (700 cases of late syphilis being detected in one city hospital alone in 4 years).

2. That the F.T.A. (ABS) test is the best serological test in late syphilis, but that it is not infallible.

3. That motile spirochetes may be found in clinically progressing neuro-syphilis with normal C.S.F. tests, and in eyes showing no biomicroscopic abnormalit:es.

4. That the F.A. tissue stain is a definite advance in the diagnosis of syphilis. 5. Treponemes have been found in the C.S.F. in the aqueous humour, liver, lymph

node, aorta, spinal cord, nasopharynx--thus showing that treponemes are found in areas which have a good vascular supply and are not protected by any barrier. These treponemes have been found after the administration of what is considered adequate therapy.

Having very impressively proved all these points, the book does not end on a negative note, but continues to discuss some practical steps to be taken in treatment. First, possible causes for this failure to respond to treatment are discussed under four headings,

1. Changes in the organism's metabolism. 2. Altered rate of division. 3. Alterations in life cycle. 4 Sequestration. Then new forms of treatment are investigated and proposed, 1. Prolonged treatment, up to two years. 2. Ampicill in and Benemid. 3. Cephalexin. 4. Erythromycin. 5. Combinations of these with steroids.

This work should be given cognisance and the author's own words at the end of the book should be given careful consideration, "It is the Author's suspicion that a very large percentage of major blinding eye diseases and of progressive neurological disease is due to the process described in this book and the importance of these observations is such that major efforts at obtaining an effective therapy for these diseases are urgently needed".

W. H: VERLING.

Preventive Myocardiology by Wilhelm Raab. Springfield, Illinois. Chas C. Thomas. $13.50.

Dr. Raab's book is an important contribution to the field of cardloiogy. It is a major attempt to focus attention on the complex physio-pathological mechanisms contributing to myocardial ischaemia. The book re-emphasises the often forgotten fact that structural anomalies of the coronary vessels, while important, are not the only pathogenic factors responsible for the development of myocardial ischaemia. One must always study the factors governing the balance between oxygen consumption and oxygen demands of the myocardium.

BOOK REVIEWS 95

Part I essentially deals with specific mechanisms leading to local and general myo- cardial hypoxia, and espec:,ally the aetiology of subendocardial ischaemia. The author argues forcibly that factors such as age, physical activity, nicotine and emotional stimuli are less important as atherogenic factors and more important as local factors affecting intraventricular compression, neurogenic and metabolic influences. This initial section discusses these factors in relation to oxygen supply and oxygen consumption of the myocardium.

A brief section is also given to the possible critical role of potassium and magnesium in relation to myocardial hypoxia.

Part 2 deals with specific aspects of ischaemic heart disease such as angina, myo- cardial infarction, arrhythmias and sudden death. The author's own strong views on the importance of adrenosympathetic activ;ty is strongly conveyed throughout this section. Indeed the entire book could be reviewed as a thesis propounding the role of adreno- sympathetic activity in the precipitation of ischaemic heart diseases. He favours, perhaps rightly, the evidence suggesting that thrombotic coronary occlqsion may not be of aetio- logical importance but rather is a secondary event. If this is so he suggests that non- occlusive masslve myocardial hypoxia may be due to such factors as a fall in coronary perfusion pressure, an abrupt rise in oxygen consumption and ~ catacholamine cardiotoxic effect of adrenocortical overactiv;ty.

The principal aim of Dr. Raab's book is to focus our attention sway from the coronary arteries to a consideration of other complex metabolic and neuto-hormonal influences. Nevertheless it is clear that he regards coronary artery rigidity and /or occlusion as a sine qua non to the development of myocardial disease.

Preventive cardiology has come to be recognised as an important speciality in the field of cardiovascular disease. This book, together w;th Stamler's "Lectures on Preventive Cardiology", is stimulating reading for the student of cardiology who may be interested in ploughing an unploughed field.

NOEL HICKEY.

Antimicrobial Therapy by B. M. Kagan et al. Philadelphia and London. W. B. Saunders. s

This 450 page publication by multiple authors consists of two sections. The first gives short general reviews of each of the two main groups of antibiotics and some other chemotherapeutic agents. The second consists of a collection of brief surveys of their usage in certain clinical situations. There are no less than 46 contr ibutors--al l from the United States with the exception of a single pair from Glasgow. This scheme may cut down production t ime which is clearly important in a rapidly developing subject. How successful this has been is indicated by the fact that in, for instance, the Glasgow article one-third of the references are from 1969 publications. Full reference lists are a feature throughout the book. The editor is a paediatrician and this aspect is throughout particularly well covered, nearly one-third of the contributors having this special interest.

The preface sets an ambitions standard--"There has long been a clear need for a comprehensive text on antimicrobal therapy. It is hoped that this book will fulfill that need. In spite of the publication of a wealth of isolated data no single text exists in which all the essential areas are covered".

In fact a great deal of interesting and authoritative information is given but such stated aims justify a number of criticisms. These are mainly as regards comprehension. To g;ve some examples, there seems uncertainty about the scope of the book. Most con- tributors interpret this as antibacterial therapy, yet many deal at some length with fungi. Protozoal infections are almost ignored and acute viral agents receive no mention. The one article which defines antimicrobal includes bacteria, protozoa and fungi. Apart from the standard sensitivity tables syphilis only receives a few lines of considerat ion--under infections of the brain other than meningitis. Venereal disease does not merit a section on its own. Despite its American origin it is surprising to find no mention at all of fusidic acid. Finally, although a triviality, most readers would surely be irritated to find space given to a 7 page review article on antirnicrobial agents in orthopaedics to such an extent as "nfection of a joint with pus forming organisms is called pyogenic arthritis".

J. G. KIRKER

96 IRISH JOURNAL OF MEDICAL SCIENCE

Neurophysiology for Medical Graduates by Edwin de Caire. 1970. Johannesburg. W;t- watersrand University Press.

This book is based on a lecture course that Mr. de Caire gave to medical graduates working for specialist diplomas. One of the first surprises on reading the text is how readable it is for a treatise on neurophysiology. For this, the author deserves great credit. He has a gift for writing and for explaining. Most medical graduates and indeed under- graduates, find neurophysiology an unsatisfying subject. Authors of phys!ological texts often assume too high a level of knowledge of physics, chemistry and mathematics in their readers. Mr. de Caire takes pains to avoid this pitfall. Physical princ!ples which are neces- sary to understand the behaviour of neurones are explained it, simple language. His treatment of the central nervous system is not fragmented into to(, many isolated pieces. The whole is enlivened by humour, both verbal and pictorial.

The first 50 or so pages deal with the physiology of simple neurones and transmission at synapses. The remaining 220 or so pages deal with reflex ~ctiv;ty and the organization of the sensory and motor systems. There is a good chapter on pain but there is little attempt to force physiological explanations on clinical syndromes.

In general, this is a very useful book which will give pleasure and enlightenment to those medical students and graduates who would like to under,~tand the nervous system.

IAN RODDIE.

Longitudinal Study of Refraction and its Components during Growl h by A. Sorsby and G. A. Leary. London. Medical Research Council, SRS 309. HMSO. 9/-.

At a meeting held in the Sheraton Park Hotel, Washington DC in October 1966, spon- sored by the U.S. Department of Health, Professor Sorsby and associates recommended that there be "large scale longitudinal studies of refractive errors and the components of {he refractive apparatus etc." The present report is an investigation along these lines ~)eing a follow up study on 129 children between the ages of 3 and 15 years. The usual information obtained was by refraction, measurements of axial !ength, corneal power and lens power.

The overall results in this study were that the majority showed relatively little increase in refraction and the minority a more marked increase, the mean being about 0.6 diopters and 2.5 diopters respectively.

The smaller group represented about 25 per cent of children examined. In this group anomalous axial elongation was present but "it did not often lead to anomalous axial lengths or to myopia".

"Nothing is as yet known of the infantile phase of axial 91ongation". No doubt future studies will help to elucidate its significance.

G. E. HEWSON.

Current Medical Treatment. Edited by C. W. H. Harvard. London. 3rd Ed. Staples Press. s Paper back ed. 45/-.

Three editions in five years demonstrates the appeal of this excellent book. All facets of therapy are considered and, where appropriate, advice for surgical or radio-therapy is given.

Many useful tables and diets are included; for example, on6 shows factors which interfere with oral anti-coagulant control.

The chapters on anti-microbial and cortico-steroid therapy are particularly worth reading, as is the chapter on electrolytic disturbance.

One can always find something at which to carp, and I was a little surprised to see amphetamine being recommended for obesity, and to find no mention of the intra-dermal methods of T.A.B. immunisation !

This is a most valuable up to the minute book, which will b - most useful to the busy G.P. or houseman. However, I feel that future editions could benefit by reduction of the length of many of the articles, for example, tuberculosis, occupies 23 pages !

W. A. RYAN.