DEVELOPMENT OF NEW DRUGS

1
38 any part of the skin. The response was blocked by subcutaneous procaine. The intradermal injection of 0-02 ml. of heparinised plasma, derived from a sample of the patient’s blood which had been kept at 38°C for 90 minutes, " produced a slight erythema comparable to that produced by saline ", whereas the injection of heparinised plasma, derived from the patient’s blood when it had been kept at 4°C for 90 minutes and then rewarmed, " produced significantly greater erythema ". This response was not found in normal subjects reinjected with their own plasma from chilled whole-blood samples. Chilled plasma freshly drawn from the patient (and, it is implied, containing few platelets) did not result in erythema when injected into his skin. No cryoglobulins, cold haemagglutinins, or cold hsemolysins were found; and no degranulation was seen when the basophil leuco- cytes were chilled in an ice bath for 15 minutes, indicating that the cutaneous response in this patient was distinct from the cold-urticaria reaction.2 4 Shelley and Caro suggest that cooling of the skin of their patient caused local vasoconstriction which then induced axon-reflex vasodilatation and sweating. They argue that, since intradermal serotonin will cause similar axon-reflex flares, liberation of this substance may well be the basis of the lesion. Circulating serotonin is normally bound to platelets; if the patient’s platelets were abnormally unstable in the cold, their breakdown could release serotonin and so enable it to produce its unpleasant effects. Unfortunately, Shelley and Caro were not able to study the patient as fully as they wished, and for the present this interesting hypothesis lacks proof. They do not say whether the sweating-so striking a feature in the areas of skin exposed to cold-was reproduced by the intradermal injection of serotonin. A variety of serotonin antagonists failed to abolish the abnormal response when given orally, but their effect when given intradermally might repay study. The crucial experiment, however, would be the measurement of free plasma-serotonin 5 after platelet-rich plasma had been cooled to various temperatures. DEVELOPMENT OF NEW DRUGS ONE of the vices of civilisation is to take too much for granted. Because so many things are now made in factories rather than under our eyes, we underestimate the ingenuity and toil that so often go into their making. A case in point is the modern drug; and the Practitioner has done a service by devoting much of its January issue to articles explaining the almost fabulous effort required to produce the tablets, ampoules, capsules, elixirs, and suspensions which are now so much a part of our daily lives. Dr. W. P. Kennedy, who opens the series, recalls an occasion on which a tablet of cortisone was exhibited with a label " This tablet cost$1,000,000 "-which, when one considers the facts, seems a very modest estimate. He quotes figures showing that in 1960 a group of British pharmaceutical firms spent about t71 í million on the discovery and development of new and important drugs; and the other Practitioner articles make it clear that expenditure on such a scale is a necessity in view of the commercial hazards involved and the complexity of the trials needed. In the medical profession, most of us pay too little 4. Shelley, W. B., Juhlin, L. Nature, Lond. 1961, 191, 1056. 5. Robertson, J. I. S., Andrews, T. M. Lancet, 1961, i, 578. attention to these trials until-as happens so rarely- something goes seriously wrong. Naturally, some of the articles reflect the concern aroused everywhere last year by the disaster with thalidomide, and Prof. George Brownlee refers to the possible introduction of a pro- bationary period of perhaps five years after a drug is released. On this he says: " Four stages in the development of a new drug may be traced. They are the experimental animal tests, the clinical investigation tests in man, the clinical trials, and the stage at which the drug is generally prescribed. It is evident that all active drugs are toxic and are metabolized and their metabolic products also may be toxic. It is seen that toxicities may be observed at all four stages and although those seen in animals are likely always to be seen in man, those seen in man may often not be reproducible in animals. For these reasons it is unlikely that the predictable and the unpredictable toxicities of drugs will have been seen in man until a period of years has elapsed. Would it not be wise to look on those years as a probationary period ?" SURGERY OF RENAL-ARTERY ANEURYSM ANEURYSM of the renal artery can no longer be con- sidered rare: at least 180 cases have been reported.! In about a third of these the sac was calcified and partly thrombosed, and the diagnosis could be made with some certainty from the ring-shadow appearance on plain X-ray. But in the remainder the sac was not calcified, and a quarter of these presented acutely with rupture of the aneurysm and intra-abdominal haemorrhage. Even a pea- sized aneurysm can be responsible for such catastrophe, and (as in the similar and sometimes coincident condition of splenic-artery aneurysm) the victim is quite often a young pregnant woman. The mortality for the whole reported series of ruptures was forbiddingly high at 75%. Other modes of presentation included are intermittent upper-abdominal pain, hsematuria, hypertension (particu- larly when the artery is stenosed proximal to the aneurysm), and renal atrophy. Ring opacity in the renal hilus can also be due to calcified nodes or cysts, tuberculoma, calcified hxmatoma, or the calcified tortuous renal artery itself; aortography may be necessary before these can be distinguished. Aortography has also shown that, in most renal aneurysms, by the time the wall is calcified it is also -fortunately-strengthened by contained thrombus. This is commonly so in elderly patients, and no operation is then necessary; but should such a condition be suspected in a pregnant woman, then exploratory opera- tion must be seriously contemplated. The surgeon may well wonder what to do when he finds the aneurysm. Experience of 115 cases showed that nephrectomy was the safest course 2: of 53 cases so treated only 3 were fatal, compared with 9 of 19 cases in which some conservative operation was attempted. In 1957 Poutasse 3 reported a personal series of 12 cases of renal- artery aneurysm. These included 2 cases where, although the sac was more than 2-5 cm. in diameter, it was dis- sected free from the side of the renal artery; the lateral defect was then closed with a vascular suture. In each case, subsequent intravenous pyelography displayed normal renal outline and function; and, in 1, aortography showed that the renal circulation was normal besides. Operations of this type were tried, and met with success, 1. Harrow, B. R., Sloane, J. S. J. Urol. 1959, 81, 35. 2. Abeshouse, B. S. Urol. cutan. Rev. 1951, 55, 451. 3. Poutasse, E. F. J. Urol. 1957, 77, 697.

Transcript of DEVELOPMENT OF NEW DRUGS

Page 1: DEVELOPMENT OF NEW DRUGS

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any part of the skin. The response was blocked bysubcutaneous procaine. The intradermal injection of0-02 ml. of heparinised plasma, derived from a sampleof the patient’s blood which had been kept at 38°C for90 minutes,

" produced a slight erythema comparable tothat produced by saline ", whereas the injection of

heparinised plasma, derived from the patient’s bloodwhen it had been kept at 4°C for 90 minutes and then

rewarmed, " produced significantly greater erythema ".This response was not found in normal subjects reinjectedwith their own plasma from chilled whole-blood samples.Chilled plasma freshly drawn from the patient (and, it isimplied, containing few platelets) did not result in

erythema when injected into his skin. No cryoglobulins,cold haemagglutinins, or cold hsemolysins were found;and no degranulation was seen when the basophil leuco-cytes were chilled in an ice bath for 15 minutes, indicatingthat the cutaneous response in this patient was distinctfrom the cold-urticaria reaction.2 4

Shelley and Caro suggest that cooling of the skin of theirpatient caused local vasoconstriction which then inducedaxon-reflex vasodilatation and sweating. They argue that,since intradermal serotonin will cause similar axon-reflexflares, liberation of this substance may well be the basisof the lesion. Circulating serotonin is normally boundto platelets; if the patient’s platelets were abnormallyunstable in the cold, their breakdown could releaseserotonin and so enable it to produce its unpleasanteffects. Unfortunately, Shelley and Caro were not ableto study the patient as fully as they wished, and for thepresent this interesting hypothesis lacks proof. They donot say whether the sweating-so striking a feature in theareas of skin exposed to cold-was reproduced by theintradermal injection of serotonin. A variety of serotoninantagonists failed to abolish the abnormal response whengiven orally, but their effect when given intradermallymight repay study. The crucial experiment, however,would be the measurement of free plasma-serotonin 5after platelet-rich plasma had been cooled to various

temperatures.

DEVELOPMENT OF NEW DRUGS

ONE of the vices of civilisation is to take too much for

granted. Because so many things are now made infactories rather than under our eyes, we underestimate the

ingenuity and toil that so often go into their making.A case in point is the modern drug; and the Practitioner

has done a service by devoting much of its January issueto articles explaining the almost fabulous effort requiredto produce the tablets, ampoules, capsules, elixirs, andsuspensions which are now so much a part of our dailylives. Dr. W. P. Kennedy, who opens the series, recallsan occasion on which a tablet of cortisone was exhibitedwith a label " This tablet cost$1,000,000 "-which,when one considers the facts, seems a very modestestimate. He quotes figures showing that in 1960 a

group of British pharmaceutical firms spent aboutt71 í million on the discovery and development of newand important drugs; and the other Practitioner articlesmake it clear that expenditure on such a scale is a necessityin view of the commercial hazards involved and the

complexity of the trials needed.In the medical profession, most of us pay too little

4. Shelley, W. B., Juhlin, L. Nature, Lond. 1961, 191, 1056.5. Robertson, J. I. S., Andrews, T. M. Lancet, 1961, i, 578.

attention to these trials until-as happens so rarely-something goes seriously wrong. Naturally, some of thearticles reflect the concern aroused everywhere last yearby the disaster with thalidomide, and Prof. GeorgeBrownlee refers to the possible introduction of a pro-bationary period of perhaps five years after a drug isreleased. On this he says:

" Four stages in the development of a new drug may betraced. They are the experimental animal tests, the clinicalinvestigation tests in man, the clinical trials, and the stage atwhich the drug is generally prescribed. It is evident that allactive drugs are toxic and are metabolized and their metabolicproducts also may be toxic. It is seen that toxicities may beobserved at all four stages and although those seen in animalsare likely always to be seen in man, those seen in man mayoften not be reproducible in animals. For these reasons it isunlikely that the predictable and the unpredictable toxicitiesof drugs will have been seen in man until a period of years haselapsed. Would it not be wise to look on those years as a

probationary period ?"

SURGERY OF RENAL-ARTERY ANEURYSM

ANEURYSM of the renal artery can no longer be con-sidered rare: at least 180 cases have been reported.! Inabout a third of these the sac was calcified and partlythrombosed, and the diagnosis could be made with somecertainty from the ring-shadow appearance on plainX-ray. But in the remainder the sac was not calcified, anda quarter of these presented acutely with rupture of theaneurysm and intra-abdominal haemorrhage. Even a pea-sized aneurysm can be responsible for such catastrophe,and (as in the similar and sometimes coincident conditionof splenic-artery aneurysm) the victim is quite often ayoung pregnant woman. The mortality for the wholereported series of ruptures was forbiddingly high at 75%.Other modes of presentation included are intermittentupper-abdominal pain, hsematuria, hypertension (particu-larly when the artery is stenosed proximal to the aneurysm),and renal atrophy. Ring opacity in the renal hilus canalso be due to calcified nodes or cysts, tuberculoma,calcified hxmatoma, or the calcified tortuous renal arteryitself; aortography may be necessary before these can bedistinguished. Aortography has also shown that, in mostrenal aneurysms, by the time the wall is calcified it is also-fortunately-strengthened by contained thrombus.This is commonly so in elderly patients, and no operationis then necessary; but should such a condition be

suspected in a pregnant woman, then exploratory opera-tion must be seriously contemplated.The surgeon may well wonder what to do when he finds

the aneurysm. Experience of 115 cases showed that

nephrectomy was the safest course 2: of 53 cases so treatedonly 3 were fatal, compared with 9 of 19 cases in whichsome conservative operation was attempted. In 1957Poutasse 3 reported a personal series of 12 cases of renal-artery aneurysm. These included 2 cases where, althoughthe sac was more than 2-5 cm. in diameter, it was dis-sected free from the side of the renal artery; the lateraldefect was then closed with a vascular suture. In each

’ case, subsequent intravenous pyelography displayednormal renal outline and function; and, in 1, aortographyshowed that the renal circulation was normal besides.

Operations of this type were tried, and met with success,1. Harrow, B. R., Sloane, J. S. J. Urol. 1959, 81, 35.2. Abeshouse, B. S. Urol. cutan. Rev. 1951, 55, 451.3. Poutasse, E. F. J. Urol. 1957, 77, 697.