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Kimmelstiel- Wilson lesions.6 One of these was previouslyinadequately controlled on 50-130 units a day ; yet heshowed no ketonuria during thirty days without insulin,despite the presence of an abscess and fever. Even on ahigh fat diet for four days there was still no ketonuriaor change in the carbon dioxide combining-power of theblood. Again in the other five cases, which were milder,ketonuria did not develop when insulin was withheld.The diabetes associated with Kimmelstiel-Wilson lesionsseems to behave, therefore, as if there is not a completelack of intrinsic insulin, although at the start it .may beof the insulin-deficient type.
Until we have reports of plasma-insulin assays in suchpatients we are left to wonder whether perhaps they areproducing excessive quantities of glycogenolytic factorfrom the pancreatic oc cells, which have also been creditedwith ketosis-preventing properties, or whether by anincreased turnover rate of the Krebs tricarboxylic-acidcycle they dispose of the intermediates of fat metabolism 8with unusual efficiency.
6. Dana, G. W., Eversole, S. L., Zubrod, C. G. Bull. Johns Hopk.Hosp. 1952, 90, 98.
7. Thorogood, E., Zimmerman, B. Endocrinol. 1945, 37, 191.8. Beatty, C. H., West, E. S. J. biol. Chem. 1951, 190, 603.9. See annotation, Lancet, 1951, i, 1356.10. New York Times, Dec. 16, 1951.11. Toolan, J. M., Zimmering, P., Wortis, S. B. N.Y. St. J. Med.
1952, 52, 72.
DRUG ADDICTION IN ADOLESCENTS
A LOT of publicity has been given in recent months tothe prevalence in large American cities, especially NewYork, of addiction to such drugs as marihuana and heroinamong what are nowadays known as
teen-agers." 9Prof. A. R. Lindesmith,10 of Indiana University, suggeststhat the relatively high incidence of drug addiction in theU.S.A. is due to the police policy of prohibition, whichdrives it underground so that it becomes a rich source ofrevenue for racketeers. The addict is thus brought intocontact with the criminal underworld by craving for hisdrug ; moreover, to earn enough to pay for it, he willhimself take to peddling drugs and try to spread the habitamong his acquaintances, or embark on other criminalways of making money. The U.S.A. is supposed to haveat least 48,000, and more probably 100,000, addicts ;and Mayor Impelliteri’s committee of inquiry estimatedthat there were 45,000-90,000 in New York City alone ;in the first nine months of 1951, 2837 narcotics cases wereentered in that city’s police records. F.B.I. figures forthe first half of 1951 show that almost half the narcoticsoffenders were under 25 years old.Toolan et al.ll remark on the recent sudden increase in
heroin (diacetylmorphine) addiction ; from 1941 to 1950an average of 20 patients was admitted to Bellevue
Hospital for heroin or morphine addiction. In peopleunder 21 years of age no such case was detected between1940 and 1948 ; in 1949 there was 1 case, and in 195011 cases ; but in the first seven months of 1951 260 ofthese youngsters were admitted, their ages ranging from14 to 20. Of 36 consecutive male admissions described
by Toolan et al. all but 2 were Negro or Puerto Rican ;and all were from Harlem, where young people sufferfrom discrimination against their racial groups and therate of crime and disease is higher than anywhere elsein New York. Few withdrawal symptoms were foundamong these adolescents : many experienced no illeffects ; some were restless and had increased sweatingand lacrimation ; about one in five required small dosesof amylobarbitone. One serious complication was
encountered : 3 youths who had shared the same
hypodermic needle developed hepatitis, from which 1died with acute liver atrophy. The development of theaddiction begins with the youngsters being introduced todrugs by their friends or by a pedlar, who gives themdrugs free in order to initiate them. According to an
account in the New Y orlcer 12 they usually start by smokingmarihuana cigarettes (" reefers ") ; then they are inducedto try heroin (" horse "), first by sniffing it (a " snort "),next by subcutaneous injection (" skin-popping "), andfinally by direct intravenous injection (" main-lining ").The addict injects himself, using an eye-dropper fittedto a hypodermic needle, which may be shared withothers and is seldom sterilised. There is a feeling ofanxiety immediately after taking the drug, then euphoriaand an increased sense of self-confidence. A feeling offloating through space is often described. The boyslose their aggressive and sexual drives, taking littleinterest in girls. They may also find it difficult to urinate,for the drug causes spasm of the vesical sphincter.13Depression follows the euphoria, and in an attempt toovercome this larger and more frequent doses are taken.When this true addiction has developed boys commonlybecome delinquent, peddling the drug to friends, truant-ing and stealing in their attempt to get enough moneyto keep them in the drug.
Toolan and his co-workers found that these boys,compared with a control group, were non-aggressive andpassive, having weak and superficial relationships sociallybut a close, empathic relationship with their mothers.They live a fantasy life, with grandiose day-dreams,becoming increasingly isolated and withdrawn from socialcontacts and from the real world, in which they feelinferior and insecure. While " high " they prefer to bealone in a darkened room, listening to the radio andchain-smoking. As a group, these boys are not hoodlumsor incorrigible psychopaths but are suffering fromcharacter disorders of a neurotic type peculiar to theadolescent who is growing up in a difficult community.Toolan and his associates point out that in adolescencethe character structure is not fixed but is in process of
adjustment, and that severe psychological disturbancesat this age may clear up without psychotherapy. At thesame time, heroin addiction with its attendant socialwithdrawal during the period of adolescent adjustmentmay have very crippling effects on the personality. Theyrecommend strenuous police action to eradicate the
illegal sale of narcotics ; educational programmes directedat adolescents and at those responsible for their welfare;the expansion of psychiatric facilities for treatment;and treatment centres for reablement, with trial visitsto the home. The severe restrictive legislation recentlydemanded by the attorney-general, Mr. N. L. Goldstein,includes educative and therapeutic measures, but alsothe possibility of life-sentence for a third offence againstthe narcotic laws. The curable addict is to be givencompulsory treatment and reablement; the incurableis to be isolated from the public. It is to be hoped thatthe penal element in these proposals will not drive thenarcotics traffic still deeper into the underworld and addto the hopeless sense of isolation of its victims. If theaddict has to have his drug-failing a cure--it is surelybetter for him to get it honestly from his doctor than fromthe pedlar at the corner of the block.
In the wider sphere of international control the latestreport by the Permanent Central Opium Board 14 revealsa disquieting state of affairs. Among the countries whichhave failed to supply statistics are the main producersof raw materials for drugs of addiction. The governmentof India, for example,
" does not seem to be in a positionto ascertain the production, stocks, exports, &c., of rawopium." Neither Peru nor Bolivia-the main producersof coca leaves-has provided statistics ; but Peru hasmade the production of crude cocaine a State monopoly.In Persia 333 tons of raw opium " disappeared " during1950 ; and in Italy 164 kg. of diacetylmorphine also
12. New Yorker, Nov. 10, 1951, p. 44.13. Sollmann, T. A Manual of Pharmacology. Philadelphia, 1940.14. Permanent Central Opium Board : Report to the Economic and
Social Council on Statistics of Narcotics for 1950 and theWork of the Board in 1951. United Nations, Geneva, 1951.
"disappeared." In that year the declared productionof diacetylmorphine for the whole world was 453 kg. ;and at its meeting last month the W.H.O. Expert Com-mittee on Drugs Liable to Produce Addiction recom-mended that this drug should no longer be used formedical purposes, since it can now be replaced by othermorphine derivatives or by new synthetic substances.Altogether fifty countries have given notice that theyhave discontinued, or are willing to discontinue, themedical use of diacetylmorphine. Clearly, however,nothing short of total suppression of manufacture
throughout the world will ensure that this drug does notfall into addicts’ hands ; and there is little present hopeof such unanimous action. Meanwhile in the U.S.A. adrive against drug pedlars is reported 15 to be causinga sharp reduction in the number of teen-agers needingadmission to hospital.
15. New York Times, Feb. 10, 1952.16. Stoll, A., Becker, B., Kussmaul, W. Verh. schweiz. naturf. Ges.
1941, p. 235.17. Straub, W., Triendl, E. Arch. exp. Path. Pharmak. 1937,
185, 1.18. Fairbairn, J. W., Saleh, M. R. I. J. Pharm. Pharmacol. 1951,
3, 918.19. Lou, T. C. Ibid, 1949, 1, 673.20. Fairbairn, J. W., Michaels, I. Ibid, 1950, 2, 807.21. Fairbairn, J. W., Lou, T, C, Ibid, 1951, 3, 93, 225.22. Lou, T. C., Fairbairn, J. W. Ibid, p. 295.23. Fairbairn, J. W., Michaels, I. Ibid, 1950, 2, 813.24. Ryan, H. A. Pharm. J. 1951, 167, 115.
THE anthracene purgatives, of which aloes, rhubarb,cascara sagrada, and senna are the most familiar in
England, owe their activity to the " emodins," a groupof glycosides of di- or tri-hydroxyanthraquinone, ofwhich each contains two or three examples. Variousmixtures of "emodins" are also used as laxatives, but,as often happens in therapeutics, the active principles areon the whole less efficient than the crude drugs. In thiscase the explanation may lie in the relative insolubilityof the active principles in the intestinal contents. Sennaprovides an exception to this general rule, for its glyco-sides, sennosides A and B, which were first isolated by Stolland colleagues 16 ten years ago, are reliable as laxativeswhether they are given by mouth or subcutaneously.They are absorbed into the blood-stream and re-excretedinto the gut, but otherwise their mode of action is stilluncertain. Straub and Triendl 1-7 thought that they stimu-late the nervous mechanism of peristalsis, producing agood imitation of normal defsecation. Lately Fairbairn andSaleh 18 have shown that senna contains a small amountof a third glycoside, another anthracene derivative,which exerts a synergistic effect on sennosides A and B ;by mixing the two sennosides with 14% of the thirdglycoside their biological activity is increased by two-thirds.In view of the clinical value and respectable antiquity
of senna it is surprising that no method of assay hasyet been worked out and included in one of the pharma-copoeias. While there was no standardised preparationthe dosage was bound to be rather haphazard. Fairbairnand others,19 20 however, have devised satisfactorychemical and biological methods for the assay ofsenna, and also of rhubarb 21 and cascara.22 Fairbairnand Michaels 23 assayed the B.P. preparations of senna bythese methods and found that the liquid extracts containedless than a tenth and the concentrated infusions lessthan a sixth of their expected glycosidal content. Someproprietary preparations tested were much more effectivethan the official ones, though they were still only 30-40% asactive as the theoretical maximum. The only preparationwhich retained the full laxative activity of crude sennawas a granular product made from the pod after theinactive seeds have been removed. The remainingpericarp, powdered and standardised, is said 24 to retainits activity for long periods. This is used for preparingthe granules. The great advantage of prescribing a
standardised preparation of constant laxative actionis that, once the dose for each patient is decided, thereshould be no griping, since this seems to be a symptomof overdosage.
1. Khanolkar, V. R. Studies in the Histology of Early Lesions inLeprosy. Spec. Rep. Ser. Indian Coun. med. Res. no. 19, 1951.
2. Armstrong, T. G., Wilmot, A. J., Elsdon-Drew, R. Lancet, 1950,ii, 10.
3. Killough, J. H. Proc. R. Soc. Med. 1952, 45, 109.4. Most, H., Miller, J. W., Grossman, E. J. Amer. J. trop. Med.
1950, 30, 491. Ley, H. L., Sayer, W. J., Hobson, A. C. S.,Vanreenen, R. M., Tipton, V. J., Frick L. P., Ballard, E. L.,Traub, R. Antibiotics Chemotherap. 1951, 1, 281.
THE BEGINNINGS OF LEPROSY
IN his brief monograph on the histology of earlyleprosy,l profusely and beautifully illustrated, Dr.Khanolkar quote’s the words of Anatole France : ’’ Thereare some that will say ... this is not the true doctrine.There are others who will say I have said nothing morethan what everyone already knows." The passage givesus a glimpse of the mind of a patient worker, who,reviewing the history of a subject, gathers what seemsworth retaining from the past, adds his own carefullydocumented findings, and so produces an outstandingcontribution to medical knowledge. He sets out theevidence showing that the leprosy bacillus enters thebody through the skin and has a predilection forsubcutaneous nerve tissue, particularly early in lifewhen there is a continuous process of degeneration andregeneration, and in areas where the skin is subjectto minute injuries and friction. Leprosy is neuralin its inception, and Mycobacterium leprae first appearsin clinical lesions in the small nerve plexuses inthe skin, travelling up the finest nerve twigs in an
ascending infection. This carefully reasoned hypothesisis substantiated by Dr. Khanolkar’s painstaking studiesof sections from early lesions. The silent phase of thedisease-before actual clinical symptoms manifest them-selves-is lucidly explained and finely illustrated bydrawings. Why some lesions become tuberculoid andothers lepromatous is logically set forth, showing thata classification of leprosy is practicable and must bebased-like the Havana and South American classifica-tions-on the immunology of the disease, due stress
being placed on the lepromin test. Dr. Khanolkar showsthat the development of leprosy in the body depends onthe bacilli being able to burst out from the subcutaneousnerves and nerve plexuses of the skin into the dermis.The subsequent extension of the disease is determined bythe response of the tissue to its mycobacterial invader.If the tissue response is weak, lepromatous leprosyensues: if it is vigorous, the tuberculoid type is likelyto develop. Dr. Khanolkar’s evidence that the bacillican remain in the granular form in the nerves shouldencourage the clinician to be cautious not to discontinue
sulphone therapy too soon and so increase the likelihoodof relapse.
This monograph may well prove a landmark in leprosyresearch.
ANTIBIOTICS IN AMCEBIASIS
FOR some years almost every new sulphonamide orantibiotic has been hailed as the drug of choice for treatingthe acute stage of amcebiasis, but none has proved ideal.It is now recognised that drug treatment should aimat eradicating the secondary bacterial invaders as wellas the pathogenic amoebae themselves ’*
Several workers have found aureomycin a veryactive amoebicide. Armstrong et al.2 report from Durbanan immediate-cure-rate with this antibiotic of about 94% ;but the relapse-rate is also high, and whether it ispreferable to other amoebicides remains undecided.3 Theantibiotic spectrum of aureomycin is similar to that ofchloramphenicol ; but chloramphenicol is less effectiveagainst the disease in man, though in mice it seemed moreactive than aureomycin as a prophylactic against infec-