1460

range. It is much

more

likely

that

physiologically meaningful

interactions of triazolam (K=0’47 nmol/1) take place at the y-aminobutyric acid (GABAA) receptors in the brain at these concentrations.8 Food and Drug Administration statistics are cited as implying significantly greater reports of inflammatory reactions with triazolam. However, while acknowledging the "rough and ready" nature of the data, Adam and Oswald do not fairly address the substantial limitations of voluntary medical events reports. It stretches the imagination to associate reported "hostility reactions" with the PAF-antagonist property of triazolam. The comparison to thalidomide is inappropriate. The controversy over possible adverse effects of triazolam has yet to be resolved. Neuroscience Research Unit, Department of Psychiatry, College of Medicine, University of Vermont, Burlington, Vermont 05405, USA

ROBERT H. LENOX

226: 1454-56. 4. Heuer HO. Pharmacology of hetrazepmes as PAF-antagonists. In: Braquet P, ed. CRC handbook of PAF and PAF antagonists. Florida: CRC Press, 1991: 171-202. 5. van der Kroef C Het Halcion-syndroom-een iatrogene epidiemie in Nederland. Tijdschr Alcohol Drugs 1982; 8: 156-62. 6. Adam K, Oswald I. Can a rapidly-eliminated hypnotic cause daytime anxiety?

Pharmacopsychiatry 1989, 22: 115-19. Greenblatt DJ, Miller LG, Shader RI. Neurochemical and pharmacokinetic correlates of the clinical action of benzodiazepine hypnotic drugs. Am J Med 1990; 88 (suppl 3A): 18s-24s. 8. Arendt RM, Greenblatt DJ, Liebisch DC, Luu MD, Paul SM. Determinants of benzodiazepine brain uptake: lipophilicity versus binding affinity. Psychopharmacology 1987; 93: 72-76. 7.

Inefficacy of amodiaquine against chloroquine-resistant malaria SIR,-Dr Fadat and colleagues (Oct 26, p 1092) recommend the

amodiaquine to treat chloroquine-resistant Plasmodium falciparum malaria in West Africa. A more judicious use of antimalarial drugs seems to be necessary for the treatment of chloroquine-resistant disease, especially in view of the similarity in chemical structure between chloroquine and amodiaquine. As Fadat et al note, the apparent efficacy of amodiaquine in their study may result from a short follow-up and acquired immunity of the patients, which is known to enhance the efficacy of antimalarial drugs. However, with the spread of chloroquine resistance in Africa, partial immunity may be inadequate to increase the action of marginally effective drugs. In-vitro efficacy of chloroquine and monodesethylamodiaquine, the biologically active metabolite of amodiaquine, was evaluated in our laboratory in March to October, 1991. 44 fresh clinical isolates of P falciparum, mostly from West Africa, were obtained before treatment from non-immune travellers returning to France. Drug susceptibility was measured by semimicro test with tritium-labelled hypoxanthine as an index of parasite maturation.1 28 isolates were resistant to chloroquine (table); 23 of these were resistant to monodesethylamodiaquine, and susceptibility to monodesethylamodiaquine of the 5 chloroquine-resistant isolates was borderline (range 41-56 nmol/1). All chloroquine-susceptible isolates were also sensitive to monodesethylamodiaquine. of

IN-VITRO SUSCEPTIBILITY OF P FALCIPARUM TO CHLOROQUINE (CQ) AND MONODESETHYLAMODIAQUINE(MDAQ)

mean,

drug sensitivity of P falciparum: evaluation of a semi-microtest. Am J Trop Med Hyg 1983; 32: 447-51. 2. Childs GE, Boudreau EF, Milhous WK, et al. A comparison of the in vitro activities of amodiaquine and desethylamodiaquine against isolates of Plasmodium falciparum Am J Trop Med Hyg 1989; 40: 7-11. 3. World Health Organisation Practical chemotherapy of malaria. Geneva: WHO, Tech Rep Ser 1990: 805. new

review of its effects, antagonists and possible future clinical implications. Drugs 1991; 42: 9-29, 175-204. 2 Snyder F, ed. Platelet-activating factor and related lipid mediators. New York: Plenum, 1987. 3. Kornecki E, Ehrlich YH, Lenox RH. Platelet-activating factor-induced aggregation of human platelets specifically inhibited by triazolobenzodiazepines. Science 1984;

Threshold resistance

LEONARDO K. BASCO

1. Le Bras J, Deloron P. In vitro study of

a

*Geometnc

Laboratory of Parasitology, Hôpital Bichat-Claude Bernard, 75018 Paris, France

1. Koltai M, Hosford D, Guinot P, Esanu A, Braquet P. Platelet activating factor (PAF):

use

Monodesethylamodiaquine was about three times less active against chloroquine-resistant parasites than chloroquine-susceptible isolates. An analysis of concentration-response data by Spearman’s rank-order correlation test showed a positive correlation between the responses to chloroquine and monodesethylamodiaquine (r=0-86, p 1 OU nmol/l tor CU, >60 nmol/I tor M IJA(1 95% confidence intervals in parentheses (nmol/l)

Correction of vesicoureteric reflux by

endoscopic injection SIR,-Last year you published a report by Puril on endoscopic correction of primary vesicoureteric reflux (VUR) by subureteric injection of polytetrafluoroethylene, the so-called "sting" procedure. That report and previous ones2.3 described success in correcting reflux but made no mention of renal damage or urinary tract infection (UTI). Since reflux by itself poses no threat to renal growth or function4,5 these seem important omissions. This procedure is now done at many centres away from a research setting and we have audited operations done in the Portsmouth health district. With the consent of our colleagues we compiled information from hospital and general practitioners’ notes and from laboratory records. 14 patients (3 male, 11female) had had "sting" procedures since 1987. 3 females were aged 18, 22, and 30 years; the other 8 patients were aged 4-10 years. 6 were under the care of a urologist only and 8 were under the joint care of a urologist and a paediatrician. 13 presented with UTI; all had VUR of grade 3 or 4. 1 adult patient had no evidence of UTI; her operation was undertaken for severe loin pain. 10 patients had preoperative evidence of renal damage, as determined by ultrasound scan, intravenous urography, or radionucleide scan. 9 patients had a trial of "effective" low-dose antibacterial prophylaxis (defmed as an appropriate antibacterial regimen, with arrangement for regular monitoring of midstream urine cultures) before surgery was decided on. 6 of these patients were under the care of a paediatrician. This regimen was successful in 6 of the 9 patients. The indications for the operation were: persistent UTI with no trial of prophylaxis (4 patients), persistent UTI despite prophylaxis (3), successful prophylaxis but persistent VUR (4), successful prophylaxis but mild chronic renal failure (2), and loin pain without UTI (1). The 14 patients have been followed up for 377 patient-months

(range 6-48). Postoperative micturating cystourethography was on 9 patients and reflux had greatly improved in 6 and had disappeared in 3. Of the remaining 5 patients, 3 were boys with renal scarring; all were on successful prophylaxis postoperatively under the care of paediatricians and had remained free of infection (cystourethography not justified in view of the risk of inducing infection by catheterisation6). 1 adult patient had only minor reflux with no UTI preoperatively or postoperatively. 1 girl was referred by a paediatrician outside the district and has apparently not been followed up. 5 patients had some form of renal imaging after the operation, at varying time intervals; 3 showed apparent new renal scarring, though pre-existing scars might have become more obvious by the time of the postoperative investigation, and 2 showed unchanged renal damage. Effective prophylaxis was instituted postoperatively in 7 patients, 5 of whom were under the care of paediatricians and 1 of a nephrologist to whom she had been transferred because of mild chronic renal failure. 7 (50%) of the patients had one or more done

1461

episodes of UTI during follow-up. Many of these episodes were accompanied by fever, suggesting renal infection. 5 patients had no recurrence of UTI; all were on prophylaxis under the care of a paediatrician. 1 patient had no UTI either preoperatively or postoperatively, and no postoperative MSUs were received in the laboratory from 1 patient. This small study suggests that the "sting" operations were rightly

undertaken for severe degrees of reflux, although a decision to operate when a patient is on successful prophylaxis might be

disputed and some of these patients had UTIs during follow-up. The possibility that further renal damage had occurred subsequent to surgery in 3 patients, the fact that 50% of patients had further UTIs (some with fever), and the success of antibacterial prophylaxis when undertaken by paediatricians suggest to us that prophylaxis should be instituted and maintained in all patients who undergo this operation, and that this is most likely to be achieved if the patient is under the joint care of a urologist (or paediatric surgeon) and a

paediatrician (or nephrologist). Public Health Laboratory and Department of Urology, St Mary’s General Hospital, Portsmouth P03 6AQ, UK

ROSALIND MASKELL J. VINNICOMBE G. F. ABERCROMBIE B. H. WALMSLEY

Index,

on

Fig 1-Yamaguchi indices. is 0-1600, range

(K+xHC03)-(creatininex 0-088)

calculated as 90% and 3% survival limits

labelled A and B, respectively. =survivors (unexpected ones numbered 1, 2, and

3); . =deaths.

1. Puri P. Endoscopic correction of primary vesicoureteric reflux by subureteric injection of polytetrafluoroethylene. Lancet 1990; 335: 1320-22. 2. O’Donnell B, Puri P. Treatment of vesicoureteric reflux by endoscopic injection of Teflon. Br Med J 1984; 289: 7-9. 3. O’Donnell B, Puri P Endoscopic correction of primary vesicoureteric reflex: results in 94 ureters. Br Med J 1986; 293: 1404-07. 4. Smellie JM, Edwards D, Normand KS, Prescod N. Effect of vesicoureteric reflux on renal growth in children with urinary tract infection. Arch Dis Child 1981; 56: 593-98. 5. Claësson I, Jacobsson B, Jodal U, Winberg J. Compensatory kidney growth in children with urinary tract infection and unilateral renal scarring: an epidemiologic study. Kidney Int 1981; 20: 759-64. 6 Maskell R, Pead L, Vinnicombe J. Urinary infection after micturating cystography. Lancet 1978; ii 1191-92

Survival from severe paraquat intoxication in

heavy drinkers SIR,-Since 1987 twenty-five cases of acute paraquat poisoning have been treated at this hospital. In each case, the outcome was predicted, at the time of admission, by applying the index developed by Yamaguchi et al,l and paraquat concentration/time survival curves.2-4 The Yamaguchi index is based on serum concentrations of potassium, bicarbonate, and creatinine and on the time since ingestion of paraquat. The patients were treated with combinations of Fuller’s earth, gastric lavage, forced diuresis, and corticosteroids/ immunosuppressive drugs,s the choice depending on the time since intoxication and the prognosis. Fourteen patients died. The Yamaguchi index and prognostic curves accurately predicted the outcome in all but three patients who survived despite consistent prognostic indications that they would not and despite the clinical severity of their illness (trench mouth, severe oesophagitis, pulmonary restriction syndrome, renal insufficiency). On their admission to hospital 24, 26, and 48 hours, respectively, after ingestion of paraquat their Yamaguchi indices were under published survival limits and their serum paraquat concentrations were above the limit for survival (figs 1 and 2). The signs of poisoning reached a peak within a week of ingestion and then resolved; by 16, 20, and 22 days, respectively, Yamaguchi indices, serum biochemistry, and clinical status were all normal. The three unexpected survivors were male agricultural workers from the Antilles, aged 39, 43, and 45 years, respectively, who had drunk more than 20 ml ’Gramoxone’ (20% v/v paraquat) in a suicide attempt. The three patients were chronic rum drinkers who drank 80 g ethanol per day. Ethanol intake was assessed from interviews with the family and the patient. All three had serum y-glutamyltranspeptidase activity above 40 IU/1 and mean corpuscular volumes above 100 fl. Rum drinking apart, we could find no distinguishing features between these three unexpected survivors and the other twenty-two patients. Perhaps heavy alcohol consumption protects against paraquat toxicity. If so, elucidation of the mechanism might improve the

Fig 2-Serum paraquat concentrations

in three

unexpected

survivors.

SIPP=severity index of paraquat poisoning (colorimetric method). Proudfoot’s

from 4 to 24 hours extended to Sherman’s

Pr-Sh

=

curve

(radioimmunoassays).

curve

of patients with paraquat poisoning. Del Villano et al6 reported significant increase in cupro-zinc superoxide dismutase (SOD-1) in black heavy drinkers compared with controls or white alcholics. Induction of enzymes such as SOD that protect against free-radical damage may underlie the survival of these three black heavy drinkers. Other factors in the alcohol/free radical equation may also be relevant-for instance, these Antillean alcoholics may have had very different tocopherol, selenium, and iron status from those studied elsewhere. treatment

a

We thank Prof Golden

(Aberdeen) for his comments.

Biochemistry and Resuscitation Services, CHRU Pointe à Pitre, 97110 Guadeloupe, French West Indies

C. RAGOUCY-SENGLER B. PILEIRE J. B. DAIJARDIN

Yamaguchi H, Sato S, Watanabe S, Naito H. Pre-embarkment prognostication for acute paraquat poisoning. Hum Exp Toxicol 1990; 9: 381-84. 2. Proudfoot AT, Stewart MS, Lewit T, Widdop B. Paraquat poisoning: significance of plasma-paraquat concentrations. Lancet 1979; ii: 330-32. 3. Schermann JM, Houze P, Bismuth C, Bourdon R. Prognostic value of plasma and 1.

urine paraquat concentration. Hum Toxicol 1987; 6: 91-93. 4. Sawada Y, Yamamoto I, Hirokane T, et al. Seventy index of paraquat poisoning. Lancet 1988; i: 1333. 5. Addo E, Poon-King T. Leucocyte suppression in treatment of 72 patients with paraquat poisoning. Lancet 1986; i: 1117-20. 6. Del Villano BC, Tishfield JA, Schacter LP, Stilwil D, Miller SI. Cuprozinc superoxide dismutase: a possible biologic marker for alcholism (studies in black patients). Alcoholism Clin Exp Res 1979; 3: 291-96.

Correction of vesicoureteric reflux by endoscopic injection.

1460 range. It is much more likely that physiologically meaningful interactions of triazolam (K=0’47 nmol/1) take place at the y-aminobutyric ac...
309KB Sizes 0 Downloads 0 Views