False positives with current carbocisteine protocol for sulphoxidation phenotyping. SIR,-A genetic polymorphism of sulphoxidation has been described in man ...
1107
in a known asthmatic and severe dizziness in 2 subjects. All three reactions occurred in subjects treated for the first time. These results are consistent with the safety of ivermectin for routine large-scale treatment of onchocerciasis.
S-carboxymethyl-L-cysteine sulphoxidation and debrisoquine 4-hydroxylation in a Caucasian population. Xenobiotica 1985; 15: 445-50. 4. Mitchell SC, Waring RH. The deficiency of sulfoxidation of S-carboxymethyl-Lcysteine. Pharmacol Ther 1989; 43: 237-49. 5. Emery P, Panaya GS, Huston G, et al. D-Penicillamine induced toxicity in rheumatoid arthritis: the role of sulphoxidation status and HLA-DR2. J Rheumatol
G. DE SOLE K. Y. DADZIE J. GIESE J. REMME
1984; 11: 626-32. Ayesh R, Mitchell SC, Wanng RH, Withrington RH, Seifert MH, Smith RL. Sodium aurothiomalate toxicity and sulphoxidation capacity in rheumatoid arthritic parents. Br Rheumatol 1987; 26: 197-201. J 7. Scadding GK, Ayesh R, Brostoff J, Mitchell SC, Waring RH, Smith RL Poor sulphoxidation ability in patients with food sensitivity, Br Med J 1988; 297: 105-07. 8. Olomu AB, Bickers CR, Waring RH, et al. High incidence of poor sulphoxidation in patients with primary biliary cirrhosis. N Engl J Med 1988; 318: 1089-92 9. Steventon G, Waring RH, Williams AC, Pall HS, Adams D. Xenobiotic metabolism m motor neuron disease. Lancet 1988; ii: 644-47 10. Tumbull LB, Teng L, Kinzie JM, Pitts JE, Pinchbeck GM, Bruce RB. Excretion and biotransformation of carboxymethylcysteine in rat, dog, monkey and man.
were asthma
Onchocerciasis Control Programme
in
West Africa.
Ouagadougou, Burkina Faso
1 Merck, Sharp and Dohme. Mectizan:(R), Product monograph. Rahway NJ: Merck & Co, 1988 2 De Sole G, Remme J, Awadzi K, et al. Adverse reactions after mass treatment of onchocerciasis with ivermectin. Combined results from 8 community trials. Bull WHO 1989; 67: 707-19.
Organisation Report of a meeting of the TDR/OCP/OCT subcommittee for monitoring of community trials of ivermectin. Unpublished mimeographed document. (TDR/OCP/OCT/IVERMECTIN/89.3). Geneva. WHO, 1989
3 World Health
positives with current carbocisteine protocol for sulphoxidation phenotyping
False
SIR,-A genetic polymorphism of sulphoxidation has been described in
and the mucolytic drug carbocisteine (Scarboxymethyl-L-cysteine) is currently utilised to discriminate poor from extensive sulphoxidiser phenotypes.1-3 The procedure involves measuring carbocisteine sulphoxide concentrations in a 0-8 h urine collection after oral carbocisteine. In Britain up to half the population have the poor sulphoxidiser phenotype:4 their urine contains hardly any of these sulphoxide metabolites. Interest in this polymorphism lies in the potential of identifying patients at risk of toxicity from organosulphur drugs such as penicillamine5 and aurothiomalateIn addition there have been reports of empirical associations between poor sulphoxidation status and food allergy,’ primary biliary cirrhosis,s and motoneuron disease." man
We were prompted to reinvestigate carbocisteine polymorphism because early study had yielded an observation never pursuednamely, a decline with time in the ratio of carbocisteine to total urinary ssS,10 suggesting that metabolites may become increasingly important at later times. Moreover, poor sulphoxidisers are frequently associated with a lower than expected recovery of drug-related material in the first 8 h urine . In a pilot study we have investigated 15 Swiss and 25 British healthy volunteers given 750 mg carbocisteine by mouth. 0-8 h and 0-16 h urines were analysed by paper chromatography2 and by thin-layer chromatography (to be reported elsewhere). The 0-8 h urines revealed that 12/15 Swiss and 7/25 British volunteers were poor sulphoxidisers. However, considerable amounts of metabolites emerged in the second collection period, whereby only 1 Swiss and 3 British volunteers remained poor sulphoxidisers. The currently widely used 0-8 h protocol is therefore inappropriate, producing inordinately high numbers of false-positive poor sulphoxidisers. Since we have incorporated the laboratory methodology used by othcrs,1-9 it is inconceivable that they too would not have misclassified their patients. Since the biological basis of the lag excretion remains nebulous, it is unclear what role a disease under investigation might play in retarding the elimination of carbocisteine metabolites, leading to false-positive associations between drug metabolism and disease. All these associations need to be re-evaluated in the light of the findings reported here. Department of Clinical Pharmacology, University of Berne, Berne, Switzerland
6.
Xenobiotica 1978; 8: 621-28.
Reluctance to prescribe suppressive oral acyclovir for recurrent genital herpes SIR,-Patients with frequently recurring genital herpes have repeated bouts of pain and genital ulceration often associated with profound emotional and sexual disturbance.1 The introduction of suppressive oral acyclovir has revolutionised the treatment of this condition. Most patients have no recurrences on treatment, and in those who do the outbreaks
are
short-lived and minor z-5In
our
experience patients on treatment become less depressed and are able to have normal sexual relations. Despite these benefits there is often a reluctance on the part of general practitioners and genitourinary physicians to prescribe suppressive oral acyclovir for this disabling chronic illness. We recommend that all patients with frequently recurring genital herpes-ie, at least 8 recurrences yearly--should be considered for treatment. Patients with less frequent recurrences should be assessed individually. The initial assessment and decision to treat should be made by a specialist in genitourinary medicine and subsequent follow-up arranged either through the clinic or the general practitioner. Before treatment is started diagnosis should be confirmed by viral culture and the frequency of recurrences established by suitable follow-up. Why are doctors reluctant to prescribe acyclovir? Two factors are sometimes mentioned-namely, the cost of the drug and that some people do not believe that genital herpes is serious enough to warrant therapy. The drug is expensive, but I do not believe that this is any justification for withholding treatment. With respect to the seriousness and chronicity of genital herpes the evidence speaks for itself. Academic
Department of Genitourinary Medicine, University College & Middlesex School of Medicine, James Pringle House, Middlesex Hospital, London W1 N 8AA, UK
ADRIAN MINDEL
A, Coker DM, Faherty A, Williams P. Recurrent genital herpes’ clinical and virologiral features in men and women. Gemtowinary Med 1988, 64: 103-06. 2. Douglas JM, Critchlow C, Benedetti J, et al. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl JMed 1 Mindel
1984; 310: 1551-56. SE, Takiff HE, Seidlin M, et al. Suppression of frequently recurring genital herpes. A placebo-controlled double-blind trial of oral acyclovir. N Engl J Med 1984; 310: 1545-50. 4. Mindel A, Weller IVD, Faherty A, et al. Prophylactic oral acyclovir in recurrent genital herpes. Lancet 1984; ii: 57-59. 5. Mindel A, Faherty A, Camey O, Patou G, Freris M, Williams P. Dosage and safety of long-term suppressive acyclovir therapy for recurrent genital herpes. Lancet 1988;
3. Straus
1: 926-28.
ADRIAN KUPFER
Pharmacogenetics Research Unit, Department of Pharmacological Sciences, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne NE2 4HH, UK
congruence of
Conjunctival naloxone is no decision aid in opioid addiction test of opioid addiction has been by challenge with a narcotic antagonist, and clinically more practicable methods that are acceptable to patients and staff are required. Changes in pupil diameter after topical instillation of naloxone have been reported to identify opioid dependence.l Creighton and Ghodse1 reported effects 45 min after topical naloxone in addicts but we find that the pupillary response to intravenous naloxone peaks after 15 min and then falls away.’ To
SiR,—The only objective
JEFFREY
R. IDLE
1 Waring RH, Mitchell SC, Shah RR, Idle JR, Smith RL. Polymorphic sulphoxidation of S-carboxymethyl-L-cysteine in man. Biochem Pharmacol 1982; 31: 3151-54. 2 Mitchell SC, Waring RH, Haley CS, Idle JR, Smith RL. Genetic aspects of the polymodally distributed sulphoxidation of S-carboxymethyl-L-cysteine in man. Br J Clin Pharmacol 1984; 18: 507-21 3 Haley CS, Waring RH, Mitchell SC, Shah RR, Idle JR, Smith RL. Lack of
intravenous
