720
PRAZEPAM, A PRECURSOR OF DESMETHYLDIAZEPAM
SiR,-Tyrer, writing on the Benzodiazepine Bonanza,’ stressed the similar clinical action of the many benzodiazepine derivatives available for treatment of anxiety and insomnia. The fact that several benzodiazepines share a common metabolic pathway could partly explain this clinical similarity.l.2
N-desmethyldiazepam (nordiazepam) is especially important because it is a major metabolite of clorazepate, diazepam, and medazepam, and a minor metabolite of chlordiazepoxide. Recently prazepam (’Verstran’) has been marketed in the United States as a new benzodiazepine anxiolytic. Early studies of radioactively labelled prazepam in man3.4 suggested that it had a unique pharmacokinetic profile. However, these studies did not specifically identify or measure the compounds present in human blood that account for the pharmacological activity of prazepam. We have investigated this question in studies of fasting volunteers given single 20 mg doses of prazepam. Venous blood-samples were drawn over the next 7 days. Plasma concentrations of intact, pharmacologically active (unconjugated) benzodiazepine compounds were determined by electron-capture gas-liquid chromatography.5 Results
were
similar in all volunteers. Neither prazepam
nor
hydroxylated metabolites (3-hydroxyprazepam and oxazepam) were found in any samples. Desmethyldiazepam was the only unconjugated benzodiazepine present: concentrations rose, then fell slowly over 7 days, consistent with the long elimination half-life of this compound6. (see figure). its
two
methyldiazepam,6,7 making these drugs (as well as other longacting benzodiazepines) suitable for single daily dose anxiolytic therapy. Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, U.S.A.
DAVID
Psychopharmacology Research Laboratory, Massachusetts Mental Health Center, Boston
RICHARD I. SHADER
J. GREENBLATT
INCREASE OF VENTRICULAR EXTRASYSTOLES AFTER DISOPYRAMIDE
SiR,—Dr Siklos and his colleagues (Jan. 14, p. 98) described ventricular tachycardia after disopyramide. I have seen a 49-year-old previously healthy man who was referred with ventricular extrasystoles. Examination findings were normal except for extrasystoles (10-29/min). Electrocardiogram (E.C.G.) showed that the extrasystoles were unifocal and from the left ventricle. Lignocaine infusion had no effect on the extrasystoles, produced nausea, and was stopped. Procainamide produced no improvement, even with the addition of hydantoin. All other drugs were then stopped and disopyramide was started (100 mg, three times daily). The frequency of the extrasystoles doubled, reaching 56/min and the patient felt unwell. Treatment was changed to propranolol (40 mg three times daily) and the frequency of the extrasystoles dropped back to 10-15/min. In an exercise test later, there were no E.C.G. changes typical of coronary heart-disease. The extrasystoles did not disappear during exercise. It seems that disopyramide is capable of increasing myocardial irritability, and I agree with Siklos et al. that not all patients should be given disopyramide after a myocardial infarction. Porvoo District Hospital, 06200 Porvoo 20, Finland
MAUNO HÄRKÖNEN
MUCOCUTANEOUS LYMPH-NODE SYNDROME WITH POSITIVE WEEL-FELIX REACTION BUT NEGATIVE LEPTOSPIRA STUDIES
Plasma concentrations of desmethyldiazepam after a single 20 mg dose. Also shown is computer-determined pharmacokinetic function of best fit (solid line).
SIR,-A review of mucocutaneous lymph-node syndrome (M.L.N.s., Kawasaki’s disease) in the United States referred to the Weil-Felix reaction.8 Wong et al. have commented on the many similarities between M.L.N.S. and leptospirosis and they suggest that some cases diagnosed as M.L.N.S. may have had leptospirosis.9 One patient with signs and symptoms similar to M.L.N.s. has been subsequently shown to have leptospirosis.’" We have tested this hypothesis further. Three patients with typical M.L.N.s. had positive Weil-Felix reactions (fourfold titre rise to Proteus OX-19 and OX-K in case 1; Proteus OX-19 titre of 1/80 over two weeks, decreasing to 1/40 at day 30 in case 2; Proteus OX-19 titre of 1/160 at one and five weeks and Proteus OX-2 increasing from zero to 1/40 over the same time period). This reaction is seen in Borrelia infection, Proteus urinaryinfections, severe liver disease, and rickettsial diseases, besides leptospirosis.I11Microscopic examination of blood smear for Borrelia, urine cultures for Proteus species, and liver-function tests ruled out the first three possibilities. Acute and convalescent sera showed negative complement-fixation titres to Rocky Mountain spotted fever (R.M.S.F.), Colorado tick fever, tract
Thus prazepam is not pharmacokinetically unique. Like clorazepate, prazepam serves as a precursor for desmethyldiazepam, which accounts for the clinical pharmacological activity. Hydroxylated metabolites of prazepam are present in plasma and urine, but only as pharmacologically inactive glucuronide conjugates.1,2 Multiple-dose therapy with prazepam, as
with clorazepate, will lead
to
extensive accumulation of des-
Tyrer, P. Lancet, 1974, ii, 709. Greenblatt, D. J., Shader, R. I. Southern med. J. (in the press). DiCarlo, F. J., Viau, J.-P., Epps, J. E., Haynes, L. J. Clin. Pharmac. Ther. 1970, 11, 890. 4. DiCarlo, F. J., Viau, J.-P., Epps, J. E., Haynes, L. J. Ann. N.Y. Acad. Sci. 1971, 179, 487. 5. Greenblatt, D. J. J. pharm. Sci. (in the press). 1. 2. 3.
Carrigan, P. J., Chao, G. C., Barker, W. M., Hoffman, D. J., Chun, A. H. C. J. clin. Pharmac. 1977, 17, 118. 7. Post, C., Lindgren, S., Bertler, A., Malmgren, H. Psychopharmacology, 1977, 53, 105. 8. Bergeson, P. S., Schoemke, S. L. J. Am. med. Ass. 1977, 237, 2299. 9. Wong, M. L., Kaplan, S., Dunkle, L. M., Stechenberg, B. W., Feigin, R. D., J. Pediat. 1977, 90, 532. 10. Humphry, T., Sanders, S., Stadius, M. ibid. 1977, 91, 853. 11. Marymont, J. H. in Todd-Sanford Clinical Diagnosis by Laboratory Means (edited by I. Davidsohn and J. B. Henry); p. 1192. Philadelphia, 1974. 6.
.
PRAZEPAM, A PRECURSOR OF DESMETHYLDIAZEPAM
SiR,-Tyrer, writing on the Benzodiazepine Bonanza,’ stressed the similar clinical action of the many benzodiazepine derivatives available for treatment of anxiety and insomnia. The fact that several benzodiazepines share a common metabolic pathway could partly explain this clinical similarity.l.2
N-desmethyldiazepam (nordiazepam) is especially important because it is a major metabolite of clorazepate, diazepam, and medazepam, and a minor metabolite of chlordiazepoxide. Recently prazepam (’Verstran’) has been marketed in the United States as a new benzodiazepine anxiolytic. Early studies of radioactively labelled prazepam in man3.4 suggested that it had a unique pharmacokinetic profile. However, these studies did not specifically identify or measure the compounds present in human blood that account for the pharmacological activity of prazepam. We have investigated this question in studies of fasting volunteers given single 20 mg doses of prazepam. Venous blood-samples were drawn over the next 7 days. Plasma concentrations of intact, pharmacologically active (unconjugated) benzodiazepine compounds were determined by electron-capture gas-liquid chromatography.5 Results
were
similar in all volunteers. Neither prazepam
nor
hydroxylated metabolites (3-hydroxyprazepam and oxazepam) were found in any samples. Desmethyldiazepam was the only unconjugated benzodiazepine present: concentrations rose, then fell slowly over 7 days, consistent with the long elimination half-life of this compound6. (see figure). its
two
methyldiazepam,6,7 making these drugs (as well as other longacting benzodiazepines) suitable for single daily dose anxiolytic therapy. Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, U.S.A.
DAVID
Psychopharmacology Research Laboratory, Massachusetts Mental Health Center, Boston
RICHARD I. SHADER
J. GREENBLATT
INCREASE OF VENTRICULAR EXTRASYSTOLES AFTER DISOPYRAMIDE
SiR,—Dr Siklos and his colleagues (Jan. 14, p. 98) described ventricular tachycardia after disopyramide. I have seen a 49-year-old previously healthy man who was referred with ventricular extrasystoles. Examination findings were normal except for extrasystoles (10-29/min). Electrocardiogram (E.C.G.) showed that the extrasystoles were unifocal and from the left ventricle. Lignocaine infusion had no effect on the extrasystoles, produced nausea, and was stopped. Procainamide produced no improvement, even with the addition of hydantoin. All other drugs were then stopped and disopyramide was started (100 mg, three times daily). The frequency of the extrasystoles doubled, reaching 56/min and the patient felt unwell. Treatment was changed to propranolol (40 mg three times daily) and the frequency of the extrasystoles dropped back to 10-15/min. In an exercise test later, there were no E.C.G. changes typical of coronary heart-disease. The extrasystoles did not disappear during exercise. It seems that disopyramide is capable of increasing myocardial irritability, and I agree with Siklos et al. that not all patients should be given disopyramide after a myocardial infarction. Porvoo District Hospital, 06200 Porvoo 20, Finland
MAUNO HÄRKÖNEN
MUCOCUTANEOUS LYMPH-NODE SYNDROME WITH POSITIVE WEEL-FELIX REACTION BUT NEGATIVE LEPTOSPIRA STUDIES
Plasma concentrations of desmethyldiazepam after a single 20 mg dose. Also shown is computer-determined pharmacokinetic function of best fit (solid line).
SIR,-A review of mucocutaneous lymph-node syndrome (M.L.N.s., Kawasaki’s disease) in the United States referred to the Weil-Felix reaction.8 Wong et al. have commented on the many similarities between M.L.N.S. and leptospirosis and they suggest that some cases diagnosed as M.L.N.S. may have had leptospirosis.9 One patient with signs and symptoms similar to M.L.N.s. has been subsequently shown to have leptospirosis.’" We have tested this hypothesis further. Three patients with typical M.L.N.s. had positive Weil-Felix reactions (fourfold titre rise to Proteus OX-19 and OX-K in case 1; Proteus OX-19 titre of 1/80 over two weeks, decreasing to 1/40 at day 30 in case 2; Proteus OX-19 titre of 1/160 at one and five weeks and Proteus OX-2 increasing from zero to 1/40 over the same time period). This reaction is seen in Borrelia infection, Proteus urinaryinfections, severe liver disease, and rickettsial diseases, besides leptospirosis.I11Microscopic examination of blood smear for Borrelia, urine cultures for Proteus species, and liver-function tests ruled out the first three possibilities. Acute and convalescent sera showed negative complement-fixation titres to Rocky Mountain spotted fever (R.M.S.F.), Colorado tick fever, tract
Thus prazepam is not pharmacokinetically unique. Like clorazepate, prazepam serves as a precursor for desmethyldiazepam, which accounts for the clinical pharmacological activity. Hydroxylated metabolites of prazepam are present in plasma and urine, but only as pharmacologically inactive glucuronide conjugates.1,2 Multiple-dose therapy with prazepam, as
with clorazepate, will lead
to
extensive accumulation of des-
Tyrer, P. Lancet, 1974, ii, 709. Greenblatt, D. J., Shader, R. I. Southern med. J. (in the press). DiCarlo, F. J., Viau, J.-P., Epps, J. E., Haynes, L. J. Clin. Pharmac. Ther. 1970, 11, 890. 4. DiCarlo, F. J., Viau, J.-P., Epps, J. E., Haynes, L. J. Ann. N.Y. Acad. Sci. 1971, 179, 487. 5. Greenblatt, D. J. J. pharm. Sci. (in the press). 1. 2. 3.
Carrigan, P. J., Chao, G. C., Barker, W. M., Hoffman, D. J., Chun, A. H. C. J. clin. Pharmac. 1977, 17, 118. 7. Post, C., Lindgren, S., Bertler, A., Malmgren, H. Psychopharmacology, 1977, 53, 105. 8. Bergeson, P. S., Schoemke, S. L. J. Am. med. Ass. 1977, 237, 2299. 9. Wong, M. L., Kaplan, S., Dunkle, L. M., Stechenberg, B. W., Feigin, R. D., J. Pediat. 1977, 90, 532. 10. Humphry, T., Sanders, S., Stadius, M. ibid. 1977, 91, 853. 11. Marymont, J. H. in Todd-Sanford Clinical Diagnosis by Laboratory Means (edited by I. Davidsohn and J. B. Henry); p. 1192. Philadelphia, 1974. 6.
.
