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THIOPROLINE TOXICITY
778 GENETICALLY DETERMINED IMPAIRED DRUG
SULPHOXIDATION
SIR,—The metabolic oxidation of debrisoquine is regulated by a single autosomal genel with two alleles: the DH allele determines rapid and extensive oxidation while the DL allele determines an impaired oxidation capacity.2 DL homozygotes display an impaired ability to hydroxylate debrisoquine. The debrisoquine gene regulates or influences the oxidative metabolism of several other drugs,3but so far all the oxidations shown to be influenced by this gene have been at carbon centres. Does this gene influence oxidation at other types of centre, such as nitrogen or sulphur? We have investigated the sulphoxidation of the mucolytic drug ’Mucodyne’ (S-carboxymethyl-L-cysteine) in two panels, each of four subjects, known to be extensive metabolisers (EM) or poor metabolisers (PM) with respect to debrisoquine oxidation. S-carboxymethyl-L-cysteine is metabolised in man to at least nine metabolites, four of which are sulphoxides, products of
hydroxylation
sulphoxidation.4 Each volunteer took a 750 mg capsule of mucodyne, and urine was collected for 8 h and analysed for S-carboxymethyl-L-cysteine and metabolites. Volunteers of EM phenotype eliminated a mean of 53% (range 35-85%) of the dose in the 8 h period, with 22% (18-27%) as sulphoxides. Those of PM phenotype excreted 53% (35-98%) with only 2 - 2% (1 - 3-4 - 2%) as sulphoxides. This ten-fold difference between the two phenotypes with respect to sulphoxide output after an oral dose of mucodyne suggests that sulphoxidation of this compound is regulated by the same gene that controls the oxidation of debrisoquine and other drugs. This observation may be of clinical significance: sulphoxidation occurs with several drugs (e.g., phenothiazines and ethionamide) and the reaction is thought to be important in relation to the metabolic activation and toxicity of certain sulphur-containing drugs, narticularlv the thioamides.5 Department of Biochemistry, University of Birmingham, Birmingham B 15 2YY
R. H. WARING
Department of Pharmacology, St Mary’s Hospital Medical School, London W2 1PG
thioproline7—i.e.,
noted. Our study confirms the findings of Sappino and Smith8 on the lack of therapeutic effect of thioproline and the toxicity of this drug for the central nervous system, and demonstrates another toxic effect, renal function disturbance. S. NASCA V. GALICHET J. C. JARDILLIER E. GARBE P. CONINX
Regional Cancer Centre, Institut Jean Godinot, 51056-Reims, France
PERSISTENCE OF HEPATITIS B VIRUS ANTIGENS IN DRIED BLOOD
SIR,-We would like to add a footnote to the letter by Dr Bondand colleagues (March 7, p. 550). We have demonstrated
S. C. MITCHELL
his
J. R. IDLE
immunologically intact dried HBsAg and HBeAg on the surface of blood group typing cards of chronically HBV-infected haemodialysis patients. The typing cards of two HBsAg andHBeAg carriers (A and B) were collected over a period of some weeks and the dried blood smears were cut out, pooled, soaked in saline, and centrifuged. The supernatants were screened for HBsAg (’Ausria II’; Abbott) and HBeAg.Both markers were clearly demonstrated
R. L. SMITH
THIOPROLINE TOXICITY
SIR,—The results obtained with thioproline (thiazolidine-4cell carcinoma, particularly in head and neck cancer, and the apparent lack of drug toxicity reported by Brugarolas and Gosalvezprompted us to do a pilot study in pa-
carboxylic acid) in squamous tients with measurable
No regression was observed with any of the three schedules. 7 of the patients who received thioproline intramuscularly had squamous cell carcinoma of the head and neck and had not been treated previously. Toxic manifestations, essentially neurological symptoms and renal function abnormality, were noted, for oral and intramuscular routes, in 18 patients. Central nervous system side-effects were observed in 10 patients, and included confusion, lethargy, and tremor, severe in 2, moderate in 3, and mild in 5. In one patient, we unsuccessfully tried to identify formaldehyde in the cerebrospinal fluid. The neurological symptoms resolved when treatment was stopped. Abnormal serum creatinine levels were noted in 9 patients. This could have been partly due to the neoplastic disease or to other medication in 4 patients but seemed to be solely related to thioproline in the other 5, in 4 of whom serum creatinine levels returned to normal 2-3 weeks after thioproline administration was stopped. 3 patients had both neurological symptoms and renal function disturbance. None of the other toxic signs and symptoms metabolic acidosis, hyporeported with glycaemia, seizures, epilepsy, deafness, and hypoacusia-were
evaluable lesions of advanced cancer. Thioproline was given daily in four equally divided doses either orally at 20 mg/kg daily for 21-42 consecutive days or intramuscularly at 40 mg/kg daily of thioproline sodium salt for 14-42 consecutive days or for two to four courses of 7 consecutive days 2 weeks apart. From March to September, 1980, 48 patients with histologically proven cancer were entered in this study. 22 patients were treated orally and 26 patients were given injections over 14-42 days consecutively (9 patients) or as two to four courses (17 patients). 28 patients had squamous cell carcinoma of head and neck, oesophagus, skin, or cervix. 15 patients had not been previously treated.
in the supernatant (table). HBV MARKERS ON DRIED BLOOD SMEARS
or
1. Evans DAP, Mahgoub A, Sloan TP, Idle JR, Smith RL. A family and population study of the genetic polymorphism of debrisoquine oxidation in a British white population. J Med Genet 1980; 17: 102-05. 2. Mbanefo C, Bababunmi, EA, Mahgoub A, Sloan TP, Idle JR, Smith RL. A study of the debrisoquine hydroxylation polymorphism in a Nigerian population. Xenobiotica 1980; 10: 811-18. 3. Smith RL, Idle JR. The debrisoquine hydroxylation gene: a gene of multiple effect. In: Davis M, Tredgar JM, Williams R, eds. Drug reactions and the liver. Tunbndge Wells: Pitman Medical, 1981, (in press). 4. Waring RH. Variation in the human metabolism of S-carboxymethyl cysteine. Eur J Drug Metab Pharmacokinet 1980; 5: 49-52. McGovack 5. TH, Chevalley J Untoward hematologic responses to the antithyroid compounds. Am J Med 1954; 17: 36-40. 6. Brugarolas A, Gosalvez M. Treatment of cancer by an inducer of reverse transformation. Lancet 1980; i: 68-69.
*P/N ratios ≥2. 1 are
positive.
Since it is not known whether these dried proteins are associated with infectivity (though Bond’s results suggest that they may be) blood typing cards should be handled with care and not stored in patients’ records without being covered.
Max von Pettenkofer Institute, 8000 Munich 2, West Germany
R. ZACHOVAL G. FROSNER F. DEINHARDT
Department of Internal Medicine, Ludwig-Maximilians-Universität,
D.HÖSS
Munich
7 Gamier
R, Conso F, Efthymiou ML, Fournier E. Thioproline. Lancet 1980, i. 365 Sappino AP, Smith IE. Thioproline in squamous cell cancer. Lancet 1980, u: 417 1. Mushawar IK, Overby, LR, Frösner GG, Demhardt F, Ling Ch.-M. Prevalence of hepatitis B e antigen and its antibody as detected by radioimmunoassay. J Med Virol 8
1978;
2: 77-87.
SULPHOXIDATION
SIR,—The metabolic oxidation of debrisoquine is regulated by a single autosomal genel with two alleles: the DH allele determines rapid and extensive oxidation while the DL allele determines an impaired oxidation capacity.2 DL homozygotes display an impaired ability to hydroxylate debrisoquine. The debrisoquine gene regulates or influences the oxidative metabolism of several other drugs,3but so far all the oxidations shown to be influenced by this gene have been at carbon centres. Does this gene influence oxidation at other types of centre, such as nitrogen or sulphur? We have investigated the sulphoxidation of the mucolytic drug ’Mucodyne’ (S-carboxymethyl-L-cysteine) in two panels, each of four subjects, known to be extensive metabolisers (EM) or poor metabolisers (PM) with respect to debrisoquine oxidation. S-carboxymethyl-L-cysteine is metabolised in man to at least nine metabolites, four of which are sulphoxides, products of
hydroxylation
sulphoxidation.4 Each volunteer took a 750 mg capsule of mucodyne, and urine was collected for 8 h and analysed for S-carboxymethyl-L-cysteine and metabolites. Volunteers of EM phenotype eliminated a mean of 53% (range 35-85%) of the dose in the 8 h period, with 22% (18-27%) as sulphoxides. Those of PM phenotype excreted 53% (35-98%) with only 2 - 2% (1 - 3-4 - 2%) as sulphoxides. This ten-fold difference between the two phenotypes with respect to sulphoxide output after an oral dose of mucodyne suggests that sulphoxidation of this compound is regulated by the same gene that controls the oxidation of debrisoquine and other drugs. This observation may be of clinical significance: sulphoxidation occurs with several drugs (e.g., phenothiazines and ethionamide) and the reaction is thought to be important in relation to the metabolic activation and toxicity of certain sulphur-containing drugs, narticularlv the thioamides.5 Department of Biochemistry, University of Birmingham, Birmingham B 15 2YY
R. H. WARING
Department of Pharmacology, St Mary’s Hospital Medical School, London W2 1PG
thioproline7—i.e.,
noted. Our study confirms the findings of Sappino and Smith8 on the lack of therapeutic effect of thioproline and the toxicity of this drug for the central nervous system, and demonstrates another toxic effect, renal function disturbance. S. NASCA V. GALICHET J. C. JARDILLIER E. GARBE P. CONINX
Regional Cancer Centre, Institut Jean Godinot, 51056-Reims, France
PERSISTENCE OF HEPATITIS B VIRUS ANTIGENS IN DRIED BLOOD
SIR,-We would like to add a footnote to the letter by Dr Bondand colleagues (March 7, p. 550). We have demonstrated
S. C. MITCHELL
his
J. R. IDLE
immunologically intact dried HBsAg and HBeAg on the surface of blood group typing cards of chronically HBV-infected haemodialysis patients. The typing cards of two HBsAg andHBeAg carriers (A and B) were collected over a period of some weeks and the dried blood smears were cut out, pooled, soaked in saline, and centrifuged. The supernatants were screened for HBsAg (’Ausria II’; Abbott) and HBeAg.Both markers were clearly demonstrated
R. L. SMITH
THIOPROLINE TOXICITY
SIR,—The results obtained with thioproline (thiazolidine-4cell carcinoma, particularly in head and neck cancer, and the apparent lack of drug toxicity reported by Brugarolas and Gosalvezprompted us to do a pilot study in pa-
carboxylic acid) in squamous tients with measurable
No regression was observed with any of the three schedules. 7 of the patients who received thioproline intramuscularly had squamous cell carcinoma of the head and neck and had not been treated previously. Toxic manifestations, essentially neurological symptoms and renal function abnormality, were noted, for oral and intramuscular routes, in 18 patients. Central nervous system side-effects were observed in 10 patients, and included confusion, lethargy, and tremor, severe in 2, moderate in 3, and mild in 5. In one patient, we unsuccessfully tried to identify formaldehyde in the cerebrospinal fluid. The neurological symptoms resolved when treatment was stopped. Abnormal serum creatinine levels were noted in 9 patients. This could have been partly due to the neoplastic disease or to other medication in 4 patients but seemed to be solely related to thioproline in the other 5, in 4 of whom serum creatinine levels returned to normal 2-3 weeks after thioproline administration was stopped. 3 patients had both neurological symptoms and renal function disturbance. None of the other toxic signs and symptoms metabolic acidosis, hyporeported with glycaemia, seizures, epilepsy, deafness, and hypoacusia-were
evaluable lesions of advanced cancer. Thioproline was given daily in four equally divided doses either orally at 20 mg/kg daily for 21-42 consecutive days or intramuscularly at 40 mg/kg daily of thioproline sodium salt for 14-42 consecutive days or for two to four courses of 7 consecutive days 2 weeks apart. From March to September, 1980, 48 patients with histologically proven cancer were entered in this study. 22 patients were treated orally and 26 patients were given injections over 14-42 days consecutively (9 patients) or as two to four courses (17 patients). 28 patients had squamous cell carcinoma of head and neck, oesophagus, skin, or cervix. 15 patients had not been previously treated.
in the supernatant (table). HBV MARKERS ON DRIED BLOOD SMEARS
or
1. Evans DAP, Mahgoub A, Sloan TP, Idle JR, Smith RL. A family and population study of the genetic polymorphism of debrisoquine oxidation in a British white population. J Med Genet 1980; 17: 102-05. 2. Mbanefo C, Bababunmi, EA, Mahgoub A, Sloan TP, Idle JR, Smith RL. A study of the debrisoquine hydroxylation polymorphism in a Nigerian population. Xenobiotica 1980; 10: 811-18. 3. Smith RL, Idle JR. The debrisoquine hydroxylation gene: a gene of multiple effect. In: Davis M, Tredgar JM, Williams R, eds. Drug reactions and the liver. Tunbndge Wells: Pitman Medical, 1981, (in press). 4. Waring RH. Variation in the human metabolism of S-carboxymethyl cysteine. Eur J Drug Metab Pharmacokinet 1980; 5: 49-52. McGovack 5. TH, Chevalley J Untoward hematologic responses to the antithyroid compounds. Am J Med 1954; 17: 36-40. 6. Brugarolas A, Gosalvez M. Treatment of cancer by an inducer of reverse transformation. Lancet 1980; i: 68-69.
*P/N ratios ≥2. 1 are
positive.
Since it is not known whether these dried proteins are associated with infectivity (though Bond’s results suggest that they may be) blood typing cards should be handled with care and not stored in patients’ records without being covered.
Max von Pettenkofer Institute, 8000 Munich 2, West Germany
R. ZACHOVAL G. FROSNER F. DEINHARDT
Department of Internal Medicine, Ludwig-Maximilians-Universität,
D.HÖSS
Munich
7 Gamier
R, Conso F, Efthymiou ML, Fournier E. Thioproline. Lancet 1980, i. 365 Sappino AP, Smith IE. Thioproline in squamous cell cancer. Lancet 1980, u: 417 1. Mushawar IK, Overby, LR, Frösner GG, Demhardt F, Ling Ch.-M. Prevalence of hepatitis B e antigen and its antibody as detected by radioimmunoassay. J Med Virol 8
1978;
2: 77-87.