- Email: [email protected]
SALIVARY CONCENTRATIONS OF ANTIEPILEPTIC DRUGS
639
permit the responses P<0.05; regression 50% P<0.02) conclusion that chemotherapy is improved by taking into
tive
account the circadian
rhythm of tumoral proliferation.
Institute de Pathologie,
Université de Liège, et Clinique Sainte Elisabeth,
C. FOCAN
4020 Liège, Belgium
CLINICAL USEFULNESS OF SERUM-DIGOXIN
SIR,-Your editorial of Aug. 21 (p. 405) was appreciated. Especially cogent, I think, were your remarks on the clinical usefulness of "correctly interpreted" measurements of serumdigoxin. You put the weight of your opinion behind the moderate view-neither complete espousal nor utter rejection of serum-digoxin levels-and left assessment of laboratory value in the hands of the experienced physician, which is where it
belongs.
Had Lasagna qualified his similar remarks in an editorial which accompanied the provocative paper of Ingelfinger and Goldman,2 the case for clinical evaluation of laboratory values would have emerged much more clearly. I am sure that physicians are impatient with the clinical pharmacologists for creating confusion-particularly when they criticise published papers, tell us how to do it better, but then do not attempt it. I would plead for interpretation of serum-digoxin levels with intervening clinical judgment. If the physician’s judgment differs from the laboratory value, this should (and often does) force him to evaluate the test results more critically and brings them into line with the patient’s problem. This must result in better patient care.3 L’ntike Ingelfinger and Goldman, I believe that digoxin serum levels are of value in diagnosing digitalis intoxication; indeed, they may assist in the evaluation of management of overt toxicity with digoxin-specific antibodies.4
SIR There is now good evidence that phenytoin treatment of epilepsy is assisted by routine monitoring of the plasma drug concentration.1-6 Present methods for estimating plasmaphenytoin measure total drug levels, whereas only the non-protein-bound (free) fraction is considered to be biologically active. Since salivary phenytoin levels correlate closely with plasma-freeand cerebrospinal-fluid levels,. Dr Reynolds and her colleagues (Aug. 21, p. 384) have suggested that phenytoin therapy could be more appropriately monitored by measurement of drug concentrations in mixed saliva. If generally adopted, this method will generate large numbers of samples which cannot be accommodated readily by current gas-chromatographic techniques. In contrast, the radioimmunoassay for salivary phenytoin which we have described elsewhere9 is well suited for this application, as it is simple, specific, and sensitive (detection limit 0.4 nmol/1). Results on up to 100 samples can be obtained in less than 3 h. The small volume of sample required for radioimmunoassay (40 µl saliva for duplicate determination) makes unnecessary the external stimulation with citric acid advocated by Reynolds and her colleagues
Division of Cardiology, University of Arkansas for Medical Sciences/
V.A. Hospital Complex, Little Rock, Arkansas
JAMES
72206, U.S.A.
E. DOHERTY
SALIVARY CONCENTRATIONS OF ANTIEPILEPTIC DRUGS
SIR,—With reference to the article by Dr Reynolds and her colleagues (Aug. 21, p. 384), we should like to suggest that
Correlation between rate of phenytoin parotid saliva in one subject.
0, first experiment. Linear regression equation, 0444, with correlation coefficient (r)
salivary levels are especially valuable for monitoring antiepileptic-drug levels in outpatients, who can easily collect saliva samples at home. Plasma-levels of phenytoin, phenobarbitone, and primidone can be predicted from salivary concentrations regardless of other medication.5 With antiepileptic drugs which are not protein-bound, such as primidone or ethosuximide, salivary and plasma levels should be identical. In fact, 50 ethosuximide concentrations in saliva and plasma of 30 patients showed excellent agreement,
y = 1.956x —
with
in order
a
coefficient
of correlation
of
0.97,
105±22%
mean±S.D.) of the plasma-concentration being found in the saliva. Owing to a low pKa value of 46, salivary levels of 28), dipropylacetate were only 0.9±0.5% (meanis.D., n even though about 6% of the plasma-concentration is reportedlv unbound,6 Therefore dipropylacetate levels cannot be =
(D.P.H.) secretion and flow-rate of
=
0.999.
2 h later. Linear regression equation, y = 1.688x+ 0.024, with r = 0.999. The gradients of the lines represent the mean D.P.H. concentration (nmol/ml) in the parotid fluid during the time of the experiment.
, repeat
experiment
(Reproduced by kind Clinical Pharmacology.)
permission
of the
Editor, British Journal of
to obtain adequate volumes of saliva for gas chromatography (0.5—2.0ml). Using this radioimmunoassay and techniques for collection of saliva from individual glands, we have investigated certain aspects of salivary phenytoin secretion which help to validate
the
use
of saliva measurements. 10
conveniently monitored in saliva. Buchthal, F., Svensmark, O., Schiller, P. J. Archs Neurol., Chicago, 1960, 2, 624. 2. Kutt, H., Penry, J. K. ibid. 1974, 31, 383. 3. Lund, L. ibid. p. 289. 4. Richens, A., Dunlop, A. Lancet, 1975, ii, 247. 5. Lancet, 1975, ii, 264. 6. Reynolds, E. H., Chadwick, D., Galbraith, A. W. Lancet, 1976, i, 923. 7. Bochner, F., Hooper, W. D., Sutherland, J. M., Eadie, M. J., Tyrer, J. H. Archs Neurol., Chicago, 1974, 31, 57. 8. Lambie, D. G., Paxton, J. W., Nanda, R. N., Johnson, E. H., Ratcliffe, J. G., Melville, I. D., Morrice, G. D. Scott. med. J. 1976, 21, 93. 9. Paxton, J. W., Rowell, F. J., Ratcliffe, J. G., Lambie, D. G., Nanda, R., Melville, I. D., Johnson, R. M. Eur. J. clin. Pharmac. (in the press). 10. Paxton, J. W., Whiting, B., Stephen, K. Br. J. clin. Pharmac. (in the press). 1.
Abtellung für Neurologie, Klinikum Charlottenburg, Freie Universität Berlin, 1000 Berlin 19, West Germany
DIETER SCHMIDT
1 Lasagna, L New Engl. J. Med. 1976, 294, 867. 2 Ingelfinger, J., Goldman, P. ibid. p. 867. 3 Doherty, J. E. in Controversy in Cardiology (edited by
E.
Chung). New
York, 1976. 4 Smith, T. W., Haber, E., Yeatman, L., Butler, V. P., Jr. New Engl. J. Med. 1976, 294, 797 5 Schmidt, D., Kupferberg, H. J. Epilepsia, 1975, 16, 735. 6 Gugler, R Personal communication.
640
(1) Phenytoin is present in excretion from individual parotid and submandibular glands. Phenytoin in mixed saliva does not therefore arise simply from exudation of the drug into gingival fluid.
(2) Phenytoin levels are similar in parotid and submandibular saliva and are greater (mean 16%) than in mixed saliva, possibly because of adsorption of phenytoin on cell debris in mixed saliva. (3) Phenytoin levels in parotid, submandibular, and mixed salivary samples are independent of volume produced. (4) There is a linear relationship between rate of phenytoin secretion by parotid and submandibular glands and salivaryflow rate produced by different degrees of stimulation with citric acid (see fig.). These data provide further evidence that mixed (or parotid) saliva, with or without citric-acid stimulation, is a suitable fluid for routine monitoring of phenytoin therapy, offering the advantage of non-invasive sampling. We agree with Reynolds and her colleagues that the salivary estimation may provide a more accurate index of biologically available phenytoin in situations where protein binding of the drug is abnormal or where there is drug interaction. We suggest that the radioimmunoassay technique for salivary phenytoin measurement has considerable practical advantages over conventional gas-chromatographic methods for routine monitoring purposes. Department of Materia Medica, University of Glasgow, Stobhill General Hospital, Glasgow G21 3UW
JAMES W. PAXTON
Stobhill General Hospital
BRIAN WHITING FREDERICK J. ROWELL JOHN G. RATCLIFFE
Department of Oral Medicine, University of Glasgow Dental School
KENNETH W. STEPHEN
R.I.A.
Unit,
CORRELATIONS BETWEEN DISTURBED HÆM SYNTHESIS AND FETAL MALFORMATION
SIR,—Analysis of animal models of genetically determined environmentally induced birth defects aid the identification of critical developmental processes which are especially sensitive to perturbation and which, when disturbed, permanently damage organogenesis and growth. Identification of these critical processes and their incorporation into screening tests could help in the search for teratogens. Mutations affecting blood formation in prenatal mice are widely used in studies of the regulation of haematopoiesis’ but in the flexed-tailed mouse (gene symbol f/f) severe prenatal siderocytic anaemia is accompanied by retarded fetal growth2 and abnormal development of the vertebral column.3 Prenatal and
anæmia per se is not the cause of these defects since in more severely anaemic mutant mice fetal growth and skeletal development are normal.* Prenatal f/f tissues show reduced activity of two enzymes early in the pathway of haem synthesisnamely, &Dgr;-aminolævulinate (A.L.A.) synthetase and &Dgr;-A.L.A. dehydratase.-’ Haem is an essential component of other proteinsynthesising systems67 as well as heemoproteins. The retarded fetal growth and skeletal abnormalities of f/f mice could, therefore, arise from a primary defect in haem synthesis. If normal haem synthesis is a prerequisite for normal growth and development in a variety of mammalian tissues a single mode of action of a number of established but seemingly unrelated teratogens becomes apparent.
1. 2. 3. 4.
Bannerman, R. M., Edwards, J. A. Br. J. Hœmat. 1976, 32, 299. Tarbutt, R. G., Cole, R. J. Cell Tissue Kinet. 1972, 5, 491. Gruneberg, H. The Pathology of Development. New York, 1963. Cole, R. J., Tarbutt, R. G., Cheek, E., White, S. Cell Tissue Kinet. 1974, 7, 165. 5. Cole, R. J., Garlick, J., Cheek, E. J. Embryol. exp. Morphol. 1975, 34, 373. 6. Beuzard, Y., Rodvien, R., London, I, M. Proc. natn. Acad. Sci. U.S.A. 1973, 70, 1022. 7. Raffel, C., Stein, S., Kampfer, R. ibid. 1974, 71, 4020.
Several enzymes in the haem synthetic pathway are susceptible to inhibition by lead,8 and the A-A.L.A. dehydratase level is a sensitive indicator of exposure. Lead is a potent teratogen (e.g., abnormalities of sacral and caudal vertebrae in the hamster, an effect which is potentiated by cadmium,9 and hydrocephalus and meningocoeles in the chick embryo). Several workers have considered environmental contamination bv
heavy metals, especially lead, as a contributory factor to human congenital defects, without suggesting specific biochemical mechanisms. The apparent geographic and socioeconomic correlations of high incidences of neural tube and spinal defects with soft or acidic water,’O old housing with lead plumbing, industrial pollution, and maternal anaemia could result from the impact of lead on haem synthesis. Chronic alcoholism is frequently associated with sideroblastic anaemia, indicating deranged hæm synthesis" and alcohol acts synergistically with lead in occupationally exposed workers. The fetal alcohol syndromel2 is consistent with a similar metabolic disturbance in fetal tissue. Continued exposure to oestrogen/progestagen contraceptives in early pregnancy has been reported to give rise to significantly increased incidence of congenital heart-disease, DiGeorge syndrome, and the "VACTERL" anomaly,13 and androgen/oestrogen pregnancy testing drugs have also shown teratogenic effects. Steroid hormones are potent inducers of A-A.L.A. synthetase. Testosterone and 5a and 5&bgr; androstanediol are the most effective inducers of this enzyme in human fetal tissue"’ so that oestrogens and progestagens could easily perturb the normal regulation of haem synthesis during development. There is also a marked preponderance of female cases of neural tube and spinal defects, especially in areas of high incidence. These correlations suggest that drugs and environmental contaminants which perturb haem synthesis might in certain circumstances-for example, by synergism or genetically determined sensitivity-act as potent teratogens. Developmental Genetics Laboratory School of Biological Sciences, University of Sussex, Brighton
ROBIN COLE
Centre for Medical Research, University of Sussex
JANE COLE
PROPRANOLOL IN COCAINE TOXICITY
SIR We have found, in
over SO cases, that propranolol and reverses the cardiovascular pressor specifically safely effects of cocaine (i.e., amphetamine tachycardia) that place at risk patients taking this drug. Central cardiovascular hypermetabolism is the most serious consequence in a patient who has taken cocaine, either as a casually self-administered drug or as a topical anaesthetic before endoscopy. The classical cocaine reaction, with initial stimulatory effects followed, sometimes, by profound depressant action, can often confuse the physician, but once this potential crisis has passed and n is clear that one is indeed faced with a case of chronic toxicin (the "overamped", "wired" individual with the cocaine "leaps") then prompt intervention is indicated, for it is this patient at this time who is the prime candidate for cerebrovascular accident, imminent death from cardiac arrhythmia, or high-output congestive heart-failure. In our experience, unique in its accessibility to an iltiath using cocaine population, we have found the following regimen to be effective and safe-namely, 1 mg propranolol hydrochloride/min intravenously (up to a maximum dose of 8 mg in
8. Waldron, H. A., Stoffen, D. Sub-clinical Lead Poisoning. London, 1974 9. Ferm, V. H. Experientia, 1969, 25, 56. 10. Lowe, C. R., Roberts, C. J., Lloyd, S. Br. med. J. 1971, ii, 357 11. Echner, E. R., Hillman, R. S. Am. J. Med. 1971, 50, 218. 12. Jones, K. L., Smith, D. W. Lancet, 1973, ii, 999. 13 Nora, J. J., Nora, A. H. ibid. 1973, i, 941. 14. Congote, L. F., Stern, M. D., Solomons, S. Biochemistry, 1974. 13, 4255.
permit the responses P<0.05; regression 50% P<0.02) conclusion that chemotherapy is improved by taking into
tive
account the circadian
rhythm of tumoral proliferation.
Institute de Pathologie,
Université de Liège, et Clinique Sainte Elisabeth,
C. FOCAN
4020 Liège, Belgium
CLINICAL USEFULNESS OF SERUM-DIGOXIN
SIR,-Your editorial of Aug. 21 (p. 405) was appreciated. Especially cogent, I think, were your remarks on the clinical usefulness of "correctly interpreted" measurements of serumdigoxin. You put the weight of your opinion behind the moderate view-neither complete espousal nor utter rejection of serum-digoxin levels-and left assessment of laboratory value in the hands of the experienced physician, which is where it
belongs.
Had Lasagna qualified his similar remarks in an editorial which accompanied the provocative paper of Ingelfinger and Goldman,2 the case for clinical evaluation of laboratory values would have emerged much more clearly. I am sure that physicians are impatient with the clinical pharmacologists for creating confusion-particularly when they criticise published papers, tell us how to do it better, but then do not attempt it. I would plead for interpretation of serum-digoxin levels with intervening clinical judgment. If the physician’s judgment differs from the laboratory value, this should (and often does) force him to evaluate the test results more critically and brings them into line with the patient’s problem. This must result in better patient care.3 L’ntike Ingelfinger and Goldman, I believe that digoxin serum levels are of value in diagnosing digitalis intoxication; indeed, they may assist in the evaluation of management of overt toxicity with digoxin-specific antibodies.4
SIR There is now good evidence that phenytoin treatment of epilepsy is assisted by routine monitoring of the plasma drug concentration.1-6 Present methods for estimating plasmaphenytoin measure total drug levels, whereas only the non-protein-bound (free) fraction is considered to be biologically active. Since salivary phenytoin levels correlate closely with plasma-freeand cerebrospinal-fluid levels,. Dr Reynolds and her colleagues (Aug. 21, p. 384) have suggested that phenytoin therapy could be more appropriately monitored by measurement of drug concentrations in mixed saliva. If generally adopted, this method will generate large numbers of samples which cannot be accommodated readily by current gas-chromatographic techniques. In contrast, the radioimmunoassay for salivary phenytoin which we have described elsewhere9 is well suited for this application, as it is simple, specific, and sensitive (detection limit 0.4 nmol/1). Results on up to 100 samples can be obtained in less than 3 h. The small volume of sample required for radioimmunoassay (40 µl saliva for duplicate determination) makes unnecessary the external stimulation with citric acid advocated by Reynolds and her colleagues
Division of Cardiology, University of Arkansas for Medical Sciences/
V.A. Hospital Complex, Little Rock, Arkansas
JAMES
72206, U.S.A.
E. DOHERTY
SALIVARY CONCENTRATIONS OF ANTIEPILEPTIC DRUGS
SIR,—With reference to the article by Dr Reynolds and her colleagues (Aug. 21, p. 384), we should like to suggest that
Correlation between rate of phenytoin parotid saliva in one subject.
0, first experiment. Linear regression equation, 0444, with correlation coefficient (r)
salivary levels are especially valuable for monitoring antiepileptic-drug levels in outpatients, who can easily collect saliva samples at home. Plasma-levels of phenytoin, phenobarbitone, and primidone can be predicted from salivary concentrations regardless of other medication.5 With antiepileptic drugs which are not protein-bound, such as primidone or ethosuximide, salivary and plasma levels should be identical. In fact, 50 ethosuximide concentrations in saliva and plasma of 30 patients showed excellent agreement,
y = 1.956x —
with
in order
a
coefficient
of correlation
of
0.97,
105±22%
mean±S.D.) of the plasma-concentration being found in the saliva. Owing to a low pKa value of 46, salivary levels of 28), dipropylacetate were only 0.9±0.5% (meanis.D., n even though about 6% of the plasma-concentration is reportedlv unbound,6 Therefore dipropylacetate levels cannot be =
(D.P.H.) secretion and flow-rate of
=
0.999.
2 h later. Linear regression equation, y = 1.688x+ 0.024, with r = 0.999. The gradients of the lines represent the mean D.P.H. concentration (nmol/ml) in the parotid fluid during the time of the experiment.
, repeat
experiment
(Reproduced by kind Clinical Pharmacology.)
permission
of the
Editor, British Journal of
to obtain adequate volumes of saliva for gas chromatography (0.5—2.0ml). Using this radioimmunoassay and techniques for collection of saliva from individual glands, we have investigated certain aspects of salivary phenytoin secretion which help to validate
the
use
of saliva measurements. 10
conveniently monitored in saliva. Buchthal, F., Svensmark, O., Schiller, P. J. Archs Neurol., Chicago, 1960, 2, 624. 2. Kutt, H., Penry, J. K. ibid. 1974, 31, 383. 3. Lund, L. ibid. p. 289. 4. Richens, A., Dunlop, A. Lancet, 1975, ii, 247. 5. Lancet, 1975, ii, 264. 6. Reynolds, E. H., Chadwick, D., Galbraith, A. W. Lancet, 1976, i, 923. 7. Bochner, F., Hooper, W. D., Sutherland, J. M., Eadie, M. J., Tyrer, J. H. Archs Neurol., Chicago, 1974, 31, 57. 8. Lambie, D. G., Paxton, J. W., Nanda, R. N., Johnson, E. H., Ratcliffe, J. G., Melville, I. D., Morrice, G. D. Scott. med. J. 1976, 21, 93. 9. Paxton, J. W., Rowell, F. J., Ratcliffe, J. G., Lambie, D. G., Nanda, R., Melville, I. D., Johnson, R. M. Eur. J. clin. Pharmac. (in the press). 10. Paxton, J. W., Whiting, B., Stephen, K. Br. J. clin. Pharmac. (in the press). 1.
Abtellung für Neurologie, Klinikum Charlottenburg, Freie Universität Berlin, 1000 Berlin 19, West Germany
DIETER SCHMIDT
1 Lasagna, L New Engl. J. Med. 1976, 294, 867. 2 Ingelfinger, J., Goldman, P. ibid. p. 867. 3 Doherty, J. E. in Controversy in Cardiology (edited by
E.
Chung). New
York, 1976. 4 Smith, T. W., Haber, E., Yeatman, L., Butler, V. P., Jr. New Engl. J. Med. 1976, 294, 797 5 Schmidt, D., Kupferberg, H. J. Epilepsia, 1975, 16, 735. 6 Gugler, R Personal communication.
640
(1) Phenytoin is present in excretion from individual parotid and submandibular glands. Phenytoin in mixed saliva does not therefore arise simply from exudation of the drug into gingival fluid.
(2) Phenytoin levels are similar in parotid and submandibular saliva and are greater (mean 16%) than in mixed saliva, possibly because of adsorption of phenytoin on cell debris in mixed saliva. (3) Phenytoin levels in parotid, submandibular, and mixed salivary samples are independent of volume produced. (4) There is a linear relationship between rate of phenytoin secretion by parotid and submandibular glands and salivaryflow rate produced by different degrees of stimulation with citric acid (see fig.). These data provide further evidence that mixed (or parotid) saliva, with or without citric-acid stimulation, is a suitable fluid for routine monitoring of phenytoin therapy, offering the advantage of non-invasive sampling. We agree with Reynolds and her colleagues that the salivary estimation may provide a more accurate index of biologically available phenytoin in situations where protein binding of the drug is abnormal or where there is drug interaction. We suggest that the radioimmunoassay technique for salivary phenytoin measurement has considerable practical advantages over conventional gas-chromatographic methods for routine monitoring purposes. Department of Materia Medica, University of Glasgow, Stobhill General Hospital, Glasgow G21 3UW
JAMES W. PAXTON
Stobhill General Hospital
BRIAN WHITING FREDERICK J. ROWELL JOHN G. RATCLIFFE
Department of Oral Medicine, University of Glasgow Dental School
KENNETH W. STEPHEN
R.I.A.
Unit,
CORRELATIONS BETWEEN DISTURBED HÆM SYNTHESIS AND FETAL MALFORMATION
SIR,—Analysis of animal models of genetically determined environmentally induced birth defects aid the identification of critical developmental processes which are especially sensitive to perturbation and which, when disturbed, permanently damage organogenesis and growth. Identification of these critical processes and their incorporation into screening tests could help in the search for teratogens. Mutations affecting blood formation in prenatal mice are widely used in studies of the regulation of haematopoiesis’ but in the flexed-tailed mouse (gene symbol f/f) severe prenatal siderocytic anaemia is accompanied by retarded fetal growth2 and abnormal development of the vertebral column.3 Prenatal and
anæmia per se is not the cause of these defects since in more severely anaemic mutant mice fetal growth and skeletal development are normal.* Prenatal f/f tissues show reduced activity of two enzymes early in the pathway of haem synthesisnamely, &Dgr;-aminolævulinate (A.L.A.) synthetase and &Dgr;-A.L.A. dehydratase.-’ Haem is an essential component of other proteinsynthesising systems67 as well as heemoproteins. The retarded fetal growth and skeletal abnormalities of f/f mice could, therefore, arise from a primary defect in haem synthesis. If normal haem synthesis is a prerequisite for normal growth and development in a variety of mammalian tissues a single mode of action of a number of established but seemingly unrelated teratogens becomes apparent.
1. 2. 3. 4.
Bannerman, R. M., Edwards, J. A. Br. J. Hœmat. 1976, 32, 299. Tarbutt, R. G., Cole, R. J. Cell Tissue Kinet. 1972, 5, 491. Gruneberg, H. The Pathology of Development. New York, 1963. Cole, R. J., Tarbutt, R. G., Cheek, E., White, S. Cell Tissue Kinet. 1974, 7, 165. 5. Cole, R. J., Garlick, J., Cheek, E. J. Embryol. exp. Morphol. 1975, 34, 373. 6. Beuzard, Y., Rodvien, R., London, I, M. Proc. natn. Acad. Sci. U.S.A. 1973, 70, 1022. 7. Raffel, C., Stein, S., Kampfer, R. ibid. 1974, 71, 4020.
Several enzymes in the haem synthetic pathway are susceptible to inhibition by lead,8 and the A-A.L.A. dehydratase level is a sensitive indicator of exposure. Lead is a potent teratogen (e.g., abnormalities of sacral and caudal vertebrae in the hamster, an effect which is potentiated by cadmium,9 and hydrocephalus and meningocoeles in the chick embryo). Several workers have considered environmental contamination bv
heavy metals, especially lead, as a contributory factor to human congenital defects, without suggesting specific biochemical mechanisms. The apparent geographic and socioeconomic correlations of high incidences of neural tube and spinal defects with soft or acidic water,’O old housing with lead plumbing, industrial pollution, and maternal anaemia could result from the impact of lead on haem synthesis. Chronic alcoholism is frequently associated with sideroblastic anaemia, indicating deranged hæm synthesis" and alcohol acts synergistically with lead in occupationally exposed workers. The fetal alcohol syndromel2 is consistent with a similar metabolic disturbance in fetal tissue. Continued exposure to oestrogen/progestagen contraceptives in early pregnancy has been reported to give rise to significantly increased incidence of congenital heart-disease, DiGeorge syndrome, and the "VACTERL" anomaly,13 and androgen/oestrogen pregnancy testing drugs have also shown teratogenic effects. Steroid hormones are potent inducers of A-A.L.A. synthetase. Testosterone and 5a and 5&bgr; androstanediol are the most effective inducers of this enzyme in human fetal tissue"’ so that oestrogens and progestagens could easily perturb the normal regulation of haem synthesis during development. There is also a marked preponderance of female cases of neural tube and spinal defects, especially in areas of high incidence. These correlations suggest that drugs and environmental contaminants which perturb haem synthesis might in certain circumstances-for example, by synergism or genetically determined sensitivity-act as potent teratogens. Developmental Genetics Laboratory School of Biological Sciences, University of Sussex, Brighton
ROBIN COLE
Centre for Medical Research, University of Sussex
JANE COLE
PROPRANOLOL IN COCAINE TOXICITY
SIR We have found, in
over SO cases, that propranolol and reverses the cardiovascular pressor specifically safely effects of cocaine (i.e., amphetamine tachycardia) that place at risk patients taking this drug. Central cardiovascular hypermetabolism is the most serious consequence in a patient who has taken cocaine, either as a casually self-administered drug or as a topical anaesthetic before endoscopy. The classical cocaine reaction, with initial stimulatory effects followed, sometimes, by profound depressant action, can often confuse the physician, but once this potential crisis has passed and n is clear that one is indeed faced with a case of chronic toxicin (the "overamped", "wired" individual with the cocaine "leaps") then prompt intervention is indicated, for it is this patient at this time who is the prime candidate for cerebrovascular accident, imminent death from cardiac arrhythmia, or high-output congestive heart-failure. In our experience, unique in its accessibility to an iltiath using cocaine population, we have found the following regimen to be effective and safe-namely, 1 mg propranolol hydrochloride/min intravenously (up to a maximum dose of 8 mg in
8. Waldron, H. A., Stoffen, D. Sub-clinical Lead Poisoning. London, 1974 9. Ferm, V. H. Experientia, 1969, 25, 56. 10. Lowe, C. R., Roberts, C. J., Lloyd, S. Br. med. J. 1971, ii, 357 11. Echner, E. R., Hillman, R. S. Am. J. Med. 1971, 50, 218. 12. Jones, K. L., Smith, D. W. Lancet, 1973, ii, 999. 13 Nora, J. J., Nora, A. H. ibid. 1973, i, 941. 14. Congote, L. F., Stern, M. D., Solomons, S. Biochemistry, 1974. 13, 4255.