168
and, since it may give benefit, I think it is justifiable to give dexamethasone as adjuvant treatment in cerebral malaria. However, prompt specific treatment with intra-
quinine (or chloroquine if the infection is acquired in Africa) is much the most important factor in recovery from severe falciparum malaria. Liverpool School of Tropical Medicine,
venous
Pembroke Place, Liverpool L3 5QA.
H. ALISTAIR REID.
PLASMA-DIAZEPAM LEVELS
SIR,-Iwas interested to read of plasma-diazepam levels following intramuscular injection by nurses and doctors (Dec. 14, p. 1461). Professor Dundee and his colleagues appear to have overlooked
critical variable. From their results plasma levels seem to be a function of needle size, not administration by a nurse or a doctor, since nurses used a 3 cm. needle, doctors a 4 cm. needle for intramuscular injection into the buttock. Although doctors " injected into the upper outer quadrant " and nurses were given " no " it is standard nursing procedure to specific instructions 2 use that site. 1.
Philadelphia, Pennsylvania 19147,
MARTHA LIBBY COOPERMAN.
CORYNEBACTERIUM PARVUM AND ANÆSTHETICS
SiR,—Vaccines consisting of killed suspensions of Corynebacterium parvum are now undergoing clinical evaluation as potential immunotherapeutic agents for various neoplastic conditions. Consequently, we wish to report our finding that mice given C. parvum by intravenous injection become lethally sensitive to normally safe anaesthetic doses of pentobarbitone (’Nembutal’) and tribromoethanol (’ Avertin ’). Hamilton3 and Castro4 have also noted that C. parvum treated mice are abnormally sensitive to pentobarbitone. In our study, groups of 10 CBA mice were treated with 75 mg. per kg. of sodium pentobarbitone 7 or 13 days after they had received 0-7 mg (0-2 ml.) C. parvum (Wellcome, strain CN6134) by intravenous injection. All died without recovering from the anaesthetic. When the pentobarbitone was given 14 days after intravenous C. parvum, 80% of the mice died. There were no deaths among mice given the anaesthetic on the same day or three days after intravenous C. parvum or among the control mice given the anxsthetic only. Halving the dose of C. parvum (0.35 mg.) resulted in fewer but still a significant number of deaths among mice given the anaesthetic 3 to 28 days later. An alternative anxsthetic, avertin (200 mg. tribromoethanol and 100 mg. amylene hydrate in 10% ethyl alcohol per kg.), also proved lethal to mice given C. parvum between 3 and 13 days previously. Similar results were also obtained with avertin and sodium pentobarbitone in C. parvum-treated C57BI and Porton albino mice. C. parvum, irrespective of dose or time of injection, did not sensitise any mice to ether; in fact, C. parvum-treated mice of all three strains recovered normally from ether anaesthesia. The livers of all C. parvum-treated mice fatally sensitised Culver, V. Modern Bedside Nursing; p. 316. Philadelphia, 1974. Thompson, E., Rosdahl, C. Textbook of Basic Nursing; p. 335. Philadelphia, 1973. 3. Hamilton, D. N. H. Personal communication, 1974. 4. Castro, J. E. Eur. J. Cancer, 1974, 10, 115. 1. 2.
the anaesthetic
size, and whitish
were
enlarged
areas were
Wellcome Research Laboratories,
Langley Court, Beckenham,
a
Department of Psychiatry, Albert Einstein Medical Center, U.S.A.
up to three times normal noted round the periphery of the lobes. Mice which recovered from the anaesthetic, however, had normal or slightly enlarged livers. Pentobarbitone and tribromoethanol are detoxified in the liver. Given intravenously, C. parvum apparently interferes with the process of detoxification, and anaesthetic death may ensue. Ether, on the other hand, is mainly expelled through the lungs and does not depend on the liver for breakdown. Reactions in mice may not be paralleled in man, but there may be a potential risk in giving anxsthetics or sedatives to C. parvum-treated patients where those substances depend on the liver for catabolism. Caution should therefore be exercised in the use of such compounds in patients lately treated with intravenous C. parvum. to
Kent BR3 3BS.
BETTY MOSEDALE M. A. SMITH.
OXPRENOLOL AND LEVODOPA IN PARKINSONIAN PATIENTS
SIR,-In contrast to earlier reports,1-3 Professor Marsden and his group4 could detect no additional improvement in the clinical signs of Parkinson’s disease, including tremor, when propranolol was administered with levodopa. Because of this divergence, we thought it timely to report briefly an apparent lack of additional effect when levodopa is supplemented with another &bgr;-blocking drug, oxprenolol. Because of unconfirmed reports that oxprenolol lowers plasma and urinary catecholamine levels in normal subjects,5 we also examined the effect of oxprenolol on levodopa metabolism in these patients. In an initial study, four parkinsonian patients on their personal optimum dosage of levodopa participated in a double-blind crossover trial with oxprenolol (40 mg. four times daily) and a placebo preparation, each administered for six weeks. Urine was collected for a single twenty-fourhour period during treatment with each drug regimen and examined gas-chromatographically 6,7 for catecholamines and their metabolites. Since the initial results pointed to an increased output of dopamine and its acidic metabolites during oxprenolol ingestion, a second study of five additional patients on levodopa with added oxprenolol for a period of three weeks was undertaken. Twenty-four-hour urine collections were made before, after, and several times during treatment. It was then found that there were wide day-today fluctuations in the relative and absolute proportions of free and conjugated catecholamines and their metabolites, with no consistent pattern. During oxprenolol administration there was neither subjective improvement in parkinsonian state nor any objective evidence of benefit in physical signs assessed
according to an arbitrary five-point scale. Thus, oxprenolol does not appear to modify the effect of levodopa in parkinsonism either biochemically or clinically. Queen Charlotte’s Maternity Hospital, London W6 0XG. Hammersmith Hospital, London W12 OHS. Cross Hospital, London W6 8RF.
Charing
1. 2. 3. 4. 5. 6. 7.
M. SANDLER. LINDA E. FELLOWS.
D. B. CALNE. L. J. FINDLEY.
Abramsky, O., Carmon, A., Lavy, S. J. neurol. Sci. 1971, 14, 491. Kissel, P., Tridon, P., Masingue, M., André, J. M. Nouv. Presse méd. 1972, 1, 1943. Kissel, P., Tridon, P., André, J. M. Lancet, 1974, i, 403. Marsden, C. D., Parkes, J. D., Rees, J. E. ibid. 1974, ii, 410. McMillin, W. P. in Private Report to CIBA Laboratories Ltd. Karoum, R., Anah, C. O., Ruthven, C. R. J., Sandler, M. Clinica chim. Acta, 1969, 24, 341. Wong, K. P., Ruthven, C. R. J., Sandler, M. ibid. 1973, 47, 215.
and, since it may give benefit, I think it is justifiable to give dexamethasone as adjuvant treatment in cerebral malaria. However, prompt specific treatment with intra-
quinine (or chloroquine if the infection is acquired in Africa) is much the most important factor in recovery from severe falciparum malaria. Liverpool School of Tropical Medicine,
venous
Pembroke Place, Liverpool L3 5QA.
H. ALISTAIR REID.
PLASMA-DIAZEPAM LEVELS
SIR,-Iwas interested to read of plasma-diazepam levels following intramuscular injection by nurses and doctors (Dec. 14, p. 1461). Professor Dundee and his colleagues appear to have overlooked
critical variable. From their results plasma levels seem to be a function of needle size, not administration by a nurse or a doctor, since nurses used a 3 cm. needle, doctors a 4 cm. needle for intramuscular injection into the buttock. Although doctors " injected into the upper outer quadrant " and nurses were given " no " it is standard nursing procedure to specific instructions 2 use that site. 1.
Philadelphia, Pennsylvania 19147,
MARTHA LIBBY COOPERMAN.
CORYNEBACTERIUM PARVUM AND ANÆSTHETICS
SiR,—Vaccines consisting of killed suspensions of Corynebacterium parvum are now undergoing clinical evaluation as potential immunotherapeutic agents for various neoplastic conditions. Consequently, we wish to report our finding that mice given C. parvum by intravenous injection become lethally sensitive to normally safe anaesthetic doses of pentobarbitone (’Nembutal’) and tribromoethanol (’ Avertin ’). Hamilton3 and Castro4 have also noted that C. parvum treated mice are abnormally sensitive to pentobarbitone. In our study, groups of 10 CBA mice were treated with 75 mg. per kg. of sodium pentobarbitone 7 or 13 days after they had received 0-7 mg (0-2 ml.) C. parvum (Wellcome, strain CN6134) by intravenous injection. All died without recovering from the anaesthetic. When the pentobarbitone was given 14 days after intravenous C. parvum, 80% of the mice died. There were no deaths among mice given the anaesthetic on the same day or three days after intravenous C. parvum or among the control mice given the anxsthetic only. Halving the dose of C. parvum (0.35 mg.) resulted in fewer but still a significant number of deaths among mice given the anaesthetic 3 to 28 days later. An alternative anxsthetic, avertin (200 mg. tribromoethanol and 100 mg. amylene hydrate in 10% ethyl alcohol per kg.), also proved lethal to mice given C. parvum between 3 and 13 days previously. Similar results were also obtained with avertin and sodium pentobarbitone in C. parvum-treated C57BI and Porton albino mice. C. parvum, irrespective of dose or time of injection, did not sensitise any mice to ether; in fact, C. parvum-treated mice of all three strains recovered normally from ether anaesthesia. The livers of all C. parvum-treated mice fatally sensitised Culver, V. Modern Bedside Nursing; p. 316. Philadelphia, 1974. Thompson, E., Rosdahl, C. Textbook of Basic Nursing; p. 335. Philadelphia, 1973. 3. Hamilton, D. N. H. Personal communication, 1974. 4. Castro, J. E. Eur. J. Cancer, 1974, 10, 115. 1. 2.
the anaesthetic
size, and whitish
were
enlarged
areas were
Wellcome Research Laboratories,
Langley Court, Beckenham,
a
Department of Psychiatry, Albert Einstein Medical Center, U.S.A.
up to three times normal noted round the periphery of the lobes. Mice which recovered from the anaesthetic, however, had normal or slightly enlarged livers. Pentobarbitone and tribromoethanol are detoxified in the liver. Given intravenously, C. parvum apparently interferes with the process of detoxification, and anaesthetic death may ensue. Ether, on the other hand, is mainly expelled through the lungs and does not depend on the liver for breakdown. Reactions in mice may not be paralleled in man, but there may be a potential risk in giving anxsthetics or sedatives to C. parvum-treated patients where those substances depend on the liver for catabolism. Caution should therefore be exercised in the use of such compounds in patients lately treated with intravenous C. parvum. to
Kent BR3 3BS.
BETTY MOSEDALE M. A. SMITH.
OXPRENOLOL AND LEVODOPA IN PARKINSONIAN PATIENTS
SIR,-In contrast to earlier reports,1-3 Professor Marsden and his group4 could detect no additional improvement in the clinical signs of Parkinson’s disease, including tremor, when propranolol was administered with levodopa. Because of this divergence, we thought it timely to report briefly an apparent lack of additional effect when levodopa is supplemented with another &bgr;-blocking drug, oxprenolol. Because of unconfirmed reports that oxprenolol lowers plasma and urinary catecholamine levels in normal subjects,5 we also examined the effect of oxprenolol on levodopa metabolism in these patients. In an initial study, four parkinsonian patients on their personal optimum dosage of levodopa participated in a double-blind crossover trial with oxprenolol (40 mg. four times daily) and a placebo preparation, each administered for six weeks. Urine was collected for a single twenty-fourhour period during treatment with each drug regimen and examined gas-chromatographically 6,7 for catecholamines and their metabolites. Since the initial results pointed to an increased output of dopamine and its acidic metabolites during oxprenolol ingestion, a second study of five additional patients on levodopa with added oxprenolol for a period of three weeks was undertaken. Twenty-four-hour urine collections were made before, after, and several times during treatment. It was then found that there were wide day-today fluctuations in the relative and absolute proportions of free and conjugated catecholamines and their metabolites, with no consistent pattern. During oxprenolol administration there was neither subjective improvement in parkinsonian state nor any objective evidence of benefit in physical signs assessed
according to an arbitrary five-point scale. Thus, oxprenolol does not appear to modify the effect of levodopa in parkinsonism either biochemically or clinically. Queen Charlotte’s Maternity Hospital, London W6 0XG. Hammersmith Hospital, London W12 OHS. Cross Hospital, London W6 8RF.
Charing
1. 2. 3. 4. 5. 6. 7.
M. SANDLER. LINDA E. FELLOWS.
D. B. CALNE. L. J. FINDLEY.
Abramsky, O., Carmon, A., Lavy, S. J. neurol. Sci. 1971, 14, 491. Kissel, P., Tridon, P., Masingue, M., André, J. M. Nouv. Presse méd. 1972, 1, 1943. Kissel, P., Tridon, P., André, J. M. Lancet, 1974, i, 403. Marsden, C. D., Parkes, J. D., Rees, J. E. ibid. 1974, ii, 410. McMillin, W. P. in Private Report to CIBA Laboratories Ltd. Karoum, R., Anah, C. O., Ruthven, C. R. J., Sandler, M. Clinica chim. Acta, 1969, 24, 341. Wong, K. P., Ruthven, C. R. J., Sandler, M. ibid. 1973, 47, 215.
