- Email: [email protected]
FAILED LEVODOPA THERAPY IN STRIATO-NIGRAL DEGENERATION
1355 cellular structures. The mutant strain was also more sensitive to a group of hydrazine antidepressants-pheni-
prazine, phenelzine, mebanazine, isocarboxazid, and benzylhydrazine (a metabolite of isocarboxazid)-as well as to
antituberculous hydrazine. In view of these findings, which suggest that certain commonly used hydrazine medicinal agents are capable of altering the D.N.A. of living cells, and because a relationship between reactivity towards D.N.A. and carcinogenic potential has been established, it would seem proper to re-evaluate the potential tumour-inducing ability of hydrazine antidepressants and of isoniazid. Moreover, in the meantime advantage should be taken of the availability of alternative drugs devoid of the hydrazine moiety. These suggestions seem especially appropriate since the agents in question are ! taken over extended periods of time-a situation which conceivably could favour carcinogenesis. I This work was aided by a grant from the Damon Runyon
isoniazid,
some cases of striato-nigral degeneration, which are not easily differentiated from classic idiopathic parkinsonism
before necropsy.
an
Memorial Fund for Cancer Research. H. S. R. is a research career development awardee of the U.S. Public Health Service
(2-K3-GM 29, 024). Department of Microbiology, College of Physicians and Surgeons, HERBERT S. ROSENKRANZ Columbia University, HOWARD S. CARR. New York, N.Y. 10032.
FAILED LEVODOPA THERAPY IN STRIATO-NIGRAL DEGENERATION SIR,-Levodopa was ineffective in two patients with parkinsonism who were found to have striato-nigral
Department of Neurology, Neurological Institute, Kyushu University, Fukuoka 812, Japan.
K. N. T. T. Y.
IZUMI INOUE SHIRABE MlYAZAKI KUROIWA.
D-PROPRANOLOL AND ANXIETY
SiR,-The reported beneficial effect of D-L-propranolol, daily, in anxiety 1,2 has been attributed to the drug’s p-blocking action. This is consistent with the finding that sinus tachycardia in anxious patients is abolished by intravenous administration of the drug.3 p-blockade is largely due to the L-isomer of propranolol; there is little evidence of &bgr;-blockade by the D-form.o1 It is therefore of theoretical, as well as practical, interest to investigate the effect of D-propranolol in anxiety. A pilot study in 10 patients has been completed using a cross-over design and double-blind technique similar to that reported in the earlier papery but with oral administration of D-propranolol 40 mg. four times daily in one treatment period and matching placebo capsules in the other. The Middlesex Hospital questionnaire 6.6 was given to all patients after clinical assessment but before inclusion in the trial (see table) and demonstrated a high level of freefloating anxiety and somatic concomitants.
20 mg. four times
MEAN SCORES ON MIDDLESEX HOSPITAL
QUESTIONNAIRE**
degeneration
at necropsy. Case 1-A 53-year-old man with parkinsonism was severely disabled. The illness had begun 2 years previously. Clinically he showed pronounced bradykinesia and rigidity. There was no tremor. Deep reflexes were normal, but plantar reflexes were extensor bilaterally. Levodopa, in doses up to 6-4 g. daily, was given for 11 months without any response. He died suddenly at home. At necropsy the brain weighed 1180 g. Macroscopic examination showed slight atrophy. Microscopically, the substantia nigra revealed striking lesions in which almost all the melanin-containing cells were absent. Nerve cells were also absent, and gliosis was seen in the putamen bilaterally. Brownish pigmented granules were present in the globus pallidus and subthalamic area. There was mild degeneration of nerve cells in the locus coeruleus and in the Purkinje cells and white matter of the cerebellum. In addition, the corticospinal tracts of the medulla oblongata were pale in sections stained for myelin. The
clinicopathological diagnosis
was
striato-nigral degenera-
tion. Case 2-A 56-year-old woman had parkinsonism with severe disability. Like the other patient she showed pro-
bradykinesia and rigidity but no tremor. Deep hyperactive, and the plantar reflex was equivocally extensor on the left. 2-6 g. of levodopa was given daily, without effect, till her death from pneumonia. The pathological diagnosis was striato-nigral degeneration and olivo-ponto-cerebellar atrophy. Treatment failures with levodopa in parkinsonism have been discussed from many aspects, including drug tolerance,l misdiagnosis,2 concurrent use of pyridoxine,3 and poor absorption.4 The group of patients whose parkinsonism is not improved by levodopa may contain
nounced reflexes
1.
were
Yahr,
M. D. in L-Dopa and Parkinsonism (edited by A. Barbeau and F. H. McDowell); p. 5. Philadelphia, 1970. 2. Markham, C. H. ibid. p. 10. 3. Duvoisin, R. C., Yahr, M. D., Cote, L. D. Trans. Am. neurol. Ass. 1969, 94, 81.
4.
Rivera-Calimlim, L., Dujovne, Bianchine, J. R. Br.
C. A., Morgan, med. J. 1970, iv, 93.
J. P., Lasagna, L.,
Patients
were
matched for age, sex, marital status, and personally events in the trial period.
important life
Random
blood-samples were taken from the patients to plasma levels and to confirm that they were taking medication as prescribed. It is interesting to note that before breaking the code the assessing psychiatrist had strong reservations about one patient’s reliability in taking medication, and subsequently this patient was found to have the lowest plasma level of D-propranolol. Using a closed sequential design the earlier trial1 demonstrated the investigator’s preference for D-L propranolol as the more effective treatment, becoming statistically significant after 15 had completed their treatments. No statistically significant preference for either D-propranolol or placebo became apparent during this pilot study. No preference was expressed by either patient or assessor in 4 cases. Of those who expressed preferences, 2 favoured the first treatment period and 4 the second. In terms of treatment, 4 preferred D-propranolol and 2 placebo. 5 patients reported no side-effects and 2 reported increasing depression during the second period (when they were on placebo). This was judged to be part of their progressing affective disorder and not due to the D-propranolol. Anxiety and depression continued to increase after cessation of the trial. 1 other patient developed vomiting
assess
1. 2. 3.
Granville-Grossman, K., Turner, P. Lancet, 1966, i, 788. Wheatley, D. Br. J. Psychiat. 1969, 115, 1411. Turner, P., Granville-Grossman, K., Smart, J. Lancet, 1965, ii,
4. 5. 6.
Barrett, A. M., Cullum, V. Br. J. Pharmac. 1968, 34, 43. Crown, S., Crisp, A. Br. J. Psychiat. 1966, 112, 917. Crown, S., Duncan, K. P., Howell, R. W. ibid. 1970, 116,
1316.
33.
prazine, phenelzine, mebanazine, isocarboxazid, and benzylhydrazine (a metabolite of isocarboxazid)-as well as to
antituberculous hydrazine. In view of these findings, which suggest that certain commonly used hydrazine medicinal agents are capable of altering the D.N.A. of living cells, and because a relationship between reactivity towards D.N.A. and carcinogenic potential has been established, it would seem proper to re-evaluate the potential tumour-inducing ability of hydrazine antidepressants and of isoniazid. Moreover, in the meantime advantage should be taken of the availability of alternative drugs devoid of the hydrazine moiety. These suggestions seem especially appropriate since the agents in question are ! taken over extended periods of time-a situation which conceivably could favour carcinogenesis. I This work was aided by a grant from the Damon Runyon
isoniazid,
some cases of striato-nigral degeneration, which are not easily differentiated from classic idiopathic parkinsonism
before necropsy.
an
Memorial Fund for Cancer Research. H. S. R. is a research career development awardee of the U.S. Public Health Service
(2-K3-GM 29, 024). Department of Microbiology, College of Physicians and Surgeons, HERBERT S. ROSENKRANZ Columbia University, HOWARD S. CARR. New York, N.Y. 10032.
FAILED LEVODOPA THERAPY IN STRIATO-NIGRAL DEGENERATION SIR,-Levodopa was ineffective in two patients with parkinsonism who were found to have striato-nigral
Department of Neurology, Neurological Institute, Kyushu University, Fukuoka 812, Japan.
K. N. T. T. Y.
IZUMI INOUE SHIRABE MlYAZAKI KUROIWA.
D-PROPRANOLOL AND ANXIETY
SiR,-The reported beneficial effect of D-L-propranolol, daily, in anxiety 1,2 has been attributed to the drug’s p-blocking action. This is consistent with the finding that sinus tachycardia in anxious patients is abolished by intravenous administration of the drug.3 p-blockade is largely due to the L-isomer of propranolol; there is little evidence of &bgr;-blockade by the D-form.o1 It is therefore of theoretical, as well as practical, interest to investigate the effect of D-propranolol in anxiety. A pilot study in 10 patients has been completed using a cross-over design and double-blind technique similar to that reported in the earlier papery but with oral administration of D-propranolol 40 mg. four times daily in one treatment period and matching placebo capsules in the other. The Middlesex Hospital questionnaire 6.6 was given to all patients after clinical assessment but before inclusion in the trial (see table) and demonstrated a high level of freefloating anxiety and somatic concomitants.
20 mg. four times
MEAN SCORES ON MIDDLESEX HOSPITAL
QUESTIONNAIRE**
degeneration
at necropsy. Case 1-A 53-year-old man with parkinsonism was severely disabled. The illness had begun 2 years previously. Clinically he showed pronounced bradykinesia and rigidity. There was no tremor. Deep reflexes were normal, but plantar reflexes were extensor bilaterally. Levodopa, in doses up to 6-4 g. daily, was given for 11 months without any response. He died suddenly at home. At necropsy the brain weighed 1180 g. Macroscopic examination showed slight atrophy. Microscopically, the substantia nigra revealed striking lesions in which almost all the melanin-containing cells were absent. Nerve cells were also absent, and gliosis was seen in the putamen bilaterally. Brownish pigmented granules were present in the globus pallidus and subthalamic area. There was mild degeneration of nerve cells in the locus coeruleus and in the Purkinje cells and white matter of the cerebellum. In addition, the corticospinal tracts of the medulla oblongata were pale in sections stained for myelin. The
clinicopathological diagnosis
was
striato-nigral degenera-
tion. Case 2-A 56-year-old woman had parkinsonism with severe disability. Like the other patient she showed pro-
bradykinesia and rigidity but no tremor. Deep hyperactive, and the plantar reflex was equivocally extensor on the left. 2-6 g. of levodopa was given daily, without effect, till her death from pneumonia. The pathological diagnosis was striato-nigral degeneration and olivo-ponto-cerebellar atrophy. Treatment failures with levodopa in parkinsonism have been discussed from many aspects, including drug tolerance,l misdiagnosis,2 concurrent use of pyridoxine,3 and poor absorption.4 The group of patients whose parkinsonism is not improved by levodopa may contain
nounced reflexes
1.
were
Yahr,
M. D. in L-Dopa and Parkinsonism (edited by A. Barbeau and F. H. McDowell); p. 5. Philadelphia, 1970. 2. Markham, C. H. ibid. p. 10. 3. Duvoisin, R. C., Yahr, M. D., Cote, L. D. Trans. Am. neurol. Ass. 1969, 94, 81.
4.
Rivera-Calimlim, L., Dujovne, Bianchine, J. R. Br.
C. A., Morgan, med. J. 1970, iv, 93.
J. P., Lasagna, L.,
Patients
were
matched for age, sex, marital status, and personally events in the trial period.
important life
Random
blood-samples were taken from the patients to plasma levels and to confirm that they were taking medication as prescribed. It is interesting to note that before breaking the code the assessing psychiatrist had strong reservations about one patient’s reliability in taking medication, and subsequently this patient was found to have the lowest plasma level of D-propranolol. Using a closed sequential design the earlier trial1 demonstrated the investigator’s preference for D-L propranolol as the more effective treatment, becoming statistically significant after 15 had completed their treatments. No statistically significant preference for either D-propranolol or placebo became apparent during this pilot study. No preference was expressed by either patient or assessor in 4 cases. Of those who expressed preferences, 2 favoured the first treatment period and 4 the second. In terms of treatment, 4 preferred D-propranolol and 2 placebo. 5 patients reported no side-effects and 2 reported increasing depression during the second period (when they were on placebo). This was judged to be part of their progressing affective disorder and not due to the D-propranolol. Anxiety and depression continued to increase after cessation of the trial. 1 other patient developed vomiting
assess
1. 2. 3.
Granville-Grossman, K., Turner, P. Lancet, 1966, i, 788. Wheatley, D. Br. J. Psychiat. 1969, 115, 1411. Turner, P., Granville-Grossman, K., Smart, J. Lancet, 1965, ii,
4. 5. 6.
Barrett, A. M., Cullum, V. Br. J. Pharmac. 1968, 34, 43. Crown, S., Crisp, A. Br. J. Psychiat. 1966, 112, 917. Crown, S., Duncan, K. P., Howell, R. W. ibid. 1970, 116,
1316.
33.