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PRACTOLOL TREATMENT IN ASTHMATICS
1264 PRACTOLOL TREATMENT IN ASTHMATICS
SIR,ńWe should like to endorse Dr. Chang’s plea (Aug. 7, p. 321) for caution in the use of practolol in asthmatics. Over the past 2 years
Fig. 1-Demyelination of fasciculus
gracilis and part
fasciculus cuneatus in cervical cord of dog
no.
of
1.
Duration of symptoms, 159 days. Woelke stain.
we have used practolol in some 40 Because of its cardioselective prohypertensive patients. made use of it in 3 patients with we have cautious perties a past history of asthma and in 4 patients with chronic bronchitis. In 4 of these 7 patients practolol has appeared to precipitate or aggravate bronchospasm. Case 1.-A man now aged 52 presented in 1961 with malignant hypertension. He had a casual blood-pressure (B.P.) of 240/150 mm. Hg, cardiomegaly, congestive changes in both lung-fields, and small pleural effusions. An intravenous pyelogram (l.v.p.) was normal. For some years the B.P. was moderately well controlled on a diuretic with, in turn, guanethidine, methyldopa, bethanidine, and debrisoquine. He continued to smoke 20 cigarettes a day, had a moderate cough and occasional sputum, and developed winter bronchitis. Angina began in 1969. His therapy was
changed in April, 1970,
Fig. 2-Demyelination of optic tract in dog no. 2. Duration of symptoms, 65 days. Optic tract arrowed. Woelke stain.
All the animals with chronic poisoning which died or killed showed degenerative changes in the nervous system. The severity of the degeneration depended on the duration of symptoms. 6 dogs and 1 monkey which had been affected for a relatively short time showed symmetrical and systemic changes in the fasciculus gracilis of the cervical cord-i.e., the systemic process began distally in the nerve fibres, damaging the axons first then myelin There was also degeneration in dorsal-root sheaths. ganglia, although optic and peripheral neuropathies were not obvious. But 3 dogs and 1 cat which had had symptoms for longer (65-165 days) showed more advanced degeneration in the fasciculus gracilis, accompanied by distinct demyelination (fig. 1) and accumulation of fat granules. The optic tract was also affected (fig. 2), as were the corticospinal Detracts, dorsal-root ganglia, and peripheral nerves. generative changes in the optic tract were similar to those in the fasciculus gracilis. Inflammatory changes were not seen in these areas of degeneration. The myelo-optic neuropathy seen in these animals has not previously been noted in animal experiments, and is well in accord with the changes observed in S.M.O.N. in man. Therefore, clioquinol may well be a causative and accelerating factor in this syndrome in Japan. were
JUN TATEISHI Department of Neuropsychiatry, Okayama University Medical School, Okayama, Japan.
SHIGETOSHI KURODA AKIRA SAITO SABURO OTSUKI.
to oxprenolol, the thiazide being continued. The dose of oxprenolol was gradually increased over the next eleven months to 80 mg. three times a day, but he then developed severe wheezing. Practolol 300 mg. three times a day was substituted, but the wheezing persisted unabated; after 12 days the practolol was stopped. He has since been able to take oxprenolol at a reduced dose of 40 mg. three times a day. Case 2.-A 40-year-old woman was referred from the psychiatric outpatient department because of a casual blood-pressure reading of 220/140 mm. Hg. She was taking amitriptyline and chlorpromazine. She had had bronchitis for 11-12 years and a moderately severe attack of asthma 8 years previously but no recent wheezing. She smoked 40 cigarettes a day. Physical examination revealed no abnormality apart from her agitated mental state. Fundi showed minor A-V crossing changes only. Renal function and urinary catecholamines and vanillylmandelic acid were normal. The B.P. was very variable, and cyclopenthiazide-K 0’75 mg. per day did not control it. Practolol 50 mg. twice daily was added to her regimen, most other antihypertensive drugs being contraindicated by her antidepressant therapy. Within 2 days she had developed a wheeze, which wore off 1 day after stopping practolol. A further 2-day challenge with practolol 50 mg. twice daily had a similar result. Case 3.-A man now aged 31 had been attending for treatment of hypertension since the age of 28. His B.P. had been found to be raised during a hospital admission for nasal polypectomy. He had no symptoms apart from those related to the nasal polypi. He had a past history of asthma until the age of 21 but had had no wheeze since that time. Physical examination showed no abnormality. Investigations showed normal renal function, normal l.v.p., and normal chest X-ray. He was treated initially with clonidine, which caused some sedation, and subsequently with bethanidine and cyclopenthiazide. He felt that bethanidine was making his nasal congestion worse, and oxprenolol was substituted, initially 40 mg. a day and increasing to 120 mg. a day. After three months he developed quite severe asthma. Oxprenolol was stopped and bethanidine restarted: the asthma settled, but nasal stuffiness once again became The bethanidine dose was reduced and troublesome. was started, initially 100 mg. a day. Over one practolol month, the dose of practolol was increased to 300 mg. a day; but he developed daily asthma, especially severe about an hour after his evening practolol. Practolol was stopped and the asthma abated. Case 4.-A man now aged 68 presented with a casual blood-pressure of 220/116 mm. Hg in 1966. He had a 10-year history of winter bronchitis and mild wheeze. He was a non-smoker. Blood-pressure control was unsatis-
1265
variety of antihypertensive drugs including reserpine, methyldopa, guanethidine, and bethanidine. His therapy was changed to cyclopenthiazide 0-5 mg. daily and practolol 150 mg. daily. After one month on this therapy he developed bronchitis. The associated wheeze was much worse than that usually associated with his winter bouts of
factory
on a
bronchitis. Hypertension Clinic, Dunedin Public Hospital,
Dunedin, New Zealand.
HENDRIKA J. WAAL-MANNING F. O. SIMPSON.
INHIBITION OF TRANSFORMATION OF NORMAL LYMPHOCYTES BY PLASMA FACTOR FROM PATIENTS WITH HODGKIN’S DISEASE AND CANCER al.l reported that plasma from SiR,-Whittaker cancer patients inhibited, in vitro, the stimulation by phytohaemagglutinin (P.H.A.) of lymphocytes from healthy donors. We have demonstrated the same effect with plasma from patients with Hodgkin’s disease2 and cancer.3 Plasma from these patients also inhibited specific lymphocyte transformation with tuberculin (P.P.D.).4 Experiments et
the isolation and characterisation of this factor led to the conclusion that a2-M-globulin can be precipitated by P.H.A. This precipitate has concentration-dependent effects on the R.N.A. metabolism of lymphocytes.5 Using specific antigen (P.P.D.), we showed that plasma of patients with Hodgkin’s disease inhibited lymphocyte stimulation.4 We have now isolated a fraction of the plasma of patients with cancer or Hodgkin’s disease which inhibits the stimulation of normal P.p.D.-sensitive lymphocytes by P.P.D. in vitro. Using Sephadex G 200, this inhibitory factor was isolated by gel filtration of the patient’s plasma. Chromato-
measured after 120 hours of incubation. All procedures were done at 37 °C. The results in 3 patients with cancer and 3 patients with Hodgkin’s disease are shown in the table. Lymphocytes from a P.p.D.-sensitive healthy donor resuspended in autologous plasma regularly exhibited stimulation and thymidine incorporation in vitro. Lymphocytes from the same donor incubated in the patient’s plasma showed only a low incorporation rate. Using the fractions isolated by gel filtration of the patient’s plasma, only the 4th fraction showed an inhibitory effect comparable to that of whole plasma, which nearly corresponds to the values in normal controls without antigen. Because of its great elution volume, this fraction cannot contain 1X2-M-globulin. We suppose that it must be a (poly-)peptide. The inhibitory effect of this peptide fraction as well as that of the whole plasma was also observed in cultures stimulated with P.H.A.
Medizinische Universitätsklinik und Poliklinik (Innere Medizin I), 665
Homburg/Saar, West Germany.
PROBENECID TEST IN PARKINSON’S DISEASE
on
EFFECTS OF PATIENTS’ PLASMA AND PLASMA FRACTIONS ON P.P.D. STIMULATION OF SENSITISED LYMPHOCYTES FROM HEALTHY
DONOR**
*
14C-thymidine incorporation, in d.p.m.
graphy revealed four peaks corresponding to 19S globuThese lins, 7S globulins, albumins, and peptides. fractions, as well as the whole plasma, were tested for their ability to inhibit lymphocyte stimulation in vitro with P.P.D., by methods previously described.6 Cultures were prepared with 150 (g. purified tuberculin per 4 x 105 lymphocytes in 10 ml. of culture medium consisting of 8 ml. TC 199 and 2 ml. plasma or plasma fraction. The 4C_thymidine incorporation of the P.P.D. cultures was 1. 2. 3.
Whittaker, M. G., Rees, K., Clark, C. G. Lancet, 1971, i, 892. Pappas, A., Scheurlen, P. G. Verh. dt. Ges. inn. Med. 1968, 74, 1254. Scheurlen, P. G. 10th International Cancer Congress, Houston, Texas, 1970; abstr. p. 191. 4. Scheurlen, P. G., Pappas, A. Verh. dt. Ges. inn. Med. (in the press) 5. Havemann, K., Dosch, H. M., Bürger, S. Z. ges. exp. Med. 1970, 153, 197.; Havemann, K., Bürger, S., Dosch, H. M. ibid. p. 308. 6. Scheurlen, P. G., Pappas, A., Wegener, D. Klin. Wschr. 1969, 47, 799.
P. G. SCHEURLEN W. SCHNEIDER A. PAPPAS.
SIR,-The probenecid-induced accumulation of homovanillic acid (H.v.A.) in lumbar spinal fluid has been used to estimate central dopamine turnover in parkinsonian patients, and has lately been recommended by Lakke et al. as a means of predicting the therapeutic response to levodopa. Such a prognostic test has obvious importance, since approximately a third of patients with Parkinson’s disease do not respond satisfactorily to levodopa treatment. Although our use of the probenecid test in parkinsonian patients confirms the presence of a striking reduction in H.V.A. formation, we have been unable to substantiate its reliability as a predictor of the response to levodopa. In our studies, consenting individuals received a lumbar puncture at about 9 A.M. and again at 6 P.M. 2 g. of probenecid was administered immediately after the initial lumbar puncture and again 3 and 6 hours later. Patients remained recumbent in bed throughout the study as well as during the preceding 10-12 hours. In 11 individuals with typical parkinsonism, the probenecid-induced rise in H.V.A. was only 93 ±20 ng. per ml. as compared with 166 ± 24 ng. per ml. in 8 control subjects (p < 005). Further analysis of these results indicates a significant (r= 0-81; inverse correlation between the probenecidP<0’01) induced accumulation of H.V.A. and pretreatment severity of parkinsonian signs, such that patients with the most advanced disease tended to have the least H.V.A. increase. In 8 of these individuals we have been able to compare probenecid test results with their subsequent response to levodopa. No correlation could be discerned between either percentage change or absolute amount of change in parkinsonian signs and the probenecid-induced H.V.A. increment
(P> 0,05).
Since probenecid interferes with the efflux of H.V.A. from the mammalian central nervous system without substantially altering its rate of formation,4 it has been assumed that the H.V.A. increase during probenecid administration provides some index to the rate ofH.v.A. formation and thus to the central turnover of dopamine.5 Although the accuracy of this assumption remains untested in man, our Olsson, R., Roos, B.-E. Nature, 1968, 219, 502. Lakke, J. P. W., Korf, J., van Pragg, H. M. Lancet, July 17, 1971, p. 164. 3. Mendell, J. R., Chase, T. N., Engel, W. K. Archs Neurol., Chicago, 1971, 25, 320. 4. Werdinius, B. Acta pharm. 1967, 25, 18. 5. Sharman, D. F. in Metabolism of Amines in the Brain (edited by G. Hooper); p. 34. London, 1969. 1. 2.
SIR,ńWe should like to endorse Dr. Chang’s plea (Aug. 7, p. 321) for caution in the use of practolol in asthmatics. Over the past 2 years
Fig. 1-Demyelination of fasciculus
gracilis and part
fasciculus cuneatus in cervical cord of dog
no.
of
1.
Duration of symptoms, 159 days. Woelke stain.
we have used practolol in some 40 Because of its cardioselective prohypertensive patients. made use of it in 3 patients with we have cautious perties a past history of asthma and in 4 patients with chronic bronchitis. In 4 of these 7 patients practolol has appeared to precipitate or aggravate bronchospasm. Case 1.-A man now aged 52 presented in 1961 with malignant hypertension. He had a casual blood-pressure (B.P.) of 240/150 mm. Hg, cardiomegaly, congestive changes in both lung-fields, and small pleural effusions. An intravenous pyelogram (l.v.p.) was normal. For some years the B.P. was moderately well controlled on a diuretic with, in turn, guanethidine, methyldopa, bethanidine, and debrisoquine. He continued to smoke 20 cigarettes a day, had a moderate cough and occasional sputum, and developed winter bronchitis. Angina began in 1969. His therapy was
changed in April, 1970,
Fig. 2-Demyelination of optic tract in dog no. 2. Duration of symptoms, 65 days. Optic tract arrowed. Woelke stain.
All the animals with chronic poisoning which died or killed showed degenerative changes in the nervous system. The severity of the degeneration depended on the duration of symptoms. 6 dogs and 1 monkey which had been affected for a relatively short time showed symmetrical and systemic changes in the fasciculus gracilis of the cervical cord-i.e., the systemic process began distally in the nerve fibres, damaging the axons first then myelin There was also degeneration in dorsal-root sheaths. ganglia, although optic and peripheral neuropathies were not obvious. But 3 dogs and 1 cat which had had symptoms for longer (65-165 days) showed more advanced degeneration in the fasciculus gracilis, accompanied by distinct demyelination (fig. 1) and accumulation of fat granules. The optic tract was also affected (fig. 2), as were the corticospinal Detracts, dorsal-root ganglia, and peripheral nerves. generative changes in the optic tract were similar to those in the fasciculus gracilis. Inflammatory changes were not seen in these areas of degeneration. The myelo-optic neuropathy seen in these animals has not previously been noted in animal experiments, and is well in accord with the changes observed in S.M.O.N. in man. Therefore, clioquinol may well be a causative and accelerating factor in this syndrome in Japan. were
JUN TATEISHI Department of Neuropsychiatry, Okayama University Medical School, Okayama, Japan.
SHIGETOSHI KURODA AKIRA SAITO SABURO OTSUKI.
to oxprenolol, the thiazide being continued. The dose of oxprenolol was gradually increased over the next eleven months to 80 mg. three times a day, but he then developed severe wheezing. Practolol 300 mg. three times a day was substituted, but the wheezing persisted unabated; after 12 days the practolol was stopped. He has since been able to take oxprenolol at a reduced dose of 40 mg. three times a day. Case 2.-A 40-year-old woman was referred from the psychiatric outpatient department because of a casual blood-pressure reading of 220/140 mm. Hg. She was taking amitriptyline and chlorpromazine. She had had bronchitis for 11-12 years and a moderately severe attack of asthma 8 years previously but no recent wheezing. She smoked 40 cigarettes a day. Physical examination revealed no abnormality apart from her agitated mental state. Fundi showed minor A-V crossing changes only. Renal function and urinary catecholamines and vanillylmandelic acid were normal. The B.P. was very variable, and cyclopenthiazide-K 0’75 mg. per day did not control it. Practolol 50 mg. twice daily was added to her regimen, most other antihypertensive drugs being contraindicated by her antidepressant therapy. Within 2 days she had developed a wheeze, which wore off 1 day after stopping practolol. A further 2-day challenge with practolol 50 mg. twice daily had a similar result. Case 3.-A man now aged 31 had been attending for treatment of hypertension since the age of 28. His B.P. had been found to be raised during a hospital admission for nasal polypectomy. He had no symptoms apart from those related to the nasal polypi. He had a past history of asthma until the age of 21 but had had no wheeze since that time. Physical examination showed no abnormality. Investigations showed normal renal function, normal l.v.p., and normal chest X-ray. He was treated initially with clonidine, which caused some sedation, and subsequently with bethanidine and cyclopenthiazide. He felt that bethanidine was making his nasal congestion worse, and oxprenolol was substituted, initially 40 mg. a day and increasing to 120 mg. a day. After three months he developed quite severe asthma. Oxprenolol was stopped and bethanidine restarted: the asthma settled, but nasal stuffiness once again became The bethanidine dose was reduced and troublesome. was started, initially 100 mg. a day. Over one practolol month, the dose of practolol was increased to 300 mg. a day; but he developed daily asthma, especially severe about an hour after his evening practolol. Practolol was stopped and the asthma abated. Case 4.-A man now aged 68 presented with a casual blood-pressure of 220/116 mm. Hg in 1966. He had a 10-year history of winter bronchitis and mild wheeze. He was a non-smoker. Blood-pressure control was unsatis-
1265
variety of antihypertensive drugs including reserpine, methyldopa, guanethidine, and bethanidine. His therapy was changed to cyclopenthiazide 0-5 mg. daily and practolol 150 mg. daily. After one month on this therapy he developed bronchitis. The associated wheeze was much worse than that usually associated with his winter bouts of
factory
on a
bronchitis. Hypertension Clinic, Dunedin Public Hospital,
Dunedin, New Zealand.
HENDRIKA J. WAAL-MANNING F. O. SIMPSON.
INHIBITION OF TRANSFORMATION OF NORMAL LYMPHOCYTES BY PLASMA FACTOR FROM PATIENTS WITH HODGKIN’S DISEASE AND CANCER al.l reported that plasma from SiR,-Whittaker cancer patients inhibited, in vitro, the stimulation by phytohaemagglutinin (P.H.A.) of lymphocytes from healthy donors. We have demonstrated the same effect with plasma from patients with Hodgkin’s disease2 and cancer.3 Plasma from these patients also inhibited specific lymphocyte transformation with tuberculin (P.P.D.).4 Experiments et
the isolation and characterisation of this factor led to the conclusion that a2-M-globulin can be precipitated by P.H.A. This precipitate has concentration-dependent effects on the R.N.A. metabolism of lymphocytes.5 Using specific antigen (P.P.D.), we showed that plasma of patients with Hodgkin’s disease inhibited lymphocyte stimulation.4 We have now isolated a fraction of the plasma of patients with cancer or Hodgkin’s disease which inhibits the stimulation of normal P.p.D.-sensitive lymphocytes by P.P.D. in vitro. Using Sephadex G 200, this inhibitory factor was isolated by gel filtration of the patient’s plasma. Chromato-
measured after 120 hours of incubation. All procedures were done at 37 °C. The results in 3 patients with cancer and 3 patients with Hodgkin’s disease are shown in the table. Lymphocytes from a P.p.D.-sensitive healthy donor resuspended in autologous plasma regularly exhibited stimulation and thymidine incorporation in vitro. Lymphocytes from the same donor incubated in the patient’s plasma showed only a low incorporation rate. Using the fractions isolated by gel filtration of the patient’s plasma, only the 4th fraction showed an inhibitory effect comparable to that of whole plasma, which nearly corresponds to the values in normal controls without antigen. Because of its great elution volume, this fraction cannot contain 1X2-M-globulin. We suppose that it must be a (poly-)peptide. The inhibitory effect of this peptide fraction as well as that of the whole plasma was also observed in cultures stimulated with P.H.A.
Medizinische Universitätsklinik und Poliklinik (Innere Medizin I), 665
Homburg/Saar, West Germany.
PROBENECID TEST IN PARKINSON’S DISEASE
on
EFFECTS OF PATIENTS’ PLASMA AND PLASMA FRACTIONS ON P.P.D. STIMULATION OF SENSITISED LYMPHOCYTES FROM HEALTHY
DONOR**
*
14C-thymidine incorporation, in d.p.m.
graphy revealed four peaks corresponding to 19S globuThese lins, 7S globulins, albumins, and peptides. fractions, as well as the whole plasma, were tested for their ability to inhibit lymphocyte stimulation in vitro with P.P.D., by methods previously described.6 Cultures were prepared with 150 (g. purified tuberculin per 4 x 105 lymphocytes in 10 ml. of culture medium consisting of 8 ml. TC 199 and 2 ml. plasma or plasma fraction. The 4C_thymidine incorporation of the P.P.D. cultures was 1. 2. 3.
Whittaker, M. G., Rees, K., Clark, C. G. Lancet, 1971, i, 892. Pappas, A., Scheurlen, P. G. Verh. dt. Ges. inn. Med. 1968, 74, 1254. Scheurlen, P. G. 10th International Cancer Congress, Houston, Texas, 1970; abstr. p. 191. 4. Scheurlen, P. G., Pappas, A. Verh. dt. Ges. inn. Med. (in the press) 5. Havemann, K., Dosch, H. M., Bürger, S. Z. ges. exp. Med. 1970, 153, 197.; Havemann, K., Bürger, S., Dosch, H. M. ibid. p. 308. 6. Scheurlen, P. G., Pappas, A., Wegener, D. Klin. Wschr. 1969, 47, 799.
P. G. SCHEURLEN W. SCHNEIDER A. PAPPAS.
SIR,-The probenecid-induced accumulation of homovanillic acid (H.v.A.) in lumbar spinal fluid has been used to estimate central dopamine turnover in parkinsonian patients, and has lately been recommended by Lakke et al. as a means of predicting the therapeutic response to levodopa. Such a prognostic test has obvious importance, since approximately a third of patients with Parkinson’s disease do not respond satisfactorily to levodopa treatment. Although our use of the probenecid test in parkinsonian patients confirms the presence of a striking reduction in H.V.A. formation, we have been unable to substantiate its reliability as a predictor of the response to levodopa. In our studies, consenting individuals received a lumbar puncture at about 9 A.M. and again at 6 P.M. 2 g. of probenecid was administered immediately after the initial lumbar puncture and again 3 and 6 hours later. Patients remained recumbent in bed throughout the study as well as during the preceding 10-12 hours. In 11 individuals with typical parkinsonism, the probenecid-induced rise in H.V.A. was only 93 ±20 ng. per ml. as compared with 166 ± 24 ng. per ml. in 8 control subjects (p < 005). Further analysis of these results indicates a significant (r= 0-81; inverse correlation between the probenecidP<0’01) induced accumulation of H.V.A. and pretreatment severity of parkinsonian signs, such that patients with the most advanced disease tended to have the least H.V.A. increase. In 8 of these individuals we have been able to compare probenecid test results with their subsequent response to levodopa. No correlation could be discerned between either percentage change or absolute amount of change in parkinsonian signs and the probenecid-induced H.V.A. increment
(P> 0,05).
Since probenecid interferes with the efflux of H.V.A. from the mammalian central nervous system without substantially altering its rate of formation,4 it has been assumed that the H.V.A. increase during probenecid administration provides some index to the rate ofH.v.A. formation and thus to the central turnover of dopamine.5 Although the accuracy of this assumption remains untested in man, our Olsson, R., Roos, B.-E. Nature, 1968, 219, 502. Lakke, J. P. W., Korf, J., van Pragg, H. M. Lancet, July 17, 1971, p. 164. 3. Mendell, J. R., Chase, T. N., Engel, W. K. Archs Neurol., Chicago, 1971, 25, 320. 4. Werdinius, B. Acta pharm. 1967, 25, 18. 5. Sharman, D. F. in Metabolism of Amines in the Brain (edited by G. Hooper); p. 34. London, 1969. 1. 2.