827
x-fetoprotein level is used for be dated accurately, and
must
such an
screening
ultrasonic
the pregnancy be
scan seems to
the best method for this. Fletcher puts the costs at £ 10 000 per year for 3000 patients; this is only 3-33 per patient, a very small sum compared with the total average cost of a pregnancy to the N.H.S. The establishment of accurate dates and the early detection or exclusion of placenta prsevia might reduce the average number of days spent in hospital during a pregnancy, and this saving may more than offset the cost of the ultrasonic service. If even a proportion of cases of spina bifida are detected before 22 weeks, and the pregnancies terminated as a result, the saving to the N.H.S. will be considerable. These points should be impressed upon administrators. Department of Radiology, East
Glamorgan General Hospital
D. LL. COCHLIN
PROPRANOLOL THERAPY FOR HYPERPARATHYROIDISM ?
SiR,—j-adrenergic stimulation increases parathyroid hor(P.T.H.) secretion by activating adenyl cyclase. Adrenaline (epinephrine) and isoproterenol stimulation of P.T.H. secretion from isolated parathyroid cells can be blocked by propranolol.’ This &bgr;-adrenergic effect appears to be independent of calcium since &bgr;-blockade does not alter the tissue response to calcium and high calcium concentrations do not suppress the response to &bgr;-stimulation.2 Systemic isoproterenol mone
and adrenaline in the rat also increase P.T.H. secretion, which can be blocked by propranolol. In man, intradermal adrenaline or isoproterenol raise serum-p.T.H. whereas intravenous propranolol decreases the circulating basal level of P.T.H.4 These effects appear to be independent of changes in serumcalcium since the therapeutic doses of adrenaline and isoproterenol used in asthma raise serum-p.T.H. without affecting serum-calcium.5 Our study of a single patient with hyperparathyroidism suggests that the &bgr;-adrenergic influences in normal individuals continue to operate in states of overproduction of P.T.H. The patient, a 49-year-old male, had angina pectoris and hyperparathyroidism. On first examination, serum-calcium was 11.8 mg/dl (normal 8-5-10-5), serum-phosphorus was normal (3.0 mg/dl) and total protein, serum-albumin, plasma-creatinine, and plasma-alkaline-phosphatase were normal. In repeated tests on 5 different days, his serum-calcium was 10.8-12.4 mg/dl. P.T.H. levels, measured by a carboxy terminal assay at the Nichols Institute, were 317 and 375 jjdeq/ml when serum-calcium was 11.0 and 10.8 mg/dl, respectively (normal P.T.H. by this assay is 25-90 µleq/ml for normal serum-calcium). Moderate osteopenia of the spine was noted on
X-ray. The patient’s angina could not be controlled with nitroglycerin derivatives but propranolol (120 mg/day) brought relief from pain. P.T.H. and serum-calcium measured monthly during propranolol therapy were 79p.leq/ml and 10.6mg/dl, respectively ; 99 and 10.3; 102 and 9-7. Propranolol reduced both P.T.H. and serum-calcium to near normal. We cannot be certain that this patient had primary hyperparathyroidism-the recurrent severe angina may have chronically increased adrenergic activity, resulting in excessive P.T.H. secretion. The treatment for hyperparathyroid patients with mild hypercalcsemia who are without symptoms is controversial ; both surgery and close medical follow-up have been advocated for primary hyperparathyroidism. Our experience with this patient suggests that propranolol reduces P.T.H. and 1. Sherwood, L. M., Abe, M. J. clin. Invest. 1972, 51, 292A. 2. Kukreja, S. C., and others. Proc. Soc. exp. Biol. Med. 1976, 151, 326. 3. Harney, A. N., and others. Clin. Res. 1977, 25, 563A. 4. Kukreja, S. C., and others. J. clin. Endocrin. Metab. 1975, 10, 478. 5. Williams, G. A., and others. Clin. Res. 1974, 22, 652A.
serum-calcium in hyperparathyroidism. p-blockade should be tested more widely in symptom-free patients with biochemical evidence of slight primary hyperparathyroidism and the incidence of hyperparathyroidism in patients with chronic adrenergic overactivity should be determined. University Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107, U.S.A.
F. CARO ANATOLE BESARAB
JOSE
LOW-DOSE ORAL PROPRANOLOL
SIR,-We read with interest the comments by Professor George (April 1, p. 715) about our Feb. 25 paper on low-dose propranolol. We dispute the existence, not of the hepatic-first pass effect for propranolol, but only of a threshold for this effect. The need to saturate this threshold with an oral dose of 30 mg has been emphasised by Nies and Shand.’ We made no attempt to calculate areas beneath concentration-time curves in our study : indeed we clearly state that only a single plasma-propranolol was determined in each subject. However, both Chidsey et al. and Gomeni et al.,3 using gas/liquid chromatography have done pharmacokinetic studies and did estimate areas beneath concentration-time curves, and neither group could find evidence of a saturable threshold effect. Gomeni et al. found no difference in the bioavailability of oral doses of 10, 20, and 40 mg. However, in neither of these studies was an attempt made to quantitate beta-adrenoceptor blockade. The data from our study are presented against this background of uncertainty regarding a threshold effect. We found unequivocal evidence of the blockade of cardiac and renal receptors both at rest and after a standardised isoprenaline challenge. At this time plasma-propranolol concentrations were below the accurate detection limits of the fluorimetric assay, upon which most of the classical views on the pharmacokinetics of propranolol are based.4-6 George also states that our observation of betaadrenoceptor blockade by this very low dose of oral propranolol is not new, citing the studies of Patersen et al.6and Leonetti et al.’ yet, as he states, these workers gave doses of 40 mg (i.e., eight times the dose we used). We cannot accept George’s statement that the fixed-dose isoprenaline technique "does not contribute findings which are of clinical significance". Firstly, this technique permits an assessment of the effect of beta-blockers on both cardiac and renal beta-adrenoceptors,8 and this may be particularly relevant to the study of hypertension. Secondly, it is arguable that isoprenaline challenge such as the one used more faithfully reproduces the bursts of adenergic activity provoked by motorcar driving, sexual activity, and even violin playing. The classical technique of assessing beta-blockade by the determination of isoprenaline dose-ratios has obvious merit, but it is difficult to see the relevance of a five or even fifty fold increase in the dose of isoprenaline required to restore a given increase in heartrate, to the effects of endogenous catecholamines released during life’s stresses. Moreover, Chidsey et al.9 have demonstrated clear pharmacological effects at blood levels only 2-3 times those we observed. Thus median effective doses (E.D.50) for the suppression of exercise tachycardia and of plasma-renin were only 8 and 11 ng/ml, respectively. We tentatively suggested that these low-dose effects deserve further study, particularly in that they might contribute to our understanding of the mechanisms of action of beta-blockers. Nies, A. S. Shand, A. G. Circulation, 1975, 52, 6. Chidsey, C. A., and others ibid p. 313. 3. Gomeni, R., Bianchetti, G., Sega, R., Morselli, P. L. J. Pharmacokin. Biopharm. 1977, 5, 183. 4. Shand, D. G., Rangno, R. E., Evans, G. H. Pharmacology, 1972, 8, 244. 5. Shand, D. G., and others Drug Metab. Dispos. 1973, i, 679. 6. Paterson, J. W., and others Eur. J. clin. Pharmac. 1970, 2, 127. 7. Leonetti, G., and others Clin. Sci. mol. Med. 1975, 48, 491. 8. Davies, R., and others Clin. Endocr. 1977, 6, 345. 9. Chidsey, C. A., and others Postgrad. med. J. 1976, 52, suppl. 4, p. 26. 1. 2.
x-fetoprotein level is used for be dated accurately, and
must
such an
screening
ultrasonic
the pregnancy be
scan seems to
the best method for this. Fletcher puts the costs at £ 10 000 per year for 3000 patients; this is only 3-33 per patient, a very small sum compared with the total average cost of a pregnancy to the N.H.S. The establishment of accurate dates and the early detection or exclusion of placenta prsevia might reduce the average number of days spent in hospital during a pregnancy, and this saving may more than offset the cost of the ultrasonic service. If even a proportion of cases of spina bifida are detected before 22 weeks, and the pregnancies terminated as a result, the saving to the N.H.S. will be considerable. These points should be impressed upon administrators. Department of Radiology, East
Glamorgan General Hospital
D. LL. COCHLIN
PROPRANOLOL THERAPY FOR HYPERPARATHYROIDISM ?
SiR,—j-adrenergic stimulation increases parathyroid hor(P.T.H.) secretion by activating adenyl cyclase. Adrenaline (epinephrine) and isoproterenol stimulation of P.T.H. secretion from isolated parathyroid cells can be blocked by propranolol.’ This &bgr;-adrenergic effect appears to be independent of calcium since &bgr;-blockade does not alter the tissue response to calcium and high calcium concentrations do not suppress the response to &bgr;-stimulation.2 Systemic isoproterenol mone
and adrenaline in the rat also increase P.T.H. secretion, which can be blocked by propranolol. In man, intradermal adrenaline or isoproterenol raise serum-p.T.H. whereas intravenous propranolol decreases the circulating basal level of P.T.H.4 These effects appear to be independent of changes in serumcalcium since the therapeutic doses of adrenaline and isoproterenol used in asthma raise serum-p.T.H. without affecting serum-calcium.5 Our study of a single patient with hyperparathyroidism suggests that the &bgr;-adrenergic influences in normal individuals continue to operate in states of overproduction of P.T.H. The patient, a 49-year-old male, had angina pectoris and hyperparathyroidism. On first examination, serum-calcium was 11.8 mg/dl (normal 8-5-10-5), serum-phosphorus was normal (3.0 mg/dl) and total protein, serum-albumin, plasma-creatinine, and plasma-alkaline-phosphatase were normal. In repeated tests on 5 different days, his serum-calcium was 10.8-12.4 mg/dl. P.T.H. levels, measured by a carboxy terminal assay at the Nichols Institute, were 317 and 375 jjdeq/ml when serum-calcium was 11.0 and 10.8 mg/dl, respectively (normal P.T.H. by this assay is 25-90 µleq/ml for normal serum-calcium). Moderate osteopenia of the spine was noted on
X-ray. The patient’s angina could not be controlled with nitroglycerin derivatives but propranolol (120 mg/day) brought relief from pain. P.T.H. and serum-calcium measured monthly during propranolol therapy were 79p.leq/ml and 10.6mg/dl, respectively ; 99 and 10.3; 102 and 9-7. Propranolol reduced both P.T.H. and serum-calcium to near normal. We cannot be certain that this patient had primary hyperparathyroidism-the recurrent severe angina may have chronically increased adrenergic activity, resulting in excessive P.T.H. secretion. The treatment for hyperparathyroid patients with mild hypercalcsemia who are without symptoms is controversial ; both surgery and close medical follow-up have been advocated for primary hyperparathyroidism. Our experience with this patient suggests that propranolol reduces P.T.H. and 1. Sherwood, L. M., Abe, M. J. clin. Invest. 1972, 51, 292A. 2. Kukreja, S. C., and others. Proc. Soc. exp. Biol. Med. 1976, 151, 326. 3. Harney, A. N., and others. Clin. Res. 1977, 25, 563A. 4. Kukreja, S. C., and others. J. clin. Endocrin. Metab. 1975, 10, 478. 5. Williams, G. A., and others. Clin. Res. 1974, 22, 652A.
serum-calcium in hyperparathyroidism. p-blockade should be tested more widely in symptom-free patients with biochemical evidence of slight primary hyperparathyroidism and the incidence of hyperparathyroidism in patients with chronic adrenergic overactivity should be determined. University Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107, U.S.A.
F. CARO ANATOLE BESARAB
JOSE
LOW-DOSE ORAL PROPRANOLOL
SIR,-We read with interest the comments by Professor George (April 1, p. 715) about our Feb. 25 paper on low-dose propranolol. We dispute the existence, not of the hepatic-first pass effect for propranolol, but only of a threshold for this effect. The need to saturate this threshold with an oral dose of 30 mg has been emphasised by Nies and Shand.’ We made no attempt to calculate areas beneath concentration-time curves in our study : indeed we clearly state that only a single plasma-propranolol was determined in each subject. However, both Chidsey et al. and Gomeni et al.,3 using gas/liquid chromatography have done pharmacokinetic studies and did estimate areas beneath concentration-time curves, and neither group could find evidence of a saturable threshold effect. Gomeni et al. found no difference in the bioavailability of oral doses of 10, 20, and 40 mg. However, in neither of these studies was an attempt made to quantitate beta-adrenoceptor blockade. The data from our study are presented against this background of uncertainty regarding a threshold effect. We found unequivocal evidence of the blockade of cardiac and renal receptors both at rest and after a standardised isoprenaline challenge. At this time plasma-propranolol concentrations were below the accurate detection limits of the fluorimetric assay, upon which most of the classical views on the pharmacokinetics of propranolol are based.4-6 George also states that our observation of betaadrenoceptor blockade by this very low dose of oral propranolol is not new, citing the studies of Patersen et al.6and Leonetti et al.’ yet, as he states, these workers gave doses of 40 mg (i.e., eight times the dose we used). We cannot accept George’s statement that the fixed-dose isoprenaline technique "does not contribute findings which are of clinical significance". Firstly, this technique permits an assessment of the effect of beta-blockers on both cardiac and renal beta-adrenoceptors,8 and this may be particularly relevant to the study of hypertension. Secondly, it is arguable that isoprenaline challenge such as the one used more faithfully reproduces the bursts of adenergic activity provoked by motorcar driving, sexual activity, and even violin playing. The classical technique of assessing beta-blockade by the determination of isoprenaline dose-ratios has obvious merit, but it is difficult to see the relevance of a five or even fifty fold increase in the dose of isoprenaline required to restore a given increase in heartrate, to the effects of endogenous catecholamines released during life’s stresses. Moreover, Chidsey et al.9 have demonstrated clear pharmacological effects at blood levels only 2-3 times those we observed. Thus median effective doses (E.D.50) for the suppression of exercise tachycardia and of plasma-renin were only 8 and 11 ng/ml, respectively. We tentatively suggested that these low-dose effects deserve further study, particularly in that they might contribute to our understanding of the mechanisms of action of beta-blockers. Nies, A. S. Shand, A. G. Circulation, 1975, 52, 6. Chidsey, C. A., and others ibid p. 313. 3. Gomeni, R., Bianchetti, G., Sega, R., Morselli, P. L. J. Pharmacokin. Biopharm. 1977, 5, 183. 4. Shand, D. G., Rangno, R. E., Evans, G. H. Pharmacology, 1972, 8, 244. 5. Shand, D. G., and others Drug Metab. Dispos. 1973, i, 679. 6. Paterson, J. W., and others Eur. J. clin. Pharmac. 1970, 2, 127. 7. Leonetti, G., and others Clin. Sci. mol. Med. 1975, 48, 491. 8. Davies, R., and others Clin. Endocr. 1977, 6, 345. 9. Chidsey, C. A., and others Postgrad. med. J. 1976, 52, suppl. 4, p. 26. 1. 2.
