- Email: [email protected]
REPROTEROL FOR REFRACTORY HEART FAILURE
170
explanation for our findings might be that part of the abnormality complex produced by the extra chromosome 18 overlaps the abnormality complex of CF, such that trisomy 18 cases could be regarded as exhibiting a partial form of CF.
PROSTACYCLIN AND MATERNAL LUPUS ANTICOAGULANT
Another
A. F. H.
is
supported by
the
Cystic
A. F. HEELEY
Department of Histopathology, University Hospital, Nottingham
D. G. FAGAN
REPROTEROL FOR REFRACTORY HEART FAILURE
SIR,-Salbutamol and pirbuterol are cited in your Nov 5 editorial as the two agonists extensively evaluated in heart failure. Reproterol is a P2-selective agonist with an unusual mechanism of action2probably connected with its chemical structure, in which the resorcinol moiety is joined by a propyl bridge to a dimethylxanthine group.
92-receptor
We have experience with the medium-term (up to 3 months) use of reproterol in fourteen patients with chronic refractory heart failure (New York Heart Association class II four patients, class III six patients, and class IV four patients). Usual diuretic and digitalis treatments were continued and reproterol (20 mg thrice daily by mouth) was added. Cardiac performance (ejection fractions, cardiac index, and circulation time) was studied by a cardio-scintigraphic method using a gamma counter (Searle LFOV) and a 93Tc-albumin intravenous bolus; an echocardiographic study of cardiac diameters was also done. The table shows the findings before and at the end of reproterol treatment. DIAMETERS,
to
and
colleagues (Sept 3,
p 576) prostacyclin metabolites
measure
are
in
pregnancies
Fibrosis Research Trust.
Regional Neonatal Screening Laboratory, Peterborough District Hospital, Peterborough PE3 6DA
CARDIAC FUNCTION, HEART
critical of our women with circulating lupus anticoagulant who had successful after treatment with aspirin and prednisone. The report they cite as evidence that the levels of 6-keto- PGF I a (the major metabolite of prostacyclin) measured in plasma by gas chromatography/mass (to spectrometry (GC/MS) normally increase in late 244 pg/ml) was subsequently invalidated by a report from workers in the same department who found concentrations of about 5 pg/ml, a value consistent with that of other workers3 who also used gas
SIR,-Dr Ros
failure
AND NYHA GRADINGS
BEFORE AND AFTER REPROTEROL: MEANS±SD
pregnancy
chromatography. Weattempted to assay 6-keto-PGF 1 and 2,3-dinor-6-keto-PGF10’ a in 4 ml of pregnancy plasma by radioimmunoassay (RIA)4 after purification by ’Sep Pak’ extraction and rpHPLC (high pressure liquid chromatography). Mean values (±SD) for the two metabolites were 65±30 pg/ml and 50±17 pg/ml, respectively, but non-specific immunoreactivity amounting to about 50 pg/ml removed any confidence in the results. Seiss and DraySsucceeded in measuring plasma levels of 6-ketoPGFI, in men by RIA after rpHPLC by using large volumes (50-100 ml) of plasma. The mean value of4-7±3’22 pg/ml accords well with those obtained recently by GC/MS. It appears that prostacyclin metabolites in patients’ plasma cannot be measured by RIA in samples of a size acceptable to many ethics committees. Furthermore, when the more sensitive and specific GC/MS method, which requires a smaller sample volume (10-20 ml plasma), is used, the standard deviation of control values is such that it is most unlikely that any reduction in concentration of 6-ketoPGF I" in association with circulating lupus anticoagulant could be detected. We are investigating the possibility that the more readily measured urinary metabolites of prostacyclin will be useful in determining whether lupus anticoagulant inhibits prostacyclin production in vivo. Postgraduate School of Obstetrics and Gynaecology, University of Auckland,
Auckland 3, New Zealand
G. C. LIGGINS S. J. M. SKINNER W. F. LUBBE
ADRENALINE AND POTASSIUM
SIR,-Your Dec
-
-
I
I
I
* 11 cases
No tachyphylaxis was experienced up to 3 months, in contrast to experience with the other (32-agonists.3 Reproterol, which seems to lack the arrhythmogenicity of other such compounds, may be a useful drug in refractory, chronic heart failure.4
Medical
Division, Hospital, Cesena, Italy Civil
General
Pathology Institute II,
University of Rome
E. PRETOLANI I. ZOLI G. BATTISTINI R. MOSCATELLI G. IOSA G. CECCARELLI M. CIAMPINI
2.
Klinger KH Synthesen von broncospasmolitisch wirksamen &bgr; phenylaethilammoalkyl-xantinen. Arzn Forsch 1977; 27: 4. Marmo E, di Mezza F, Giordano L, et al. In vitro effects of reproterol upon tracheobronchial, cardiac and cerebral adenyl cyclase. Res Commun Chem Pathol Pharmacol 1982; 35: 389. Alexander RW, Mudege GM, et al Acute and chronic effects of pirbuterol
3. Colucci WS,
4.
on left ventricular ejection-fraction and clinical status in severe heart failure. Am Heart J 1981; 102: 564. Citone C, Carelh M, di Marcotullio G, Milazzotto F Valutazione all ’ECG dinamico degli effetti del reproterolo sul sistema di conduzione cardiaco. Communication to VI Congress of the Italian Society of Pneumology (Rome, Nov 7, 1983). Med Torac (in press).
(p 1401) editorial provides a comprehensive
would like to add some of our recent observations. In six healthy volunteers the rapid fall in plasma potassium which occurs during insulin-induced hypoglycaemia was abolished (see table) by previous administration of propranolol (40 mg orally, three times daily, for 10 days). Since a 30-50 fold rise in plasma adrenaline concentration occurs during hypoglycaemic stress,and in view of the effect of non-specific &bgr;-blockade, our observation is probably another example of a 02-receptor-mediated hypokalaemic response. Such rapid fluctuations in plasma potassium concentrations may, as suggested in the editorial, be clinically relevant (eg, arrhythmogenic) and contribute to the mortality of hypoglycaemia. We have also examined, retrospectively, the relation between plasma potassium and serum thyroxine (T4) concentrations in view of the reported potentiation of the metabolic effects of 1. Lewis PJ, Boylan P, Fredman LA, Hensby CN, Downing I. Prostacyclin in pregnancy
Br
Med J1980; 280:
2. Barrow
1.
17
of the relation between adrenaline and potassium. We
account
1581-82.
SE, Blair IA, Waddell KA, Shepherd GL, Lewis PJ, Dollery CT. Prostacyclin in late pregnancy: Analysis of 6-oxo-prostaglandin F1&agr; in maternal plasma. In Lewis PJ, Moncada S, O’Grady J, eds. Prostacyclin in pregnancy. New York: Raven Press, 1983: 79. 3. Christ-Hazelhof E, Nugturen DH. Prostacyclin is not a circulating hormone. Prostaglandins 1981; 22: 739-46. 4. Liggins GC, Campos GA, Roberts CM, Skinner SJ. Production rates of prostaglandin F, 6-keto-PGF1&agr; and thromboxane B2 by perfused human endometrium Prostaglandins 1980; 19: 461-77 5. Seiss W, Dray F. Very low levels of 6-keto-prostaglandin F1 &agr; in human plasma. J Lab Clin Med 1982; 99: 388-98 6. Garber AJ, Cryer PE, Santiago JV, Haymond MW, Pagliara AS, Kipnis DM. The role of adrenergic mechanisms in the substrate and hormonal response to insulininduced hypoglycemia in man. J Clin Invest 1976; 58: 7-15.
explanation for our findings might be that part of the abnormality complex produced by the extra chromosome 18 overlaps the abnormality complex of CF, such that trisomy 18 cases could be regarded as exhibiting a partial form of CF.
PROSTACYCLIN AND MATERNAL LUPUS ANTICOAGULANT
Another
A. F. H.
is
supported by
the
Cystic
A. F. HEELEY
Department of Histopathology, University Hospital, Nottingham
D. G. FAGAN
REPROTEROL FOR REFRACTORY HEART FAILURE
SIR,-Salbutamol and pirbuterol are cited in your Nov 5 editorial as the two agonists extensively evaluated in heart failure. Reproterol is a P2-selective agonist with an unusual mechanism of action2probably connected with its chemical structure, in which the resorcinol moiety is joined by a propyl bridge to a dimethylxanthine group.
92-receptor
We have experience with the medium-term (up to 3 months) use of reproterol in fourteen patients with chronic refractory heart failure (New York Heart Association class II four patients, class III six patients, and class IV four patients). Usual diuretic and digitalis treatments were continued and reproterol (20 mg thrice daily by mouth) was added. Cardiac performance (ejection fractions, cardiac index, and circulation time) was studied by a cardio-scintigraphic method using a gamma counter (Searle LFOV) and a 93Tc-albumin intravenous bolus; an echocardiographic study of cardiac diameters was also done. The table shows the findings before and at the end of reproterol treatment. DIAMETERS,
to
and
colleagues (Sept 3,
p 576) prostacyclin metabolites
measure
are
in
pregnancies
Fibrosis Research Trust.
Regional Neonatal Screening Laboratory, Peterborough District Hospital, Peterborough PE3 6DA
CARDIAC FUNCTION, HEART
critical of our women with circulating lupus anticoagulant who had successful after treatment with aspirin and prednisone. The report they cite as evidence that the levels of 6-keto- PGF I a (the major metabolite of prostacyclin) measured in plasma by gas chromatography/mass (to spectrometry (GC/MS) normally increase in late 244 pg/ml) was subsequently invalidated by a report from workers in the same department who found concentrations of about 5 pg/ml, a value consistent with that of other workers3 who also used gas
SIR,-Dr Ros
failure
AND NYHA GRADINGS
BEFORE AND AFTER REPROTEROL: MEANS±SD
pregnancy
chromatography. Weattempted to assay 6-keto-PGF 1 and 2,3-dinor-6-keto-PGF10’ a in 4 ml of pregnancy plasma by radioimmunoassay (RIA)4 after purification by ’Sep Pak’ extraction and rpHPLC (high pressure liquid chromatography). Mean values (±SD) for the two metabolites were 65±30 pg/ml and 50±17 pg/ml, respectively, but non-specific immunoreactivity amounting to about 50 pg/ml removed any confidence in the results. Seiss and DraySsucceeded in measuring plasma levels of 6-ketoPGFI, in men by RIA after rpHPLC by using large volumes (50-100 ml) of plasma. The mean value of4-7±3’22 pg/ml accords well with those obtained recently by GC/MS. It appears that prostacyclin metabolites in patients’ plasma cannot be measured by RIA in samples of a size acceptable to many ethics committees. Furthermore, when the more sensitive and specific GC/MS method, which requires a smaller sample volume (10-20 ml plasma), is used, the standard deviation of control values is such that it is most unlikely that any reduction in concentration of 6-ketoPGF I" in association with circulating lupus anticoagulant could be detected. We are investigating the possibility that the more readily measured urinary metabolites of prostacyclin will be useful in determining whether lupus anticoagulant inhibits prostacyclin production in vivo. Postgraduate School of Obstetrics and Gynaecology, University of Auckland,
Auckland 3, New Zealand
G. C. LIGGINS S. J. M. SKINNER W. F. LUBBE
ADRENALINE AND POTASSIUM
SIR,-Your Dec
-
-
I
I
I
* 11 cases
No tachyphylaxis was experienced up to 3 months, in contrast to experience with the other (32-agonists.3 Reproterol, which seems to lack the arrhythmogenicity of other such compounds, may be a useful drug in refractory, chronic heart failure.4
Medical
Division, Hospital, Cesena, Italy Civil
General
Pathology Institute II,
University of Rome
E. PRETOLANI I. ZOLI G. BATTISTINI R. MOSCATELLI G. IOSA G. CECCARELLI M. CIAMPINI
2.
Klinger KH Synthesen von broncospasmolitisch wirksamen &bgr; phenylaethilammoalkyl-xantinen. Arzn Forsch 1977; 27: 4. Marmo E, di Mezza F, Giordano L, et al. In vitro effects of reproterol upon tracheobronchial, cardiac and cerebral adenyl cyclase. Res Commun Chem Pathol Pharmacol 1982; 35: 389. Alexander RW, Mudege GM, et al Acute and chronic effects of pirbuterol
3. Colucci WS,
4.
on left ventricular ejection-fraction and clinical status in severe heart failure. Am Heart J 1981; 102: 564. Citone C, Carelh M, di Marcotullio G, Milazzotto F Valutazione all ’ECG dinamico degli effetti del reproterolo sul sistema di conduzione cardiaco. Communication to VI Congress of the Italian Society of Pneumology (Rome, Nov 7, 1983). Med Torac (in press).
(p 1401) editorial provides a comprehensive
would like to add some of our recent observations. In six healthy volunteers the rapid fall in plasma potassium which occurs during insulin-induced hypoglycaemia was abolished (see table) by previous administration of propranolol (40 mg orally, three times daily, for 10 days). Since a 30-50 fold rise in plasma adrenaline concentration occurs during hypoglycaemic stress,and in view of the effect of non-specific &bgr;-blockade, our observation is probably another example of a 02-receptor-mediated hypokalaemic response. Such rapid fluctuations in plasma potassium concentrations may, as suggested in the editorial, be clinically relevant (eg, arrhythmogenic) and contribute to the mortality of hypoglycaemia. We have also examined, retrospectively, the relation between plasma potassium and serum thyroxine (T4) concentrations in view of the reported potentiation of the metabolic effects of 1. Lewis PJ, Boylan P, Fredman LA, Hensby CN, Downing I. Prostacyclin in pregnancy
Br
Med J1980; 280:
2. Barrow
1.
17
of the relation between adrenaline and potassium. We
account
1581-82.
SE, Blair IA, Waddell KA, Shepherd GL, Lewis PJ, Dollery CT. Prostacyclin in late pregnancy: Analysis of 6-oxo-prostaglandin F1&agr; in maternal plasma. In Lewis PJ, Moncada S, O’Grady J, eds. Prostacyclin in pregnancy. New York: Raven Press, 1983: 79. 3. Christ-Hazelhof E, Nugturen DH. Prostacyclin is not a circulating hormone. Prostaglandins 1981; 22: 739-46. 4. Liggins GC, Campos GA, Roberts CM, Skinner SJ. Production rates of prostaglandin F, 6-keto-PGF1&agr; and thromboxane B2 by perfused human endometrium Prostaglandins 1980; 19: 461-77 5. Seiss W, Dray F. Very low levels of 6-keto-prostaglandin F1 &agr; in human plasma. J Lab Clin Med 1982; 99: 388-98 6. Garber AJ, Cryer PE, Santiago JV, Haymond MW, Pagliara AS, Kipnis DM. The role of adrenergic mechanisms in the substrate and hormonal response to insulininduced hypoglycemia in man. J Clin Invest 1976; 58: 7-15.