- Email: [email protected]
ADRENALINE AND POTASSIUM
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.
171 PLASMA POTASSIUM CONCENTRATION CHANGES DURING INSULIN-
contamination of certain extracts is our data do not confirm Legator’s, and we conclude that mould extracts do not pose an aflatoxin risk to patients being treated by injection immunotherapy. While
INDUCED HYPOGLYCAEMIA BEFORE AND AFTER BETA-BLOCKADE
aflatoxin
theoretically possible,
National Center for Drugs and Biologics, Food and Drug Administration,
JOHN C. PETRICCIANI
Bethesda, Maryland 20205, USA
I
,
THERAPEUTIC ROLE OF MEASLES VACCINE IN HODGKIN’S DISEASE
,
Reference range for plasma potassium 3 - 8-5’ 0 mmol/). *p=0’05 for 0-m 30 mm values (Mann-Whuney test).
catecholamines by thyroid hormones.7 Plasma potassium concentrations in two patient groups were compared-sixteen patients with serum T4 concentrations greater than 150 nmol/1 (reference range 58-128 nmol/1) (group A) and twenty-three patients with serum T4 concentrations in the range 80-110 nmol/1 (group B). These ranges were selected to avoid overlap with hyperthyroid/hypothyroid states. Patients with other disease states detectable by screening the blood biochemistry results available were excluded. Patients in group A had significantly (p<0 003; Mann-Whitney test) lower plasma potassium concentrations (median 3 - 7, range 3 - 3-4 - 4 mmol/1) than patients in group B (4 -1; 3, 0-5 . 0 mmol/1). Confirmation of our hypothesis must come from carefully controlled studies and from the demonstration that (32-blockade corrects the relative hypokalaemia. Again it is tempting to suggest that this hypokalaemia may be clinically relevant and that it may contribute to the cardiac manifestations (arrhythmias, cardiac failure) of thyrotoxicosis. Hypokalaemia may also be related to the proximal myopathy observed in thyrotoxicosis and may, to some extent, explain the reversal of this manifestation after control of
thyrotoxicosis. Metabolic Unit, Department of Chemical Pathology, Royal Free Hospital,
London NW3 2QG
SIR,-Remission of Hodgkin’s disease has been reported after measles in five patients, and the use of live attenuated measles vaccine as an adjunct to chemotherapy has been suggested, 1,2 though the mechanism remains an enigma. Measles virus is a good and IFN may prove a valuable (class A) inducer of interferon anti-tumour agent in man, whether by a direct antiproliferative effect on malignant cells, by its extensive immunomodulatory effects, or by a combination of both.IFN has not been thoroughly studied in Hodgkin’s disease, but anecdotal experience suggests its We’have studied the levels of the IFN-induced enzyme, 2’-5’-oligo-A synthetase, in mononuclear cells of two women immunised with live attenuated rubella vaccine. Sequential determinations have shown a prolonged, threefold increase of enzyme activity from pre-immunisation level, which indicates considerable endogenous IFN production. attenuated measles virus was shown to induce circulating IFN in non-immune children.7 Regression of Hodgkin’s disease after measles may be due to IFN. Instead of exposing these immunocompromised patients to the risks of live measles vaccine, IFN therapy should be studied as
(IFN)3
efficacy.5
.
Similarly,
an
adjunct
to
chemotherapy.
Cancer Research Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
D. P. MIKHAILIDIS P. DANDONA
A. SCHATTNER
PHARMACOKINETICS AND "POTENCY" OF CONTRACEPTIVE STEROIDS not considered in recent Lancet correspondence breast cancer and oral contraceptives is the variation between women in their handling of contraceptive steroids. We 8have shown that women given the same oral contraceptive preparation in the same dose have an eight-fold variation in plasma norethisterone levels and a ten-fold variation in plasma levonorgestrel levels. These pharmacokinetic differences are largely due to variations in metabolic degradation by enzymes within the gut wall and the liver. We do not know the relevance of high plasma (and thus high tissue) concentrations of progestagens, with respect to their toxicity, but clearly kinetic factors must be taken into account when the "potency" of a steroid to which a woman is exposed is calculated.
SIR,-One issue
on
AFLATOXINS NOT IN ALLERGENIC MOULD EXTRACTS
SIR,-Dr Legator and colleagues (Oct 15, p 915) suggest that some allergenic extracts from moulds contain aflatoxin B-1, which might pose a health risk when used in immunotherapy. Legator advised the Food and Drug Administration (FDA) of these findings and provided the name of the manufacturer and the lot numbers of the twelve samples tested. We attempted to confirm these findings by testing material obtained directly from Legator’s laboratory and samples from the manufacturer and from distributors. The FDA tests revealed aflatoxin B-1 in one sample only, at a concentration of 3 - 2 parts per million. That sample was obtained from Legator’s laboratory and came from a container which had already been opened. No aflatoxins were detected in an unopened vial of the same lot of extract obtained from commercial distribution channels when tested at FDA. Of the other three samples found positive for aflatoxin B-1 by Legator, only 2 were still available from his laboratory; we detected aflatoxin in neither. Of the eight samples found negative by Legator all were also negative when the FDA tested unopened samples retrieved from the manufacturer. The high performance liquid chromatography method used in Legator and the FDA’s thin-layer chromatography method can detect aflatoxins at 1 part per 1000 million (ppb) and it is difficult to explain why the two sets of results were so different, especially since Legator et al found levels 54 to more than 1000 times higher than the level of detectability (1 ppb). 7
Landsberg L, Young JB. Catecholamines and the adrenal medulla. In. Bondy PK, Rosenberg LE, eds. Metabolic control and disease, 8th ed. Philadelphia: WB Saunders, 1980: 1621-93.
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3BX
D. J. BACK A. BRECKENRIDGE M. ORME M. A. SHAW
Abdurrahman MB, Yakubu AM, Fleming AF. Regression of Hodgkin’s disease after measles. Lancet 1981, i: 1112. 2. Greentree LB. Hodgkin’s disease: Therapeutic role of measles vaccine. Am J Med 1
Taqi AM,
1983; 75: 928. 3. Ho M, Armstrong JA. Interferon. Annu Rev Microbiol 4. Borden EC. Interferons: Rationale for clinical trials in Med 1979; 91: 472-79
1975, 29: 131-61 neoplastic disease. Ann Intern
5. Blomgren H, Cantell K, Johansson B, Lagergren C, Ringborg U, Strander H. Interferon therapy in Hodgkin’s disease: a case report Acta Med Scand 1976, 199: 527-32.
A, Wallach D, Merlin G, Hahn T, Levin S, Revel M. Assay of an interferon induced enzyme in white blood cells as a diagnostic aid in viral diseases L ancet 1981; ii. 497-500 7. Petralli JK, Merigan TC, Wilbur JR. Action of endogenous interferon against vaccinia infection in children Lancet 1965; ii. 401-05. 8. Back DJ, Breckenridge AM, Crawford FE, MacIver M, Orme MLE, Rowe PH. Interindividual variation and drug interactions with hormonal steroid contraceptives. Drugs 1981; 21: 46-61. 6. Schattner
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.
171 PLASMA POTASSIUM CONCENTRATION CHANGES DURING INSULIN-
contamination of certain extracts is our data do not confirm Legator’s, and we conclude that mould extracts do not pose an aflatoxin risk to patients being treated by injection immunotherapy. While
INDUCED HYPOGLYCAEMIA BEFORE AND AFTER BETA-BLOCKADE
aflatoxin
theoretically possible,
National Center for Drugs and Biologics, Food and Drug Administration,
JOHN C. PETRICCIANI
Bethesda, Maryland 20205, USA
I
,
THERAPEUTIC ROLE OF MEASLES VACCINE IN HODGKIN’S DISEASE
,
Reference range for plasma potassium 3 - 8-5’ 0 mmol/). *p=0’05 for 0-m 30 mm values (Mann-Whuney test).
catecholamines by thyroid hormones.7 Plasma potassium concentrations in two patient groups were compared-sixteen patients with serum T4 concentrations greater than 150 nmol/1 (reference range 58-128 nmol/1) (group A) and twenty-three patients with serum T4 concentrations in the range 80-110 nmol/1 (group B). These ranges were selected to avoid overlap with hyperthyroid/hypothyroid states. Patients with other disease states detectable by screening the blood biochemistry results available were excluded. Patients in group A had significantly (p<0 003; Mann-Whitney test) lower plasma potassium concentrations (median 3 - 7, range 3 - 3-4 - 4 mmol/1) than patients in group B (4 -1; 3, 0-5 . 0 mmol/1). Confirmation of our hypothesis must come from carefully controlled studies and from the demonstration that (32-blockade corrects the relative hypokalaemia. Again it is tempting to suggest that this hypokalaemia may be clinically relevant and that it may contribute to the cardiac manifestations (arrhythmias, cardiac failure) of thyrotoxicosis. Hypokalaemia may also be related to the proximal myopathy observed in thyrotoxicosis and may, to some extent, explain the reversal of this manifestation after control of
thyrotoxicosis. Metabolic Unit, Department of Chemical Pathology, Royal Free Hospital,
London NW3 2QG
SIR,-Remission of Hodgkin’s disease has been reported after measles in five patients, and the use of live attenuated measles vaccine as an adjunct to chemotherapy has been suggested, 1,2 though the mechanism remains an enigma. Measles virus is a good and IFN may prove a valuable (class A) inducer of interferon anti-tumour agent in man, whether by a direct antiproliferative effect on malignant cells, by its extensive immunomodulatory effects, or by a combination of both.IFN has not been thoroughly studied in Hodgkin’s disease, but anecdotal experience suggests its We’have studied the levels of the IFN-induced enzyme, 2’-5’-oligo-A synthetase, in mononuclear cells of two women immunised with live attenuated rubella vaccine. Sequential determinations have shown a prolonged, threefold increase of enzyme activity from pre-immunisation level, which indicates considerable endogenous IFN production. attenuated measles virus was shown to induce circulating IFN in non-immune children.7 Regression of Hodgkin’s disease after measles may be due to IFN. Instead of exposing these immunocompromised patients to the risks of live measles vaccine, IFN therapy should be studied as
(IFN)3
efficacy.5
.
Similarly,
an
adjunct
to
chemotherapy.
Cancer Research Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
D. P. MIKHAILIDIS P. DANDONA
A. SCHATTNER
PHARMACOKINETICS AND "POTENCY" OF CONTRACEPTIVE STEROIDS not considered in recent Lancet correspondence breast cancer and oral contraceptives is the variation between women in their handling of contraceptive steroids. We 8have shown that women given the same oral contraceptive preparation in the same dose have an eight-fold variation in plasma norethisterone levels and a ten-fold variation in plasma levonorgestrel levels. These pharmacokinetic differences are largely due to variations in metabolic degradation by enzymes within the gut wall and the liver. We do not know the relevance of high plasma (and thus high tissue) concentrations of progestagens, with respect to their toxicity, but clearly kinetic factors must be taken into account when the "potency" of a steroid to which a woman is exposed is calculated.
SIR,-One issue
on
AFLATOXINS NOT IN ALLERGENIC MOULD EXTRACTS
SIR,-Dr Legator and colleagues (Oct 15, p 915) suggest that some allergenic extracts from moulds contain aflatoxin B-1, which might pose a health risk when used in immunotherapy. Legator advised the Food and Drug Administration (FDA) of these findings and provided the name of the manufacturer and the lot numbers of the twelve samples tested. We attempted to confirm these findings by testing material obtained directly from Legator’s laboratory and samples from the manufacturer and from distributors. The FDA tests revealed aflatoxin B-1 in one sample only, at a concentration of 3 - 2 parts per million. That sample was obtained from Legator’s laboratory and came from a container which had already been opened. No aflatoxins were detected in an unopened vial of the same lot of extract obtained from commercial distribution channels when tested at FDA. Of the other three samples found positive for aflatoxin B-1 by Legator, only 2 were still available from his laboratory; we detected aflatoxin in neither. Of the eight samples found negative by Legator all were also negative when the FDA tested unopened samples retrieved from the manufacturer. The high performance liquid chromatography method used in Legator and the FDA’s thin-layer chromatography method can detect aflatoxins at 1 part per 1000 million (ppb) and it is difficult to explain why the two sets of results were so different, especially since Legator et al found levels 54 to more than 1000 times higher than the level of detectability (1 ppb). 7
Landsberg L, Young JB. Catecholamines and the adrenal medulla. In. Bondy PK, Rosenberg LE, eds. Metabolic control and disease, 8th ed. Philadelphia: WB Saunders, 1980: 1621-93.
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3BX
D. J. BACK A. BRECKENRIDGE M. ORME M. A. SHAW
Abdurrahman MB, Yakubu AM, Fleming AF. Regression of Hodgkin’s disease after measles. Lancet 1981, i: 1112. 2. Greentree LB. Hodgkin’s disease: Therapeutic role of measles vaccine. Am J Med 1
Taqi AM,
1983; 75: 928. 3. Ho M, Armstrong JA. Interferon. Annu Rev Microbiol 4. Borden EC. Interferons: Rationale for clinical trials in Med 1979; 91: 472-79
1975, 29: 131-61 neoplastic disease. Ann Intern
5. Blomgren H, Cantell K, Johansson B, Lagergren C, Ringborg U, Strander H. Interferon therapy in Hodgkin’s disease: a case report Acta Med Scand 1976, 199: 527-32.
A, Wallach D, Merlin G, Hahn T, Levin S, Revel M. Assay of an interferon induced enzyme in white blood cells as a diagnostic aid in viral diseases L ancet 1981; ii. 497-500 7. Petralli JK, Merigan TC, Wilbur JR. Action of endogenous interferon against vaccinia infection in children Lancet 1965; ii. 401-05. 8. Back DJ, Breckenridge AM, Crawford FE, MacIver M, Orme MLE, Rowe PH. Interindividual variation and drug interactions with hormonal steroid contraceptives. Drugs 1981; 21: 46-61. 6. Schattner