- Email: [email protected]
MEXILETINE FOR CONTROL OF VENTRICULAR DYSRHYTHMIAS IN PREGNANCY
647
THE CLOFIBRATE PROBLEM
SIR,- The W.H.O. cooperative trial
on clofibrate for primary heart disease of ischxmic (Aug. 23) describes how prevention investigation of one problem was followed by another, unexpected, result. Here we seem to have an interesting example of serendipity
in
reverse.
Inevitably, results like these achieve a prominence in the lay Press that is out of proportion with their relevance, and Professor Oliver in particular is to be congratulated on having handled a tendentious radio interview ("the operation was successful but the patient died"), with equanimity and due reference to the facts and their limitations. To explain the increased mortality amongst clofibrate-treated male hypercholesterolaemic subjects, two hypotheses have so far been-namely, a long-term toxic effect of the drug and/or long-term depletion of body cholesterol. I would like to suggest a third possibility. Amongst large numbers of subjects chosen in this way, there would presumably be some in whom raised serum cholesterol serves to correct or compensate for some other metabolic disorder, and might therefore be best left alone. A similar large group of men with polycythxmia, for example, could contain individuals with chronic respiratory failure, and amongst those chosen for a therapeutic study of refractory anaemia there could lurk unspecified cases of severe renal impairment. In both cases, correction of the presenting blood abnormality could adversely affect the outcome of the underlying diseases. Might analogous diseases have existed undetected in some of the hypercholesterolaemic men treated with clofibrate? Retrospective clarification of this type of problem could well be impossible or unethical, but more detailed investigation of hyperlipidasmia might yield interesting results. 7 Chad
Road, BlrmmghamBI53HR
G. E. OWEN WILLIAMS
INCREASED CSF &ggr;-AMINOBUTYRIC ACID AFTER TREATMENT WITH &ggr;-VINYL GABA
SIR,-It has been suggested that to increase endogenous y-aminobutyric acid (GABA) in the central nervous system would be therapeutically useful in some neuropsychiatric conditions, including Huntington’s chorea, 1,2 parkinsonian tremor and rigidity, epilepsy,3 and schizophrenia.4One approach to increasing GABA in the brain is to inhibit its degradation with potent inhibitors of GABA transaminase (GABA-T). Such inhibitors can increase brain GABA concentrations several fold in laboratory animals.5 Attempts to use GABA-T inhibitors clinically have been disap6 pointing. Thus, treatment with amino-oxyacetic acid or y-acetylenic GABAwas ineffective in Huntington’s disease. Results with isoniazid
were
equivocal.s,9
Such studies,
however,
CSF GABA before and after
y-vinyl GABA.
demonstrated that rat brain and CSF concentrations of GABA are significantly correlated after systemic administration ofaa GABA-T inhibitor. 10 We wondered if administration of a GABA-T inhibitor to man led to dose-related increases in CSF GABA concentrations, which would probably reflect similar changes in brain GABA. We administered the enzyme-activated, irreversible GABA-T inhibitor, y-vinyl GABA (RMI 71.754),"orally to ten patients at doses of 1, 2, or 6 g/day for 3 days (two equal daily doses). Before treatment and within 24 h after the last dose, samples of CSF were obtained by lumbar puncture and frozen immediately.12 The free GABA concentration was assayed on the day of collection by ion-
viously
exchange fluorimetry.
10
CSF GABA concentrations were always increased by treatment with y-vinyl GABA (see figure). The mean increase was doserelated, being 68, 108, and 201 pmol/ml, respectively, after 1,2, and 6 g/day of y-vinyl GABA. In individual patients, the increases ranged from 2 to 5 fold. Parallel increases of 0-alanine and homocarnosine in the CSF were also observed. These results suggest that oral administration of y-vinyl GABA does increase GABA concentrations in the human brain and could achieve any therapeutic benefits associated with such an increase. J. GROVE G. TELL P. J. SCHECHTER Centre de Recherche Merrell International, 67084
Strasbourg, France
only be interpreted if alterations in CNS GABA concentrations are verified for the doses and regimens used. Our laboratory has pre-
J. KOCH-WESER
can
J. M. Neurology Clinic, Hôpital Civil, Strasbourg
1 Barbeau A GABA and Huntington’s chorea. Lancet 1973; ii: 1499-1500 2 Enna SJ, Bird ED, Bennett JP, Bylund DB, Yamamura HI, Iversen LL, Snyder SH. Huntington’s chorea Changes in neurotransmitter receptors in the brain. NEngl J Med 1976, 294: 1305-09. 3 Meldrum BS. Gamma-aminobutyric acid and the search for new anti-convulsant drugs. Lancet 1978, i 304-06 4 Roberts E. An hypothesis suggesting that there is a defect in the GABA system in schizophrenia Neurosci Res Prog Bull 1972, 10: 468-81 5 Schechter PJ, Tranier Y, Jung MJ, Böhlen P Audiogenic seizure protection by elevated brain GABA concentration in mice: Effects of &ggr;-acetylenic GABA and &ggr;-vinyl GABA, two irreversible GABA-T inhibitors. Eur J Pharmacol 1977; 45: 319-28. 6 Perry TL, Wright JM, Hansen S, Allan BM, Baird PA, MacLeod PM. Failure of aminooxyacetic acid therapy in Huntington disease. Neurology 1980; 30: 772-75. 7 Tell G, Bohlen P, Schechter PJ, Koch-Weser J, Agid Y, Bonnet AM, Coquillat G, Chazot G, Fischer C Treatment of Huntington’s disease with &ggr;-acetylenic GABA, an irreversible inhibitor of GABA-transaminase Increased CSF GABA and homocarnosine without clinical amelioration. Neurology (in press) 8 Perry TL, Wright JM, Hansen S, MacLeod PM Isoniazid therapy of Huntington disease. Neurology 1979, 29: 370-75 9 Enna SJ, Ferkany JW, Van Woert M, Butler FJ Measurement of GABA in biological fluids Effects of GABA-transaminase inhibitors. In: Chase TN, Wexler NS, Barbeau A, eds Advances in neurology. vol XXIII. New York Raven Press, 1979: 741-50
WARTER
C. MARESCAUX L. RUMBACH
MEXILETINE FOR CONTROL OF VENTRICULAR DYSRHYTHMIAS IN PREGNANCY
SIR,-Mexiletine is well recognised as a treatment for ventricular dysrhthmias, but the application of this drug in pregnancy has not previously been documented. We report a patient who had
paroxysmal ventricular tachycardia of
aetiology during the third rhythmia was successfully propranolol and mexiletine.
uncertain
trimester of pregnancy. The dyscontrolled with a combination of
10 Bohlen P, Huot S, Palfreyman MG. The relationships between GABA concentrations in brain and cerebrospinal fluid. Brain Res 1979; 167: 297-305. 11. Jung MJ, Lippert B, MetcalfBW, Böhlen P, Schechter PJ &ggr;-vinyl GABA (4-aminohex5-enoic acid), a new selective irreversible inhibitor of GABA-T Effects on brain GABA metabolism in mice. J Neurochem 1977; 29: 797-802. 12. Hare TA, Wood JH, Ballenger JC, Post RM &ggr;-Aminobutyric acid in human cerebrospinal fluid: Normal values Lancet 1979; ii: 534-35
648 fetal
bradycardia
is well
recognised.
Our data indicate that
mexiletine, too, may be safely used during the third trimester of pregnancy and the puerperium. Mexiletine, like propranolol, is lipid-soluble’ and freely crosses the placenta. Thus, mex-
ECG
recording before mexiletine showing ventricular tachycardia.
and
propranolol therapy,
A 34-year-old woman was admitted to hospital during the 32nd week of pregnancy with intermittent palpitations and shortness of breath. Two previous pregnancies had been uncomplicated and she had had no serious illness in the past. On examination she was in sinus rhythm with frequent ventricular premature beats (VPBs). Blood pressure was 130/70 mm Hg, and heart sounds were normal. There were no signs of heart failure. The electrocardiogram confirmed VPBs but was otherwise normal and was unchanged from one recorded six years previously when VPBs were also demonstrated. The chest radiograph, sector echocardiogram, and serum potassium were normal. Electrocardiographic monitoring over the next 24 h demonstrated frequent episodes of ventricular tachycardia which did not respond to a lignocaine infusion (see figure). Control of the ventricular dysrhythmias was finally achieved with a combination of oral propranolol 40 mg three times a day and oral mexiletine 200 mg three times a day. On this regimen, "trough" plasma-mexiletine concentrations were maintained in the range 0.3 to 0-6 mg/1, and the patient experienced no further palpitations. 24 h ambulatory electrocardiograms showed stable sinus rhythm with only occasional VPBs. The patient was discharged from hospital well. In the 39th week of pregnancy she went into spontaneous labour and gave birth to a normal male child. During the first 6 h after delivery the infant was well, though the heart rate was noted to be only 90 beats/min. An electrocardiogram was normal. Thereafter, the heart rate increased to 120 beats/min and remained normal throughout the puerperium. The infant was breast-fed. Mexiletine levels were measured’ in the maternal and infant’s serum and in the breast milk both at birth and 6 weeks later (see table). The use of propranolol in pregnancy2 and the puerperium3 is well documented, and in most cases the effects on the fetus, labour, and the newborn child are inconsequential though
iletine levels in the maternal and cord blood were equal. Labour was normal and only in the early hours of the puerperium was slowing of the infant’s heart rate observed-probably as a result of propranolol delivered to the fetus in utero. Mexiletine is excreted in breast milk but, like propranolol, in insufficient quantity to be measurable in the serum of the breast-fed infant. Thus, after the first few hours of the puerperium the heart rate of the infant was consistently normal. Though caution should still be exercised, mexiletine appears safe in pregnancy, and breast-feeding can proceed normally. Department of Cardiology, King’s College Hospital, Poisons Unit,
Guy’s Hospital,
DW, Flanagan RJ, Hayler AM, Loizon M. A simple gas-liquid chromatographic method for the measurement of mexiletine and lignocaine in blood plasma or serum. J Chromatogr 1979; 169: 295-301. 2. Eliahou HE, Silverberg DS, Reisin E, Romen I, Mashiach S, Serr DM. Propranolol for the treatment of hypertension in pregnancy. Br J Obstet Gynæcol 1978; 85: 431-36. 3. Bauher JH, Pape B, Zajicek J, Groshong T. Propranolol in human plasma and breast milk. Am J Cardiol 1979; 43: 860-62.
DAVID W. HOLT
London SE1
GONADOTROPHIN AND SEX RATIO
SIR,-The monthly sex ratios for white and black births in the United States during 1974-781 were not significantly correlated. In this they differ from the earlier findings of Statist The table below does not show the individual sex ratios for each of the 60 months, merely the 5-year averages for each calendar month. The respective peaks of sex ratio occur at about the same time of the year but not the respective troughs. This imperfect, or only partial, fit between the two series argues that the cause or causes of seasonality in the sex ratio of live births in the U.S. are not the same for White and Black. If seasonality in maternal gonadotrophin levels is to be regarded as more than a minor contributing cause of seasonality in sex ratio (Dr James, Aug. 23, p. 430) we will need evidence that White women do not have the same seasonality in the gonadotrophin factor as Black women. Apart from the matter of seasonality, James’ hypothesis is supported by the relatively low sex ratio of Black births. Institute of Obstetrics and Hammersmith Hospital, London W12 0HS
4. 1. Holt
ADAM D. TIMMIS GRAHAM JACKSON
London SE5
Gynaecology,
Kaye CM, Kiddie MA, Turner P. Postgrad Med J 1977; 53: 56-58.
BREAST MILK
* "Trough" values. ND=not detectable (limit of sensitivity 0-05
mg/1).
Variable
pharmacokinetics of mexiletine
1. Slatis HM. Seasonal variation in the American live birth sex ratio. Am J Hum Genet 1953, 5: 21-33. 2. National Center for Health Statistics. Vital statistics of the United States, natality volumes for 1974 and 1975. (The data for 1976-78 were supplied direct by N.C.H.S., Hyattsville, Maryland.) AVERAGE SEX RATIOS OF LIVE
(EXPRESSED MEXILETINE LEVELS IN MATERNAL AND INFANT SERUM AND
W. R. LYSTER
BIRTHS,
AS MALES PER
BY
100
COLOUR, 1974-78
FEMALES)
THE CLOFIBRATE PROBLEM
SIR,- The W.H.O. cooperative trial
on clofibrate for primary heart disease of ischxmic (Aug. 23) describes how prevention investigation of one problem was followed by another, unexpected, result. Here we seem to have an interesting example of serendipity
in
reverse.
Inevitably, results like these achieve a prominence in the lay Press that is out of proportion with their relevance, and Professor Oliver in particular is to be congratulated on having handled a tendentious radio interview ("the operation was successful but the patient died"), with equanimity and due reference to the facts and their limitations. To explain the increased mortality amongst clofibrate-treated male hypercholesterolaemic subjects, two hypotheses have so far been-namely, a long-term toxic effect of the drug and/or long-term depletion of body cholesterol. I would like to suggest a third possibility. Amongst large numbers of subjects chosen in this way, there would presumably be some in whom raised serum cholesterol serves to correct or compensate for some other metabolic disorder, and might therefore be best left alone. A similar large group of men with polycythxmia, for example, could contain individuals with chronic respiratory failure, and amongst those chosen for a therapeutic study of refractory anaemia there could lurk unspecified cases of severe renal impairment. In both cases, correction of the presenting blood abnormality could adversely affect the outcome of the underlying diseases. Might analogous diseases have existed undetected in some of the hypercholesterolaemic men treated with clofibrate? Retrospective clarification of this type of problem could well be impossible or unethical, but more detailed investigation of hyperlipidasmia might yield interesting results. 7 Chad
Road, BlrmmghamBI53HR
G. E. OWEN WILLIAMS
INCREASED CSF &ggr;-AMINOBUTYRIC ACID AFTER TREATMENT WITH &ggr;-VINYL GABA
SIR,-It has been suggested that to increase endogenous y-aminobutyric acid (GABA) in the central nervous system would be therapeutically useful in some neuropsychiatric conditions, including Huntington’s chorea, 1,2 parkinsonian tremor and rigidity, epilepsy,3 and schizophrenia.4One approach to increasing GABA in the brain is to inhibit its degradation with potent inhibitors of GABA transaminase (GABA-T). Such inhibitors can increase brain GABA concentrations several fold in laboratory animals.5 Attempts to use GABA-T inhibitors clinically have been disap6 pointing. Thus, treatment with amino-oxyacetic acid or y-acetylenic GABAwas ineffective in Huntington’s disease. Results with isoniazid
were
equivocal.s,9
Such studies,
however,
CSF GABA before and after
y-vinyl GABA.
demonstrated that rat brain and CSF concentrations of GABA are significantly correlated after systemic administration ofaa GABA-T inhibitor. 10 We wondered if administration of a GABA-T inhibitor to man led to dose-related increases in CSF GABA concentrations, which would probably reflect similar changes in brain GABA. We administered the enzyme-activated, irreversible GABA-T inhibitor, y-vinyl GABA (RMI 71.754),"orally to ten patients at doses of 1, 2, or 6 g/day for 3 days (two equal daily doses). Before treatment and within 24 h after the last dose, samples of CSF were obtained by lumbar puncture and frozen immediately.12 The free GABA concentration was assayed on the day of collection by ion-
viously
exchange fluorimetry.
10
CSF GABA concentrations were always increased by treatment with y-vinyl GABA (see figure). The mean increase was doserelated, being 68, 108, and 201 pmol/ml, respectively, after 1,2, and 6 g/day of y-vinyl GABA. In individual patients, the increases ranged from 2 to 5 fold. Parallel increases of 0-alanine and homocarnosine in the CSF were also observed. These results suggest that oral administration of y-vinyl GABA does increase GABA concentrations in the human brain and could achieve any therapeutic benefits associated with such an increase. J. GROVE G. TELL P. J. SCHECHTER Centre de Recherche Merrell International, 67084
Strasbourg, France
only be interpreted if alterations in CNS GABA concentrations are verified for the doses and regimens used. Our laboratory has pre-
J. KOCH-WESER
can
J. M. Neurology Clinic, Hôpital Civil, Strasbourg
1 Barbeau A GABA and Huntington’s chorea. Lancet 1973; ii: 1499-1500 2 Enna SJ, Bird ED, Bennett JP, Bylund DB, Yamamura HI, Iversen LL, Snyder SH. Huntington’s chorea Changes in neurotransmitter receptors in the brain. NEngl J Med 1976, 294: 1305-09. 3 Meldrum BS. Gamma-aminobutyric acid and the search for new anti-convulsant drugs. Lancet 1978, i 304-06 4 Roberts E. An hypothesis suggesting that there is a defect in the GABA system in schizophrenia Neurosci Res Prog Bull 1972, 10: 468-81 5 Schechter PJ, Tranier Y, Jung MJ, Böhlen P Audiogenic seizure protection by elevated brain GABA concentration in mice: Effects of &ggr;-acetylenic GABA and &ggr;-vinyl GABA, two irreversible GABA-T inhibitors. Eur J Pharmacol 1977; 45: 319-28. 6 Perry TL, Wright JM, Hansen S, Allan BM, Baird PA, MacLeod PM. Failure of aminooxyacetic acid therapy in Huntington disease. Neurology 1980; 30: 772-75. 7 Tell G, Bohlen P, Schechter PJ, Koch-Weser J, Agid Y, Bonnet AM, Coquillat G, Chazot G, Fischer C Treatment of Huntington’s disease with &ggr;-acetylenic GABA, an irreversible inhibitor of GABA-transaminase Increased CSF GABA and homocarnosine without clinical amelioration. Neurology (in press) 8 Perry TL, Wright JM, Hansen S, MacLeod PM Isoniazid therapy of Huntington disease. Neurology 1979, 29: 370-75 9 Enna SJ, Ferkany JW, Van Woert M, Butler FJ Measurement of GABA in biological fluids Effects of GABA-transaminase inhibitors. In: Chase TN, Wexler NS, Barbeau A, eds Advances in neurology. vol XXIII. New York Raven Press, 1979: 741-50
WARTER
C. MARESCAUX L. RUMBACH
MEXILETINE FOR CONTROL OF VENTRICULAR DYSRHYTHMIAS IN PREGNANCY
SIR,-Mexiletine is well recognised as a treatment for ventricular dysrhthmias, but the application of this drug in pregnancy has not previously been documented. We report a patient who had
paroxysmal ventricular tachycardia of
aetiology during the third rhythmia was successfully propranolol and mexiletine.
uncertain
trimester of pregnancy. The dyscontrolled with a combination of
10 Bohlen P, Huot S, Palfreyman MG. The relationships between GABA concentrations in brain and cerebrospinal fluid. Brain Res 1979; 167: 297-305. 11. Jung MJ, Lippert B, MetcalfBW, Böhlen P, Schechter PJ &ggr;-vinyl GABA (4-aminohex5-enoic acid), a new selective irreversible inhibitor of GABA-T Effects on brain GABA metabolism in mice. J Neurochem 1977; 29: 797-802. 12. Hare TA, Wood JH, Ballenger JC, Post RM &ggr;-Aminobutyric acid in human cerebrospinal fluid: Normal values Lancet 1979; ii: 534-35
648 fetal
bradycardia
is well
recognised.
Our data indicate that
mexiletine, too, may be safely used during the third trimester of pregnancy and the puerperium. Mexiletine, like propranolol, is lipid-soluble’ and freely crosses the placenta. Thus, mex-
ECG
recording before mexiletine showing ventricular tachycardia.
and
propranolol therapy,
A 34-year-old woman was admitted to hospital during the 32nd week of pregnancy with intermittent palpitations and shortness of breath. Two previous pregnancies had been uncomplicated and she had had no serious illness in the past. On examination she was in sinus rhythm with frequent ventricular premature beats (VPBs). Blood pressure was 130/70 mm Hg, and heart sounds were normal. There were no signs of heart failure. The electrocardiogram confirmed VPBs but was otherwise normal and was unchanged from one recorded six years previously when VPBs were also demonstrated. The chest radiograph, sector echocardiogram, and serum potassium were normal. Electrocardiographic monitoring over the next 24 h demonstrated frequent episodes of ventricular tachycardia which did not respond to a lignocaine infusion (see figure). Control of the ventricular dysrhythmias was finally achieved with a combination of oral propranolol 40 mg three times a day and oral mexiletine 200 mg three times a day. On this regimen, "trough" plasma-mexiletine concentrations were maintained in the range 0.3 to 0-6 mg/1, and the patient experienced no further palpitations. 24 h ambulatory electrocardiograms showed stable sinus rhythm with only occasional VPBs. The patient was discharged from hospital well. In the 39th week of pregnancy she went into spontaneous labour and gave birth to a normal male child. During the first 6 h after delivery the infant was well, though the heart rate was noted to be only 90 beats/min. An electrocardiogram was normal. Thereafter, the heart rate increased to 120 beats/min and remained normal throughout the puerperium. The infant was breast-fed. Mexiletine levels were measured’ in the maternal and infant’s serum and in the breast milk both at birth and 6 weeks later (see table). The use of propranolol in pregnancy2 and the puerperium3 is well documented, and in most cases the effects on the fetus, labour, and the newborn child are inconsequential though
iletine levels in the maternal and cord blood were equal. Labour was normal and only in the early hours of the puerperium was slowing of the infant’s heart rate observed-probably as a result of propranolol delivered to the fetus in utero. Mexiletine is excreted in breast milk but, like propranolol, in insufficient quantity to be measurable in the serum of the breast-fed infant. Thus, after the first few hours of the puerperium the heart rate of the infant was consistently normal. Though caution should still be exercised, mexiletine appears safe in pregnancy, and breast-feeding can proceed normally. Department of Cardiology, King’s College Hospital, Poisons Unit,
Guy’s Hospital,
DW, Flanagan RJ, Hayler AM, Loizon M. A simple gas-liquid chromatographic method for the measurement of mexiletine and lignocaine in blood plasma or serum. J Chromatogr 1979; 169: 295-301. 2. Eliahou HE, Silverberg DS, Reisin E, Romen I, Mashiach S, Serr DM. Propranolol for the treatment of hypertension in pregnancy. Br J Obstet Gynæcol 1978; 85: 431-36. 3. Bauher JH, Pape B, Zajicek J, Groshong T. Propranolol in human plasma and breast milk. Am J Cardiol 1979; 43: 860-62.
DAVID W. HOLT
London SE1
GONADOTROPHIN AND SEX RATIO
SIR,-The monthly sex ratios for white and black births in the United States during 1974-781 were not significantly correlated. In this they differ from the earlier findings of Statist The table below does not show the individual sex ratios for each of the 60 months, merely the 5-year averages for each calendar month. The respective peaks of sex ratio occur at about the same time of the year but not the respective troughs. This imperfect, or only partial, fit between the two series argues that the cause or causes of seasonality in the sex ratio of live births in the U.S. are not the same for White and Black. If seasonality in maternal gonadotrophin levels is to be regarded as more than a minor contributing cause of seasonality in sex ratio (Dr James, Aug. 23, p. 430) we will need evidence that White women do not have the same seasonality in the gonadotrophin factor as Black women. Apart from the matter of seasonality, James’ hypothesis is supported by the relatively low sex ratio of Black births. Institute of Obstetrics and Hammersmith Hospital, London W12 0HS
4. 1. Holt
ADAM D. TIMMIS GRAHAM JACKSON
London SE5
Gynaecology,
Kaye CM, Kiddie MA, Turner P. Postgrad Med J 1977; 53: 56-58.
BREAST MILK
* "Trough" values. ND=not detectable (limit of sensitivity 0-05
mg/1).
Variable
pharmacokinetics of mexiletine
1. Slatis HM. Seasonal variation in the American live birth sex ratio. Am J Hum Genet 1953, 5: 21-33. 2. National Center for Health Statistics. Vital statistics of the United States, natality volumes for 1974 and 1975. (The data for 1976-78 were supplied direct by N.C.H.S., Hyattsville, Maryland.) AVERAGE SEX RATIOS OF LIVE
(EXPRESSED MEXILETINE LEVELS IN MATERNAL AND INFANT SERUM AND
W. R. LYSTER
BIRTHS,
AS MALES PER
BY
100
COLOUR, 1974-78
FEMALES)