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HYPOTHYROIDISM IN DIABETICS
1129
initiated, the diet selected might
not have been the ideal one for therapeutic trial in that it contained a considerable quantity of dietary cholesterol. It is suggested that subsequent dietary trials should restrict dietary cholesterol much more. The results of this study also indicate that our best attempts to prevent coronary heart-disease would probably have greater success in higher-risk individuals before the development of an actual clinical event. It is possible that the disease was already so far advanced when the study was initiated that little benefit could have been derived. We must recognise that there is little evidence to date, either in animals or in man, that advanced atherosclerotic lesions can be modified by any treatment programme, be it dietary or drug. Department of Internal Medicine, University Hospitals, WILLIAM E. CONNOR. Iowa 52241.
to use
HYPOTHYROIDISM IN DIABETICS SIR,-We were interested in the article by Dr. Hunton and his colleagues (Sept. 4) claiming a significantly greater incidence of hypothyroidism (13-6%) in 220 diabetics treated with chlorpropamide or tolbutamide than that (34°0) in 229 diabetics treated by other means. Such a conclusion warrants careful assessment, for it carries far-reaching implications. We have therefore scrutinised the data from which these conclusions are drawn, and we have some reservations in accepting them as they stand. The diagnosis of hypothyroidism was made initially from clinical examination and estimation of the " diagnostic index ’’,1 the duration of the ankle reflex, and the millivoltage of the electrocardiogram. 40% of the sulphonylurea group and 22% of the control group came under suspicion on one or more of these grounds, and all these had serum-protein-boundiodine (serum-P.B.l.) determinations done in duplicate. In only 27% of those coming under clinical suspicion of hypothyroidism was the P.B.I. found to be below 4 g. per 100 ml. serum. Yet of the 30 sulphonylurea-treated diabetics with abnormally low serum-P.B.I. concentrations no less than 10, many with the lowest content of P.B.I., had been assessed as euthyroid clinically by two independent observers. Thus there was a poor correlation between P.B.I. values and clinical assessment of thyroid status. The correlation between delay in the ankle reflex and P.B.I. was also very poor: in the 38 subjects with abnormally low P.B.I. results, the ankle reflex was of normal duration in 9 out of 26 (about 35%) in whom it was recorded. In the 8 subjects of the control group with abnormally low P.B.I. values, duration of the ankle jerk was normal in all 5 in which it was measured. Conversely all but 1 of the 19 subjects in the control group who had delayed ankle jerks had normal P.B.I. values. The screening methods for detecting subjects with abnormally low values of P.B.I. were thus fairly ineffective, and it seems likely that many more subjects with abnormally low serum-P.B.I. values would have been discovered if these estimations had been done on all the diabetics in both groups. In fact P.B.I. concentration was estimated in 87 subjects of the sulphonylurea group and in 51 of the control group. Because the P.B.I. value was taken as the decisive criterion of hypothyroidism, measurement of the total incidence of abnormally low results in both groups would only have been possible if it had been performed in all the subjects, for the screening methods correlated so poorly with the abnormally low P.B.I. figures. The concentration of sulphonylurea in the plasma could not have depressed the value of the P.B.I. on a chemical basis, for Prof. S. C. Frazer has tested up to 50 mg. of sodium tolbutamide per 100 ml. in plasma without affecting the P.B.I. determination. We feel that further work is needed with more sequential studies in individual patients before firm conclusions can be drawn about the suggested effect of the sulphonylureas on thyroid function. If the sulphonylureas do act as antithyroid drugs it is hard to understand why the incidence of enlarge1.
Murray, I. P.
C. Med.
J.
Aust.
1964, i,
827.
of the
thyroid gland was only 14% in the sulphonylurea group compared with 16% in the control group. If further work confirms the authors’ assertions, it would not necessarily be best to substitute diguanides or insulin for sulphonylureas in hypothyroid diabetics, as they suggest-it would be preferable in many instances simply to give a supplement of ment
thvroxine. The Diabetic
Clinic, Royal Infirmary,
JOHN M. STOWERS THORIR HELGASON.
Aberdeen.
DEXAMPHETAMINE SULPHATE IN MICE
SIR,-I have read with interest the letter by Dr. Nora and his colleagues (Nov. 13). This company has examined the effects of dexamphetamine sulphate (’ Dexedrine’) on the foetus. We used doses of up to 10 mg. per kg. in New Zealand white rabbits, and failed to detect any teratogenic action of the compound. Our contrasting experience of experiments with this compound shows the need for careful prospective clinical studies of possible association between the birth of abnormal human infants and the administration of drugs. No animal test can be relied upon as being predictive of the effects of drugs on the human foetus. Until there is a more fundamental understanding of this problem, all those concerned with the human use of drugs would surely agree that they should only be prescribed with caution and for real need in women who may be pregnant. Smith Kline & French Laboratories Ltd., Welwyn Garden City, Hertfordshire.
G. E. PAGET.
ACID-BASE TERMINOLOGY
SIR,-According to your special article (Nov. 13), in the Bronsted-Lowry system an acid is defined as a proton donor and a base as a proton acceptor. No doubt there are. many excellent reasons for adopting this terminology. Nevertheless the system presents problems to those who learned their biochemistry using the previous terminology. I would like to mention a few of these problems, which are seldom clearly stated or answered in expositions designed to explain the system to those who are not specialists in biochemistry: 1. When hydrogen chloride is dissolved in water, in the ordinary usage of the term an acid (hydrochloric acid) is produced. The name applies to the solution as a whole, which, if concentrated, will burn
one’s not a
clothing and one’s skin. Now the solution as a whole is certainly proton donor. A proton is a highly charged electrical particle,
and if the solution
as a
whole could donate protons it would be carryIn fact the solution is electrically
ing a high positive electrical charge.
neutral. 2. Oxidation-reduction potential can be described in terms of electron donation and acceptance. When the ferrous ion is oxidised to the ferric ion it loses an electron. The proton is an elementary particle of positive charge and the electron is an elementary particle of negative charge. The description of acid-base balance in terms of proton donation and acceptance blurs the fundamental difference from oxidation-reduction potential. 3. A solution of sodium bicarbonate is alkaline in that it can neutralise an acid such as hydrochloric acid. Which particular ion is effective in this neutralisation ? This is the point at which most popular expositions of the Brønsted-Lowry system begin. In fact the bicarbonate ion combines with the hydrogen ion and in this sense it is the bicarbonate ion which merits the term base ": hence the Bronsted-Lowry terminology. But the bicarbonate ion by itself cannot neutralise an acid. One can bubble carbon dioxide all day through the solution of hydrochloric acid, thereby producing any number of bicarbonate ions, but the hydrochloric acid would not be neutralised. It is the solution of sodium bicarbonate as a whole which produces the conditions under which the bicarbonate ion can combine with the hydrogen ion of the hydrochloric acid. It is the solution as a whole which merits the term " alkaline " or basic ". Similarly these terms can apply to a solution of sodium hydroxide. 4. In the Bronsted-Lowry system an acid is a proton donor. Thus unionised acetic acid, the hydrogen ion itself, or other weakly dissociated cations, are deemed acids. They may share certain properties or play analogous parts in certain equilibria. To group them all together and call them all acids is to ignore differences "
"
initiated, the diet selected might
not have been the ideal one for therapeutic trial in that it contained a considerable quantity of dietary cholesterol. It is suggested that subsequent dietary trials should restrict dietary cholesterol much more. The results of this study also indicate that our best attempts to prevent coronary heart-disease would probably have greater success in higher-risk individuals before the development of an actual clinical event. It is possible that the disease was already so far advanced when the study was initiated that little benefit could have been derived. We must recognise that there is little evidence to date, either in animals or in man, that advanced atherosclerotic lesions can be modified by any treatment programme, be it dietary or drug. Department of Internal Medicine, University Hospitals, WILLIAM E. CONNOR. Iowa 52241.
to use
HYPOTHYROIDISM IN DIABETICS SIR,-We were interested in the article by Dr. Hunton and his colleagues (Sept. 4) claiming a significantly greater incidence of hypothyroidism (13-6%) in 220 diabetics treated with chlorpropamide or tolbutamide than that (34°0) in 229 diabetics treated by other means. Such a conclusion warrants careful assessment, for it carries far-reaching implications. We have therefore scrutinised the data from which these conclusions are drawn, and we have some reservations in accepting them as they stand. The diagnosis of hypothyroidism was made initially from clinical examination and estimation of the " diagnostic index ’’,1 the duration of the ankle reflex, and the millivoltage of the electrocardiogram. 40% of the sulphonylurea group and 22% of the control group came under suspicion on one or more of these grounds, and all these had serum-protein-boundiodine (serum-P.B.l.) determinations done in duplicate. In only 27% of those coming under clinical suspicion of hypothyroidism was the P.B.I. found to be below 4 g. per 100 ml. serum. Yet of the 30 sulphonylurea-treated diabetics with abnormally low serum-P.B.I. concentrations no less than 10, many with the lowest content of P.B.I., had been assessed as euthyroid clinically by two independent observers. Thus there was a poor correlation between P.B.I. values and clinical assessment of thyroid status. The correlation between delay in the ankle reflex and P.B.I. was also very poor: in the 38 subjects with abnormally low P.B.I. results, the ankle reflex was of normal duration in 9 out of 26 (about 35%) in whom it was recorded. In the 8 subjects of the control group with abnormally low P.B.I. values, duration of the ankle jerk was normal in all 5 in which it was measured. Conversely all but 1 of the 19 subjects in the control group who had delayed ankle jerks had normal P.B.I. values. The screening methods for detecting subjects with abnormally low values of P.B.I. were thus fairly ineffective, and it seems likely that many more subjects with abnormally low serum-P.B.I. values would have been discovered if these estimations had been done on all the diabetics in both groups. In fact P.B.I. concentration was estimated in 87 subjects of the sulphonylurea group and in 51 of the control group. Because the P.B.I. value was taken as the decisive criterion of hypothyroidism, measurement of the total incidence of abnormally low results in both groups would only have been possible if it had been performed in all the subjects, for the screening methods correlated so poorly with the abnormally low P.B.I. figures. The concentration of sulphonylurea in the plasma could not have depressed the value of the P.B.I. on a chemical basis, for Prof. S. C. Frazer has tested up to 50 mg. of sodium tolbutamide per 100 ml. in plasma without affecting the P.B.I. determination. We feel that further work is needed with more sequential studies in individual patients before firm conclusions can be drawn about the suggested effect of the sulphonylureas on thyroid function. If the sulphonylureas do act as antithyroid drugs it is hard to understand why the incidence of enlarge1.
Murray, I. P.
C. Med.
J.
Aust.
1964, i,
827.
of the
thyroid gland was only 14% in the sulphonylurea group compared with 16% in the control group. If further work confirms the authors’ assertions, it would not necessarily be best to substitute diguanides or insulin for sulphonylureas in hypothyroid diabetics, as they suggest-it would be preferable in many instances simply to give a supplement of ment
thvroxine. The Diabetic
Clinic, Royal Infirmary,
JOHN M. STOWERS THORIR HELGASON.
Aberdeen.
DEXAMPHETAMINE SULPHATE IN MICE
SIR,-I have read with interest the letter by Dr. Nora and his colleagues (Nov. 13). This company has examined the effects of dexamphetamine sulphate (’ Dexedrine’) on the foetus. We used doses of up to 10 mg. per kg. in New Zealand white rabbits, and failed to detect any teratogenic action of the compound. Our contrasting experience of experiments with this compound shows the need for careful prospective clinical studies of possible association between the birth of abnormal human infants and the administration of drugs. No animal test can be relied upon as being predictive of the effects of drugs on the human foetus. Until there is a more fundamental understanding of this problem, all those concerned with the human use of drugs would surely agree that they should only be prescribed with caution and for real need in women who may be pregnant. Smith Kline & French Laboratories Ltd., Welwyn Garden City, Hertfordshire.
G. E. PAGET.
ACID-BASE TERMINOLOGY
SIR,-According to your special article (Nov. 13), in the Bronsted-Lowry system an acid is defined as a proton donor and a base as a proton acceptor. No doubt there are. many excellent reasons for adopting this terminology. Nevertheless the system presents problems to those who learned their biochemistry using the previous terminology. I would like to mention a few of these problems, which are seldom clearly stated or answered in expositions designed to explain the system to those who are not specialists in biochemistry: 1. When hydrogen chloride is dissolved in water, in the ordinary usage of the term an acid (hydrochloric acid) is produced. The name applies to the solution as a whole, which, if concentrated, will burn
one’s not a
clothing and one’s skin. Now the solution as a whole is certainly proton donor. A proton is a highly charged electrical particle,
and if the solution
as a
whole could donate protons it would be carryIn fact the solution is electrically
ing a high positive electrical charge.
neutral. 2. Oxidation-reduction potential can be described in terms of electron donation and acceptance. When the ferrous ion is oxidised to the ferric ion it loses an electron. The proton is an elementary particle of positive charge and the electron is an elementary particle of negative charge. The description of acid-base balance in terms of proton donation and acceptance blurs the fundamental difference from oxidation-reduction potential. 3. A solution of sodium bicarbonate is alkaline in that it can neutralise an acid such as hydrochloric acid. Which particular ion is effective in this neutralisation ? This is the point at which most popular expositions of the Brønsted-Lowry system begin. In fact the bicarbonate ion combines with the hydrogen ion and in this sense it is the bicarbonate ion which merits the term base ": hence the Bronsted-Lowry terminology. But the bicarbonate ion by itself cannot neutralise an acid. One can bubble carbon dioxide all day through the solution of hydrochloric acid, thereby producing any number of bicarbonate ions, but the hydrochloric acid would not be neutralised. It is the solution of sodium bicarbonate as a whole which produces the conditions under which the bicarbonate ion can combine with the hydrogen ion of the hydrochloric acid. It is the solution as a whole which merits the term " alkaline " or basic ". Similarly these terms can apply to a solution of sodium hydroxide. 4. In the Bronsted-Lowry system an acid is a proton donor. Thus unionised acetic acid, the hydrogen ion itself, or other weakly dissociated cations, are deemed acids. They may share certain properties or play analogous parts in certain equilibria. To group them all together and call them all acids is to ignore differences "
"