- Email: [email protected]
IMIPRAMINE
467
foetal and maternal hearts were made at the same time, confirming the purity of the acoustical response. Having reached this point, I was satisfied that the clinical use of this method depended thereafter on the application of known principles. I should like to acknowledge the assistance of Mr. S. H. Parsonage in obtaining the recordings mentioned above, and Mr. Thomas Thirsk of Croydon, now retired, who carefully manufactured the ’Soniscopes’ and microphones used by Dr. Kinnier Wilson and Mr. MacRae, and of many others who have helped in this development. Like all similar applications, success is almost always the result of good teamwork. LIONEL FOTHERGILL. Selsey, Sussex.
tation seen in overdosage indicates excitation in the cord and brain-stem-see Dr. Gittleson’s case (Sept. 19). Dr. Zelmanowits hypothesises that imipramine and phenothiazines have a causal therapeutic effect on the physiology behind the psychopathology of depressive and schizophrenic disorders. We take the view, which we feel is implicit in Dr. Strauss’s letter, that these drugs (a) abolish symptoms until a natural remission occurs, and (b) by reduction of anxiety may facilitate and expedite a remission. Herrison Hospital, Dorchester, Dorset.
-
HOW MANY MOUTHS ? leader of Sept. 19 has suggested to
me a SIR,-Your daring speculation. We have now reached the stage when an oral inhibitor of conception, by action either on ovary or testis, is a practical possibility-in other words, birth prevention by hormone control. Should we not now aim at a further step, the discovery of a hormone modifier that would abolish libido ? Theoretically it should be something that could be added to bread like calcium, to water like fluoride; and those who for a sufficiently good reason were permitted by authority to incur the possibility of conception would be allowed for the time being a ration free from the anaphrodisiac ingredient. This would make the late George Orwell’s dream of an anti-sex league an effective reality, and while a few might think the invention more appropriate for other people than for themselves, it would be a splendid refutation of any charge of hedonism if birth-control enthusiasts were to concentrate their energies upon research along lines such as these. I have an intuition that the moral theologians would
look as much askance at this idea as at other means of artificial birth prevention, since the essence of virtue, sexual and every other, is not to be without desire but effectively to discipline it. I am, however, concerned in this context solely with science. Health Department,
Darlington.
JOSEPH V.
WALKER
Medical Officer of Health.
IMIPRAMINE
SiR,łIshould
like to endorse Dr. Strauss’s remarks the value of uncontrolled pilot studies, for in these one acquires the "feel" of a drug and perhaps some finesse in handling it. However, the public acceptability of a personal clinical conviction varies with the distinction of the author, so that most of us must have recourse to
(Sept. 19)
on
chi-squared. Nonetheless, as the drug treatment of depressive states is being discussed at the moment, there is a further conclusion we should like to add. This is that imipramine (’Tofranil’) is much more likely to prove successful in a retarded than in an agitated depression. In the latter state the agitation is often increased intolerably: this may be controlled, as Dr. Zelmanowits (Sept. 19) stated, by chlorpromazine; or it may not. A drug therapy more likely speedily to ameliorate and even abolish the symptoms of agitated depression is the combination of amylobarbitone and bemegride (’ Mylomide 100 ’) without manifest hypnotic effect. The pharmacology of this is by no means clear. In answer to Dr. Zelmanowits’s doubt of our assertion that imipramine acts centrally, we take the view that sleep and psychomotor activity are central functions, that a drug reducing the former and increasing the latter does so
by central stimulation, and that the generalised jacti-
R. H. BOARDMAN A. G. FULLERTON.
BIOCHEMICAL EFFECT OF PHENYLACETIC ACID
SiR.łThe papers by Dr. Sandler and his colleagues (Sept. 12) are of great scientific interest, but they do not prove that
phenylacetic acid inhibits 5-hydroxytryptophan decarboxylase in vivo. The investigations started with the demonstration by Davison and Sandler1 that phenylacetic acid partially inhibited 5-hydroxytryptophan decarboxylase in homogenates of guineapig kidney in vitro. The lowest concentration of the inhibitor used was 50 mol. per 3 ml., and this caused a 68% inhibition of the action of the enzyme. This concentration equals 2-25 g. phenylacetic acid per litre. The dosage of phenylacetic acid given to adult patients with the carcinoid syndrome was 5 g. by mouth. If the acid is distributed through the whole body water, this corresponds to a maximum concentration of the acid in body fluids of about 125 mg. per litre. In actual fact the true concentration will always be lower than this because phenylacetic acid is very rapidly conjugated to phenylacetylglutamine, which is quickly excreted in the urine. The rate of conjugation is so rapid that it is usually impossible to detect any free phenylacetic acid in blood or urine. Ambrose et a1.2 reported a 100% recovery of the conjugates of ingested phenylacetic acid in urine, 95% being phenylacetylglutamine and 5% glucuronide. There is no evidence that phenylacetylglutamine inhibits 5-hydroxytryptophan decarboxylase either in vitro or in vivo, although this would physiologically be more relevant than inhibition by free phenylacetic acid. Therefore, the only relevance of the in-vitro experiments of Davison and Sandler to the therapeutic trial of phenylacetic acid in the carcinoid syndrome was the suggestion that this substance should be used. The biochemical results obtained in the patients indicate that there was a temporary reduction of the urinary output of 5-hydroxyindolylacetic acid (5-H.I.A.A.) in four out of six cases, and a reduction of 5-hydroxytryptamine (5-H.T.) in one case after ingestion of phenylacetic acid. This is assumed to indicate reduced production of these compounds by decarboxylation of 5-hydroxytryptophan, whilst the possibility of a temporary reduction of their clearance in the urine is never considered. More accurate information is available of the mechanisms of excretion of 5-H.l.A.A. than of 5-H.T., and therefore only the former substance will be discussed. 5-H.I.A.A. is excreted by proximal tubular secretion3 similar to diodrast, penicillin, and many conjugates of organic acids. The clearance of all these substances is specifically reduced by probenecid. In addition, they show the phenomenon of mutual competitive inhibition of the tubular transport system, excretion of large quantities of any one substance being associated with reduced clearance of the others. It is not known whether phenylacetylglutamine is such a competitive inhibitor, but this is likely from comparison with closely allied compounds. Thus, benzoylglycine (hippuric acid) and p-aminophenylacetylglycine are excreted by proximal tubular secretionand would undoubtedly compete with 5-H.I.A.A. for excretion. 1. 2.
Davison, A. N., Sandler, M. Nature, Lond., 1958, 181, 186. Ambrose, A. M., Power, F. W., Sherwin, C. P. J. biol. Chem., 1933, 101,
3. 4.
Despopoulos, A., and Weissbach, H. Amer. J. Physiol., 1957, 189, 548. Smith, H. W., Finkelstein, N., Aliminosa, N., Crawford, B., Graber, M. J. clin. Invest. 1945, 24, 388.
669.
foetal and maternal hearts were made at the same time, confirming the purity of the acoustical response. Having reached this point, I was satisfied that the clinical use of this method depended thereafter on the application of known principles. I should like to acknowledge the assistance of Mr. S. H. Parsonage in obtaining the recordings mentioned above, and Mr. Thomas Thirsk of Croydon, now retired, who carefully manufactured the ’Soniscopes’ and microphones used by Dr. Kinnier Wilson and Mr. MacRae, and of many others who have helped in this development. Like all similar applications, success is almost always the result of good teamwork. LIONEL FOTHERGILL. Selsey, Sussex.
tation seen in overdosage indicates excitation in the cord and brain-stem-see Dr. Gittleson’s case (Sept. 19). Dr. Zelmanowits hypothesises that imipramine and phenothiazines have a causal therapeutic effect on the physiology behind the psychopathology of depressive and schizophrenic disorders. We take the view, which we feel is implicit in Dr. Strauss’s letter, that these drugs (a) abolish symptoms until a natural remission occurs, and (b) by reduction of anxiety may facilitate and expedite a remission. Herrison Hospital, Dorchester, Dorset.
-
HOW MANY MOUTHS ? leader of Sept. 19 has suggested to
me a SIR,-Your daring speculation. We have now reached the stage when an oral inhibitor of conception, by action either on ovary or testis, is a practical possibility-in other words, birth prevention by hormone control. Should we not now aim at a further step, the discovery of a hormone modifier that would abolish libido ? Theoretically it should be something that could be added to bread like calcium, to water like fluoride; and those who for a sufficiently good reason were permitted by authority to incur the possibility of conception would be allowed for the time being a ration free from the anaphrodisiac ingredient. This would make the late George Orwell’s dream of an anti-sex league an effective reality, and while a few might think the invention more appropriate for other people than for themselves, it would be a splendid refutation of any charge of hedonism if birth-control enthusiasts were to concentrate their energies upon research along lines such as these. I have an intuition that the moral theologians would
look as much askance at this idea as at other means of artificial birth prevention, since the essence of virtue, sexual and every other, is not to be without desire but effectively to discipline it. I am, however, concerned in this context solely with science. Health Department,
Darlington.
JOSEPH V.
WALKER
Medical Officer of Health.
IMIPRAMINE
SiR,łIshould
like to endorse Dr. Strauss’s remarks the value of uncontrolled pilot studies, for in these one acquires the "feel" of a drug and perhaps some finesse in handling it. However, the public acceptability of a personal clinical conviction varies with the distinction of the author, so that most of us must have recourse to
(Sept. 19)
on
chi-squared. Nonetheless, as the drug treatment of depressive states is being discussed at the moment, there is a further conclusion we should like to add. This is that imipramine (’Tofranil’) is much more likely to prove successful in a retarded than in an agitated depression. In the latter state the agitation is often increased intolerably: this may be controlled, as Dr. Zelmanowits (Sept. 19) stated, by chlorpromazine; or it may not. A drug therapy more likely speedily to ameliorate and even abolish the symptoms of agitated depression is the combination of amylobarbitone and bemegride (’ Mylomide 100 ’) without manifest hypnotic effect. The pharmacology of this is by no means clear. In answer to Dr. Zelmanowits’s doubt of our assertion that imipramine acts centrally, we take the view that sleep and psychomotor activity are central functions, that a drug reducing the former and increasing the latter does so
by central stimulation, and that the generalised jacti-
R. H. BOARDMAN A. G. FULLERTON.
BIOCHEMICAL EFFECT OF PHENYLACETIC ACID
SiR.łThe papers by Dr. Sandler and his colleagues (Sept. 12) are of great scientific interest, but they do not prove that
phenylacetic acid inhibits 5-hydroxytryptophan decarboxylase in vivo. The investigations started with the demonstration by Davison and Sandler1 that phenylacetic acid partially inhibited 5-hydroxytryptophan decarboxylase in homogenates of guineapig kidney in vitro. The lowest concentration of the inhibitor used was 50 mol. per 3 ml., and this caused a 68% inhibition of the action of the enzyme. This concentration equals 2-25 g. phenylacetic acid per litre. The dosage of phenylacetic acid given to adult patients with the carcinoid syndrome was 5 g. by mouth. If the acid is distributed through the whole body water, this corresponds to a maximum concentration of the acid in body fluids of about 125 mg. per litre. In actual fact the true concentration will always be lower than this because phenylacetic acid is very rapidly conjugated to phenylacetylglutamine, which is quickly excreted in the urine. The rate of conjugation is so rapid that it is usually impossible to detect any free phenylacetic acid in blood or urine. Ambrose et a1.2 reported a 100% recovery of the conjugates of ingested phenylacetic acid in urine, 95% being phenylacetylglutamine and 5% glucuronide. There is no evidence that phenylacetylglutamine inhibits 5-hydroxytryptophan decarboxylase either in vitro or in vivo, although this would physiologically be more relevant than inhibition by free phenylacetic acid. Therefore, the only relevance of the in-vitro experiments of Davison and Sandler to the therapeutic trial of phenylacetic acid in the carcinoid syndrome was the suggestion that this substance should be used. The biochemical results obtained in the patients indicate that there was a temporary reduction of the urinary output of 5-hydroxyindolylacetic acid (5-H.I.A.A.) in four out of six cases, and a reduction of 5-hydroxytryptamine (5-H.T.) in one case after ingestion of phenylacetic acid. This is assumed to indicate reduced production of these compounds by decarboxylation of 5-hydroxytryptophan, whilst the possibility of a temporary reduction of their clearance in the urine is never considered. More accurate information is available of the mechanisms of excretion of 5-H.l.A.A. than of 5-H.T., and therefore only the former substance will be discussed. 5-H.I.A.A. is excreted by proximal tubular secretion3 similar to diodrast, penicillin, and many conjugates of organic acids. The clearance of all these substances is specifically reduced by probenecid. In addition, they show the phenomenon of mutual competitive inhibition of the tubular transport system, excretion of large quantities of any one substance being associated with reduced clearance of the others. It is not known whether phenylacetylglutamine is such a competitive inhibitor, but this is likely from comparison with closely allied compounds. Thus, benzoylglycine (hippuric acid) and p-aminophenylacetylglycine are excreted by proximal tubular secretionand would undoubtedly compete with 5-H.I.A.A. for excretion. 1. 2.
Davison, A. N., Sandler, M. Nature, Lond., 1958, 181, 186. Ambrose, A. M., Power, F. W., Sherwin, C. P. J. biol. Chem., 1933, 101,
3. 4.
Despopoulos, A., and Weissbach, H. Amer. J. Physiol., 1957, 189, 548. Smith, H. W., Finkelstein, N., Aliminosa, N., Crawford, B., Graber, M. J. clin. Invest. 1945, 24, 388.
669.