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ESSENTIAL FATTY ACIDS, LIPID METABOLISM AND ATHEROSCLEROSIS
742
Rest in bed played no part in the production of these invisible thromboses, which had such serious effects, nor did other factors that have been claimed to operate, such as sitting in cramped positions in cars or aircraft. No instance of malignant disease appeared either in necropsy or follow-up. To describe such thromboses as spontaneous is to beg the question of their origin: to explain them might throw light on the even more serious problem of postoperative emboli. "
"
St. Helier Hospital, Carshalton, Surrey.
C. P. FETCH.
about 65 mg. per 100 ml. higher than at the end of two weeks when the formula contained 80 g. of ethyl linoleate. In the second, a diabetic patient on a similar formula diet had a serum-cholesterol of 270 mg. per 100 ml. at the end of a week when the daily diet contained 75 g. of trilinolein, 235 mg. at the end of two weeks in which the diet contained 75 g. of triolein instead of the trilinolein, and 297 mg. at the end of three weeks when 75 g. of ethyl oleate was substituted. was
We
regret that these observations scarcely qualify as confirmation of our own findings and interpretation, they are not in opposition.
acceptable though
to the point are two new sets of data from our controlled dietary experiments which will be reported in full in due course but may be mentioned here.
More
own
ESSENTIAL FATTY ACIDS, LIPID METABOLISM AND ATHEROSCLEROSIS SIR,-In your issue of Feb. 15 Dr. Kinsell and his
colleagues discuss the serum-cholesterol-lowering effect of certain fatty acids and make the surprising statement (p. 338) that we (Keys et al.) and Ahrens et al.12 " have advanced the hypothesis that double bonds furnished by fatty acids are responsible for the effects observed-i.e., sufficient oleate would be quite as effective as linoleate or arachidonate. Our studies do not support such a hypothesis." of fact, this question of effect or lack of serum-cholesterol of dietary oleic acid has been a matter of friendly but rather vigorous controversy between Ahrens et al. and ourselves for the past year, notably at major symposia organised by the American Medical Association Council on Foods and Nutrition (New Orleans, March 15, 1957) and by the American College of Physicians (Boston, April 10, 1957), and at the Cleveland Symposium on the Chemistry of Lipides
As effect
a matter on
(May 7, 8, 1957). Shortly before the article by Kinsell et al. appeared, the Cleveland Symposium was published2 and in this Ahrens et al. discuss our publications and views at some length and state that we (Keys et al.) conclude further that the monoethenoid acids (almost entirely oleic acid) are neutral or totally lacking in effect, since a term describing the content of oleic acid in the dietary fat need not appear in the prediction "
equations." We have summarised 3 our analysis of the results in 41 sets of controlled dietary comparisons, each involving 12 to 27 men on each of two diets differing in fats, which yielded the prediction equation for the response of serum-cholesterol a dietary change in fats:
concentration to
2i Chol.=2-73(As)+0-01(AM)-l-31(AP)
where s, M, and P are the percentages of the total diet calories provided from saturated, mono-ethenoid, and poly-ethenoid fatty acids, respectively, and the As are the differences between the two diets being compared. We noted that " The contribution of the term for AM is statistically non-significant and recomputation with this term omitted yielded the equation:
A Chol.=2-74(As)Ń 1-31(AP)." Further, we stated, " Whether the mono-ethenoids (essentially oleic acid) have any effect is uncertain, but if there is an effect it is certainly small." Full details of the diets, methods, findings, and statistical analyses in these experiments covering the period 1951-56 have been published.4 5 Kinsell et al., besides misquoting us, report two instances in which they compared the effects on serum-cholesterol of oleic acid and linoleic acid in the diet.
first, in a boy aged 19, at the end of three weeks on a formula containing 80 g. of ethyl oleate daily the serum-cholesterol level
In the
diet
Ahrens, E. H., Jr., Hirsch, J., Insull, W., Jr., Tsaltas, T. T., Blomstrand, R., Peterson, M. L. Lancet, 1957, i, 943. 2. Ahrens, E. H., Jr., Hirsch, J., Insull, W., Jr., Peterson, M. L. in Chemistry of Lipides as related to Atherosclerosis (edited by I. H. Page); p. 222. Springfield, Ill., 1958. 3. Keys, A., Anderson, J. T., Grande, F. Lancet, 1957, i, 787. 4. Anderson, J. T., Keys, A., Grande, F. J. Nutr. 1957, 62, 421. 5. Keys, A., Anderson, J. T., Grande, F. Lancet, 1957, ii, 959. 1.
First, a switchback dietary experiment on 22 men, rigorously controlled for six weeks, conclusively showed no effect on serum-cholesterol from substitution of 68 g. of oleic acid glyceride daily for 612 calories of carbohydrate or from the reverse substitution.11 Second, we now have 12 additional sets of dietary comparisons, each involving 5 to 25 men on each of two diets differing only in the kind of fat or in the isocaloric exchange of fat for carbohydrate in the diet. Least-squares multiple regression analysis of the data in the same manner as reported previously 45 produced coefficients in a prediction equation statistically indistinguishable from those found in the earlier 41 sets of experimental comparisons, and again the monoethenoid (oleic acid) variable makes no statistical contribution
(i.e.,
zero
effect).
The conclusion is, as before, that saturated fats raise the serum-cholesterol level when isocalorically substituted for carbohydrate, that polyunsaturated fatty acids lower it, and that about 2 g. of linoleic acid is needed to offset the effect of 1 g. of stearic or palmitic acid. Finally, and again as before, we conclude that oleic acid has no significant effect in either direction; oleic acid glyceride is substantially equivalent to simple carbohydrate in effect on serum-cholesterol. We have noted that oleic acid accounts for practically all of the mono-ethenoid fatty acid in the great majority of natural food fats and oils. Rape-seed oil, which contains up to half of its fatty acids in the form of the mono-ethenoid erucic acid (a 22-carbon mono-ethenoid, docos-13-enoic) is an exception. We have no experience with rape-seed oil, but the data in the recent report by Linko though inadequate for exact com" putation, suggest that erucic acid, like oleic, is neutral " in respect to effect on the serum-cholesterol level in man. Ahrens et awl. admit that their data are in conformity with computations from our prediction equation (published before their data appeared), but object that, " Keys’ prediction could have been expressed just as accurately, and less mysteriously, in terms of iodine value of dietary fat." This is just as palpably erroneous as the misquotation of Kinsell et al. The iodine value is, of course, merely a measure of the number of double bonds in 100 g. of fat, whereas our equation ignores the double bonds in mono-ethenoid fatty acids and, in any case, refers to the amount of fat calories as a percentage of calories from all sources in the diet. Ahrens et al. may have been misled by the fact that in their experiments, in contrast with our own, they usually deal with the same amount of total fat and vary only the kind of fat. In that situation there is often a rough relationship between the iodine value and the expression 2s-p, which is an approximation to the right-hand term in our equation given above. But even when the total fat is constant the iodine value does not correspond precisely with our formulation. Consider a 3000-calorie diet in which there is a total of 133 g. of fatty-acid glycerides, half being saturated and half being linoleic acid. Let us now change the diet only by-replacing these fatty acids with 133 g. of oleic-acid glyceride (i.e., triolein). Note that fats yield 6. 7.
Keys, A., Anderson, J. T., Grande, F. (in the press). Linko, E. Acta med. scand. 1957, 159,
Proc. Soc. 474.
Exp. Biol., N.Y. 1958
743 1200 calories of the total 3000, or 40%, in both diets, and, in our terms, we have values of s==20 and p 20 with the first diet and S=0, p=O with the second. The iodine value will be identical in the two cases (=86) and, according to Ahrens et al., there will be no change in serum-cholesterol. But the equation based on our experimental results predicts a serum-cholesterol change:
A Chol.-2-74(0-20) 1’31(0-20) = - 29, average, the serum-cholesterol concentration will fall by 29 mg. per 100 ml. on the second diet. Finally, we may consider a third diet which differs from the first only in that the total fat is only 67 g. (20% of total calories). The
i.e., on the
iodine value is still 86 in both diets. Ahrens
et al. apparently predict change, or at least they provide no clue as to what may happen. But our equation predicts: A Chol.=274(10-20)---131(10-20)= -14, i.e., changing from the first to the third diet will, on the average, no
produce
a
fall of 14 mg. per 100 ml.
In view of the fact that the great current interest on these points seems to be matched by an equal degree of confusion in many quarters, we should point out that the prediction equation refers to the average changes in serum-cholesterol to be expected in men without a high serum-cholesterol within two to four weeks after a dietary change. Larger responses may be expected in hypercholosterolxmia and also, perhaps, with dietary differences maintained for very long periods of time. And, of course, there is no place here for speculations about " essential-
fatty-acid deficiency." Laboratory of Phsyiological Hygiene, University of Minnesota, Minneapolis.
ANCEL KEYS ANDERSON FRANCISCO GRANDE.
JOSEPH T.
REDUCTION OF CIRCULATING LIPIDS SIR,-With reference to the article by Dr. Oliver and Dr. Boydyour readers may be interested to hear of our
results in a similar butyric acid amide.*
therapeutic trial with 2-phenyl-n-
Of 15 men with considerable hypercholesterolaemia, 12 had had a myocardial infarction between six weeks and a year previously, but had no signs at present of cardiac failure or of angina: 1 had essential hypertension, another had essential hypercholesterolxmia without clinical manifestations, and 1 had hypercholesterolaemia with xanthoma tuberosum on the fingers and elbows. The ages of the patients varied from 36 to 63
(average 50-6). dosage of 2-phenyl-n-butyric acid amide was 1 g. every eight hours. All patients were carrying on their usual occupations; no special diet was given, but they were asked to be careful not to put on weight. 1 patient received the treatment for four weeks, 3 for two months, and the others for from three to five months. In 10 of the 15 patients, plasma-cholesterol level was reduced by 20 mg. or more per 100 ml. The initial mean total plasma-cholesterol in the 10 patients who reacted favourably was 346 mg. per 100 ml.; this dropped to 310 mg. after giving the drug. The mean initial absolute level of P-cholesterol was 310 mg. per 100 ml., dropping to 258 mg. after treatment (the B-cholesterol level was determined by analytical chemical methods after elution of the fraction from The
the paper after electrophoresis). The average total plasma-cholesterol among healthy men of European Jewish origin in Israel in the age-group 40-60 is 220 mg. per 100 ml., and of 3-cholesterol 180 mg. ; taking these levels as 100%, our results for the 10 patients were a drop in total cholesterol from 157% to 131% and a drop in P-cholesterol from 162% to 143%. The effect of 2-phenyl-n-butyric acid amide seems to be greater in patients with a high initial level of plasma cholesterol ; 4 of the 5 patients who did not react to the treatment (and only 1 of the 10 who did) had an initial plasma-cholesterol less than 300 mg. per 100 ml. *Marketed as ’Nivonorm’ by Teva, Jerusalem. Oliver, M. F., Boyd, G. S. Lancet, 1957, ii, 829. Brunner, D., Loebl, W., Schindel, L. E. (in the press).
1. 2.
Like Dr. Oliver and Dr. Boyd, we found hardly any change in the ratio between oc and P cholesterol, even where there was a significant fall in total cholesterol. We have noted this in other therapeutic trials for lowering the lipid levels, and it seems that the ratio of (x to cholesterol is one of the most stable factors of the lipid patterns. In none of the 15 patients did the lipid levels rise. We infer that 2-phenyl-n-butyric acid amide has a genuine, though not great, cholesterol-depressing effect. Our results are not so favourable as those of the French and Italian clinical workers,3-6 but we believe that n-phenyln-butyric acid amide does have some effect, especially when the Dlasma-cholesterol is verv high. DANIEL BRUNNER K. LOEBL. L. E. SCHINDEL. CORONARY-ARTERY DISEASE SiR,łIn your leading article of March 22 you quote the statement that " in the healthy organism fibrinolysis is in a dynamic equilibrium with the fibrin-depositing
coagulation process ", the implication being that so much has been established. This is rather misleading, since what is quoted is an intelligent speculation first put forward to my knowledge by Nolf in 1908, and adopted as a working hypothesis by many workers, including Astrup. However attractive the concept may seem it should be made clear that it is unsupported by direct evidence. It will be a pity if the observations of various workers on fibrinolysis in vitro, including the effect of fat, be pressed into speculative dynamic hypotheses, subsequently to be quoted as if proven. Such a tendency is likely to retard and not to advance knowledge. G. R. FEARNLEY. RECTAL METHYLPENTYNOL IN LABOUR
SIR,-The place of methylpentynol in labour is now well recognised, but rectal administration receives no mention. This route has been found effective in over 5000 women admitted to the Birmingham Maternity Hospital in the past three years. This method was first tried when it was noted that the who most often vomited the oral capsule was the nervous primigravida-the patient whose apprehension it was hoped to relieve, not increase. Bournereported that 8% of patients vomit the capsule, but a second dose is usually retained. By use of the rectal route, increase of nervous tension from this vomiting can be avoided without loss of the drug’s
patient
efficiency. Methylpentynol is given half an hour after an enema to a patient in early established labour. The usual dose is 750 mg. (i.e., 3 capsules), inserted with the finger as far. as possible beyond the anal margin. Occasionally in a very nervous primigravida 1 g. of methylpentynol is given; and, again uncommonly, the dose may be repeated in not less than three hours. When the patient’s anxiety is associated with painful contractions it is our practice to give 100 mg. of pethidine hydrochloride intramuscularly with the initial dose, for methylpentynol does not relieve pain. The drug is as efficient when given rectally as it is by mouth. The clinical impression is that labour is shortened and the incidence of postpartum haemorrhage is not increased. 3.
4. 5. 6. 7.
Cottet, J., Vignalou, J., Redel, J., Colas-Belcour. Bull. méd. hôp. Paris. 1953, 69, 903. Mathivat, A., Cottet, J. ibid. p. 1030. Cottet, J., Mathivat, A., Redel, J. Pr. méd. 1954, 62, 939. Rossi, B., Rulli, V. Amer. Heart J. 1957, 53, 277. Bourne, G. Lancet, 1954, ii, 522.
mem.
Soc.
Rest in bed played no part in the production of these invisible thromboses, which had such serious effects, nor did other factors that have been claimed to operate, such as sitting in cramped positions in cars or aircraft. No instance of malignant disease appeared either in necropsy or follow-up. To describe such thromboses as spontaneous is to beg the question of their origin: to explain them might throw light on the even more serious problem of postoperative emboli. "
"
St. Helier Hospital, Carshalton, Surrey.
C. P. FETCH.
about 65 mg. per 100 ml. higher than at the end of two weeks when the formula contained 80 g. of ethyl linoleate. In the second, a diabetic patient on a similar formula diet had a serum-cholesterol of 270 mg. per 100 ml. at the end of a week when the daily diet contained 75 g. of trilinolein, 235 mg. at the end of two weeks in which the diet contained 75 g. of triolein instead of the trilinolein, and 297 mg. at the end of three weeks when 75 g. of ethyl oleate was substituted. was
We
regret that these observations scarcely qualify as confirmation of our own findings and interpretation, they are not in opposition.
acceptable though
to the point are two new sets of data from our controlled dietary experiments which will be reported in full in due course but may be mentioned here.
More
own
ESSENTIAL FATTY ACIDS, LIPID METABOLISM AND ATHEROSCLEROSIS SIR,-In your issue of Feb. 15 Dr. Kinsell and his
colleagues discuss the serum-cholesterol-lowering effect of certain fatty acids and make the surprising statement (p. 338) that we (Keys et al.) and Ahrens et al.12 " have advanced the hypothesis that double bonds furnished by fatty acids are responsible for the effects observed-i.e., sufficient oleate would be quite as effective as linoleate or arachidonate. Our studies do not support such a hypothesis." of fact, this question of effect or lack of serum-cholesterol of dietary oleic acid has been a matter of friendly but rather vigorous controversy between Ahrens et al. and ourselves for the past year, notably at major symposia organised by the American Medical Association Council on Foods and Nutrition (New Orleans, March 15, 1957) and by the American College of Physicians (Boston, April 10, 1957), and at the Cleveland Symposium on the Chemistry of Lipides
As effect
a matter on
(May 7, 8, 1957). Shortly before the article by Kinsell et al. appeared, the Cleveland Symposium was published2 and in this Ahrens et al. discuss our publications and views at some length and state that we (Keys et al.) conclude further that the monoethenoid acids (almost entirely oleic acid) are neutral or totally lacking in effect, since a term describing the content of oleic acid in the dietary fat need not appear in the prediction "
equations." We have summarised 3 our analysis of the results in 41 sets of controlled dietary comparisons, each involving 12 to 27 men on each of two diets differing in fats, which yielded the prediction equation for the response of serum-cholesterol a dietary change in fats:
concentration to
2i Chol.=2-73(As)+0-01(AM)-l-31(AP)
where s, M, and P are the percentages of the total diet calories provided from saturated, mono-ethenoid, and poly-ethenoid fatty acids, respectively, and the As are the differences between the two diets being compared. We noted that " The contribution of the term for AM is statistically non-significant and recomputation with this term omitted yielded the equation:
A Chol.=2-74(As)Ń 1-31(AP)." Further, we stated, " Whether the mono-ethenoids (essentially oleic acid) have any effect is uncertain, but if there is an effect it is certainly small." Full details of the diets, methods, findings, and statistical analyses in these experiments covering the period 1951-56 have been published.4 5 Kinsell et al., besides misquoting us, report two instances in which they compared the effects on serum-cholesterol of oleic acid and linoleic acid in the diet.
first, in a boy aged 19, at the end of three weeks on a formula containing 80 g. of ethyl oleate daily the serum-cholesterol level
In the
diet
Ahrens, E. H., Jr., Hirsch, J., Insull, W., Jr., Tsaltas, T. T., Blomstrand, R., Peterson, M. L. Lancet, 1957, i, 943. 2. Ahrens, E. H., Jr., Hirsch, J., Insull, W., Jr., Peterson, M. L. in Chemistry of Lipides as related to Atherosclerosis (edited by I. H. Page); p. 222. Springfield, Ill., 1958. 3. Keys, A., Anderson, J. T., Grande, F. Lancet, 1957, i, 787. 4. Anderson, J. T., Keys, A., Grande, F. J. Nutr. 1957, 62, 421. 5. Keys, A., Anderson, J. T., Grande, F. Lancet, 1957, ii, 959. 1.
First, a switchback dietary experiment on 22 men, rigorously controlled for six weeks, conclusively showed no effect on serum-cholesterol from substitution of 68 g. of oleic acid glyceride daily for 612 calories of carbohydrate or from the reverse substitution.11 Second, we now have 12 additional sets of dietary comparisons, each involving 5 to 25 men on each of two diets differing only in the kind of fat or in the isocaloric exchange of fat for carbohydrate in the diet. Least-squares multiple regression analysis of the data in the same manner as reported previously 45 produced coefficients in a prediction equation statistically indistinguishable from those found in the earlier 41 sets of experimental comparisons, and again the monoethenoid (oleic acid) variable makes no statistical contribution
(i.e.,
zero
effect).
The conclusion is, as before, that saturated fats raise the serum-cholesterol level when isocalorically substituted for carbohydrate, that polyunsaturated fatty acids lower it, and that about 2 g. of linoleic acid is needed to offset the effect of 1 g. of stearic or palmitic acid. Finally, and again as before, we conclude that oleic acid has no significant effect in either direction; oleic acid glyceride is substantially equivalent to simple carbohydrate in effect on serum-cholesterol. We have noted that oleic acid accounts for practically all of the mono-ethenoid fatty acid in the great majority of natural food fats and oils. Rape-seed oil, which contains up to half of its fatty acids in the form of the mono-ethenoid erucic acid (a 22-carbon mono-ethenoid, docos-13-enoic) is an exception. We have no experience with rape-seed oil, but the data in the recent report by Linko though inadequate for exact com" putation, suggest that erucic acid, like oleic, is neutral " in respect to effect on the serum-cholesterol level in man. Ahrens et awl. admit that their data are in conformity with computations from our prediction equation (published before their data appeared), but object that, " Keys’ prediction could have been expressed just as accurately, and less mysteriously, in terms of iodine value of dietary fat." This is just as palpably erroneous as the misquotation of Kinsell et al. The iodine value is, of course, merely a measure of the number of double bonds in 100 g. of fat, whereas our equation ignores the double bonds in mono-ethenoid fatty acids and, in any case, refers to the amount of fat calories as a percentage of calories from all sources in the diet. Ahrens et al. may have been misled by the fact that in their experiments, in contrast with our own, they usually deal with the same amount of total fat and vary only the kind of fat. In that situation there is often a rough relationship between the iodine value and the expression 2s-p, which is an approximation to the right-hand term in our equation given above. But even when the total fat is constant the iodine value does not correspond precisely with our formulation. Consider a 3000-calorie diet in which there is a total of 133 g. of fatty-acid glycerides, half being saturated and half being linoleic acid. Let us now change the diet only by-replacing these fatty acids with 133 g. of oleic-acid glyceride (i.e., triolein). Note that fats yield 6. 7.
Keys, A., Anderson, J. T., Grande, F. (in the press). Linko, E. Acta med. scand. 1957, 159,
Proc. Soc. 474.
Exp. Biol., N.Y. 1958
743 1200 calories of the total 3000, or 40%, in both diets, and, in our terms, we have values of s==20 and p 20 with the first diet and S=0, p=O with the second. The iodine value will be identical in the two cases (=86) and, according to Ahrens et al., there will be no change in serum-cholesterol. But the equation based on our experimental results predicts a serum-cholesterol change:
A Chol.-2-74(0-20) 1’31(0-20) = - 29, average, the serum-cholesterol concentration will fall by 29 mg. per 100 ml. on the second diet. Finally, we may consider a third diet which differs from the first only in that the total fat is only 67 g. (20% of total calories). The
i.e., on the
iodine value is still 86 in both diets. Ahrens
et al. apparently predict change, or at least they provide no clue as to what may happen. But our equation predicts: A Chol.=274(10-20)---131(10-20)= -14, i.e., changing from the first to the third diet will, on the average, no
produce
a
fall of 14 mg. per 100 ml.
In view of the fact that the great current interest on these points seems to be matched by an equal degree of confusion in many quarters, we should point out that the prediction equation refers to the average changes in serum-cholesterol to be expected in men without a high serum-cholesterol within two to four weeks after a dietary change. Larger responses may be expected in hypercholosterolxmia and also, perhaps, with dietary differences maintained for very long periods of time. And, of course, there is no place here for speculations about " essential-
fatty-acid deficiency." Laboratory of Phsyiological Hygiene, University of Minnesota, Minneapolis.
ANCEL KEYS ANDERSON FRANCISCO GRANDE.
JOSEPH T.
REDUCTION OF CIRCULATING LIPIDS SIR,-With reference to the article by Dr. Oliver and Dr. Boydyour readers may be interested to hear of our
results in a similar butyric acid amide.*
therapeutic trial with 2-phenyl-n-
Of 15 men with considerable hypercholesterolaemia, 12 had had a myocardial infarction between six weeks and a year previously, but had no signs at present of cardiac failure or of angina: 1 had essential hypertension, another had essential hypercholesterolxmia without clinical manifestations, and 1 had hypercholesterolaemia with xanthoma tuberosum on the fingers and elbows. The ages of the patients varied from 36 to 63
(average 50-6). dosage of 2-phenyl-n-butyric acid amide was 1 g. every eight hours. All patients were carrying on their usual occupations; no special diet was given, but they were asked to be careful not to put on weight. 1 patient received the treatment for four weeks, 3 for two months, and the others for from three to five months. In 10 of the 15 patients, plasma-cholesterol level was reduced by 20 mg. or more per 100 ml. The initial mean total plasma-cholesterol in the 10 patients who reacted favourably was 346 mg. per 100 ml.; this dropped to 310 mg. after giving the drug. The mean initial absolute level of P-cholesterol was 310 mg. per 100 ml., dropping to 258 mg. after treatment (the B-cholesterol level was determined by analytical chemical methods after elution of the fraction from The
the paper after electrophoresis). The average total plasma-cholesterol among healthy men of European Jewish origin in Israel in the age-group 40-60 is 220 mg. per 100 ml., and of 3-cholesterol 180 mg. ; taking these levels as 100%, our results for the 10 patients were a drop in total cholesterol from 157% to 131% and a drop in P-cholesterol from 162% to 143%. The effect of 2-phenyl-n-butyric acid amide seems to be greater in patients with a high initial level of plasma cholesterol ; 4 of the 5 patients who did not react to the treatment (and only 1 of the 10 who did) had an initial plasma-cholesterol less than 300 mg. per 100 ml. *Marketed as ’Nivonorm’ by Teva, Jerusalem. Oliver, M. F., Boyd, G. S. Lancet, 1957, ii, 829. Brunner, D., Loebl, W., Schindel, L. E. (in the press).
1. 2.
Like Dr. Oliver and Dr. Boyd, we found hardly any change in the ratio between oc and P cholesterol, even where there was a significant fall in total cholesterol. We have noted this in other therapeutic trials for lowering the lipid levels, and it seems that the ratio of (x to cholesterol is one of the most stable factors of the lipid patterns. In none of the 15 patients did the lipid levels rise. We infer that 2-phenyl-n-butyric acid amide has a genuine, though not great, cholesterol-depressing effect. Our results are not so favourable as those of the French and Italian clinical workers,3-6 but we believe that n-phenyln-butyric acid amide does have some effect, especially when the Dlasma-cholesterol is verv high. DANIEL BRUNNER K. LOEBL. L. E. SCHINDEL. CORONARY-ARTERY DISEASE SiR,łIn your leading article of March 22 you quote the statement that " in the healthy organism fibrinolysis is in a dynamic equilibrium with the fibrin-depositing
coagulation process ", the implication being that so much has been established. This is rather misleading, since what is quoted is an intelligent speculation first put forward to my knowledge by Nolf in 1908, and adopted as a working hypothesis by many workers, including Astrup. However attractive the concept may seem it should be made clear that it is unsupported by direct evidence. It will be a pity if the observations of various workers on fibrinolysis in vitro, including the effect of fat, be pressed into speculative dynamic hypotheses, subsequently to be quoted as if proven. Such a tendency is likely to retard and not to advance knowledge. G. R. FEARNLEY. RECTAL METHYLPENTYNOL IN LABOUR
SIR,-The place of methylpentynol in labour is now well recognised, but rectal administration receives no mention. This route has been found effective in over 5000 women admitted to the Birmingham Maternity Hospital in the past three years. This method was first tried when it was noted that the who most often vomited the oral capsule was the nervous primigravida-the patient whose apprehension it was hoped to relieve, not increase. Bournereported that 8% of patients vomit the capsule, but a second dose is usually retained. By use of the rectal route, increase of nervous tension from this vomiting can be avoided without loss of the drug’s
patient
efficiency. Methylpentynol is given half an hour after an enema to a patient in early established labour. The usual dose is 750 mg. (i.e., 3 capsules), inserted with the finger as far. as possible beyond the anal margin. Occasionally in a very nervous primigravida 1 g. of methylpentynol is given; and, again uncommonly, the dose may be repeated in not less than three hours. When the patient’s anxiety is associated with painful contractions it is our practice to give 100 mg. of pethidine hydrochloride intramuscularly with the initial dose, for methylpentynol does not relieve pain. The drug is as efficient when given rectally as it is by mouth. The clinical impression is that labour is shortened and the incidence of postpartum haemorrhage is not increased. 3.
4. 5. 6. 7.
Cottet, J., Vignalou, J., Redel, J., Colas-Belcour. Bull. méd. hôp. Paris. 1953, 69, 903. Mathivat, A., Cottet, J. ibid. p. 1030. Cottet, J., Mathivat, A., Redel, J. Pr. méd. 1954, 62, 939. Rossi, B., Rulli, V. Amer. Heart J. 1957, 53, 277. Bourne, G. Lancet, 1954, ii, 522.
mem.
Soc.