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TESTING NEW DRUGS
1168
the fact that it is usually possible to calculate approximately the amount of infusion fluid required to correct given abnormalities. There is much need in clinical practice to think in quantitative terms. Until recently the basic parameters on which such calculations could be based were not readily obtainable for treatment of acidosis or alkalosis; this is no longer so since it is now easy, with appropriate apparatus, to obtain repeated measurements of blood pH and Pco2 as well as the base excess or deficit, by capillary puncture. University Departments of D. CAMPBELL Anaesthetics, and Biochemistry, J. C. EATON Pathological Biochemistry, A. C. FORRESTER. Royal Infirmary, Glasgow. TESTING NEW DRUGS
Sirdo not subscribe to the extravagant claims made statisticians for the use of statistics in scientific research, but it is disturbing to find (from p. 1048 of your issue of Nov. 17) that the joint subcommittee of the Standing Medical Advisory Committees for England and Wales and Scotland set up to advise the Health Minister on what " measures are needed to secure adequate pharmacological and safety testing and clinical trials of new drugs before their release for general use ", and to " secure early detection of adverse effects arising after their release for general use ", does not have a statistician as a member. Research reveals at least one bacteriologist, pharmaco-
by
some
logist, pharmacist, biochemist, general practitioner, professor of medicine, but apparently not a statistician. Some of the most interesting discoveries in the pharmacological field have been made with teams with at least one trained statistician, and few clinicians, I suspect, would be altogether happy in organising a drug trial without expert statistical advice. Keeping a tame statistician in the back room is a very unsatisfactory substitute for competent advice within the committee. If it should be suggested, however, that statisticians have become social outcasts as a just reward for their claims to possess the alchemist’s stone, alas I could not but agree. Faculty of Economic and Social Studies, University of Manchester.
WALLIS TAYLOR.
ON TESTING THE SENSE OF SMELL
SIR,-Iread with interest the contribution by Dr. Sumner (Nov. 3). There are several points which I think deserve mention. Some substances such as benzaldehyde and camphor excite as well as olfactory afferents in the nasal passages and should be avoided2 if one desires to test " pure " olfaction. This potential source of error in interpretation of test results will be avoided, however, if one insists on identification of the testing substance. Dr. Sumner thinks that accurate identification of substances is more satisfactory than mere recognition of the presence or absence of any odour. Proper identification of odours depends upon the processes of association, memory, and past experiences3 and may be adversely affected by diminished intelligence or dementia. Interestingly enough, however, Elsberg 4 found the lack of the ability to name familiar odours more often in those of a high degree of intelligence (learned professions) than in those with little education such as labourers. Perhaps patients unable to identify familiar odours should more
trigeminal afferents
properly
be
designated
as
having " olfactory agnosia " rather
than a primary disturbance of olfaction. The distinction between amaurosis and visual agnosia seems analogous. 1. 2. 3. 4.
Elsberg, C. A., Levy, I., Brewer, E. D. Bull. neurol. Inst. N.Y. 1935, 4, 270. Merritt, H. H., Mettler, F. A., Putnam, T. J. Fundamentals of Clinical Neurology. Philadelphia, 1952. Elsberg, C. A., Levy, I. Bull. neurol. Inst. N.Y. 1935, 4, 5. Elsberg, C. A. ibid. p. 496.
Finally, I would agree that failure to identify at least one of Dr. Sumner’s four " best odours " may indicate " that something is amiss " but not necessarily that the primary sense of olfaction is lost. Neurology Service,
William Beaumont Hospital, El Paso, Texas, U.S.A.
HARRY H. WHITE.
BLOOD-PRESSURE AMONG THE PADAUNG TRIBE
SiR,—The article by Dr. Bhattacharjee (Nov. 17) is of interest. Despite his protestations to the contrary,
some
he has demonstrated that the mean blood-pressure of 35-year-old Padaung women is higher than what we are used to seeing. Could it not be that here is an example of natural selection ? Mild hypertension in young women may be a tribal characteristic which has been selected over the generations, and now appears in these women whether they wear rings or not. Apparently those who wore the rings were more likely to be wed; mild hypertension may have enabled more rings to be worn with comfort, thus selecting those with a constitutional predisposition to hypertension to be more likely to reproduce. MARVIN E.
JAFFE.
ROLE OF CHLORIDE IN CORRECTION OF ALKALOSIS ASSOCIATED WITH POTASSIUM DEPLETION
SIR,-Dr. Aber and his colleagues (Nov. 17, p. 1028) attribute the failure of potassium glutamate to lower the blood pH of potassium-depleted patients to a lack of chloride. They do not, however, discuss the fate of the glutamate. Each glutamate ion when metabolised must liberate a hydroxyl ion, and since this has a strong affinity for hydrogen ion (i.e., water is a weak acid), there will be a corresponding loss of hydrogen ion in the body. Chloride ion, on the other hand, has little affinity for hydrogen ion (i.e., hydrochloric acid is strong), and will therefore mop none up, and have no direct effect on pH. 100 mEq. of glutamate should therefore cause a net loss in the body of an equivalent amount of hydrogen ion; and this is reflected in the urinary figures (which incidentally suggest that enough potassium has been given to allow the tubules to conserve
hydrogen ion).
The glutamate will also, by its metabolism, form carbonic acid which can supply someof the needed hydrogen ions, but of course only by an equivalent production of bicarbonate ion. The net result on pH will depend on the buffer state of the patient, on any movement of hydrogen ion from the cells in response to potassium, and on the efficiency of the kidneys; but the overall effect of using glutamate must be to delay the fall of blood pH. Chloride is undoubtedly an important ion, but these experiments do not show its role clearly. It would be interesting to treat the next patient with potassium chloride and sodium glutamate simultaneously, to see whether the fall of pH is prompt, as Dr. Aber might anticipate, or delayed until renal function is fully restored. Sodium glutamate alone might well be dangerous in a potassium-depleted patient. Since the lungs excrete only carbon dioxide and water, there can be no loss of hydrogen ion through them; however, the distribution of hydrogen ion between water and undissociated carbonic acid is affected by the alveolar partial pressure of carbon dioxide. When there is an overall lack of hydrogen ion, an inevitable way of keeping the free fraction as high as possible (i.e., the pH as low as possible) is to dissociate more carbonic acid into hydrogen and bicarbonate ions; and one might therefore expect a low pC02 with a raised bicarbonate level as the patients showed. The body has, of course, to rid
the fact that it is usually possible to calculate approximately the amount of infusion fluid required to correct given abnormalities. There is much need in clinical practice to think in quantitative terms. Until recently the basic parameters on which such calculations could be based were not readily obtainable for treatment of acidosis or alkalosis; this is no longer so since it is now easy, with appropriate apparatus, to obtain repeated measurements of blood pH and Pco2 as well as the base excess or deficit, by capillary puncture. University Departments of D. CAMPBELL Anaesthetics, and Biochemistry, J. C. EATON Pathological Biochemistry, A. C. FORRESTER. Royal Infirmary, Glasgow. TESTING NEW DRUGS
Sirdo not subscribe to the extravagant claims made statisticians for the use of statistics in scientific research, but it is disturbing to find (from p. 1048 of your issue of Nov. 17) that the joint subcommittee of the Standing Medical Advisory Committees for England and Wales and Scotland set up to advise the Health Minister on what " measures are needed to secure adequate pharmacological and safety testing and clinical trials of new drugs before their release for general use ", and to " secure early detection of adverse effects arising after their release for general use ", does not have a statistician as a member. Research reveals at least one bacteriologist, pharmaco-
by
some
logist, pharmacist, biochemist, general practitioner, professor of medicine, but apparently not a statistician. Some of the most interesting discoveries in the pharmacological field have been made with teams with at least one trained statistician, and few clinicians, I suspect, would be altogether happy in organising a drug trial without expert statistical advice. Keeping a tame statistician in the back room is a very unsatisfactory substitute for competent advice within the committee. If it should be suggested, however, that statisticians have become social outcasts as a just reward for their claims to possess the alchemist’s stone, alas I could not but agree. Faculty of Economic and Social Studies, University of Manchester.
WALLIS TAYLOR.
ON TESTING THE SENSE OF SMELL
SIR,-Iread with interest the contribution by Dr. Sumner (Nov. 3). There are several points which I think deserve mention. Some substances such as benzaldehyde and camphor excite as well as olfactory afferents in the nasal passages and should be avoided2 if one desires to test " pure " olfaction. This potential source of error in interpretation of test results will be avoided, however, if one insists on identification of the testing substance. Dr. Sumner thinks that accurate identification of substances is more satisfactory than mere recognition of the presence or absence of any odour. Proper identification of odours depends upon the processes of association, memory, and past experiences3 and may be adversely affected by diminished intelligence or dementia. Interestingly enough, however, Elsberg 4 found the lack of the ability to name familiar odours more often in those of a high degree of intelligence (learned professions) than in those with little education such as labourers. Perhaps patients unable to identify familiar odours should more
trigeminal afferents
properly
be
designated
as
having " olfactory agnosia " rather
than a primary disturbance of olfaction. The distinction between amaurosis and visual agnosia seems analogous. 1. 2. 3. 4.
Elsberg, C. A., Levy, I., Brewer, E. D. Bull. neurol. Inst. N.Y. 1935, 4, 270. Merritt, H. H., Mettler, F. A., Putnam, T. J. Fundamentals of Clinical Neurology. Philadelphia, 1952. Elsberg, C. A., Levy, I. Bull. neurol. Inst. N.Y. 1935, 4, 5. Elsberg, C. A. ibid. p. 496.
Finally, I would agree that failure to identify at least one of Dr. Sumner’s four " best odours " may indicate " that something is amiss " but not necessarily that the primary sense of olfaction is lost. Neurology Service,
William Beaumont Hospital, El Paso, Texas, U.S.A.
HARRY H. WHITE.
BLOOD-PRESSURE AMONG THE PADAUNG TRIBE
SiR,—The article by Dr. Bhattacharjee (Nov. 17) is of interest. Despite his protestations to the contrary,
some
he has demonstrated that the mean blood-pressure of 35-year-old Padaung women is higher than what we are used to seeing. Could it not be that here is an example of natural selection ? Mild hypertension in young women may be a tribal characteristic which has been selected over the generations, and now appears in these women whether they wear rings or not. Apparently those who wore the rings were more likely to be wed; mild hypertension may have enabled more rings to be worn with comfort, thus selecting those with a constitutional predisposition to hypertension to be more likely to reproduce. MARVIN E.
JAFFE.
ROLE OF CHLORIDE IN CORRECTION OF ALKALOSIS ASSOCIATED WITH POTASSIUM DEPLETION
SIR,-Dr. Aber and his colleagues (Nov. 17, p. 1028) attribute the failure of potassium glutamate to lower the blood pH of potassium-depleted patients to a lack of chloride. They do not, however, discuss the fate of the glutamate. Each glutamate ion when metabolised must liberate a hydroxyl ion, and since this has a strong affinity for hydrogen ion (i.e., water is a weak acid), there will be a corresponding loss of hydrogen ion in the body. Chloride ion, on the other hand, has little affinity for hydrogen ion (i.e., hydrochloric acid is strong), and will therefore mop none up, and have no direct effect on pH. 100 mEq. of glutamate should therefore cause a net loss in the body of an equivalent amount of hydrogen ion; and this is reflected in the urinary figures (which incidentally suggest that enough potassium has been given to allow the tubules to conserve
hydrogen ion).
The glutamate will also, by its metabolism, form carbonic acid which can supply someof the needed hydrogen ions, but of course only by an equivalent production of bicarbonate ion. The net result on pH will depend on the buffer state of the patient, on any movement of hydrogen ion from the cells in response to potassium, and on the efficiency of the kidneys; but the overall effect of using glutamate must be to delay the fall of blood pH. Chloride is undoubtedly an important ion, but these experiments do not show its role clearly. It would be interesting to treat the next patient with potassium chloride and sodium glutamate simultaneously, to see whether the fall of pH is prompt, as Dr. Aber might anticipate, or delayed until renal function is fully restored. Sodium glutamate alone might well be dangerous in a potassium-depleted patient. Since the lungs excrete only carbon dioxide and water, there can be no loss of hydrogen ion through them; however, the distribution of hydrogen ion between water and undissociated carbonic acid is affected by the alveolar partial pressure of carbon dioxide. When there is an overall lack of hydrogen ion, an inevitable way of keeping the free fraction as high as possible (i.e., the pH as low as possible) is to dissociate more carbonic acid into hydrogen and bicarbonate ions; and one might therefore expect a low pC02 with a raised bicarbonate level as the patients showed. The body has, of course, to rid