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CLINICAL TRIALS
1146
all. Our own tradition, however, is right in bidding seek the rational explanation by all relevant means, taking precautions to discover unwanted effects and allow for those of accompanying impurities.
used
at
us
Annotations CLINICAL TRIALS
THE techniques of clinical trials are becoming steadily more versatile and sophisticated, but the queue of problems to which they need to be applied is lengthening. Two main factors are at work: pharmaceutical research is producing drugs that seem worth testing at a faster rate than they can be tested; and there are not enough trained investigators who can do the work properly. Nothing has so far been done to remedy this situation, because it seems to be nobody’s responsibility. Neither the National Health Service nor the universities give particular encouragement to clinical trials, though personal enthusiasm among clinicians in academic departments, teaching hospitals, and non-teaching hospitals has accomplished a good deal with ad-hoc support from various sources. The biggest and most impressive entrepreneur in the field is the Medical Research Council, which pioneered large-scale controlled clinical trials. Recently specialist associations have also carried out such trials; but, though these are important, they deal with only part of the problem. Support for particular clinical trials is often available from the drug firms concerned, but many workers feel that this can easily lead to a conflict of interest. On another page of this issue, Dr. Binns and Professor Butterfield discuss the present difficulties and conclude that additional resources are probably needed-more academic departments, a fellowship scheme, and an Institute of Therapeutics. Such measures could also bridge the gulf between academic departments and non-teaching hospitals, whose vast clinical material is at present contributing relatively little to the advance of medicine.! We strongly support the suggestion of Binns and Butterfield that a small committee of the highest standing should make a detailed assessment of present so that soundly based and resources and needs, authoritative recommendations can follow. INHIBITION OF HÆMOPOIESIS BY OXYGEN
LONG-CONTINUED reduction of arterial P02, whether associated with residence at high altitudes or cardiopulmonary inadequacy, results in an unequal increase of all the blood constituents; the most serious is a substantial rise in the red-blood cell-count. Initially this rise compensates partly for the lowered P02 by increasing the oxygen capacity of the blood, but it also causes increased viscosity which can lead to tissue anoxia by reducing cardiac output. The classical method of dealing with this state of affairs is venesection. Unfortunately this procedure, is not without risk; hence Chamberlain and Millard2! have adopted a new approach. Since the initial change; is a reduction of arterial P02 it would be logical to seek to raise this to normal. When the hypoxsemia is due to an increase in the gradient of P02 between the alveolar 1. See Lancet, 1963, i, 1039. Chamberlain, D. A., Millard, F. J. C. Quart. J. Med. 1963, 32, 346.
2.
air and the arterial blood, this can be done by raising the percentage of oxygen in the inspired air. This method-was tried some fifty years ago 4; but the work was not followed up, presumably because it is difficult to supply a high Po2 over long periods. Chamberlain and Millard used the new Venturi mask to give seven patients 35% oxygen for twenty hours a day for periods of six weeks. In six of the seven this treatment brought about a substantial reduction in total red-cell volume, and in four there was both subjective and objective improvement. It would be interesting to see whether oxygen therapy can decrease the increased plasma-volume which was a characteristic feature of the plethora in some of the patients with long-standing hypoxxmia studied by Shaw and Simpson.5 The finding by Dillthat the initial effect of hypoxia in older subjects is a rise of blood-volume with a fall in haemoglobin level suggests that oxygen therapy may occasionally result in a rise in haemoglobin. The method introduced by Chamberlain and Millard may turn out to be of real value in the treatment ofpolycythsmia secondary to hypoxia; but clearly it should meanwhile be applied only with careful measurement of all relevant factors. GENETICS OF DISEASE VECTORS
MODERN control of disease vectors leans heavily on insecticides; but the emergence of resistance and of toxic hazards has stimulated a search for alternative measures. This subject was discussed in a World Health Organisation symposium,’ in which one of the dominent themes was the importance of vector genetics. As a result W.H.O. appointed a scientific group to review the relevance of the genetics of medically important insects to their control. This group has now reported8 It considers first the mode of inheritance of resistance against insecticides. Though more data are always helpful, the usual pattern of inheritance seems reasonably well established. As the report puts it: " These and other studies in the genetics of resistance have added greatly to the understanding of field phenomena that have developed in vector control; whether they can precisely indicate counter-measures is problematical." There’s the rub! Investigations of resistance to insecticides have brought to light the numerous lacunse in our knowledge of the genetics of mosquitoes and other vectors. As soon as a vector species is examined carefully, it is invariably found to consist of a mosaic of races of indefinite subspecific rank, in which the various strains are commonly isolated by cytoplasmic incompatibility. Differences between these races may be vital in regard to vector potential, which depends on biological characters such as infectibility or behaviour rather than on the morphological characters by which species are defined in the museum. The first dividends of these researches should be improved understanding; later they may have practical uses. Thus, by intense breeding and release of a given strain in a region populated by a genetically incompatible
strain, cytoplasmic incompatibility might be applied to the control of insects. (The report suggests applications of this idea to incompatible races of Aedes scutellaris and 3. Bence, J. Dtsch. med. Wschr. 1906, 32, 1451. 4. Barcroft, J., Hunt, G. H., Dufton, D. Quart. J. Med. 1920, 13, 179 5. Shaw, D. B., Simpson, T. Quart. J. Med. 1961, 30, 135. 6. Dill, D. B. Fed. Proc. 1963, 22, abstr. 1761. 7. See Lancet, Feb. 15, 1964, p. 373. 8. Tech. Rep. Wld Hlth Org. 1964, no. 268.
all. Our own tradition, however, is right in bidding seek the rational explanation by all relevant means, taking precautions to discover unwanted effects and allow for those of accompanying impurities.
used
at
us
Annotations CLINICAL TRIALS
THE techniques of clinical trials are becoming steadily more versatile and sophisticated, but the queue of problems to which they need to be applied is lengthening. Two main factors are at work: pharmaceutical research is producing drugs that seem worth testing at a faster rate than they can be tested; and there are not enough trained investigators who can do the work properly. Nothing has so far been done to remedy this situation, because it seems to be nobody’s responsibility. Neither the National Health Service nor the universities give particular encouragement to clinical trials, though personal enthusiasm among clinicians in academic departments, teaching hospitals, and non-teaching hospitals has accomplished a good deal with ad-hoc support from various sources. The biggest and most impressive entrepreneur in the field is the Medical Research Council, which pioneered large-scale controlled clinical trials. Recently specialist associations have also carried out such trials; but, though these are important, they deal with only part of the problem. Support for particular clinical trials is often available from the drug firms concerned, but many workers feel that this can easily lead to a conflict of interest. On another page of this issue, Dr. Binns and Professor Butterfield discuss the present difficulties and conclude that additional resources are probably needed-more academic departments, a fellowship scheme, and an Institute of Therapeutics. Such measures could also bridge the gulf between academic departments and non-teaching hospitals, whose vast clinical material is at present contributing relatively little to the advance of medicine.! We strongly support the suggestion of Binns and Butterfield that a small committee of the highest standing should make a detailed assessment of present so that soundly based and resources and needs, authoritative recommendations can follow. INHIBITION OF HÆMOPOIESIS BY OXYGEN
LONG-CONTINUED reduction of arterial P02, whether associated with residence at high altitudes or cardiopulmonary inadequacy, results in an unequal increase of all the blood constituents; the most serious is a substantial rise in the red-blood cell-count. Initially this rise compensates partly for the lowered P02 by increasing the oxygen capacity of the blood, but it also causes increased viscosity which can lead to tissue anoxia by reducing cardiac output. The classical method of dealing with this state of affairs is venesection. Unfortunately this procedure, is not without risk; hence Chamberlain and Millard2! have adopted a new approach. Since the initial change; is a reduction of arterial P02 it would be logical to seek to raise this to normal. When the hypoxsemia is due to an increase in the gradient of P02 between the alveolar 1. See Lancet, 1963, i, 1039. Chamberlain, D. A., Millard, F. J. C. Quart. J. Med. 1963, 32, 346.
2.
air and the arterial blood, this can be done by raising the percentage of oxygen in the inspired air. This method-was tried some fifty years ago 4; but the work was not followed up, presumably because it is difficult to supply a high Po2 over long periods. Chamberlain and Millard used the new Venturi mask to give seven patients 35% oxygen for twenty hours a day for periods of six weeks. In six of the seven this treatment brought about a substantial reduction in total red-cell volume, and in four there was both subjective and objective improvement. It would be interesting to see whether oxygen therapy can decrease the increased plasma-volume which was a characteristic feature of the plethora in some of the patients with long-standing hypoxxmia studied by Shaw and Simpson.5 The finding by Dillthat the initial effect of hypoxia in older subjects is a rise of blood-volume with a fall in haemoglobin level suggests that oxygen therapy may occasionally result in a rise in haemoglobin. The method introduced by Chamberlain and Millard may turn out to be of real value in the treatment ofpolycythsmia secondary to hypoxia; but clearly it should meanwhile be applied only with careful measurement of all relevant factors. GENETICS OF DISEASE VECTORS
MODERN control of disease vectors leans heavily on insecticides; but the emergence of resistance and of toxic hazards has stimulated a search for alternative measures. This subject was discussed in a World Health Organisation symposium,’ in which one of the dominent themes was the importance of vector genetics. As a result W.H.O. appointed a scientific group to review the relevance of the genetics of medically important insects to their control. This group has now reported8 It considers first the mode of inheritance of resistance against insecticides. Though more data are always helpful, the usual pattern of inheritance seems reasonably well established. As the report puts it: " These and other studies in the genetics of resistance have added greatly to the understanding of field phenomena that have developed in vector control; whether they can precisely indicate counter-measures is problematical." There’s the rub! Investigations of resistance to insecticides have brought to light the numerous lacunse in our knowledge of the genetics of mosquitoes and other vectors. As soon as a vector species is examined carefully, it is invariably found to consist of a mosaic of races of indefinite subspecific rank, in which the various strains are commonly isolated by cytoplasmic incompatibility. Differences between these races may be vital in regard to vector potential, which depends on biological characters such as infectibility or behaviour rather than on the morphological characters by which species are defined in the museum. The first dividends of these researches should be improved understanding; later they may have practical uses. Thus, by intense breeding and release of a given strain in a region populated by a genetically incompatible
strain, cytoplasmic incompatibility might be applied to the control of insects. (The report suggests applications of this idea to incompatible races of Aedes scutellaris and 3. Bence, J. Dtsch. med. Wschr. 1906, 32, 1451. 4. Barcroft, J., Hunt, G. H., Dufton, D. Quart. J. Med. 1920, 13, 179 5. Shaw, D. B., Simpson, T. Quart. J. Med. 1961, 30, 135. 6. Dill, D. B. Fed. Proc. 1963, 22, abstr. 1761. 7. See Lancet, Feb. 15, 1964, p. 373. 8. Tech. Rep. Wld Hlth Org. 1964, no. 268.