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Veratrum in Hypertension
568 service would also depend on further surveys and experiments. All factories are obliged by law to maintain certain standards of healthy environment, and if they employ people in certain processes with special risks, or if they employ young persons at all, they have to consult the appointed factory doctor. Services like those established in some of the larger
factories might be neither practicable nor appropriate in smaller factories which need some further provision. Attention is drawn to the group services for smaller factories at Slough, Bridgend, and Hillington, and the committee would like to see further group experiments made on a scale that the average small employer is willing and able to afford. They realise, however, that before health supervision beyond the minimum already provided can be extended, even moderately, there will have to be a big increase in the numbers of doctors and nurses available to industry. " Meanwhile, any detailed planning of a nation-wide scheme remains largely academic." The one positive recommendation is that there should be a standingjoint advisory committee to coordinate the development of the industrial health services : it should be composed of persons appointed by the Ministry of Health and the Ministry of Labour, together with representatives of the Ministry of Fuel
and Power, employers, workers, doctors, and nurses ; and there should be strong medical representation A similar committee should be appointed for on it. Scotland in which the Department of Health for Scotland would take the place of the Ministry of Health. The chairmen of these committees should not be drawn from any of the departments represented on them. The main function of the committees would be to correlate advice to be afterwards given by on major developments affecting industrial health, with special regard to the best use of medical man-power. Unfortunately, this method of coordination by advisory committees is at best only a half-hearted one, and it would probably have been better to give one department the main responsibility for the development of the services. The outcome of the Dale Committee’s deliberations really depends on how the Prime Minister deals with the " detailed If consideration of the coordinating machinery." this is not done effectively the Dale report will go down in the history of industrial medicine as another lost opportunity.
departments
Veratrum in Hypertension THE blood-pressure of most hypertensive patients can be lowered temporarily by rest and freedom from everyday cares, aided perhaps by venesection or drugs. It is in seeking to make the change permanent, with reasonable safety, while avoiding intolerable sideeffects, that difficulties arise. Moreover, as TURNER1 has pointed out, high blood-pressure is only one of the manifestations of hypertensive disease. Reducing the pressure may not relieve the patient’s symptoms, and may be dangerous. Such considerations have not deterred clinicians from cautious trials of the potent which were discussed in Feb. of 17. This week two article leading even with supervision indicate that, correspondents in hospital, administration of such compounds may
methonium
compounds,
our
1. Turner, R.
Lancet, 1950, ii, 353.
have a fatal outcome ; and on p. 549 Dr. KAUNTZE and Dr. TROUNCE draw attention to the possible advantages Veratrum viride is no of veratrum preparations. novelty ; it was familiar to our grandfathers as a remedy for hypertension. Twenty years ago Dr. DouTrrwAiTE2 reported unfavourably on its efficacy in this condition, and for a time its reputation languished ; but in 1949 work in America gave a fresh turn to its fortunes. How the veratrum alkaloids exert their hypotensive action is not certain. It is agreed, however, that the effect is not sympatholytic. According to GOUTIER3 these drugs act largely by heightening the response of plain muscle to potassium ions. WILKINS et a1.4 suggest that they act through a central " mechanism not hitherto recognised, aided perhaps by peripheral vasodilation. Thus, it is claimed, they reduce hypertension while largely avoiding the undesirable side-effects of the simple vasodilators ; and bloodpressure can be reduced without impairing the cardiac output or the circulation in the major organs. The slowing of the heart which these alkaloids induce, and which is abolished by atropine, is thought by WILKINS and his associates to be due to action on the vagus centres. This " prevents the tachycardia and palpitation that ordinarily results from reflexes arising in the aortic and carotid areas when such a lowering of arterial pressure occurs." Apparently, therefore, these compounds can " maintain the patient in a state of circulatory equilibrium but with a lower arterial pressure." There is evidence for this view. For instance, after the blood-pressure has been significantly depressed by parenteral injection of a veratrum alkaloid, a normal " cold pressor" rise can, according to MEiLMAN and KRAYER,5 be obtained from the new levels. WILKINS et al. reported that " postural hypotension did not develop following sub-toxic dosage" ; but MEILMAN and KRAYER claimed only that the postural response " did not differ much " from that before the preparation was administered. The bradycardia, they maintained, is not responsible for the lowered pressure, since this remains low after the pulse has been quickened with "
atropine. WILKINS and his associates insist that their laboratory work on veratrum viride was done with " the same old drug." But for their clinical trial MEiLMAN and KRAYER used a pure ester alkaloid of veratrum, which they called ’Protoveratrine.’ KRAYER et a1.6 had previously shown experimentally that " not all
alkaloids, but only some of the ester alkaloids " were " capable of eliciting the reflex decrease in blood-pressure and heart-rate." It has not yet proved possible to administer protoveratrine orally. Given intravenously it produced virtually no side-effects in doses sufficient to cause a conspicuous fall in pathologically raised blood-pressure. Moreover, in a high proportion of cases the fall was accompanied by relief of headache and reversion of flat or inverted T waves in the electrocardiograph. The response was evident in about ten minutes and lasted from one to three hours. In America several attempts have been veratrum
2. Douthwaite, A. H. Brit. med. J. 1929, ii, 844. 3. Goutier, R. Brit. J. Pharmacol. 1950, 5, 33. 4. Wilkins, R. W., Freis, E. D., Stanton, J. R. J. Amer. med. Ass. 1949, 140, 261. 5. Meilman, E., Krayer, O. Circulation, 1950, 1, 187. 6. Krayer O., Wood, E. H., Montes, G. J. Pharmacol. 1943, 79, 215.
569
made to find a veratrum compound that is both effective and safe when given by mouth. FREis and STANTON7 studied the effect of a biologically standardised preparation of veratrum in a powder with tetraiodo-pyrrole. Of 34 ambulant hypertensives who received this substance, 30 had a significant fall
blood-pressure and 27 experienced subjective improvement ; 13 had toxic reactions. This was encouraging, but CoE and his colleagues8 have since in
control series in which the effects of oral compared with those of similar placebo Of 25 patients to whom veratrum was tablets. administered, only 2 had a significant fall in bloodpressure ; 16 noted symptomatic improvement, but similar benefit was reported by 14 out of 23 patients in the control group. Nausea and vomiting proved troublesome ; and some way of eliminating these toxic effects will have to be found before a fully effective dosage of veratrum in this form can be given by mouth. In his survey Dr. KAUNTZE has used a ’potent extract prepared by STUTZMAN et awl. which has been given the proprietary nameV eriloid.’ STUTZMAN offers a new hypothesis to account for the hypotensive effect of veriloid. Moreover the experience of Dr. KAUNTZE differs somewhat from that of the American workers ; for he finds that the low pressures obtained with the extract were not maintained under atropinisation. On the other hand he agrees with the Americans in his observation that there was" no postural change in the blood-pressure comparable with that after the injections of hexamethonium." Moreover there was a sharp response to ephedrine. If veratrum has an advantage over methonium it would seem to lie in the lesser risk of postural hypotension. In potency, method of dosage, and variability of effect the two forms of treatment seem to have much in common. Neither touches the cause of the disease. Both, if they achieve their object, must threaten the patient with such risks as vascular thrombosis and extrarenal uraemia. The side-effects, too, are evenly balanced. If veratrum is bad for peptic ulceration and can cause vomiting in its own right, at least it does not precipitate bromism, nor " methonium paralytic ileus." In short, both these types of preparation offer encouragement but as yet
published veratrum
no
a
were
fulfilment.
Bacteriophage THERE is
a tendency to discard the name and to refer collectively to these bacteriophage ’’ the as bacterial viruses ; for " bacteriaorganisms of the is one eating only properties of the group, and one that occurs principally under experimental conditions in the laboratory. To the microbiologist this group of viruses is at present important not so much because of their ability to destroy bacteria as because they provide a model system in which to study the relationship of a virus with its cell host. Using the technique described by FISK 10 it can be shown that many bacteria carry bacteriophage without undergoing lysis ; so, unless we believe in
now
"
spontaneous generation, 7. 8.
or
in
some
autocatalytic
Freis, E. O., Stanton, J. R. Amer. Heart J. 1948, 36, 723. Coe, W. S., Best, M., Kinsman, J. M. J. Amer. med. Ass. 1950, 143, 5. 9. Stutzman, J. W., Maison, G. L., Bauer, R. O. Proc. New Engl. cardiovasc. Soc. February, 1950. 10. Fisk, R. T. J. inf. Dis. 1942, 71, 153.
process in the bacterial cell, it is clear that these viruses
are
ordinarily
in
symbiosis
with the bacteria.
itself apparently unaffected, the bacterial strain which carries phage is capable of causing lysis if mixed with a similar bacterial strain. To explain how a strain can carry phage without being attacked by it, two hypotheses are offered. The first is that the bacterial culture consists of two populations, one of which is resistant to the phage while the other is sensitive, and the phage is propagated by multiplication in the sensitive organisms which are derived by mutation from phage-resistant bacteria. The second possibility is that the phage-carrying strains are equivalent to an immune carrier, there being little multiplication until the phage meets a sensitive strain. This second hypothesis finds support in the work of GRATIA 11and others who have shown that phages can be carried by bacterial spores, and then have the same resistance to heat and other agents as the spore. The immune bacterial carrier may have a chemical grouping at its surface to which the phage attaches itself and by which it is prevented from entering the bacterial cell. Electron-microscope studies have shown that the bacterial viruses vary as much in form as the animal viruses. RusKA, i2 in photographs of Bacterium colii bacteriophages, demonstrated variations from tadpoleshaped viruses to small round bodies; the tail, though resembling a flagellum, does not give motility to the virus. Both WYCKOFF 13 and MERLING,14 from electron-microscope studies of the reproduction of bacteriophage, have suggested that multiplication is by binary fission ; but this has not been confirmed. DOERMANN 1’ has attacked the same problem by mechanically breaking up the bacterial cell after the bacteriophage particle has entered it. Apparently, after the phage enters the cell it loses its identity, and it only reappears shortly before the cell would normally burst to liberate fresh phage particles. (This finding fits in with HoYLE’s 16 observation of the appearance of the soluble antigen of influenza virus before the infectious particles appear in chick-embryo cultures.) The lysis of the bacterial cell does not seem to be due to any enzymic action of the phage ;-. nor apparently is it due to the cell becoming full of phage particles, since COHFN 17 has shown that in an oxygen-deficient cell a single phage particle causes immediate lysis-and thereby destroys itself. An understanding of virus metabolism might give a key to the preparation of compounds which would prevent the intracellular growth of viruses. A step in the right direction is the work of DELBRUCK 18 and his colleagues in the development of the onestep growth-curve technique, which has shown that after the bacterium is infected there is a latent period before fresh virus is produced; and then, quite suddenly, virus is released from all cells infected at the same time. The increase in phage numbers proceeds of a series by steps, the interval between steps being of the same duration, and characteristic for each bacteriophage, under constant conditions. By using
Though
11. Gratia, A. Ann. Inst. Pasteur, 1936, 57, 652. 12. Ruska, H. Naturwiss. 1941, 29, 367. 13. Wyckoff, R. W. G. Nature, Lond. 1948, 162, 649. 14. Merling, K. B. E. Brit. J. exp. Path. 1949, 30, 139. 15. Doermann, H. A. Carnegie Inst. Wash. Yearb. 1948, 16. Hoyle, L. Brit. J. exp. Path. 1948, 29, 390. 17. Cohen, S. S. Bact. Rev. 1949, 13, 1. 18. Delbruck, M. J. gen. Physiol. 1939, 22, 365.
47, 176.
factories might be neither practicable nor appropriate in smaller factories which need some further provision. Attention is drawn to the group services for smaller factories at Slough, Bridgend, and Hillington, and the committee would like to see further group experiments made on a scale that the average small employer is willing and able to afford. They realise, however, that before health supervision beyond the minimum already provided can be extended, even moderately, there will have to be a big increase in the numbers of doctors and nurses available to industry. " Meanwhile, any detailed planning of a nation-wide scheme remains largely academic." The one positive recommendation is that there should be a standingjoint advisory committee to coordinate the development of the industrial health services : it should be composed of persons appointed by the Ministry of Health and the Ministry of Labour, together with representatives of the Ministry of Fuel
and Power, employers, workers, doctors, and nurses ; and there should be strong medical representation A similar committee should be appointed for on it. Scotland in which the Department of Health for Scotland would take the place of the Ministry of Health. The chairmen of these committees should not be drawn from any of the departments represented on them. The main function of the committees would be to correlate advice to be afterwards given by on major developments affecting industrial health, with special regard to the best use of medical man-power. Unfortunately, this method of coordination by advisory committees is at best only a half-hearted one, and it would probably have been better to give one department the main responsibility for the development of the services. The outcome of the Dale Committee’s deliberations really depends on how the Prime Minister deals with the " detailed If consideration of the coordinating machinery." this is not done effectively the Dale report will go down in the history of industrial medicine as another lost opportunity.
departments
Veratrum in Hypertension THE blood-pressure of most hypertensive patients can be lowered temporarily by rest and freedom from everyday cares, aided perhaps by venesection or drugs. It is in seeking to make the change permanent, with reasonable safety, while avoiding intolerable sideeffects, that difficulties arise. Moreover, as TURNER1 has pointed out, high blood-pressure is only one of the manifestations of hypertensive disease. Reducing the pressure may not relieve the patient’s symptoms, and may be dangerous. Such considerations have not deterred clinicians from cautious trials of the potent which were discussed in Feb. of 17. This week two article leading even with supervision indicate that, correspondents in hospital, administration of such compounds may
methonium
compounds,
our
1. Turner, R.
Lancet, 1950, ii, 353.
have a fatal outcome ; and on p. 549 Dr. KAUNTZE and Dr. TROUNCE draw attention to the possible advantages Veratrum viride is no of veratrum preparations. novelty ; it was familiar to our grandfathers as a remedy for hypertension. Twenty years ago Dr. DouTrrwAiTE2 reported unfavourably on its efficacy in this condition, and for a time its reputation languished ; but in 1949 work in America gave a fresh turn to its fortunes. How the veratrum alkaloids exert their hypotensive action is not certain. It is agreed, however, that the effect is not sympatholytic. According to GOUTIER3 these drugs act largely by heightening the response of plain muscle to potassium ions. WILKINS et a1.4 suggest that they act through a central " mechanism not hitherto recognised, aided perhaps by peripheral vasodilation. Thus, it is claimed, they reduce hypertension while largely avoiding the undesirable side-effects of the simple vasodilators ; and bloodpressure can be reduced without impairing the cardiac output or the circulation in the major organs. The slowing of the heart which these alkaloids induce, and which is abolished by atropine, is thought by WILKINS and his associates to be due to action on the vagus centres. This " prevents the tachycardia and palpitation that ordinarily results from reflexes arising in the aortic and carotid areas when such a lowering of arterial pressure occurs." Apparently, therefore, these compounds can " maintain the patient in a state of circulatory equilibrium but with a lower arterial pressure." There is evidence for this view. For instance, after the blood-pressure has been significantly depressed by parenteral injection of a veratrum alkaloid, a normal " cold pressor" rise can, according to MEiLMAN and KRAYER,5 be obtained from the new levels. WILKINS et al. reported that " postural hypotension did not develop following sub-toxic dosage" ; but MEILMAN and KRAYER claimed only that the postural response " did not differ much " from that before the preparation was administered. The bradycardia, they maintained, is not responsible for the lowered pressure, since this remains low after the pulse has been quickened with "
atropine. WILKINS and his associates insist that their laboratory work on veratrum viride was done with " the same old drug." But for their clinical trial MEiLMAN and KRAYER used a pure ester alkaloid of veratrum, which they called ’Protoveratrine.’ KRAYER et a1.6 had previously shown experimentally that " not all
alkaloids, but only some of the ester alkaloids " were " capable of eliciting the reflex decrease in blood-pressure and heart-rate." It has not yet proved possible to administer protoveratrine orally. Given intravenously it produced virtually no side-effects in doses sufficient to cause a conspicuous fall in pathologically raised blood-pressure. Moreover, in a high proportion of cases the fall was accompanied by relief of headache and reversion of flat or inverted T waves in the electrocardiograph. The response was evident in about ten minutes and lasted from one to three hours. In America several attempts have been veratrum
2. Douthwaite, A. H. Brit. med. J. 1929, ii, 844. 3. Goutier, R. Brit. J. Pharmacol. 1950, 5, 33. 4. Wilkins, R. W., Freis, E. D., Stanton, J. R. J. Amer. med. Ass. 1949, 140, 261. 5. Meilman, E., Krayer, O. Circulation, 1950, 1, 187. 6. Krayer O., Wood, E. H., Montes, G. J. Pharmacol. 1943, 79, 215.
569
made to find a veratrum compound that is both effective and safe when given by mouth. FREis and STANTON7 studied the effect of a biologically standardised preparation of veratrum in a powder with tetraiodo-pyrrole. Of 34 ambulant hypertensives who received this substance, 30 had a significant fall
blood-pressure and 27 experienced subjective improvement ; 13 had toxic reactions. This was encouraging, but CoE and his colleagues8 have since in
control series in which the effects of oral compared with those of similar placebo Of 25 patients to whom veratrum was tablets. administered, only 2 had a significant fall in bloodpressure ; 16 noted symptomatic improvement, but similar benefit was reported by 14 out of 23 patients in the control group. Nausea and vomiting proved troublesome ; and some way of eliminating these toxic effects will have to be found before a fully effective dosage of veratrum in this form can be given by mouth. In his survey Dr. KAUNTZE has used a ’potent extract prepared by STUTZMAN et awl. which has been given the proprietary nameV eriloid.’ STUTZMAN offers a new hypothesis to account for the hypotensive effect of veriloid. Moreover the experience of Dr. KAUNTZE differs somewhat from that of the American workers ; for he finds that the low pressures obtained with the extract were not maintained under atropinisation. On the other hand he agrees with the Americans in his observation that there was" no postural change in the blood-pressure comparable with that after the injections of hexamethonium." Moreover there was a sharp response to ephedrine. If veratrum has an advantage over methonium it would seem to lie in the lesser risk of postural hypotension. In potency, method of dosage, and variability of effect the two forms of treatment seem to have much in common. Neither touches the cause of the disease. Both, if they achieve their object, must threaten the patient with such risks as vascular thrombosis and extrarenal uraemia. The side-effects, too, are evenly balanced. If veratrum is bad for peptic ulceration and can cause vomiting in its own right, at least it does not precipitate bromism, nor " methonium paralytic ileus." In short, both these types of preparation offer encouragement but as yet
published veratrum
no
a
were
fulfilment.
Bacteriophage THERE is
a tendency to discard the name and to refer collectively to these bacteriophage ’’ the as bacterial viruses ; for " bacteriaorganisms of the is one eating only properties of the group, and one that occurs principally under experimental conditions in the laboratory. To the microbiologist this group of viruses is at present important not so much because of their ability to destroy bacteria as because they provide a model system in which to study the relationship of a virus with its cell host. Using the technique described by FISK 10 it can be shown that many bacteria carry bacteriophage without undergoing lysis ; so, unless we believe in
now
"
spontaneous generation, 7. 8.
or
in
some
autocatalytic
Freis, E. O., Stanton, J. R. Amer. Heart J. 1948, 36, 723. Coe, W. S., Best, M., Kinsman, J. M. J. Amer. med. Ass. 1950, 143, 5. 9. Stutzman, J. W., Maison, G. L., Bauer, R. O. Proc. New Engl. cardiovasc. Soc. February, 1950. 10. Fisk, R. T. J. inf. Dis. 1942, 71, 153.
process in the bacterial cell, it is clear that these viruses
are
ordinarily
in
symbiosis
with the bacteria.
itself apparently unaffected, the bacterial strain which carries phage is capable of causing lysis if mixed with a similar bacterial strain. To explain how a strain can carry phage without being attacked by it, two hypotheses are offered. The first is that the bacterial culture consists of two populations, one of which is resistant to the phage while the other is sensitive, and the phage is propagated by multiplication in the sensitive organisms which are derived by mutation from phage-resistant bacteria. The second possibility is that the phage-carrying strains are equivalent to an immune carrier, there being little multiplication until the phage meets a sensitive strain. This second hypothesis finds support in the work of GRATIA 11and others who have shown that phages can be carried by bacterial spores, and then have the same resistance to heat and other agents as the spore. The immune bacterial carrier may have a chemical grouping at its surface to which the phage attaches itself and by which it is prevented from entering the bacterial cell. Electron-microscope studies have shown that the bacterial viruses vary as much in form as the animal viruses. RusKA, i2 in photographs of Bacterium colii bacteriophages, demonstrated variations from tadpoleshaped viruses to small round bodies; the tail, though resembling a flagellum, does not give motility to the virus. Both WYCKOFF 13 and MERLING,14 from electron-microscope studies of the reproduction of bacteriophage, have suggested that multiplication is by binary fission ; but this has not been confirmed. DOERMANN 1’ has attacked the same problem by mechanically breaking up the bacterial cell after the bacteriophage particle has entered it. Apparently, after the phage enters the cell it loses its identity, and it only reappears shortly before the cell would normally burst to liberate fresh phage particles. (This finding fits in with HoYLE’s 16 observation of the appearance of the soluble antigen of influenza virus before the infectious particles appear in chick-embryo cultures.) The lysis of the bacterial cell does not seem to be due to any enzymic action of the phage ;-. nor apparently is it due to the cell becoming full of phage particles, since COHFN 17 has shown that in an oxygen-deficient cell a single phage particle causes immediate lysis-and thereby destroys itself. An understanding of virus metabolism might give a key to the preparation of compounds which would prevent the intracellular growth of viruses. A step in the right direction is the work of DELBRUCK 18 and his colleagues in the development of the onestep growth-curve technique, which has shown that after the bacterium is infected there is a latent period before fresh virus is produced; and then, quite suddenly, virus is released from all cells infected at the same time. The increase in phage numbers proceeds of a series by steps, the interval between steps being of the same duration, and characteristic for each bacteriophage, under constant conditions. By using
Though
11. Gratia, A. Ann. Inst. Pasteur, 1936, 57, 652. 12. Ruska, H. Naturwiss. 1941, 29, 367. 13. Wyckoff, R. W. G. Nature, Lond. 1948, 162, 649. 14. Merling, K. B. E. Brit. J. exp. Path. 1949, 30, 139. 15. Doermann, H. A. Carnegie Inst. Wash. Yearb. 1948, 16. Hoyle, L. Brit. J. exp. Path. 1948, 29, 390. 17. Cohen, S. S. Bact. Rev. 1949, 13, 1. 18. Delbruck, M. J. gen. Physiol. 1939, 22, 365.
47, 176.