- Email: [email protected]
The Interaction of Drugs
82
applied to the stable state when there is probably equilibrium across cell membranes. The exchangeable pool and the turnover are diminished in overt hypoparathyroidism 13 and it would be interesting to know whether the same is true, in lesser degree, of partial parathyroid insufficiency. The fact that the severity of the symptoms is not necessarily related to serum-calcium levels might be accounted for by other factors affecting neuromuscular irritability, such as the presence of mild myxoedema. A more cogent reason for seeking latent hypoparathyroidism is that infection or pregnancy may precipitate overt hypoparathyroidism in an apparently cured patient.14 Those at risk should perhaps be warned, and if the E.D.T.A. test cannot be done subjects with serumcalcium levels in the lower normal range should be kept under observation. The E.D.T.A. test is dangerous to those whose serum-calcium levels are already low. FOURMAN and his colleagues in Cardiff 14 15 and MICHIE and his co-workers in Aberdeen 16 emphasise that overt hypoparathyroidism after thyroidectomy is rarely transient and that low parathyroid reserve can usually be demonstrated months or years after operation. On the other hand, if the insufficiency is symptomless immediately after operation the function of the gland usually recovers within 3 months. FpuRMAN’s group suggest that 3 months after operation is the best time for routine calcium estimation (rather than the 3 weeks recommended by LACHMANN), since most subjects will have recovered their normal parathyroid reserve by this time, and delayed cases should then be detectable. Moreover, hyperplasia of the remaining parathyroid tissue may depend on the stimulus of low calcium concentrations, and mild asymptomatic hypocalcasmia may be better left untreated for at least 2 years.14 Very low calcium levels should be corrected because of the risk of cataracts, fits, and mental disease. The treatment may require large doses of vitamin D as well as calcium, and be
carefully supervised. The’reported prevalence of hypoparathyroidism after thyroid surgery has varied widely. On the basis of calcium-depletion tests the Cardiff workers found that it was 24%. so Most centres reported lower figures, and this led to a reappraisal of the operative technique in Cardiff and reduction of the prevalence to 4%. This success demonstrates how the right surgical procedure can conserve parathyroid function. Removal of the the is cause,’’-19 and infarction glands probably rarely is a more likely explanation. Although the parathyroids are usually supplied by the inferior thyroid artery, 17 ligation of this vessel does not affect the glands because there must
is extensive anastomosis with branches from the tracheal and oesophageal vessels.17 19 Damage to the single endartery to each gland will cause infarction, and the risk of this probably increases if haemostatic ligatures and 13.
Milhaud, G., Bourichon, J. C. r. hebd. Séanc. Acad. Sci. Paris, 1964, 258,
14. 15.
Wade, J. S. H., Fourman, P., Deane, L. Br. J. Surg. 1965, 52, 493. Wade, J. S. H., Goodall, P., Deane, L., Dauncey, T. M., Fourman, P. ibid. p. 497. Michie, W., Stowers, J. M., Frazer, S. C., Gunn, A. ibid. p. 503. Halstead, W. S., Evans, H. M. Ann. Surg. 1907, 46, 489. Curtis, G. M. Illinois med. J. 1931, 59, 361. Wade, J. S. H. Br. J. Surg. 1960, 48, 25.
3398.
16. 17. 18. 19.
applied close to the parathyroids.15 It may be significant that hypoparathyroidism is most common after operation on toxic goitres iei9; haemostasis is especially difficult in these cases. Although the incidence of hypoparathyroidism can be reduced by good surgical technique, the onus is on the surgeon to look for this condition in all his patients at risk. A minimum precaution is estimation of serumcalcium 3 months after operation. Patients in whom overt hypoparathyroidism develops soon after operation are unlikely to recover full parathyroid function, and they should be kept under observation.
sutures are
The Interaction of Drugs POLYPHARMACY is not a feature of our generation alone. For centuries doctors have prescribed more than one drug at a time, and it was this practice, in part, that led to the development of homoeopathic medicine. A Use of the last century Hommopathic Guide for Family " states authoritatively that alternate administration is the only method of combining the action of two or more medicines. They cannot, in any case whatever, be mixed with propriety ". Nevertheless, many important therapeutic advances have been due to the use of rational and careful combinations of drugs. It is important, however, that the clinical effects of drug interactions should be carefully assessed if toxic effects are to be reduced and therapeutic benefits exploited. Earlier this year a symposium1 at the Royal Society of Medicine was devoted to this subject and the proceedings have now been published as a special supplement2 to the Proceedings. The " dark ages " of ignorance of the basic mechanisms in interaction are passing. Combination therapy has been particularly fruitful with antibiotics and in the treatment of hypertension and acute leukaemia. MARY BARBER3 reviewed the importance of combinations of two bactericidal antibiotics in the treatment of severe infections, such as bacterial endocarditis, when infecting bacteria may not be readily killed by a single drug. Whenever possible, double sensitivity tests should be applied to the organism concerned. Antibiotic combinations also delay the emergence of resistant strains, not only in tuberculosis but also in staphylococcal and coliform infections. In the treatment of hypertension4 combined treatment often reduces the required dose of each drug and averts their side-effects. Moreover, DOLLERY4 points out that such treatment may be more economical than giving a single drug. There is little doubt that the addition of a thiazide diuretic enhances the hypotensive effect of ganglion-blocking and adrenergicblocking drugs. While the prognosis of acute leuktmia in adults is appalling,5 there is reason for cautious optimism in childhood leukaemia.6ZUBRODreviewed the results obtained by the acute leukxmia task force 1. See Lancet, 1965, i, 906. 2. Proc. R. Soc. Med. 1965, 58, 943. 3. Barber, M. ibid. p. 990. 4. Dollery, C. T. ibid. p. 983. 5. Lancet, 1965, ii, 938.
6. 7.
Hardisty, R. M. ibid. p. 1134. Zubrod, C. G. Proc. R. Soc. Med. 1965, 58,
988.
83
in the U.S.A. in studies of L 1210 mouse leukaemia, which proved to be an excellent predictive model for the childhood disease. Examination of the kinetics of cell generation, leukaemic cell population size, and fractional
destruction by individual antileukaemic drugs have created a rational basis for combination therapy. BuRcHENALhas now reported 101 patients with known acute leukaemia who had survived 5-14 years, of whom 64 had no signs of the disease. Toxic as well as therapeutic interactions may be As early as 1938, GADDUM and KWIATpredictable. KOWSKI 9 observed that some drugs might produce pharmacological effects by inhibiting catabolism of catecholamines, and, in retrospect, most of the interactions of the monoamine-oxidase inhibitorswith other drugs and food substances 10 could have been predicted and avoided. On the other hand, there are big species differences in the metabolic pathways of catecholamines, and here particularly trial in man is the only way of establishing drug interaction in man. If it is not performed in a regulated experiment, trials will be continuously performed in the clinical use of the new drug until all possibilities have been explored, and results collated ".11 Unfortunately too few regulated experiments have been conducted, and wisdom has often "
dawned after the unwanted event. The toxic interactions of the monoamine-oxidase inhibitors has attracted much interest (a London teaching hospital asked its final-year nurses to write an essay on " cerebral
and cheese ") and stimulated valuable research; but these drugs are of limited value which restricts the number of side-effects. That is not true of interactions between other more commonly used psychotropic agents,12particularly when barbiturates are involved; but their scientific evaluation is extremely difficult. Sensitive psychophysiological 13 14 and psychosensory 15 tests indicate possible ways in which inter-
haemorrhage
actions of centrally acting drugs may be studied from both therapeutic and toxic aspects. The greater our understanding of a drug’s mechanism of action and metabolic pathway, the more predictable are its possible toxic interactions. The relation between digitalis and potassium explains the increased toxicity of digitalis when associated with potassium depletion produced by diuretics. Many drugs are bound to plasmaproteins, and may be displaced from them by other drugs with a higher affinity for the protein. Such displacement may be particularly dangerous if the unbound active moiety is a small fraction of the total, since displacement of only a small proportion may then double or treble its unbound concentration at the target site.16 EISEN 17 has reported severe. bleeding in patients under treatment with warfarin which had been displaced by 8.
Burchenal, J. Proceedings of Fifth National Cancer Conference, Phila-
delphia, 1965. 9. Gaddum, J. W., Kwiatkowski, H. J. J. Physiol. 1938, 94, 87. 10. Sjoqvist, F. Proc. R. Soc. Med. 1965, 58, 967. 11. Modell, W. Clin. Pharmacol. Ther. 1964, 5, 265. 12. Shepherd, M. Proc. R. Soc. Med. 1965, 58, 964. 13. Dick, P., Shepherd, M. Psychopharmacologia, 1965, 8, 32. 14. Dickens, D. W., Lader, M. H., Steinberg, H. Br. J. Pharmacol. Chemother, 24, 14.
15. Turner, P. J. Pharm. Pharmacol. 1965, 17, 388. 16. Brodie, B. B. Proc. R. Soc. Med. 1965, 58, 946. 17. Eisen, N. G. J. Am. med. Ass. 1964, 189, 64.
phenylbutazone or oxyphenbutazone so that its anticoagulant activity was greatly enhanced. A closely bound sulphonamide such as sulphaphenazole can induce hypoglycxmic coma by displacing tolbutamide from plasma-protein.188 Sulphonamides, salicylates, and other agents which readily combine with albumin should not be given to the newborn, because displacement of bilirubin and its diffusion into the brain may produce kernicterus.19 Displacement may sometimes help, as when however, phenylbutazone raises the level of unbound sulphonamide or penicillin and thus enhances their antibiotic activity. Anti-inflammatory action of such drugs as salicylates, phenylbutazone, and indomethacin may be due to their ability to displace corticosteroids from their plasma-protein binding, allowing their more ready dispersal into tissues.16 Another interesting aspect of drug metabolism is enzyme stimulation and inhibition. 20 A drug may inof metabolism or that of another drug by increasing or decreasing the amount of drug-metabolising enzyme in liver microsomes. For example, phenobarbitone so accelerates the metabolism of subsequent doses of hexobarbitone as to abolish almost completely its pharmacological activity.21 Phenobarbitone acts similarly on the activity of liver enzymes responsible for metabolising coumarin derivatives, and BURNS and CONNEY 20 describe a patient whose prothrombin-time and plasma-dicoumarol level were significantly lowered by giving 60 mg. of phenobarbitone daily for four weeks. This observation explains earlier reports of barbiturates decreasing the activity of coumarin drugs. 22 Other drugs whose metabolism is increased by barbiturates are diphenylhydantoin and griseofulvin. Phenylbutazone has a similar action on the rate of destruction of other drugs. Many hitherto unexplained variations in drug activity may be the result of this phenomenon, evoked not only by other drugs but also by substances in the environment, such as insecticides.23 The ability of drugs to inhibit the metabolism of other drugs, and thus enhance their activity, has been demonstrated in animals and in man; and this may offer another explanation for the potentiation of the anticoagulant action of coumarin derivatives by oxyphenbutazone.1 1 24 25 Some compounds, it seems, inhibit metabolism of certain drugs when given to animals in a single large dose, but stimulate metabolism when given over a longer period.2s 2’ Changes in acid-base balance within the body may affect the efficacy and toxicity of drugs.28 Absorption of weak acids and bases from the gastrointestinal tract, their distribution between extracellular and intracellular fluid, and their urinary excretion are modified crease or
decrease its
own rate
18. Christensen, L. K., Hansen, J. M., Kristensen, M. Lancet, 1963, ii, 1298. 19. Odell, G. B. J. clin. Invest. 1959, 38, 823. 20. Burns, J. J., Conney, A. H. Proc. R. Soc. Med. 1965, 58, 955. 21. Conney, A. H., Davison, C., Gastel, R., Burns, J. J. J. Pharmacol. exp. Ther. 130, 1. 22. Avellaneda, M. Medicina, B. Aires, 1955, 15, 109. 23. Hart, L. G., Schultice, R. W., Fouts, J. R. Toxicol. appl. Pharmacol. 1963, 5, 371. 24. Fox, S. L. J. Am. med. Ass. 1964, 188, 320. 25. Weiner, M., Siddiqui, A. A., Bostanci, N., Dayton, P. G. Fedn Proc. Fedn Am. Socs exp. Biol. 24, 153. 26. Serrone, D. M., Fujimoto, J. M. Biochem. Pharmacol. 1962, 11, 609. 27. Kato, R., Chiesara, E., Vassanelli, P. ibid. 1964, 13, 69. 28. Milne, M. D. Proc. R. Soc. Med. 1965, 58, 961.
84
their degree of ionisation. Particularly dramatic are the changes in the rate of urinary excretion of amphetamine which may be produced by altering urine pH.29 30 Drugs which modify urine pH, such as carbonicanhydrase inhibitors, may therefore influence the rate of excretion and possibly the duration of action of amphetamine. Similarly, a drug which alters the renal clearancerate of another drug may modify its action. Recent work 31 suggests that corticosteroids may increase the clearance-rate of salicylates, and their withdrawal may lead to signs of salicylate intoxication. Whatever its inherent dangers, combination therapy is here to stay as combined preparations or as the separate administration of more than one drug. The introduction of more potent drugs, with their greater risk of interaction with other agents at different sites, " necessitates a firmer association between basic pharmacology and clinical medicine. This could be established by the development of departments in clinical pharmacology at university centres. A largely increased teaching and research programme devoted to mechanisms of action of drugs in man is an excellent method to safeguard pharmacotherapy, far superior to the other alternative, the withdrawal of useful drugs from the market ".10
by
Annotations HOW MANY MORE COLD VIRUSES?
DESPITE much research on common colds and related diseases, there is still no answer to the question: What causes them ? Since the introduction of tissue culture many new viruses have been cultivated, and it is now known that colds and sore throats can be produced by parainfluenza viruses, respiratory syncytical virus, and adenoviruses or enteroviruses. Even so, a study in Britain showed that, even when tests for all these were applied, a virus was isolated from only about a quarter of all patients with colds.32 Organ-cultures of human respiratory epithelium have been shown to support the growth of representative strains of all the viruses mentioned above, which infect and often destroy the ciliated mucus-secreting epithelium of such cultures. (By contrast the cells of tissue cultures are in a dedifferentiated state and show little or none of the physiological activity of the cells of the tissue from which they are derived.) The ciliated cells of such organ-cultures support the growth of rhinoviruses which do not multiply in tissue cultures of human lung-fibroblasts or kidneycells, and in addition an apparently new type of etherlabile virus produces colds of a slightly different clinical type from that caused by rhinoviruses. Elsewhere in this issue Dr. Tyrrell and Dr. Bynoe, of the Common Cold Research Unit, Salisbury, describe further studies with organ-cultures of human respiratory epithelium. They tested a series of 33 specimens mostly taken from patients with naturally acquired colds. They obtained a virus from 10 specimens (i.e., about a third) by using tissue cultures, but by using organ-cultures they 29. 30.
Beckett, A. H., Rowand, M., Turner, P. Lancet, 1965, i, 303. Asatoor, A. M., Galman, B. R., Johnson, J. R., Milne, M. D. Br. J. Pharmacol. Chemother, 1965, 24, 293. 31. Klinenberg, J. R., Miller, F. J. Am. med. Ass. 1965, 194, 601. 32. Medical Research Council Working Party on Acute Respiratory Virus Infections. Br. med. J.
1965, ii,
319.
cultivated
agent from 25 specimens (i.e., three9 of the " new " agents turned out to be rhinoviruses which were eventually persuaded to grow in tissue cultures of human cells, but the remaining 6 were recognised only because they caused colds in volunteers. Further tests with volunteers showed that about half the specimens which yielded virus in organ-cultures contained no virus which could cause colds. Owing to the technical difficulties it may be some time before we learn exactly what viruses the Salisbury workers have cultivated, but it seems clear that organcultures of the type they use can support the growth of a great many viruses which previous techniques would not. This represents an important step towards answering the question: What causes colds ? an
quarters).
A ROOMFUL OF MERCURY
THE
danger
using metallic mercury in a confined always appreciated. From Manchester,
of
space is still not
Butterworth et al.1 report an incident in which the local authority used its powers under the Offices, Shops, and Railway Premises Act of 1963 to intervene and forestall mercury poisoning in two technicians. The men were engaged in operating an electrical display sign. The technical transfer of information to the screen involved the use of rolls of specially prepared paper and large quantities of metallic mercury. The paper became contaminated in use and was therefore subsequently passed through a mechanical scraping device; mercury collected below this in an open tray. Even after this process globules of mercury could still be seen on the used paper lying piled below the workbench. The mercury was itself cleaned daily by passage through a domestic-type nylon sieve. The straining was done by hand and took 1 1/2 hours. All these manipulations were carried out in a room measuring 12 ft. 3 in. by 9 ft. There In cold was one small window and no extractor fan. weather the door was kept shut. The technicians had only aprons to protect their clothing and nowhere outside the work-room to hang their coats. They were provided with soap and towels but these too had to be kept in the room; and there was no washing place near at hand. Each employee worked a six-day week either from 10 A.M. to 5 P.M. or from 5 P.M. to midnight. The health department found a working atmosphere in the control room containing about 800 (.Lg. of inorganic mercury per c.m. of air. (The highest concentration permitted in factories is 100 (.Lg. per c.m.) Rugs on the floor were heavily contaminated and globules of mercury lay on the floor and workbench. Fortunately, neither technician had been doing the job for more than a few months, and in neither was significant physical or mental abnormality detected. The urine of each contained large amounts of mercury but no trace of albumin. Meanwhile, their employers readily agreed to overhaul working conditions as the inspectors had recommended. The mercury switches were to be enclosed and extraction ventilation installed; a mechanical cleaner was to replace the nylon sieve; and the room was to be cleaned out with a mercury fixative, and non-absorbent floor-covering provided. Finally, other authorities were alerted to what may, in the operation of this type of sign, be going on behind the scenes. 1.
Butterworth, A., Christian, G. A., Essex-Cater, A. J. Med. Offr, 1965. 15, 223.
applied to the stable state when there is probably equilibrium across cell membranes. The exchangeable pool and the turnover are diminished in overt hypoparathyroidism 13 and it would be interesting to know whether the same is true, in lesser degree, of partial parathyroid insufficiency. The fact that the severity of the symptoms is not necessarily related to serum-calcium levels might be accounted for by other factors affecting neuromuscular irritability, such as the presence of mild myxoedema. A more cogent reason for seeking latent hypoparathyroidism is that infection or pregnancy may precipitate overt hypoparathyroidism in an apparently cured patient.14 Those at risk should perhaps be warned, and if the E.D.T.A. test cannot be done subjects with serumcalcium levels in the lower normal range should be kept under observation. The E.D.T.A. test is dangerous to those whose serum-calcium levels are already low. FOURMAN and his colleagues in Cardiff 14 15 and MICHIE and his co-workers in Aberdeen 16 emphasise that overt hypoparathyroidism after thyroidectomy is rarely transient and that low parathyroid reserve can usually be demonstrated months or years after operation. On the other hand, if the insufficiency is symptomless immediately after operation the function of the gland usually recovers within 3 months. FpuRMAN’s group suggest that 3 months after operation is the best time for routine calcium estimation (rather than the 3 weeks recommended by LACHMANN), since most subjects will have recovered their normal parathyroid reserve by this time, and delayed cases should then be detectable. Moreover, hyperplasia of the remaining parathyroid tissue may depend on the stimulus of low calcium concentrations, and mild asymptomatic hypocalcasmia may be better left untreated for at least 2 years.14 Very low calcium levels should be corrected because of the risk of cataracts, fits, and mental disease. The treatment may require large doses of vitamin D as well as calcium, and be
carefully supervised. The’reported prevalence of hypoparathyroidism after thyroid surgery has varied widely. On the basis of calcium-depletion tests the Cardiff workers found that it was 24%. so Most centres reported lower figures, and this led to a reappraisal of the operative technique in Cardiff and reduction of the prevalence to 4%. This success demonstrates how the right surgical procedure can conserve parathyroid function. Removal of the the is cause,’’-19 and infarction glands probably rarely is a more likely explanation. Although the parathyroids are usually supplied by the inferior thyroid artery, 17 ligation of this vessel does not affect the glands because there must
is extensive anastomosis with branches from the tracheal and oesophageal vessels.17 19 Damage to the single endartery to each gland will cause infarction, and the risk of this probably increases if haemostatic ligatures and 13.
Milhaud, G., Bourichon, J. C. r. hebd. Séanc. Acad. Sci. Paris, 1964, 258,
14. 15.
Wade, J. S. H., Fourman, P., Deane, L. Br. J. Surg. 1965, 52, 493. Wade, J. S. H., Goodall, P., Deane, L., Dauncey, T. M., Fourman, P. ibid. p. 497. Michie, W., Stowers, J. M., Frazer, S. C., Gunn, A. ibid. p. 503. Halstead, W. S., Evans, H. M. Ann. Surg. 1907, 46, 489. Curtis, G. M. Illinois med. J. 1931, 59, 361. Wade, J. S. H. Br. J. Surg. 1960, 48, 25.
3398.
16. 17. 18. 19.
applied close to the parathyroids.15 It may be significant that hypoparathyroidism is most common after operation on toxic goitres iei9; haemostasis is especially difficult in these cases. Although the incidence of hypoparathyroidism can be reduced by good surgical technique, the onus is on the surgeon to look for this condition in all his patients at risk. A minimum precaution is estimation of serumcalcium 3 months after operation. Patients in whom overt hypoparathyroidism develops soon after operation are unlikely to recover full parathyroid function, and they should be kept under observation.
sutures are
The Interaction of Drugs POLYPHARMACY is not a feature of our generation alone. For centuries doctors have prescribed more than one drug at a time, and it was this practice, in part, that led to the development of homoeopathic medicine. A Use of the last century Hommopathic Guide for Family " states authoritatively that alternate administration is the only method of combining the action of two or more medicines. They cannot, in any case whatever, be mixed with propriety ". Nevertheless, many important therapeutic advances have been due to the use of rational and careful combinations of drugs. It is important, however, that the clinical effects of drug interactions should be carefully assessed if toxic effects are to be reduced and therapeutic benefits exploited. Earlier this year a symposium1 at the Royal Society of Medicine was devoted to this subject and the proceedings have now been published as a special supplement2 to the Proceedings. The " dark ages " of ignorance of the basic mechanisms in interaction are passing. Combination therapy has been particularly fruitful with antibiotics and in the treatment of hypertension and acute leukaemia. MARY BARBER3 reviewed the importance of combinations of two bactericidal antibiotics in the treatment of severe infections, such as bacterial endocarditis, when infecting bacteria may not be readily killed by a single drug. Whenever possible, double sensitivity tests should be applied to the organism concerned. Antibiotic combinations also delay the emergence of resistant strains, not only in tuberculosis but also in staphylococcal and coliform infections. In the treatment of hypertension4 combined treatment often reduces the required dose of each drug and averts their side-effects. Moreover, DOLLERY4 points out that such treatment may be more economical than giving a single drug. There is little doubt that the addition of a thiazide diuretic enhances the hypotensive effect of ganglion-blocking and adrenergicblocking drugs. While the prognosis of acute leuktmia in adults is appalling,5 there is reason for cautious optimism in childhood leukaemia.6ZUBRODreviewed the results obtained by the acute leukxmia task force 1. See Lancet, 1965, i, 906. 2. Proc. R. Soc. Med. 1965, 58, 943. 3. Barber, M. ibid. p. 990. 4. Dollery, C. T. ibid. p. 983. 5. Lancet, 1965, ii, 938.
6. 7.
Hardisty, R. M. ibid. p. 1134. Zubrod, C. G. Proc. R. Soc. Med. 1965, 58,
988.
83
in the U.S.A. in studies of L 1210 mouse leukaemia, which proved to be an excellent predictive model for the childhood disease. Examination of the kinetics of cell generation, leukaemic cell population size, and fractional
destruction by individual antileukaemic drugs have created a rational basis for combination therapy. BuRcHENALhas now reported 101 patients with known acute leukaemia who had survived 5-14 years, of whom 64 had no signs of the disease. Toxic as well as therapeutic interactions may be As early as 1938, GADDUM and KWIATpredictable. KOWSKI 9 observed that some drugs might produce pharmacological effects by inhibiting catabolism of catecholamines, and, in retrospect, most of the interactions of the monoamine-oxidase inhibitorswith other drugs and food substances 10 could have been predicted and avoided. On the other hand, there are big species differences in the metabolic pathways of catecholamines, and here particularly trial in man is the only way of establishing drug interaction in man. If it is not performed in a regulated experiment, trials will be continuously performed in the clinical use of the new drug until all possibilities have been explored, and results collated ".11 Unfortunately too few regulated experiments have been conducted, and wisdom has often "
dawned after the unwanted event. The toxic interactions of the monoamine-oxidase inhibitors has attracted much interest (a London teaching hospital asked its final-year nurses to write an essay on " cerebral
and cheese ") and stimulated valuable research; but these drugs are of limited value which restricts the number of side-effects. That is not true of interactions between other more commonly used psychotropic agents,12particularly when barbiturates are involved; but their scientific evaluation is extremely difficult. Sensitive psychophysiological 13 14 and psychosensory 15 tests indicate possible ways in which inter-
haemorrhage
actions of centrally acting drugs may be studied from both therapeutic and toxic aspects. The greater our understanding of a drug’s mechanism of action and metabolic pathway, the more predictable are its possible toxic interactions. The relation between digitalis and potassium explains the increased toxicity of digitalis when associated with potassium depletion produced by diuretics. Many drugs are bound to plasmaproteins, and may be displaced from them by other drugs with a higher affinity for the protein. Such displacement may be particularly dangerous if the unbound active moiety is a small fraction of the total, since displacement of only a small proportion may then double or treble its unbound concentration at the target site.16 EISEN 17 has reported severe. bleeding in patients under treatment with warfarin which had been displaced by 8.
Burchenal, J. Proceedings of Fifth National Cancer Conference, Phila-
delphia, 1965. 9. Gaddum, J. W., Kwiatkowski, H. J. J. Physiol. 1938, 94, 87. 10. Sjoqvist, F. Proc. R. Soc. Med. 1965, 58, 967. 11. Modell, W. Clin. Pharmacol. Ther. 1964, 5, 265. 12. Shepherd, M. Proc. R. Soc. Med. 1965, 58, 964. 13. Dick, P., Shepherd, M. Psychopharmacologia, 1965, 8, 32. 14. Dickens, D. W., Lader, M. H., Steinberg, H. Br. J. Pharmacol. Chemother, 24, 14.
15. Turner, P. J. Pharm. Pharmacol. 1965, 17, 388. 16. Brodie, B. B. Proc. R. Soc. Med. 1965, 58, 946. 17. Eisen, N. G. J. Am. med. Ass. 1964, 189, 64.
phenylbutazone or oxyphenbutazone so that its anticoagulant activity was greatly enhanced. A closely bound sulphonamide such as sulphaphenazole can induce hypoglycxmic coma by displacing tolbutamide from plasma-protein.188 Sulphonamides, salicylates, and other agents which readily combine with albumin should not be given to the newborn, because displacement of bilirubin and its diffusion into the brain may produce kernicterus.19 Displacement may sometimes help, as when however, phenylbutazone raises the level of unbound sulphonamide or penicillin and thus enhances their antibiotic activity. Anti-inflammatory action of such drugs as salicylates, phenylbutazone, and indomethacin may be due to their ability to displace corticosteroids from their plasma-protein binding, allowing their more ready dispersal into tissues.16 Another interesting aspect of drug metabolism is enzyme stimulation and inhibition. 20 A drug may inof metabolism or that of another drug by increasing or decreasing the amount of drug-metabolising enzyme in liver microsomes. For example, phenobarbitone so accelerates the metabolism of subsequent doses of hexobarbitone as to abolish almost completely its pharmacological activity.21 Phenobarbitone acts similarly on the activity of liver enzymes responsible for metabolising coumarin derivatives, and BURNS and CONNEY 20 describe a patient whose prothrombin-time and plasma-dicoumarol level were significantly lowered by giving 60 mg. of phenobarbitone daily for four weeks. This observation explains earlier reports of barbiturates decreasing the activity of coumarin drugs. 22 Other drugs whose metabolism is increased by barbiturates are diphenylhydantoin and griseofulvin. Phenylbutazone has a similar action on the rate of destruction of other drugs. Many hitherto unexplained variations in drug activity may be the result of this phenomenon, evoked not only by other drugs but also by substances in the environment, such as insecticides.23 The ability of drugs to inhibit the metabolism of other drugs, and thus enhance their activity, has been demonstrated in animals and in man; and this may offer another explanation for the potentiation of the anticoagulant action of coumarin derivatives by oxyphenbutazone.1 1 24 25 Some compounds, it seems, inhibit metabolism of certain drugs when given to animals in a single large dose, but stimulate metabolism when given over a longer period.2s 2’ Changes in acid-base balance within the body may affect the efficacy and toxicity of drugs.28 Absorption of weak acids and bases from the gastrointestinal tract, their distribution between extracellular and intracellular fluid, and their urinary excretion are modified crease or
decrease its
own rate
18. Christensen, L. K., Hansen, J. M., Kristensen, M. Lancet, 1963, ii, 1298. 19. Odell, G. B. J. clin. Invest. 1959, 38, 823. 20. Burns, J. J., Conney, A. H. Proc. R. Soc. Med. 1965, 58, 955. 21. Conney, A. H., Davison, C., Gastel, R., Burns, J. J. J. Pharmacol. exp. Ther. 130, 1. 22. Avellaneda, M. Medicina, B. Aires, 1955, 15, 109. 23. Hart, L. G., Schultice, R. W., Fouts, J. R. Toxicol. appl. Pharmacol. 1963, 5, 371. 24. Fox, S. L. J. Am. med. Ass. 1964, 188, 320. 25. Weiner, M., Siddiqui, A. A., Bostanci, N., Dayton, P. G. Fedn Proc. Fedn Am. Socs exp. Biol. 24, 153. 26. Serrone, D. M., Fujimoto, J. M. Biochem. Pharmacol. 1962, 11, 609. 27. Kato, R., Chiesara, E., Vassanelli, P. ibid. 1964, 13, 69. 28. Milne, M. D. Proc. R. Soc. Med. 1965, 58, 961.
84
their degree of ionisation. Particularly dramatic are the changes in the rate of urinary excretion of amphetamine which may be produced by altering urine pH.29 30 Drugs which modify urine pH, such as carbonicanhydrase inhibitors, may therefore influence the rate of excretion and possibly the duration of action of amphetamine. Similarly, a drug which alters the renal clearancerate of another drug may modify its action. Recent work 31 suggests that corticosteroids may increase the clearance-rate of salicylates, and their withdrawal may lead to signs of salicylate intoxication. Whatever its inherent dangers, combination therapy is here to stay as combined preparations or as the separate administration of more than one drug. The introduction of more potent drugs, with their greater risk of interaction with other agents at different sites, " necessitates a firmer association between basic pharmacology and clinical medicine. This could be established by the development of departments in clinical pharmacology at university centres. A largely increased teaching and research programme devoted to mechanisms of action of drugs in man is an excellent method to safeguard pharmacotherapy, far superior to the other alternative, the withdrawal of useful drugs from the market ".10
by
Annotations HOW MANY MORE COLD VIRUSES?
DESPITE much research on common colds and related diseases, there is still no answer to the question: What causes them ? Since the introduction of tissue culture many new viruses have been cultivated, and it is now known that colds and sore throats can be produced by parainfluenza viruses, respiratory syncytical virus, and adenoviruses or enteroviruses. Even so, a study in Britain showed that, even when tests for all these were applied, a virus was isolated from only about a quarter of all patients with colds.32 Organ-cultures of human respiratory epithelium have been shown to support the growth of representative strains of all the viruses mentioned above, which infect and often destroy the ciliated mucus-secreting epithelium of such cultures. (By contrast the cells of tissue cultures are in a dedifferentiated state and show little or none of the physiological activity of the cells of the tissue from which they are derived.) The ciliated cells of such organ-cultures support the growth of rhinoviruses which do not multiply in tissue cultures of human lung-fibroblasts or kidneycells, and in addition an apparently new type of etherlabile virus produces colds of a slightly different clinical type from that caused by rhinoviruses. Elsewhere in this issue Dr. Tyrrell and Dr. Bynoe, of the Common Cold Research Unit, Salisbury, describe further studies with organ-cultures of human respiratory epithelium. They tested a series of 33 specimens mostly taken from patients with naturally acquired colds. They obtained a virus from 10 specimens (i.e., about a third) by using tissue cultures, but by using organ-cultures they 29. 30.
Beckett, A. H., Rowand, M., Turner, P. Lancet, 1965, i, 303. Asatoor, A. M., Galman, B. R., Johnson, J. R., Milne, M. D. Br. J. Pharmacol. Chemother, 1965, 24, 293. 31. Klinenberg, J. R., Miller, F. J. Am. med. Ass. 1965, 194, 601. 32. Medical Research Council Working Party on Acute Respiratory Virus Infections. Br. med. J.
1965, ii,
319.
cultivated
agent from 25 specimens (i.e., three9 of the " new " agents turned out to be rhinoviruses which were eventually persuaded to grow in tissue cultures of human cells, but the remaining 6 were recognised only because they caused colds in volunteers. Further tests with volunteers showed that about half the specimens which yielded virus in organ-cultures contained no virus which could cause colds. Owing to the technical difficulties it may be some time before we learn exactly what viruses the Salisbury workers have cultivated, but it seems clear that organcultures of the type they use can support the growth of a great many viruses which previous techniques would not. This represents an important step towards answering the question: What causes colds ? an
quarters).
A ROOMFUL OF MERCURY
THE
danger
using metallic mercury in a confined always appreciated. From Manchester,
of
space is still not
Butterworth et al.1 report an incident in which the local authority used its powers under the Offices, Shops, and Railway Premises Act of 1963 to intervene and forestall mercury poisoning in two technicians. The men were engaged in operating an electrical display sign. The technical transfer of information to the screen involved the use of rolls of specially prepared paper and large quantities of metallic mercury. The paper became contaminated in use and was therefore subsequently passed through a mechanical scraping device; mercury collected below this in an open tray. Even after this process globules of mercury could still be seen on the used paper lying piled below the workbench. The mercury was itself cleaned daily by passage through a domestic-type nylon sieve. The straining was done by hand and took 1 1/2 hours. All these manipulations were carried out in a room measuring 12 ft. 3 in. by 9 ft. There In cold was one small window and no extractor fan. weather the door was kept shut. The technicians had only aprons to protect their clothing and nowhere outside the work-room to hang their coats. They were provided with soap and towels but these too had to be kept in the room; and there was no washing place near at hand. Each employee worked a six-day week either from 10 A.M. to 5 P.M. or from 5 P.M. to midnight. The health department found a working atmosphere in the control room containing about 800 (.Lg. of inorganic mercury per c.m. of air. (The highest concentration permitted in factories is 100 (.Lg. per c.m.) Rugs on the floor were heavily contaminated and globules of mercury lay on the floor and workbench. Fortunately, neither technician had been doing the job for more than a few months, and in neither was significant physical or mental abnormality detected. The urine of each contained large amounts of mercury but no trace of albumin. Meanwhile, their employers readily agreed to overhaul working conditions as the inspectors had recommended. The mercury switches were to be enclosed and extraction ventilation installed; a mechanical cleaner was to replace the nylon sieve; and the room was to be cleaned out with a mercury fixative, and non-absorbent floor-covering provided. Finally, other authorities were alerted to what may, in the operation of this type of sign, be going on behind the scenes. 1.
Butterworth, A., Christian, G. A., Essex-Cater, A. J. Med. Offr, 1965. 15, 223.