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Expectorants Old and New
880
biopsy tube in 31 patients who had had a partial gastrectomy. In 17 an iron-deficiency anaemia had developed at various times from two to nine years after the operation : in 14 of them the jejunal mucosa was normal, and in 2 it was cedematous ; atrophy was present in only 1 patient who, five years after operation, had a severe iron-deficiency anaemia with hoemoglobin of 42%, koilonychia, a sore tongue, and angular stomatitis ; but 2 other equally anaemic patients had normal mucosa. 9 patients had no anaemia, but hyperwith WooD’s
There are two distinct types of sputum, which have different chemical and rheological properties. Sputum which is clear and gelatinous is highly viscid and adhesive ;it consists of a mucoprotein gel which normally contains water. The more water the gel contains the less viscid the secretion becomes, and when it loses water
through drying
its
viscosity
increases.
Sputum
which is opaque and yellow is less viscid and adhesive than mucoid sputum, and it consists of coarse bundles of deoxyribonucleoprotein and pus cells. A specific aemia with or without oedema of the mucosa was deoxyribonuclease (streptodornase) may be given by recorded in 2 of them and jejunitis in 1. Among 5 aerosol when the secretion is purulent,13 but no patients with steatorrhoea following gastrectomy, mucinase acts specifically against mucoid sputum; 1 had an atrophic jejunal mucosa and 1 had jejunitis. this is countered bv aerosol inhalation of a fine water No correlation was found between the time since opera- or saline mist to reduce viscidity by hydrating the gel, tion and the appearance of jejunal changes. These or by aerosol inhalation of trypsin-14-11 Trypsin is in. results are somewhat conflicting, and BAIRD and active in purulent sputum," since pus contains DODGE cautiously conclude that iron-deficiency trypsin inhibitors. anaemia and steatorrhcea after partial gastrectomy When the sputum is viscid, the cough reflex is " cannot regularly be attributed to structural alterainactive, or there is respiratory paralysis, sputum is tions in the jejunal mucosa." retained in the lungs ;under these circumstances it may These reports remind us that anæmia is a complicaimpede ventilatory efficiency and cause death from tion to be reckoned with in partial and total gastrecasphyxia, occlude a major bronchus and cause massive tomy. Anaemia after total gastrectomy is easy to or lobar collapse, or by interference with ciliary understand, since the operation removes so much of activity in the smaller bronchi give rise to segmental the mucosa that secretion of the intrinsic factor essencollapse and diffuse bronchopneumonia. In the bedtial for the absorption of vitamin B12 is severely ridden and bronchitics, patients who have had reduced.8 The cause of anaemia after partial gastrec- abdominal aged, operations, and those with paralysed tomy is less clearly defined ; continuing blood-loss from respiratory muscles, problems in the treatment of mucosa exposed to an unusual environment, perhaps sputum retention loom large. We have published gastritis leading to loss of function of secreting cells, recently papers dealing with certain aspects of these and, occasionally, jejunal abnormalities, may all be problems. Dr. PALMER 1’ found that alevaire (which responsible. Fortunately the treatment is straight- contains a detergent, sodium bicarbonate, and water) forward ; the iron-deficiency anaemia mostly responds by aerosol inhalation facilitated the expectoration of to oral iron, and the occasional megaloblastic anaemia viscid mucoid sputum in chronic bronchitics. This was to parenteral vitamin Bi2. Prevention of the anaemia shown to be due probably to simple hydration of the is certainly important and is best secured by arranging viscid by the water contained in the aerosol, for an annual blood-count for patients who have had rather sputum than to an effect from the detergent or the this operation. sodium bicarbonate. During a week’s aerosol inhala tion there was no constant reduction in the viscosity of Expectorants Old and New morning specimens of sputum, but the viscosity of the Since ALSTEAD9 10 suggested that the expectorants sputum produced immediately after an hour’s aerosol commonly given by mouth did not increase the volume inhalation was considerably reduced. Dr. FORBES and of sputum in chronic bronchitis, their value has been Dr. WISE 18 gave patients with chronic chest diseases questioned and their popularity has waned. An various expectorants by mouth and by aerosol inhalaexpectorant is a substance which assists in the removal tion. All sputum expectorated in each of secretion or exudate from the respiratory passages : hour period was collected ;its volume was measured it may do so by producing an irritant cough, by increasand the viscosity of the total specimen determined. secretion from the ing respiratory glands, thereby They found no constant reduction in viscosity with any making the sputum more fluid and less tenacious, or by of the substances tried-probably because, as PALMER’S a direct action on the sputum when given by aerosol work suggests, changes in viscosity are very transitory, inhalation. Drugs such as ammonium chloride, iodides, and can be demonstrated only immediately after the and ipecacuanha are thought to make the sputum less ! aerosol inhalation. viscid by increasing the output of fluid in the respiraIn a further paper Dr. HARWOOD STEVENSON and tory tract.l1 Whereas the effect of these substances by Dr. KINNIER WILSON 19 discuss their experience of the mouth may not be impressive, sodium iodide intramanagement of respiratory infection in the chronic venously in doses of 1 g. causes a big increase in the stage of poliomyelitis. They advocate chemotherapy, volume of the bronchial secretion.12 Steam, detergent assisted coughing, and postural drainage, aided by solutions (such asAlevaire ’), and enzymes (such as aerosol inhalation of trypsin and isoprenaline, and at trypsin and deoxyribonuclease) are given by aerosol times oral promethazine. Treatment by assisted inhalation to reduce the viscidity of the sputum by a direct physical or enzymatic action. 13. Armstrong, J. B., White, J. C. Lancet, 1950, ii, 739,
twenty-four-
8. 9. 10. 11.
Callender, S., Turnbull, A., Wakisaka, G. Clin. Sci. 1954, 13, 221. Alstead, S. Lancet, 1939, ii, 932.
Alstead, S. ibid. 1941, i, 308. Basch, E. P., Holinger, P., Poncher, H. G. Amer. J. Dis. Child. 1941, 62, 1149. 12. Baker, J. M., Roettig, L. C., Curtiss, G. M. Ann. Surg. 1951, 134, 641.
14. Limber, C. R., Reiser, H. G., Roettig, L. C., Curtiss, G. M. J. Amer. med. Ass. 1952, 149, 816. 15. Unger, L., Unger, A. M. ibid. 1953, 152, 1109. 16. Varga, C., Wild, J. Amer. J. Dis. Child. 1953, 86, 273. 17. Palmer, K. N. V. Lancet, 1957, i, 611. 18. Forbes, J., Wise, L. ibid. Oct. 19, 1957, p. 767 19. Harwood Stevenson, F., Kinnier Wilson, A. B. ibid. Oct. 26, 1957, p. 820.
881
coughing and postural drainage and by aerosol inhalation of isoprenaline has been shown to be a very effective method of preventing the retention of secretion and subsequent pulmonary collapse after abdominal operations-a combination of physiotherapy and isoprenaline being more effective than either given Singly.20 HARWOOD STEVENSON and KINNIER WILSON are impressed by the value of trypsin, which they suggest helps to liquefy the sputum. A similarly favourable impression has been reported by others.14-16 It is by no means certain, however, that this effect can be ascribed to the proteolytic action of trypsin. LIMBER et al.14 report that inhalation of trypsin results in coughing and direct stimulation of the respiratory passages with resultant secretion of fluid. Also, the beneficial effect from hydration of the mucoprotein gel by the water in the aerosol mist may be of greater importance than the proteolytic action of trypsin. FoRBES and WISE 18 remark that trypsin probably acts mainly as a respiratory-tract irritant, and that its chief virtue is that it stimulates coughing. Apparently, therefore, it cannot yet be confidently stated that trypsin, by virtue of its proteolytic action, is of value in the treatment of patients with mucoid sputum. 20. Palmer, K. N. V., Sellick, B. A. ibid. 1953, i, 164.
Annotations P.A.S. AND THE PATIENT
THE need for a long period of chemotherapy in pulmonary tuberculosis is now accepted, and the aim in most patients with active lesions is to maintain treatment for two years or more. On the other hand, many months of bed rest is now seldom necessary. Even patients with extensive disease can usually be allowed up after about two months, and those who have an operation can be prepared for it and recover from it more rapidly than before. Patients with less widespread lesions are probably best admitted to hospital for a few weeks so that the initial difficulties of drug therapy can be overcome, and to accustom them to the daily routine of administration. This arrangement has many advantages for the patient and it is a relatively cheap form of treatment which has, in the main, proved quite surprisingly successful. Thus, a group of patients treated in 1955-56 for the most part by ambulatory methods did just as well as a broadly comparable group of 1954-55 patients who had spent six times as long in bed.’ Clearly much of this success is due to the effectiveness of chemotherapy given under wellmanaged outpatient conditions. In the early stages, particularly when the patient is admitted to hospital for a short period, it is often the custom to give streptomycin with either or both of the other drugs ; when the patient is being treated as an outpatient streptomycin may be continued for a time, but it is usual to change before long to purely oral chemotherapy. Certain disadvantages then arise, mainly because of the bulk of p-aminosalicylic acid (P.A.S.) that has to be given and its unpleasant side-effects. Unfortunately, P.A.S. is a gastric and intestinal irritant, affecting some patients more than others, and its long-continued use may involve discomfort that becomes intolerable ; nausea, anorexia, looseness of the bowels, and gastric and intestinal flatulence can be troublesome. In an article on p. 871 Dr. Dixon and his colleagues point out how the success of P.A.S. therapy has always been threatened by these tiresome toxic effects ; and they have found by testing patients’ urine that only 50% of£ outpatients were
adhering strictly 1.
to their
P.A.S.
Wynn-Williams, N., Young,
schedule.
This disturb-
R. D. Tubercle, 1957, 38, 333.
Unfortunately trypsin gives rise to side-reactions, including dyspnoea, fever, hoarseness, and nasal and eyelid irritation14 18 21; and FARBER et al.22 suggest that with inhaled trypsin irritative effects are so common as to outweigh any possible advantages. -Furthermore FARBER et aI.21 have found pronounced alteration of the epithelial cells (atypical metaplasia and dyskeratosis) in sputum smears in patients receiving trypsin alone and trypsin with deoxyribonuclease by inhalation. These changes persisted in the sputum six months
after the inhalations were discontinued. Obviously the effect of these enzymes on the tracheobronchial tree should be further evaluated. Thus, in the management of retained secretion in the lungs, the treatment of choice would seem to consist in postural drainage with assisted coughing combined with the aerosol inhalation of a water-mist containing an antispasmodic such as isoprenaline, adequate fluid intake by mouth, and the avoidance of drugs such as morphine and pethidine which increase sputum
viscosity. 23
.
21. Farber, S. M., Pharr, S. L., Trant, H. F., Wood, D. A., Gorman, R. D. Lab. Invest. 1954, 3, 33. 22. Farber, S. M., Gorman, R. D., Wood, D. A., Grimes, O. F., Pharr, S. L. J. thorac. Surg. 1954, 27, 45. 23. Blanshard, G. Arch. Middx Hosp. 1955, 5, 222.
ingly low proportion will no doubt stimulate other chest physicians to examine more closely their outpatient chemotherapy. In doing so it would be specially valuable to elicit the reasons why a particular patient is not taking his P.A.f1.., so that something can be done to improve matters. Some physicians may feel that a careful analysis of the reasons is essential before the advice of Dr. Dixon and his colleagues to abandon the routine use of P.A.S. in outpatients is widely accepted, particularly since the longcontinued administration of streptomycin in older patients is apt to cause labyrinthine disturbance. Oral chemotherapy, even with its known handicaps, is often successful ; and it is also convenient and cheap-a year’s supply of P.A.S. and isoniazid, even in cachet form, costs less than a week’s stay in hospital. Nor has the taking of drugs irregularly been shown to produce resistance when they are combined in one cachet or powder ; it may do, but the results of treatment seem too good for resistance induced in this way to be at all common. Dr. Dixon and his colleagues refer to unexpected bacterial resistance revealed during relapse, but they do not assess the extent of this danger. Further inquiry might well reveal that when the drugs are given in combined form resistance is less likely to
develop. determining why P.A.S. simple matters should not be In
is not taken as prescribed, overlooked. Some patients, even after instruction, will be found to be taking the drugs before meals ; others find the four-times-a-day schedule awkward in practice, and there seems a good case for changing to twice or at most thrice daily routines ; giving the drugs four times a day usually means that the whole daily dose is taken during one half of the twenty-four hours and none during the other half. It seems more logical to have two peak periods twelve hours apart-e.g., four 15 g. P.A.s.-isoniazid cachets twice a day (after breakfast and the main evening meal) instead of two four times a day. This would also get over the difficulty some patients have in finding a suitable opportunity to take the drugs during the day ; the drugs could be kept at home, and wife, husband, or parent could help to see that they were taken regularly. Moreover, in patients who have recurrent toxic symptoms the possibility of allowing relief periods of several days should be considered ; many such patients resort to these gaps anyway, though they may not always admit to it, hence accounting for a proportion
biopsy tube in 31 patients who had had a partial gastrectomy. In 17 an iron-deficiency anaemia had developed at various times from two to nine years after the operation : in 14 of them the jejunal mucosa was normal, and in 2 it was cedematous ; atrophy was present in only 1 patient who, five years after operation, had a severe iron-deficiency anaemia with hoemoglobin of 42%, koilonychia, a sore tongue, and angular stomatitis ; but 2 other equally anaemic patients had normal mucosa. 9 patients had no anaemia, but hyperwith WooD’s
There are two distinct types of sputum, which have different chemical and rheological properties. Sputum which is clear and gelatinous is highly viscid and adhesive ;it consists of a mucoprotein gel which normally contains water. The more water the gel contains the less viscid the secretion becomes, and when it loses water
through drying
its
viscosity
increases.
Sputum
which is opaque and yellow is less viscid and adhesive than mucoid sputum, and it consists of coarse bundles of deoxyribonucleoprotein and pus cells. A specific aemia with or without oedema of the mucosa was deoxyribonuclease (streptodornase) may be given by recorded in 2 of them and jejunitis in 1. Among 5 aerosol when the secretion is purulent,13 but no patients with steatorrhoea following gastrectomy, mucinase acts specifically against mucoid sputum; 1 had an atrophic jejunal mucosa and 1 had jejunitis. this is countered bv aerosol inhalation of a fine water No correlation was found between the time since opera- or saline mist to reduce viscidity by hydrating the gel, tion and the appearance of jejunal changes. These or by aerosol inhalation of trypsin-14-11 Trypsin is in. results are somewhat conflicting, and BAIRD and active in purulent sputum," since pus contains DODGE cautiously conclude that iron-deficiency trypsin inhibitors. anaemia and steatorrhcea after partial gastrectomy When the sputum is viscid, the cough reflex is " cannot regularly be attributed to structural alterainactive, or there is respiratory paralysis, sputum is tions in the jejunal mucosa." retained in the lungs ;under these circumstances it may These reports remind us that anæmia is a complicaimpede ventilatory efficiency and cause death from tion to be reckoned with in partial and total gastrecasphyxia, occlude a major bronchus and cause massive tomy. Anaemia after total gastrectomy is easy to or lobar collapse, or by interference with ciliary understand, since the operation removes so much of activity in the smaller bronchi give rise to segmental the mucosa that secretion of the intrinsic factor essencollapse and diffuse bronchopneumonia. In the bedtial for the absorption of vitamin B12 is severely ridden and bronchitics, patients who have had reduced.8 The cause of anaemia after partial gastrec- abdominal aged, operations, and those with paralysed tomy is less clearly defined ; continuing blood-loss from respiratory muscles, problems in the treatment of mucosa exposed to an unusual environment, perhaps sputum retention loom large. We have published gastritis leading to loss of function of secreting cells, recently papers dealing with certain aspects of these and, occasionally, jejunal abnormalities, may all be problems. Dr. PALMER 1’ found that alevaire (which responsible. Fortunately the treatment is straight- contains a detergent, sodium bicarbonate, and water) forward ; the iron-deficiency anaemia mostly responds by aerosol inhalation facilitated the expectoration of to oral iron, and the occasional megaloblastic anaemia viscid mucoid sputum in chronic bronchitics. This was to parenteral vitamin Bi2. Prevention of the anaemia shown to be due probably to simple hydration of the is certainly important and is best secured by arranging viscid by the water contained in the aerosol, for an annual blood-count for patients who have had rather sputum than to an effect from the detergent or the this operation. sodium bicarbonate. During a week’s aerosol inhala tion there was no constant reduction in the viscosity of Expectorants Old and New morning specimens of sputum, but the viscosity of the Since ALSTEAD9 10 suggested that the expectorants sputum produced immediately after an hour’s aerosol commonly given by mouth did not increase the volume inhalation was considerably reduced. Dr. FORBES and of sputum in chronic bronchitis, their value has been Dr. WISE 18 gave patients with chronic chest diseases questioned and their popularity has waned. An various expectorants by mouth and by aerosol inhalaexpectorant is a substance which assists in the removal tion. All sputum expectorated in each of secretion or exudate from the respiratory passages : hour period was collected ;its volume was measured it may do so by producing an irritant cough, by increasand the viscosity of the total specimen determined. secretion from the ing respiratory glands, thereby They found no constant reduction in viscosity with any making the sputum more fluid and less tenacious, or by of the substances tried-probably because, as PALMER’S a direct action on the sputum when given by aerosol work suggests, changes in viscosity are very transitory, inhalation. Drugs such as ammonium chloride, iodides, and can be demonstrated only immediately after the and ipecacuanha are thought to make the sputum less ! aerosol inhalation. viscid by increasing the output of fluid in the respiraIn a further paper Dr. HARWOOD STEVENSON and tory tract.l1 Whereas the effect of these substances by Dr. KINNIER WILSON 19 discuss their experience of the mouth may not be impressive, sodium iodide intramanagement of respiratory infection in the chronic venously in doses of 1 g. causes a big increase in the stage of poliomyelitis. They advocate chemotherapy, volume of the bronchial secretion.12 Steam, detergent assisted coughing, and postural drainage, aided by solutions (such asAlevaire ’), and enzymes (such as aerosol inhalation of trypsin and isoprenaline, and at trypsin and deoxyribonuclease) are given by aerosol times oral promethazine. Treatment by assisted inhalation to reduce the viscidity of the sputum by a direct physical or enzymatic action. 13. Armstrong, J. B., White, J. C. Lancet, 1950, ii, 739,
twenty-four-
8. 9. 10. 11.
Callender, S., Turnbull, A., Wakisaka, G. Clin. Sci. 1954, 13, 221. Alstead, S. Lancet, 1939, ii, 932.
Alstead, S. ibid. 1941, i, 308. Basch, E. P., Holinger, P., Poncher, H. G. Amer. J. Dis. Child. 1941, 62, 1149. 12. Baker, J. M., Roettig, L. C., Curtiss, G. M. Ann. Surg. 1951, 134, 641.
14. Limber, C. R., Reiser, H. G., Roettig, L. C., Curtiss, G. M. J. Amer. med. Ass. 1952, 149, 816. 15. Unger, L., Unger, A. M. ibid. 1953, 152, 1109. 16. Varga, C., Wild, J. Amer. J. Dis. Child. 1953, 86, 273. 17. Palmer, K. N. V. Lancet, 1957, i, 611. 18. Forbes, J., Wise, L. ibid. Oct. 19, 1957, p. 767 19. Harwood Stevenson, F., Kinnier Wilson, A. B. ibid. Oct. 26, 1957, p. 820.
881
coughing and postural drainage and by aerosol inhalation of isoprenaline has been shown to be a very effective method of preventing the retention of secretion and subsequent pulmonary collapse after abdominal operations-a combination of physiotherapy and isoprenaline being more effective than either given Singly.20 HARWOOD STEVENSON and KINNIER WILSON are impressed by the value of trypsin, which they suggest helps to liquefy the sputum. A similarly favourable impression has been reported by others.14-16 It is by no means certain, however, that this effect can be ascribed to the proteolytic action of trypsin. LIMBER et al.14 report that inhalation of trypsin results in coughing and direct stimulation of the respiratory passages with resultant secretion of fluid. Also, the beneficial effect from hydration of the mucoprotein gel by the water in the aerosol mist may be of greater importance than the proteolytic action of trypsin. FoRBES and WISE 18 remark that trypsin probably acts mainly as a respiratory-tract irritant, and that its chief virtue is that it stimulates coughing. Apparently, therefore, it cannot yet be confidently stated that trypsin, by virtue of its proteolytic action, is of value in the treatment of patients with mucoid sputum. 20. Palmer, K. N. V., Sellick, B. A. ibid. 1953, i, 164.
Annotations P.A.S. AND THE PATIENT
THE need for a long period of chemotherapy in pulmonary tuberculosis is now accepted, and the aim in most patients with active lesions is to maintain treatment for two years or more. On the other hand, many months of bed rest is now seldom necessary. Even patients with extensive disease can usually be allowed up after about two months, and those who have an operation can be prepared for it and recover from it more rapidly than before. Patients with less widespread lesions are probably best admitted to hospital for a few weeks so that the initial difficulties of drug therapy can be overcome, and to accustom them to the daily routine of administration. This arrangement has many advantages for the patient and it is a relatively cheap form of treatment which has, in the main, proved quite surprisingly successful. Thus, a group of patients treated in 1955-56 for the most part by ambulatory methods did just as well as a broadly comparable group of 1954-55 patients who had spent six times as long in bed.’ Clearly much of this success is due to the effectiveness of chemotherapy given under wellmanaged outpatient conditions. In the early stages, particularly when the patient is admitted to hospital for a short period, it is often the custom to give streptomycin with either or both of the other drugs ; when the patient is being treated as an outpatient streptomycin may be continued for a time, but it is usual to change before long to purely oral chemotherapy. Certain disadvantages then arise, mainly because of the bulk of p-aminosalicylic acid (P.A.S.) that has to be given and its unpleasant side-effects. Unfortunately, P.A.S. is a gastric and intestinal irritant, affecting some patients more than others, and its long-continued use may involve discomfort that becomes intolerable ; nausea, anorexia, looseness of the bowels, and gastric and intestinal flatulence can be troublesome. In an article on p. 871 Dr. Dixon and his colleagues point out how the success of P.A.S. therapy has always been threatened by these tiresome toxic effects ; and they have found by testing patients’ urine that only 50% of£ outpatients were
adhering strictly 1.
to their
P.A.S.
Wynn-Williams, N., Young,
schedule.
This disturb-
R. D. Tubercle, 1957, 38, 333.
Unfortunately trypsin gives rise to side-reactions, including dyspnoea, fever, hoarseness, and nasal and eyelid irritation14 18 21; and FARBER et al.22 suggest that with inhaled trypsin irritative effects are so common as to outweigh any possible advantages. -Furthermore FARBER et aI.21 have found pronounced alteration of the epithelial cells (atypical metaplasia and dyskeratosis) in sputum smears in patients receiving trypsin alone and trypsin with deoxyribonuclease by inhalation. These changes persisted in the sputum six months
after the inhalations were discontinued. Obviously the effect of these enzymes on the tracheobronchial tree should be further evaluated. Thus, in the management of retained secretion in the lungs, the treatment of choice would seem to consist in postural drainage with assisted coughing combined with the aerosol inhalation of a water-mist containing an antispasmodic such as isoprenaline, adequate fluid intake by mouth, and the avoidance of drugs such as morphine and pethidine which increase sputum
viscosity. 23
.
21. Farber, S. M., Pharr, S. L., Trant, H. F., Wood, D. A., Gorman, R. D. Lab. Invest. 1954, 3, 33. 22. Farber, S. M., Gorman, R. D., Wood, D. A., Grimes, O. F., Pharr, S. L. J. thorac. Surg. 1954, 27, 45. 23. Blanshard, G. Arch. Middx Hosp. 1955, 5, 222.
ingly low proportion will no doubt stimulate other chest physicians to examine more closely their outpatient chemotherapy. In doing so it would be specially valuable to elicit the reasons why a particular patient is not taking his P.A.f1.., so that something can be done to improve matters. Some physicians may feel that a careful analysis of the reasons is essential before the advice of Dr. Dixon and his colleagues to abandon the routine use of P.A.S. in outpatients is widely accepted, particularly since the longcontinued administration of streptomycin in older patients is apt to cause labyrinthine disturbance. Oral chemotherapy, even with its known handicaps, is often successful ; and it is also convenient and cheap-a year’s supply of P.A.S. and isoniazid, even in cachet form, costs less than a week’s stay in hospital. Nor has the taking of drugs irregularly been shown to produce resistance when they are combined in one cachet or powder ; it may do, but the results of treatment seem too good for resistance induced in this way to be at all common. Dr. Dixon and his colleagues refer to unexpected bacterial resistance revealed during relapse, but they do not assess the extent of this danger. Further inquiry might well reveal that when the drugs are given in combined form resistance is less likely to
develop. determining why P.A.S. simple matters should not be In
is not taken as prescribed, overlooked. Some patients, even after instruction, will be found to be taking the drugs before meals ; others find the four-times-a-day schedule awkward in practice, and there seems a good case for changing to twice or at most thrice daily routines ; giving the drugs four times a day usually means that the whole daily dose is taken during one half of the twenty-four hours and none during the other half. It seems more logical to have two peak periods twelve hours apart-e.g., four 15 g. P.A.s.-isoniazid cachets twice a day (after breakfast and the main evening meal) instead of two four times a day. This would also get over the difficulty some patients have in finding a suitable opportunity to take the drugs during the day ; the drugs could be kept at home, and wife, husband, or parent could help to see that they were taken regularly. Moreover, in patients who have recurrent toxic symptoms the possibility of allowing relief periods of several days should be considered ; many such patients resort to these gaps anyway, though they may not always admit to it, hence accounting for a proportion