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CRIPPLING DISEASES
145
THE
LANCET
LONDON:SATURDAY, JANUARY
30,
1943
PROPAMIDINE AND WOUNDS of the diamidine comdiscovered first by KING, LouBlE and pounds from the clue thatSynthalin’ started who YoRKE, THE
therapeutic properties were
(a guanidine compound)
was
actively trypanocidal.
Further work by A. J. EwiNs and his colleagues led to the production of a large number of substances, of which the three most active are diamidino-stilbene
(stilbamidine), diamidino-diphenoxy-pentane (pentamidine) and diamidino-diphenoxy-propane (prop amidine). These compounds have been found to be curative for a variety of protozoal infections such as kala-azar (for which they will possibly replace the antimonials previously used), sleeping sickness, and babesiasis of animals ; in addition they exert a limited activity against malaria in monkeys and in More recently, the scope of these compounds has been extended by the discovery that-they possess also a strong bacteriostatic action, first described last year by FULLER.2 Their antibacterial action has been studied intensively in the laboratories of MAY and- BAKER Ltd. ; and as a result of this work one of the compounds, propamidine, was considered to show promise as a wound antiseptic. This impression is well confirmed in a series of four papers, printed in our present issue, recounting the clinical application of propamidine under a variety of conditions. It is applied to the wound or burn, in a jelly or cetylalcohol preparation, on alternate days for ten days. This treatment is effective in removing streptococci from the wound ; often but not always it removes staphylococci; it has little action against proteus or pyocyanea. In the concentration suggested (0’1%) no harm is done to granulation tissue nor is phagocytosis lessened ; higher concentrations may however cause local necrosis and irritation of the adjacent skin. The antibacterial action is not inhibited by pus or by p-aminobenzoic acid, and it is not affected by the presence of sulphonamide resistance. Judging by the clinical results the compound has been of striking value both in treating old infected wounds and in dressing fresh burns. The chief weakness noted to date is the failure to control infection with proteus or pyocyanea which, although mainly saprophytic, may give enough trouble to hinder skin grafting. The extent to which absorption of the drug may occur from the wound into the general circulation is at present unknown, since no method of estimating small concentrations of propamidine is available. That absorption is limited and spread over a considerable period is made probable by the work of HAWKING, HENRY and their collaborators 34 on the related compound stilbamidine, whose presence is betrayed by its fluorescence. Stilbamidine, when introduced into the body, is stored particularly in the liver and kidney, man.
much is absorbed by the red blood-cells, and about 10% of the dose injected is excreted in the urine during the first three days ; probably propamidine follows a 1. King, H, Lourie, E. M. and Yorke. W. Ann. trop. Med. Parasit. 1938, 32, 177. Fuller, A. T. Biochem. J. 1942, 36, 548. Hawking, F. and Smiles, J. Ann. trop. Med. Parasit. 1941, 35, 45. Henry, A. J. and Grindley, D. N. Ibid, 1942, 36, 102.
2. 3. 4.
similar course. No general toxic effects are recorded in the present series of papers. Judging by experiments with mice and streptococci2 propamidine and its similars seem unlikely to exert a therapeutic effect upon bacterial infections when administered systemically by intravenous injection. After injection (tolerated dose about 2 mg. per kg.) of the drug for sleeping sickness, immediate collapse has occurred, resembling histamine shock but soon passing off ; after pentamidine violent itching may occur (LouRiE 5). Late toxic effects have been rare, but in animals degeneration of the liver and kidneys have been observed ; NAPIER and GUPTA6 have reported several cases of neuritis in the trigeminal nerve. Such symptoms are not likely to occur when propamidine is applied locally by the technique described above unless very large areas are treated, but the possibility should be borne in mind. The whole investigation so far has been a pretty piece of teamwork and further progress will be followed with zest.
CRIPPLING DISEASES ANY disease or disorder which leads to incapacity could be called a crippling disease-a patient’s capacity for work might be limited by cardiac, pulmonary or renal disorder-but the term is conveniently restricted to disablement of the locomotor system. Among the more important causes are the chronic rheumatic diseases, including rheumatoid arthritis, osteo-arthritis and non-articular rheumatism affecting the fibrous tissues and muscles, ligaments, nerves and the capsules of thejoints. The size of the problem they create has often been noted ; probably no. single medical disorder leads to greater suffering to the patient, or loss of efficiency and cost to the country. It has been estimated that more than a million patients in England consult their doctors annually because of the chronic rheumatic diseases, and that’ a_ sixth of the total invalidity of the insured population is -due to this cause. The cost, in England and Wales, is at least :1:20,000,000 annually. DAVIDSON and DUTHIE7 investigated the incidence of the rheumatic diseases in the north-east of Scotland and calculated that in the whole country at least 300,000 persons annually required medical treatment. Most of the patients were suffering from non-articular rheumatism, but many thousands were incapacitated by more serious forms of arthritis. This finding is confirmed in the official publications of the Department of Health for Scotland, which state that 14% of the total invalidity of persons insured under the NHI Act was due to rheumatism, and that 50,000 insured persons in Scotland were totally incapacitated every year, the average period of incapacity being 60 days. Three million working days were lost annually because of the ravages of the chronic rheumaticdiseases, and the annual economic loss to Scotland was estimated at :1:3,000,000, with resulting misery to patients and
dependents. No official attempt has been made so far to tackle the problem, and it was in the hope of stimulating the official conscience that the Empire Rheumatism Council published in 1940 a plan for national action8 which sets out simply a few facts about causation and Lourie, E. M. Ibid, 1942, 36, 113. 6. Napier L. E. and Gupta, P. C. S. Indian Med. Gaz. 1942, 77, 71. 7. Davidson, L. S. P. J. R. Inst. Publ. Hlth Hyg. 1940, 3, 245. 8. Rheumatism : A Plan for National Action. London, 1940.
5.
146 the limited facilities for treatmentavailable and and the British Orthopaedic Association have now set concludes with a general plan for the control of this up will formulate a comprehensive scheme for the group of disorders. The monograph has stimulated prevention and control of crippling diseases acceptable medical thought and iai eighteen months has had to to the Ministry of Health and the Department of be reprinted three times. But it must not be overHealth of Scotland, so that it can be incorporated and diseases disorders -forthwith in the postwar national medical service. that other looked causing the locomotor deserve attention of system incapacity in any national scheme. Crippling may result from THE DYSENTERY CARRIER birth defects, injuries, acquired postural IN bacillary dysentery the infection is confined to congenital disorders, trauma including fractures, and infective the bowel without as a rule any systemic spread, diseases such as tuberculosis and poliomyelitis. and when the dysentery bacilli continue to be excreted Treatment of crippling due to this group has in the after the patient is clinically well the organisms are past been left in the charge of the surgeon, presumably living on the bowel mucosa or in unhealed whereas treatment of the rheumatic diseases has been ulcers. FAlRLEY’s 1 experience with the sigmoidoscope mainly in the hands of the physician. In the future that the dysentery ulcer may be present when there is it is to be hoped that compartments will disappear no clinical evidence of it is confirmed by BREWER2 and that teams of surgeons and physicians trained who recommends a and intensive course of prolonged in the investigation and treatment of diseases of the for such cases. Even the so, sulphaguanidine many locomotor system will work together. The physician mild Flexner and Sonne infections indicate that the specialising in the chronic rheumatic diseases realises convalescent carrier state must often occur without the help he receives from his orthopaedic colleagues any persisting lesion in the mucosa, and this belief is in the control of spasm, pain and swelling of thejoints supported by the commonness of symptomless carriers by means of properly applied plaster splints, traction among contacts of clinically infected cases. Unlike and manipulation. These orthopaedic measures are the systemic enteric infections, persistence of the But if the carrier state for more than 6 months is rare in an important advance in treatment. bacillary orthopaedic surgeon is to obtain the best results, he dysentery, and when it happens is probably always must have sound medical advisers who will help him associated with ulceration of the bowel and interto recognise and correct malnutrition, anaemia or mittent diarrhoea so that the case is really one of hidden infection. Economic advantage will follow chronic dysentery. But if " chronic dysentery thejoint use of clinics, equipment and technical staff carrier " is a misnomer, convalescent carriers are which form the background of both the medical and common enough, and more than half the clinically surgical treatment of the crippling diseases. infected cases may still be excreting the organism The importance of such cooperation has been 3-4 weeks after onset. In the contact carrier recognised by the Scottish Orthopaedic Council, the infectivity is more evanescent, although a few cases -are British Orthopaedic Association and the Empire persistently positive for weeks. When infection 1111GL1111t4U1J111 MiC lai5u LIWU UUUIUM IIUVFC VVlllll%11, attacks a community the brunt of it falls on the recently issued a joint memorandum 9 on the subject. younger children, and both clinical cases and carriers The basic features of their plan is to establish iri each become much less common in the older age-groups ; medical region of the country one or more base should subsequent outbreaksin the same develop hospitals for the treatment of the crippling diseases. community, the incidence of clinical infection is These would be staffedjointly by orthopaedic surgeons much less than in the original epidemic For example, and physicians trained in the diagnosis, prevention in one institution, 48 (22%) of the 220 originally and treatment of the crippling diseases. Special infected cases had clinical symptoms, but only 3 hospitals are required, these bodies consider, because (4%) of 76 cases subsequently attacked.3 Thus the treatment of the crippling diseases calls for a long dysentery may be endemic in an institution with a period in hospital. Moreover, until large numbers of high carrier-rate but few clinical cases until there is such patients are congregated in a single institution a large admission of new patients when the infection under controlled conditions no satisfactory advance flares up again-a not uncommon happening in in the discovery of causal factors or of the value of mental hospitals. various therapeutic measures can be expected. At As the spread of dysentery is mostly by contact the periphery of the medical regions diagnostic centres from cases and carriers, the detection and control of with limited facilities for treating outpatients would the unsuspected convalescent and contact carriers is be established. These centres would be visited at a matter of prime importance. Detection has been regular intervals by the specialist staff of the base greatly facilitated by the introduction of the desoxyhospital, who would diagnose the type of disease and cholate-citrate agar,4and in searching for carriers decide whether the patient should be treated at the with this medium a specimen of faeces is probably base hospital, the’ peripheral outpatient clinic, or in to the rectal swab, for there is little risk preferable the patient’s home. The family doctors in the region of the relatively scanty dysentery bacilli being masked would be consulted and by securing their interest, and by the profuse coliform flora. In young children, by giving postgraduate instruction on the spot, the however, it may be more convenient to use the rectal first step towards successful treatment would have swab ; and, provided the specimen is kept moist, there been made-namely, early diagnosis. is no great urgency in getting it to the laboratory, It is to be hoped that thejoint standing advisory for both Flexner and Sonne bacilli remain alive in committee which the Empire Rheumatism Council
orthopaedic
9. Obtainable from the secretaries of the joint committee, Mr. Norman Capener, FRCS, The Princess Elizabeth Orthopedic Hospital, Buckerell Bore, Exeter, and Sir Frank Fox, 106, Finchley Road, London, N.W.3.
1. Fairley, N. H. Lancet, 1942, 2, 648. 2. Brewer, A. E. Brit. med. J. 1943, i, 36. 3. Hardy, A. V., Shapiro, R. L., Chant, H. and Siegel, M. Publ. Hlth Rep., Wash. 1942, 57, 1079. 4. Hynes, M. J. Path. Bact. 1942, 54, 193.
THE
LANCET
LONDON:SATURDAY, JANUARY
30,
1943
PROPAMIDINE AND WOUNDS of the diamidine comdiscovered first by KING, LouBlE and pounds from the clue thatSynthalin’ started who YoRKE, THE
therapeutic properties were
(a guanidine compound)
was
actively trypanocidal.
Further work by A. J. EwiNs and his colleagues led to the production of a large number of substances, of which the three most active are diamidino-stilbene
(stilbamidine), diamidino-diphenoxy-pentane (pentamidine) and diamidino-diphenoxy-propane (prop amidine). These compounds have been found to be curative for a variety of protozoal infections such as kala-azar (for which they will possibly replace the antimonials previously used), sleeping sickness, and babesiasis of animals ; in addition they exert a limited activity against malaria in monkeys and in More recently, the scope of these compounds has been extended by the discovery that-they possess also a strong bacteriostatic action, first described last year by FULLER.2 Their antibacterial action has been studied intensively in the laboratories of MAY and- BAKER Ltd. ; and as a result of this work one of the compounds, propamidine, was considered to show promise as a wound antiseptic. This impression is well confirmed in a series of four papers, printed in our present issue, recounting the clinical application of propamidine under a variety of conditions. It is applied to the wound or burn, in a jelly or cetylalcohol preparation, on alternate days for ten days. This treatment is effective in removing streptococci from the wound ; often but not always it removes staphylococci; it has little action against proteus or pyocyanea. In the concentration suggested (0’1%) no harm is done to granulation tissue nor is phagocytosis lessened ; higher concentrations may however cause local necrosis and irritation of the adjacent skin. The antibacterial action is not inhibited by pus or by p-aminobenzoic acid, and it is not affected by the presence of sulphonamide resistance. Judging by the clinical results the compound has been of striking value both in treating old infected wounds and in dressing fresh burns. The chief weakness noted to date is the failure to control infection with proteus or pyocyanea which, although mainly saprophytic, may give enough trouble to hinder skin grafting. The extent to which absorption of the drug may occur from the wound into the general circulation is at present unknown, since no method of estimating small concentrations of propamidine is available. That absorption is limited and spread over a considerable period is made probable by the work of HAWKING, HENRY and their collaborators 34 on the related compound stilbamidine, whose presence is betrayed by its fluorescence. Stilbamidine, when introduced into the body, is stored particularly in the liver and kidney, man.
much is absorbed by the red blood-cells, and about 10% of the dose injected is excreted in the urine during the first three days ; probably propamidine follows a 1. King, H, Lourie, E. M. and Yorke. W. Ann. trop. Med. Parasit. 1938, 32, 177. Fuller, A. T. Biochem. J. 1942, 36, 548. Hawking, F. and Smiles, J. Ann. trop. Med. Parasit. 1941, 35, 45. Henry, A. J. and Grindley, D. N. Ibid, 1942, 36, 102.
2. 3. 4.
similar course. No general toxic effects are recorded in the present series of papers. Judging by experiments with mice and streptococci2 propamidine and its similars seem unlikely to exert a therapeutic effect upon bacterial infections when administered systemically by intravenous injection. After injection (tolerated dose about 2 mg. per kg.) of the drug for sleeping sickness, immediate collapse has occurred, resembling histamine shock but soon passing off ; after pentamidine violent itching may occur (LouRiE 5). Late toxic effects have been rare, but in animals degeneration of the liver and kidneys have been observed ; NAPIER and GUPTA6 have reported several cases of neuritis in the trigeminal nerve. Such symptoms are not likely to occur when propamidine is applied locally by the technique described above unless very large areas are treated, but the possibility should be borne in mind. The whole investigation so far has been a pretty piece of teamwork and further progress will be followed with zest.
CRIPPLING DISEASES ANY disease or disorder which leads to incapacity could be called a crippling disease-a patient’s capacity for work might be limited by cardiac, pulmonary or renal disorder-but the term is conveniently restricted to disablement of the locomotor system. Among the more important causes are the chronic rheumatic diseases, including rheumatoid arthritis, osteo-arthritis and non-articular rheumatism affecting the fibrous tissues and muscles, ligaments, nerves and the capsules of thejoints. The size of the problem they create has often been noted ; probably no. single medical disorder leads to greater suffering to the patient, or loss of efficiency and cost to the country. It has been estimated that more than a million patients in England consult their doctors annually because of the chronic rheumatic diseases, and that’ a_ sixth of the total invalidity of the insured population is -due to this cause. The cost, in England and Wales, is at least :1:20,000,000 annually. DAVIDSON and DUTHIE7 investigated the incidence of the rheumatic diseases in the north-east of Scotland and calculated that in the whole country at least 300,000 persons annually required medical treatment. Most of the patients were suffering from non-articular rheumatism, but many thousands were incapacitated by more serious forms of arthritis. This finding is confirmed in the official publications of the Department of Health for Scotland, which state that 14% of the total invalidity of persons insured under the NHI Act was due to rheumatism, and that 50,000 insured persons in Scotland were totally incapacitated every year, the average period of incapacity being 60 days. Three million working days were lost annually because of the ravages of the chronic rheumaticdiseases, and the annual economic loss to Scotland was estimated at :1:3,000,000, with resulting misery to patients and
dependents. No official attempt has been made so far to tackle the problem, and it was in the hope of stimulating the official conscience that the Empire Rheumatism Council published in 1940 a plan for national action8 which sets out simply a few facts about causation and Lourie, E. M. Ibid, 1942, 36, 113. 6. Napier L. E. and Gupta, P. C. S. Indian Med. Gaz. 1942, 77, 71. 7. Davidson, L. S. P. J. R. Inst. Publ. Hlth Hyg. 1940, 3, 245. 8. Rheumatism : A Plan for National Action. London, 1940.
5.
146 the limited facilities for treatmentavailable and and the British Orthopaedic Association have now set concludes with a general plan for the control of this up will formulate a comprehensive scheme for the group of disorders. The monograph has stimulated prevention and control of crippling diseases acceptable medical thought and iai eighteen months has had to to the Ministry of Health and the Department of be reprinted three times. But it must not be overHealth of Scotland, so that it can be incorporated and diseases disorders -forthwith in the postwar national medical service. that other looked causing the locomotor deserve attention of system incapacity in any national scheme. Crippling may result from THE DYSENTERY CARRIER birth defects, injuries, acquired postural IN bacillary dysentery the infection is confined to congenital disorders, trauma including fractures, and infective the bowel without as a rule any systemic spread, diseases such as tuberculosis and poliomyelitis. and when the dysentery bacilli continue to be excreted Treatment of crippling due to this group has in the after the patient is clinically well the organisms are past been left in the charge of the surgeon, presumably living on the bowel mucosa or in unhealed whereas treatment of the rheumatic diseases has been ulcers. FAlRLEY’s 1 experience with the sigmoidoscope mainly in the hands of the physician. In the future that the dysentery ulcer may be present when there is it is to be hoped that compartments will disappear no clinical evidence of it is confirmed by BREWER2 and that teams of surgeons and physicians trained who recommends a and intensive course of prolonged in the investigation and treatment of diseases of the for such cases. Even the so, sulphaguanidine many locomotor system will work together. The physician mild Flexner and Sonne infections indicate that the specialising in the chronic rheumatic diseases realises convalescent carrier state must often occur without the help he receives from his orthopaedic colleagues any persisting lesion in the mucosa, and this belief is in the control of spasm, pain and swelling of thejoints supported by the commonness of symptomless carriers by means of properly applied plaster splints, traction among contacts of clinically infected cases. Unlike and manipulation. These orthopaedic measures are the systemic enteric infections, persistence of the But if the carrier state for more than 6 months is rare in an important advance in treatment. bacillary orthopaedic surgeon is to obtain the best results, he dysentery, and when it happens is probably always must have sound medical advisers who will help him associated with ulceration of the bowel and interto recognise and correct malnutrition, anaemia or mittent diarrhoea so that the case is really one of hidden infection. Economic advantage will follow chronic dysentery. But if " chronic dysentery thejoint use of clinics, equipment and technical staff carrier " is a misnomer, convalescent carriers are which form the background of both the medical and common enough, and more than half the clinically surgical treatment of the crippling diseases. infected cases may still be excreting the organism The importance of such cooperation has been 3-4 weeks after onset. In the contact carrier recognised by the Scottish Orthopaedic Council, the infectivity is more evanescent, although a few cases -are British Orthopaedic Association and the Empire persistently positive for weeks. When infection 1111GL1111t4U1J111 MiC lai5u LIWU UUUIUM IIUVFC VVlllll%11, attacks a community the brunt of it falls on the recently issued a joint memorandum 9 on the subject. younger children, and both clinical cases and carriers The basic features of their plan is to establish iri each become much less common in the older age-groups ; medical region of the country one or more base should subsequent outbreaksin the same develop hospitals for the treatment of the crippling diseases. community, the incidence of clinical infection is These would be staffedjointly by orthopaedic surgeons much less than in the original epidemic For example, and physicians trained in the diagnosis, prevention in one institution, 48 (22%) of the 220 originally and treatment of the crippling diseases. Special infected cases had clinical symptoms, but only 3 hospitals are required, these bodies consider, because (4%) of 76 cases subsequently attacked.3 Thus the treatment of the crippling diseases calls for a long dysentery may be endemic in an institution with a period in hospital. Moreover, until large numbers of high carrier-rate but few clinical cases until there is such patients are congregated in a single institution a large admission of new patients when the infection under controlled conditions no satisfactory advance flares up again-a not uncommon happening in in the discovery of causal factors or of the value of mental hospitals. various therapeutic measures can be expected. At As the spread of dysentery is mostly by contact the periphery of the medical regions diagnostic centres from cases and carriers, the detection and control of with limited facilities for treating outpatients would the unsuspected convalescent and contact carriers is be established. These centres would be visited at a matter of prime importance. Detection has been regular intervals by the specialist staff of the base greatly facilitated by the introduction of the desoxyhospital, who would diagnose the type of disease and cholate-citrate agar,4and in searching for carriers decide whether the patient should be treated at the with this medium a specimen of faeces is probably base hospital, the’ peripheral outpatient clinic, or in to the rectal swab, for there is little risk preferable the patient’s home. The family doctors in the region of the relatively scanty dysentery bacilli being masked would be consulted and by securing their interest, and by the profuse coliform flora. In young children, by giving postgraduate instruction on the spot, the however, it may be more convenient to use the rectal first step towards successful treatment would have swab ; and, provided the specimen is kept moist, there been made-namely, early diagnosis. is no great urgency in getting it to the laboratory, It is to be hoped that thejoint standing advisory for both Flexner and Sonne bacilli remain alive in committee which the Empire Rheumatism Council
orthopaedic
9. Obtainable from the secretaries of the joint committee, Mr. Norman Capener, FRCS, The Princess Elizabeth Orthopedic Hospital, Buckerell Bore, Exeter, and Sir Frank Fox, 106, Finchley Road, London, N.W.3.
1. Fairley, N. H. Lancet, 1942, 2, 648. 2. Brewer, A. E. Brit. med. J. 1943, i, 36. 3. Hardy, A. V., Shapiro, R. L., Chant, H. and Siegel, M. Publ. Hlth Rep., Wash. 1942, 57, 1079. 4. Hynes, M. J. Path. Bact. 1942, 54, 193.