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ASSESSMENT OF AN ISOTHIAZOLE THIOSEMICARBAZONE IN THE PROPHYLAXIS OF CONTACTS OF VARIOLA MAJOR
1072
Summary This paper reports the therapeutic assessment in smallpox of ’ M & B 7714 ’ (4-bromo-3-methylisothiazole5-carboxaldehyde thiosemicarbazone) in a controlled double-blind trial on 1293 patients with smallpox. Assessment was made by fatality-rate (with reference to vaccinial status, clinical type, age, and day of disease on admission), the numbers of afebrile cases, the mean number of febrile days, the mean maximum height of temperature reached on any one day, and the mean day to complete scabbing of lesions. There was evidence that the drug had some beneficial effect but none of the findings
statistically significant. Apart from the increase in serum-bilirubin with high doses, some nausea and vomiting, and 4 cases of allergic dermatitis, the drug in this therapeutic trial did not present any significant toxic factors.
was
We thank the Indian Council for Medical Research under whose the clinical trials were undertaken, and especially to Dr. C. Pandit for his guidance and valuable suggestions, and the Government of India, Government of Madras, and the Commissioner of the Corporation of Madras for permission to undertake these trials; the director of the Microbiological Research Establishment, Porton Down, for facilities for carrying out a number of aspects of this investigation; and Miss Lalitha, the medical and nursing staff of the Infectious Diseases Hospital, Tondiarpet, Madras, and Mr. K. Corbett and the staff of the research group of May & Baker Ltd. for their assistance.
auspices
Requests for reprints should be addressed to Dr. J. May & Baker Ltd., Dagenham, Essex.
A. McFadzean,
REFERENCES
R., McFadzean, J. A., Squires, S. (1965) Ann. N.Y. Acad. Sci. 130, 118. Slack, R., Wooldridge, K. R. H., McFadzean, J. A., Squires, S. (1964) Nature, Lond. 204, 587. Westwood, J. C. N., Bowen, E. T., Boulter, E. A. (1966) Unpublished. Phipps, P. H., Boulter, E. A. (1957) J. Hyg., Camb. 55, 123.
Rao,
A.
-
ASSESSMENT OF AN ISOTHIAZOLE THIOSEMICARBAZONE IN THE PROPHYLAXIS OF CONTACTS OF VARIOLA MAJOR A. RAMACHANDRA RAO M.B. Madras HEALTH
OFFICER, CORPORATION OF MADRAS
G. D. W. MCKENDRICK M.A., B.M. Oxon., M.R.C.P. CONSULTANT
PHYSICIAN,
ST.
ANN’S HOSPITAL,
TOTTENHAM
L. VELAYUDHAN
KUMARI KAMALAKSHI
M.B. Madras
B.Sc.
ASSISTANT RESEARCH OFFICER
RESEARCH ASSISTANT
INDIAN COUNCIL FOR MEDICAL RESEARCH
Hamre
al. (1950) showed that certain thiosemicarbaactive against vaccinia virus and the search for more active compounds led to the development of 4-bromo3-methylisothiazole-5-carboxaldehyde thiosemicarbazone M & B 7714 ’) (Caton et al. 1965, Slack et al. 1964). This compound had a clear-cut activity against neurovaccinia and smallpox in mice when given orally (Rao et al. 1965), but a controlled therapeutic trial in smallpox in man was disappointing (Rao et al. 1965, Rao et al. 1966). Testing a similar compound, 1-methylisatin 3-thiosemicarbazone (methisazone), Bauer et al. (1963) showed a striking prophylactic effect when the drug was given in the incubation period. We decided to carry out a controlled, double-blind, prophylactic trial in smallpox contacts in the hope that administration of M & B 7714 during the et
zones were
TABLE I-THE DISTRIBUTION OF CONTACTS WITH INCIDENCE OF SMALLPOX RELATED TO AGE
incubation period might lessen the attack rate or modify the severity of the illness should smallpox be contracted. Methods
people studied were all the family contacts of smallpox patients (the index cases) admitted to the Infectious Diseases Hospital, Tondiarpet, Madras, India between February, 1964, and April, 1965, who showed no evidence of previous successful vaccination or of previous smallpox. It was felt that a much more accurate assessment of any prophylactic effect would be obtained by using only previously unprotected contacts, approximately 30% of whom could be expected to get smallpox. The definition of unvaccinated was as given by Rao et al. (1966). With the numbers involved a strict surveillance of contacts became possible. For the purposes of the trial the hospital day was defined as being 24 hours from 4 P.M. During an evening visit to the hospital all index cases admitted during the preceding 24-hour period were seen, addresses were checked, and any visiting relatives were interviewed. The next morning the families were visited at home by a team consisting of a doctor, a nurse, and a health inspector and any unprotected family contacts were accepted for the trial. Where there were more than two such contacts they were accepted in order of age. The name, age, date of vaccination (not usually done by the first visit), and degree of exposure were recorded and contacts were allotted in strict rotation to a previously prepared randomised schedule as a result of which they received either suspension A or suspen7714 sion B. The active suspension contained 1 g. of M & B was as identical 5 ml. and the control per suspension (placebo) as possible in colour and taste. Although the trial set out to be double-blind this proved impossible in practice since the active suspension produced nausea and vomiting in some people. The greatest care was The
therefore taken to ensure that no member of the team knew to which group, control or drug, the next unprotected contact would be allotted. In this way no bias could enter into a decision whether or not to accept a contact in whom the evidence of previous successful vaccination was doubtful. After TABLE II-THE RELATIONSHIP BETWEEN THE DAY OF DISEASE OF THE
INDEX CASE WHEN TREATMENT WAS STARTED AND THE INCIDENCE OF SMALLPOX
1073 acceptance, contacts were given the appropriate suspension and observed for a few minutes to ensure there was no immediate vomiting. When this occurred the dose was repeated. All doses were administered by the nurse and all contacts were seen daily for 16 days by the team when they were inspected, their temperatures recorded, and, later, the results of vaccination were noted. Vaccinating was done independently by the health
TABLE IV-THE INCIDENCE OF SMALLPOX AND FATALITY IN DRUG-TREATED
CONTACTS RELATED TO COMPLETION OF THE COURSE
authorities. The
degree of exposure
to
infection
was
graded crudely in
accordance with the approximate length of close contact between the contact and the index case (see table v). For con-
venience, the day of exposure to smallpox was taken
as the day of onset of fever of the index case. House visits took place at a rate of three to five per hour depending on the number of new houses to be found and the number of contacts needing the suspension. It was often necessary to visit schools and market places to find an absent contact.
Dosage
The drug or placebo
was
administered in
a
single dose daily.
TABLE III-THE NUMBER OF CONTACTS WHO GOT SMALLPOX, WITH REFERENCE TO THE PRESUMED DAY OF INCUBATION PERIOD WHEN TREATMENT WAS STARTED *
6 6 contacts who got smallpox (4 controls and 2 treated) completed their treatment more than 12 days before they developed the disease and have been excluded from this table; there were no deaths in these cases.
Toxic Effects In this prophylactic trial the drug was not well tolerated. 74% of contacts vomited at some time, mostly an hour or two after taking the drug. 52% of all those treated refused to complete the course. Nearly all contacts, however, absorbed at least one dose. Besides nausea and vomiting, which were the most severe toxic symptoms, 14% had a transient drug rash. 2 children in the drug group had febrile convulsions and died, but it is impossible to assess the significance of these deaths. Results
438 unprotected contacts were seen. 41 of these were excluded from the trial-5 because the " index case " proved not to have smallpox and 36 because they refused all treatment. Of the remaining 397 contacts 196 received the drug under trial and 201 the placebo. Table i shows that the two groups were similar as regards age. The incidence of smallpox in the two groups was 29-9% for the controls and 20-4% for the treated group; this difference was significant at the 5% level. The fatality-rates among the cases of smallpox were similar in the two groups (20% for controls and 175;o for the treated group).
Table 11 relates the probable day of the incubation period when treatment was started to the incidence of smallpox. With a presumed incubation period of 12 days (and knowing that most contacts are unlikely to be infected by the index case before the third day) one can assume that most contacts treated on or before the 9th day of the illness of the index case were receiving the drug in the first 6 days of their incubation period. This is the time when prophylactic therapy might be expected to be most
effective. In this group, 13 of 105 untreated contacts got smallpox and 4 died; in treated contacts 13 of 114 had smallpox and 1 died. The incidence of smallpox in those where treatment was started later in the incubation period was smaller in the treated group (27/82 as against 47/96), but the number of deaths was similar. There is accurate information about the day on which treatment was started for those who did get smallpox (table ill). The incidence and mortality-rate is slightly less all the way through for the treated cases. Administration of drug in the first 6 days of the incubation did not prevent illness in 23 contacts nor death in 5 of these. As mentioned above the drug produced nausea and vomiting with the result that 52% of the contacts did not complete the course. Table iv relates the incidence of smallpox in the two groups who received complete and incomplete dosage. No prophylactic advantage was apparent in those who had completed the full course. Discussion
These results do not parallel the striking prophylactic effect of the related compound 1-methylisatin 3-thiosemicarbazone (methisazone) reported by Bauer et al. (1963). Their investigation included all contacts irrespective of their vaccinial state. There were 78 cases of smallpox with 12 deaths in 1126 controls as opposed to 3 mild cases among 1101 treated contacts. There were certain differences between their investigation and ours. The TABLE VI-THE INCIDENCE OF SMALLPOX RELATED TO CLOSENESS OF CONTACT
+ + + =Contacts who slept in the same sleeping-area as the index case and who have spent most days in or around the house. + + =Those with similar sleeping-arrangements to the above but who were out most of the day. + =All other family contacts.
1074 treatment
and control groups
were not
allocated at random
(those refusing treatment were assigned to the control group), and contacts were not visited daily. The drug was left at the patient’s house and the number of doses actually taken was ascertained by question at the second visit 14-16 days later. Bauer et al. (1963) state that " the drug was well accepted and normally the full course was taken ". In a small series in South Africa, Ferguson (1964) could not confirm the prophylactic effect of methisazone. 4 out of 43 contacts receiving the drug on the 6th day or earlier in the incubation period had smallpox and 1 died. Thiosemicarbazones are not pleasant to take and often In the present trial anticause nausea and vomiting. emetics administered immediately before the drug did not seem to influence the incidence of late vomiting. In a small trial of the effect of methisazone on vaccination in Glasgow (Landsman and Grist 1964) all but 1 of 19 medical students abandoned treatment after 1-4 doses because of severe vomiting, despite the use of cyclizine. The dosage scheme was similar to that used by Bauer et al. (1963) in Madras. There is no doubt that methisazone and M & B 7714 exert a prophylactic effect against pox-virus infections in mice. One would expect the drug when given before vaccination in man to lessen the success-rate, but there was no significant difference with either drug. In the present series (table v) the vaccination success-rate was similar in the treated and control groups. All were primary vaccinations. In the series reported by Bauer et al. (1963) primary vaccinations produced figures similar to our own. In the drug group they found 68% successful vaccinations compared to our figure of 77% and in the control group 76% successful vaccinations compared to 79%. Poor absorption from vomiting cannot be held responsible for the poor results in the present trial (table iv). With the daily inspection and temperature recording of contacts missed cases were unlikely. Cases of smallpox were often hidden-the team being told that the person had " left Madras " quite fit. It was never assumed that a contact was well when he was not available and this lack of faith in human nature proved justified on a number of occasions (1patient with smallpox was unearthed from beneath a pile of melons). The importance of really close contact in the spread of smallpox is shown in table vi. The incidence was much higher amongst those who slept near the index case than in other members of the family.
Summary and Conclusions This paper describes the prophylactic assessment of 7714’ (4-bromo-3-methylisothiazole-5-carbox’M&B aldehyde thiosemicarbazone) in contacts of variola major in the city of Madras. The persons treated were all family contacts of smallpox patients and the trial was restricted to those contacts who had not previously been vaccinated. The trial was double blind and the contacts were visited daily for 16 days and a clinical assessment was made at each visit. The compound was administered as a suspension at a single dose of 4 g. daily for 3 days with smaller doses for younger age-groups. The drug was not well tolerated, vomiting being the major side-effect. 196 contacts received the drug and 201 had the placebo. In the drug-treated group there were 40 cases of smallpox with 7 deaths and in the placebo 60 cases with 12 deaths. The difference in the incidence of smallpox was significant at the 5 % level but there was no significant difference in the case fatality rates.
Because of the toxic effects of the compound and the relatively small reduction of case incidence achieved, M & B 7714 is not recommended in the routine prophylaxis of smallpox although its use might be indicated in special circumstances. Confirmation of the value of other thiosemicarbazones is required before any change is made in the present accepted methods of control of major
smallpox. We thank the Indian Council for Medical Research under whose
auspices the trial was undertaken; May & Baker Ltd., Dagenham, Essex, for supplies of drug and apparatus; the Government of India, Government of Madras, and the Corporation of Madras; the field workers Mrs. Bradberry, Miss Appaswamy, and Miss Lalitha; Mrs. L. St. Vincent and the staff of the virus laboratory of the Infectious Diseases Hospital, Tondiarpet, for their assistance in laboratory diagnosis; and Dr. Ian Sutherland for advice on randomisation procedures. Requests for reprints should be addressed to Dr. G. D. W. McKendrick, St. Ann’s Hospital, London N.15. REFERENCES
Bauer, D. J., St. Vincent, L., Kempe, C. H., Downie, A. W. (1963) Lancet ii, 494. Caton, M. P. L., Jones, D. H., Slack, R., Squires, S., Wooldridge, K. R H., (1965) J. med. Chem. 8, 680. Ferguson, D. L. (1964) S. Afr. med. J. 38, 868. Hamre, D., Bernstein, J., Donovick, R. (1950) Proc. Soc. exp. Biol., N.Y. 73, 275. Landsman, J. B., Grist, N. R. (1964) Lancet, i, 330. Rao, A. R., McFadzean, J. A., Kamalakshi, K. (1966) ibid., i, 1068. Squires, S. (1965) Ann. N.Y. Acad. Sci. 130, 118. Slack, R., Wooldridge, K. R. H., McFadzean, J. A., Squires, S. (1964) Nature, Lond. 204, 587. -
-
COMBINED ACTION OF METHYLDOPA AND BETHANIDINE Evidence for
a
Synergistic
Effect
A. BRECKENRIDGE M.B., B.Sc. St. And., M.R.C.P. REGISTRAR AND TUTOR IN MEDICINE
C. T. DOLLERY M.B., B.Sc. Birm., M.R.C.P. LECTURER IN CLINICAL THERAPEUTICS POSTGRADUATE MEDICAL SCHOOL. DUCANE ROAD. LONDON
W.12
TREATMENT of severe hypertension often requires the of more than one drug both because of the difficulty of achieving control with a single agent and the possibility of reducing the incidence of side-effects by combining lower doses of different drugs. Methyldopa is widely and successfully used in the treatment of hypertension but resistance to its action happens sufficiently often to be a problem (Dollery 1965). Bethanidine is a powerful sympathetic adrenergic-blocking drug with an action similar to guanethidine but of shorter duration (Boura et al. 1961). Chance clinical observations suggested there might be a synergistic effect of the two drugs and we have investigated this further. use
Patients and Methods Patients
patients, 10 men and 2 women, were selected for study they were relatively resistant to methyldopa. All had severe hypertension; 5 had grade in retinal changes and 7 had 12
because
n changes. 5 had a blood-urea of more than 40 mg. per 100 ml. (in 2, blood-urea was greater than 100 mg.per 100 ml.). 2 patients had chronic renal disease thought to be the cause of their hypertension but no aaiological factor had been identified in the other 10.
grade
Clinical Investigations The first part of the study concerned 10 patients who had an unsatisfactory fall in their blood-pressure (B.P.) when treated
Summary This paper reports the therapeutic assessment in smallpox of ’ M & B 7714 ’ (4-bromo-3-methylisothiazole5-carboxaldehyde thiosemicarbazone) in a controlled double-blind trial on 1293 patients with smallpox. Assessment was made by fatality-rate (with reference to vaccinial status, clinical type, age, and day of disease on admission), the numbers of afebrile cases, the mean number of febrile days, the mean maximum height of temperature reached on any one day, and the mean day to complete scabbing of lesions. There was evidence that the drug had some beneficial effect but none of the findings
statistically significant. Apart from the increase in serum-bilirubin with high doses, some nausea and vomiting, and 4 cases of allergic dermatitis, the drug in this therapeutic trial did not present any significant toxic factors.
was
We thank the Indian Council for Medical Research under whose the clinical trials were undertaken, and especially to Dr. C. Pandit for his guidance and valuable suggestions, and the Government of India, Government of Madras, and the Commissioner of the Corporation of Madras for permission to undertake these trials; the director of the Microbiological Research Establishment, Porton Down, for facilities for carrying out a number of aspects of this investigation; and Miss Lalitha, the medical and nursing staff of the Infectious Diseases Hospital, Tondiarpet, Madras, and Mr. K. Corbett and the staff of the research group of May & Baker Ltd. for their assistance.
auspices
Requests for reprints should be addressed to Dr. J. May & Baker Ltd., Dagenham, Essex.
A. McFadzean,
REFERENCES
R., McFadzean, J. A., Squires, S. (1965) Ann. N.Y. Acad. Sci. 130, 118. Slack, R., Wooldridge, K. R. H., McFadzean, J. A., Squires, S. (1964) Nature, Lond. 204, 587. Westwood, J. C. N., Bowen, E. T., Boulter, E. A. (1966) Unpublished. Phipps, P. H., Boulter, E. A. (1957) J. Hyg., Camb. 55, 123.
Rao,
A.
-
ASSESSMENT OF AN ISOTHIAZOLE THIOSEMICARBAZONE IN THE PROPHYLAXIS OF CONTACTS OF VARIOLA MAJOR A. RAMACHANDRA RAO M.B. Madras HEALTH
OFFICER, CORPORATION OF MADRAS
G. D. W. MCKENDRICK M.A., B.M. Oxon., M.R.C.P. CONSULTANT
PHYSICIAN,
ST.
ANN’S HOSPITAL,
TOTTENHAM
L. VELAYUDHAN
KUMARI KAMALAKSHI
M.B. Madras
B.Sc.
ASSISTANT RESEARCH OFFICER
RESEARCH ASSISTANT
INDIAN COUNCIL FOR MEDICAL RESEARCH
Hamre
al. (1950) showed that certain thiosemicarbaactive against vaccinia virus and the search for more active compounds led to the development of 4-bromo3-methylisothiazole-5-carboxaldehyde thiosemicarbazone M & B 7714 ’) (Caton et al. 1965, Slack et al. 1964). This compound had a clear-cut activity against neurovaccinia and smallpox in mice when given orally (Rao et al. 1965), but a controlled therapeutic trial in smallpox in man was disappointing (Rao et al. 1965, Rao et al. 1966). Testing a similar compound, 1-methylisatin 3-thiosemicarbazone (methisazone), Bauer et al. (1963) showed a striking prophylactic effect when the drug was given in the incubation period. We decided to carry out a controlled, double-blind, prophylactic trial in smallpox contacts in the hope that administration of M & B 7714 during the et
zones were
TABLE I-THE DISTRIBUTION OF CONTACTS WITH INCIDENCE OF SMALLPOX RELATED TO AGE
incubation period might lessen the attack rate or modify the severity of the illness should smallpox be contracted. Methods
people studied were all the family contacts of smallpox patients (the index cases) admitted to the Infectious Diseases Hospital, Tondiarpet, Madras, India between February, 1964, and April, 1965, who showed no evidence of previous successful vaccination or of previous smallpox. It was felt that a much more accurate assessment of any prophylactic effect would be obtained by using only previously unprotected contacts, approximately 30% of whom could be expected to get smallpox. The definition of unvaccinated was as given by Rao et al. (1966). With the numbers involved a strict surveillance of contacts became possible. For the purposes of the trial the hospital day was defined as being 24 hours from 4 P.M. During an evening visit to the hospital all index cases admitted during the preceding 24-hour period were seen, addresses were checked, and any visiting relatives were interviewed. The next morning the families were visited at home by a team consisting of a doctor, a nurse, and a health inspector and any unprotected family contacts were accepted for the trial. Where there were more than two such contacts they were accepted in order of age. The name, age, date of vaccination (not usually done by the first visit), and degree of exposure were recorded and contacts were allotted in strict rotation to a previously prepared randomised schedule as a result of which they received either suspension A or suspen7714 sion B. The active suspension contained 1 g. of M & B was as identical 5 ml. and the control per suspension (placebo) as possible in colour and taste. Although the trial set out to be double-blind this proved impossible in practice since the active suspension produced nausea and vomiting in some people. The greatest care was The
therefore taken to ensure that no member of the team knew to which group, control or drug, the next unprotected contact would be allotted. In this way no bias could enter into a decision whether or not to accept a contact in whom the evidence of previous successful vaccination was doubtful. After TABLE II-THE RELATIONSHIP BETWEEN THE DAY OF DISEASE OF THE
INDEX CASE WHEN TREATMENT WAS STARTED AND THE INCIDENCE OF SMALLPOX
1073 acceptance, contacts were given the appropriate suspension and observed for a few minutes to ensure there was no immediate vomiting. When this occurred the dose was repeated. All doses were administered by the nurse and all contacts were seen daily for 16 days by the team when they were inspected, their temperatures recorded, and, later, the results of vaccination were noted. Vaccinating was done independently by the health
TABLE IV-THE INCIDENCE OF SMALLPOX AND FATALITY IN DRUG-TREATED
CONTACTS RELATED TO COMPLETION OF THE COURSE
authorities. The
degree of exposure
to
infection
was
graded crudely in
accordance with the approximate length of close contact between the contact and the index case (see table v). For con-
venience, the day of exposure to smallpox was taken
as the day of onset of fever of the index case. House visits took place at a rate of three to five per hour depending on the number of new houses to be found and the number of contacts needing the suspension. It was often necessary to visit schools and market places to find an absent contact.
Dosage
The drug or placebo
was
administered in
a
single dose daily.
TABLE III-THE NUMBER OF CONTACTS WHO GOT SMALLPOX, WITH REFERENCE TO THE PRESUMED DAY OF INCUBATION PERIOD WHEN TREATMENT WAS STARTED *
6 6 contacts who got smallpox (4 controls and 2 treated) completed their treatment more than 12 days before they developed the disease and have been excluded from this table; there were no deaths in these cases.
Toxic Effects In this prophylactic trial the drug was not well tolerated. 74% of contacts vomited at some time, mostly an hour or two after taking the drug. 52% of all those treated refused to complete the course. Nearly all contacts, however, absorbed at least one dose. Besides nausea and vomiting, which were the most severe toxic symptoms, 14% had a transient drug rash. 2 children in the drug group had febrile convulsions and died, but it is impossible to assess the significance of these deaths. Results
438 unprotected contacts were seen. 41 of these were excluded from the trial-5 because the " index case " proved not to have smallpox and 36 because they refused all treatment. Of the remaining 397 contacts 196 received the drug under trial and 201 the placebo. Table i shows that the two groups were similar as regards age. The incidence of smallpox in the two groups was 29-9% for the controls and 20-4% for the treated group; this difference was significant at the 5% level. The fatality-rates among the cases of smallpox were similar in the two groups (20% for controls and 175;o for the treated group).
Table 11 relates the probable day of the incubation period when treatment was started to the incidence of smallpox. With a presumed incubation period of 12 days (and knowing that most contacts are unlikely to be infected by the index case before the third day) one can assume that most contacts treated on or before the 9th day of the illness of the index case were receiving the drug in the first 6 days of their incubation period. This is the time when prophylactic therapy might be expected to be most
effective. In this group, 13 of 105 untreated contacts got smallpox and 4 died; in treated contacts 13 of 114 had smallpox and 1 died. The incidence of smallpox in those where treatment was started later in the incubation period was smaller in the treated group (27/82 as against 47/96), but the number of deaths was similar. There is accurate information about the day on which treatment was started for those who did get smallpox (table ill). The incidence and mortality-rate is slightly less all the way through for the treated cases. Administration of drug in the first 6 days of the incubation did not prevent illness in 23 contacts nor death in 5 of these. As mentioned above the drug produced nausea and vomiting with the result that 52% of the contacts did not complete the course. Table iv relates the incidence of smallpox in the two groups who received complete and incomplete dosage. No prophylactic advantage was apparent in those who had completed the full course. Discussion
These results do not parallel the striking prophylactic effect of the related compound 1-methylisatin 3-thiosemicarbazone (methisazone) reported by Bauer et al. (1963). Their investigation included all contacts irrespective of their vaccinial state. There were 78 cases of smallpox with 12 deaths in 1126 controls as opposed to 3 mild cases among 1101 treated contacts. There were certain differences between their investigation and ours. The TABLE VI-THE INCIDENCE OF SMALLPOX RELATED TO CLOSENESS OF CONTACT
+ + + =Contacts who slept in the same sleeping-area as the index case and who have spent most days in or around the house. + + =Those with similar sleeping-arrangements to the above but who were out most of the day. + =All other family contacts.
1074 treatment
and control groups
were not
allocated at random
(those refusing treatment were assigned to the control group), and contacts were not visited daily. The drug was left at the patient’s house and the number of doses actually taken was ascertained by question at the second visit 14-16 days later. Bauer et al. (1963) state that " the drug was well accepted and normally the full course was taken ". In a small series in South Africa, Ferguson (1964) could not confirm the prophylactic effect of methisazone. 4 out of 43 contacts receiving the drug on the 6th day or earlier in the incubation period had smallpox and 1 died. Thiosemicarbazones are not pleasant to take and often In the present trial anticause nausea and vomiting. emetics administered immediately before the drug did not seem to influence the incidence of late vomiting. In a small trial of the effect of methisazone on vaccination in Glasgow (Landsman and Grist 1964) all but 1 of 19 medical students abandoned treatment after 1-4 doses because of severe vomiting, despite the use of cyclizine. The dosage scheme was similar to that used by Bauer et al. (1963) in Madras. There is no doubt that methisazone and M & B 7714 exert a prophylactic effect against pox-virus infections in mice. One would expect the drug when given before vaccination in man to lessen the success-rate, but there was no significant difference with either drug. In the present series (table v) the vaccination success-rate was similar in the treated and control groups. All were primary vaccinations. In the series reported by Bauer et al. (1963) primary vaccinations produced figures similar to our own. In the drug group they found 68% successful vaccinations compared to our figure of 77% and in the control group 76% successful vaccinations compared to 79%. Poor absorption from vomiting cannot be held responsible for the poor results in the present trial (table iv). With the daily inspection and temperature recording of contacts missed cases were unlikely. Cases of smallpox were often hidden-the team being told that the person had " left Madras " quite fit. It was never assumed that a contact was well when he was not available and this lack of faith in human nature proved justified on a number of occasions (1patient with smallpox was unearthed from beneath a pile of melons). The importance of really close contact in the spread of smallpox is shown in table vi. The incidence was much higher amongst those who slept near the index case than in other members of the family.
Summary and Conclusions This paper describes the prophylactic assessment of 7714’ (4-bromo-3-methylisothiazole-5-carbox’M&B aldehyde thiosemicarbazone) in contacts of variola major in the city of Madras. The persons treated were all family contacts of smallpox patients and the trial was restricted to those contacts who had not previously been vaccinated. The trial was double blind and the contacts were visited daily for 16 days and a clinical assessment was made at each visit. The compound was administered as a suspension at a single dose of 4 g. daily for 3 days with smaller doses for younger age-groups. The drug was not well tolerated, vomiting being the major side-effect. 196 contacts received the drug and 201 had the placebo. In the drug-treated group there were 40 cases of smallpox with 7 deaths and in the placebo 60 cases with 12 deaths. The difference in the incidence of smallpox was significant at the 5 % level but there was no significant difference in the case fatality rates.
Because of the toxic effects of the compound and the relatively small reduction of case incidence achieved, M & B 7714 is not recommended in the routine prophylaxis of smallpox although its use might be indicated in special circumstances. Confirmation of the value of other thiosemicarbazones is required before any change is made in the present accepted methods of control of major
smallpox. We thank the Indian Council for Medical Research under whose
auspices the trial was undertaken; May & Baker Ltd., Dagenham, Essex, for supplies of drug and apparatus; the Government of India, Government of Madras, and the Corporation of Madras; the field workers Mrs. Bradberry, Miss Appaswamy, and Miss Lalitha; Mrs. L. St. Vincent and the staff of the virus laboratory of the Infectious Diseases Hospital, Tondiarpet, for their assistance in laboratory diagnosis; and Dr. Ian Sutherland for advice on randomisation procedures. Requests for reprints should be addressed to Dr. G. D. W. McKendrick, St. Ann’s Hospital, London N.15. REFERENCES
Bauer, D. J., St. Vincent, L., Kempe, C. H., Downie, A. W. (1963) Lancet ii, 494. Caton, M. P. L., Jones, D. H., Slack, R., Squires, S., Wooldridge, K. R H., (1965) J. med. Chem. 8, 680. Ferguson, D. L. (1964) S. Afr. med. J. 38, 868. Hamre, D., Bernstein, J., Donovick, R. (1950) Proc. Soc. exp. Biol., N.Y. 73, 275. Landsman, J. B., Grist, N. R. (1964) Lancet, i, 330. Rao, A. R., McFadzean, J. A., Kamalakshi, K. (1966) ibid., i, 1068. Squires, S. (1965) Ann. N.Y. Acad. Sci. 130, 118. Slack, R., Wooldridge, K. R. H., McFadzean, J. A., Squires, S. (1964) Nature, Lond. 204, 587. -
-
COMBINED ACTION OF METHYLDOPA AND BETHANIDINE Evidence for
a
Synergistic
Effect
A. BRECKENRIDGE M.B., B.Sc. St. And., M.R.C.P. REGISTRAR AND TUTOR IN MEDICINE
C. T. DOLLERY M.B., B.Sc. Birm., M.R.C.P. LECTURER IN CLINICAL THERAPEUTICS POSTGRADUATE MEDICAL SCHOOL. DUCANE ROAD. LONDON
W.12
TREATMENT of severe hypertension often requires the of more than one drug both because of the difficulty of achieving control with a single agent and the possibility of reducing the incidence of side-effects by combining lower doses of different drugs. Methyldopa is widely and successfully used in the treatment of hypertension but resistance to its action happens sufficiently often to be a problem (Dollery 1965). Bethanidine is a powerful sympathetic adrenergic-blocking drug with an action similar to guanethidine but of shorter duration (Boura et al. 1961). Chance clinical observations suggested there might be a synergistic effect of the two drugs and we have investigated this further. use
Patients and Methods Patients
patients, 10 men and 2 women, were selected for study they were relatively resistant to methyldopa. All had severe hypertension; 5 had grade in retinal changes and 7 had 12
because
n changes. 5 had a blood-urea of more than 40 mg. per 100 ml. (in 2, blood-urea was greater than 100 mg.per 100 ml.). 2 patients had chronic renal disease thought to be the cause of their hypertension but no aaiological factor had been identified in the other 10.
grade
Clinical Investigations The first part of the study concerned 10 patients who had an unsatisfactory fall in their blood-pressure (B.P.) when treated