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METHISAZONE IN PREVENTION OF VARIOLA MINOR AMONG CONTACTS
976
rectal lesions 10-3 months. Over a fifth of colon and rectal cases were further delayed before a diagnosis was made. In lesions of the colon this delay was eight months, and in rectal cases 10-3 months. A total delay of fifteen months and twenty-one months occurred in a fifth of colon and rectal cases respectively. In lesions of the colon the delay was at the hospital, and in rectal cases the general practitioner was responsible for the delay. There was no delay in this series between diagnosis and the institution of treatment. Delay significantly resulted in a more advanced stage of the disease at the time of treatment and correspondingly worsened the prognosis.
We therefore studied the action of this compound as a among persons who had been in contact with alastrim (variola minor)-a nosological entity distinct from but closely related to variola major, which exists in endemic form in Sao Paulo, Brazil (Ribas 1910, Downie et al. 1963). Methods We followed in general the methods used by Bauer et al.
prophylactic agent
(1963). Contacts of alastrim patients resident in the city of Sao Paulo were visited in their homes during the days following the admission of the patients to the Emilio Ribas Isolation Hospital. The sex, vaccination status, previous illness, and present of health of the contacts were recorded. The drug was given to contacts of odd-numbered index cases, and contacts of the even-numbered index cases were not given treatment but observed as controls. The initial decision to select the contacts of the odd-numbered cases as the treatment group was made by tossing a coin. Contacts were then assigned to treatment and control groups in strict order of admission of the index cases. Methisazone was given by mouth in two equal doses to a total amount of 6 g., an equivalent amount being given to contacts below 10 years of age. The first dose was generally taken in the presence of the visiting physician in the afternoon, and the second dose was left with the contacts with instructions to take it in the morning. For various reasons 53-3% of the treated contacts took only the first dose-that is, 3 g. or its state
We should like to thank Miss Ruth Bell, of the Royal Marsden Hospital for her help with the statistics. Requests for reprints should be addressed to D.C. R-J. at the Westminster Hospital, St. John’s Gardens, London, S.W.I. REFERENCES
Aylett, S. O. (1954) Surgery of the Caecum and Colon; p. 48. Edinburgh.
METHISAZONE IN PREVENTION OF VARIOLA MINOR AMONG CONTACTS LUIZ AUGUSTO RIBEIRO
DO
VALLE
M.D. São Paulo
equivalent.
OF THE INSTITUTO ADOLFO LUTZ
PEDRO RAPOSO
DE
With the object of preventing side-effects such as nausea and vomiting, cyclizine hydrochloride was given at the beginning of the investigation in doses of 100-200 mg., and later chloropromazine in doses of 25-50 mg. or their equivalent. The contacts were revisited 14-16 days later. The amount of drug actually taken was ascertained and recorded, together
MELO
M.D. Recife OF THE SECTION OF EPIDEMIOLOGY AND GENERAL PROPHYLAXIS
LUIS FLORÊNCIO
SALLES GOMES
DE
M.D. São Paulo
with the side-effects and the results of any vaccination which had been carried out by the public-health authorities after the recent exposure to infection. Contacts who stated that they had had alastrim previously, or who had already developed the disease on the day of the first visit, were excluded from the study. Cases of alastrim which developed among the contacts within 14 days of the first visit were recorded. Altogether, 976 contacts satisfied the criteria for acceptance into the study, and originated from 106 patients with alastrim admitted between Feb. 10, 1964, and Feb. 15, 1965. Of these contacts, 520 were in the control group. Treatment with methisazone was offered to 456 contacts, and was accepted by 384; of these, 190 took two doses of 3 g. or equivalent, and 194 took one dose of 3 g. or equivalent. The remaining 68 contacts who refused treatment were not transferred to the control group, and the data relating to them were analysed
OF THE INSTITUTO ADOLFO LUTZ
LUIS MORATO
PROENÇA
M.D. São Paulo OF THE GENERAL DIRECTORATE
DEPARTMENT OF
HEALTH, SÃO PAULO, S.P.,
SINCE 1950, when the
activity
BRAZIL
of p-aminobenzaldehyde
thiosemicarbazone against vaccinia virus was first described (Hamre et al. 1950) the action of thiosemicarbazones against viruses of the variola-vaccinia group has been thoroughly studied in the laboratory (Minton et al. 1953, Thompson et al. 1953, Bauer 1955, Bauer and Sadler
1960a, 1960b, Bach and Magee 1962). On the basis of this work, Bauer et al. (1963) investi-
gated in India the action of methisazone (1-methylisatin 3-thiosemicarbazone,’Marboran’, compound 33T57) given in doses of 6-24 g. in preventing variola major among persons who had been in contact with the infection, and obtained extremely favourable results.
separately. The age distributions of the two groups of treated and control contacts resulting from the procedure of alternate allocation were homogeneous, as shown in table i.
TABLE I-TREATMENT AND AGE OF CONTACTS
Figures in parentheses: Or equivalent.
*
cases
of alastrim.
977 TABLE II-TREATMENT AND VACCINATION STATUS OF CONTACTS
in parentheses: Figures * Or equivalent.
Results
The results of the trial are summarised in table II, in which the data are analysed according to the amount of drug taken and the vaccination status of the contacts. The tables do not include 4 treated contacts who took only a quarter of the intended dose (1-5 g. or equivalent) of the drug, none of whom developed alastrim. The numbers were too small to permit comparison with the other groups, and for this reason could not be analysed. Among 190 contacts who took 6 g. of methisazone or equivalent there were 5 (2-6%) cases of alastrim, and among 194 who took 3g. or equivalent there were 3 (1’5%) cases; 42 (8-1%) cases occurred among 520 contacts in the control group, and 7 (10-3%) cases among the 68 contacts who were assigned to the treatment group but refused to take the drug. No deaths occurred in either the treatment or control groups, for fatal cases are rare in alastrim. The usual case mortality of the disease in the area in which the study was carried out is approximately 1 % of cases notified and
admitted
to
hospital.
spite of the simultaneous administration of cyclizine hydrochloride or chlorpromazine, nausea and vomiting occurred in 66% of the contacts treated with methisazone. In
The
Discussion age-distributions of the treatment and control
groups were subjected to statistical analysis, applying the test of Kolmogorov-Smirnov (Guedenko 1962). The probability associated with the age-distributions of the 2 x 3 g. treatment group and the control group was 73%, and for the 3 g. treatment group and control group 3-7%. Both these percentages exceeded the level of significance of 2-5% adopted for each analysis, so that the comparisons are not independent, and subsequent correction of the groups is unnecessary. Since the treatment and control groups could thus be shown to be homogeneous in respect of age-distribution it was possible to proceed to the direct comparison of the results. At the initial planning of this study it was considered that the most interesting group under observation would be that of the contacts who had never been vaccinated before the time of the first visit, or did not show any marks of a previous successful vaccination. In fact, in these individuals considered simply as unvaccinated persons, only one variable, the drug, would be influencing the results. It is therefore appropriate to analyse in the first place the data relating to this group of contacts, amounting to 406 persons in all. Of these, 219 belonged to the control group, and 187 took part or all of the assigned dose of
cases
of alastrim.
methisazone. Among the 219 control contacts 38 (17-4%) developed alastrim, compared with 7 (3-7%) cases among the 187 contacts in the treatment group. Statistical analysis of these figures gives a value of Z2 for two degrees of freedom of 19-489, which is significant at the level of 0-01%, thus indicating that the drug, the sole variable, acted favourably in reducing the incidence of contact cases of alastrim. When the results obtained in previously unvaccinated contacts of the treatment group with the doses of 3 g. and 6 g. are studied separately, it will be seen that 5 cases of alastrim occurred among 92 contacts who took 6 g. or equivalent, and 2 cases occurred among 95 who took 3 g. or equivalent, whereas among 219 previously unvaccinated the control group there were 38 cases. These data were analysed by the method of multiple comparisons proposed by Gold (1962), and it was found that treatment with methisazone reduced the incidence of contact cases of alastrim with a degree of significance contacts of
of 5%. Similarly, when the total number of
contacts
not
vaccinated before exposure to infection are considered, including now those who received primary vaccination after exposure to infection, regardless of whether it was successful or not, it will be seen that 42 (15-7%) of the 267 relevant contacts in the control group developed alastrim. On the other hand, 5 (4-8%) cases of alastrim occurred among 105 similar contacts who received the total course of treatment of 6 g. or equivalent and 3 (2-7%) cases occurred among 110 who took 3 g. or equivalent. Statistical analysis of the data relating to the treatment and control groups showed once more that the value of X2for two degrees of freedom (18-742) was significant at the 0-01% level. Also, separate comparisons of the two subdivisions of the treatment group carried out by the method of multiple comparisons showed that they differed significantly at the 5% level from the control group. It is interesting to note that no cases of alastrim were observed among previously vaccinated contacts, either in the treatment or in the control group. This shows an interesting difference from the figures quoted by Bauer et al. (1963) who observed 1 mild case of variola major among 841 treated contacts who had been vaccinated previously, and 42 cases with 1 death among 856 such contacts in the control group. An incidental observation made in a children’s hospital in Sao Paulo is worth mentioning. After the occurrence of a case of alastrim in the ward, 11 unvaccinated infants (included in tables i and 11) aged 4-11 months who had
978 been exposed to infection were treated with methisazone. None developed alastrim, although they were of an age. at which they should have been highly susceptible to infection. Conclusions Under the conditions prevailing in Sao Paulo in which the trial was carried out, statistical analysis of the results indicates that methisazone in doses of 3 g. or 6 g. or equivalent had a favourable effect in reducing the incidence of alastrim amongst persons who had been exposed to the
infection. The observations of Bauer et al. (1963) are therefore confirmed by the results obtained in the present investigation. It may be noted that Ferguson (1964) observed 4 cases of smallpox among 43 contacts treated with methisazone during an outbreak of smallpox in Port Elizabeth, South Africa, in 1964, and he concluded that the results of
chemoprophylaxis
were
disappointing.
However,
our
results show that a few cases are still to be expected in treated contacts, and the true incidence in the absence of treatment cannot be obtained from Ferguson’s data because of the absence of a comparable control group.
Summary The action of small doses of methisazone was studied in 976 contacts of patients with alastrim (variola minor) in Sao Paulo, Brazil, between Feb. 10,1964, and Feb. 15,1965. Of 406 contacts who had not previously been vaccinated and were not vaccinated after exposure, 187 were treated with methisazone in doses of 3 g. or 6 g. or equivalent, and 219 were left untreated as a control group; 7 cases of alastrim occurred among the contacts treated with methisazone, and 38 cases among the controls. Of 482 previously unvaccinated contacts (including the above), some of whom were vaccinated after exposure, regardless of the results, 215 were treated with methisazone as above, and 267 were left untreated as controls; 8 cases of alastrim occurred among the treated contacts and 42 cases among the controls. The differences in the incidence of alastrim in the treated and control groups were significant at the 0-01% level, showing that methisazone is effective in the prevention of alastrim in the doses employed and under the conditions prevailing in Sao Paulo where the trial was carried out. There was no significant difference between the agedistributions of the contacts in the treatment and control groups, and the incidence of alastrim in the two groups could therefore be compared without correction. No cases of alastrim occurred in contacts, whether treated or not, who had been successfully, vaccinated at some time before exposure, even when they are not revaccinated after exposure. The main side-effects were nausea and vomiting, which occurred in two-thirds of the treated contacts, and did not respond to treatment with cyclizine hydrochloride or
chlorpromazine.
AUGMENTED HISTAMINE RESPONSE AFTER INCOMPLETE VAGOTOMY P. R. F. BELL Sheff., F.R.C.S.
R. G. CHECKETTS
M.B.
REGISTRAR
M.B. Sheff. RESEARCH ASSISTANT
D. JOHNSTON Glasg., F.R.C.S.E.
M.B.
LECTURER
H. L. DUTHIE M.D., Ch.M. Glasg., F.R.C.S. PROFESSOR OF SURGERY
UNIVERSITY DEPARTMENT OF SURGERY, ROYAL INFIRMARY, SHEFFIELD
THE initial reduction in acid secretion after complete vagotomy has been shown to be maintained for at least three years (Gelb and Janowitz 1964, Bell 1964). In fact Bell (1964) has shown a tendency for a further reduction with time. The long-term effect of incomplete vagotomy is not quite so clear. The same authors have reported a rise in acid secretion with the passage of time in some patients. We here report a series of 42 patients showing no significant long-term change in the output of gastric acid after incomplete vagotomy. Materials and Methods Clinical Material Over a 5-year period, 42 male patients with duodenal ulcer were selected on the basis of a positive insulin test indicating incomplete vagotomy. In all of them the output of acid by the stomach in response to augmented doses of histamine was measured preoperatively and 10 days after operation. A further test was carried out between 4 and 63 months after vagotomy. Augmented Histamine Test This was performed as described by Kay (1953). After a 12-hour fast, a ’Neoplex’ gastric tube was inserted into the stomach via the nostril, constant suction being maintained by means of an electric pump. After removal of the fasting secretion, two 15-minute aspirates were removed for calculation of the spontaneous secretion. At this time 100 mg. of mepyramine maleate (’Anthisan’) was given by intramuscular injection. The gastric aspirate collected in the next half-hour was discarded. A subcutaneous injection of histamine acid 0-04 phosphate, mg. per kg. body-weight was then given subcutaneously and three successive 15-minute samples of gastric juice collected. The acid was titrated with 0-01 N sodium hydroxide using Topfer’s reagent as indicator. The sum of the last two samples was taken as the maximal acid response and expressed as milliequivalents of acid. Insulin Test Aftera 12-hour fast, gastric secretion was removed as described above. After aspiration of three basal 15-minute samples, 20 units of soluble insulin was given intravenously. Collection of successive 15-minute aspirates then continued for 2 hours. The acid concentration of each 15-minute sample was determined as above. Results
All
patients
gave
a
positive insulin
response
as
defined
DR. DO VALLE AND OTHERS: REFERENCES
Bach, M. K., Magee, W. E. (1962) Proc. Soc. exp. Biol. Med. 110, 565. Bauer, D. J. (1955) Br. J. exp. Path. 36, 105. Sadler, P. W. (1960a) Lancet, i, 1110. (1960b) Brit. J. Pharmacol. 15, 101. Leone St. Vincent, Kempe, C. H., Downie, A. W. (1963) Lancet 494. ii, Downie, A. W., Dumbell, K. R., Ayrosa Galvão, P. A., Zatz, I. (1963) Trop. Geog. Med. 15, 25. Ferguson, D. L. (1964) S. Afr. med. J. 38, 868. Gold, Ruth (1962) in On Comparing Multinomial Probabilities; p. 1. School of Aerospace Medicine, Brooks Air Force Base, Texas. Guedenko, B. V. (1962) The Theory of Probability; p. 395. New York. Hamre, D., Bernstein, J., Donovick, R. (1950) Proc. Soc. exp. Biol. Med. —
We thank Dr. Otavio Martins Toledo, director of the Emilio Ribas Isolation Hospital, for permission to visit the patients and examine the hospital records; Prof. Elza Berquó and Prof. Rubens Murillo Marques, of the Department of Applied Statistics of the Faculty of Public Health and Hygiene of the University of Sao Paulo, for the statistical analyses; Snra Yara Karmann, for her devoted assistance; and Sr. Luiz Rodolpho Cavalieri, who helped us to carry out this work. We also thank the Wellcome Foundation for the supplies of methisazone and other drugs used in the trial. Requests for reprints should be addressed to L. A. R. do V., Instituto Adolfo Lutz, Sao Paulo, Brazil.
— —
—
73, 275. Minton, S. A., Jr., Officer, J. E., Thompson, R. L. (1953) J. Immunol. 70, 222. Ribas, E. (1910) Archos Soc. Med. Cirurg. S. Paulo, 1, 210. Thompson, R. L., Minton, S. A., Officer, J. E., Hitchings, G. H. (1953) J. Immunol. 70, 229.
rectal lesions 10-3 months. Over a fifth of colon and rectal cases were further delayed before a diagnosis was made. In lesions of the colon this delay was eight months, and in rectal cases 10-3 months. A total delay of fifteen months and twenty-one months occurred in a fifth of colon and rectal cases respectively. In lesions of the colon the delay was at the hospital, and in rectal cases the general practitioner was responsible for the delay. There was no delay in this series between diagnosis and the institution of treatment. Delay significantly resulted in a more advanced stage of the disease at the time of treatment and correspondingly worsened the prognosis.
We therefore studied the action of this compound as a among persons who had been in contact with alastrim (variola minor)-a nosological entity distinct from but closely related to variola major, which exists in endemic form in Sao Paulo, Brazil (Ribas 1910, Downie et al. 1963). Methods We followed in general the methods used by Bauer et al.
prophylactic agent
(1963). Contacts of alastrim patients resident in the city of Sao Paulo were visited in their homes during the days following the admission of the patients to the Emilio Ribas Isolation Hospital. The sex, vaccination status, previous illness, and present of health of the contacts were recorded. The drug was given to contacts of odd-numbered index cases, and contacts of the even-numbered index cases were not given treatment but observed as controls. The initial decision to select the contacts of the odd-numbered cases as the treatment group was made by tossing a coin. Contacts were then assigned to treatment and control groups in strict order of admission of the index cases. Methisazone was given by mouth in two equal doses to a total amount of 6 g., an equivalent amount being given to contacts below 10 years of age. The first dose was generally taken in the presence of the visiting physician in the afternoon, and the second dose was left with the contacts with instructions to take it in the morning. For various reasons 53-3% of the treated contacts took only the first dose-that is, 3 g. or its state
We should like to thank Miss Ruth Bell, of the Royal Marsden Hospital for her help with the statistics. Requests for reprints should be addressed to D.C. R-J. at the Westminster Hospital, St. John’s Gardens, London, S.W.I. REFERENCES
Aylett, S. O. (1954) Surgery of the Caecum and Colon; p. 48. Edinburgh.
METHISAZONE IN PREVENTION OF VARIOLA MINOR AMONG CONTACTS LUIZ AUGUSTO RIBEIRO
DO
VALLE
M.D. São Paulo
equivalent.
OF THE INSTITUTO ADOLFO LUTZ
PEDRO RAPOSO
DE
With the object of preventing side-effects such as nausea and vomiting, cyclizine hydrochloride was given at the beginning of the investigation in doses of 100-200 mg., and later chloropromazine in doses of 25-50 mg. or their equivalent. The contacts were revisited 14-16 days later. The amount of drug actually taken was ascertained and recorded, together
MELO
M.D. Recife OF THE SECTION OF EPIDEMIOLOGY AND GENERAL PROPHYLAXIS
LUIS FLORÊNCIO
SALLES GOMES
DE
M.D. São Paulo
with the side-effects and the results of any vaccination which had been carried out by the public-health authorities after the recent exposure to infection. Contacts who stated that they had had alastrim previously, or who had already developed the disease on the day of the first visit, were excluded from the study. Cases of alastrim which developed among the contacts within 14 days of the first visit were recorded. Altogether, 976 contacts satisfied the criteria for acceptance into the study, and originated from 106 patients with alastrim admitted between Feb. 10, 1964, and Feb. 15, 1965. Of these contacts, 520 were in the control group. Treatment with methisazone was offered to 456 contacts, and was accepted by 384; of these, 190 took two doses of 3 g. or equivalent, and 194 took one dose of 3 g. or equivalent. The remaining 68 contacts who refused treatment were not transferred to the control group, and the data relating to them were analysed
OF THE INSTITUTO ADOLFO LUTZ
LUIS MORATO
PROENÇA
M.D. São Paulo OF THE GENERAL DIRECTORATE
DEPARTMENT OF
HEALTH, SÃO PAULO, S.P.,
SINCE 1950, when the
activity
BRAZIL
of p-aminobenzaldehyde
thiosemicarbazone against vaccinia virus was first described (Hamre et al. 1950) the action of thiosemicarbazones against viruses of the variola-vaccinia group has been thoroughly studied in the laboratory (Minton et al. 1953, Thompson et al. 1953, Bauer 1955, Bauer and Sadler
1960a, 1960b, Bach and Magee 1962). On the basis of this work, Bauer et al. (1963) investi-
gated in India the action of methisazone (1-methylisatin 3-thiosemicarbazone,’Marboran’, compound 33T57) given in doses of 6-24 g. in preventing variola major among persons who had been in contact with the infection, and obtained extremely favourable results.
separately. The age distributions of the two groups of treated and control contacts resulting from the procedure of alternate allocation were homogeneous, as shown in table i.
TABLE I-TREATMENT AND AGE OF CONTACTS
Figures in parentheses: Or equivalent.
*
cases
of alastrim.
977 TABLE II-TREATMENT AND VACCINATION STATUS OF CONTACTS
in parentheses: Figures * Or equivalent.
Results
The results of the trial are summarised in table II, in which the data are analysed according to the amount of drug taken and the vaccination status of the contacts. The tables do not include 4 treated contacts who took only a quarter of the intended dose (1-5 g. or equivalent) of the drug, none of whom developed alastrim. The numbers were too small to permit comparison with the other groups, and for this reason could not be analysed. Among 190 contacts who took 6 g. of methisazone or equivalent there were 5 (2-6%) cases of alastrim, and among 194 who took 3g. or equivalent there were 3 (1’5%) cases; 42 (8-1%) cases occurred among 520 contacts in the control group, and 7 (10-3%) cases among the 68 contacts who were assigned to the treatment group but refused to take the drug. No deaths occurred in either the treatment or control groups, for fatal cases are rare in alastrim. The usual case mortality of the disease in the area in which the study was carried out is approximately 1 % of cases notified and
admitted
to
hospital.
spite of the simultaneous administration of cyclizine hydrochloride or chlorpromazine, nausea and vomiting occurred in 66% of the contacts treated with methisazone. In
The
Discussion age-distributions of the treatment and control
groups were subjected to statistical analysis, applying the test of Kolmogorov-Smirnov (Guedenko 1962). The probability associated with the age-distributions of the 2 x 3 g. treatment group and the control group was 73%, and for the 3 g. treatment group and control group 3-7%. Both these percentages exceeded the level of significance of 2-5% adopted for each analysis, so that the comparisons are not independent, and subsequent correction of the groups is unnecessary. Since the treatment and control groups could thus be shown to be homogeneous in respect of age-distribution it was possible to proceed to the direct comparison of the results. At the initial planning of this study it was considered that the most interesting group under observation would be that of the contacts who had never been vaccinated before the time of the first visit, or did not show any marks of a previous successful vaccination. In fact, in these individuals considered simply as unvaccinated persons, only one variable, the drug, would be influencing the results. It is therefore appropriate to analyse in the first place the data relating to this group of contacts, amounting to 406 persons in all. Of these, 219 belonged to the control group, and 187 took part or all of the assigned dose of
cases
of alastrim.
methisazone. Among the 219 control contacts 38 (17-4%) developed alastrim, compared with 7 (3-7%) cases among the 187 contacts in the treatment group. Statistical analysis of these figures gives a value of Z2 for two degrees of freedom of 19-489, which is significant at the level of 0-01%, thus indicating that the drug, the sole variable, acted favourably in reducing the incidence of contact cases of alastrim. When the results obtained in previously unvaccinated contacts of the treatment group with the doses of 3 g. and 6 g. are studied separately, it will be seen that 5 cases of alastrim occurred among 92 contacts who took 6 g. or equivalent, and 2 cases occurred among 95 who took 3 g. or equivalent, whereas among 219 previously unvaccinated the control group there were 38 cases. These data were analysed by the method of multiple comparisons proposed by Gold (1962), and it was found that treatment with methisazone reduced the incidence of contact cases of alastrim with a degree of significance contacts of
of 5%. Similarly, when the total number of
contacts
not
vaccinated before exposure to infection are considered, including now those who received primary vaccination after exposure to infection, regardless of whether it was successful or not, it will be seen that 42 (15-7%) of the 267 relevant contacts in the control group developed alastrim. On the other hand, 5 (4-8%) cases of alastrim occurred among 105 similar contacts who received the total course of treatment of 6 g. or equivalent and 3 (2-7%) cases occurred among 110 who took 3 g. or equivalent. Statistical analysis of the data relating to the treatment and control groups showed once more that the value of X2for two degrees of freedom (18-742) was significant at the 0-01% level. Also, separate comparisons of the two subdivisions of the treatment group carried out by the method of multiple comparisons showed that they differed significantly at the 5% level from the control group. It is interesting to note that no cases of alastrim were observed among previously vaccinated contacts, either in the treatment or in the control group. This shows an interesting difference from the figures quoted by Bauer et al. (1963) who observed 1 mild case of variola major among 841 treated contacts who had been vaccinated previously, and 42 cases with 1 death among 856 such contacts in the control group. An incidental observation made in a children’s hospital in Sao Paulo is worth mentioning. After the occurrence of a case of alastrim in the ward, 11 unvaccinated infants (included in tables i and 11) aged 4-11 months who had
978 been exposed to infection were treated with methisazone. None developed alastrim, although they were of an age. at which they should have been highly susceptible to infection. Conclusions Under the conditions prevailing in Sao Paulo in which the trial was carried out, statistical analysis of the results indicates that methisazone in doses of 3 g. or 6 g. or equivalent had a favourable effect in reducing the incidence of alastrim amongst persons who had been exposed to the
infection. The observations of Bauer et al. (1963) are therefore confirmed by the results obtained in the present investigation. It may be noted that Ferguson (1964) observed 4 cases of smallpox among 43 contacts treated with methisazone during an outbreak of smallpox in Port Elizabeth, South Africa, in 1964, and he concluded that the results of
chemoprophylaxis
were
disappointing.
However,
our
results show that a few cases are still to be expected in treated contacts, and the true incidence in the absence of treatment cannot be obtained from Ferguson’s data because of the absence of a comparable control group.
Summary The action of small doses of methisazone was studied in 976 contacts of patients with alastrim (variola minor) in Sao Paulo, Brazil, between Feb. 10,1964, and Feb. 15,1965. Of 406 contacts who had not previously been vaccinated and were not vaccinated after exposure, 187 were treated with methisazone in doses of 3 g. or 6 g. or equivalent, and 219 were left untreated as a control group; 7 cases of alastrim occurred among the contacts treated with methisazone, and 38 cases among the controls. Of 482 previously unvaccinated contacts (including the above), some of whom were vaccinated after exposure, regardless of the results, 215 were treated with methisazone as above, and 267 were left untreated as controls; 8 cases of alastrim occurred among the treated contacts and 42 cases among the controls. The differences in the incidence of alastrim in the treated and control groups were significant at the 0-01% level, showing that methisazone is effective in the prevention of alastrim in the doses employed and under the conditions prevailing in Sao Paulo where the trial was carried out. There was no significant difference between the agedistributions of the contacts in the treatment and control groups, and the incidence of alastrim in the two groups could therefore be compared without correction. No cases of alastrim occurred in contacts, whether treated or not, who had been successfully, vaccinated at some time before exposure, even when they are not revaccinated after exposure. The main side-effects were nausea and vomiting, which occurred in two-thirds of the treated contacts, and did not respond to treatment with cyclizine hydrochloride or
chlorpromazine.
AUGMENTED HISTAMINE RESPONSE AFTER INCOMPLETE VAGOTOMY P. R. F. BELL Sheff., F.R.C.S.
R. G. CHECKETTS
M.B.
REGISTRAR
M.B. Sheff. RESEARCH ASSISTANT
D. JOHNSTON Glasg., F.R.C.S.E.
M.B.
LECTURER
H. L. DUTHIE M.D., Ch.M. Glasg., F.R.C.S. PROFESSOR OF SURGERY
UNIVERSITY DEPARTMENT OF SURGERY, ROYAL INFIRMARY, SHEFFIELD
THE initial reduction in acid secretion after complete vagotomy has been shown to be maintained for at least three years (Gelb and Janowitz 1964, Bell 1964). In fact Bell (1964) has shown a tendency for a further reduction with time. The long-term effect of incomplete vagotomy is not quite so clear. The same authors have reported a rise in acid secretion with the passage of time in some patients. We here report a series of 42 patients showing no significant long-term change in the output of gastric acid after incomplete vagotomy. Materials and Methods Clinical Material Over a 5-year period, 42 male patients with duodenal ulcer were selected on the basis of a positive insulin test indicating incomplete vagotomy. In all of them the output of acid by the stomach in response to augmented doses of histamine was measured preoperatively and 10 days after operation. A further test was carried out between 4 and 63 months after vagotomy. Augmented Histamine Test This was performed as described by Kay (1953). After a 12-hour fast, a ’Neoplex’ gastric tube was inserted into the stomach via the nostril, constant suction being maintained by means of an electric pump. After removal of the fasting secretion, two 15-minute aspirates were removed for calculation of the spontaneous secretion. At this time 100 mg. of mepyramine maleate (’Anthisan’) was given by intramuscular injection. The gastric aspirate collected in the next half-hour was discarded. A subcutaneous injection of histamine acid 0-04 phosphate, mg. per kg. body-weight was then given subcutaneously and three successive 15-minute samples of gastric juice collected. The acid was titrated with 0-01 N sodium hydroxide using Topfer’s reagent as indicator. The sum of the last two samples was taken as the maximal acid response and expressed as milliequivalents of acid. Insulin Test Aftera 12-hour fast, gastric secretion was removed as described above. After aspiration of three basal 15-minute samples, 20 units of soluble insulin was given intravenously. Collection of successive 15-minute aspirates then continued for 2 hours. The acid concentration of each 15-minute sample was determined as above. Results
All
patients
gave
a
positive insulin
response
as
defined
DR. DO VALLE AND OTHERS: REFERENCES
Bach, M. K., Magee, W. E. (1962) Proc. Soc. exp. Biol. Med. 110, 565. Bauer, D. J. (1955) Br. J. exp. Path. 36, 105. Sadler, P. W. (1960a) Lancet, i, 1110. (1960b) Brit. J. Pharmacol. 15, 101. Leone St. Vincent, Kempe, C. H., Downie, A. W. (1963) Lancet 494. ii, Downie, A. W., Dumbell, K. R., Ayrosa Galvão, P. A., Zatz, I. (1963) Trop. Geog. Med. 15, 25. Ferguson, D. L. (1964) S. Afr. med. J. 38, 868. Gold, Ruth (1962) in On Comparing Multinomial Probabilities; p. 1. School of Aerospace Medicine, Brooks Air Force Base, Texas. Guedenko, B. V. (1962) The Theory of Probability; p. 395. New York. Hamre, D., Bernstein, J., Donovick, R. (1950) Proc. Soc. exp. Biol. Med. —
We thank Dr. Otavio Martins Toledo, director of the Emilio Ribas Isolation Hospital, for permission to visit the patients and examine the hospital records; Prof. Elza Berquó and Prof. Rubens Murillo Marques, of the Department of Applied Statistics of the Faculty of Public Health and Hygiene of the University of Sao Paulo, for the statistical analyses; Snra Yara Karmann, for her devoted assistance; and Sr. Luiz Rodolpho Cavalieri, who helped us to carry out this work. We also thank the Wellcome Foundation for the supplies of methisazone and other drugs used in the trial. Requests for reprints should be addressed to L. A. R. do V., Instituto Adolfo Lutz, Sao Paulo, Brazil.
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