A double blind controlled clinical trial to assess the role of antihistamines

as a supplement in the treatment of leprosy was conducted in multibacillary

cases of leprosy. In all, 120 patients with lepromatous or borderline

leprosy were randomly allocated to a regimen of clofazimine and dapsone for

12 months with or without a supplement of pheniramine maleate for the first 3

months. During the 12-month period, 92% of the patients who received the

supplement and 86% of the patients who had not received it had moderate or

marked clinical improvement. The BI values decreased from 4.1 to 3.4 and 4.2

to 3.3, respectively. The results over the 12-month period showed that the addition

of the antihistamine had not enhanced the efficacy of the regimen as evidenced

by clinical and bacteriological findings

Bhatia, V N

Chandrasekaran, V

Hari, Lalitha

Kumar, Ashok

Nagarajan, M

Prabhakar, R

Roy, R G

Somasundaram, P R

Thomas, A

NIRT Institutional Repository

Vol. 60 No. 4 INDIAN JOURNAL OF LEPROSY October 1988A DOUBLEBLIND CONTROLLED CLINICAL TRIAL TO ASSESSTHE ROLE OF ANTI-HISTAMINES IN THE TREATMENT OF MULTI-BACILLARY LEPROSYA. THOMAS1, M. NAGARAJAN 2, V. CHANDRASEKARAN3, LALITHA  HARI4,P.R. SOMASUNDARAM5, R. PRABHAKAR6, ASHOK KUMAR7, V.N. BHATIA8AND R.G. Roy9ABSTRACT : A double blind controlled clinical trial to assess the role of anti-histamines as a supplement in the treatment of leprosy was conducted in multi-bacillary cases of leprosy.In all, 120 patients with lepromatous or borderlineleprosy were randomly allocated to a regimen of clofazimine and dapsone for12 months with or without a supplement of pheniramine maleate for the first 3months. During the 12-month period, 92% of the patients who received thesupplement and 86% of the patients who had not received it had moderate ormarked clinical improvement.The BI values decreased from 4.1 to 3.4 and 4.2to 3.3, respectively.The results over the 12-month period showed that the addi-tion of the antihistamine had not enhanced the efficacy of the regimen as evidencedby clinical and bacteriological findings.INTRODUCTIONLepromatous leprosy represents the florid form of leprosy with awell-defined immunological defect which appears to lie either in the macro-phages or in the T-lymphocytes.Increased levels of immunoglobulins,including IgE, are found in lepromatous patients (Jopling, 1984). It isknown that IgE releases histamine from mast cells and basophils on contactwith an antigen.On the basis of experimental work in vitro, Veeraraghavan (1985)suggested that release of histamine at the sites of immediate hypersensiti-1. Dr. A. Thomas, Senior Research Officer,2. Mr. M. Nagarajan, Technical Officer,3. Mr. V. Chandrasekaran, Technical Assistant,4. Mrs. Lalitha Hari, Assistant Research Officer,5. Mr. P.R. Somasundaram, Deputy Director,6. Dr. R. Prabhakar, Director,Tuberculosis Research Centre, Madras - 600 031.7. Dr. Ashok Kumar, Assistant Director,8. Dr. V.N. Bhatia, Deputy Director,9. Dr. R.G. Roy, Director,Central Leprosy Teaching and Research Institute, Chengalpattu - 603 001.499Vol. 60 No. 4 INDIAN JOURNAL OF LEPROSY October 1988vity reaction could possibly generate histamine-induced suppressor activityby lymphocytes, which may play a regulatory role in the subsequent deve-lopment of cellular immune response.Furthermore, it has been suggest-ed by Veeraraghavan (1983) that histamine and heparin are growth-stimu-lants for M. leprae and that histamine H-1 and H-2 receptor antagonistshave a marked inhibitory effect on the growth of the organisms in vitro.It was reported that anti-histamines, particularly pheniramine maleate,produced marked clinical and bacteriological improvement in lepromatousleprosy patients (Gangadhara Sharma, 1982).Therefore, a controlled clini-cal trial was conducted to evaluate the potential beneficial effect of pheni-ramine maleate in the treatment of lepromatous or borderline lepromatousleprosy patients. The results up to 12 months are reported here.Aims and Objectives :To assess the effect of a supplement of pheni-ramine maleate (anti-histamine) on the therapeutic efficacy of a regimen ofclofazimine and dapsone in the treatment of multibacillary leprosy.MATERIALS AND METHODSThe study was conducted concurrently at two places, namely theLeprosy Unit of the Tuberculosis Research Centre at the Govt. RoyapettahHospital, Madras, and the Rural Field Operational Area of the CentralLeprosy Teaching and Research Institute, Thirumani, Chengalpattu, comp-rising 54 villages in Sriperumbudur Taluk of Chengalpattu District, TamilNadu.Eligibility Criteria :Multibacillary leprosy patients aged 15 yearsand above, who were classified clinically and histopathologically as BL orLL type with a bacteriological index of 2.5 or more on Ridley’s scale (1964)were included in the trial.Pregnant women and those suffering fromdiseases such as tuberculosis, severe protein energy malnutrition, diabetesor hypertension and those with hepatic damage were not included in thetrial.Chemotherapeutic regimens :The patients were allocated at randomto receive one of the following two regimens:A H C D  : Clofazimine (C) and Diamino-diphenyl-sulphone (D) dailyfor 12 months, with the addition of pheniramine maleate(AH) daily for the first 3 months.CD : Clofazimine and Diamino-diphenyl-sulphone daily for12 months, with the addition of a calcium lactate tabletdaily for the first 3 months.500THOMAS ET AL—ROLE OF ANTI-HISTAMINES IN THE TREATMENT OF LEPROSYThe study was conducted double-blind to avoid any possibility ofbias. Thus neither the doctors, clinic staff and para-medical workers northe patients knew whether an individual patient was receiving the anti-histamine or the calcium lactate tablet. Each day’s drugs for the first 3months for each patient were pre-packed at the Tuberculosis ResearchCentre, Madras.Clofazimine and DDS were given in a dose of 100 mg daily, anti-his-tamine 50 mg daily and a matching tablet of calcium lactate.All the drugs were given daily in a single dose.The drugs were ad-ministered under supervision during the first 3 months.Duri g 4-12 months,patients being treated at the Govt. Royapettah Hospital attended twice aweek, received that day’s drugs under supervision, and collected drugs forthe rest of the days for self-administration.For patients in the villages, aparamedical worker visited the house of each patient daily in the first 3 monthsto administer the drugs under supervision, and weekly during the following9 months to supply drugs for self-administration.Allocation of treatment regimens : The patients were randomlyallocated to the above two treatment regimens at the Tuberculosis Re-search Centre, Madras, after stratification according to the history of pre-vious anti-leprosy chemotherapy as (a) less than one year, (b) 1 to 5 years,and (c) more than 5 years.Assessments and examinations(a) On admission :All the patients underwent (i) a general medicalcheckup to exclude other health problems, (ii) clinical assessment of leprosy,(iii) examination of skin smears from six active sites for lepra bacilli to de-termine the bacteriological index (BI) and morphological index (MI), (iv)estimation of haemoglobin and total and differential white blood cells counts,(v) urine tests for albumin and sugar, (vi) Mitsuda lepromin test, (vii) skinbiopsy for histopathological examination, and (viii) colour transparenciesof lesions.In addition, a clinical examination for leprosy was undertaken onadmission by an independent assessor, who was unaware of the treatmentregimen and the bacteriological findings.(b) During treatment :The clinical, bacteriological, blood and urineexaminations were undertaken every three months. All the patients wereclinically examined by the independent assessor and clinical photographswere taken at 3, 6 and 12 months.501Vol. 60 No. 4 INDIAN JOURNAL OF LEPROSY October 1988RESULTSStudy population :In all, 120 patients were admitted to the trial.Of these, 17 patients were excluded; 2 patients died of causes unrelated toleprosy (one with burns and the other of cardio-pulmonary failure) and 15patients (7 AHCD, 8 CD) becameunto-operative and discharged them-selves against medical advice (10 patients stopped attending during the first3 months, 3 during 4-6 months and 2 in 9-12 months).Thus there remained103 patients (52 AHCD, 51 CD) for analysis.Of the 103 patients, 89 were males; 38 patients were under 30 yearsof age, 29 were aged 30-39 years, and the reamining 36 were aged 40 yearsor more. The mean age was 34 years (range 15-65 years) and the meanweight 44.5 kg (range 29.2-83.3 kg). All the 103 patients gave a historyof previous dapsone monotherapy for periods of less than one year (40),1 to 5 years (29), and more than 5 years (34).In all, 88 patients had histopathology findings; 62 (32 AHCD, 30 CD)(70 %) were classified as lepromatous, 13 (4 AHCD, 9 CD) (15 %) as bor-derline lepromatous and 13 (7 AHCD, 6 CD) (15 %) as indeterminate.Drug regularity :A total of 27 (52%) patients in the AHCD regi-men and 23 (45%) patients in the CD regimen did not miss a single doseduring the first 3 months; the remaining 25 (48%) patients in the AHCDand 28 (55%) patients in the CD regimen received 80-99% of the scheduledchemotherapy. Over the period of 12 months, 13 (25%) patients in theAHCD and 12 (24%) patients in CD regimen did not miss a single dose38 (73%) patients in the AHCD and 38 (75%) patients in the CD regimenreceived 80-99% and 1 patient in each regimen had less than 80% (78%and 77%) of their scheduled chemotherapy. Thus the regularity in the 2regimens was similar.Clinical progress :The independent assessor classified as havingmoderate or marked clinical improvement 36 (69%) AHCD and 33 (65%)CD patients at 3 months, 81% and 88% at 6 months, and 92% and 86%at 12 months, respectively. Thus the clinical improvement was similar inthe 2 regimens.Bacterial indices : The mean BI was high and similar at the time ofadmission, viz., 4.1 for AHCD and 4.2 for CD patients. There was a steadyfall in the BI values, the fall being 0.2 by 3 months, 0.3 by 6 months and0.7 by 12 months for the AHCD regimen; the corresponding figures for theCD regimen were 0.2, 0.4 and 0.9.Thus the reduction was similar in the2 regimens.502THOMAS ET AL—ROLE OF ANTI-HISTAMINES IN THE TREATMENT OF LEPROSYMorphological indices :The morphological indices (Ml) weredetermined for 54 patients;a high proportion of the patients hadlow MI.ENL reactions during treatment :Of the 103 patients, 42 (19 AHCD,23 CD) had ENL reactions.The incidence of reactions was similar in thetwo regimens. The reactions were controlled with chloroquine, anti-his-tamines, analgesics, prednisolone and/or thalidomide, the chemotherapybeing continued.DISCUSSIONThe study presented in this report was conducted to elucidate the roleof anti-histamines in the treatment of bacilliferous lepromatous leprosycases, having been designed to avoid bias at any stage. Gangadhara Sharma(1982) had reported marked clinical and bacteriological improvement onconcurrent administration of pheniramine maleate with anti-leprotic drugsin lepromatous leprosy patients.However, there were no controls whohad not received the anti-histamine supplement.The fi dings of the presentstudy do not confirm the findings of the above study.Several workers have investigated the role of histamine and anti-histamines in mycobacterial infection.Increased levels of histamine andhistaminases in tuberculosis and lepromatous leprosy cases were reportedby Rai et al. (1977). Kato (1957) reported immunosuppression with anti-histamines in guinea-pigs infected with M. lepraemurium.However, thefindings were not corroborated by Kirchheimer (1964).Veeraraghavan(1983) had reported growth-promoting effect with the addition of hista-mine to culture media used for in vitro cultivation of M. leprae which wasnot substantiated by Prabhakar et l. (1983) and Katoch and Desikan(1983). Furthermore, though histamine could induce suppressor T-cellsin vitro as observed by Nanda and Nath (1982), it probably does not alterthe delayed type of hypersensitivity response to M. l prae (Guimaraes,1961). Converse et al. (1987) have recently reported that administrationof Cimetidine abolished the suppressive effect of mediators released bymononuclear cells from lepromatous leprosy patients. However, the the-rapeutic implication of this observation needs to be established. Thus itmay be seen that several observations regarding the possible beneficialeffect with anti-histamines in the treatment of leprosy have been report-ed which were not substantiated subsequently by other workers, and manyhypotheses purported need to be confirmed by conducting meticulouslydesigned studies.503Vol. 60 No. 4 INDIAN JOURNAL OF LEPROSY October 1988ACKNOWLEDGEMENTThe authors gratefully acknowledge the valuable contributions of theindependent assessors Dr. K. Ramanujam, Dr. H.K. Kar and Dr. M.D.Gupte. The invaluable assistance of Dr. A. Balakrishnan, Medical Officer,Mr. A.S.L. Narayana and Mr. S. Sivasubramanian, Statisticians; Mrs. S.Sivagama Sundari, Laboratory Technician; Miss Theresa Xavier, MedicalSocial Worker; and the Nursing and Paramedical staff is gratefully acknow-ledged. The authors are grateful to Mrs. M.J. Nirmala for secretarial assis-tance.REFERENCES1. CONVERSE, P.J., MASHANA, R.M. AND BJUNE, G.J. (1987). Correspondence.Int. J. Lepr., 55 : 3.2. GANGADHARA SHARMA, C.S. (1982). Pheniramine maleate in the treatment oflepromatous leprosy.Studies on Leprosy, Research Publication, V.H.S. Medical Centre,Madras, 64-67.3. GUIMARAES, N. (1961). Effect of anti-histamine drugs on lepromin reaction.Int. J. Lepr., 21 : 117.4. JOPLING, W.H. (1984). Hand book of leprosy, Third edition : William Heine-mann Medical Books Ltd., London : 60.5. KATO, L. (1957).Experimental transmission of murine leprosy to the guinea-pig by means of induced macrophage exudate and suppression of the natural defencemechanisms. Int. J. Lepr., 25 : 193-206.6. KATOCH, V.M. AND DESIKAN, K.V. (1983).Observations on the cultivation ofM. leprae in Medium V. (Veeraraghavan). Lepr. India., 55 : 292-298.7. KIRCHHEIMER, W.F. (1964). Resistance of anti-histamine treated guinea-pigsagainst infection with mycobacterium Ieprae and M. lepraemurium. Int. J. Lepr., 32 : 18.8. NANDA, N.K. AND INDIRA NATH (1982). Specific modulation of antigen sti-mulated human lymphocyte response by histamine. Ind. J. Med. Res., 75 : 703-711.9. PRABHAKAR , R. LALITHA , H. AND DANIEL  HERBERT. (1983). Observations onthe culture of M. leprae in medium V. Lepr. India., 55 : 450-454.10. RAI, V. GURUMOHAN SINGH, SINGH, R.H., AND UDUPA. K.N. (1977). Bloodhistamine and histaminase in leprosy patients-a short communication. Ind. J. Med.Res., 66 : 978-982.504THOMAS ET AL—ROLE OF ANTI-HISTAMINES IN THE TREATMENT OF LEPROSY11. RIDLEY , D.S. (1964). Bacterial Indices. In : Chochrane. R.G. and Davey,T.F., (Editors) ‘Leprosy in theory and Practice’. John Wright and Sons Ltd., Bristol :620-2.12. VEERARAGHAVAN, N. (1985). Studies on Leprosy, Research Publication V.H.S.Medical Centre, Supplement 2, Madras : 33-34.13. VEERARAGHAVAN. N. (1983). Method of cultivation of M. leprae. CurrentScience, 52 : 60-63.505

A double-blind controlled clinical trial to assess the role of anti-histamines in the treatment of multi-bacillary leprosy

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A double-blind controlled clinical trial to assess the role of anti-histamines in the treatment of multi-bacillary leprosy

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