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PubMed1997

The activity of triple combinations of antifolate biguanides, with and without folinic acid, against plasmodium falciparum in vitro.

At least two triple combinations of biguanides, proguanil-atovaquone-dapsone and PS-15-atovaquone-dapsone, may be useful in treating drug-resistant infections of falciparum malaria. Each of these triple combinations can be considered as two synergistic combinations: proguanil-atovaquone and cycloguanil-dapsone, and PS-15-atovaquone and WR99210-dapsone, respectively. Since folinic acid might mitigate the possible side-effects produced by such drug combinations, both combinations were administered, with and without folinic acid, to 16 Saimiri sciureus monkeys. The antimalarial activity in serum samples collected from each monkey, 3, 6 and 24 h after drug administration, was then determined in vitro, against Plasmodium falciparum. The addition of folinic acid had no apparent affect on the antimalarial activity of the triple combinations tested. Such combinations may be useful against Pneumocystis carinii and Toxoplasma gondii in immunocompromised patients, as well as against malaria.

Animals↗
PubMed1993

The use of a three compartment in vitro model to investigate the role of hepatic drug metabolism in drug-induced blood dyscrasias.

1. N-hydroxylation is thought to be an essential step in the haemotoxicity of dapsone (DDS). To investigate both metabolism-dependent and cell-selective drug toxicity in vitro we have developed a three-compartment system in which an hepatic drug metabolizing system is contained within a central compartment separated by semipermeable membranes from compartments containing mononuclear leucocytes (MNL) and red blood cells (RBC). 2. Metabolism of dapsone (100 microM) by rat liver microsomes resulted in toxicity to RBC cells (47.3 +/- 2.1% methaemoglobin), but there was no significant toxicity toward MNL (3.7 +/- 1.3% cell death) compared with control values (1.6 +/- 0.9%). However, when RBC were replaced with buffer in the third compartment there was significantly greater (P < 0.001) white cell toxicity (17.6 +/- 0.6% cell death), demonstrating the protection of MNL by RBC. Metabolism of dapsone by human liver microsomes again resulted in RBC toxicity (12.5 +/- 3.3% methaemoglobin) but no significant MNL toxicity (2.9 +/- 0.8% cell death). Replacement of RBC resulted in a significant (P < 0.001) increase in MNL toxicity (6.5 +/- 0.7% cell death). Addition of synthetic dapsone hydroxylamine (30 microM) in the absence of a metabolizing system and with no RBC in the third compartment resulted in significant (P < 0.001) toxicity toward MNL (43.36 +/- 5.82% cell death) compared with control (1.8 +/- 1.1%). The presence of RBC in the third compartment resulted in a significant (P < 0.001) decrease in MNL toxicity (17.6 +/- 2.2% cell death), with 40.1 +/- 3.7% methaemoglobin in the RBC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

A convenient five-drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study.

AIMS: To assess the feasibility of administering at the same time low doses of five probe drugs, metoprolol (25 mg), chlorzoxazone (250 mg), tolbutamide (250 mg), dapsone (100 mg) and caffeine (100 mg) to determine simultaneously the activities of CYP2D6, CYP2E1, CYP2C9, CYP3A4, CYP1A2, N-acetyltransferase-2 and xanthine oxidase. METHODS: Ten healthy young non-smoking males received the following drugs or combinations of drugs over a 5-week period: week 1) metoprolol; 2) tolbutamide; 3) caffeine, chlorzoxazone and dapsone; 4) caffeine, chlorzoxazone, dapsone and metoprolol; 5) caffeine, chlorzoxazone, dapsone, metoprolol and tolbutamide. The drugs were self-administered at bedtime and urine was collected for the following 8 h. RESULTS: Mean molar phenotypic ratios obtained after administering metoprolol (mean change of -11%) or tolbutamide (mean change of -0.3%) alone, were not significantly different from those obtained when other drugs were co-administered (P > 0.05). The mean within-subject coefficients of variation were 33%, 18%, 22%, 13%, 16%, 13% and 5% for CYP3A4, CYP2D6, CYP2C9, CYP2E1, CYP1A2, N-acetyltransferase 2 and xanthine oxidase metabolic ratios, respectively. No significant interactions (P > 0.5) were observed during the simultaneous administration of various combinations of the five probe drugs. CONCLUSIONS: We propose that this cocktail, composed of five widely available drugs, constitutes a promising means of simultaneously determining the activities of the major CYP enzymes in large populations.

Adult↗
PubMed1977

Gluten-free diet in dermatitis herpetiformis. I. Clinical response of skin lesions in 81 patients.

Eighty-one patients with dermatitis herpetiformis were treated with a gluten-free diet (GFD) for periods varying from 6 to 36 months. At the end of the treatment the daily requirement of dapsone was significantly lower in patients treated with a GFD than in 49 patients on a normal diet. 93% of the patients on a GFD were able to reduce the dose of dapsone whereas only 16% of the patients on a normal diet were able to do this. Complete remissions occurred only in patients on a GFD. 28% of the patients on a GFD were able to stop dapsone completely and were continuously asymptomatic when they observed a strict diet. A response to a GFD was noted on the mean daily requirement of dapsone as soon as the treatment was initiated although the length of time for an individual response varied. After one year on a GFD the patients needed on average about 40% and after 3 years about 20% of the dose required to control skin symptoms at the beginning of the diet. The patients responded to a GFD irrespective of changes found in the jejunal mucosa and irrespective of the presence of absence of HLA-B8.

Adolescent↗
PubMed1981

Disodium cromoglycate in dermatitis herpetiformis.

Eleven patients with dermatitis herpetiformis, all requiring dapsone to control their rash and taking a normal diet, were given disodium cromoglycate (DSCG) 1.5-1.6 g daily. Eight out of the eleven patients continued to take DSCG for periods varying from 6-11 months, the other three patients chose to discontinue the DSCG before 6 months. Of the eight patients taking DSCG for at least 6 months, none was able to stop taking dapsone. In three of the eight, the dapsone requirements were unaltered, whilst in two it decreased and in three it increased. The mean daily dose of dapsone was 105 mg/day before DSCG and 141 mg/day after DSCG. In the eight patients who took DSCG for at least 6 months, intestinal biopsies were performed before and after this drug. The macroscopic appearance was unchanged in four, improved in two and worse in two. The mean interepithelial lymphocyte count was 346 before and 342 after DSG.

Adult↗
PubMed1993

Pyrimethamine inhibits renal secretion of creatinine.

The mechanism of increased serum creatinine after administration of pyrimethamine and dapsone was evaluated for six healthy volunteers. Serum parameters, urine sediment, and clearances of creatinine, inulin, and para-aminohippurate were assessed prior to and 28 h after the ingestion of a single, combined dose of 100 mg of pyrimethamine and 200 mg of dapsone. In a second series, the same renal function tests were performed for nine human immunodeficiency virus-infected men before and after 1 month of prophylactic treatment with a weekly dose of 75 mg of pyrimethamine and 200 mg of dapsone to evaluate sustained effects on renal function. Serum creatinine increased within 28 h from 81 +/- 14 to 102 +/- 16 mumol/liter (P = 0.002) in the healthy volunteers. Blood urea nitrogen, beta 2-microglobulin, and urine remained normal. Creatinine clearance decreased from 125 +/- 27 to 91 +/- 26 ml/min (P < 0.02) without changes in inulin clearance. The effect was reversible within 21 days and attributable to pyrimethamine, as determined by administration of each drug alone. The sustained effect of four doses of pyrimethamine and dapsone in human immunodeficiency virus-infected patients consisted of an analogous rise in serum creatinine from 69 +/- 17 to 87 +/- 32 mumol/liter (P < 0.05). Both creatinine and inulin clearances, however, were unchanged, representing a new equilibrium between creatinine production and elimination at a higher level in serum. Pyrimethamine, thus, may reversibly inhibit renal tubular secretion of creatinine without affecting the glomerular filtration rate. This physiologic effect in pyrimethamine-treated patients must be differentiated from possible organ-related nephropathies.

Adult↗
PubMed1995

In vitro activities of novel antifolate drug combinations against Plasmodium falciparum and human granulocyte CFUs.

The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combination with dihydropteroate synthetase inhibitors, against the Kenyan K39 strain of Plasmodium falciparum (pyrimethamine resistant) and against normal replicating human bone marrow cells in in vitro culture has been studied. Therapeutic indices and rank order of synergistic potency were derived. Trimethoprim, pyrimethamine, and the quinazolines WR159412 and WR158122 had the smallest therapeutic indices (1.39, 4.38, 2.56, and 90.0, respectively), while the three triazines clociguanil, WR99210, and chlorcycloguanil had the largest (3,562, 3,000, and 2,000, respectively). In rank order of decreasing activity against P. falciparum, the six most potent drug combinations were WR99210-dapsone, chlorcycloguanil-dapsone, WR158122-dapsone, WR159412-dapsone, WR159412-sulfamethoxazole, and chlorcycloguanil-sulfamethoxazole; pyrimethamine-sulfadoxine was the least potent combination. These experiments form a basis for the selection of rapidly eliminated antifolate combinations for further clinical testing.

Animals↗
PubMed1978

Rifampicin for lepromatous leprosy: nine years' experience.

Over 100 patients with lepromatous leprosy were treated with rifampicin in a series of pilot, uncontrolled, and controlled trials in 1968-77. The rapid bactericidal effect of rifampicin on Mycobacterium leprae was confirmed. Clinical improvement became apparent sometimes as early as 14 days after the start of treatment. Nevertheless, a few persisting viable M leprae were detected as long as five years after the start of treatment with rifampicin either by itself or in combination with the bacteriostatic drug thiambutosine. Treatment with rifampicin and dapsone for six months reduced the number of persisting leprosy bacteria more than treatment with dapsone alone. Although rifampicin proved more effective than dapsone, it is unlikely that used by itself if can significantly shorten the length of treatment in lepromatous leprosy. Therefore initial intensive combined treatment with two or more bactericidal drugs (including rifampicin) warrants further investigation in both untreated leprosy and lepromatous leprosy resistant to dapsone.

Animals↗
PubMed1999

Successful treatment of subcorneal pustular dermatosis (Sneddon-wilkinson disease) by acitretin: report of a case.

We report a case of subcorneal pustular dermatosis (SPD) first treated with dapsone with poor response. Dapsone was changed to acitretin, which dramatically improved the lesions in a few days. Dapsone is the first-line treatment in SPD, but it may be ineffective in some cases and its toxicity is important. Therapeutic alternatives are limited and less effective (systemic corticosteroids, phototherapy). Our observation underlines the usefulness of retinoids, when dapsone is ineffective or poorly tolerated. Their effectiveness is comparable, but they are effective more rapidly and are better tolerated. A dose maintenance is necessary to avoid relapses. Their action in SPD remains unclear but may be due to the inhibition of neutrophil functions.

Acitretin↗
PubMed1999

Effects of a novel pyridylsulphonyl thiazole derivative, FR115092, on autoimmune and mitomycin C-induced thrombocytopenia in mice.

Dapsone (4,4'-diaminodiphenyl sulphone), an antileprotic and antimalarial drug, has been reported to be of therapeutic benefit in idiopathic thrombocytopenic purpura in the clinic. However, adverse reactions such as haemolytic anaemia have often been observed. In this study, we found that dapsone increased the number of platelets and decreased the number of red blood cells in male (NZWxBXSB)F1 (W/BF1) mice, an animal model of idiopathic thrombocytopenic purpura. In studies to prepare derivatives of dapsone with weaker side effects than the parent compound, FR115092 (2-[5-(2-pyridylsulphonyl)thiazolyl]amine) was discovered. The effect of FR115092 on the number of blood cells was studied and compared with dapsone in mice. FR 115092 increased the number of platelets without reducing the number of red blood cells in W/BF1 mice. This drug significantly suppressed the increase in circulating autoantibodies against platelets and increased the number of megakaryocytes. Furthermore, FR115092 inhibited the reduction of the number of platelets in mitomycin C-induced thrombocytopenic mice, as a consequence of its enhancement of growth and maturation of megakaryocytes. These findings suggest that FR115092 may be effective against various thrombocytopenias, without inducing haemolytic anaemia.

Animals↗
PubMedDate not supplied

Drug resistant-Mycobacterium leprae--results of mouse footpad studies from a laboratory in south India.

Out of 265 biopsies of leprosy patients received at the Experimental Pathology Laboratory of Schieffelin Leprosy Research and Training Centre from 1987 to 1997 for evaluating resistant strains of M. leprae, using the mouse footpad technique, 49 showed resistant strains of M leprae to varying concentrations of dapsone, rifampicin and clofazimine. 23 (47%) of these were from a control area. With 369 skin-smear positive multibacillary (MB) patients as the risk group (denominator), 23 (6.23%) were resistant to one or more drugs. 18 (4.88%) had dapsone resistance, 5 (1.36%) were resistant to rifampicin and 9 (2.44%) had resistance to low concentrations of clofazimine (0.0001%). Out of the 23 biopsies with drug resistance from the control area, primary dapsone resistance was seen in 7 (30%) biopsies and secondary dapsone resistance in 11 (48%). Primary rifampicin resistance was seen in 4 (17.4%) patients, secondary rifampicin resistance in 1 (4.35%) and primary clofazimine resistance in 7 (30%). 3 (13%) of the strains showed secondary clofazimine resistance. One biopsy had resistant strains to all the three drugs. In a control area where properly supervised effective multidrug therapy (MDT) was regularly administered over the years, the emergence of drug resistance is negligible. It may not be the case if the content, duration and regularity of the drug regimen were not satisfactory. Aware of the possible shortcomings in mass administration of MDT, it is emphasized that mouse footpad studies on drug resistance should be made available at least in endemic areas where the incidence of the disease has not changed despite good MDT coverage in order to monitor the emergence of drug resistance. Research into molecular biological identification of drug resistant-M.leprae should be intensified. These steps would help to institute timely measures to check the spread of any drug-resistant organisms in the community.

Animals↗
PubMed2006

Epidemiology of leprosy and response to treatment in Hong Kong.

OBJECTIVES: To review the reported trend of leprosy in Hong Kong. DESIGN: Retrospective study. SETTING: Three major leprosy clinics in Hong Kong. PATIENTS: Leprosy patients registered between 1970 and 2004. MAIN OUTCOME MEASURES: Incidence, rate of deformities, distribution of leprosy subtypes, age distribution, and relapses after therapy. RESULTS: The incidence of leprosy has decreased from 3.2 per 100,000 population in 1970 to 0.088 per 100,000 population in 2004. The proportion of the three subtypes of leprosy has remained roughly equal. There have been 87 relapses within this period with 54 (62%) cases of lepromatous leprosy, 22 (25%) borderline leprosy, and 11 (13%) tuberculoid leprosy. The overall relapse rate was 6.7% (0.2 per 100 person-years); this can be subdivided as a relapse rate for multidrug therapy of 3.2% (0.33 per 100 person-years) and for dapsone monotherapy of 8.3% (0.2 per 100 person-years). The mean interval to relapse for multidrug therapy and dapsone monotherapy was 1.83 and 5.8 years, respectively. The mean duration till relapse for patients on dapsone monotherapy was 15.6 years. CONCLUSION: Treatment with recommended WHO-multidrug therapy is effective and well tolerated. Dapsone monotherapy is no longer effective. Leprosy is well controlled in Hong Kong but continued surveillance is required to detect relapses and to ensure good patient compliance with treatment.

Clofazimine↗
PubMed1991

A case of relapse with drug-susceptible M. leprae after multidrug therapy.

A male born in 1930 was diagnosed as smear-positive borderline leprosy in 1971, and was treated with dapsone and/or sulfamethoxypyridazine from 1972 to 1980 with clinical improvement. However, new skin lesions with smears strongly positive appeared in August 1980, and he was diagnosed as having downgraded to lepromatous (LL) leprosy, but the bacilli recovered from the skin biopsy were fully susceptible to both dapsone and rifampin by mouse foot pad technique. Between 1981 and 1983, the patient was treated with 24 months of rifampin 600 mg and dapsone 100 mg daily, supplemented with prothionamide 500 mg daily during the initial 3 months, and his skin lesions gradually improved during treatment with the combined regimen. Afterward, the patient was kept under surveillance without treatment. From 1984 to 1986, his skin smears were negative, and no bacilli could be found from a skin biopsy taken in 1985. Then in 1987, 52 months after stopping treatment, new skin lesions appeared with a high concentration of Mycobacterium leprae (2 x 10(6)/mg tissue). The drug-susceptibility test again demonstrated that the organisms were fully susceptible to both dapsone and rifampin. Apparently the relapse was due to remultiplication of drug-susceptible persisters.

Adult↗
PubMed1990

Joint chemotherapy trials in lepromatous leprosy conducted in Thailand, the Philippines, and Korea.

Chemotherapy trials in lepromatous leprosy using various combinations of existing antileprosy drugs were conducted jointly by Korea, The Philippines, and Thailand. The general objective of these trials was to determine the most effective and practicable regimen or regimens for field application. Lepromatous patients were divided into two groups: Group I was comprised of new, untreated patients infected with dapsone-sensitive Mycobacterium leprae and Group II consisted of relapsed patients with dapsone-resistant disease. Four different regimens were administered to each group for 5 years. Comparison among the regimens was based on antileprotic efficacy, drug safety, acceptability, field practicability, and economic feasibility. No significant differences were noted among the various regimens as judged by the reduction in the bacterial index (BI), clinical response, and change in biopsy index. Toxicity was seen only in the regimens containing prothionamide and rifampin. The regimens were acceptable to the patients and all were found practical for field use. Clofazimine, even in low doses, was found to suppress the frequency and severity of erythema nodosum leprosum. A multidrug regimen effective against both new and relapsed cases of lepromatous leprosy, whether dapsone sensitive or dapsone resistant, is recommended for field use. Given priority, the cost of the regimens is affordable in the three countries.

Adolescent↗
PubMed1989

Combined regimens of one year duration in the treatment of multibacillary leprosy--I. Combined regimens with rifampicin administered during one year.

In 1981, 1982 and 1983, 216 multibacillary patients in Anjouan (Comores) and Burundi were treated for 8 weeks with daily rifampicin (600 mg) ethionamide (500 mg) and dapsone (100 mg) or clofazimine (100 mg) followed for 44 weeks by once weekly rifampicin (600 mg) and daily ethionamide (500 mg) and dapsone (100 mg) or clofazimine (100 mg). There were 109 previously untreated patients and 107 patients who had dapsone monotherapy, 16 of whom were infected with proven dapsone resistant Mycobacterium leprae. Clinical and bacteriological results were excellent but hepatotoxicity of this regimen remains a problem. No relapses were observed during a 2 to 6 years (mean: 4.29 years) follow-up period after the end of treatment (upper 95% confidence limit of 0.40 per 100 persons years). It is concluded that multibacillary leprosy can be successfully treated with a regimen of one year duration, but less toxic regimens, more easily applicable in the field, are necessary.

Clinical Trials as Topic↗
PubMed1989

Study of multidrug therapy in paucibacillary leprosy.

A study was undertaken to evaluate the efficacy of multidrug therapy (MDT) in paucibacillary leprosy. Out of 155 fresh cases studied 48 had indeterminate, 38 tuberculoid and 69 had borderline tuberculoid leprosy. Out of 155 cases, 64 patients in the first group were treated with dapsone 100 mg daily for 12 months. In the second group, 91 patients were given MDT, consisting of rifampicin 600 mg once a month and dapsone 100 mg daily for consecutive 12 months. The cases receiving dapsone and the cases having MDT remained clinically active at the end of 6 months in 56.1% and 37.2% respectively; 13.1% of cases having single lesion and 66.3% of patients with multiple lesions were found to be active after 6 months of MDT. At the end of one year 79.6% cases receiving dapsone and 91.2% cases having MDT became inactive.

Administration, Oral↗
PubMed1989

Impact of multidrug therapy on leprosy in Baroda district (Gujarat).

Though much information is available on MDT organising, it poses a challenge to the field staff due to limited field trials conducted and varied field conditions. The MDT project was begun on 11th June, 1984 in Baroda by the Govt. of India, with active assistance of State Government, the World Health Organisation and the Swedish International Development Agency. The Drug combinations for MB cases were Rifampicin 600 mg, Clofazamine 300 mg and dapsone 100 mg daily for 14 days intensive supervised therapy followed by once a month (Pulse) supervised dose of Rifampicin 100 mg, Clof. 300 mg and dapsone 100 mg for minimum period of 2 years or more if indicated and Clof 50 mg daily with dapsone 100 mg daily unsupervised for minimum period of 2 years or more if indicated, for PB cases, dapsone 100 mg daily for 6 months along with Rifampicin 600 mg supervised (Pulse) once a month for minimum period of 6 months or more if indicated. Total number of active cases at commencement of MDT was 10706, out of these 10348 (96.37%) brought under MDT till Dec. 1987. Amongst 10348, old active cases 9112 (88.05%) are cured with MDT, (3110 MB + 6002 PB) 180 old MB cases BI is still positive inspite of completed 24 pulse. The rest 1056 (10.23%) stopped the treatment for various reasons. 790 (74.81%) cases have left the villages to earn their livelihood, 30 (2.86%) were being treated by skin specialist, 86 (7.19%) refuse to continue the treatment inspite of best efforts of field staff. New cases detected since June 1984 till Dec. 1987 are 7628, out of which 7549 (96.28%) brought under treatment. Now cases cured till Dec. 1987 are 4640 (1120 MB + 3520 PB) 17 cases relapsed after MDT (15 PB + 2 MB). 280 (1.56%) cases got complications, 250 developed reactions, 3 cases Jaundice, 15 cases Gastritis and rest 12 got moderate to severe anaemia. The prevalence rate came down from 5.81 to 1.01% per thousand population till Dec., 1987. The deformity rate came down amongst new cases from 6.15 to 1.50% till Dec. 1987. regularity of treatment among PB cases is 90.84% as compared to 90.48% for MB cases. The study showed that MDT can be implemented in tribal, rural and urban populations with high rate of compliance.

Clofazimine↗
PubMed1977

The infectivity of drug resistant cases.

The present study shows that leprosy bacilli resistant to dapsone, multiply in mouse foot-pad as equally as the dapsone sensitive bacilli would multiply suggesting that the dapsone resistant case will be as infective as the dapsone sensitive case.

Animals↗