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PubMedDate not supplied

[Advances in the chemotherapy of leprosy].

The chemotherapy of multibacillary leprosy with dapsone alone has resulted after 15-20 years in the selection and the diffusion of dapsone resistant Mycobacterium leprae. To overcome dapsone resistance, to prevent the selection of organisms resistant to other drugs and to kill the largest proportion of sensitive M. leprae, the chemotherapy of leprosy must rely, as chemotherapy of tuberculosis, upon the combination of several drugs. Rifampicin is included in all drug combinations recommended by WHO. The drug combinations have to be given for at least six months in patients with paucibacillary leprosy and two years in patients with multibacillary leprosy.

Anti-Bacterial Agents↗
PubMedDate not supplied

Evaluation of multidrug therapy with rifampicin, clofazimine and D.D.S. in multibacillary leprosy cases.

Rifampicin, Clofazimine and D.D.S. have been tried in fifteen active untreated lepromatous cases for a period of two years. Compared to dapsone monotherapy remarkable clinical and bacteriological improvement was observed with this combined therapy with attainment of negative BI in ten cases. Use of this combination therapy is thus advocated to achieve noninfectivity in a shorter period and to prevent emergence of dapsone resistance thereby causing the path of leprosy control before it becomes unmanageable due to dapsone resistance.

Adolescent↗
PubMed1995

[The frequency of the appearance of perforating foot ulcers in patients with Hansen's disease as a function of treatment with disulone alone or with polychemotherapy].

Between 1986 and 1989, in 5 departments of Senegal, 436 new cases of leprosy were detected, of whom 225 were put under dapsone monotherapy and 211 under multidrug therapy (MDT). Of them, 190 could be followed-up during 2 years by means of annual bacteriological and clinical examination, including neurological assessment. In 2 years, the onset of 10 (5.3%) chronic plantar ulcers (CPU) was observed: 4 (4%) among the 99 patients under dapsone monotherapy and 6 (6.6%) among the 91 under MDT (no significant difference). Of the 10 CPU, 3 (2%) appeared among the 149 patients without any disability at detection while 7 (17%) were observed among the 41 others who presented a grade 1 disability at detection (p < 0.01). Of the 6 CPU appeared in the patients under MDT, 5 (22%) were observed among the 23 who presented a grade 1 disability at detection and 1 (1.5%) among the 68 who did not (p < 0.01). This difference was not noted in the patients under dapsone monotherapy. Our results need to be confirmed by other studies including a higher number of patients followed-up during a longer period of time. Nevertheless, they suggest that MDT could prevent the onset of CPU, but only in patients without any disability at detection. Therefore, they reemphasize the importance of early detection of the disease in leprosy control programmes.

Chronic Disease↗
PubMed1994

Sulfone syndrome in a patient receiving steroids for pemphigus.

A male patient who was being treated with oral prednisone for erosive mucocutaneous pemphigus lesions developed fever, jaundice, a rash, and anemia within 2 wk of starting dapsone therapy. These signs are typical of the sulfone syndrome, which is a potentially fatal condition due to dapsone hypersensitivity. The incidence of sulfone syndrome is increasing in frequency but has not previously been reported in pemphigus. This patient developed the syndrome early and while on oral steroids, which are sometimes used as a treatment for the sulfone syndrome, and without any evidence of a hypersensitivity reaction. Physicians should be aware of the potentially fatal sulfone syndrome in patients who are on dapsone therapy and who have abnormal liver tests, fever, and a rash.

Aged↗
PubMed1994

[Clinical course of Horton disease. Apropos of 42 cured patients].

We report a prospective study of 42 patients with biopsy-proven giant cell arteritis (CGA) who recovered for more than one year (mean follow up of 71 months since withdrawal of steroid treatment). It was used the same regimen of prednisone and well closely monitored along the whole treatment. In 22 patients, dapsone was given concomitantly with prednisone. Mean duration of steroid therapy was 23.1 months (range: 6-57 months); it was significantly decreased with treatment by dapsone (12 months and 12 days). Age, sex, initial clinical and biological (acute phase reactants) findings did not provide useful information for predicting steroid treatment needed for recovery. Thirty-six relapses were observed in 22 patients (60%) during treatment or after its withdrawal. Incidence of relapses declined during steroid treatment and relapses were (only) observed over first 6 months after steroid withdrawal. Three amaurosis fugax occurred at the beginning of treatment and an axillar bilateral stenosis was also observed. Forty-eight side effects of corticosteroids were recorded in 26 patients (63%): myopathy (n = 12), bone complications (n = 11), metabolic complications (n = 9). Twelve patients (63%) had experienced side effects of dapsone. This study emphasized the difficulty in treating CGA. Close monitoring is required. A steroid regimen is recommended.

Aged↗
PubMed1994

Antimycobacterial therapy in Crohn's disease: results of a controlled, double-blind trial with a multiple antibiotic regimen.

UNLABELLED: Several recent reports have suggested an association of atypical mycobacteria with Crohn's disease. OBJECTIVES: The goal of this double-blind, placebo-controlled trial was to determine the efficacy of treatment with antimycobacterial drugs in maintaining clinical remission and in reducing active inflammatory lesions. METHODS: Forty patients (15 male) with refractory, steroid-dependent Crohn's disease were randomized to receive 2 months of tapering steroids plus either a 9-month regimen of ethambutol, clofazimine, dapsone and 1-day dose only of rifampicin (n = 22), or identical placebo. RESULTS: Three patients (two on active drug) were unable to discontinue steroids, and one patient on active drug was withdrawn for side effects during the first 2 months. Three of the remaining 19 patients on active drug relapsed during the study period, compared with 11 of 17 on placebo (log likelihood ratio = 4.6; p = 0.03). Another patient was withdrawn in remission at 5 months for anemia related to dapsone. Nine patients whose disease relapsed or persisted on placebo were crossed over to active drug; five achieved sustained remission, two failed, and two were withdrawn for side effects. Substantial endoscopic or radiologic healing did not occur. CONCLUSION: This study suggests that the treatment regimen with rifampicin, ethambutol, clofazimine, and dapsone is effective in relief of symptoms and maintenance of remission in some Crohn's disease patients.

Adult↗
PubMed1998

Pro- and anti-oxidant effects of some antileprotic drugs in vitro and their influence on super oxide dismutase activity.

The effect of ofloxacin (CAS 82419-36-1), dapsone (CAS 80-08-0), rifampicin (CAS 13282-46-1) and clofazimine (CAS 2030-63-9) on the generation of superoxide anions was studied in vitro. The drugs were incubated with a superoxide generating system (photochemical reaction between riboflavin and dianisidine). The change in optical density was measured. The optical density was increased with dapsone and ofloxacin and decreased in presence of clofazimine and rifampicin. This result indicates that ofloxacin and dapsone have an antioxidant property, whereas clofazimine and rifampicin behave as pro-oxidants.

Antioxidants↗
PubMed1995

Enzyme kinetic properties of human recombinant arylamine N-acetyltransferase 2 allotypic variants expressed in Escherichia coli.

Arylamine N-acetyltransferase (NAT2) catalyses the N-acetylation of primary arylamine and hydrazine drugs and chemicals. N-Acetylation is subject to polymorphism, and humans can be categorized as either fast or slow acetylators according to their ability to N-acetylate certain arylamine substrates in vivo. Genetic variants at the polymorphic NAT2 locus have been described. We expressed five of the most common NAT2 variants (NAT2 4, NAT2 5A, NAT2 5B, NAT2 6A and NAT2 7B) in Escherichia coli as a convenient source of the human variants. The apparent Km values (at 100 microM acetyl CoA as co-substrate) of the different NAT2 variants for sulphamethazine, dapsone, p-anisidine, 2-aminofluorene, procainamide and isoniazid were determined. Data show that the apparent Km of the slow variant NAT2 7B for the arylamine sulphamethazine was 10-fold lower than all the other allotypes. The apparent Km for the structurally related sulphone antibiotic dapsone was 5-fold lower for the slow variant NAT2 7B when compared with the wild-type NAT2 4. These results indicate that the NAT2 7B specific amino acid substitution, Gly286-Glu, is important in promoting the binding of sulphamethazine and dapsone to the active site.

Arylamine N-Acetyltransferase↗
PubMed2005

Mutations in genes related to drug resistance in Mycobacterium leprae isolates from leprosy patients in Korea.

OBJECTIVE: Identification of the presence and drug resistance of Mycobacterium leprae is key to the diagnosis and treatment of leprosy in non-endemic country like Korea. The aim of this study was to screen the drug target DNA such as folP, rpoB, gyr, and 23S rRNA of drug resistance strain of M. leprae. PATIENTS AND METHODS: Sequences of those genes were analyzed for the 104 bacterial index positive cases out of 171 leprosy patients in Korea using touchdown PCR, single stranded conformational polymorphism. RESULTS: Twenty (19.2%) cases have shown the mutations in folP gene of dapsone-resistant M. leprae in which three (2.89%) cases were mutations in two genes, folP and rpoB, of multidrugs resistant strains to dapsone and rifampin, and two (1.92%) cases in folP and gyr genes of resistance to dapsone and oflaxacin, respectively. Besides double mutation for folP gene was one case (0.96%) and for rpoB gene one case, respectively. There was no mutant isolates in 23S rRNA gene against clarithromycin. CONCLUSIONS: This result should leads to a better understanding of the status of multidrug resistant leprosy in Korea and may assist in the rapid diagnosis of drug resistant M. leprae and the choice of the appropriate treatment regimens.

Adult↗
PubMed2001

Treatment of ocular cicatricial pemphigoid with sulfasalazine.

PURPOSE: To assess the outcome of patients with ocular cicatricial pemphigoid (OCP) treated with sulfasalazine as an alternative to dapsone. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Nine patients with biopsy-proven OCP and previous dapsone-related adverse effects (hemolysis and gastrointestinal disturbances) treated with oral sulfasalazine. METHODS: Clinical data were abstracted from patients' medical records. MAIN OUTCOME MEASURES: Patients' symptoms, ocular inflammation, conjunctival scarring, complete blood cell count (including reticulocyte count). RESULTS: At the initiation of sulfasalazine therapy, ocular inflammation was controlled in all patients but one. Mean follow-up was 12 months (range, 2-35 months). Median oral sulfasalazine dosage was 3 g (range, 1-4 g). The disease remained controlled with sulfasalazine alone in four patients (45%). Two patients (22%) required adjunctive oral cyclophosphamide. Adverse effects necessitating drug withdrawal occurred in three patients (33%): hemolysis in two and gastrointestinal disturbances in one. CONCLUSIONS: Sulfasalazine may be useful in OCP patients with previous dapsone-related adverse effects.

Administration, Oral↗
PubMed1993

Efficacy and safety of rechallenge with low-dose trimethoprim-sulphamethoxazole in previously hypersensitive HIV-infected patients.

OBJECTIVE: This study was undertaken to determine whether patients infected with HIV and with prior hypersensitivity to trimethoprim-sulphamethoxazole (TMP-SMX) can be rechallenged successfully with TMP-SMX, what factors predict successful rechallenge, and whether hypersensitivity is due to TMP or to SMX. DESIGN: A prospective, open study. SETTING: A tertiary referral hospital. PATIENT: Thirty-one HIV-infected patients with a history of non-life-threatening hypersensitivity to TMP-SMX. INTERVENTIONS: Patients received TMP (300 mg twice a week) for 2 weeks and, where no major reaction occurred, subsequently with TMP-SMX (160 and 800 mg per tablet, one tablet two times a day, twice a week). Patients who developed significant and persistent hypersensitivity ceased SMX and were subsequently challenged with TMP-dapsone (300 and 100 mg, respectively, twice a week). MAIN OUTCOME MEASURES: That rechallenge is more likely to be successful in those with advanced HIV disease. RESULTS: Five out of 31 (16%) patients developed hypersensitivity to TMP, and two ceased TMP as a result. Fifteen of the 26 (58%) patients who received subsequent TMP-SMX developed hypersensitivity, 12 of whom ceased TMP-SMX because of this reaction. Hypersensitivity to TMP-SMX was significantly less common in those with a CD4+ cell count < 20 x 10(6)/l than in those with a CD4+ cell count > 20 x 10(6)/l (31 versus 85%; P = 0.03). Hypersensitivity to TMP-dapsone occurred in two out of nine patients with hypersensitivity to TMP-SMX on rechallenge. One patient developed transient dyspnoea following a dose of SMX, but no other serious adverse drug reaction occurred. CONCLUSIONS: Rechallenge with TMP-SMX appears safe in HIV-infected patients with a history of non-life-threatening hypersensitivity and is most likely to be successful in patients with a low CD4+ lymphocyte count. The data suggest a low rate cross-hypersensitivity between SMX and dapsone, at least at the doses used.

AIDS-Related Opportunistic Infections↗
PubMed2005

Sulfasalazine and dermatitis herpetiformis.

Dermatitis herpetiformis that is unable to be controlled using dapsone and a gluten-free diet presents a therapeutic challenge. Three cases that responded well to sulfasalazine are presented. Two cases, who were unable to tolerate dapsone, had a rapid response to sulfasalazine, without apparent side-effects. The third case with dapsone-responsive blistering dermatoses, presumed to be dermatitis herpetiformis on the basis of serology, showed an excellent clinical response to sulfasalazine, but after 6 weeks of therapy had to cease it because of side-effects. Sulfasalazine is metabolized variably to sulfapyridine, a sulphonamide known to be an effective therapy for dermatitis herpetiformis but no longer available. Sulfasalazine should be considered as a management option for dermatitis herpetiformis.

Administration, Oral↗
PubMed1997

Clinically used antimicrobial drugs against experimental pneumocystosis, singly and in combination: analysis of drug interactions and efficacies.

We analyzed single drugs and combinations of drugs used clinically in the treatment of opportunistic infections and other conditions for their activities against Pneumocystis carinii pneumonia in immunosuppressed rats. When they were used alone, atovaquone, rifabutin, and dapsone were more active than clarithromycin or trimethoprim. Drug combinations were evaluated for synergistic activity by an analysis of variance model for two-way factorial experiments and a response surface model. Atovaquone combined with trimethoprim trimethoprim and some combinations of dapsone and clarithromycin was synergistic; however, the activities of combinations of atovaquone and rifabutin, atovaquone and clarithromycin, and atovaquone and dapsone were simply additive. Lovastatin, which inhibits 3-hydroxy-methylglutaryl coenzyme A reductase, was inactive whether it was used alone or in combination with other agents. None of the synergistic drug combinations was as effective as trimethoprim-sulfamethoxazole. We conclude that the rat model can be used to test combinations of anti-P. carinii agents for synergistic activity by well-established statistical techniques. While some combinations of clinically used antimicrobial drugs have enhanced anti-P. carinii activity, further studies are needed before clinical trials can be contemplated.

Animals↗
PubMed2000

Quality of pharmacotherapy consultations provided by drug information centers in the United States.

We evaluated the performance of 116 U.S. drug information centers in responding to specific questions about drugs. The primary measures were correctness of responses and extent of probing for patient data. Questions addressed the effect of ranitidine on blood alcohol concentrations, the potential interaction between didanosine and dapsone, prevention of nonsteroidal antiinflammatory drug (NSAID)-induced peptic ulcers, and use of erythromycin for diabetic gastroparesis. The percentages of centers providing correct overall responses were 70% for the ranitidine question, 90% for the didanosine-dapsone question, 8% for the NSAID question, and 20% for the erythromycin question. For the three patient-specific questions, the percentages of centers eliciting vital patient data were 27% for the didanosine-dapsone question, 86% for the NSAID question, and 5% for the erythromycin question. In providing pharmacotherapy consultations, drug information centers generally failed to obtain pertinent patient data, thereby risking incorrect responses and inappropriate recommendations.

Drug Information Services↗
PubMed1991

Current concepts in the pathogenesis of leprosy. Clinical, pathological, immunological and chemotherapeutic aspects.

In recent years there have been notable advances in the laboratory investigation and field management of leprosy. Progress, however, continues to be hindered by the lack of efficient methods for early diagnosis and implementation of control and treatment measures. Diagnosis is still made on the same principles as a century ago (clinical and histopathological findings), and only 1 in 3 known patients worldwide receives optimal chemotherapy. In 1988, nearly 1 in 10 newly diagnosed patients already had debilitating deformities. Contributing factors are operational, administrative and financial difficulties in implementing multidrug therapeutic regimens, inadequately trained personnel, and lack of priority and political commitment to leprosy control. The formulation and implementation of multidrug therapy is the most important development in leprosy in the past 10 years. Dapsone monotherapy was the mainstay for treatment and control for approximately 40 years, but secondary dapsone-resistant strains, first noted in 1964, now infect as many as 50% of all new patients. Multidrug regimens recommended by the WHO consist of various combinations of therapy using dapsone, rifampicin, clofazimine and a thionamide. Duration of therapy is limited to 6 months for paucibacillary and 2 years or more for multibacillary patients; relapse rates thus far are low. The average cost of treatment worldwide, including the cost of drugs, is estimated at $US150 per patient. The recent annual drop of nearly 8% in newly registered patients may be due to the implementation of these therapeutic regimens. Newer drugs that may be introduced into these regimens include fluoroquinolones, minocycline and clarithromycin. While knowledge of the microbiology of the leprosy bacillus and host response has advanced remarkably, there is little improvement in the understanding or amelioration of social aspects of leprosy. Better treatment and control reduces the stigma, but improvements in the attitudes of patients and society towards leprosy are as important as advances in medical science in achieving ultimate eradication of the disease.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Lagophthalmos in a multibacillary population under multidrug therapy in the People's Republic of China.

Lagophthalmos may be the most common potentially blinding ocular condition in leprosy. The magnitude of the problem among multibacillary patients has not been determined. We sought to ascertain the magnitude of lagophthalmos in a multibacillary leprosy patient population under multidrug therapy (MDT) (both newly diagnosed and with a prior history of dapsone monotherapy) in China and assess factors associated with its presence. In a survey of 640 multibacillary patients 3.8% of the newly diagnosed patients and 10.2% of the patients with prior dapsone monotherapy had lagophthalmos. Corneal disease and vision loss were common in both groups. Poor compliance with MDT, duration between onset and diagnosis, and duration on dapsone monotherapy were associated with the presence of lagophthalmos. Our findings suggest that there may be a threshold at which MDT must be maintained to prevent lagophthalmos. Early leprosy diagnosis and treatment would also lessen the incidence of lagophthalmos in these patients. The high proportion of lagophthalmos patients with corneal disease suggests that there has been inadequate eye care for these patients.

Adult↗
PubMed1994

Prophylaxis for opportunistic infections in patients with HIV infection.

OBJECTIVE: To review the efficacy of chemoprophylaxis for opportunistic infections in persons infected with human immunodeficiency virus (HIV). DATA SOURCES: English-language articles on the prevention of HIV-related opportunistic infections were identified through MEDLINE (1985 to 1993) and through review of abstracts presented at the International Conferences on AIDS, the Interscience Conferences on Antimicrobial Agents and Chemotherapy, and the National Conference on Human Retroviruses and Related Diseases. STUDY SELECTION: Importance was assigned in descending order to controlled clinical trials, uncontrolled trials and retrospective studies, and prospective observational studies. DATA SYNTHESIS: Persons infected with HIV who are at risk for Pneumocystis carinii pneumonia should receive prophylaxis, preferably with trimethoprim-sulfamethoxazole. Alternative agents are aerosolized pentamidine, dapsone, and dapsone-pyrimethamine. Patients who are seropositive for Toxoplasma gondii may benefit from primary prophylaxis against toxoplasmosis using trimethoprim-sulfamethoxazole or dapsone-pyrimethamine. Life-long secondary prophylaxis is indicated for all patients previously treated for toxoplasmic encephalitis. Long-term suppressive therapy is required for all patients with cryptococcal meningitis and histoplasmosis, and many patients with recurrent mucosal candidiasis also benefit from long-term suppression. The role of primary prophylaxis of fungal infections, however, is uncertain. Rifabutin has been approved to prevent disseminated infection with Mycobacterium avium complex and is indicated for all patients with CD4 counts less than 100/mm3. Chemoprophylaxis with isoniazid for 12 months is indicated in all patients infected with HIV who have or are at high risk for M. tuberculosis infection. No effective primary prophylactic agent is available for cytomegalovirus disease, although several investigational drugs are being studied. Acyclovir is effective in decreasing recurrences of herpes simplex virus infection. The incidence of common bacterial infections is decreased by trimethoprim-sulfamethoxazole. Pneumococcal polysaccharide vaccine is recommended for adult patients infected with HIV, and Haemophilus influenzae type b conjugate vaccine is recommended for children infected with HIV. CONCLUSIONS: A growing number of infections related to the acquired immunodeficiency syndrome are preventable with currently available agents. Issues of drug interactions, toxicity, and cost-effectiveness will become increasingly important in the management of patients with advanced HIV disease.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

[Adverse effects of Disulone; results of the France pharmacovigilance inquiry. Regional Centers of Pharmacovigilance].

Disulone (dapsone + ferrous oxalate) is a sulphone marketed in France since 1958 and authorized in P. Carinii prophylaxis in HIV+ cotrimoxazole intolerant patients, bullous dermatosis, leprosy and polychondritis. Between 1983 and 1998, 249 adverse reactions were reported to French pharmacovigilance centres and Aventis, the manufacturer. Every side-effect was reviewed and the causal relationship was assessed on the basis of the French method for causality assessment. Main side-effects were divided as follows: 117 blood dyscrasias (generally neutropenia and agranulocytosis, rarely methaemoglobinaemia, haemolysis, macrocytosis, anaemia, aplastic anaemia, haemochromatosis and sulphaemoglobinaemia); 29 hypersensitivity syndrome; 39 cutaneous reactions, generally rash; 27 liver injuries (cholestatic, cytolytic and mixed hepatitis); 27 neurological and psychiatric side-effects including 7 axonal neuropathy; 10 gastrointestinal effects, generally nausea and vomiting. Five deaths were reported (4 septicaemia including one case not due to dapsone and 1 digestive bleeding due to underlying disease). In the other cases the outcome was favourable. The results were compared with the published references. It would seem to be important to reinforce information to prescribers about the possible serious adverse reactions with dapsone, particularly hypersensitivity syndrome and agranulocytosis, that can cause death if the drug is not stopped in time.

AIDS-Related Opportunistic Infections↗