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PubMed2006

Effect of conjugated equine estrogens on oxidative metabolism in middle-aged and elderly postmenopausal women.

The effects of conjugated equine estrogens (CEE) 0.625 mg daily on cytochrome P450 (CYP) were quantified in 12 middle-aged and 13 elderly postmenopausal women at baseline and 6 months later. CYP phenotype was characterized by caffeine (CYP1A2), chlorzoxazone (CYP2E1), dapsone (CYP, N-acetyltransferase 2), dextromethorphan (CYP2D6), and mephenytoin (CYP2C19) metabolism. CEE significantly decreased CYP1A2 (caffeine metabolic ratio: 0.57 +/- 0.20 before, 0.40 +/- 0.20 after, P = .001) and significantly increased CYP2D6 (dextromethorphan/dextrorphan ratio: 0.0116 +/- 0.0143 before, 0.0084 +/- 0.0135 after, P = .022) metabolism. CEE had no overall effect on CYP2C19, CYP2E1, CYP-mediated dapsone metabolism, and N-acetyltransferase 2. The dextromethorphan metabolic ratio decreased only in the seniors. The dapsone recovery ratio decreased in the middle-aged group and increased in the seniors. CEE significantly influenced CYP1A2, CYP2D6, and CYP-mediated dapsone oxidative metabolism but not CYP2C19, CYP2E1, or N-acetyltransferase 2 metabolism in postmenopausal women. Age influenced CYP2D6 metabolism and dapsone hydroxylation.

Aged↗
PubMed1993

Therapeutic monitoring and pharmacist intervention in a Hansen's disease clinic.

OBJECTIVE: To describe the role of the clinical pharmacist in a Hansen's disease (HD, leprosy) clinic and to describe the development, validation, and operation of a dapsone compliance monitoring program. RATIONALE: HD remains a major, worldwide healthcare problem. Dapsone is the drug of choice for treatment of HD; however, high rates of noncompliance with this agent have been reported by many treatment centers. The assessment of compliance in HD patients is important to help distinguish between treatment failure secondary to noncompliance or to the development of resistance. SETTING: In the US, the Chicago Regional Hansen's Disease Center at the University of Illinois at Chicago is one of ten centers that provide comprehensive care to patients diagnosed with this condition. This article reviews the clinical pharmacy services and dapsone compliance program in the clinic encompassing the years 1983-93. RESULTS: The clinical pharmacist provides a variety of clinical services in the clinic as well as coordinating the clinical research program. A pharmacist-generated dapsone compliance program led to improvement in compliance rates and clinical outcome. This improvement in compliance has been sustained over an extended period of time. CONCLUSIONS: The clinical pharmacy services performed in the HD clinic provide a model for pharmacy involvement in other chronic disease states. The dapsone compliance program has been successful in improving patient care and obtaining reimbursement for clinical pharmacy services.

Academic Medical Centers↗
PubMed2002

Drug susceptibility of Mycobacterium leprae: a retrospective analysis of mouse footpad inoculation results from 1983 to 1997.

We analysed the results of mouse foot pad (MFP) tests performed between 1983 and 1997 in our laboratory for the cases referred with clinical suspicion of relapse/drug resistance. A total of 214 cases, with clinical suspicion of relapse/drug resistance were investigated for susceptibility to the drugs of MDT by MFP inoculation. Among 96 inoculations that showed conclusive results, 81 (84%) were fully sensitive to dapsone, suggesting that most of the clinically suspected relapse is due to drug susceptible Mycobacterium leprae. Of the remaining 15 strains (16%) found resistant to dapsone, 13 (87%) were of high grade resistance and one strain each of intermediate grade and low grade dapsone resistance, suggesting that most of the dapsone resistance is secondary in nature. No case of rifampicin resistance was found. Only one case of combined dapsone and unconfirmed clofazimine resistance was found. No other combined multidrug resistance was observed in our analysis.

Adult↗
PubMed1991

Primary prophylaxis for Pneumocystis carinii pneumonia in HIV-infected people with CD4 counts below 200/mm3: a cost-effectiveness analysis.

We developed a decision-analytic model to assess the effectiveness and costs of dapsone, trimethoprim-sulfamethoxazole, or aerosolized pentamidine as initial prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected people without prior symptoms AIDS and with CD4 counts less than 200/mm3. Each strategy increased life expectancy by about 18% compared with no prophylaxis; annual per-person costs were $440, $700, and $1,680 for dapsone, trimethoprim-sulfamethoxazole, and aerosolized pentamidine, respectively. These cost differences make a strategy beginning with dapsone most cost effective, with an incremental cost-effectiveness ratio of $13,400 per life year saved compared with no prophylaxis. Aerosolized pentamidine was substantially less cost effective, but the incremental cost effectiveness ratios were highly dependent on estimates for quality of life, efficacy, toxicity, and compliance. We conclude that, based on currently available data, initial prophylaxis with either dapsone or trimethoprim-sulfamethoxazole is most cost effective. For every 100,000 people treated, starting prophylaxis with trimethoprim-sulfamethoxazole or dapsone--with crossover to aerosolized pentamidine if oral therapy is not tolerated--may save between $98 million and $124 million per year.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Multiple relapses in borderline leprosy--a case report.

A case of borderline lepromatous leprosy with a history of 5 years duration of disease, was first seen in 1971 and treated with graded doses of dapsone in the OP Clinic of the Institute. He became inactive and bacteriologically negative in 3 years. While continuing on dapsone therapy he relapsed into active dapsone resistant leprosy 3 1/2 years later. He was admitted in the hospital and given Rifampicin 600 mg. daily for 15 days along with dapsone 100 mg. daily. He again became inactive and bacteriologically negative within 3 years. 3 years later under regular dapsone therapy he relapsed again for the second time into active BT leprosy, but remained bacteriologically negative. He was given 3 drug regimen subsequently and became clinically inactive within 15 months.

Adolescent↗
PubMed1986

[Disulon in the treatment of Horton's disease. Experience with 20 patients].

Disulon (Dapsone) was used in 20 patients with Horton's disease, with the object of reducing steroid therapy. In a retrospective series, Dapsone was prescribed in 12 patients with severe complications of steroid therapy; it was possible to reduce the dose of steroids by about 50 p. 100 in under 3 months without causing a flare-up of the disease. In a prospective series of 8 patients, Dapsone was given at the outset with Prednisone; the results were compared with a control series of 8 patients--the dose of steroids could be reduced earlier, the total duration of steroid therapy was shorter, and the total dose of steroids was lower. The main side effect of Dapsone is haemolysis which may give rise to anaemia, the severity of which is usually dose-dependent. A daily dosage of 75 to 100 mg would seem to provide a good compromise between the anti-inflammatory and haemolytic effects. Dapsone should always be given in association with steroids in the treatment of temporal arteritis; a closer biological surveillance of patients treated with association is necessary.

Aged↗
PubMedDate not supplied

[Results of animal experimentation activities at the Institut Marchoux in Bamako (1982-1984)].

The Institut Marchoux animal research unit report of activities 1982-1984 shows increasing results in mouse-foods-pads inoculations. Among 17 multibacillary cases, 16 were clinically dapsone-resistant suspected. In 9 cases there was no multiplication; however in 4 cases, multiplication were observed in the untreated controled mice group but no multiplication in dapsone groups. Three cases were fully dapsone-resistant in all concentrations tested. In one case we have detected a partial DDS resistance. No multiplication in the mice group with 10(-2) dapsone dict, but multiplication in 10(-3) and 10(-4) dapsone dict.

Animals↗
PubMedDate not supplied

[Acceptability, compliance and tolerance of daily polychemotherapy by leprosy patients in Guadeloupe].

From January 1980 to December 1984, 418 leprosy patients were treated in Guadeloupe with a daily multiple drug regimen using rifampin as an essential drug. The analysis of the data collected during this period of times gives the possibility of estimating the patient's approval, tolerance and attendance to this treatment. The approval is satisfactory in new cases of leprosy and in ancient cases relapsed under dapsone monotherapy but less in inactive ancient patients already treated with dapsone monotherapy. Attendance of the 418 patients to the multiple drug regimen is satisfactory too and similar to the attendance of patients treated with dapsone monotherapy in Guadeloupe and to the attendance of patients with monthly multiple drug regimen in another Caribbean country. Reactions did not occur with higher gravity or frequency than in patients under dapsone monotherapy. The high incidence of hepatitis (14%) due to the toxicity of protionamide in the combination rifampin-protionamide-dapsone make obligatory the monthly assessment of the liver functions in multibacillary patients treated with such a drug combination.

Chemical and Drug Induced Liver Injury↗
PubMed2000

A role for bioactivation and covalent binding within epidermal keratinocytes in sulfonamide-induced cutaneous drug reactions.

Cutaneous reactions are the most common manifestation of delayed-type hypersensitivity caused by sulfamethoxazole and dapsone. In light of the recognized metabolic and immunologic activity of the skin, we investigated the potential role of normal human epidermal keratinocytes in the development of these reactions. Adult and neonatal normal human epidermal keratinocytes metabolized sulfamethoxazole and dapsone to N-4-hydroxylamine and N-acetyl derivatives in a time-dependent manner. The latter was catalyzed by N-acetyltransferase 1 alone as normal human epidermal keratinocytes did not express mRNA for N-acetyltransferase 2. Investigation of metabolism-dependent toxicity of sulfamethoxazole and dapsone, and subsequent incubation of normal human epidermal keratinocytes with the respective hydroxylamine metabolites, demonstrated that these cells were resistant to the cytotoxic effects of sulfamethoxazole hydroxylamine but not dapsone hydroxylamine. With prior depletion of glutathione, however, normal human epidermal keratinocytes became susceptible to the toxicity of sulfamethoxazole hydroxylamine. Covalent adduct formation by sulfamethoxazole hydroxylamine was detected in normal human epidermal keratinocytes, even in the absence of cell death, and was increased with glutathione depletion. Major protein targets of sulfamethoxazole hydroxylamine were observed in the region of 160, 125, 95, and 57 kDa. Dapsone hydroxylamine also caused covalent adduct formation in normal human epidermal keratinocytes. Together, these observations provide a basis for our hypothesis that normal human epidermal keratinocytes are involved in the initiation and propagation of a cutaneous hypersensitivity response to these drugs.

Adult↗
PubMed1994

Multidrug therapy and eye disease in leprosy: a cross-sectional study in the People's Republic of China.

BACKGROUND: Factors associated with leprosy-related eye disease in a multidrug therapy (MDT) treated population in China were assessed to determine if status prior to inclusion in the MDT programme (newly diagnosed leprosy patient or leprosy patient on prior dapsone monotherapy) contributed to the prevalence of ocular pathology. METHODS: Trained leprosy paramedical workers in Sichuan Province examined 974 leprosy patients in a standardized fashion. Univariate analyses and multiple logistic regression were used to assess the contribution of demographic and clinical parameters to leprosy-related eye disease. RESULTS: In both groups (prior dapsone and new MDT) leprosy-related eye disease was associated with a longer distance to leprosy health worker or health centre. Among patients with a history of prior dapsone monotherapy, age and duration on dapsone monotherapy were also associated with leprosy-related ocular morbidity. Among newly diagnosed leprosy patients the prevalence of ocular morbidity remained between 8% and 11% regardless of when the patient started MDT. CONCLUSIONS: Our findings suggest that, even when case detection is good, ocular pathology will still occur in MDT treated leprosy patients. There remains an important role for health workers in the prevention of ocular morbidity. Our data also demonstrated that pooling of results from all patients (newly diagnosed and on prior dapsone monotherapy) in a leprosy control programme will likely give rise to inadequate estimates of risk of ocular disease due to variable clinical disease histories in these groups.

Adult↗
PubMed1992

The ability to 4-hydroxylate debrisoquine is related to recurrence of bladder cancer.

Oxidative metabolism by cytochrome P450 enzymes is often involved in the activation of environmental procarcinogens. Debrisoquine, mephenytoin, and dapsone were used as in vivo probes for the activities of P4502D6, 2CMP, and 3A4, respectively, as well as dapsone for N-acetyltransferase, in order to assess the relationship between such activities and the relative risk of recurrence of bladder cancer. Urinary recovery ratios of debrisoquine and dapsone and the R/S ratio of mephenytoin were measured in an 0-8 h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg), and the administration of dapsone (100 mg) one week later, to patients undergoing local surgical resection of transitional cell bladder cancer of G-I, G-II, or G-III histopathology. In addition, plasma levels of dapsone and mono-acetyldapsone were determined in an 8 h plasma sample to determine the N-acetylation phenotype. Patients were followed for 3 years, to the time of tumour recurrence, or death. Three patients were lost to follow-up; of the remaining 95 patients, 55 had tumour recurrence. The debrisoquine recovery ratio was significantly greater in patients with recurrence than in individuals who remained disease-free. Among the 65 patients with non-aggressive (G-I and G-II) histopathology, two patients were lost to follow-up and 32 had tumour recurrence. In this subgroup, the debrisoquine recovery ratio was again found to be significantly greater in those individuals with tumour recurrence (p < 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1997

Acetylator phenotype in relation to age and gender in the Baltimore Longitudinal Study of Aging.

This study investigated in healthy Caucasians the possible occurrence of age and gender-associated differences in NAT2 acetylator phenotype. Acetylator phenotype was determined after a single oral dose of 100 mg dapsone during testing of oral glucose tolerance in 510 Caucasian volunteers aged from 19 to 93 years, 339 men and 171 women, from the Baltimore Longitudinal Study of Aging. Participants were classified as slow or rapid acetylators according to the ratio of monoacetyldapsone to dapsone concentration in plasma. The ratio dividing the two groups, 0.30, was chosen after inspection of a probit plot and histogram of the monoacetyldapsone/dapsone ratios. Fifty-one percent of the participants were slow acetylators and 49% were rapid acetylators. Because there was no significant difference between the sexes in the monoacetyl-dapsone/dapsone ratios, all 510 participants were pooled into a single group for further analysis. In the combined analysis, there was a small decline in the prevalence of the slow acetylator phenotype with age, but this age effect accounted for less than 1% of the total variance in the monoacetyldapsone/dapsone ratio (r2 = 0.009). Also, it was shown in a group of 20 participants that administration of glucose with dapsone does not influence the determination of acetylator phenotype. In a large healthy Caucasian. American population, there was no biologically important effect of age or sex on the distribution of NAT2 acetylator phenotype.

Adult↗
PubMed1993

Superoxide is an antagonist of antiinflammatory drugs that inhibit hypochlorous acid production by myeloperoxidase.

Myeloperoxidase, the most abundant enzyme in neutrophils, catalyses the conversion of hydrogen peroxide and chloride to hypochlorous acid. This potent oxidant has the potential to cause considerable tissue damage in many inflammatory diseases. We have investigated the ability of dapsone, diclofenac, primaquine, sulfapyridine and benzocaine to inhibit hypochlorous acid production by stimulated human neutrophils. The drugs were also tested against purified myeloperoxidase using xanthine oxidase to generate hydrogen peroxide and superoxide. The inhibitory effects of the drugs on hypochlorous acid production, either by cells stimulated with phorbol myristate acetate or by myeloperoxidase and xanthine oxidase, were significantly less than those determined with myeloperoxidase and reagent hydrogen peroxide. Comparable potency was observed only when superoxide dismutase was present to remove superoxide. We also observed that with the xanthine oxidase system, inhibition of hypochlorous acid production by dapsone decreased markedly as the concentration of myeloperoxidase increased. Dapsone was a poor inhibitor of hypochlorous acid production by neutrophils stimulated with opsonized zymosan, regardless of the presence of superoxide dismutase. With this phagocytic stimulus, catalase inhibited hypochlorous acid formation by only 60%, which indicates that a substantial amount of the hypochlorous acid detected originated from within phagosomes. Thus, it is apparent that dapsone is unable to affect intraphagosomal conversion of hydrogen peroxide to hypochlorous acid. All the drugs inhibit myeloperoxidase reversibly by trapping it as its inactive redox intermediate, compound II. We propose that superoxide limits the potency of the drugs by reducing compound II back to the active enzyme. Furthermore, under conditions where the activity of myeloperoxidase exceeds that of the hydrogen peroxide-generating system, which is most likely to occur in phagosomes, partial inhibition of myeloperoxidase need not affect hypochlorous acid production. We conclude that drugs that inhibit myeloperoxidase by converting it to compound II are unlikely to be effective against hypochlorous acid-mediating tissue damage.

Anti-Inflammatory Agents↗
PubMed1991

Effect of anti-leprosy drugs on superoxide anion production by rat peritoneal macrophage with special reference to light exposed clofazimine.

The present study describes the in vitro effect of anti-leprosy drugs on superoxide anion (O2-) production by rat resident peritoneal macrophages. Of the three drugs tested i.e. clofazimine, rifampicin and dapsone, the first was most effective in increasing O2- production in a dose dependent manner, while rifampicin had some stimulatory effect and dapsone exhibited minimal action. Furthermore, when clofazimine and dapsone were added together it was observed that the increase of O2- production by macrophages due to clofazimine was not significantly altered by the addition of dapsone. Moreover, it was found that killed Mycobacterium leprae could induce a lesser amount of O2- production in comparison to that of Staphylococcus aureus and the enhancement of O2- release due to clofazimine was stimulus dependent. This increase of O2- release after addition of clofazimine was inhibited by the addition of p-bromophenacyl bromide. Another interesting finding was that the enhancement of O2- production by clofazimine gradually decreased as clofazimine was exposed to light for days. On further investigation it was found that ultraviolet, NMR, infrared and mass spectra of the light unexposed and exposed drug were similar, but the diffusion current of the polarogram of light exposed drug was remarkably more than that observed in light unexposed drug, indicating, thereby, a possible increase in the electron accepting capacity of the light reacted molecule. As far as we know this is the first report describing the effect of light exposed clofazimine on the respiratory burst activity of macrophages.

Animals↗
PubMed1997

Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes.

OBJECTIVES: To determine whether the probe drugs caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin can be simultaneously administered as a metabolic cocktail to estimate in vivo cytochrome P450 (CYP) and N-acetyltransferase enzyme activities. METHODS: Fourteen healthy nonsmoking male volunteers (mean age +/- SD, 21.6 +/- 2.2 years) received 100 mg caffeine, 250 mg chlorzoxazone, 100 mg dapsone, 10 mg debrisoquin, and 100 mg mephenytoin individually and in four and five-drug combinations in a randomized manner using a 7 x 7 Latin square. Each drug or drug combination was given orally after an overnight fast, with a minimum 1-week washout between administrations. In each session, urine was collected from 0 to 8 hours and plasma was obtained at 4 and 8 hours after drug administration. Plasma and metabolite concentrations were used to estimate phenotypic trait measures for the efficiency of each drug's metabolism. RESULTS: The phenotypic indexes determined for caffeine, chlorzoxazone, dapsone, debrisoquin, and mephenytoin were not significantly different when given alone than when given in combination. The median percentage change of the trait measures observed during administration of all five compounds compared with individual administration ranged from -10.7% for the 6-hydroxychlorzoxazone to chlorzoxazone plasma ratio to +2.2% for the debrisoquin recovery ratio. CONCLUSIONS: The results of this study show that caffeine, chlorzoxazone, dapsone, debrisoquin, and mephenytoin in low doses can be simultaneously administered without metabolic interaction. This cocktail approach can thus simultaneously provide independent in vivo phenotypic measures for multiple CYP enzymes and N-acetyltransferase.

Adult↗
PubMed2004

[Disulone].

For 60 years, dapsone has been used as a both antibacterial and anti-inflammatory agent. Dapsone (4,4'-diaminodiphenylsulfone, DDS) continues to be used successfully to treat a wide range of dermatologic disorders, notably those characterized by abnormal neutrophil and eosinophil polynuclear accumulation. A considerable number of other inflammatory as well as bullous dermatoses, of which dermatitis herpetiformis is the best known, have been shown to respond in varying degrees to dapsone, although the indication for the molecule has not been demonstrated in of them all. This article reviews current knowledge on the pharmacokinetics, mechanism of action and side effects of dapsone in dermatology. Despite the lack of controlled studies, the aim of this study is to specify and classify the pathological states in which disulone could be indicated.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

Use of cyclophosphamide in azathioprine failures in pemphigus.

Four patients with pemphigus vulgaris are presented in which diagnosis was confirmed histologically and immunopathologically. Although these patients responded to high-dose prednisone therapy during the initial stages of acute disease, the addition of azathioprine failed to allow lower steroid doses and did not result in prolonged, complete remission. Indeed, the disease was exacerbated during azathioprine therapy, and significant side effects from prolonged high-dose steroid therapy were observed. Both clinical and serologic remission resulted from the addition of cyclophosphamide and dapsone to prednisone therapy. Thus, when azathioprine fails to produce remission or a steroid-sparing effect, cyclophosphamide may be an effective alternative. During a prolonged follow-up period, no recurrences of pemphigus have been observed, and no significant side effects of cyclophosphamide (Cytoxan) have been encountered. The addition of dapsone produced enhanced anti-inflammatory effects without increasing the existing or potential side effects of steroid therapy. Dapsone was easily withdrawn at the onset of remission. Thus the anti-inflammatory effect of dapsone may prove valuable in patients for whom steroids are contraindicated, who develop significant side effects during long-term steroid therapy, or for whom increases of dose threaten to enhance the possibility of catastrophic side effects.

Adult↗
PubMed1993

Absence of correlations among three putative in vivo probes of human cytochrome P4503A activity in young healthy men.

In vitro studies with human liver microsomes have shown that erythromycin N-demethylation, dapsone N-hydroxylation, and the 6 beta-hydroxylation of cortisol are all primarily mediated by P4503A4. Trait measurements to assess the in vivo level of activity of these separate oxidations have also been developed previously. This study investigated the relationships among the three phenotypic trait measurements in 30 young healthy white men. The frequency distributions of the trait values were all unimodal, with a twofold range for the erythromycin breath test and the urinary dapsone recovery ratio; the urinary 6 beta-hydroxycortisol/cortisol ratio was more variable, with a 17-fold range of values. No statistically significant correlations were observed among any of the trait measurements (dapsone recovery ratio versus erythromycin breath test: r = -0.07, p = 0.7; urinary 6 beta-hydroxycortisol/cortisol ratio versus erythromycin breath test: r = -0.12, p = 0.6; urinary 6 beta-hydroxycortisol/cortisol ratio versus dapsone recovery ratio: r = 0.13, p = 0.5. This lack of any relationship was unexpected and the reason(s) is unknown; however, it is possible that factors such as route of administration and extrahepatic metabolism in the intestinal epithelium and kidney are involved. Further studies are required to identify and validate the use of an appropriate in vivo probe of P4503A4 in humans.

Adult↗