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PubMed1996

Metabolic interactions of putative cytochrome P4503A substrates with alternative pathways of dapsone metabolism in human liver microsomes.

The cytochrome P4503A (CYP3A) subfamily of enzymes are responsible for the metabolism of a large number of endogenous and exogenous compounds, and activation of some procarcinogens; but the activity is not well understood. N-Hydroxylation of dapsone in human liver microsomes has been shown to be mediated largely by CYP3A4. We have also observed the formation of an as yet unidentified metabolite of dapsone, whose formation is inhibited by antibody to CYP3A4, by these microsomes. This study investigated the influence of various (22) CYP3A putative substrates on the formation of both metabolites of dapsone in human liver microsomes. The compounds fall into four different categories on the basis of the pattern of their inhibitory interaction with the formation of both metabolites: those that inhibited both metabolites; those that inhibited N-hydroxylamine alone; those that inhibited the unidentified metabolite alone; and those with no significant effect on either metabolite. Some others were stimulatory. These results are consistent with two alternative but not mutually exclusive hypotheses: 1) different isoforms of CYP3A are involved in the formation of the alternative metabolites and the pattern of interaction observed was caused by the particular isoform(s) that each compound interacted with; or 2) formation of the alternative metabolites is a result of dapsone's interaction with and orientation at the enzyme's active site and the pattern of interaction observed is a consequence of changes in orientation caused by these compounds. This study provides relevant observations that must be considered in understanding mechanisms of CYP3A-mediated metabolism.

Catalysis↗
PubMed1996

Primary dapsone resistance in Cebu, The Philippines; cause for concern.

At a time when primary dapsone resistance was prevalent in many leprosy endemic areas, Cebu in The Philippines reported only 3.6% in the period 1975-1978 and later 8.1% in the period 1979-1982. In our current study of patients in the period 1988-1992, the number increased dramatically to 52.7%. In addition, 7.9% of the isolates are highly resistant to dapsone, a level of resistance not seen in earlier studies. This finding could have severe ramifications to the World Health Organization's multidrug therapy (WHO-MDT) mode of treatment, where dapsone is one of the principal drugs. Moreover, the increase in primary dapsone resistance may be a contributing factor in the recent finding that there has been no decline in the number of new cases found in Cebu, even after the implementation of WHO-MDT in 1985. There is a need for new drugs that could be included in the multidrug treatment for multibacillary and paucibacillary leprosy.

Animals↗
PubMed1997

Poor efficacy of antimalarial biguanide-dapsone combinations in the treatment of acute, uncomplicated, falciparum malaria in Thailand.

Combinations of dapsone with proguanil or chlorproguanil have proved effective in the treatment of chloroquine-resistant falciparum malaria in Africa and for prophylaxis in Asia. These combinations have not been used for treatment in areas with multi-drug-resistant parasites such as in Thailand. Combinations of dapsone (approximately 4 mg/kg) plus ether proguanil (approximately 8 mg/kg; DP regimen; N = 10) or chlorproguanil (approximately 1.4 mg/kg; DC regimen; N = 16) were given once a day for 3 days to adult Thai patients with acute, uncomplicated, falciparum malaria. The two regimens were well tolerated and had no side-effects, but the cure rates, assessed at 28-day follow-up, were only 10% for DP (60% with RI response and 30% with RII) and 14% for DC (29% with RI response and 57% with RII). The mean (S.D.) fever-clearance times in those patients who were cured (S) or whose infections recrudesced (RI response) were 103 (56) h for those given DP and 90 (42) h for 6 those given DC. The corresponding parasite-clearance times were 83 (46) for DP and 53 (21) h for DC. In-vitro susceptibility testing of isolates obtained both before treatment and at recrudescence demonstrated marked resistance to cycloguanil, dapsone, chloroquine and mefloquine. The results demonstrate that short-course treatment with dapsone plus either proguanil or chlorproguanil is ineffective for the treatment of falciparum malaria in Thailand.

Adolescent↗
PubMed2006

The Dapsone hypersensitivity syndrome revisited: a potentially fatal multisystem disorder with prominent hepatopulmonary manifestations.

4,4'-Diaminodiphenylsulphone (Dapsone) is widely used for a variety of infectious, immune and hypersensitivity disorders, with indications ranging from Hansen's disease, inflammatory disease and insect bites, all of which may be seen as manifestations in certain occupational diseases. However, the use of dapsone may be associated with a plethora of adverse effects, some of which may involve the pulmonary parenchyma. Methemoglobinemia with resultant cyanosis, bone marrow aplasia and/or hemolytic anemia, peripheral neuropathy and the potentially fatal dapsone hypersensitivity syndrome (DHS), the focus of this review, may all occur individually or in combination. DHS typically presents with a triad of fever, skin eruption, and internal organ (lung, liver, neurological and other systems) involvement, occurring several weeks to as late as 6 months after the initial administration of the drug. In this sense, it may resemble a DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms). DHS must be promptly identified, as untreated, the disorder could be fatal. Moreover, the pulmonary/systemic manifestations may be mistaken for other disorders. Eosinophilic infiltrates, pneumonitis, pleural effusions and interstitial lung disease may be seen. This syndrome is best approached with the immediate discontinuation of the offending drug and prompt administration of oral or intravenous glucocorticoids. An immunological-inflammatory basis of the syndrome can be envisaged, based on the pathological picture and excellent response to antiinflammatory therapy. Since dapsone is used for various indications, physicians from all specialties may encounter DHS and need to familiarize themselves with the salient features about the syndrome and its management.

Journal Article↗
PubMed1997

Methemoglobinemia associated with dapsone treatment in solid organ transplant recipients: a two-case report and review.

Dapsone, a sulfone antibiotic, has been increasingly used in solid-organ transplant recipients for the primary prevention of Pneumocystis carinii pneumonia, especially in patients with documented sulfa allergy. A known side effect of dapsone therapy, however, is methemoglobinemia, a condition leading to impaired tissue oxygen delivery. This report documents two cases of dapsone-induced methemoglobinemia in patients after solid organ transplantation with emphasis on the importance of clinical recognition and benefits of treatment. Further, the pathophysiology and causes of this condition are extensively reviewed.

Aged↗
PubMed1981

Acetylator phenotyping: a comparison of the isoniazid and dapsone tests.

A comparison was made between the results of acetylator phenotyping by isoniazid (INH) half-life measurements based on 5 samples (0-6 h), and by determination of the ratio of monoacetylated (MAD) to unchanged dapsone (DDS) in a single sample obtained 3 h after dapsone intake. In each of 44 subjects examined, there was unequivocal agreement about classification of the subject as a rapid (INH t1/2 less than 2 h; MAD/DDS greater than 0.3) or slow (INH t1/2 greater than 2 h; MAD/DDS less than 0.3) acetylator. It appears that the single-sample (3 h) dapsone test is as reliable as the more laborious and time-consuming INH test for acetylator phenotyping.

Acetylation↗
PubMed1993

Activity of subinhibitory concentrations of dapsone alone and in combination with cell-wall inhibitors against Mycobacterium avium complex organisms.

MICs of dapsone (p-p'-diaminodiphenylsulfone) were determined radiometrically for ten strains each of the Mycobacterium avium complex (MAC) and Mycobacterium tuberculosis. MICs ranged from 50 to 250 micrograms/ml for Mycobacterium tuberculosis and from 2 to 100 micrograms/ml for MAC. However, at a concentration as low as 1.5 micrograms/ml dapsone significantly inhibited growth of MAC bacteria when used in combination with other drugs specifically acting at the mycobacterial cell-wall level. The latter drugs were used in subinhibitory concentrations, and included m-fluorophenylalanine (an inhibitor of mycoside-C biosynthesis), ethambutol (an inhibitor of arabinogalactan biosynthesis), and ethionamide (an inhibitor of mycolic acid biosynthesis). Using a radiometric method (Bactec 460-TB), the activity of dapsone was found to be enhanced for 2/10 strains in the presence of m-fluorophenylalanine, for 3/10 strains in the presence of ethambutol and for 5/10 strains in the presence of ethionamide. A satisfactory correlation between the radiometric data and bacterial viable counts was established.

Cell Wall↗
PubMed1978

The anti-inflammatory profile of dapsone in animal models of inflammation.

Dapsone has been shown to possess anti-inflammatory activity in a variety of animal models. It possesses oral anti-oedema activity especially pronounced in novel models of acute inflammation, viz. anti-IgG and reversed passive Arthus oedemas. However, it is not very active in the guinea pig u.v. erythema model. It is effective in chronic models such as adjuvant arthritis and the cotton pellet granuloma although multiple administration may also produce cyanosis. Antipyretic and analgesic effects for dapsone have been demonstrated and are similar to those produced by phenylbutazone. It inhibits zymosan-induced beta-glucuronidase release from cultured macrophages and also the activity of this enzyme. Dapsone does not appear to be ulcerogenic in the rat.

Animals↗
PubMed2001

[Acne inversa: a dapsone-sensitive dermatosis].

Acne inversa is a chronic disease with a major impact on the quality of life. Therapeutic options were long restricted to local disinfectants and systemic antibiotics, as well as repeated incision and drainage which produce only short term benefits. Retinoids, antiandrogens and radiation therapy are only partially successful. The best approach appears to be surgical removal of the entire apocrine sweat gland apparatus. Dapsone is used in dermatology to treat inflammatory dermatoses such as dermatitis herpetiformis and pyoderma gangrenosum, and was formerly the treatment of choice for acne conglobata. We report its successful use in acne inversa. Five female patients aged 23-40 years with acne inversa for a mean of 9.6 years were included. All patients showed an almost complete resolution of their symptoms within 2-4 weeks. All patients rated the treatment results with dapsone as good or very good. The treatment was well tolerated and no important side effects occurred. Because of its lack of teratogenicity, dapsone may be the most favorable treatment option in young women with acne inversa.

Acne Vulgaris↗
PubMed1988

Dapsone inhibits LTB4 binding and bioresponse at the cellular and physiologic levels.

Radioligand binding studies using human neutrophils exposed to 10-100 microM dapsone indicated that this anti-inflammatory compound antagonized association of LTB4 (leukotriene B4) with its specific receptor sites. Binding inhibition was manifested in reduced biologic response of the neutrophils as determined in LTB4-stimulated chemotaxis. In addition, a physiologic model of LTB4-dependent inflammation in mice was antagonized by systemic administration of dapsone. These data suggest that inhibition of LTB4 binding may represent the cellular mechanism of action responsible for the anti-inflammatory effects of dapsone.

Animals↗
PubMedDate not supplied

A double-blind study on the efficacy of oral dapsone in cutaneous leishmaniasis.

One hundred and twenty patients with localized cutaneous leishmaniasis were randomly allocated to receive tablets of dapsone (100 mg) or matching placebo tablets every 12 h for 6 weeks. No topical medication was used. Demonstration of Leishmania from skin lesions by the slit smear technique was mandatory for inclusion. Before, periodically during, and one month after completion of therapy an overall clinical assessment, haemoglobin determination, leucocyte count, and liver function tests were performed. 49 patients (82%) of those receiving dapsone were assessed as cured by clinical and parasitological criteria. Oral dapsone has certain advantages over other current forms of treatment: it is economical and widely available in countries where cutaneous leishmaniasis is common, and it is effective by mouth and well tolerated.

Administration, Oral↗
PubMed1995

Dapsone-induced methemoglobinemia: an anesthetic risk.

Dapsone is used to treat several systemic inflammatory diseases, many of which have head and neck manifestations, such as leprosy, systemic lupus erythematosus, rhinosporidiosis, relapsing polychondritis, dermatitis herpetiformis, pemphigus vulgaris and bullous pemphigoid. It has also been recently used prophylactically alone or in combination against malaria and in AIDS patients against Pneumocystis carinii infections. This is significant to the otolaryngologist-head and neck surgeon since approximately 40% of AIDS patients will have head and neck manifestations. Thus, the likelihood that otolaryngologists will be treating patients who are taking dapsone regularly is significant. We present a case of a 16-year-old female who presented with a presumptive diagnosis of discoid lupus for biopsy confirmation of her disease. Induction of general anesthesia was complicated by methemoglobinemia, an uncommon side effect of dapsone. We will discuss recognition and prevention of this side effect, its potential anesthetic implications, complications and treatment.

Adolescent↗
PubMed1993

Simultaneous determination of dapsone, monoacetyldapsone and pyrimethamine in whole blood and plasma by high-performance liquid chromatography.

A sensitive, selective and rapid reversed-phase high-performance liquid chromatographic method was developed for the simultaneous analysis of dapsone, monoacetyldapsone and pyrimethamine in human whole blood and plasma. The procedure involved extraction of the compounds and the internal standard, monopropionyldapsone, with tert.-butylmethyl ether under alkaline conditions. A newly marketed column, Supelcosil LC-ABZ (Supelco, 15 cm x 4.6 mm I.D.), was employed. The mobile phase, consisting of acetonitrile-methanol-phosphate buffer (2:1:7, v/v/v), was delivered at a flow-rate of 1.2 ml/min, and ultraviolet absorbance was monitored at 286 nm. The limit of determination using a 150-microliters sample was 10 ng/ml (40 nM) for dapsone and pyrimethamine and 8 ng/ml (28 nM) for monoacetyldapsone. Given that only a small amount of blood is required in this method, it could now be applied in studies involving blood level monitoring and pharmacokinetics in children on Maloprim (dapsone-pyrimethamine) prophylaxis in malaria endemic areas.

Anti-Infective Agents↗
PubMed1994

Determination of dapsone in serum and saliva using reversed-phase high-performance liquid chromatography with ultraviolet or electrochemical detection.

A simple, extractionless method for the determination of dapsone in serum and saliva is described. Reversed-phase high-performance liquid chromatography is used with UV detection at 295 nm or electrochemical detection at 0.7 V. Diazoxide in buffer is the internal standard for UV detection and practolol for electrochemical detection. Sample preparation is minimal with protein precipitation of serum samples whilst saliva samples are simply diluted with addition of an internal standard. Low-level serum and saliva samples are front-cut on-line with a 3 cm laboratory-made precolumn in the loop position on a standard Valco injection valve. Isocratic separation is achieved on a 250 mm x 4.6 mm I.D. stainless-steel Spherisorb S5 ODS-1 column. The mobile phase for high levels of dapsone is acetonitrile-elution buffer (12:88, v/v) at 2 ml/min and a column temperature of 40 degrees C for both serum and saliva separations. For the low-level assays using electrochemical detection and solid-phase clean-up, the mobile phase is acetonitrile-methanol-elution buffer (9:4:87, v/v/v). The UV and electrochemical detection limits are 25 ng/ml and 200 pg/ml, respectively, in both serum and saliva. This simple method is applicable to the routine monitoring of dapsone levels in serum from leprotic patients and electrochemical detection gives a simple, reliable method for the monitoring of trough values in subjects on anti-malarial prophylaxis.

Chromatography, High Pressure Liquid↗
PubMed1995

A fatal case of drug-induced multi-organ damage in a patient with Hansen's disease: dapsone syndrome or rifampicin toxicity?

An elderly patient with borderline tuberculoid Hansen's disease (leprosy) developed the diaminodiphenylsulphone syndrome after approximately 8 weeks of multi-drug therapy comprising dapsone and rifampicin. Postmortem histological examination, following autopsy, demonstrated features consistent with drug-induced hepatitis, tubulo-interstitial nephritis and myocarditis. Although these could have been engendered by dapsone toxicity, it was thought that a concommitant adverse reaction to rifampicin, which is known to be hepatotoxic, nephrotoxic and possibly capable of predisposing to the dapsone syndrome, could not be excluded.

Acute Kidney Injury↗
PubMed1995

Severe accidental dapsone overdose.

Acute poisoning from excessive dapsone (4,4-diaminodiphenylsulfone) intake in uncommon in the United States; no cases were reported during 1992. However, with the increasing use of dapsone for diseases other than leprosy and dermatitis herpetiformis, such as acne vulgaris, psoriasis, and Pneumocystis carinii pneumonia infection in acquired immunodeficiency syndrome, clinicians should be aware of potential toxicities. This report describes a case of accidental dapsone intoxication resulting in severe cyanosis with a modest elevation in methemoglobin concentration.

Charcoal↗
PubMedDate not supplied

Recurrent methemoglobinemia after acute dapsone intoxication in a child.

Dapsone is a synthetic sulfone increasingly used in the treatment of a wide variety of dermatologic disorders. The case of a child with dapsone-induced recurrent methemoglobinemia is presented with a discussion of dapsone toxicity and its treatment. In addition, the diagnostic value of pulse oximetry in the presence of dysfunctional hemoglobins is discussed.

Child, Preschool↗
PubMedDate not supplied

[Mucous membrane pemphigoid: clinical manifestations and treatment with corticosteroids, dapsone and cyclophosphamide in 5 patients].

INTRODUCTION: Cicatricial pemphigoid includes several processes which are characterized by the presence of subepidermal bullae, and which affect the mucous membranes and, more rarely, the skin. At present, the term mucous membrane pemphigoid (MMP) is more accepted than other names used in the past, as they do not clearly define the broad spectrum presented by this disease. MMP can cause significant dysfunctions, primarily in the mucous membranes. Therefore, it is necessary to diagnose the disease as soon as possible, in order to quickly initiate systemic immunosuppressive treatment. MATERIAL AND METHODS: We present our experience with 5 patients with MMP. We analyze the clinical manifestations and the response to immunosuppressive treatment during the evolution of the disease. RESULTS: The patients were aged 41 to 69 years. The most frequent location of the lesions was the oral mucosa (80 %) and the ocular mucosa (80 %), followed by the pharyngeal mucosa (60 %), laryngeal mucosa (40 %), skin, anal mucosa (20 %) and genital mucosa (20 %). Three patients received systemic corticosteroids, dapsone and cyclophosphamide, and several sessions of plasmapheresis were also associated in one patient. One patient was controlled with topical corticosteroids and dapsone. CONCLUSIONS: Many patients with MMP can present with severe secondary complications. For this reason, the diagnosis must be confirmed quickly and the appropriate treatment started as soon as possible. The association of corticosteroids, dapsone and cyclophosphamide is a combination that gives very good results.

Adrenal Cortex Hormones↗