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PubMed1989

In-vitro activity of dapsone and two potentiators against Mycobacterium avium complex.

The efficacy of dapsone against Mycobacterium avium, M. intracellulare, M. kansasii, M. fortuitum and M. tuberculosis was determined by disc elution in agar. The minimal inhibitory concentration at which 90% of the colony forming units were inhibited (90MIC) by dapsone was 8 mg/l for M. avium, M. intracellulare and M. kansasii and greater than or equal to 32 mg/l for M. tuberculosis and M. fortuitum. The 90MICs were confirmed by culturing these test organisms with dapsone in the BACTEC 460 system. Reduction of the 90MIC from 8 mg/l to 2 mg/l was observed by combining dapsone with either or both of the potentiators tested. The dapsone-potentiator combinations had no effect on the bacteria with 90MICs of greater than or equal to 32 mg/l. The clinical relevance of this drug combination against M. avium complex infections remains to be evaluated.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Experimental evaluation of roxithromycin combined with dapsone or sulphamethoxazole on Pneumocystis carinii and Toxoplasma gondii dual infections in a rat model.

We have developed a dual infection model in immunosuppressed rats for evaluating drugs against Pneumocystis carinii and Toxoplasma gondii, two important opportunistic pathogens in patients with AIDS. Using this model, we reported that the macrolide roxithromycin was effective at a daily dose of 400 mg/kg in preventing the development of T. gondii infection but did not have a prophylactic effect against P. carinii in the same rats. A lower dose (200 mg/kg/day) had only marginal effects. Extending these experiments, we have now shown that roxithromycin at doses of 400 or 200 mg/kg/day combined with dapsone at doses of 5, 25 or 50 mg/kg/day completely prevented the development of T. gondii infection, with no parasites being detected in any of the tissues sampled. Roxithromycin at either dose combined with dapsone at 25 or 50 mg/kg/day was also effective in preventing the development of P. carinii infection in the lungs. The lowest dose of dapsone (5 mg/kg/day) was not fully effective. Pyrimethamine-dapsone, a combination used clinically, was tested in the same experiment, and gave results comparable to those with roxithromycin-dapsone combinations. In a further experiment combining roxithromycin with sulphamethoxazole, roxithromycin was effective in preventing the T. gondii infection, even when given at only 200 mg/kg/day with 20 mg/kg/day of sulphamethoxazole. When the dose of sulphamethoxazole was reduced to 2 mg/kg/day and given with roxithromycin 200 mg/kg/day, T. gondii infection developed in two of the five rats treated. P. carinii infection was prevented by sulphamethoxazole at 20 mg/kg/day but not completely by 2 mg/kg/day. Roxithromycin also has activity against Mycobacterium avium, another important cause of opportunistic infections in AIDS patients, and the compound penetrates mammalian cells well. Taken together with the favourable pharmacokinetic profile of roxithromycin, these results suggest that it may have a clinical utility, when used with other agents, in controlling the development of opportunistic infections caused by M. avium complex, T. gondii and P. carinii in HIV-infected individuals.

Animals↗
PubMed1987

Dapsone-associated Heinz body hemolytic anemia in a Cambodian woman with hemoglobin E trait.

A Cambodian woman with hemoglobin E trait (AE) and leprosy developed a Heinz body hemolytic anemia while taking a dose of dapsone (50 mg/day) not usually associated with clinical hemolysis. Her red blood cells (RBCs) had increased incubated Heinz body formation, decreased reduced glutathione (GSH), and decreased GSH stability. The pentose phosphate shunt activity of the dapsone-exposed AE RBCs was increased compared to normal RBCs. Although the AE RBCs from an individual not taking dapsone had increased incubated Heinz body formation, the GSH content and GSH stability were normal. The pentose phosphate shunt activity of the non-dapsone-exposed AE RBCs was decreased compared to normal RBCs. Thus, AE RBCs appear to have an increased sensitivity to oxidant stress both in vitro and in vivo, since dapsone does not cause hemolytic anemia at this dose in hematologically normal individuals. Given the influx of Southeast Asians into the United States, oxidant medications should be used with caution, especially if an infection is present, in individuals of ethnic backgrounds that have an increased prevalence of hemoglobin E.

2,3-Diphosphoglycerate↗
PubMed1994

Dapsone therapy causing sulfone syndrome and lethal hepatic failure in an HIV-infected patient.

A 34-year-old woman with HIV infection and no other opportunistic infections presented a classic sulfone syndrome, manifested by fever, rash, hemolytic anemia, and fulminant hepatitis due to dapsone hypersensitive reaction, with a fatal outcome. We believe this is the first reported fatal complication of dapsone in an HIV-infected patient. We to bring attention to this potentially fatal drug complication, which may become more common with widespread use of dapsone in HIV-infected patients. The package insert for dapsone recommends laboratory surveillance (hematologic and liver-related tests) during the first 4 to 6 weeks of therapy, and every 3 to 4 months thereafter. Our case report suggests that closer follow-up of patients receiving dapsone might be indicated.

AIDS-Related Opportunistic Infections↗
PubMed2006

Methemoglobinemia associated with dapsone therapy in a child with pneumonia and chronic immune thrombocytopenic purpura.

This report describes a case of methemoglobinemia in association with dapsone therapy. The patient, an immunocompromised child with chronic immune thrombocytopenic purpura, presented with fever, cough, perioral cyanosis, bilateral lower lobe rales, and low O2 saturation by pulse oximetry (89%). His medications included prednisone and rituximab for chronic immune thrombocytopenic purpura, and dapsone for Pneumocystis carinii pneumonia prophylaxis. Because of his lack of dyspnea and tachypnea, and the temporal association of his perioral cyanosis with the initiation of dapsone therapy, a methemoglobin (MetHb) level was obtained and found to be elevated at 9.6%. The authors discuss the mechanism and treatment of methemoglobinemia secondary to dapsone. They also stress the importance of monitoring for signs and symptoms of methemoglobinemia in immunocompromised patients on dapsone therapy for P. carinii pneumonia prophylaxis.

Anti-Infective Agents↗
PubMed1980

A comparison of IgA positive and IgA negative dapsone responsive dermatoses.

A study of thirty-three patients with a clinical diagnosis of dermatitis herpetiformis (DH) referred to our DH clinic over the las 11 years is reported. Twenty-six were referred by other consultant dermatologists. The diagnosis had been made by the clinical features and response of the rash to dapsone. Seventeen patients were found to have IgA in the uninvolved skin (IgA positive) and in sixteen no IgA was found (IgA negative). The duration of the rash prior to referral to the DH clinic was 3 months to 19 years (mean 5.0 years) for the IgA negative patients and 2 months to 22 years (mean 5.2 years) for the IgA positive group. The length of follow-up was 3 months to 11 years (mean 5.0 years) for the IgA negative, and 2--11 years (mean 5.6 years) for the IgA positive group. During follow-up the rash cleared completely and required no treatment in seven of the sixteen IgA negative patients. Thirteen of these sixteen patients no longer required dapsone, but six patients were receiving alternative treatment. In the three patients still taking dapsone IgA has not been found on subsequent biopsy. Of the seventeen IgA positive patients only three were able to stop dapsone during follow-up and in these three the IgA was still detected in the skin. Small intestinal mucosa was abnormal in eight of eleven IgA positive patients, but was normal in all thirteen IgA negative patients in whom jejunal biopsies were performed. An alternative diagnosis to DH has subsequently been made in thirteen of the sixteen IgA negative patients. Although the significance of IgA in the skin in DH is not known it appears to be part of the disease process. Patients who have a rash suggestive of DH and which is dapsone responsive, but in whom IgA is not found in the uninvolved skin, usually turn out to have a dermatosis other than dermatitis herpetiformis. Referral to a unit with expertise in immunofluorescence techniques of skin biopsies would appear to be helpful.

Adolescent↗
PubMed1993

Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance.

Dapsone is useful in the treatment of a number of inflammatory conditions which are characterized by neutrophil infiltration. It is the drug of choice for suppression of the symptoms of dermatitis herpetiformis, as it inhibits the process by which neutrophils leave the circulation and migrate to lesional sites. It also prevents the tissue destruction normally caused by the neutrophils' respiratory burst. Although dapsone can cause a number of serious idiosyncratic reactions, such as agranulocytosis, tolerance of the drug at higher doses is more usually determined by its haematological side-effects of methaemoglobinaemia and haemolysis. These effects are due entirely to the hepatic N-hydroxylation of dapsone to a hydroxylamine metabolite, some of which escapes from the liver and rapidly enters red cells. Attempts have been made to counteract the haemotoxic effects of the metabolite by the use of antioxidants such as vitamins E and C. Recently, the co-administration of a metabolic inhibitor such as cimetidine has been shown to reduce significantly dapsone-dependent methaemoglobinaemia, without any change in drug efficacy. It remains to be seen if this approach will be adopted clinically, to improve patient tolerance of high dapsone dosage.

Dapsone↗
PubMed2005

Dapsone suppresses human neutrophil superoxide production and elastase release in a calcium-dependent manner.

BACKGROUND: Dapsone (4,4'-diaminodiphenyl sulphone) is a powerful therapeutic tool in many skin diseases including neutrophilic dermatoses. The drug has an outstanding therapeutic efficacy against many skin diseases characterized by neutrophil-rich infiltrates; however, mechanisms of its action are poorly understood. OBJECTIVES: We investigated the effects of dapsone on respiratory and secretory functions of human neutrophils triggered by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), the physiological agonist C5a, and phorbol myristate acetate (PMA). METHODS: Human neutrophils were isolated from venous blood obtained from healthy donors. We detected extracellular production of superoxide (O(2) (-)) by cytochrome C reduction assay, and intracellular production of O(2) (-) by flow cytometry. Neutrophil elastase release was measured by the cleavage of the specific elastase substrate N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanilide. Measurement of cytosolic free calcium concentration was performed using the calcium-reactive fluorescence probe, Fluo-3. RESULTS: Dapsone suppressed intra- and extracellular production of O(2) (-) and elastase release triggered by fMLP and C5a, but not by PMA. Both fMLP and C5a signalled the above pathways by inducing calcium influx, but PMA functions bypassed calcium influx. Dapsone was capable of antagonizing the induction of calcium influx. CONCLUSIONS: These findings suggest that one mechanism of the anti-inflammatory action of dapsone is inhibition of calcium-dependent functions of neutrophils including release of tissue-damaging oxidants and proteases in the affected skin.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Comparing the anticonvulsive effects of dapsone on amygdala-kindled seizures and hippocampal-kindled seizures in rats.

Dapsone, an antileprosy drug, was administered to rats with amygdala (AM)-kindled seizures or hippocampal (HIPP)-kindled seizures to elucidate its anticonvulsive efficacy. Adult male Wistar rats were subjected to kindling stimulations 2 weeks after electrode-implantation. The subjects were tested once a day for 7 successive days after inducing three generalized (stage 5) seizures to study the effects of dapsone. Dapsone had an inhibitory effect on stage 5 seizures at 12.50 mg/kg in the AM-kindled rats and at 6.25 mg/kg and 9.375 mg/kg in the HIPP-kindled rats. Thus, there was a distinct difference in the effective dose for generalized seizures between the AM-kindled rats and the HIPP-kindled rats. The inhibitory action of dapsone on stage 5 seizures may be due mainly to the elevation of the afterdischarge-triggering threshold at the stimulation site of the AM or HIPP. Such inhibitory action appears prominently at serum concentrations of about 13 micrograms/ml in AM-kindled rats and about 6 micrograms/ml in HIPP-kindled rats. The level of 6 micrograms/ml almost equals the therapeutic serum concentration of dapsone used in the treatment of leprosy.

Amygdala↗
PubMed1996

Studies on the toxicity of analogues of dapsone in-vitro using rat, human and heterologously expressed metabolizing systems.

Three metabolizing systems (rat, heterologously expressed CYP3A4 and human liver) were used to evaluate 12 analogues of dapsone (4,4'diaminodiphenylsulphone) in-vitro. Methaemoglobin formation in a two-compartment and cytotoxicity in a single-compartment model were studied using human erythrocytes and neutrophils, respectively, as target cells. In the two-compartment system using rat microsomes as a generating system and methaemoglobin as an endpoint, the least potent methaemoglobin formers tested were the 2-methyl-4-propylamino (AXDD14), 2-hydroxy-4-4'amino (ABDD5) derivatives and a sulphone/trimethoprim derivative (K-130). Dapsone itself, a 2-methoxy-4-ethylamino (W10) and a 2-hydroxyl-4-ethylamino compound (ABDD39) were the most toxic. In the single-compartment cytotoxicity test using rat microsomes, AXDD14 was again among the least toxic, as was a 2-methyl 4-cyclopentyl derivative (AXDD17) and surprisingly ABDD39. The most cytotoxic compounds again included dapsone itself as well as two 2-trifluoromethyl derivatives. The only significant methaemoglobin formation and cytotoxicity shown with the heterologously expressed human CYP 3A4 was with AXDD14, which was extensively activated. Interestingly, metabolism of dapsone was low using the expressed CYP 3A4. In the two-compartment system using human liver microsomes, AXDD14, K-130 and ABDD5 were oxidized to a significantly lesser extent compared with dapsone and these preliminary findings indicate that future development of these compounds may be worthwhile.

Animals↗
PubMed1996

A dapsone-induced blood dyscrasia in the mouse: evidence for the role of an active metabolite.

In the female mouse, dapsone (50-500 mg kg-1, p.o.) caused a dose-related methaemoglobinaemia which peaked at 0.5-1 h with recovery to baseline values occurring by 4 h. Cimetidine (100 mg kg-1, p.o.), a known inhibitor of several hepatic P450 isozymes administered 1 h before dapsone, prevented the methaemoglobinaemia. In-vitro, dapsone required activation by mouse hepatic microsomes to cause methaemoglobin formation in mouse erythrocytes and cytotoxicity to human mononuclear leucocytes. In both instances, the toxic effects were markedly reduced by cimetidine. Daily dosing of mice with dapsone (50 mg kg-1, p.o.) for 3 weeks induced a blood dyscrasia, characterized by a fall of platelet and white blood cell counts, which was inhibited by cimetidine (100 mg kg-1, p.o. daily). It is concluded that an active metabolite of dapsone arising from a P450-dependent pathway is involved in the genesis not only of the methaemoglobinaemia but also the blood dyscrasia arising from repeated administration of the drug in this species.

Animals↗
PubMed1985

Enhancement by clofazimine and inhibition by dapsone of production of prostaglandin E2 by human polymorphonuclear leukocytes in vitro.

The effects of the antileprosy agents clofazimine and dapsone (1 to 10 micrograms/ml) on the spontaneous and stimulated release of prostaglandin E2 (PG E2) by human polymorphonuclear leukocytes (PMNL) in vitro have been investigated. PMNL were obtained from normal adult volunteers and three patients with leprosy (two borderline lepromatous and one subpolar lepromatous leprosy). The synthetic chemotactic tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) at a concentration of 10(-7) M was used as the stimulant of PG E2 synthesis. None of the test agents at the concentrations used inhibited the binding of radiolabeled FMLP to PMNL. However, dapsone at 5 and 10 micrograms/ml inhibited the spontaneous and FMLP-induced release of PG E2 by PMNL. Clofazimine, on the other hand, significantly increased both the spontaneous and the FMLP-induced synthesis of PG E2 by PMNL. The enhancing effects of clofazimine on FMLP-mediated synthesis of PG E2 were particularly striking and were observed at concentrations of 1 to 10 micrograms of the drug per ml. Measurements of PMNL spontaneous and FMLP-induced synthesis of PG E2 in the presence of both clofazimine and dapsone (5 micrograms/ml) indicated that the two drugs are mutually antagonistic. PMNL from both normal control subjects and patients with leprosy were equally sensitive to these effects of clofazimine and dapsone. The immunostimulatory and immunosuppressive properties of dapsone and clofazimine, respectively, may be related to the opposite effects of these agents on PG E2 synthesis in human leukocytes.

Clofazimine↗
PubMed1991

Anti-Toxoplasma effects of dapsone alone and combined with pyrimethamine.

The efficacy of dapsone alone or combined with pyrimethamine against Toxoplasma gondii was investigated experimentally. For in vitro studies, a sensitive immunoassay was used for assessment of Toxoplasma growth in tissue cultures; dapsone was found to have a significant inhibitory effect at a concentration of 0.5 micrograms/ml in the cultures, and the 50% inhibitory concentration was estimated to be 0.55 micrograms/ml. When pyrimethamine and dapsone were combined, an important synergistic effect which was associated with morphological alterations of the parasites was observed. In vivo studies were performed in a murine model of acute toxoplasmosis in which a tissue culture method was used to estimate the parasite burden in the blood, lungs, and brains of infected mice. Dapsone alone, which was administered at 100 mg/kg/day for 10 days from day 1 after infection, was unable to prevent parasite dissemination and only delayed the time to death of treated mice compared with the time of death of untreated controls. When dapsone and pyrimethamine (18.5 mg/kg/day) were administered in combination from day 4 after infection, parasites were cleared from blood and organs within 6 days, but relapses were observed 15 days after the cessation of therapy. When treatment was started at day 1 after infection, 100% of mice survived and relapses were not observed, suggesting a good efficacy of this combination for preventive therapy.

Animals↗
PubMed1994

Levels of dapsone and pyrimethamine in serum during once-weekly dosing for prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis.

Concentrations of dapsone, monoacetyldapsone, and pyrimethamine were determined in 36 serum samples from human immunodeficiency virus-infected patients on prophylaxis with once-weekly administration of dapsone-pyrimethamine (200 mg of dapsone-75 mg of pyrimethamine). During day 1 after ingestion, median levels of 1,038 ng of dapsone per ml and 356 ng of pyrimethamine per ml were found. During days 6 to 7, the dapsone level fell to < 20 ng/ml in five of nine serum samples, but the pyrimethamine level remained elevated (125 ng/ml). Concurrent, but separately ingested, didanosine administration did not seem to decrease the drug concentrations.

Adult↗
PubMed1996

Population pharmacokinetics of dapsone administered biweekly to human immunodeficiency virus-infected patients.

The population pharmacokinetics of dapsone were examined in human immunodeficiency virus-infected patients receiving dapsone at a dosage of 100 mg twice weekly for the prevention of Pneumocystis carinii pneumonia. Nonlinear mixed-effect modeling was used to determine the best pharmacostatistical model for the data. A one-compartment open model with first-order absorption and elimination was used as the structural pharmacokinetic model. Several covariates were tested for their influence on pharmacokinetic parameters. Rifampin was found to increase the values of clearance/bioavailability (CL/F) and volume of distribution/ bioavailability (V/F) by approximately 70%. CL/F and V/F were 1.83 liters/h and 69.6 liters, respectively, for patients not taking rifampin. The effect of rifampin on the pharmacokinetic parameters of dapsone was appreciably less than expected on the basis of studies with healthy volunteers. Increased bilirubin levels were associated with a significant decrease in the absorption rate constant (Ka). However, this finding may be considered clinically irrelevant because the post hoc Bayesian estimates of Ka for patients with high bilirubin levels ( > 1.2 mg/dl) were at the lower bound of the values for patients with normal bilirubin levels. The value of Ka was 0.957 h-1 for a patient with a bilirubin level of 0.7 mg/dl. After inclusion of covariates in the model, the interpatient variability was 35% for CL/F, not significant for V/F, and 85% for Ka. Simulation of plasma concentration-versus-time curves indicated that the administration of 100 mg of dapsone biweekly is associated with sustained dapsone levels in the plasma of the majority of the patients. Dosage adjustments for patients concomitantly treated with rifampin may be necessary.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Preventive effect of dapsone on renal scarring following mannose-sensitive piliated bacterial infection.

Renal scarring has been thought to occur in the later stages of chronic pyelonephritis. We previously reported that mannose-sensitive (MS) piliated bacteria promoted renal scarring, which was prevented by antioxidants. The preventive effect of diaphenylsulfone (dapsone), which has a scavenging activity on active oxygen species, on renal scarring was examined. Female Sprague-Dawley rats were inoculated with clinical isolates of Serratia marcescens which had both MS and mannose-resistant pili or with recombinant strains which had MS pili on their surface; they were then administered 20 mg/kg of dapsone or not. Dapsone significantly suppressed scarring following infection of the kidney. The bacterial counts in the kidneys were not different in dapsone-treated and nontreated rats. We conclude that dapsone is effective in preventing renal scarring, and it is suggested that the clinical use of this drug may prevent renal scar formation following pyelonephritis.

Animals↗
PubMedDate not supplied

Lack of effect of proguanil on the pharmacokinetics of dapsone in healthy volunteers.

The multiple-dose kinetics of dapsone (DDS) and its principal metabolite monoacetyldapsone (MADDS) were determined in 6 healthy volunteers after daily administration of low-dose dapsone (10 mg). Comparison with a previous study involving the same volunteers on a daily regimen of proguanil (200 mg) plus dapsone (10 mg) revealed no statistically significant differences in the maximum plasma concentrations, area under the plasma drug concentration curves and elimination half-lives of both DDS and MADDS in the presence of proguanil. Although these findings suggest that proguanil does not alter the pharmacokinetics of DDS and MADDS, the possibility that proguanil affects the disposition of hydroxylated metabolites of dapsone, which appear to mediate dapsone toxicity, cannot be excluded.

Acetylation↗
PubMed1986

Dapsone in the treatment of cutaneous lupus erythematosus.

Thirty-three patients with chronic discoid lupus erythematosus (DLE) who had received dapsone for 1-27 months were reviewed. The dapsone treatment gave excellent results in 8 patients (24%), some effect in 8 patients (24%), while no response was seen in 17 patients (52%). Of the patients who had earlier been treated with hydroxychloroquine (HCQ), 76% responded excellently to the treatment. Of 6 patients who received a combined dapsone and HCQ therapy, 2 responded well. Six patients (18%) terminated the dapsone treatment because of side effects, none of which were serious. It is concluded that dapsone might be an alternative or a supplement to HCQ in the treatment of DLE, when the latter causes adverse reactions or fails to be effective. However, we find that HCQ remains the drug of choice when systemic treatment is needed.

Adult↗