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Spectrophotometric determination of dapsone in pharmaceutical products using sodium 1,2-naphthoquinone-4-sulfonic as the chromogenic reagent.

Spectrophotometric determination of dapsone is described. The dapsone reacts with sodium 1,2-naphthoquinone-4-sulfonic in pH 6.98 buffer solution to form a salmon pink compound, and its maximum absorption wavelength is at 525 nm, epsilon525=3.68 x 10(4) l mol(-1) cm(-1). The absorbance of dapsone from 0.40 to 10 microg ml(-1) obeys Beer's law. The linear regression equation of the calibration graph is C=0.2334 A + 0.01288, with a linear regression correlation coefficient of 0.9998, the detection limit is 0.24 microg ml(-1), and recovery is from 99.2 to 102.4%. Effects of pH, surfactant, organic solvents, foreign ions, and standing time on the determination of dapsone have been examined. This method is simple and can be used for the determination of dapsone in injection solution of dapsone. The results obtained by this method agreed with those by the official method (dead-stop titration method [The Chinese Pharmacopoeia, Pharmacopoeia Commission, Ministry of Health, vol. 2, fifth ed., PRC Chemical Industry Press, Beijing, 2000, p.720]).

Antimalarials↗

Artesunate-dapsone-proguanil treatment of falciparum malaria: genotypic determinants of therapeutic response.

The combination of chlorproguanil and dapsone is being considered as an alternative antimalarial to sulfadoxine-pyrimethamine in Africa, because of its greater efficacy against resistant parasites, and its shorter half-lives, which exert less selective pressure for the emergence of resistance. A triple artesunate-chlorproguanil-dapsone combination is under development. In a previous study of relatively low-dose chlorproguanil-dapsone in multidrug-resistant falciparum malaria in Thailand failure rates were high. Proguanil is inexpensive, widely available and very similar to chlorproguanil. The safety and efficacy of artesunate-dapsone-proguanil (artesunate 4 mg/kg, dapsone 2.5mg/kg, proguanil 8 mg/kg daily for three days), was studied prospectively in 48 Thai adult patients with acute falciparum malaria followed daily for 28 days. Eleven of these had a recrudescence of their infection. Genotyping of Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) indicated that the Pfdhfr I164L mutation was the main determinant of therapeutic outcome; all 11 failures carried this mutation (failure rate 11/37; 30%) whereas none of the 11 infections with 'wild type' 164 genotypes failed. The addition of artesunate considerably augments the antimalarial activity of the biguanide-dapsone combination, but this is insufficient for infections with parasites carrying the highly antifol-resistant Pfdhfr I164L mutation.

Adolescent↗

Dapsone in rheumatoid arthritis.

Dapsone, a synthetic sulfone with chemical similarities to sulfapyridine, has been used for a number of years to treat leprosy and dermatitis herpetiformis. Recently, a number of prospective, randomized, double-blind trials have shown their success in the management of rheumatoid arthritis, with dapsone being superior to placebo and comparable to chloroquine and hydroxychloroquine. Its mode of anti-inflammatory actions in rheumatoid arthritis is not clearly understood, but modulation of neutrophil activity or inhibition of neutrophil inflammatory product formation or release appear to play a role. The major limiting side effect is hemolytic anemia, which may be mitigated through careful patient selection, conservative drug dosing, close monitoring, and possibly, concurrent administration of antioxidants or cytochrome P450 inhibitors. Methemoglobinemia is another common finding among patients receiving dapsone therapy, but rarely does it result in prominent symptoms other than transient pallor. Less common adverse events to dapsone include the idiosyncratic reactions of leukopenia and agranulocytosis, cutaneous eruptions, peripheral neuropathy, psychosis, toxic hepatitis, cholestatic jaundice, nephrotic syndrome, renal papillary necrosis, severe hypoalbuminemia without proteinuria, an infectious mononucleosis-like syndrome, and minor neurological and gastrointestinal complaints. In this report, two patients with advanced rheumatoid arthritis, who were safely and effectively treated with dapsone after failure with other second-line agents, are described and the literature is reviewed. We suggest that dapsone is an effective second-line agent in the treatment of rheumatoid arthritis.

Anti-Inflammatory Agents, Non-Steroidal↗

Dapsone-mediated agranulocytosis: risks, possible mechanisms and prevention.

Agranulocytosis is a rare, severe and unpredictable idiosyncratic reaction associated with drug therapy that can lead to life-threatening illness. Typically, the patient presents with a fever and evidence of infection 1-3 months after initiation of drug administration with a neutrophil count below 0.5x10(9) l. Of the drugs linked with this disease, aminopyrine, dipyrone, clozapine, anti-thyroid agents, sulphonamides and dapsone are the best documented. Generally, agranulocytosis is associated with older individuals (>60 years) and those of non-Caucasian descent. The incidence of agranulocytosis in subjects taking oral dapsone in combination with maloprim for malaria is 1 -- 10-20,000 while leprosy patients treated with dapsone exhibit virtually zero risk of agranulocytosis. However, dapsone is unusual in that during the rare but severe inflammatory disease, dermatitis herpetiformis (DH), the risk of agranulocytosis is multiplied between 25 and 33 fold compared with normal patients. It is conceivable that dapsone might exhibit a similar risk in coeliac disease, a condition related to DH. As dapsone plasma levels in DH subjects can be high (2-10 microg/ml) the increased risk of agranulocytosis could be related to drug dosage, or increased immune responsiveness. The high risks in DH patients probably necessitate monitoring of neutrophil cell population in the first 3 months of therapy, while topical usage of the drug in acne treatment in otherwise healthy patients predominantly below the age of 25 is at the opposite end of the risk scale, probably as low as 1 in 10-20,000 patients.

Agranulocytosis↗

Dapsone prevents morphological lesions and lipid peroxidation induced by quinolinic acid in rat corpus striatum.

Increasing doses of dapsone were tested on rats administered intrastriatally with quinolinic acid in order to evaluate a possible protective action of this drug on the striatal lesions produced after the excessive activation of N-methyl-D-aspartate receptors. Morphological lesions were evaluated 7 days after the intrastriatal injection of quinolinate (240 nmol/microl) by light microscopy, and the ratio of neuronal damage per field was also estimated as a quantitative index of the striatal toxicity. Quinolinate alone produced extensive necrosis and loss of striatal neurons. No protective effects on the striatal tissue from quinolinate-treated rats were observed at lower doses of dapsone (6.25 and 9.375 mg/kg). However, at higher doses (12.5 and 25 mg/kg), dapsone prevented significantly the striatum from quinolinate toxicity. Dapsone alone had no effect on the striatal tissue from control rats. A single dose of dapsone (12.5 mg/kg) was tested also on the index of lipid peroxidation 2 h after the striatal injection of quinolinate, resulting in a significant protection (78% vs. QUIN). Findings of this study, in accordance with our previous reports, demonstrate the ability of dapsone to prevent the neuronal damage associated with the excitatory action of quinolinate via overactivation of NMDA receptors, and provide evidences to support the hypothesis that this drug is acting against the pattern of toxicity elicited by agonists of glutamate receptors.

Animals↗

Dapsone for Pneumocystis carinii prophylaxis in children undergoing bone marrow transplantation.

Children who undergo bone marrow transplantation (BMT) are at risk for Pneumocystis carinii pneumonia (PCP). Prophylaxis using trimethoprim/sulfamethoxazole (TMP/SMX) is highly effective but the incidence of adverse drug reactions is significant. We retrospectively reviewed 33 pediatric BMT (25 allogeneic and eight autologous) in whom dapsone was used for PCP prophylaxis because patients were unable to receive TMP/SMX. Dapsone was administered at 50 mg/m2 p.o. once a week from engraftment to 180 days post-autologous BMT, and to 1 year or throughout the duration of immunosuppressive treatment post-allogeneic BMT. With a total of 7268 patient days of dapsone prophylaxis and a median follow-up of 353 days post-BMT, no proven PCP was diagnosed. Sixteen cases of chest radiograph abnormalities were noted in this patient population but none was attributed to PCP. Dapsone was well tolerated by all children with no serious adverse effects; however, one patient developed Toxoplasma gondii encephalitis during dapsone prophylaxis. Dapsone warrants further evaluation as an alternative for PCP prophylaxis in pediatric BMT patients intolerant of TMP/SMX. Additional prophylaxis should be considered for patients at high risk for T. gondii encephalitis.

Anti-Infective Agents↗

The IL-8 release from cultured human keratinocytes, mediated by antibodies to bullous pemphigoid autoantigen 180, is inhibited by dapsone.

Bullous pemphigoid (BP) is a subepidermal blistering disease associated with autoantibodies to the hemidesmosomal 180 kD BP autoantigen (BP180). However, the binding of autoantibodies to BP180 alone is not sufficient for blister formation in this disease and the infiltration of neutrophils into the skin is required. Dapsone and nicotinamide inhibit neutrophil chemotaxis and are used effectively in treating BP. IL-8 is a known chemoattractant for neutrophils and has been implicated in the inflammatory process of both human and experimental murine BP. We have recently shown that antibodies to BP180 mediate a dose and time-dependent release of IL-6 and IL-8 from cultured normal human epidermal keratinocytes (NHEK). In the present study, we addressed the question whether dapsone or nicotinamide influence this cytokine release. We demonstrate that dapsone, but not nicotinamide, in its pharmacological range, inhibits the IL-8, but not the IL-6 release from NHEK, induced by anti-BP180 IgG, in a dose-dependent fashion as detected by ELISA. IL-8 mRNA levels, as determined by RT-PCR, were the same in cells treated with BP IgG alone compared to cells treated with BP IgG plus dapsone. This observation suggests that dapsone inhibits the BP IgG-induced IL-8 release from cultured NHEK by mechanisms at the post-transcriptional level. Our findings contribute to the understanding how dapsone leads to a reduced influx of neutrophils into BP lesions and, finally, to the cessation of blister formation in this disease.

Animals↗

Cutaneous involvement of dermatomyositis can respond to Dapsone therapy.

BACKGROUND: Dapsone (4,4-diaminodiphenylsulfone) is a sulfone antibiotic used in the treatment of leprosy, but dermatologists more commonly utilize its anti-inflammatory properties particularly directed against leukocytes to treat various bullous disorders, erythema nodosum, pyoderma gangrenosum, Sweet's syndrome, cutaneous vasculitis, and cutaneous forms of lupus erythematosus. The cutaneous manifestations of dermatomyositis are often resistant to antimalarial and immunosuppressive therapies. METHODS: Two patients with cutaneous dermatomyositis unresponsive to combination therapy with prednisone, hydroxychloroquine, quinacrine, and immunosuppressive medications had Dapsone added to their therapy. RESULTS: Both patients showed rapid improvement with the addition of Dapsone. Each had an exacerbation of their cutaneous dermatomyositis on Dapsone with withdrawal and subsequent improvement when the Dapsone was reinstituted. CONCLUSIONS: Dapsone therapy for cutaneous dermatomyositis may have a wider role in treatment for these patients refractory to prednisone and antimalarial therapy.

Adult↗

Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. The PRIO Study Group.

BACKGROUND: Pneumocystis carinii pneumonia and toxoplasmic encephalitis are frequent life-threatening opportunistic infections in patients with human immunodeficiency virus (HIV) infection. Primary prophylaxis against P. carinii pneumonia is now common, but there are few data on regimens for primary prophylaxis against toxoplasmosis. METHODS: We conducted a randomized trial that compared two prophylactic regimens: dapsone (50 mg per day) plus pyrimethamine (50 mg per week) was compared with aerosolized pentamidine (300 mg per month). The patients had symptomatic HIV infection, no history of P. carinii pneumonia or symptomatic toxoplasmosis, and CD4+ counts below 200 per cubic millimeter (0.2 x 10(9) per liter). RESULTS: In an intention-to-treat analysis, after a median follow-up of 539 days P. carinii pneumonia developed in 10 patients in each group, whereas toxoplasmosis developed in 32 of 176 patients in the pentamidine group and 19 of 173 patients in the dapsone-pyrimethamine group. Those assigned to pentamidine had a risk of P. carinii pneumonia that was similar to the risk in those assigned to dapsone-pyrimethamine (adjusted relative risk, 1.13; 95 percent confidence interval, 0.44 to 2.92; P = 0.79), but a higher risk of toxoplasmosis (adjusted relative risk, 1.81; 95 percent confidence interval, 1.12 to 2.94; P = 0.02). Among the 262 patients with serologic evidence of past exposure to Toxoplasma gondii, the relative risk of symptomatic toxoplasmosis was 2.37 times higher in those assigned to pentamidine (95 percent confidence interval, 1.3 to 4.4; P = 0.006). More patients discontinued dapsone-pyrimethamine than pentamidine because of toxicity (42 vs. 3; P < 0.001). Survival was similar in the two groups. CONCLUSIONS: For primary prevention of P. carinii pneumonia, dapsone-pyrimethamine is as effective, though not as well tolerated, as aerosolized pentamidine. Dapsone-pyrimethamine also prevents first episodes of toxoplasmosis.

AIDS-Related Complex↗

Hidradenitis suppurativa treated with dapsone: A case series of five patients.

OBJECTIVE: To evaluate the efficacy of dapsone in the treatment of hidradenitis suppurativa refractory to therapy with oral antibiotics and isotretinoin. METHODS: A retrospective review was performed of five patients treated with dapsone between 2002 and 2005. Clinical improvement and adverse events were recorded by the physician. Patients were asked to retrospectively rate their symptoms prior to and after starting dapsone. RESULTS: Improvement was noted in all five patients within 4-12 weeks at doses ranging between 25 and 150 mg/day. All patients required maintenance therapy with dapsone at doses between 50 and 150 mg/day to sustain their disease control. Patient-reported symptoms improved in all cases after dapsone initiation, supporting physician observed clinical improvement. Treatment was well tolerated in all patients with no significant adverse effects noted. The median follow-up period was 24 months. CONCLUSION: Dapsone appears to be an effective and safe alternative therapeutic option for hidradenitis suppurativa and may be particularly useful for women in the reproductive age group.

Adult↗

High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis.

Chemoprophylaxis for Pneumocystis carinii pneumonia (PCP) is routinely given after allogeneic blood or marrow transplantation. We evaluated the effectiveness of dapsone prophylaxis (50 mg orally twice daily, 3 times per week) compared with twice-weekly trimethoprim-sulfamethoxazole (TMP-SMZ) in preventing PCP after allogeneic blood or marrow transplantation. Patients included all (n=646) who received allogeneic blood or marrow transplants between 1 September 1993 and 31 December 1996 who survived at least 100 days after transplantation. A cohort of 111 dapsone recipients was compared with the remaining 535 who received TMP-SMZ. Ten patients developed PCP; 8 were taking dapsone. PCP incidence in the TMP-SMZ cohort was 0.37% versus 7.2% for dapsone. The relative risk for PCP associated with dapsone use was 18.8 (P<.001) and was not accounted for by age, clinical extensive chronic graft-versus-host disease, donor source, or malignant relapse. Dapsone prophylaxis at this dosage is associated with significantly higher rates of PCP than is TMP-SMZ after allogeneic marrow transplantation. We advise caution in prescribing alternatives to TMP-SMZ prophylaxis in this setting.

Adult↗

Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review.

Dapsone, with or without trimethoprim or pyrimethamine, has strong anti-Pneumocystis carinii activity, as demonstrated by in vitro methods, animal studies, and clinical trials. The drug blocks folic acid synthesis of P. carinii by inhibition of dihydropteroate synthetase activity. Dapsone is efficiently absorbed (70%-80%) from the gastrointestinal tract, reaches peak serum concentration in 2-6 hours, and is adequately distributed to the fluid of the alveolar spaces. Synergistic effects against P. carinii are noted when trimethoprim is combined with dapsone. This combination is recommended for therapeutic use for P. carinii pneumonia (PCP) as an alternative for patients who cannot take trimethoprim-sulfamethoxazole (TMP-SMZ). Evidence from more than 40 studies of dapsone as prophylaxis for PCP in AIDS patients shows that dapsone, either alone or in combination with pyrimethamine, is as effective as aerosolized pentamidine or atovaquone but slightly less effective than TMP-SMZ. Adverse effects include rash, anemia, methemoglobinemia, agranulocytosis, and hepatic dysfunction. Desensitization can be accomplished with many cases. Dapsone is the most cost-effective prophylaxis currently available for PCP.

Animals↗

In-vitro activity of atovaquone, sulphamethoxazole and dapsone alone and combined with inhibitors of dihydrofolate reductase and macrolides against Pneumocystis carinii.

The anti-Pneumocystis carinii activity of atovaquone, dapsone and sulphamethoxazole alone and combined with dihydrofolate reductase (DHFR) inhibitors and macrolides was investigated against five clinical isolates of P. carinii. The susceptibility tests were performed by inoculation of the organisms on to cell monolayer and parasite count after 72 h incubation at 37 degrees C. Culture plates were added to Dulbecco's modified Eagle's medium containing serial dilutions of atovaquone, dapsone and sulphamethoxazole alone or in combination with diaveridine, pyrimethamine, trimethoprim, azithromycin, clarithromycin and roxithromycin. Atovaquone, dapsone and sulphamethoxazole were found to be effective at levels well below the concentrations that could be achieved clinically, while DHFR inhibitors were shown to combine effectively with dapsone and sulphamethoxazole. No synergy could be demonstrated between atovaquone and DHFR inhibitors or macrolides. A mild synergic effect was noted when macrolides were combined with dapsone and sulphamethoxazole. Pyrimethamine (0.5 mg/L) combined with dapsone and trimethoprim (0.5 mg/L) combined with sulphamethoxazole exerted the strongest inhibitory effect.

Anti-Bacterial Agents↗

Toxicity and efficacy of daily vs. weekly dapsone for prevention of Pneumocystis carinii pneumonia in children infected with human immunodeficiency virus. ACTG 179 Study Team. AIDS Clinical Trials Group.

BACKGROUND: Dapsone is an alternative drug for Pneumocystis carinii pneumonia (PCP) prophylaxis in individuals intolerant to trimethoprim-sulfamethoxazole (T/S). There are, however, few data on the pharmacokinetics, toxicity or efficacy of dapsone in children. Design. Randomized, multicenter trial comparing daily (1 or 2 mg/kg) with weekly (4 mg/kg) dapsone regimens in 94 HIV-infected children intolerant to T/S. METHODS: Hematologic and hepatic toxicity was monitored, as well as the occurrence of skin rash, PCP or death. RESULTS: Initial pharmacokinetic data indicated that adequate serum dapsone concentrations were not achieved with the daily 1-mg/kg regimen; the daily dose was then increased to 2 mg/kg. Both short and long term hematologic toxicities were marginally greater in children receiving the daily 2 mg/kg compared with the weekly regimen. Allergic skin rashes were similar in children receiving the daily and weekly regimens (17% in both) and were not associated with prior history of rash with T/S. PCP occurred most frequently with the daily 1-mg/kg regimen (22.0 cases/100 patient years), least frequently with the daily 2-mg/kg regimen (0 case/100 patient years) and at intermediate frequency with the weekly regimen (9.5 cases/100 patient years). More deaths were observed in patients receiving the daily than the weekly regimen (8 vs. 2, respectively), although the deaths were not directly attributable to dapsone treatment. CONCLUSION: Although a weekly dapsone regimen of 4 mg/kg produced less hematologic toxicity than a daily regimen of 2 mg/kg, this advantage was offset by a trend toward higher breakthrough rates of PCP.

AIDS-Related Opportunistic Infections↗

Dapsone- and primaquine-induced methemoglobinemia in HIV-infected individuals.

Clinically significant methemoglobinemia can develop as a result of medications. Although dapsone and primaquine are known to produce methemoglobinemia in susceptible individuals, methemoglobinemia has been reported only rarely in the human immunodeficiency virus (HIV) population. We describe five cases of methemoglobinemia caused by either primaquine or dapsone alone or in combination. The initial methemoglobin level ranged from 15.3% in the patient whose methemoglobinemia was caused by primaquine alone to 33.1%. Five patients developed symptomatic methemoglobinemia requiring hospitalization for 1 to 12 days. Two cases resulted from intentional overdoses of dapsone, and three developed within several days of commencing primaquine while dapsone remained present in the bloodstream. The four severe cases required intravenous methylene blue, supplemental oxygen, plus erythrocyte transfusions, whereas the mild case responded to oxygen therapy plus discontinuation of the precipitating drugs. Blood gases and pulse oximetry do not aid in the diagnosis, which requires cooximetry. Our study indicates that dapsone and primaquine alone or in combination can produce clinically significant methemoglobinemia in HIV-infected individuals, either in the setting of an overdose or when primaquine is instituted before dapsone has been cleared from the bloodstream.

AIDS-Related Opportunistic Infections↗

Dapsone therapy for children with immune thrombocytopenic purpura.

Dapsone has been shown to be effective in treating adults with immune thrombocytopenic purpura (ITP). This retrospective review describes the authors' experience using dapsone in children with refractory, symptomatic ITP. Seven children were treated with dapsone. Dapsone was discontinued in two patients because of methemoglobinemia. In the remaining five patients, three achieved platelet counts of more than 100 x 10(3)/microL. Discontinuation resulted in a rapid decline in platelet counts in all three patients. Two of the three responded to a second round of treatment. Additional study of dapsone in children is warranted. Children receiving dapsone should be monitored for methemoglobinemia.

Adolescent↗

Dapsone in Behçet's disease: a double-blind, placebo-controlled, cross-over study.

The study was designed to investigate the effects of dapsone in the treatment of mucocutaneous manifestations of Behçet's disease and the possible prophylactic role of dapsone in a double blind/placebo controlled clinical trial. Twenty patients diagnosed according to the International Study Group criteria as Behçet's disease were included in the study. Patients were randomly allocated to receive either dapsone 100 mg daily or placebo for three months in a double-blind manner. After three months, patients were crossed over and followed for a further three months. Patients were followed up in each visit by assessing the number, size, duration and frequency of oral and genital ulcers, other cutaneous manifestations, and systemic manifestations of the disease. A pathergy test was done on each visit. Laboratory investigations included hemoglobin concentration, white blood cell count, ESR, and C-reactive protein. In dapsone-treated patients, there were significant reductions in the oral and genital ulcer parameters as well as the incidence of other cutanous and systemic manifestations. In the placebo-treated group, there were no significant changes in these parameters. The pathergy test result as well as those of other laboratory tests were all decreased in the dapsone-treated group. Although this study was a small scale study, it shows that dapsone was effective in treatment of mucocutaneous manifestations of Behçet's disease and possibly in prophylaxis against systemic manifestations of the disease. This result should lead to a larger scale study with a longer duration of follow-up.

Administration, Oral↗

Dapsone hypersensitivity syndrome: a clinico-epidemiological review.

Diaminodiphenyl sulphone (dapsone) is a drug of choice in the treatment of leprosy. It is also useful for the treatment of many neutrophilic and other dermatoses. Dapsone hypersensitivity syndrome is a rare but well recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepato-splenomegaly. Twenty-six patients with dapsone hypersensitivity syndrome were studied for clinical profile, outcome, and prognosis. The male:female ratio was 2.2:1, and the mean age was 33.19 years (range 13 to 64 years). The interval between start of dapsone therapy and appearance of symptoms varied from 2-7 weeks (mean 29.82 days). Twenty-four patients received dapsone as a part of multi-drug therapy for leprosy; the other two patients received dapsone for lichen planus and acne vulgaris. Exfoliative dermatitis was the most common cutaneous manifestation followed by erythematous maculo-papular eruption and Stevens-Johnson syndrome-like lesion. The other common systemic manifestations were: fever (26 cases), itching (22 cases), lymphadenopathy (21 cases), jaundice (21 cases), pallor (20 cases), hepatomegaly (19 cases), and pedal edema (14 cases). Investigation profile revealed elevated levels of serum liver enzymes in 100% of patients, elevated erythrocyte sedimentation rate in 92.3%, raised bilirubin in 84.6%, leucocytosis in 69.23%, low hemoglobin (<9 gm/dl) in 46.15% and hypoproteinemia in 42.3%. Eosinophilia, hemolytic anemia, and reticulocytosis count were found in 4 patients each. All the patients had favorable outcomes except three who died due to hepatic failure. Medical personnel must be aware of this potentially fatal syndrome, because it can cause considerable morbidity and mortality.

Adolescent↗