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PubMedDate not supplied

[What do we know today about diaminodiphenylsulfone?].

INTRODUCTION: Diaminodiphenylsulfone or dapsone is a chemical analogue of sulfapyridine, synthesized in 1908. Dapsone is a bacteriostatic agent that proved to be efficient in treating leprosy and malaria, but today it is used in treating dermatologic noninfectious inflammatory diseases. PHARMACOLOGY: Dapsone is orally used in a dose of 50-400 mg per day in treatment of dermatologic diseases, and also in a dose of 50-100 mg per day in leprosy treatment. Dapsone is mainly eliminated from the body by urine and smaller part by faeces. Pharmacological interaction was reported when it is used with rifampicin and probenecid. MECHANISM OF ACTION: The bacteriostatic effect of dapsone is well known. It involves inhibition of folic acid synthesis in susceptible organisms. The anti-inflammatory effect of dapsone, which proves to be efficient in treating noninfectious inflammatory diseases, has not been explained completely yet. There are some pieces of evidence that anti-inflammatory action is not connected with its antibacteriological action. CLINICAL USE: Based on previous studies about therapy efficiency of dapsone in treating some diseases, there are two groups of diseases: the group responding well to dapsone (leprosy, malaria, DH, linear IgA-dermatosis, erythema elevatum diutinum, bullous systemic lupus erythematosus) and a group responding with average good response to dapsone (pyoderma gangrenosum, bullous and cicatricial pemphigoid, acne conglobata, discoid cutaneous lupus erythematosus, subcorneal pustulosis dermatosis, granuloma faciale, rheumatoid arthritis, polychondritis, leucocytoclastic vasculitis). ADVERSE EFFECTS: Adverse effects depend on the dose and they rarely occur at doses less than 100 mg per day. They are mainly shown on skin, nervous system, digestive system, hepatobiliary system, and kidney and hematologic system. The most important adverse effects are hemolytic anaemia and methemoglobinemia. Hemolysis usually occurs at doses of 200 mg and more per day. In patients with glucose-6-phosphate dehydrogenase deficiency, hemolysis may be provoked by a dose less than 50 mg per day. For prevention, before using dapsone in therapy, clinical examination with history, blood parameters, liver and renal parameters and determination of glucose-6-phosphate dehydrogenase level are recommended. CONCLUSION: The use of dapsone is absolutely indicated in DH treatment and erythema elevatum diutinum. Because of anti-inflammatory effects, dapsone can also be used in treating other inflammatory noninfectious dermatoses when one should take care about "therapy efficiency/adverse effect" balance using the correct dose, monitoring relevant clinical and laboratory parameters and educating patients.

Anti-Infective Agents↗
PubMed2004

Effector-mediated alteration of substrate orientation in cytochrome P450 2C9.

Cytochrome P450 2C9 (CYP2C9)-mediated flurbiprofen 4'-hydroxylation is activated by the presence of dapsone resulting in reduction of the K(m) for flurbiprofen hydroxylation and an increase in V(m). Previous spectral binding studies have demonstrated that the binding of flurbiprofen with CYP2C9 is increased (decrease in K(S)) by the presence of dapsone. We hypothesized that the two compounds are simultaneously in the active site with the presence of dapsone causing flurbiprofen to be oriented more closely to the heme. T(1) relaxation rates determined by NMR were used to estimate the distances of protons on these compounds from the paramagnetic heme-iron center. Samples contained 0.014 microM CYP2C9 and 145 microM flurbiprofen in the presence and absence of 100 microM dapsone. Estimated distances of various flurbiprofen protons from the heme ranged from 4.2 to 4.5 A in the absence of dapsone and from 3.2 to 3.8 A in the presence of dapsone. The 4' proton of flurbiprofen, the site of metabolism, showed one of the greatest differences in distance from the heme in the presence of dapsone, 3.50 A, as compared to the absence of dapsone, 4.41 A. Dapsone protons were less affected, being 4.40 A from the heme in the absence of flurbiprofen and 4.00-4.01 A from the heme in the presence of flurbiprofen. Molecular modeling studies were also performed to corroborate the relative orientations of flurbiprofen and dapsone in the active site of CYP2C9. Shift of the 4' proton of flurbiprofen closer to the heme iron of CYP2C9 in the presence of dapsone may play a role in activation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Comparison of dosages, intervals, and drugs in the prevention of Pneumocystis carinii pneumonia.

The efficacies of trimethoprim (TMP)-sulfamethoxazole (SMZ), TMP-dapsone, dapsone, and pentamidine were compared for the prevention of Pneumocystis carinii pneumonia in the corticosteroid-treated-rat model. While 11 (73%) of 15 untreated control animals had P. carinii pneumonia after 10 weeks of immunosuppression, none of the animals given 125 mg of dapsone per kg daily, weekly, biweekly, or monthly had evidence of infection. Of the 10 rats given a single dose of dapsone 23 and 50 days after immunosuppression was started, 5 (50%) had P. carinii pneumonia. When three drugs were given separately to groups of 10 rats in single doses biweekly, P. carinii pneumonia occurred in 40% of those treated with TMP-SMZ and in none of those treated with TMP-dapsone; although only 2 of those treated with pentamidine survived for evaluation, both had P. carinii pneumonia. The experiments showed that dapsone is highly effective in chemoprophylaxis for P. carinii pneumonia when given at monthly intervals or more frequently and that dapsone and TMP-dapsone are more effective than is TMP-SMZ when given at biweekly intervals. It seems reasonable to expect that biweekly doses of dapsone or TMP-dapsone would provide an effective and reasonably safe chemoprophylaxis regimen for patients at high risk for P. carinii pneumonia, and studies to test such a scheme are justifiable. Biweekly doses are preferred over monthly doses to allow for occasional inadvertent omission of doses expected from patients.

Amidines↗
PubMed1999

In vitro and in vivo activity of K-130, a dihydrofolate reductase inhibitor, against Mycobacterium leprae.

The antimicrobial effects of a new dihydrofolate reductase inhibitor, K-130 (2,4-diaminodiphenyl sulfone substituted 2,4-diamino-5-benzylpyrimidine), alone and in combination with dapsone (CAS 80-08-0) against both dapsone-sensitive and dapsone-resistant strains of Mycobacterium leprae were evaluated in vitro, in cell-free culture system, and in vivo, in mouse foot pads. The minimal inhibitory concentration of K-130 against dapsone-sensitive as well as dapsone resistant strains of M, leprae was 0.03 microgram/ml, and the activity was bactericidal in both cases. However, when combined with dapsone, K-130 exhibited synergism in case of dapsone-sensitive M. leprae, while in case of dapsone-resistant M. leprae, the effect was merely additive. Similar synergistic effects were also observed in the mouse foot pad system for both types of M. leprae strains.

Animals↗
PubMed1994

An international randomized study with long-term follow-up of single versus combination chemotherapy of multibacillary leprosy.

A total of 307 patients with lepromatous leprosy and borderline lepromatous leprosy were randomized to dapsone monotherapy or to one of two types of drug combinations. A 3-year treatment phase was followed by a 5-year observation phase. The evaluation included 233 patients for whom together there were 1,404 years of observation. A total of 1,956 blinded histopathological specimens were processed centrally. When entering the trial isolates from 13 patients (5.6%) showed dapsone resistance in the mouse footpad test, and these patients were evaluated separately. Dapsone monotherapy (68 patients) had the same frequency of cure as the combination of dapsone and rifampin (77 patients) or the four-drug regimen consisting of dapsone, rifampin, isoniazid, and prothionamide (75 patients). We did not find a significant difference in the clearance of bacteria either between the monotherapy and the two-drug combination or the monotherapy and the four-drug combination. Six months after the initiation of treatment, disease in 15% of the patients who received dapsone monotherapy but none of the patients who received combined treatment were clinically progressive. After another 1 to 9 months of treatment the disease in all patients was stable or regressive. There was no difference in the type or frequency of reactions. Only after the end of the scheduled observation phase three relapses were reported. All three treatment regimens well tolerated. Dapsone monotherapy is highly effective in the treatment of multibacillary leprosy under the conditions of well-controlled treatment. Combination regimens seem only to accelerate the regression of the active disease when they are compared with monotherapy with dapsone. The mouse footpad test does not reflect the clinical resistance and cannot be recommended for use in making therapeutic decisions.

Adolescent↗
PubMed1989

Clinical pharmacokinetic considerations in the treatment of patients with leprosy.

On the basis of the efficacy of the available agents, the World Health Organization has recommended only 4 drugs for combined chemotherapy of leprosy: rifampicin, dapsone, clofazimine and ethionamide/prothionamide. Thiacetazone and isoniazid are also used to a lesser extent by some physicians. Pyrazinamide may find a place in treating 'persister' bacilli. Dapsone is absorbed slowly after oral administration. Peak plasma drug concentration is reached at about 4 hours; absorption half-life is 1.1 hours; elimination half-life is about 30 hours. Oral availability is around 90%. Dapsone is approximately 70% protein-bound, while its monoacetylated metabolite is almost entirely bound. Dapsone crosses the placenta and is excreted into breast milk. It is metabolised via acetylation and N-hydroxylation, but acetylation polymorphism has no effect on dapsone handling by leprosy patients. Dapsone penetrates into sciatic nerves of experimental animals but its presence has not been demonstrated in Schwann cells. Oral doses of rifampicin are rapidly and completely absorbed. The bioavailability is greater when the drug is given before meals; peak concentrations occur at 1 to 2 hours. 80 to 90% of rifampicin is bound to plasma proteins, and the drug is found in saliva, cerebrospinal fluid and breast milk. Its main metabolite, desacetyl rifampicin, also exhibits antimycobacterial activity in tuberculosis. Rifampicin induces its own metabolism, as well as that of dapsone and steroids. Absorption of dapsone and rifampicin is reported to be reduced in leprosy patients. Clofazimine has been in use in leprosy treatment since 1960. In higher doses it exerts an anti-inflammatory action which is useful in treating leprosy patients in reaction. Oral absorption of the drug is slow and dose-dependent; faecal excretion also increases with dose. Single- and multiple-dose studies have shown a plasma half-life of around 10 days. Bioavailability of the drug is higher when given with food than when fasting; the peak plasma concentration occurs at 4 to 8 hours when the drug is administered with breakfast. After absorption, the drug is thought to circulate in protein-bound form, accounting for the fact that it is deposited in various tissues. Uneven distribution and prolonged retention in the tissues are special features of clofazimine metabolism. One unconjugated and 2 conjugated metabolites have been detected in urine, and the urinary excretion of both the parent compound and its metabolites is around 1% of the dose.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗
PubMed1983

Mutagenic activity of antileprosy drugs and their derivatives.

We tested the mutagenic activity of antileprosy drugs (clofazimine, ethionamide, prothionamide, prothionamide-S-oxide, rifampin, and dapsone and many of its derivatives) using the Ames Salmonella/microsome assay system. None of these, including N-acetylated and N-hydroxylated derivatives of dapsone, were found to be positive with or without metabolic activation of this test. However, the sulfoxide and sulfide analogs of dapsone were found to be mutagenic with metabolic activation. These two analogs could not be detected in pharmaceutical preparations of dapsone (less than 0.01%), nor could they be found (in either unconjugated or conjugated form) in urine from volunteers taking a single oral dose of 50 mg of dapsone or from patients receiving daily oral doses of 100 mg of dapsone. Also, urine concentrates from volunteers taking 50 mg of dapsone did not exhibit mutagenic activity in the Ames screen. These results indicate that patients receiving antileprosy therapy with clofazimine, dapsone, ethionamide, prothionamide, and/or rifampin are not being exposed to mutagenic (and thereby possible carcinogenic) drugs.

Clofazimine↗
PubMed2005

[Cicatricial pemphigoid: treatment with mycophenolate mofetil].

BACKGROUND: The severity of cicatricial pemphigoid (CP) varies. First-intent treatment of mild or moderate cases is dapsone. In life or sight-threatening cases, intravenous cyclophosphamide pulses are efficient but may have digestive side effects and imply repeated hospitalizations. Mycophenolate mofetil (MMF) is an oral and well tolerated immunosuppressant agent which has proved its efficacy in pemphigus and some bullous pemphigoid. In CP, encouraging case reports have been previously published. We report herein a retrospective study about 14 patients who have received MMF since 2000. PATIENTS AND METHODS: There were 5 men and 9 women, with a mean age of 69 years. MMF was introduced in 3 different clinical situations: immediately in relay to cyclophosphamide in 7 patients with severe CP (group I); in case of a mild-severe relapse at distance from with dranal of cyclophosphamide in 3 patients (group II); as first-intent immunosuppressant agent in 4 patients whose disease was not under control with high-dose dapsone, but not life - or sight-threatening (group III). In all these patients, the disease was invalidating and not controlled by dapsone +/- sulfasalazine, but did not threaten life or sight. The aim was to achieve satisfying control of the disease with an oral and well tolerated immunosuppressant agent, and to maintain good quality of life. The dose of MMF was 1.5 or 2 g per day. The criteria of MMF efficacy was the healing of previous lesions and the absence of new progressive lesions. RESULTS: MMF was efficient in obtaining or maintaining a good control of the disease in 10/14 patients, as long as the underlying treatment with dapsone (2 mg/kg/d) was maintained. In 7/10 cases, it was possible to decrease the dapsone dose in order to improve hematological tolerance. In the 3 other cases, a relapse occurred when the dose of dapsone was decreased. MMF was inefficient in controling the disease in 4/14 patients (29 p. 100). Clinical and biological tolerance of MMF was good in 13/14 patients. DISCUSSION: In this series, MMF was proposed to heterogenous patients, who presented at that time a mild-moderate disease and for whom we wanted in improve the quality of life. MMF seems to be an interesting drug, capable of obtaining or maintaining satisfactory control of the disease and permitting the decrease of dapsone doses in some mild-severe CP. However MMF must not replace cyclophosphamide in severe sight or life-threatening forms of CP.

Administration, Oral↗