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PubMed1995

Effects of the antacids in didanosine tablets on dapsone pharmacokinetics.

OBJECTIVE: To investigate 1) the effects of the magnesium-aluminum antacids in didanosine tablets on dapsone absorption in healthy volunteers and 2) the effects of the antacid formulation of active didanosine tablets on dapsone pharmacokinetics in patients seropositive for human immunodeficiency virus (HIV). DESIGN: Two separate, randomized, two-period, two-treatment, crossover studies with a 21-day washout period between treatments. SETTING: Clinical investigation unit of a university hospital. PARTICIPANTS: Six healthy men and six HIV-positive men. MEASUREMENTS: Serial dapsone plasma concentrations were measured when dapsone, 100 mg, was administered alone and with either the third of four doses of didanosine placebo tablets (group 1) or the 27th of 28 doses of active didanosine tablets (group 2). In each study, pharmacokinetic variables were determined using noncompartmental methods and compared by analysis of variance. RESULTS: When dapsone was administered alone, pharmacokinetic variables did not significantly differ from those with dapsone given in either combination (P > 0.10 for all comparisons). CONCLUSIONS: Didanosine, antacids, and other excipients in the currently used didanosine chewable tablets did not significantly affect plasma concentrations of dapsone.

Absorption↗
PubMed1992

Dapsone syndrome in Vanuatu: a high incidence during multidrug treatment (MDT) of leprosy.

Side-effects of leprosy treatment with dapsone are said to be uncommon, with drug allergy occurring in only one of every several hundred patients treated with dapsone. The dapsone or sulphone syndrome (DDS) has been recognized since the earliest days of sulphone therapy but until recently its incidence had been decreasing. In Vanuatu, during the years 1988-1991, nine leprosy patients have developed the dapsone syndrome, four of whom have died. During the last 4 years only 37 patients were started on treatment, which is an incidence of the dapsone syndrome of 24% with a fatality rate of 11%. All the patients were being given multi-drug treatment (MDT) of daily dapsone (100 mg) and clofazimine (50 mg) and monthly rifampicin (600 mg) and clofazimine (300 mg). There has been speculation that the increased incidence of what was previously described as a rare reaction is due to the use of MDT, and the reasons for this are discussed. We feel the increase in the number of reactions in Vanuatu since starting MDT is probably due to the high starting dose of 100 mg of dapsone, possibly enhanced by the combination with clofazimine and rifampicin and a genetic susceptibility of the Melanesian population.

Adolescent↗
PubMed1992

Oral dapsone versus nebulized pentamidine for Pneumocystis carinii pneumonia prophylaxis: an open randomized prospective trial to assess efficacy and haematological toxicity.

OBJECTIVE: To compare the haematological toxicity and efficacy of oral dapsone and nebulized pentamidine as Pneumocystis carinii pneumonia (PCP) prophylaxis in HIV-infected patients receiving zidovudine. DESIGN: Randomized, prospective. SETTING: Infectious diseases hospital with participants drawn from both inpatient and outpatient departments. PATIENTS: Those eligible were starting treatment with zidovudine, needed PCP prophylaxis (CD4+ count < 200 x 10(6)/l or < 20% total lymphocyte count or previous episode of PCP), and had a normal glucose-6-phosphate dehydrogenase screen. Of the 98 patients enrolled, 96 returned for follow-up. INTERVENTIONS: Fifty patients received dapsone (100mg orally twice weekly) and 46 pentamidine (400 mg nebulized monthly). Follow-up was for a median of 18 months. MAIN OUTCOME MEASURES: The development of PCP, transfusion requirements, monthly complete blood cell counts, serious adverse reactions and death were recorded. RESULTS: Nine (18%) dapsone and eight (17%) pentamidine recipients developed PCP. There was no significant difference in number of patients transfused (12 dapsone and nine pentamidine recipients) or transfusion-free survival. At exit from the study, mean haemoglobin (11.7 versus 12.4 g/dl), white blood cell (3.9 versus 3.7 x 10(9)/l) and platelet (195 versus 184 x 10(9)/l) counts did not differ for the dapsone and pentamidine arms, respectively. There was no significant difference in the occurrence of serious adverse reactions (six in the dapsone and eight in the pentamidine arm). CONCLUSIONS: Dapsone can be recommended in preference to pentamidine as PCP prophylaxis on the basis of equivalent efficacy, absence of excessive haematological toxicity, low cost and ease of administration.

AIDS-Related Opportunistic Infections↗
PubMed1991

Reassessment of dapsone as a marker of acetylator phenotypes.

The ratio of metabolite to parent dapsone concentrations at 3 hours after dosing has been used as a marker of acetylator phenotypes. The absorption of dapsone is somewhat erratic with peak concentrations often found after the 3-hour determination. The present study done in 30 healthy, male volunteers compared ratios of metabolite to parent dapsone concentrations 3 hours after dosing with AUC values calculated during a 24-hour period as well as extrapolated to infinity. A single oral dose of 100 mg of dapsone was given to fasting subjects and serial blood samples were obtained over a 24-hour period and assayed by high-performance liquid chromatography for parent and acetylated metabolite. Dapsone pharmacokinetic parameters of AUC (23.4 +/- 8.6 micrograms.h/ml), half-life (24.8 +/- 11.5 hours) and apparent clearance values (81 +/- 30 ml/min) were consistent with those reported previously. Using established criteria for acetylation phenotyping, 20 percent of the subjects (6 of 30) demonstrated rapid acetylation. Bimodality in the ratios, independent of the experimental indices used to differentiate genetic metabolism, was not readily apparent. The data suggest that large variability in the pharmacokinetics of dapsone may sufficiently obscure the evidence of polymorphic metabolism. The use of dapsone as a marker of acetylator phenotyping should be limited to patient populations.

Acetylation↗
PubMed1988

Influence of acetylator phenotype of the leprosy patient on the emergence of dapsone resistant leprosy.

The half time of disappearance of dapsone and monoacetyl dapsone and the acetylator phenotype of the leprosy patients who harboured dapsone sensitive and dapsone resistant M. leprae was assessed in 27 subjects. Sixteen patients were rapid acetylators, five were slow and six were intermediate acetylators. The mean T 1 1/2 lives of dapsone (30.26 +/- 11.0) and monoacetyl dapsone (31.11 +/- 12.0) were also studied in the above patients. The percentage of different acetylators in both resistant and sensitive groups were similar showing no correlation between the emergence of drug resistance and the phenotype of the patient. The mean time of disappearance of DDS and MAD in the different acetylators did not show significant difference. The ratios of MAD/DDS in an individual at 3, 6 or 24 hours after the dose were similar. The mean T 1 1/2 lives of DDS and MAD in resistant and sensitive patients also showed no difference. Neither T 1 1/2 lives of DDS or MAD nor the acetylator phenotype seem to influence the emergence of dapsone resistance.

Acetylation↗
PubMed1988

Metabolism of dapsone to a hydroxylamine by human neutrophils and mononuclear cells.

Dapsone is an effective anti-inflammatory agent in conditions in which inflammation is mediated by neutrophils. Dapsone also has been associated with agranulocytosis. We found that neutrophils, which had been activated by a phorbol ester or opsonized zymosan, oxidized dapsone to its nitroderivative. It appears as if this is due to oxidation of dapsone by myeloperoxidase to the hydroxylamine, followed by nonenzymatic oxidation of the hydroxylamine to the nitroderivative. The hydroxylamine can be isolated if ascorbic acid is added to the incubations. Monocytes also contain myeloperoxidase and activated mononuclear leukocytes also metabolize dapsone to the hydroxylamine. Dapsone also causes a mononucleosis-like syndrome. The reactive hydroxylamine could be responsible for both the pharmacologic and toxic properties of dapsone.

Anti-Inflammatory Agents↗
PubMed1983

Sex differences in the absorption of dapsone after intramuscular injection.

A trial was performed with a long-acting dapsone (DDS) injection, consisting of an aqueous suspension of dapsone crystals, in doses of 900 mg and 1200 mg. Forty-one Ethiopian leprosy patients, 13 women and 28 men, participated in the study. There appeared to be a large discrepancy in the serum concentration curves of dapsone between men and women. Following injection of 900 mg dapsone in men, a peak of 2.28 +/- 1.06 micrograms/ml (mean +/- S.D.) was observed in the first week. After two weeks the serum concentrations had fallen to 0.42 +/- 0.29 micrograms/ml, and after four weeks they fell to 0.11 +/- 0.09 micrograms/ml. Following injection in women, the curves were smooth with a peak in the first week of only 1.04 +/- 0.40 micrograms/ml, while the serum concentrations after four weeks were still 0.42 +/- 0.23 micrograms/ml. The differences between the mean curves of men and women were statistically significant (p less than 0.001). The 1200 mg dapsone injections were only given to men. The explanation of the sex difference in intramuscular absorption can probably be found in the differences in the thickness of gluteal fat in men and women. In these Ethiopian leprosy patients, the non-protein-bound fraction of dapsone comprised 17 +/- 4%. In saliva, 19.5 +/- 7.0% of the dapsone level in serum was found. Methemoglobin levels were raised but did not reach levels of clinical importance. No other significant side effects were observed.

Absorption↗
PubMed1995

Protective effect of fluoroquinolones on dapsone induced erythrolysis.

Various quinolones have varied effects on the preservative activity of blood cells. Nalidixic acid causes hemolysis in G-6PD deficient patients where as ofloxacin has been found to possess preservative action of WBCs. The present study was undertaken to see the effect of various fluoroquinolones on RBC membrane. The effect of quinolones like ciprofloxacin, ofloxacin and norfloxacin and nalidixic acid in the dose of 5 micrograms/ml was studied on dapsone induced, in vitro hemolysis of rabbit RBC, using the osmotic fragility test. The mean corpusular fragility (MCF) with various agents were as follows: (mean +/- SE) saline; 5.23 +/- 0.21; dapsone, 6.57 +/- 0.23; ofloxacin, 3.81 +/- 0.13; ofloxacin and dapsone, 5.13 +/- 0.11; nalidixic acid, 6.28 +/- 0.16; nalidixic acid and dapsone, 6.65 +/- 0.13; ciprofloxacin, 3.52 +/- 0.22; ciprofloxacin and dapsone, 4.80 +/- 0.2; norfloxacin, 1.97 +/- 0.23; norfloxacin and dapsone, 4.27 +/- 0.20. The MCF data and shift of the osmotic fragility curves (to the left) show that dapsone induced erythrolysis is significantly protected by ciprofloxacin, ofloxacin and norfloxacin but not by nalidixic acid.

Animals↗
PubMed1996

Relationship between high incidence of adverse dapsone reactions and slow acetylate phenotype or low plasma/lymphocyte glutathione level.

OBJECTIVE: To investigate the relationship between high incidence of adverse dapsone reactions in acquired immunodeficiency syndrome (AIDS) patients and slow acetylate phenotype or low plasma/lymphocyte glutathione level of these patients. METHODS: Twenty-one cases of advanced AIDS patients (CD4 < 200/microliter) were involved in this study, all Europeans except one black, were acetylate phenotyped via analysis of caffeine metabolites, named 5-Acetylamino-6-formylamino-3-methyluracil, 1-Methylxanthine and 5-Acetylamino-6-amino-3-methyluracil, in human urine collected 2 hours after a cup of caffeine-spiked coffee and their plasma/lymphocyte glutathione concentrations were determined, by high performance liquid chromatographic method. RESULTS: Of the 21 AIDS patients, 15 are slow acetylators, accounting for 74.8%. One of 6 rapid acetylators has adverse dapsone reactions, acounting for 17%, compared with 46% for slow acetylators (7/15). The concentrations of glutathione in plasma/lymphocyte (6.97 +/- 0.95 mumol and 28.75 +/- 2.78 nmol/mg protein) in AIDS patients with adverse dapsone reactions are significantly lower than those (10.90 +/- 1.45 mumol and 32.15 +/- 2.21 nmol/mg protein) of AIDS patients without adverse dapsone reactions, and also than those (11.85 +/- 1.83 mumol and 33.76 +/- 2.32 nmol/mg protein) of health controls. CONCLUSIONS: Slow acetylators, which lead to accumulation of toxic dapsone metabolites and those subjects who are lower in glutathione level in plasma/lymphocyte because of certain kind of diseases as advanced AIDS are risk population of adverse dapsone reactions. Routinely determining human acetylate phenotype status might be helpful in adjusting and modifying dapsone dosage regimen.

Acetylation↗
PubMed1997

Comparison of the metabolism and toxicity of dapsone in rat, mouse and man.

The metabolism and toxicity of dapsone was compared in vitro and in vivo in rat, mouse and man. Metabolism was assessed by high-pressure liquid chromatography-mass spectrometry and methemoglobin formation has been used as a toxic endpoint. The greatest toxicity in vitro was seen in microsomes prepared from male Wistar rats (36.6 +/- 1.5% methemoglobin), although toxicity was also seen in microsomes from the female rat (8.2 +/- 1.3%), male CD1 (4.2 +/- 1.6%) and human (10. 9 +/- 1.1%). The rank order of toxicity agreed with the formation of the hydroxylamine metabolite in vitro. All microsomes were also capable of catalyzing the reverse reaction, i.e., reduction of the hydroxylamine to dapsone. However, in vivo administration of dapsone resulted in significant (P < 0.05) methemoglobinemia only in male rats and humans. This species difference in the susceptibility to dapsone toxicity could not be attributed solely to the sensitivity of the target erythrocytes, because the order of sensitivity to dapsone hydroxylamine was human > mouse > rat. Analysis of bile and urine revealed the formation of dapsone hydroxylamine and its glucuronide in male rats and humans, but not in female rats or mice. This species difference in the metabolism and toxicity of dapsone has important implications in the safety evaluation of related compounds for man.

Acetylation↗
PubMed1997

Neuroprotective effect of dapsone against quinolinate- and kainate-induced striatal neurotoxicities in rats.

We tested the ability of dapsone, a well-known antibiotic and antiinflammatory drug, to attenuate both the quinolinic acid (an NMDA agonist of glutamate receptors)- and kainic acid (a non-NMDA agonist of glutamate receptors)-induced in vivo neurotoxicities in rats. Circling behaviour and striatal gamma-aminobutyric acid (GABA) depletion were considered as behavioural and neurochemical end-points of brain toxicity. Rotation behaviour, evaluated six days after the intrastriatal injection of quinolinic acid (130 +/- 19 ipsilateral turns/hr), was attenuated by doses of 12.5 mg/kg and 25 mg/kg of dapsone (50 +/- 9 and 63 +/- 9 turns/hr, respectively). Striatal GABA levels (237.3 +/- 15.1 micrograms/g in control rats), found depleted at day 7 after quinolinic acid (98.3 +/- 8.6 micrograms/g), were also protected by dapsone at doses of 12.5 and 25 mg/kg (167.7 +/- 19.5 and 236.4 +/- 46.6 micrograms/g, respectively). No protective effects were observed on quinolinic acid-induced neurotoxicity, as evaluated by both parameters, at lower doses of dapsone (6.25 and 9.375 mg/kg). The action of dapsone, at the dose of 12.5 mg/kg, was also measured on kainic acid-induced depletion of the striatal GABA levels. Animals treated with dapsone + kainic acid (182.8 +/- 27.1 micrograms/g) showed significant attenuation of GABA depletion, as compared to rats treated with kainic acid alone (122.2 +/- 19.9 micrograms/g). These findings provide evidences to suggest that dapsone is acting as a neuroprotective agent against excitotoxicity induced by glutamate receptor agonists.

Animals↗
PubMed1997

Anti-inflammatory action of dapsone: inhibition of neutrophil adherence is associated with inhibition of chemoattractant-induced signal transduction.

Dapsone has clinical utility as an anti-inflammatory agent but the mechanism of this action remains unknown. We have previously reported that dapsone inhibits beta2 integrin (CD11b/CD18)-mediated adherence of human neutrophils in vitro and now describe studies designed to discover how dapsone-mediated inhibition of this neutrophil function occurs. Results indicate that dapsone interferes with the activation or function of the G-protein (Gi type) that initiates the signal transduction cascade common to chemotactic stimuli. They also show that dapsone-mediated suppression of this pathway inhibits the generation of second messengers essential to the activation of beta2 integrin molecules, as well as respiratory and secretory functions of neutrophils exposed to chemoattractants. We propose that the inhibition of chemoattractant-induced signal transduction by dapsone suppresses neutrophil recruitment and local production of toxic respiratory and secretory products in the affected skin of dermatitis herpetiformis and other neutrophilic dermatoses.

Anti-Infective Agents↗
PubMed1986

Sustained-release delivery systems, II: In vitro dissolution of 4,4'-sulfonylbisbenzamine (dapsone)--N-dodecanoyl-4,4'-sulfonylbisbenzamine comelts.

An approach under investigation in our laboratory is the development of slowly dissolving particles containing an active drug, mixed or coated with a less soluble derivative or derivatives, that may hydrolyze back to the active drug following solution. Such particles have potential for sustained release by a number of routes of administration, including intramuscular injection. In the present work, the in vitro dissolution of particles of 4,4'-sulfonylbisbenzamine (dapsone) (1) and various comelts of 4,4'-sulfonylbisbenzamine (dapsone) (1) and N-dodecanoyl-4,4'-sulfonylbisbenzamine (the monolauryl derivative of dapsone) (3) was studied using a continuous flow-through cell under laminar flow conditions. Dissolution of particles of dapsone showed a biphasic pattern when plotted according to the Hixson-Crowell cube root equation. Dissolution rates of dapsone (1) from the comelts were found to correlate with the physical state of 1 in the solid binary dispersion. Comelts of 1:3 with a content higher than 36.5% w/w 1 (the eutectic mixture) had initial rates of dissolution which appeared to be dependent on the porosity of the particles. However, once this initial phase passed, the total amount dissolved increased as the amount of noneutectic 1-rich solid solution in the comelt increased. This suggests that 1 in the eutectic mixture has a slower dissolution rate than when present in the noneutectic, or excess 1-rich solid solution form. The comelts with a content of dapsone at or below the eutectic mixture dissolved more slowly and their dissolution rates were less dependent on concentration of 1. The mechanism of release of 1 from 1:3 comelts appeared to be matrix diffusion-controlled.

Dapsone↗
PubMed1988

Influence of once-monthly rifampicin and daily clofazimine on the pharmacokinetics of dapsone in leprosy patients in Nigeria.

In leprosy patients in Nigeria the influence of daily clofazimine and of once-monthly rifampicin on the pharmacokinetics of dapsone has been investigated. Three days after rifampicin the elimination half-life of dapsone was reduced from 40.4 to 25.3 h (n = 23). Correspondingly, the plasma dapsone 24 h after the last dose had fallen significantly from 2.63 to 2.02 mg/l. Clofazimine did not cause change in the pharmacokinetics of dapsone. It was concluded that, although rifampicin had a considerable influence on the pharmacokinetics of dapsone, there is no reason to adjust the dose of dapsone during multidrug therapy of leprosy.

Adolescent↗
PubMed2005

[Dapsone-induced agranulocytosis. The role of xenobiotic-metabolizing enzymes demonstrated by a case report].

A 34-year-old female patient with a three year history of generalized granuloma annulare was treated systemically with dapsone (DADPS). Six weeks after the onset of treatment, the patient developed an extensive tonsillitis of the base of the tongue with fever and malaise. Routine laboratory work showed a leukocytopenia with agranulocytosis. Further investigation revealed a marked decrease of the enzyme activity of N-acetyltransferase 2, which plays an important role in dapsone metabolism. Treatment included the cessation of dapsone, antibiotic coverage, and G-CSF leading to the rapid improvement of symptoms and normalization of leukocyte counts. Dapsone-induced angina agranulocytotica is a rare event and is interpreted as an idiosyncratic reaction. Depending on genetic polymorphisms of various enzymes, dapsone can be metabolized to immunologically or toxicologically relevant intermediates. Because of the risk of severe hematologic reactions, dapsone should only be employed for solid indications and with appropriate monitoring.

Adult↗
PubMed1983

Inhibition of rat mast cell arachidonic acid cyclooxygenase by dapsone.

Dapsone (diaminodiphenylsulfone) has been used therapeutically for a variety of disorders in which mast cell participation has been demonstrated, including bullous pemphigoid and some form of necrotizing vasculitis. The mechanism of action of dapsone in these disorders is unknown but potentially relates to inhibition of mast cell activation and prevention of generation and/or release of mast cell mediators. Evidence for this possibility has been obtained in rat mast cells in which dapsone in a concentration-dependent manner prevented generation of prostaglandin D2 PGD2 from exogenous or endogenous arachidonic acid with 50% inhibition achieved at 1 and 0.2 to 0.4 mM, respectively. Dapsone inhibited cyclooxygenase conversion of arachidonic acid to PGD2 but not the GSH-dependent conversion of 14C-PGH2 to PGD2 by PGH-D isomerase in broken cell preparations. Dapsone prevented the immunologic generation of PGD2 from antigen-challenged rat mast cells but did not affect the release of histamine. Thus dapsone may exert some of its therapeutic effects by prevention of mast cell PGD2 generation.

Animals↗
PubMed1996

Dapsone penetrates cerebrospinal fluid during Pneumocystis carinii pneumonia prophylaxis.

Dapsone has been proposed as a prophylactic agent for both Pneumocystis carinii pneumonia (PCP) and reactivation cerebral toxoplasmosis. To determine whether dapsone penetrates the central nervous system, cerebrospinal fluid (CSF) and serum samples were drawn from patients taking dapsone for PCP prophylaxis. These samples were quantitatively assayed using high-performance liquid chromatography. Five AIDS patients and one cardiac transplant patient had CSF assayed for dapsone. Only one had evidence of CSF inflammation, resulting from a paraspinal abscess. Doses ranged from 50 mg 3 days/week to 100 mg/day, and levels were 0.30-1.61 mu g/ml, which are in the range of inhibition of Toxoplasma gondii tachyzoites. This is the first report to demonstrate that dapsone enters the CSF, and supports preliminary clinical evidence that dapsone may have protective activity against cerebral toxoplasmosis when used for PCP prophylaxis.

Adult↗
PubMed2004

Neuroprotective effect of dapsone in an occlusive model of focal ischemia in rats.

Dapsone (4,4'-diaminodiphenylsulfone) is employed in the chemotherapy against leprosy. Dapsone also prevents neuronal damage induced by glutamate agonists. As glutamate excitotoxicity is implicated in the damage after ischemia, we tested the ability of dapsone to prevent ischemic injury in a model of permanent middle cerebral artery (MCA) occlusion in rats. Either dapsone (9.375 or 12.5 mg/kg doses) or vehicle were i.p. administered 30 min after occlusion. Rats from the control group showed a permanent neurological deficit after occlusion, while dapsone-treated groups improved significantly. Dapsone-treated animals showed a reduction of 93% (9.375 mg/kg dose) and 92% (12.5 mg/kg dose) in the infarction volume as compared to control values.

Animals↗