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PubMed1990

The use of cimetidine as a selective inhibitor of dapsone N-hydroxylation in man.

1. The N-hydroxylation of dapsone is thought to be responsible for the methaemoglobinaemia and haemolysis associated with this drug. We wished to investigate the effect of concurrent administration of cimetidine (400 mg three times per day) on the disposition of a single dose (100 mg) of dapsone in seven healthy volunteers in order to inhibit selectively N-hydroxylation. 2. The AUC of dapsone (31.0 +/- 7.2 micrograms ml-1 h) was significantly increased (P less than 0.001) in the presence of cimetidine (43.3 +/- 8.8 micrograms ml-1 h). 3. Peak methaemoglobin levels observed after dapsone administration (2.5 +/- 0.6%) were significantly (P less than 0.05) reduced in the presence of cimetidine (0.98 +/- 0.35%). 4. The percentage of the dose excreted in urine as the glucuronide of dapsone hydroxylamine was significantly (P less than 0.05) reduced in the presence of cimetidine (34.2 +/- 9.3 vs 23.1 +/- 4.2%). 5. Concurrent cimetidine therapy might reduce some of the haematological side-effects of dapsone.

Adult↗
PubMed2005

Complications related to dapsone use for Pneumocystis jirovecii pneumonia prophylaxis in solid organ transplant recipients.

Dapsone, used for prevention of Pneumocystis jirovecii infections, has been reported to cause hemolytic anemia and methemoglobinemia; its tolerability in solid organ transplant recipients is not well described. We investigated dapsone-related adverse events in patients undergoing solid organ transplantation from 1999 to 2004. Transplant providers identified patients for the investigators who then reviewed the patients' hospital and outpatient records. Sixteen solid organ transplant recipients fit case definitions for dapsone-related hemolytic anemia (n = 11) or methemoglobinemia (n = 5). Median time from event to dapsone discontinuation was 15 days; all patients improved after drug discontinuation. G6PD enzyme activity was normal in all patients whose test results were available. Dapsone may be associated with hemolytic anemia or methemoglobinemia, even with normal G6PD levels. These events are often not promptly recognized, and drug discontinuation is delayed. Dapsone-related hemolytic anemia or methemoglobinemia should be considered in solid organ transplant recipients with unexplained anemia or hypoxia.

Adult↗
PubMed2002

Activation of CYP2C9-mediated metabolism by a series of dapsone analogs: kinetics and structural requirements.

Cytochrome P450 2C9-mediated metabolism has been shown to be activated in the presence of the effector dapsone. However, it has yet to be established what effector structural features are necessary to activate CYP2C9 activity. To address this question, kinetic studies were conducted with nine analogs of dapsone containing various functional properties (three sulfone compounds, three carbonyl compounds, and three sulfonamide compounds), to examine the functional groups important for enzyme activation by the effector (dapsone). Results show that phenylsulfone (dapsone without the para-amino groups) activates flurbiprofen 4'-hydroxylation comparable to dapsone but inhibits naproxen demethylation. Meanwhile, p-tolylsulfone had little effect on flurbiprofen metabolism, but activated naproxen demethylation, albeit only at high concentrations. These substrate-dependent differences in effect suggest that naproxen has a different binding orientation compared with flurbiprofen. Perhaps most interesting is that replacement of only one amino group from dapsone with a nitro group (4-(4-nitrophenylsulfonyl)-aniline) resulted in substantial inhibition of flurbiprofen 4'-hydroxylation, suggesting that electronic effects may influence activation of this substrate. Other analogs either had minor or no effect on CYP2C9-mediated metabolism. Overall, it is apparent from these studies that a sulfone group in direct association with two benzene rings with para-electron-donating groups represents the most efficient activator of CYP2C9. However, the effects of these analogs appear to be concentration- and substrate-dependent, further complicating the prediction of these types of in vitro interactions.

Algorithms↗
PubMed1981

In vitro and in vivo effects of dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy.

The effects of dapsone on polymorphonuclear leukocyte functions and lymphocyte mitogen-induced transformation were assessed in vitro and in vivo in normal individuals and in newly diagnosed untreated patients with lepromatous leprosy. The effects of dapsone on the cell-free generation of superoxide by the xanthine: xanthine oxidase system and iodination of bovine serum albumin by horseradish peroxidase were also investigated. In normal individuals dapsone mediated stimulation of polymorphonuclear leukocyte migration in vitro and vivo. Dapsone had no effect on postphagocytic hexose monophosphate shunt activity in vivo. Similar effects were found in patients with lepromatous leprosy. Dapsone also decreased the inhibitory activity of serum from patients with lepromatous leprosy on normal polymorphonuclear leukocyte migration in vitro. Progressive loss of serum-mediated inhibition of migration was observed after ingestion of dapsone by the patients. Further experiments showed that stimulation of polymorphonuclear leukocyte motility was related to inhibition of lymphocyte transformation at high concentrations in vitro, but had slight stimulatory activity on phytohemagglutinin-induced transformation in controls and patients in vivo.

Cell Movement↗
PubMed1994

Activity of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone against Toxoplasma gondii.

We examined the effect of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone, against Toxoplasma gondii. In vitro, the anti-T. gondii effects of epiroprim and dapsone were observed at nanogram-per-milliliter levels when a 72-h uracil assay and an infection rate of one parasite per 120 macrophages were used. In combination, these drugs exerted a synergistic effect that, however, was only parasitostatic. In a model of acute infection, mice were infected intraperitoneally with 10(4) parasites of the RH strain of T. gondii and were treated for 14 days by gavage (therapy divided into two daily dosages), starting 24 h after infection. Used alone, dapsone and epiroprim, each at a dose of 50 mg/kg of body weight per day, protected 10 and 0% of the mice, respectively. When these drugs were administered simultaneously, a 100% survival rate was observed. Pyrimethamine-sulfadiazine (4 and 250 mg/kg/day, respectively) protected 100% of the mice. A 3-week therapy of chronically infected mice with either epiroprim (50 mg/kg/day), dapsone (50 mg/kg/day), or pyrimethamine (15 mg/kg/day) reduced the numbers of T. gondii cysts and the inflammation in their brains. A combination of epiroprim and dapsone, both at 50 mg/kg/day, further reduced the number of brain cysts in comparison with the number after the corresponding monotherapies. Epiroprim may have a role in the prophylaxis or therapy of human toxoplasmosis, especially when combined with other drugs active against T. gondii, such as dapsone.

Animals↗
PubMed1997

Chlorproguanil-dapsone: effective treatment for uncomplicated falciparum malaria.

Pyrimethamine-sulfadoxine, the first choice for uncomplicated falciparum malaria in Africa, exerts strong selection pressure for resistance because of its slow elimination. It is likely that resistance will emerge rapidly, and there is no widely affordable replacement. Chlorproguanil-dapsone is cheap, rapidly eliminated, more potent than pyrimethamine-sulfadoxine, and could be introduced in the near future to delay the onset of antifolate resistance and as "salvage therapy" for pyrimethamine-sulfadoxine failure. A total of 448 children were randomly allocated (double blind) to either a single dose of pyrimethamine-sulfadoxine or to one of two chlorproguanil-dapsone regimens: a single dose or three doses at 24-h intervals. Reinfections are clinically indistinguishable from recrudescence and are more likely after treatment with rapidly eliminated drugs; we measured the incidence of parasitemia in 205 initially aparasitemic children to allow comparison with the three treatment groups. The patients and a community surveillance group were followed up for 28 days. At the study end point, 31.2% (95% confidence interval, 24.9-38.0) of the community surveillance group subjects were parasitemic, compared with subjects in the treatment groups, whose rates of parasitemia were 40.8% (32.9-49.0; relative risk [RR], 1.31 [0.99-1.73]) after triple-dose chlorproguanil-dapsone, 19.7% (13.5-27.2; RR, 0.63 [0.43-0.93]) after pyrimethamine-sulfadoxine, and 65.6% (57.5-73.0; RR, 2.10 [1.66-2.65]) after single-dose chlorproguanil-dapsone. Pyrimethamine-sulfadoxine and triple-dose chlorproguanil-dapsone were effective treatments. Pyrimethamine-sulfadoxine provided chemoprophylaxis during follow-up because of its slow elimination. Triple-dose chlorproguanil-dapsone should now be developed in an attempt to reduce the rate of emergence of antifolate resistance in Africa and for affordable salvage therapy in cases of pyrimethamine-sulfadoxine failure.

Antimalarials↗
PubMed1997

Penetration of dapsone into pulmonary lining fluid of human immunodeficiency virus type 1-infected patients.

We studied the penetration of dapsone into the epithelial lining fluid (ELF) of sixteen human immunodeficiency virus type 1-infected patients who had received the drug at a dose of 100 mg twice weekly as primary prophylaxis for Pneumocystis carinii pneumonia. Bronchoscopy, bronchoalveolar lavage (BAL), and venipuncture were performed for each patient at a specific time after administration of the last dose of dapsone. Dapsone concentrations in plasma and BAL were determined by high-performance liquid chromatography. The apparent volume of ELF recovered by BAL was determined by using urea as an endogenous marker. The mean concentrations of dapsone in ELF at 2 h (five patients), 4 h (three patients), 12 h (two patients), 24 h (three patients), and 48 h (three patients) were 0.95, 0.70, 1.55, 0.23, and 0.45 mg/liter, respectively, while concentrations in plasma were 1.23, 0.79, 1.31, 0.83, and 0.18 mg/liter, respectively. Dapsone concentrations in ELF were 76, 79, 115, 65, and 291% of those observed in plasma at the same times, respectively. These data show that dapsone is well distributed into ELF and that a twice-weekly 100-mg prophylactic regimen results in sustained concentrations in this compartment.

Adult↗
PubMed1999

Pharmacokinetics of dapsone administered daily and weekly in human immunodeficiency virus-infected children.

Although dapsone is a commonly used alternative agent for prophylaxis against Pneumocystis carinii pneumonia in children intolerant to trimethoprim-sulfamethoxazole, there are few data that describe dapsone pharmacokinetics in children. We studied dapsone pharmacokinetics in 30 children (median age, 2.8 years; age range, 0. 3 to 12 years) receiving a new proprietary liquid preparation by three dosing regimens (1 mg/kg of body weight daily, 2 mg/kg daily, or 4 mg/kg weekly). Dosing of children with 2 mg/kg daily or 4 mg/kg weekly resulted in peak concentrations equivalent to those reached in adults receiving 100-mg tablets daily. For the entire population, the median half-life was 22.2 h (range, 7.1 to 40.3 h), the median oral clearance was 0.0365 liter/kg/h (range, 0.0104 to 0.1021 liter/kg/h), and the median oral apparent volume of distribution was 1.13 liters/kg (range, 0.50 to 2.32 liters/kg). The median dapsone oral clearance was significantly increased in those infants less than 2 years of age compared to the oral clearance in those over 2 years of age (0.0484 versus 0.0278 liter/kg/h; P = 0.011). These data suggest that absorption of this liquid preparation is adequate and that the concentrations in the sera of children receiving 2 mg/kg daily or 4 mg/kg weekly are equivalent to those seen in adults receiving standard dapsone dosing. Dapsone oral clearance appears to be increased in children under 2 years of age.

Adolescent↗
PubMedDate not supplied

Stability of dapsone in two oral liquid dosage forms.

OBJECTIVE: Dapsone use in pediatric patients is increasing; however, the currently available tablet dosage form cannot be used in young children. The objective of our study was to determine the stability of dapsone in two oral suspensions stored at two temperatures. METHODS: Commercially available dapsone tablets (25 mg) were used to prepare the suspensions: the first in simple syrup and water with citric acid, the second in 1:1 Ora Sweet:Ora Plus to yield a concentration of 2.0 mg/mL. The dosage forms were stored in 10 amber plastic prescription bottles. Five were stored at 25 degrees C and five at 4 degrees C. Three samples were taken from each of five bottles at 0, 7, 14, 28, 42, 56, 70, and 91 days (n = 15). Dapsone concentrations in each sample were measured in duplicate by a validated and stability-indicating HPLC method; the pH of each sample was also determined. The drug was considered stable if the mean concentration > or =90% of the original concentration. RESULTS: The mean concentrations of dapsone were >95% of the initial concentrations for 91 days at both 4 degrees C and 25 degrees C in each suspension. There was a slight darkening of the samples stored at 25 degrees C. CONCLUSIONS: Dapsone was stable in two suspensions prepared from commercially available tablets for at least three months at 4 degrees C and 25 degrees C.

Administration, Oral↗
PubMedDate not supplied

Studies on the carboxymethyl chitosan-containing liposomes for their stability and controlled release of dapsone.

Stable liposomes containing carboxymethyl chitosan (CMC) were prepared and characterized. CMC was introduced in the phosphatidyl choline (PC) liposomes by different methods; firstly, CMC in a free state in the aqueous phase; secondly as a coat (coupled); and finally as a conjugate of dapsone. The stability of liposomes was assessed by their disintegration in ethanol and surfactants. Both hydrophilic bromothymol blue and lipophilic dapsone were encapsulated in these liposomes and their in vitro release studies were carried out at 37 degrees C using different media, namely, phosphate buffer (pH 7.4), 0.02 N-HCl and 1% mouse plasma. The conjugate of dapsone with CMC present in PC liposomes gave the best results in its stability as compared to other modified liposomes. The release data of dapsone also confirmed the results of the stability studies on liposomes. CMC-dapsone conjugate released the dapsone much slower in all three media than did PCCMC and PCCMC-coat liposomes.

Bromthymol Blue↗
PubMed1985

Haematological safety of long-term malarial prophylaxis with dapsone-pyrimethamine.

There are no published haematological data on the long-term (more than one year) use of dapsone-pyrimethamine (Maloprim, Folaprim; one tablet a week) for malarial prophylaxis. In a study of 373 male Papua New Guinean soldiers who had used this combination for five years, we found no haematological abnormalities attributable to dapsone-pyrimethamine. Furthermore, the haematological parameters of these soldiers were not clinically different from those of Papua New Guinean university students who did not ingest antimalarial drugs prophylactically. In a parallel study, 9 of 159 white persons (6 children and 3 adult females) who had used dapsone-pyrimethamine prophylaxis for more than one year had haematological abnormalities attributable to the drug. Additionally, the mean leucocyte count of children aged 1-9 years who took dapsone-pyrimethamine was markedly lower--although within the normal range--than that of similarly aged children who received chloroquine for malarial prophylaxis. The appreciable incidence of haematological abnormalities observed in children during malarial prophylaxis with dapsone-pyrimethamine demonstrates the need to select a dose for this group on a weight rather than an age basis and to use a liquid formulation to facilitate the administration of the appropriate dose of this combination. Haematological monitoring of the long-term use of dapsone-pyrimethamine is recommended and a suitable monitoring regimen is suggested.

Adolescent↗
PubMed1995

Dapsone syndrome in a Filipino man.

A case of dapsone syndrome occurring in a Filipino man under treatment for multibacillary (MB) leprosy is described. The patient manifested progressive fever, erythroderma and jaundice 4 weeks after initiation of multidrug therapy (MDT) with rifampicin, clofazimine and dapsone. The clinical symptoms conformed well to the dapsone syndrome first described in the 1950s and this report proves that the syndrome does still exist. There was recovery after dapsone was omitted and therapy with systemic corticosteroids was started. In view of this potentially fatal hypersensitivity reaction, this case report emphasizes the need for caution when initiating MDT or dapsone therapy. It is also suggested that any patient on MDT or dapsone needs to be referred immediately to a dermatologist or internist if the patient develops a skin rash during the first 2 months of treatment.

Adolescent↗
PubMed2001

Dapsone in treatment of chronic idiopathic thrombocytopenic purpura in adults.

BACKGROUND: When a patient is steroid-dependant, a currently available strategy in chronic idiopathic thrombocytopenic purpura (ITP) is to follow a trial and error approach with any of the known drugs which has been found effective in the condition. OBJECTIVE: To evaluate the response of chronic ITP to dapsone, an inexpensive drug now reported to be effective in the disease. DESIGN: A controlled trial of abstinence and rechallenge type. SUBJECTS: Eight subjects with chronic ITP. INTERVENTIONS: Phase I - Intake of 100 mg of dapsone daily until response (in form of rise of platelet count in blood), Phase II - Above followed by drug abstinence, minimum for four weeks, and then rechallenge with the drug. MAIN OUTCOME MEASURES: Platelet counts during various phases viz during drug intake, withdrawal and rechallenge. RESULTS: Four (50%) patients responded to treatment. The mean pre-dapsone and post-dapsone platelet counts of blood were 29.6 x 10(9)/l and 142.5 x 10(9)/l respectively during the first phase of trial. The rechallenge was done in five patients following withdrawal of drug and the mean values of platelet count before and after rechallenge were 32.2 x 10(9)/l and 83 x 10(9)/l respectively. There was a remarkable response in two patients; one is now off the drug and the other on a maintenance dose of 50 mg of dapsone daily. CONCLUSION: Dapsone caused significant rise of platelet count in some patients of chronic ITP. It can be tried as an alternative to other second-line drugs in chronic ITP.

Adolescent↗
PubMed2003

[Dapsone-induced sensory peripheral neuropathy].

INTRODUCTION: Peripheral neuropathy is a rare complication of dapsone therapy. CASE-REPORT: A 74 year-old woman was treated with dapsone, 50 mg per day, for a linear IgA dermatosis. One month later, the disease was controlled but the patient complained of a sensory peripheral neuropathy, which was documented on electromyographic studies. Dapsone was stopped and symptoms resolved within 24 hours. Three months after the beginning of linear IgA dermatosis, a colic adenocarcinoma was revealed by an acute occlusive syndrome. After surgical resection of the tumor, remission of linear IgA dermatosis was obtained with salazopyrine. DISCUSSION: This is a rare side effect of dapsone therapy. Twenty-one cases have been previously reported. In most cases, there was a pure motor or mixed neuropathy. Dapsone therapy was then stopped or decreased. Recovery usually occurs within one year after dapsone therapy is discontinued.

Aged↗
PubMed1992

The protective effect of vitamin E on the hemolysis associated with dapsone treatment in patients with dermatitis herpetiformis.

OBJECTIVE: This study looked at whether oral vitamin C and vitamin E would protect the erythrocyte from oxidant damage caused by dapsone in patients with dermatitis herpetiformis. DESIGN: Fifteen consecutive patients with dermatitis herpetiformis taking dapsone therapy received, in addition, 800 U/d of vitamin E for 4 weeks; then 1000 mg of vitamin C per day for 4 weeks, and, finally, combined vitamin E and vitamin C therapy for 4 weeks. Hemolysis indexes were assessed at baseline and after each 4-week period. RESULTS: Statistical analysis of the results suggests that oral administration of 800 units of vitamin E daily for 4 weeks confers partial protective effect against dapsone-induced hemolysis in patients with dermatitis herpetiformis. CONCLUSION: Partial protection against dapsone-induced hemolysis by orally administered vitamin E, if confirmed as being clinically relevant by further trials, may allow clinicians to continue dapsone therapy orally in patients who develop significant hemolysis. Prophylactic vitamin E to minimize potential hemolysis at the initiation of dapsone therapy may also be appropriate.

Adult↗
PubMed1990

Primary dapsone-resistant Hansen's disease in California. Experience with over 100 Mycobacterium leprae isolates.

We found that in the years 1978 through 1981 only one of 54 previously untreated patients with Hansen's disease was found to harbor dapsone-resistant Mycobacterium leprae. That single strain was only partially resistant, ie, it was resistant to 0.0001% dapsone in a mouse diet but not to higher concentrations. During the years 1983 through 1988, M leprae from 47 previously untreated patients presenting to clinics in San Francisco, Calif, and Los Angeles, Calif, grew in mice. None of these strains was found to be dapsone resistant. Thus, from 1978 through 1988 only one of 101 M leprae isolates obtained from skin biopsy specimens from patients with leprosy was found to be resistant to dapsone. We have concluded that primary dapsone resistance still does not appear to be a significant problem in California. Owing to the fact that our single resistant case and those reported from international sources are, in general, partially resistant, the potential importance of partial dapsone resistance is discussed.

Adolescent↗
PubMed1985

Relapse rate and incidence of dapsone resistance in lepromatous leprosy patients in Addis Ababa: risk factors and effect of short-term supplementary treatment.

A clinical trial was initiated at ALERT, Addis Ababa, Ethiopia, to study the effect of one-year supplementary treatment on the incidence of dapsone-resistant leprosy in lepromatous patients already on dapsone monotherapy. A total of 806 patients on dapsone therapy were assigned to one of four groups. The first group served as a control group, the second received a combination tablet of thiacetazone and INH (Thiazina) daily for 12 months, the third group received Thiazina daily for 12 months plus rifampin daily during months 1 and 7, and the fourth group received rifampin daily during months 1 and 7 but no Thiazina. Eighty-three percent of the patients were followed for five years after discontinuation of the supplementary treatment. The annual incidence of relapses and dapsone-resistant leprosy in the control group appeared to be 2.3% and 0.7%, respectively. The Thiazina treatment had no significant effect on either the overall relapse rate or the incidence of dapsone-resistant leprosy. The rifampin treatment, on the other hand, did significantly lower the relapse rate and only a single case of dapsone resistance was detected. A high incidence of relapse was found in young female patients. Nineteen of the 45 relapsed patients were bacteriologically negative at the start of the supplementary treatment and six had already been negative for over five years.

Adolescent↗
PubMed1988

Infectivity of secondary dapsone-resistant cases.

The incidence rate of leprosy among 517 household contacts of 113 cases of secondary dapsone resistance with 5074 person years at risk were studied. The incidence rate of leprosy was 4.3 per 1000 person years at risk, which is very similar to the incidence rate (4.8) among household contacts of lepromatous cases. Two, possibly three, cases of primary dapsone resistance were detected among the 27 contacts who developed multibacillary leprosy. There was no evidence of dapsone resistance among 48 paucibacillary leprosy cases assessed when treated with dapsone monotherapy. The possibility that secondary dapsone-resistant cases will infect and will result in an increase in the number of primary dapsone-resistant cases needs to be investigated further.

Adult↗