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PubMed1990

Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man.

1. The multiple-dose kinetics of dapsone (DDS), its major metabolite monoacetyldapsone (MADDS) and pyrimethamine (PYR) were studied in six healthy adult male volunteers following weekly administration of Maloprim (100 mg DDS plus 12.5 mg PYR). 2. After the last maintenance dose of Maloprim, the following kinetic parameters (mean values) were determined for DDS and PYR, respectively: maximum plasma concentration (Cmax) = 1,134 and 116 ng ml-1; elimination half-life (t1/2) = 23 and 105 h; plasma clearance (CL) = 37.6 and 15.9 ml h-1 kg-1 and apparent volume of distribution (Vss) = 1.20 and 2.29 l kg-1. The mean t1/2 of MADDS was 22 h. 3. The mean whole blood to plasma (B/P) and erythrocyte to plasma (E/P) concentration ratios for DDS were 1.04 and 1.09, respectively. MADDS had a B/P ratio of 0.69 and an E/P ratio of 0.33. The B/P and E/P ratios for PYR were 0.98 and 0.54, respectively. 4. The drug combination was assessed in vitro by measuring inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. The chloroquine (CQ)- and PYR-sensitive FC-27 isolate was completely inhibited by the sera but the drug combination was ineffective against the CQ- and PYR-resistant K1 strain. The in vitro findings suggest that Maloprim may not be effective against strains of P. falciparum with a high level of resistance to pyrimethamine.

Acetylation↗
PubMed1991

N-acetylation phenotyping using dapsone in a Jordanian population.

1. The N-acetylation of dapsone (DDS) was studied in 160 unrelated healthy Jordanian volunteers. 2. The frequency of slow acetylators determined using the plasma monoacetyldapsone (MADDS) to DDS ratio (MADDS/DDS), was 67.5% with a 95% confidence interval of 59 to 76%. Slow acetylators had an acetylation ratio of less than 0.42. 3. Applying the Hardy-Weinberg Law, the frequency of the recessive allele controlling slow acetylation was found to be 0.82 +/- 0.02. 4. The frequency distribution histogram of the plasma MADDS/DDS ratio showed an apparent trimodal pattern. The number of homozygous (n = 16) and heterozygous (n = 36) rapid acetylators derived from the observed data did not agree with those predicted for the respective rapid acetylators (n = 5 and n = 47) according to the Hardy-Weinberg Law. The suggested antimode used to discriminate the two groups was 0.82. 5. The mean plasma concentration of MADDS and the mean plasma acetylation ratio were about three times lower in slow than in rapid acetylators. However, there was no difference in mean plasma DDS concentration between slow and rapid acetylators. 6. There was a significant correlation (r = 0.853, P less than 0.001) between plasma MADDS concentration and the acetylation ratio. For DDS such a correlation was absent (r = 0.059, P = 0.23).

Acetylation↗
PubMed1976

Pemphigus controlled by dapsone.

Three uncomplicated cases of pemphigus were clinically controlled by dapsone. Improvement was associated with decreasing titres of circulating intercellular antibodies. Interestingly, the sera from one case of pemphigus foliaceus contained intercellular antibodies found in the Malpighian and basal cell layers using the fluorescent technique and in the granular layer using the peroxidase technique. These findings suggest that the intercellular antibodies in pemphigus vulgaris and pemphigus foliaceus are similar but bind at different anatomical sites.

Adult↗
PubMed1980

The potassium iodide patch test in the dermatitis herpetiformis in relation to treatment with a gluten-free diet and dapsone.

The potassium iodide patch test was studied in twenty-six patients with dermatitis herpetiformis. Histological assessment was found more sensitive than clinical. All of five patients with active disease and not on treatment had a positive test, whereas only two of six patients taking a gluten-free diet (GFD) and one of eight taking dapsone were positive. In another two patients taking a GFD, but in whom the diet had not been strict, the test was positive. All three patients in remission and both patients with the linear pattern of IgA (but with active disease) were negative. Immunofluorescence studies showed no difference in the presence, quantity, or distribution of immunoglobulin, complement or fibrinogen between the patch test site and uninvolved skin, or in the uninvolved skin between patients with and without active lesions.

Dapsone↗
PubMed1983

Pharmacokinetic observations on dapsone in dermatitis herpetiformis.

The pharmacokinetics of dapsone (DDS) and monoacetyldapsone (MADDS) following an oral dose of 150 mg DDS were studied in sixteen patients with dermatitis herpetiformis and seven normal subjects. No differences in DDS disposition were observed between the two groups. The maintenance dose of DDS for individual patients was not significantly correlated with jejunal biopsy morphology, DDS or MADDS half-lives, or the area under the plasma concentration-time curves for DDS or MADDS. DDS plasma protein binding was normal in patients and did not apparently determine the concentration of DDS in skin biopsies, for which the skin/plasma DDS concentration ratio was approximately unity. There was no undue representation of acetylator phenotype in the patient group and no correlation between maintenance dose and MADDS/DDS ratio was noted. The determinants of the maintenance DDS dose have not been found. This may relate to pharmacodynamic differences, but alternatively the concentration of oxidative metabolites rather than DDS or MADDS could be responsible for the therapeutic activity in dermatitis herpetiformis.

Adult↗
PubMed1984

Suppression of Behçet's disease with dapsone.

Seven male patients with Behçet's disease were treated with dapsone 100 mg daily. All had suppression of their pathergic reaction to a deep needle-prick, with noticeable symptomatic improvement.

Adult↗
PubMed1991

Simultaneous high performance liquid chromatographic determination of dapsone and monoacetyldapsone in human plasma and urine.

A rapid, specific and a one-stage protein precipitation method for simultaneous estimation of dapsone (DDS) and monoacetyldapsone (MAD) concentration in plasma and urine using high performance liquid chromatography (HPLC) is described. The applicability of the method for monitoring DDS and MAD blood levels in two different acetylator phenotype volunteers following the administration of 100-mg oral dose of DDS was shown. Cumulative urinary excretion of DDS and MAD were studied in the same volunteers.

Adult↗
PubMed1981

In vitro dissolution of dapsone.

Los normal samples of dapsone (DDS) were prepared in which the geometric mean diameter ranged from 20 to 50 micron while the geometric standard deviation was in the range 1.62 to 1.88. Using a simple in vitro flow-through dissolution cell at 37 degrees C, the data obtained were found to fit the Hixson-Crowell cube root dissolution law up to a critical time, Tc, where a distinct break occurred. Such a biphasic phenomenon has been predicted by other workers and is related to the time at which the smallest particles present have undergone dissolution. The initial slopes of the cube root dissolution plots were shown to be directly related to the reciprocal of the geometric mean diameter.

Dapsone↗
PubMed1990

Inhibition of dapsone-induced methaemoglobinaemia in the rat isolated perfused liver.

We have investigated the disposition of dapsone (DDS, 1 mg) in the rat isolated perfused liver in the absence and the presence of cimetidine (3 mg). After the addition of DDS alone to the liver there was a monoexponential decline of parent drug concentrations and rapid formation of DDS-NOH (within 10 min) which coincided with methaemoglobin formation (11.7 +/- 3.0%, mean +/- s.d.) which reached a maximum (22.6 +/- 9.2%) at 1 h. The appearance of monoacetyl DDS (MADDS) was not apparent until 30-45 min. Addition of cimetidine resulted in major changes in the pharmacokinetics of DDS and its metabolites. The AUC of DDS in the presence of cimetidine (1018.8 +/- 267.8 micrograms min mL-1) was almost three-fold higher than control (345.0 +/- 68.1 micrograms min mL-1, P less than 0.01). The half-life of DDS was also prolonged by cimetidine compared with control (117.0 +/- 48.2 min vs 51.2 +/- 22.9, P less than 0.05). The clearance of DDS (3.0 +/- 0.55 mL min-1) was greatly reduced in the presence of cimetidine (1.03 +/- 0.26 mL min-1 P less than 0.01). The AUC0-3h for DDS-NOH (28.3 +/- 21.2 micrograms min mL-1) was significantly reduced by cimetidine (8.1 +/- 3.40 micrograms min mL-1, P less than 0.01). In contrast, there was a marked increase in the AUC0-3h for MADDS (32.7 +/- 25.8 micrograms min mL-1) in the presence of cimetidine (166.0 +/- 26.5 micrograms min mL-1 P less than 0.01). The methaemoglobinaemia associated with DDS was reduced to below 5% by cimetidine. Hence, a shift in hepatic metabolism from bioactivation (N-hydroxylation) to detoxication (N-acetylation) caused by cimetidine, was associated with a fall in methaemoglobinaemia. These data suggest that the combination of DDS with a cytochrome P450 inhibitor might reduce the risk to benefit ratio of DDS.

Animals↗
PubMed2005

Role of human cyclooxygenase-2 in the bioactivation of dapsone and sulfamethoxazole.

Sulfamethoxazole (SMX) and dapsone (4,4'-diaminodiphenylsulfone, DDS) are believed to mediate their adverse effects subsequent to bioactivation to their respective arylhydroxylamine and arylnitroso metabolites, resulting in covalent adduct formation with intracellular proteins. Various bioactivating enzymes, such as cytochromes P450 and myeloperoxidase, have been shown to be capable of catalyzing the N-oxidation of these compounds. We assessed the role of human cyclooxygenase-2 (COX-2) in the metabolism and subsequent adduct formation of DDS and SMX using recombinant human COX-2. Using an adduct-specific enzyme-linked immunosorbent assay, we found that the complete enzyme system gave rise to covalent adducts. However, the nonspecific COX inhibitor indomethacin did not reduce the amount of covalent adduct formed. Formation of the arylhydroxylamine metabolites was demonstrated via high performance liquid chromatography coupled with UV absorption. Metabolite formation was found to be secondary to the H2O2 in the incubation mixture and was not enzyme-mediated. Hence, COX-2 does not play a direct role in the bioactivation of these parent drugs to their arylhydroxylamine metabolites.

Arachidonic Acid↗
PubMed2006

Enzyme-mediated protein haptenation of dapsone and sulfamethoxazole in human keratinocytes: I. Expression and role of cytochromes P450.

Cutaneous drug reactions (CDRs) are among the most common adverse drug reactions and are responsible for numerous minor to life-threatening complications. Several arylamine drugs, such as sulfamethoxazole (SMX) and dapsone (DDS), undergo bioactivation, resulting in adduction to cellular proteins. These adducted proteins may initiate the immune response that ultimately results in a CDR. Recent studies have demonstrated that normal human epidermal keratinocytes (NHEKs) can bioactivate these drugs, resulting in protein haptenation. We sought to identify the enzyme(s) responsible for this bioactivation in NHEKs. Using immunofluorescence confocal microscopy and an adduct-specific enzyme-linked immunosorbent assay (ELISA), we found that N-acetylation of the primary amine of SMX and DDS markedly reduced the level of protein haptenation in NHEKs. Detection of mRNA and/or protein confirmed the presence of CYP3A4, CYP3A5, and CYP2E1 in NHEKs. In contrast, although a faint band suggestive of CYP2C9 protein was detected in one NHEK sample, a CYP2C9 message was not detectable. We also examined the ability of chemical inhibitors of cytochromes P450 (aminobenzotriazole and 1-dichloroethylene) and cyclooxygenase (indomethacin) to reduce protein haptenation when NHEKs were incubated with SMX or DDS by either confocal microscopy or ELISA. These inhibitors did not significantly attenuate protein adduction with either SMX or DDS, indicating that cytochromes P450 and cyclooxygenase do not play important roles in the bioactivation of these xenobiotics in NHEKs and thus suggesting the importance of other enzymes in these cells.

Acetylation↗
PubMed2006

Enzyme-mediated protein haptenation of dapsone and sulfamethoxazole in human keratinocytes: II. Expression and role of flavin-containing monooxygenases and peroxidases.

Arylamine compounds, such as sulfamethoxazole (SMX) and dapsone (DDS), are metabolized in epidermal keratinocytes to arylhydroxylamine metabolites that auto-oxidize to arylnitroso derivatives, which in turn bind to cellular proteins and can act as antigens/immunogens. Previous studies have demonstrated that neither cytochromes P450 nor cyclooxygenases mediate this bioactivation in normal human epidermal keratinocytes (NHEKs). In this investigation, we demonstrated that methimazole (MMZ), a prototypical substrate of the flavin-containing monooxygenases (FMOs), attenuated the protein haptenation observed in NHEKs exposed to SMX or DDS. In addition, recombinant FMO1 and FMO3 were able to bioactivate both SMX and DDS, resulting in covalent adduct formation. Western blot analysis confirmed the presence of FMO3 in NHEKs, whereas FMO1 was not detectable. In addition to MMZ, 4-aminobenzoic acid hydrazide (ABH) also attenuated SMX- and DDS-dependent protein haptenation in NHEKs. ABH did not alter the bioactivation of these drugs by recombinant FMO3, suggesting its inhibitory effect in NHEKs was due to its known ability to inhibit peroxidases. Studies confirmed the presence of peroxidase activity in NHEKs; however, immunoblot analysis and reverse transcription-polymerase chain reaction indicated that myeloperoxidase, lactoperoxidase, and thyroid peroxidase were absent. Thus, our results suggest an important role for FMO3 and yet-to-be identified peroxidases in the bioactivation of sulfonamides in NHEKs.

Cells, Cultured↗
PubMed1982

Effects of clofazimine alone or combined with dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy.

The effects of clofazimine on neutrophil activities such as random motility, migration to the leukoattractants endotoxin-activated serum and N-formyl-L-methionyl-L-leucyl-L-phenylalanine phagocytosis of Candida albicans, postphagocytic hexose-monophosphate shunt activity, and myeloperoxidase-mediated iodination and the effects of clofazimine on lymphocyte transformation to mitogens were assessed in vitro and after ingestion of the drug by normal individuals and patients with lepromatous leprosy. For in vitro studies, the concentration range of the drug investigated was 10(-6) M to 10(-2) M. for in vivo studies, subjects ingested 200 mg of clofazimine daily for a period of 5 days. At concentrations of 5 X 10(-6) M to 5 X 10(-3) M clofazimine caused a progressive dose-dependent inhibition of neutrophil motility without detectable effects on phagocytosis, postphagocytic hexose-monophosphate shunt activity, or myeloperoxidase-mediated iodination. Over the same concentration range, clofazimine inhibited lymphocyte transformation. The inhibitory effect on neutrophil motility was associated with a spontaneous stimulation of oxidative metabolism and could be prevented by coincubation of dapsone with clofazimine. after ingestion of clofazimine responsiveness of lymphocytes to mitogens was decreased in normal volunteers and leprosy patients: neutrophil motility in normal individuals was likewise inhibited.

Candida albicans↗
PubMed1993

Synergistic combinations of Ro 11-8958 and other dihydrofolate reductase inhibitors with sulfamethoxazole and dapsone for therapy of experimental pneumocystosis.

We compared Ro 11-8958, an analog of trimethoprim (TMP) with improved antimicrobial and pharmacokinetic properties, other dihydrofolate reductase (DHFR) inhibitors, sulfamethoxazole (SMX), and dapsone (DAP) in the treatment of Pneumocystis carinii pneumonia in an immunosuppressed rat model. In contrast to previous reports, high dosages of the DHFR inhibitors were used in combination with fixed, low dosages of SMX (3 mg/kg of body weight per day) or DAP (25 mg/kg/day). When administered alone at these dosages, SMX and DAP reduced the median P. carinii cyst count about 5- to 15-fold. Ro 11-8958, TMP, and diaveridine used at a dosage of 20 mg/kg/day with SMX were only slightly more effective than SMX used alone. However, administration of these DHFR inhibitors at a dosage of 100 mg/kg/day with SMX lowered the cyst count about 500- to 1,000-fold, indicating a synergistic effect. Little or no synergism was found when other DHFR inhibitors (pyrimethamine, cycloguanil, and tetroxoprim) were combined with SMX. Regimens of Ro 11-8958 at a dosage of 20 mg/kg/day with DAP and of TMP or diaveridine used at a dosage of 100 mg/kg/day with DAP showed comparable anti-P. carinii activity, lowering the cyst count 100- to 200-fold. By contrast, Ro 11-8958 administered at a dosage of 100 mg/kg/day with DAP reduced the cyst count > 1,000-fold. Thus, the experimental approach used here enables the rat model of pneumocystosis to be used to compare synergistic combinations of antifolate drugs. The favorable results achieved with Ro 11-8958 indicate that it should be considered for clinical trials.

AIDS-Related Opportunistic Infections↗
PubMed1996

Antibacterial activities of epiroprim, a new dihydrofolate reductase inhibitor, alone and in combination with dapsone.

Epiroprim (EPM; Ro 11-8958) is a new selective inhibitor of microbial dihydrofolate reductase. EPM displayed excellent activity against staphylococci, enterococci, pneumococci, and streptococci which was considerably better than that of trimethoprim (TMP). EPM was also active against TMP-resistant strains, although the MICs were still relatively high. Its combination with dapsone (DDS) was synergistic and showed as in vitro activity superior to that of the TMP combination with sulfamethoxazole (SMZ). The EPM-DDS (ratio, 1:19) combination inhibited more than 90% of all important gram-positive pathogens at a concentration of 2 + 38 micrograms/ml. Only a few highly TMP-resistant staphylococci and enterococci were not inhibited. EPM was also more active than TMP against Moraxella catarrhalis, Neisseria meningitidis, and Bacteroides spp., but it was less active than TMP against all other gram-negative bacteria tested. Atypical mycobacteria were poorly susceptible to EPM, but the combination with DDS was synergistic and active at concentrations most probably achievable in biological fluids (MICs from 0.25 +/- 4.75 to 4 + 76 micrograms/ml). EPM and the EPM-DDS combination were also highly active against experimental staphylococcal infections in a mouse septicemia model. The combination EPM-DDS has previously been shown to exhibit activity in Pneumocystis carinii and Toxoplasma models and, as shown in the present study, also shows good activity against a broad range of bacteria including many strains resistant to TMP and TMP-SMZ.

Animals↗