Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multiple-dose kinetics of a daily dose of proguanil (200 mg) coadministered with dapsone (10 mg) was investigated in 6 healthy adult male volunteers. The kinetics of dapsone (DDS), monoacetyldapsone (MADDS), proguanil (PROG) and its active metabolite cycloguanil (CYCLO) were derived from plasma drug concentrations after the last maintenance dose. The following kinetic parameters (mean values) were estimated for DDS and PROG, respectively: maximum concentration (Cmax) = 285 and 151 ng/ml, minimum concentration (Cmin) = 125 and 31 ng/ml, elimination half-life (t1/2) = 23.3 and 18.3 h, plasma clearance (Cl) = 0.032 and 1.27 l/h/kg and apparent volume of distribution (Vss) = 1.05 and 33.32 l/kg. The Cmax, Cmin and t1/2 of CYCLO were 56 ng/ml, 17 ng/ml and 15.0 h, respectively. The antimalarial activity of the proguanil/dapsone combination was assessed in vitro by measuring the inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. Both FC-27 [chloroquine (CQ)- and pyrimethamine (PYR)-sensitive] and K1 (CQ- and PYR-resistant) isolates were completely inhibited by the drug combination at steady-state concentrations. These findings suggest that the drug regimen may be effective against drug-resistant falciparum malaria.
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PMID:Multiple-dose kinetics in healthy volunteers and in vitro antimalarial activity of proguanil plus dapsone. 218 99

Serum concentrations of dapsone (DDS), monoacetyldapsone (MADDS), the principal acetylated metabolite of DDS, and pyrimethamine (PYR) were measured in 55 Caucasian adults (31 males, 24 females) and 159 Papua New Guinean adults (140 males, 19 females) following the oral administration of Folaprim (100mg DDS; 12.5mg PYR). Blood samples were collected at mean sampling times of eight hours after medication and 18 hours before the next weekly dose for malaria prophylaxis. Clearance of DDS and MADDS from serum were significantly faster (p less than 0.001) in Caucasians than in Papua New Guineans. Significantly lower (p less than greater 0.001) serum concentrations of PYR were found in Papua New Guineans than in Caucasians at both sampling times, an observation which may reflect differences in the bioavailability of PYR between the two racial groups. The theoretical implications of these results are that Caucasians may be more susceptible to PYR-resistant Plasmodium falciparum malaria than Papua New Guineans whilst Papua New Guineans may be more susceptible to P. vivax; malaria than Caucasians.
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PMID:Race-linked differences in serum concentrations of dapsone, monoacetyldapsone and pyrimethamine during malaria prophylaxis. 329 3

Dapsone (DDS) has for about 4 decades been the most important antileprosy drug. Concentrations of dapsone and its monoacetyl metabolite, MADDS, can be determined in biological media by high-performance liquid chromatography. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. However, the extent of absorption has not been adequately determined. The elimination half-life of dapsone is about 30 hours. The drug shows linear pharmacokinetics within the therapeutic range and the time-course after oral administration fits a 2-compartment model. The concentration-time profile of dapsone after parenteral administration is reviewed. Of clinical importance is the development of a new long acting injection, which permits monthly supervised administration as recommended by the World Health Organization. Following dapsone injection in gluteal subcutaneous adipose tissue, a sufficiently sustained absorption for this purpose has been reported. Dapsone is about 70 to 90% protein bound and its monoacetylated metabolite (MADDS) is almost completely protein bound. The volume of distribution of dapsone is estimated to be 1.5 L/kg. It is distributed in most tissues, but M. leprae living in the Schwann cells of the nerves might be unaffected. Dapsone crosses the placenta and is excreted in breast milk and saliva. Dapsone is extensively metabolised. Dapsone, some MADDS and their hydroxylated metabolites are found in urine, partly conjugated as N-glucuronides and N-sulphates. The acetylation ratio (MADDS:dapsone) shows a genetically determined bimodal distribution and allows the definition of 'slow' and 'rapid' acetylators. As enterohepatic circulation occurs, the elimination half-life of dapsone is markedly decreased after oral administration of activated charcoal. This permits successful treatment in cases of intoxication. The daily dose of dapsone in leprosy is 50 to 100mg, but varies from 50 to 400mg in the treatment of other dermatological disorders. In malaria prophylaxis, a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly haematological effects. The dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L. Alcoholic liver disease decreases the protein binding of dapsone; coeliac disease and dermatitis herpetiformis may delay its oral absorption and severe leprosy has been reported to affect the extent of absorption.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Clinical pharmacokinetics of dapsone. 353 May 84

A reversed-phase high performance liquid chromatography method was developed to simultaneously estimate serum concentrations of dapsone (DDS), monoacetyldapsone (MADDS), and pyrimethamine (PYR) in 34 young adult Chinese men after they had taken the sixth weekly dose of Maloprim for malaria prophylaxis. Serum concentrations of DDS, MADDS, and PYR after 24 h were (mean +/- SEM) 374 +/- 31.3, 310 +/- 30.4, and 121 +/- 7.9 ng/ml, respectively. The 72-h serum concentrations of DDS, MADDS, and PYR were (mean +/- SEM) 134 +/- 21.6, 115 +/- 17.9, and 80 +/- 7.2 ng/ml, respectively. Serum concentrations of DDS and MADDS in many subjects after 120 h were less than 20 ng/ml, while mean +/- SEM concentration of PYR was 53 +/- 5.6 ng/ml. Acetylator phenotyping of the subjects showed that there were 31 (91%) fast acetylators, three (9%) intermediate acetylators, and no slow acetylators.
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PMID:Simultaneous estimation of serum concentrations of dapsone, monoacetyldapsone, and pyrimethamine in Chinese men on maloprim for malaria prophylaxis using reversed-phase high performance liquid chromatography. 390 34

The need to investigate further the phenomenon of sulfone-induced haemolysis is becoming greater as the use of sulfones may increase, particularly for malaria therapy in areas where Plasmodium falciparum is found to be resistant to chloroquine. The authors report on studies of the haemolytic effects of diaphenylsulfone (DDS) administered orally, in doses ranging from 25 mg to 300 mg daily for 21 days, to normal healthy men and to healthy Negro men with deficiency of glucose-6-phosphate dehydrogenase (G-6-PD). The latter proved more susceptible to diaphenylsulfone-induced haemolysis than did normal men. There was a direct relationship between the dose of diaphenylsulfone and the extent of haemolysis in both groups of men studied. Comparison of the haemolytic effects of diaphenylsulfone with those of the antimalarial drug primaquine revealed that, on a dose for weight basis, diaphenylsulfone is more haemolytic than primaquine in normal persons and less so in G-6-PD-deficient persons. A marked decrease in the content of reduced glutathione (GSH) in red cells, comparable to the changes in levels of erythrocytic GSH known to occur during primaquine-induced haemolysis, occurred just before and early during the acute haemolytic episode that resulted from administration of diaphenylsulfone to G-6-PD-deficient subjects; in contrast, levels of erythrocytic GSH increased early during the course of diaphenylsulfone-induced haemolysis in normal men.
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PMID:The haemolytic effects of diaphenylsulfone (DDS) in normal subjects and in those with glucose-6-phosphate-dehydrogenase deficiency. 529 1

The reasons for absenteeism during leprosy treatment were investigated in a rural area of southern India. 120 patients known as "absents" to most controls were first interviewed and the major causes for absenteeism thus determined. A questionnaire was then elaborated in view to reveal these principal causes with efficiency and was applied by 8 investigators to 1200 patients, mostly absents or irregular to medical visits. 620 were selected at random for computer analysis. Results suggest that anxiety for loss of income while attending the medical control and erroneous impression of cure as soon as skin lesions have improved could be of first importance. Nevertheless no relation appears between absenteeism and income level, number of persons depending on the patient, or type of leprosy. Adverse reactions attributed to DDS are also frequently reported, especially fever, because of confusion with leprosy reactions, malaria and any other febrile condition. Assiduity to medical visits could be determined during the year following this study in 1191 of the 1200 patients showing clear beneficial effect over this period.
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PMID:[Absenteeism during treatment for leprosy. Analysis of causes as apparent from a survey in southern India]. 681 53

Dapsone (DDS) is useful in the treatment of a number of inflammatory conditions which are characterized by neutrophil infiltration. It is the drug of choice for the treatment of leprosy and prophylaxis of malaria. Haematological side effects of methaemoglobinaemia and haemolysis have been long recognized. However, the frequency and severity of these side effects in patients already treated with DDS as a single drug or as part of a multidrug therapy (MDT) have not been well documented. We report herein an investigation of the effect of dapsone long-term treatment on the haematological and biochemical alterations in leprosy patients undergoing dapsone as a single drug (DDS group) or as part of a multidrug therapy in combination with rifampin and clofazimine (MDT group). Methaemoglobinaemia and haemolytic anaemia were the principal side effects observed. Reticulocytes were found to be elevated (> 1.5%) in 90% of the patients. Heinz bodies were also detected (6.6% of the patients). The osmotic fragility test showed a reduction in cell resistance and in the evaluation of white cells a severe eosinophilia was found. Hepatic, pancreatic and renal evaluation by the determination of biochemical parameters showed rare and occasional changes of no apparent clinical significance. We conclude that haematological side effects of dapsone are significant even at doses currently used to treat leprosy (100 mg/day) and that rifampin and clofazimine do not increase the incidence of these effects during long-term treatment.
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PMID:Haematological and biochemical alterations in leprosy patients already treated with dapsone and MDT. 937 43

The synergistic antifolate combination of chlorproguanil with dapsone (CPG-DDS; LAPDAP) is being developed by a public-private partnership as a low-cost treatment for uncomplicated falciparum malaria. LAPDAP is rapidly eliminated from the body, giving it low selection pressure for drug resistance. Clinical cases with sulphadoxine-pyrimethamine (SP)-resistant infections acquired in Africa have been predicted to be responsive to LAPDAP, and clinical evidence is available to support this. A regulatory dossier is being prepared for simultaneous submission to the UK Medicines Control Agency and African licencing authorities. The team working on LAPDAP has also started to develop the triple combination of chlorproguanil-dapsone-artesunate (CDA) as a low-cost combination therapy for uncomplicated falciparum malaria. Although LAPDAP does not have regulatory approval (and development of CDA is at an early stage), the development team is keen to communicate with public health scientists to try to anticipate the policy and implementation hurdles that lie ahead. This short paper outlines the current stages that LAPDAP and CDA have reached, and sketches the anticipated public health issues.
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PMID:Chlorproguanil-dapsone (LAPDAP) for uncomplicated falciparum malaria. 1170 51

Resistance is readily produced in rodent malaria using the single-dose, '2%-relapse technique' (2%RT) against the individual compounds chlorproguanil (CPG), chlorcycloguanil (CCG), cycloguanil, dapsone (DDS) and artesunate (ASN). Using the '4-day test', a low level of synergism or a simple additional action between CPG and DDS was observed with multiple dosing of these two compounds in a combination. Resistance to a 1 : 3 combination of CPG-DDS was selected in each of three parasite lines: Plasmodium berghei NK65, P. yoelii ssp. NS and P. chabaudi AS. Of these lines, P. chabaudi AS was found to be the most sensitive to the 1 : 3 combination in the 2%RT (and was also previously found to be the most sensitive when the compounds were used individually). Plasmodium chabaudi AS was also the line found most sensitive to a 7 : 21 : 300 combination of CPG-DDS-ASN (CDA). In mice infected with P. chabaudi AS, compared with the use of the individual components, the CPG-DDS combination only a gave a modest level of protection (as indicated by the increase in the time required to select resistance in the 2%RT) but the triple CDA combination was totally effective over the duration of the experiment. New pharmacokinetic data to be reported elsewhere indicate, however, that the antimalarial action of CPG in mice is exerted by a mechanism that is not associated with the drug's conversion to the antifolate triazine, CCG. The question thus arises as to how, in the present model, the protective action of CDA was effected. The present results nevertheless reinforce the hypothesis that a CDA combination, appropriately proportioned for human use, should be of practical value, in protecting the individual components, when used for the treatment of multidrug-resistant P. falciparum, and possibly other Plasmodium species, in endemic areas. Clinical trials, both with a CPG-DDS combination (Lapdap) and CDA, are currently under way in tropical Africa. Further studies are now required to determine whether DDS, CPG or an as-yet unidentified metabolite of CPG interact with ASN, and whether a simple double combination of ASN with one or other of these would be as protective, against the selection of resistance, as CDA.
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PMID:The chemotherapy of rodent malaria. LXIII. Drug combinations to impede the selection of drug resistance, part 6: the potential value of chlorproguanil and dapsone in combination, and with the addition of artesunate. 1600 5

Dapsone (DDS) is currently used in the treatment of leprosy, malaria and in infections with Pneumocystis jirovecii and Toxoplasma gondii in AIDS patients. Adverse effects of DDS involve methemoglobinemia and hemolysis and, to a lower extent, liver damage, though the mechanism is poorly characterized. We evaluated the effect of DDS administration to male and female rats (30 mg/kg body wt, twice a day, for 4 days) on liver oxidative stress through assessment of biliary output and liver content of reduced (GSH) and oxidized (GSSG) glutathione, lipid peroxidation, and expression/activities of the main antioxidant enzymes glutathione peroxidase, superoxide dismutase, catalase and glutathione S-transferase. The influence of DDS treatment on expression/activity of the main DDS phase-II-metabolizing system, UDP-glucuronosyltransferase (UGT), was additionally evaluated. The involvement of dapsone hydroxylamine (DDS-NHOH) generation in these processes was estimated by comparing the data in male and female rats since N-hydroxylation of DDS mainly occurs in males. Our studies revealed an increase in the GSSG/GSH biliary output ratio, a sensitive indicator of oxidative stress, and in lipid peroxidation, in male but not in female rats treated with DDS. The activity of all antioxidant enzymes was significantly impaired by DDS treatment also in male rats, whereas UGT activity was not affected in any sex. Taken together, the evidence indicates that DDS induces oxidative stress in rat liver and that N-hydroxylation of DDS was the likely mediator. Impairment in the activity of enzymatic antioxidant systems, also associated with DDS-NHOH formation, constituted a key aggravating factor.
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PMID:Dapsone induces oxidative stress and impairs antioxidant defenses in rat liver. 1860 5


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