Dapsone as treatment adjunct in ARDS.

Multiple pharmacological interventions tested over the last decades have failed to reduce ARDS mortality. This short note recounts past data indicating that (i) neutrophils home along an IL-8 gradient, (ii) in ARDS, massive neutrophil accumulation and degranulation in and along bronchoalveolar spaces contributes to damage and hypoxia, (iii) large increases in IL-8 are one of the chemotaxic signals drawing neutrophils to the ARDS lung, and (iv) old data from dermatology and glioblastoma research showed that the old drug against Hansen's disease, dapsone, inhibits neutrophils' chemotaxis to IL-8. Therefore dapsone might lower neutrophils' contributions to ARDS lung pathology. Dapsone can create methemoglobinemia that although rarely problematic it would be particularly undesirable in ARDS. The common antacid drug cimetidine lowers risk of dapsone related methemoglobinemia and should be given concomitantly.

Clinical pharmacokinetics of thalidomide

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions in being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1-2mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUCoo) of 18mg - h/L, apparent elimination half-life of 6 hours and apparent systemic clearence of 10 L/H. Thalidomide pharmacokinetics are best described by a one-comportment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacolinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than in absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accululation, with Css of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400mg. Because of the low solubility of thalidomide Cmax is less than proportional to dose, and tmax is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokonetics are not expected to change in patients with impaired liver...

Dapsone-induced acute pancreatitis.

OBJECTIVE: To report a case of acute pancreatitis associated with dapsone use. CASE SUMMARY: An 87-year-old white man was prescribed dapsone for dermatitis herpetiformis. Four weeks later, he developed acute abdominal pain requiring hospitalization. The patient had elevated serum amylase and lipase levels. Laboratory test results for other possible etiologies were negative. His symptoms resolved when dapsone was discontinued. Dapsone was reintroduced for exacerbation of dermatitis herpetiformis 4 months later. The patient again had severe abdominal pain with high amylase and lipase levels. Again, symptoms resolved following dapsone discontinuation. DISCUSSION: Only 1 other case of pancreatitis associated with dapsone was found in a MEDLINE search of the literature (1966-June 2003) using the key terms dapsone and pancreatitis. An objective causality assessment revealed dapsone to be a probable cause of acute pancreatitis, based on the Naranjo probability scale. Drugs should always be considered as causative factors for pancreatitis in patients without known risk factors. Dapsone is increasingly used as a second line of treatment of Pneumocystis carinii pneumonia (PCP). The recognition of dapsone-induced pancreatitis is of particular importance in these patients. CONCLUSIONS: While dapsone is traditionally used for the treatment of leprosy and dermatitis herpetiformis, its use for PCP prophylaxis, malaria, brown recluse spider bites, and acne is not uncommon. Pancreatitis is an uncommon adverse effect of dapsone, and greater awareness of this association will prompt a high index of suspicion in an appropriate clinical setting. Further reporting of cases and clinical research of drug-induced pancreatitis is indicated.

Efeito hemoprotetor da cimetidina na metemoglobinemia induzida pela dapsona em regime de dose única em ratos / Hemoprotective effect of cimetidine single dosis schedule on dapsone induced methemoglobinemia in rats

A dapsona (4,4-diaminodifenilsulfona), quimioterápico bacteriostático utilizado no tratamento da hanseníase, vem sendo associada a intercorrências clínicas, principalmente devido à sua hemotoxicidade caracterizada por metemoglobinemia e anemia hemolítica. A N-hidroxilação, uma das principais vias de biotransformação da dapsona, vem sendo associada constantemente a quadros de metemoglobinemia decorrentes de sua utilização. Com o objetivo de verificar-se a inibição reversível da via de bioativação toxicológica, sem alterar as vias de destoxificação do composto, a acetilação citosólica, a cimetidina foi administrada concomitantemente à dapsona em ratos machos Wistar, com peso variando entre 200 e 220 g, divididos em 8 grupos (n=6 por grupo), em estudo de dose única...

Efeito de antagonistas de receptores H2 na metemoglobinemia induzida pela dapsona em ratos / ?

Dapsona, farmaco bacteriostatico utilizado no tratamento da hanseniase, vem sendo associado a intercorrencias clinicas, principalmente devido a sua hemotoxicidade. A N-hidroxilacao, uma das principais vias de biotransformacao da dapsona vem sendo associada constantemente a quadros de metemoglobinemia decorrentes do uso da dapsona. Com objetivo de se verificar a inibicao reversivel desta via de bioativacao toxicologica, sem alterar os caminhos de detoxificacao do farmaco, a aceltilacao citosolica, a cimetidina, ranitidina e famotidina foram administradas concomitantemente a dapsona em ratos machos Wistar, com peso variando entre 200 e 250g divididos em 30 grupos (n=6), em estudo de doses unicas e multiplas. Apos as administracoes, os ratos foram submetidos a coleta de sangue

In vitro and in vivo dapsone release from hydroxyapatite reservoirs.

Dapsone is a drug which is administered orally, on a daily basis, for four to five years as a cure for leprosy. The major problems associated with dapsone therapy include hemolysis, methemoglobinemia and patient non-compliance. Cimetidine reduces the side effects of dapsone and increases its levels in the blood. A ceramic drug delivery system was developed to maintain therapeutic levels of dapsone for an extended period of time and to alleviate associated side effects. In vitro release of commercial dapsone tablets (100 mg) and cimetidine pellets (400 mg) from hydroxyapatite reservoirs was studied in 100 ml absolute ethanol at 37 degrees C. Hydroxyapatite (HA) reservoirs loaded with one dapsone tablet released the drug at the rate of 8.3 mg/day for nine days, after which a much slower release occurred for another three days. With a load of two dapsone tablets, the rate of release was 6.7 mg/day for four weeks. HA reservoirs loaded with one cimetidine pellet delivered the drug at a rate of 25 mg/day for sixteen days. Combining both drugs in a single reservoir did not affect their respective release rates. When implanted subcutaneously in rats, HA reservoirs loaded with one dapsone tablet appeared to be well tolerated. After nine weeks, 77 mg of dapsone had been released. These experiments showed that HA reservoirs can be used to deliver dapsone and cimetidine in vivo.

A study of the immunological effects of cimetidine in patients with lepromatous leprosy.

To test the capacity of cimetidine to enhance cellular immunity in patients with lepromatous leprosy (LL), cimetidine was given for one month to 29 inactive LL patients and 3 active LL patients. Immune function was monitored with skin tests (lepromin, PPD, candida, and trichopytin), lymphocyte transformation tests (phytohemagglutinin, BCG, and Dharmendra lepromin), and quantitation of peripheral blood lymphocyte subpopulations. A small but significant "booster" response to PPD was the only change observed in the study of patients with inactive disease, and leprosy-related reactions did not occur. In the few active LL patients studied, neither immune enhancement nor leprosy-related reactions were observed. The results of this investigation suggest that cimetidine can be used safely in patients with inactive lepromatous leprosy.

[Relevant inhibition of acetylcholinesterase with H2-receptor antagonists]. / Relevante Hemmung der Acetylcholinesterase durch H2-Rezeptorantagonisten?

An inhibition of acetylcholinesterase activity by ranitidine and cimetidine as described by Hansen and Bertl (Z. Gastroenterol. 21: 164, 1983; Arzneimittelforsch. 33: 161, 1983) could only be confirmed by use of 1000-fold higher concentrations of the H2-antagonists (ID50 for ranitidine: 3,2 X 10(-4) M, for cimetidine: 3,1 X 10(-2) M) than those reported by the authors. The discrepancy may be explained by the fact that the authors did not consider the dilution factor in their method. In a typical therapeutic situation in 8 patients with ranitidine 150 mg twice daily and cimetidine 400 mg twice daily an inhibiton of the acetylcholinesterase could not be demonstrated. The inhibition of the acetylcholinesterase activity by H2-antagonists is of no practical relevance.