While leprosy (Hansen’s disease) is a rare entity in Western countries, it is a significant public health problem in Third World nations such as India.
Chaulmoogra oil (with weak antileprotic property) had been used extensively in the olden days before the advent of sulfones which constitute the sheet anchor of antileprotic therapy today. Clofazimine is used in resistant cases, while drugs such as rifampicin, ethionamide, thalidomide, thiac-etazone, and sulfadoxine have also been used with varying degree of success. Newer drugs which appear promising in the treatment of leprosy include minocycline, clarithromycin, pefloxacin, and ofloxacin.
The sulfones are chemically related to sulfonamides and are derivatives of 4,4´-diaminodiphenylsulfone or dapsone, which is in fact the most widely used antileprotic even today, more than 50 years after it was first introduced. Sulfoxone sodium (not yet available in India) is used when dapsone produces severe gastric distress.
Dapsone is marketed in India by Burroughs Wellcome as 25 mg, 50 mg, and 100 mg tablets for oral administration. It is a bacteriostatic antileprotic and anti-inflammatory drug used in the treatment of leprosy, dermatitis herpetiformis, vasculitis, pemphigus, and generalised pustular psoriasis. It is also widely used in AIDS patients for the treatment and prophylaxis of PCP (Pneumocystis carinii pneumonia), and prophylaxis against toxoplasmosis.
Following absorption, dapsone is widely distributed to tissues. The concentrations in most organs approximate the plasma concentration. Dapsone readily penetrates into nerve tissue with a nerve tissue concentration approximately the same as the plasma concentration. Peak serum concentra-tions are found at 2 to 8 hours after oral dosing. The mean elimination half-life of dapsone is about 30 hours, which may be prolonged to 2 to 4 days after overdose. Dapsone is acetylated by N-acetyltransferase found in the liver and jejunal mucosa primarily to monoacetyldapsone (MADDS). It is also hydroxylated by the mixed function oxidase system in the pres-ence of oxygen and NADPH. The hydroxylated metabolite, N-hydroxydapsone (NOH-dapsone), may be responsible for the haematologic manifestations (methaemoglobinaemia and haemolysis) seen in overdose. Dapsone and monoacetyldap-sone may be excreted in the urine as glucuronide or sulfate conjugates.
Adverse effects of dapsone therapy include haemolysis (with reticulocytosis and Heinz body formation), methaemo-globinaemia, nausea, vomiting, headache, insomnia, blurred vision, and peripheral neuropathy. Occasionally Sulfonesyndrome may develop in some malnourished patients 5 to 6weeks after beginning the therapy, which is characterised by fever, exfoliative dermatitis, hepatic necrosis with jaundice, lymphadenopathy, methaemoglobinaemia, and anaemia. Dapsone has been associated with clinical exacerbation of porphyria and is NOT indicated in porphyric patients.
Cases of dapsone overdose have been reported, usually due to calculation errors resulting in vomiting, abdominal pain, haemolysis, methaemoglobinaemia, sulfhaemoglo-binaemia, deep cyanosis, restlessness, blurred vision, and convulsions. Giddiness, hallucinations, dizziness, agitation, and confusion have been reported following overdoses. Methaemoglobinaemia, haemolysis, and CNS stimulation are the most common manifestations. Death may occur. A glucose -6-phosphate dehydrogenase deficient individual has about a 2-fold increase in sensitivity toward dapsone-induced haemolytic anaemia. Animal studies have shown a decrease in methaemoglobin formation when cimetidine was given concur-rently with a once a day dosing. When tested in humans given 400 mg of cimetidine three times daily for 3 days before and 4 days after dapsone, drug concentrations increased 30% (less metabolism). This has not been tried in the overdose situation.
Dapsone is contraindicated in pregnancy due to its ability to produce anaemia or methaemoglobinaemia.
Drug-induced psychosis has been reported during both therapeutic use and following intentional ingestion (2.5 gm) resulting in extreme agitation and violence.
The usual fatal dose is 2 to 5 grams for an adult. Plasma levels of over 10 mg/L are associated with serious toxicity. Studies of haemolysis such as haptoglobin and free haemo-globin, and reticulocyte counts may be useful to monitor haemolysis. Other tests that could help aid the diagnosis of latent methaemoglobinaemia and haemolytic anaemia include red cell fragility, Heinz bodies, and lactic acid dehydrogenase. Monitor urine for haemoglobinuria. Dapsone and its metabolite monoacetyldapsone (MADDS) levels can be measured in urine, and if available may be useful to follow urinary excretion.
Treatment involves gastric decontamination and adminis-tration of methylene blue (to correct methaemoglobinaemia), at a dose of 1 to 2 mg/kg IV, given over 5 to 10 minutes. This may have to be repeated several times over every 4 hours for a number of days. Caution: Large doses of methylene blue iself may cause methaemoglobinaemia or haemolysis. Infusion of packed red blood cells may be required. If cyanosis fails to clear after treatment of presumed methaemoglobinaemia with methylene blue, or recurs late in the clinical course, sulfhae-moglobinaemia may be present. Convulsions can be controlled by diazepam or phenytoin IV in the usual doses. Blurred vision sometimes responds to prednisolone (75 mg/day for 1 week, and then tapered off). However, corticosteroids are of no use in the management of haemolysis. Ascorbic acid has been tried, but there is no clear-cut indication as to its efficacy. Oxygen inhalation therapy is not beneficial.
Decontamination with activated charcoal is useful in the early stages of dapsone overdose. Extracorporeal methods of eliminating the drug from the blood stream can be tried, but they have no proven value. However there are reports of beneficial effects with charcoal haemoperfusion and haemodialysis.
It is a phenazine dye which is used in dapsone-resistant leprosy and lepra reactions (erythema nodosum leprosum).
Adverse effects include a reddish or brownish skin discol-ouration, diarrhoea, abdominal pain, loss of weight, and bull’s eye retinopathy. There may be deposition of clofazimine crys-tals in gut wall tissue, mesenteric lymph nodes, and cytoplasm of alveolar macrophages. Clofazimine crosses the placenta and is present in breast milk. Infants may be pigmented at birth, or subsequently from ingesting breast milk.
Diagnosis can be established by thin layer chromatography, and X-ray abnormalities of small bowel (alternating segments of constriction and dilation, cogency of mucosal folds, and circumscribed “polypoid” areas).
Treatment is symptomatic and supportive. Periodic fundos-copy (every 4 months) is advised in all patients receiving clofazimine.