Aleprostatic agent is a drug that interferes with proliferation of the bacterium that causesleprosy.[1][2]
The following agents are leprostatic agents:[3]
Leprosy is a chronic infectious disease caused byMycobacterium leprae. Host defenses are crucial in determining the patient's response to the disease, the clinical presentation, and the bacillary load. These factors also influence the length of therapy and the risk of adverse reactions to medication.
M. leprae cannot be grown on routine laboratory culture media, so drug sensitivity testing in vitro is not possible. Growth and drug susceptibility testing are done by injecting into animal models. One description of a clinical picture that results fromtuberculoid leprosy is characterized by intactcell-mediated immunity, a positivelepromin skin reaction,granuloma formation, and a relative paucity ofbacilli.
At the other extreme,lepromatous leprosy is characterized by depressed cell-mediated immunity, numerous bacilli within the tissues, no granulomas, and a negative skin test for lepromin. Within these two extremes are the patients with an intermediate or borderline form of leprosy who show a variable lepromin reaction and few bacilli; they may progress to either tuberculoid or lepromatousleprosy.
Current recommendations for the treatment of leprosy suggest multidrug regimens rather thanmonotherapy because such a regimen has proven to be more effective, delays the emergence of resistance, prevents relapse, and shortens the duration of therapy. Established agents used in the treatment of leprosy aredapsone,clofazimine, andrifampicin. Treatment of tuberculoidleprosy is continued for at least 1 to 2 years, while patients with lepromatous leprosy are generally treated for 5 years. In addition tochemotherapy, patients with leprosy needpsychosocial support, rehabilitation, and surgical repair of any disfiguration.
The sulfones are structural analogues ofPABA and are competitive inhibitors offolic acid synthesis. Sulfones arebacteriostatic and are used only in the treatment of leprosy. Dapsone (Avlosulfon) is the most widely used sulfone for the long-term therapy of leprosy. Although the sulfones are highly effective against most strains of M. leprae, a small number of organisms, especially those found in lepromatous leprosy patients, are less susceptible and can persist for many years, resulting in relapse. Before the introduction of current multidrug regimens, resistance rates were as high as 20% with dapsone monotherapy.
Sulfones, such as dapsone and sulfoxone (Diasone), are well absorbed orally and are widely distributed throughout body fluids and tissues. Peak concentrations of dapsone are reached within 1 to 3 hours of oral administration and have a half-life of 21 to 44 hours; about 50% of administered dapsone is bound toserum proteins. The sulfones tend to remain in the skin, muscle, kidney, and liver up to 3 weeks after therapy is stopped. The concentration in inflamed skin is 10 to 15 times higher than that found in normal skin. The sulfones are retained in the circulation for a long time (12–35 days) because ofhepatobiliary drug recirculation. The sulfones areacetylated in the liver, and 70 to 80% of drug is excreted in the urine asmetabolites.Dapsone, combined with other antileprosy agents likerifampicin andclofazimine, is used in the treatment of both multibacillary and paucibacillary M. leprae infections.
Dapsone is also used in the treatment and prevention ofPneumocystis carinii pneumonia inAIDS patients who are allergic to or intolerant oftrimethoprim–sulfamethoxazole. Acedapsone is a derivative of dapsone that has little activity against M. leprae but is converted to an active dapsone metabolite. It is a long-acting intramuscular repository form of dapsone with ahalf-life of 46 days. It may prove useful in leprosy patients who cannot tolerate long-term oral dapsone therapy.
The sulfones can produce non-hemolyticanemia,methemoglobinemia, and sometimes acutehemolytic anemia in persons with aglucose-6-phosphate dehydrogenase deficiency. Within a few weeks of therapy some patients may develop acute skin lesions described as sulfone syndrome or dapsonedermatitis. Some rare side effects include fever,pruritus,paresthesia, reversibleneuropathy, andhepatotoxicity.
Clofazimine is a weaklybactericidal dye that has some activity against M. leprae. Its precise mechanism of action is unknown but may involvemycobacterial DNA binding. Its oral absorption is quite variable, with 9 to 70% of the drug eliminated in the feces. Clofazimine achieves significant concentrations in tissues, including thephagocytic cells; it has aplasma half-life of 70 days. It is primarily excreted in bile, with less than 1% excretion in urine.
Clofazimine is given to treat sulfone-resistant leprosy or to patients who are intolerant to sulfones. It also exerts an antiinflammatory effect and preventserythema nodosum leprosum, which can interrupt treatment with dapsone. This is a major advantage of clofazimine over other antileprosy drugs. Ulcerative lesions caused byMycobacterium ulcerans respond well to clofazimine. It also has some activity against M. tuberculosis and can be used as last resort therapy for the treatment ofMDR tuberculosis. The most disturbing adverse reaction to clofazimine is a red-brown discoloration of the skin, especially inlight-skinned persons. A rare but serious adverse reaction is acute abdominal pain significant enough to warrant exploratorylaparotomy orlaparoscopy. Other infrequent side effects includesplenic infarction,bowel obstruction,paralytic ileus, andupper GI bleeding.
Ethionamide andprothionamide are weakly bacteriocidal against M. leprae and can be used as alternatives to clofazimine in the treatment of MDR leprosy. Both cause GI intolerance and are expensive.
