Leprostatic agent
Encyclopedia
A Leprostatic agent is a drug that interferes with proliferation of the bacterium that causes leprosy
.
The following agents are leprostatic agents:
Leprosy is a chronic infectious disease caused by Mycobacterium 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 from tuberculoid leprosy
is characterized by intact cell-mediated immunity
, a positive lepromin
skin reaction, granuloma
formation, and a relative paucity of bacilli
.
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 lepromatous
leprosy.
Current recommendations for the treatment of leprosy suggest multidrug regimens rather than monotherapy 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 are dapsone
, clofazimine
, and rifampin. Treatment of tuberculoid
leprosy is continued for at least 1 to 2 years, while patients with lepromatous leprosy are generally treated for 5 years. In addition to chemotherapy
, patients with leprosy need psychosocial
support, rehabilitation, and surgical repair of any disfiguration.
and are competitive inhibitors of folic acid
synthesis. Sulfones are bacteriostatic 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 to serum 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 of hepatobiliary drug recirculation. The sulfones are acetylated in the liver, and 70 to 80% of drug is excreted in the urine as metabolites.
Dapsone, combined with other antileprosy agents like rifampin and clofazimine
, is used in the treatment of both multibacillary and paucibacillary M. leprae infections.
Dapsone is also used in the treatment and prevention of Pneumocystis carinii pneumonia in AIDS
patients who are allergic to or intolerant of trimethoprim–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 a half-life
of 46 days. It may prove useful in leprosy patients who cannot tolerate long-term oral dapsone therapy.
The sulfones can produce non-hemolytic anemia
, methemoglobinemia
, and sometimes acute hemolytic anemia
in persons with a glucose-6-phosphate dehydrogenase
deficiency. Within a few weeks of therapy some patients may develop acute skin lesions described as sulfone syndrome or dapsone dermatitis
. Some rare side effects include fever, pruritus, paresthesia
, reversible neuropathy, and hepatotoxicity
.
is a weakly bactericidal dye that has some activity against M. leprae. Its precise mechanism of action is unknown but may involve mycobacterial 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 the phagocytic cells; it has a plasma 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 prevents erythema nodosum leprosum, which can interrupt treatment with dapsone. This is a major advantage of clofazimine over other antileprosy drugs. Ulcerative lesions caused by Mycobacterium ulcerans
respond well to clofazimine. It also has some activity against M. tuberculosis and can be used as last resort therapy for the treatment of MDR tuberculosis
. The most disturbing adverse reaction to clofazimine is a red-brown discoloration of the skin, especially in
light-skinned persons. A rare but serious adverse reaction is acute abdominal pain significant enough to warrant exploratory laparotomy
or laparoscopy
. Other infrequent side effects include splenic infarction
, bowel obstruction
, paralytic ileus, and upper GI bleeding
.
and prothionamide 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.
Leprosy
Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...
.
The following agents are leprostatic agents:
- acedapsoneAcedapsoneAcedapsone is an antimicrobial drug, which also has antimalarial activity.Acedapsone, or 1399 F, is a diacetyl compound, derived from dapsone...
- clofazimineClofazimineClofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients and...
- dapsoneDapsoneDapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
- desoxyfructo-serotoninDesoxyfructo-serotoninDesoxyfructo-serotonin is a leprostatic agent....
- diucifonDiucifonDiucifon is a leprostatic agent....
- ethionamideEthionamideEthionamide is an antibiotic used in the treatment of tuberculosis.It is a prodrug.It has been proposed for use in combination with gatifloxacin.The action may be through disruption of mycolic acid.-Synthesis:...
- rifampin
- rifapentineRifapentineRifapentine is an antibiotic drug used in the treatment of tuberculosis.-History:...
- sulfameter
- thalidomideThalidomideThalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
Leprosy is a chronic infectious disease caused by Mycobacterium leprae
Mycobacterium leprae
Mycobacterium leprae, also known as Hansen’s coccus spirilly, mostly found in warm tropical countries, is a bacterium that causes leprosy . It is an intracellular, pleomorphic, acid-fast bacterium. M. leprae is an aerobic bacillus surrounded by the characteristic waxy coating unique to mycobacteria...
. 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 from tuberculoid leprosy
Tuberculoid leprosy
Tuberculoid leprosy is a skin condition characterized by solitary skin lesions that are asymmetrically distributed....
is characterized by intact cell-mediated immunity
Cell-mediated immunity
Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...
, a positive lepromin
Lepromin
The lepromin skin test is used to determine what type of leprosy a person has. It involves the injection of a standardized extract of the inactivated "leprosy bacillus", under the skin...
skin reaction, granuloma
Granuloma
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...
formation, and a relative paucity of bacilli
Bacilli
Bacilli refers to a taxonomic class of bacteria. It includes two orders, Bacillales and Lactobacillales, which contain several well-known pathogens like Bacillus anthracis .-Ambiguity:...
.
At the other extreme, lepromatous leprosy
Lepromatous leprosy
Lepromatous leprosy is a skin condition consisting of pale macules.It results from the failure of Th1 cell activation which is necessary to eradicate the parasite....
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 lepromatous
leprosy.
Kinds of antileprotic drugs
- SulfoneSulfoneA sulfone is a chemical compound containing a sulfonyl functional group attached to two carbon atoms. The central hexavalent sulfur atom is double bonded to each of two oxygen atoms and has a single bond to each of two carbon atoms, usually in two separate hydrocarbon substituents.-IUPAC name and...
- DapsoneDapsoneDapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
(DDS), - PhenazinePhenazinePhenazine , also called azophenylene, dibenzo-p-diazine, dibenzopyrazine, and acridizine, is a dibenzo annulated pyrazine and the parent substance of many dyestuffs, such as the eurhodines, toluylene red, indulines and safranines.-Synthesis:A classic method for the synthesis of phenazine is the...
derivative - ClofazimineClofazimineClofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients and...
, - Antitubercular drugs - Rifampin, EthionamideEthionamideEthionamide is an antibiotic used in the treatment of tuberculosis.It is a prodrug.It has been proposed for use in combination with gatifloxacin.The action may be through disruption of mycolic acid.-Synthesis:...
, - SolapsoneSolapsoneSolasulfone is an antileprotic drug....
, - Other antibiotics - Oflaxacin, MinocyclineMinocyclineMinocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type...
, ClarithromycinClarithromycinClarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
,
Current recommendations for the treatment of leprosy suggest multidrug regimens rather than monotherapy 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 are dapsone
Dapsone
Dapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
, clofazimine
Clofazimine
Clofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients and...
, and rifampin. Treatment of tuberculoid
leprosy is continued for at least 1 to 2 years, while patients with lepromatous leprosy are generally treated for 5 years. In addition to chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, patients with leprosy need psychosocial
Psychosocial
For a concept to be psychosocial means it relates to one's psychological development in, and interaction with, a social environment. The individual needs not be fully aware of this relationship with his or her environment. It was first commonly used by psychologist Erik Erikson in his stages of...
support, rehabilitation, and surgical repair of any disfiguration.
Dapsone and Sulfones
The sulfones are structural analogues of PABA4-Aminobenzoic acid
4-Aminobenzoic acid is an organic compound with the formula H2NC6H4CO2H. PABA is a white grey crystalline substance that is only slightly soluble in water...
and are competitive inhibitors of folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
synthesis. Sulfones are bacteriostatic 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 to serum 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 of hepatobiliary drug recirculation. The sulfones are acetylated in the liver, and 70 to 80% of drug is excreted in the urine as metabolites.
Dapsone, combined with other antileprosy agents like rifampin and clofazimine
Clofazimine
Clofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients and...
, is used in the treatment of both multibacillary and paucibacillary M. leprae infections.
Dapsone is also used in the treatment and prevention of Pneumocystis carinii pneumonia in AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
patients who are allergic to or intolerant of trimethoprim–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 a half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
of 46 days. It may prove useful in leprosy patients who cannot tolerate long-term oral dapsone therapy.
The sulfones can produce non-hemolytic anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, methemoglobinemia
Methemoglobinemia
Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood. Methemoglobin is an oxidized form of hemoglobin that has an increased affinity for oxygen, resulting in a reduced ability to release oxygen to tissues. The oxygen–hemoglobin...
, and sometimes acute hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
in persons with a glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase is a cytosolic enzyme in the pentose phosphate pathway , a metabolic pathway that supplies reducing energy to cells by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate...
deficiency. Within a few weeks of therapy some patients may develop acute skin lesions described as sulfone syndrome or dapsone dermatitis
Dermatitis
-Etymology:Dermatitis derives from Greek derma "skin" + -itis "inflammation" and genetic disorder.-Terminology:There are several different types of dermatitis. The different kinds usually have in common an allergic reaction to specific allergens. The term may describe eczema, which is also called...
. Some rare side effects include fever, pruritus, paresthesia
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
, reversible neuropathy, and hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
.
Clofazimine
ClofazimineClofazimine
Clofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients and...
is a weakly bactericidal dye that has some activity against M. leprae. Its precise mechanism of action is unknown but may involve mycobacterial 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 the phagocytic cells; it has a plasma half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
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 prevents erythema nodosum leprosum, which can interrupt treatment with dapsone. This is a major advantage of clofazimine over other antileprosy drugs. Ulcerative lesions caused by Mycobacterium ulcerans
Mycobacterium ulcerans
Mycobacterium ulcerans is a slow-growing mycobacterium that classically infects the skin and subcutaneous tissues, giving rise to indolent nonulcerated and ulcerated lesions. After tuberculosis and leprosy, Buruli ulcer is the third most common mycobacteriosis of humans. M...
respond well to clofazimine. It also has some activity against M. tuberculosis and can be used as last resort therapy for the treatment of MDR tuberculosis
Multi-drug-resistant tuberculosis
Multi-drug-resistant tuberculosis is defined as TB that is resistant at least to isoniazid and rifampicin , the two most powerful first-line anti-TB drugs...
. The most disturbing adverse reaction to clofazimine is a red-brown discoloration of the skin, especially in
light-skinned persons. A rare but serious adverse reaction is acute abdominal pain significant enough to warrant exploratory laparotomy
Laparotomy
A laparotomy is a surgical procedure involving a large incision through the abdominal wall to gain access into the abdominal cavity. It is also known as coeliotomy.- Terminology :...
or laparoscopy
Laparoscopy
Laparoscopy is an operation performed in the abdomen or pelvis through small incisions with the aid of a camera...
. Other infrequent side effects include splenic infarction
Splenic infarction
In medicine, splenic infarction is a condition in which oxygen supply to the spleen is interrupted, leading to partial or complete infarction in the organ....
, bowel obstruction
Bowel obstruction
Bowel obstruction is a mechanical or functional obstruction of the intestines, preventing the normal transit of the products of digestion. It can occur at any level distal to the duodenum of the small intestine and is a medical emergency...
, paralytic ileus, and upper GI bleeding
Upper gastrointestinal bleeding
Upper gastrointestinal bleeding refers to hemorrhage in the upper gastrointestinal tract. The anatomic cut-off for upper GI bleeding is the ligament of Treitz, which connects the fourth portion of the duodenum to the diaphragm near the splenic flexure of the colon.Upper GI bleeds are considered...
.
Ethionamide and Prothionamide
EthionamideEthionamide
Ethionamide is an antibiotic used in the treatment of tuberculosis.It is a prodrug.It has been proposed for use in combination with gatifloxacin.The action may be through disruption of mycolic acid.-Synthesis:...
and prothionamide 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.