A leprostatic agent is a drug that interferes with proliferation of the bacterium that causes
leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...
.
The following agents are leprostatic agents:
*
acedapsone
Acedapsone ( INN) is an antimicrobial drug, which also has antimalarial activity.
Acedapsone is the INN for diacetyldapsone. It was synthesized and developed in 1937 by Ernest Fourneau and his team in the pharmaceutical chemistry laboratory of ...
*
clofazimine
Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to sup ...
*
dapsone
*
desoxyfructo-serotonin
*
diucifon
*
ethionamide
Ethionamide is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy. It is taken by mouth.
Et ...
*
rifampicin
*
rifapentine
Rifapentine, sold under the brand name Priftin, is an antibiotic used in the treatment of tuberculosis. In active tuberculosis it is used together with other antituberculosis medications. In latent tuberculosis it is typically used with isoniaz ...
*
sulfameter
*
thalidomide
Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications o ...
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
Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in ...
, a positive
lepromin The lepromin skin test is used to determine what type of leprosy a person is infected with. It involves the injection of a standardized extract of the inactivated "''leprosy bacillus''" (''Mycobacterium leprae'' or "Hansen's bacillus") under the ski ...
skin reaction,
granuloma formation, and a relative paucity of
bacilli
Bacilli is a taxonomic class of bacteria that includes two orders, Bacillales and Lactobacillales, which contain several well-known pathogens such as ''Bacillus anthracis'' (the cause of anthrax). ''Bacilli'' are almost exclusively gram-positi ...
.
At the other extreme,
lepromatous leprosy
Lepromatous leprosy is a form of leprosy characterized by pale macules in the skin.
It results from the failure of Th1 cell activation which is necessary to eradicate the mycobacteria (Th1 response is required to activate macrophages that engulf ...
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
*
Sulfone
In organic chemistry, a sulfone is a organosulfur 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 ...
-
Dapsone (DDS),
*
Phenazine
Phenazine is an organic compound with the formula (C6H4)2N2. It is a dibenzo annulated pyrazine, and the parent substance of many dyestuffs, such as the toluylene red, indulines, and safranines (and the closely related eurhodines). Phenazine ...
derivative -
Clofazimine
Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to sup ...
,
*
Antitubercular drugs -
Rifampicin,
Ethionamide
Ethionamide is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy. It is taken by mouth.
Et ...
,
*
Solapsone
Solasulfone is an antileprotic drug developed from the parent compound sulphetrone. It was first described and evaluated in the 1930s and 1940s as an antibacterial agent for the treatment of tuberculosis and various other infections, and later fo ...
,
* Other antibiotics -
Oflaxacin,
Minocycline
Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as pneumonia. It is generally less preferred than the tetracycline doxycycline. It is also ...
,
Clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clarith ...
,
Current recommendations for the treatment of leprosy suggest multidrug regimens rather than
monotherapy
Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...
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
Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to sup ...
, and
rifampicin. 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 (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
, patients with leprosy need
psychosocial
The psychosocial approach looks at individuals in the context of the combined influence that psychological factors and the surrounding social environment have on their physical and mental wellness and their ability to function. This approach is ...
support, rehabilitation, and surgical repair of any disfiguration.
Dapsone and Sulfones
The sulfones are structural analogues of
PABA and are competitive inhibitors of
folic acid
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
synthesis. Sulfones are
bacteriostatic
A bacteriostatic agent or bacteriostat, abbreviated Bstatic, is a biological or chemical agent that stops bacteria from reproducing, while not necessarily killing them otherwise. Depending on their application, bacteriostatic antibiotics, disinfect ...
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
The biliary tract, (biliary tree or biliary system) refers to the liver, gallbladder and bile ducts, and how they work together to make, store and secrete bile. Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and ...
drug recirculation. The sulfones are
acetylated
:
In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposit ...
in the liver, and 70 to 80% of drug is excreted in the urine as
metabolites
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...
.
Dapsone, combined with other antileprosy agents like
rifampicin and
clofazimine
Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to sup ...
, 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
''Pneumocystis'' pneumonia (PCP), also known as ''Pneumocystis jirovecii'' pneumonia (PJP), is a form of pneumonia that is caused by the yeast-like fungus ''Pneumocystis jirovecii''.
''Pneumocystis'' specimens are commonly found in the lungs of ...
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
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
of 46 days. It may prove useful in leprosy patients who cannot tolerate long-term oral dapsone therapy.
The sulfones can produce non-
hemolytic
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
,
methemoglobinemia, and sometimes acute
hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...
in persons with a
glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) () is a cytosolic enzyme that catalyzes the chemical reaction
: D-glucose 6-phosphate + NADP+ + H2O 6-phospho-D-glucono-1,5-lactone + NADPH + H+
This enzyme participates in the pentose phospha ...
deficiency. Within a few weeks of therapy some patients may develop acute skin lesions described as sulfone syndrome or dapsone
dermatitis
Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can ...
. Some rare side effects include fever,
pruritus
Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
,
paresthesia, reversible
neuropathy, and
hepatotoxicity
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...
.
Clofazimine
Clofazimine
Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to sup ...
is a weakly
bactericidal dye that has some activity against M. leprae. Its precise mechanism of action is unknown but may involve
mycobacterial
''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis ('' M. tuberculosis'') and ...
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 (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
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
Erythema nodosum (EN) is an inflammatory condition characterized by inflammation of the fat cells under the skin, resulting in tender red nodules or lumps that are usually seen on both shins. It can be caused by a variety of conditions, and typi ...
, 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'' is a species of bacteria found in various aquatic environments. The bacteria can infect humans and some other animals, causing persistent open wounds called Buruli ulcer. ''M. ulcerans'' is closely related to '' Mycob ...
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
A laparotomy is a surgical procedure involving a surgical incision through the abdominal wall to gain access into the abdominal cavity. It is also known as a celiotomy.
Origins and history
The first successful laparotomy was performed without ane ...
or
laparoscopy
Laparoscopy () is an operation performed in the abdomen or pelvis using small incisions (usually 0.5–1.5 cm) with the aid of a camera. The laparoscope aids diagnosis or therapeutic interventions with a few small cuts in the abdomen.Medlin ...
. Other infrequent side effects include
splenic infarction,
bowel obstruction,
paralytic ileus
Ileus is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction.
The word 'ileus' is from Ancient Greek ''eileós'' (, "intestinal obstruction"). The term 'subileus' r ...
, and
upper GI bleeding.
Ethionamide and Prothionamide
Ethionamide
Ethionamide is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy. It is taken by mouth.
Et ...
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.
References
{{Antimycobacterials
Leprosy
Antileprotic drugs