Treatment of tuberculosis

Tuberculosis is caused by Mycobacterium tuberculosis and Mycobacterium bovis. Both organisms can cause tuberculosis in man and cattle. A related organism is Mycobacterium leprae, which is the cause of leprosy. 

Despite vaccination programmes in many parts of the world, tuberculosis remains the largest single cause of death by infectious disease, causing three million deaths 

---

Antituberculin Agents. Rifampin [13292-46-17, a semisynthetic derivative of rifamycin SV, is a most valuable dmg for treatment of tuberculosis, an infection caused by mycobacteria, leprosy, and an expanding range of other infections (23). Cycloserine [64-41-7] has been used to a limited extent for treatment of tuberculosis as a reserve dmg. Although cycloserine inhibits bacteria by interfering with their cell wall biosynthesis, it has toxic side effects in humans in the form of neurotoxicity. Capreomycin [11003-38-6] and to a much lesser extent viomycin [32988-50-4] both of which are peptides, have also been used for treatment of this disease. 

Aminosalicylic acid and its salts have been used in the treatment of tuberculosis, Aminosalicylic acid can be prepared by the carboxylation of m- am in oph en o1 (32). Aminosalicylic acid USP assays not less than 98.5% and not more than 100.5%, calculated on the anhydrous basis. The antitubercular agents are likely to be used as the more tolerated salts calcium [133-15-3] potassium [133-09-5] sodium [133-10-8] and the ethyl [6069-17-2] and phenyl [133-11-9] esters of -aminosalicylic acid. 

Before the discovery of streptomycin, pyrazinamide (126) was one of the front runners in the treatment of tuberculosis. A broad spectrum of biological activity has been associated with pyrazine derivatives, ranging from the herbicidal activity of (127) to antibiotic activity... 

Substitution of an amino group into the molecule affords an iigent with antibacterial activity. Although seldom used alone, l, ira- aminosalicylic acid (PAS, 7) has been employed as an adjunct Id streptomycin and isoniazid in treatment of tuberculosis. 

Phenyl 4-aminosalicylale is a drug used in the treatment of tuberculosis. Propose a synthesis of this compound starting from 4-nitrosalicylic acid. 

Stiepton dn was isolated by Waksman in 1944, and its activity against M tuberculosis ensured its use as a primaiy ding in the treatment of tuberculosis. Unfortunately, its ototoxicity and the rapid development of resistance have tended to modify its usefulness, and although it still remains a front-hne dmg against tuberculosis it is usually used in combination with isoniazid and p(4)-aminosalicyhc acid (section 11.5). Streptomycin also shows activity against other types of bacteria,... 

Kanamycin (a complex of three antibiotics. A, B and C) is active in low concentrations against various Gram-positive (including penicillin-resistant staphylococci) and Gram-negative bacteria. It is a recognized second-line dmg in the treatment of tuberculosis. 

The three standard drugs used in the treatment of tuberculosis were streptomycin (considered above), -aminosalicylic acid (PAS) and isoniazid (isonicotinylhydrazide, INH synonym, isonicotinic acid hydrazine, INAH). The tubercle bacillus rapidly becomes resistant to streptomycin, and the role of PAS was mainly that of preventing this development of resistance. The current approach is to treat tuberculosis in two phases an initial phase where a combination of three dmgs is used to reduce the bacterial level as rapidly as possible, and a continuation phase in which a combination of... 

In contrast, iproniazid, introduced in 1951 for treatment of tuberculosis, induced euphoria and was described as a psychic energiser . In fact, these patients, when given iproniazid, could become quite disruptive and this action was regarded as an undesirable side-effect However, its beneficial effects in depression were soon recognised and it was regarded as the first effective antidepressant drug. Studies of peripheral sympathetic neurons, later extended to noradrenergic neurons in the brain, showed that iproniazid irreversibly inhibits the catalytic enzyme, monoamine oxidase (MAO). Because only cytoplasmic monoamines are accessible to MAO, inhibition of this enzyme first increases the concentration of the pool of soluble transmitter but this leads to a secondary increase in the stores of vesicle-bound transmitter i.e. the pool available for impulse-evoked release (Fillenz and Stanford 1981). 

American Thoracic Society/Centers for Disease Control/Infectious Disease Society of America. Treatment of tuberculosis. Am I Respir Crit Care Med 2003 167 603-662. 

Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 2002 62 2169-2183. 

One of the mainstays in the treatment of tuberculosis is paraaminosalicylic acid (PAS). It is not, however, a pleasant drug to take. Phenyl aminosalicylate (20) was synthesized from 4-nitrosalicylic acid (18) by esterification of its acid chloride with phenol to give 19, which is converted to the desired... 

The use of combinations to prevent the emergence of resistance is widely applied but not often realized. The only circumstance where this has been clearly effective is in the treatment of tuberculosis. 

From Centers hr Disease Control and Prevention. Treatment of tuberculosis. MMWR 2003 52(RR- 7 7). 

Rifampicin appears to be particularly promising in the treatment of tuberculosis, especially in combination with isoniazid. The prolonged high blood levels attainable with a single daily dose should simplify therapy. 

Rifampin inhibits the bacterial enzyme that catalyzes DNA template-directed RNA transcription, i.e DNA-de-pendent RNA polymerase. Rifampin acts bactericidally against mycobacteria (M. tuberculosis, M. leprae), as well as many gram-positive and gram-negative bacteria It is well absorbed after oral ingestion. Because resistance may develop with frequent usage, it is restricted to the treatment of tuberculosis and leprosy (p. 280). 

Recommended Drugs for the Treatment of Tuberculosis in Children and Adult Drug Daily dose-... 

Do not use tuberculosis regimens consisting of isoniazid, ethambutol, and pyrazinamide (ie, 3-drug regimens that do not contain a rifamycin, an aminoglycoside [eg, streptomycin, amikacin, kanamycin], or capreomycin) for the treatment of patients with HIV-related tuberculosis. The minimum duration of therapy is 18 months (or 12 months after documented culture conversion) if these regimens are used for the treatment of tuberculosis. 

Treatment of tuberculosis Use in conjunction with other effective antituberculosis agents. 

Tuberculosis Treatment of tuberculosis in combination with other active agents. It is most commonly used in patients with multi-drug resistant tuberculosis (MDR-TB) or in situations when therapy with isoniazid and rifampin is not possible because of a combination of resistance and intolerance. 

Resistance The use of ethionamide alone in the treatment of tuberculosis results in rapid development of resistance. 

Mycobacterium tuberculosis Add streptomycin or ethambutol as a fourth drug in a regimen containing isoniazid (INH), rifampin, and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH or rifampin resistance is very low. Streptomycin also is indicated for therapy of tuberculosis when one or more of the above drugs is contraindicated because of toxicity or intolerance. 

In 1798, convinced that some of the gases that chemists had recently discovered might prove to be useful in the treatment of tuberculosis, Thomas Beddoes, a former lecturer in chemistry at Oxford University, founded a Pneumatic Institute in Bristol with the intention of carrying out a series of experiments. On the recommendation of a mutual acquaintance, Beddoes hired Davy as a research assistant. 

Rifabutin, a semi-synthetic derivative of rifamy-cin S, is a bactericidal antibiotic primarily used in the treatment of tuberculosis. Its effect is based on blocking the DNA-dependend RNA-polymerase of the bacteria. Rifabutin is used in the treatment of infections with Mycobacterium avium intracellulare. Rifabutin is well tolerated in patients with HIV-related tuberculosis, but patients with low CD4 cell counts have a high risk of treatment failure or relapse due to acquired rifamycin resistance. 

The reason that it was decided to discuss the treatment of tuberculosis in a chapter together with HIV/AIDS is because tuberculosis is the most deadly opportunistic infection in people with HIV/AIDS, certainly in resource poor settings. We still felt that in this chapter tuberculosis should be a section on its own as also outside the HIV/AIDS context, tuberculosis poses a grave and growing threat to global public health. 

---