Tuberculostatic effects

Compounds 33 (2.3-4.7 pg/ml) and 34 (1.2-2.3 pig/ml) were also found to have tuberculostatic effects on Mycobacterium tuberculosis47). 

Cyclic sulphides containing the IbP heterocycle in their structure (e.g., 673) can be used as immunomodulating agents (81USP4293696). IbP-2-propionic acid 674 thioamides showed a significant tuberculostatic effect (89PHA267). 

The main tuberculostatic effect of ethambutol is on proliferating, not on resting germs. Ethambutol causes a degenerative metabolism in the mycobacteriae, particularly involving the phosphate fraction. The cell division of the germs is suppressed and their vitality reduced. 

Several xanthones that possess antidepressant activity inhibit monoamine oxidases. These compounds have in vitro cytotoxicity and in vivo antitumor activity (Hostettmann and Hostettmann, 1989). The xanthone psorospermin (38) from Psorospermum febrifugum (Clusiaceae) exhibited antileukemic activity in several test systems. Other xanthones have tuberculostatic effects (Vermes and Wagner, 1986). 

The monoamine oxidases are a widespread group of enzymes which catalyse the oxidative deamination of amines to aldehydes (for reviews, see [13, 94, 121, 176, 265]). The prototype of the monoamine oxidase inhibitors, iproniazid, first attracted attention because of its tuberculostatic effect, until it was discovered that it exerted a marked antidepressant action in man. Hypotension was observed as a side effect of iproniazid and numerous other monoamine oxidase inhibitors, and this finally led to the development of one compound belonging to this group-pargyhne-which was specifically intended for use as an antihypertensive. Pargyhne has a gradual onset of action and the hypotension it produces... 

Iproniazid (4.272) was originally synthesized as a tuberculostatic drug but was found to be an antidepressant due to its inhibitory effect on monoamine oxidase. However, this compound had to be withdrawn from clinical use due to a high incidence of hepatotoxicity. The metabolism and the mechanism of toxification of iproniazid were found to be comparable to those of... 

CNS toxicity occurs because isoniazid has structural similarities to pyridoxine (vitamin Be) and can inhibit its actions. This toxicity is dose-related and more common in slow acetylators. Manifestations include peripheral neuropathy, optic neuritis, ataxia, psychosis and seizures. The administration of pyridoxine to patients receiving INH does not interfere with the tuberculostatic action of INH but it prevents and can even reverse neuritis. Hematological effects include anaemia which is also responsive to pyridoxine. In some 20% of patients antinuclear antibodies can be detected but only in a minority of these patients drug-induced lupus erythematosus becomes manifest. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

It is tuberculostatic drug effective against many atypical mycobacteria also. It acts mainly against rapidly multiplying organisms in the cavities walls. 

Blood urate concentrations can be increased because of reduced excretion of uric acid in patients taking ethambutol (390). This is probably enhanced by combined treatment with isoniazid and pyridoxine. Special attention should be paid when tuberculostatic drug combinations include pyrazinamide. However, severe untoward clinical effects are rare, except in patients with gout or renal insufficiency (391,392). 

Cycloserine This orally effective tuberculostatic agent appears to antagonize the steps in bacterial cell wall synthesis involving D-alanine. It distributes well throughout body fluids, including the CSF. Cycloserine [sye kloe SER een] is metabolized, and both parent and metabolite are excreted in urine. Accumulation occurs with renal insufficiency. Adverse effects involve CNS disturbances epileptic seizure activity may be exacerbated. Peripheral neuropathies are also a problem. 

Non-specific toxic liver damage may be evident in this connection, possible tuberculostatic toxic effects must also be considered. With severe courses of tuberculosis, peliosis hepatis is often observed. Frequently, retothelial nodules are detectable, as demonstrated for the first time in tuberculosis patients by H. Hamperl in 1953. (50) In the course of chronic pulmonary tuberculosis,infiltration of liver cells was noted, as reported in several publications. (50) It was attributed to toxic effects and/or undernourishment or malnutrition. Secondary hepatic amyloidosis, developing in the course of chronic lung tuberculosis, has also been postulated. (50) A restriction of hepatic function in chronic tuberculosis, which was first observed by E. Leuret et al. in 1922, has been described in a number of publications. (51, 60, 63) Depending on the severity and duration of the disease as well as the tuberculostatic pretreatment, we found pathological laboratory parameters in 15-20% and 25-40% of cases respectively. (50)... 

The prompt recognition of risk factors for severe complications, namely traumatic catheterization or concurrent cystitis, that increase BCG absorption, and treatment of early adverse effects, is expected to reduce the incidence of severe adverse effects. Severe local and systemic adverse effects can be successfully treated with tuberculostatic drugs for up to 6 months (14). 

Severe local and systemic adverse effects of BCG treatment can be treated successfully with tuberculostatic drugs, to most of which BCG is very susceptible, for up to 6 months (32). The effects of isoniazid on the incidence and severity of adverse effects of intravesical BCG therapy have been analysed in patients who received BCG with (n = 289) and without (n = 190) isoniazid (33). The authors concluded that prophylactic oral administration of isoniazid (300 mg/day with every BCG instillation) caused no reduction in any adverse effect of BCG. In contrast, transient liver function disturbances occurred slightly more often when isoniazid was used. The polymerase chain reaction has been used to monitor BCG in the blood after intravesical BCG instillation (22 patients) as well as after antituberculosis therapy (34). The early and fast diagnosis of BCG in the blood was considered to be potentially valuable in initiating specific early treatment of BCG complications. 

Ethambutol is tuberculostatic and acts against Mycobacterium tuberculosis and Mycobacterium kansasii as well as some strains of Mycobacterium avium complex. It has no effect on other bacteria. The sensitivities of non-tuberculous mycobacteria are variable. Ethambutol suppresses the growth of most isoniazid-resistant and streptomycin-resistant tubercle bacilli (1). 

The monoamine-oxidase inhibiting type of antidepressants originated from the unexpected central-stimulating effect observed with the tuberculostatic iso-niazid. In the preclinical study of a series of new anti-infectious sulfanilamides, a convulsive effect was observed. An analysis of this unwanted side-effect showed that the convulsions were due to hypoglycemia induced by the anti-infectious sulfanilamide. This hypoglycemic action was recognized as potentially useful... 

The early pioneering work by Zeller et al. (115) on the potent MAO inhibitory effect of iproniazid—a structural modification of the tuberculostat Isoniazid—and his realization of the physiologic consequences that might arise from such a profound alteration in catecholamine metabolism, the actual confirmation by Brodie, Pletscher, and Shore (27) of the rise in brain monoamine levels following the administration of iproniazid and JB-516 (a-methylphen-ethylhydrazine), and the early euphoric effects noted by Selikoff, Robitzek, and Omstein (96) in tuberculosis patients on iproniazid therapy led Kline and his associates (67) to investigate the possible application of iproniazid in the treatment of mental depression. It was their conclusion that MAO inhibition and antidepressant effect had a causal relationship and that a new approach for the treatment of mental depression had been uncovered. The subject of the MAO inhibitors has been reviewed extensively up to 1960 by Pletscher, Gey, and Zeller (84) and by Biel, Horita, and Drukker (21) to 1963, in comprehensive reviews of the chemistry, biochemistry, pharmacology, clinical application, and structure-activity relationships of the MAO inhibitors. 

Isoniazid, one of the most active of the tuberculostatic drugs, was discovered because it had been shown that nicotinamide exerted some tuberculostatic action (J). A deliberate search for more effective but related chemicals revealed that many pyridine derivatives, including congeners of isonicotinic acid, also were active. Further, it was known that the thiosemicarbazones could inhibit the growth of M. tuberculosis. An attempt to synthesize the thiosemicarbazone of isonicotinaldehyde provided, as the first intermediate compound, isonicotinylhydrazine, or isoniazid. 

Many acylated derivatives of quinoxaline-2,3-dithione have insecticidal and fungicidal properties. Quinoxaline-2,3-dithione cyclic trithiocarbo-nate (Eradex) (25) and 6-methylquinoxaline-2,3-dithione cyclic dithiocar-bonate (Morestan) (26) are particularly effective. 2,3-Bis(carbethoxy-thio)quinoxaline is reported to have tuberculostatic action. ... 

Viomycin is used in combination with other tuberculostatic agents in the treatment of tuberculosis. Because of its toxic side effects its use is not recommended for patients who respond to the classical forms of treatment. 

Syvalahti E, Pihlajamaki K, lisalo E. Effect of tuberculostatic agents on the re onse of serum growth hormone and immunoreactive insulin to intravenous tolbutamide, andonthehalf-life of tolbutamide, IntJ Clin Pharmacol Biopharm ( 916) 13, 83-9. 

Another pharmacotherapy of depression was developed in 1952 and was based on the observation that iproniazid (2), used as tuberculostatic, showed a favourable effect in depressed patients [2], believed to be based on monoamine oxidase (MAO) inhibition [3],... 

Parental compound, rifamycin, is produced by Screpiomyces mediier-ranei orally absorbed, bacrerioci dal agent specifically inhibits bacterial RHA polymerase tuberculostatic also penetrates white blood cells, so it is effective against intracellular pathogens see Qtapter 18,... 

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