Methdilazine

Abstract: Significant antimicrobial action was detected in vitro and in vivo in phenothiazines that are applied to humans as neuroleptics or antihistamines. Both Gram-positive and Gram-negative bacteria were equally sensitive, with the MIC varying between 25 and 100 μg/ml with most agents. Some phenothiazines were bactericidal, while others were bacteriostatic in action. Similar activity could be observed in isoflavonones obtained from the plants Sophora spp. Trifluoperazine and methdilazine exhibited antimycobacterial properties as well, and in experimental animals the latter showed definite healing properties. Chlorpromazine and thioridazine were able to eliminate R-plasmids in drug-resistant bacteria. Artificially synthesized Benzo[α]phenothiazines could effectively suppress adenovirus oncogene expression. Phenothiazines have now been shown to inhibit efflux pumps in multidrug-resistant bacteria.

Abstract: The antihistamine methdilazine (Md) was found to possess a significantly high antibacterial action when tested against 367 strains of bacteria belonging to both Gram-positive and Gram-negative genera. Different groups of bacteria could be arranged in order of their decreasing sensitivity towards Md as follows: S. aureus, V. cholerae, E. coli and Shigella. The range of minimum inhibitory concentration (micrograms/ml) varied between 25 and 200 in most cases, although few strains were sensitive even at 10 micrograms/ml level of Md. 10 different bacteria sensitive to Md and a number of antibiotics when tested for their interaction with Md on one hand and any of the antibiotics of chemotherapeutic agents on the other, it was found that Md in combination with aminoglycosides and several chemotherapeutics showed enhancement of antibacterial effects resulting in synergism. The chemotherapeutic agents bromodiphenhydramine (Bn), diphenhydramine and methyldopa showed distinct synergism when tested in combination with Md. Determination of the area of inhibition zones for the degree of synergism with Md and streptomycin (Sm) produced statistically significant result (p less than 0.01) in comparison with their individual effect. This could also be corroborated by the fractional inhibitory concentration (FIC) index which was 0.49 for Sm-Md and 0.5 for Bn-Md combinations. The synergism of Sm-Md combination was confirmed by in vivo studies.

Abstract: When tested as a microbial model for mammalian drug metabolism, the filamentous fungus Cunninghamella elegans metabolized chlorpromazine and methdilazine within 72 h. The metabolites were extracted by chloroform, separated by high-performance liquid chromatography, and characterized by proton nuclear magnetic resonance, mass, and UV spectroscopic analyses. The major metabolites of chlorpromazine were chlorpromazine sulfoxide (36%), N-desmethylchlorpromazine (11%), N-desmethyl-7-hydroxychlorpromazine (6%), 7-hydroxychlorpromazine sulfoxide (36%), N-hydroxychlorpromazine (11%), 7-hydroxychlorpromazine sulfoxide (5%), and chlorpromazine N-oxide (2%), all of which have been found in animal studies. The major metabolites of methdilazine were 3-hydroxymethdilazine (3%). (18)O(2) labeling experiments indicated that the oxygen atoms in methdilazine sulfoxide, methdilazine N-oxide, and 3-hydroxymethdilazine were all derived from molecular oxygen. The production of methdilazine sulfoxide and 3-hydroxymethdilazine was inhibited by the cytochrome P-450 inhibitors metyrapone and proadifen. An enzyme activity for the sulfoxidation of methdilazine was found in microsomal preparations of C. elegans. These experiments suggest that the sulfoxidation and hydroxylation of methdilazine and chlorpromazine by C. elegans are catalyzed by cytochrome P-450.