Fullerenes on a Nanodiamond Platform Demonstrate Antibacterial Activity with Low Cytotoxicity.

Carbon nanoparticles with antimicrobial properties, such as fullerenes, can be distinguished among the promising means of combating pathogens characterized by resistance to commercial antibiotics. However, they have a number of limitations for their use in medicine. In particular, the insolubility of carbon nanoparticles in water leads to a low biocompatibility and especially strong aggregation when transferred to liquid media. To overcome the negative factors and enhance the action of fullerenes in an extended range of applications, for example, in antimicrobial photodynamic therapy, we created new water-soluble complexes containing, in addition to C60 fullerene, purified detonation nanodiamonds (AC960) and/or polyvinylpyrrolidone (PVP). The in vitro antibacterial activity and toxicity to human cells of the three-component complex C60+AC960+PVP were analyzed in comparison with binary C60+PVP and C60+AC960. All complexes showed a low toxicity to cultured human skin fibroblasts and ECV lines, as well as significant antimicrobial activity, which depend on the type of microorganisms exposed, the chemical composition of the complex, its dosage and exposure time. Complex C60+PVP+AC960 at a concentration of 175 µg/mL showed the most stable and pronounced inhibitory microbicidal/microbiostatic effect.

Therapeutic Drug Monitoring of Olanzapine and Cytochrome P450 Genotyping in Nonsmoking Subjects.

BACKGROUND: The relationship between a daily dose of olanzapine, its serum concentration, and the genotype of young nonsmoking men treated for schizophrenia or schizophreniform disorder was investigated in day-to-day clinical practice. Pharmacogenetics was also examined for the selected patients. METHODS: A total of 49 participants were recruited as in-patients at the Mental Health Research Center (Moscow, Russia). Inclusion criteria were patients who had been diagnosed with schizophrenia or schizoaffective disorder (following DSM-IV guidelines) and were being treated with OLZ. A prospective, observational, open-study design was implemented. In line with the literature, patients were only included if they attained steady-state OLZ concentrations lasting for at least 8 days. A liquid chromatographic-tandem mass spectrometric method was developed for analyzing OLZ in human serum. The single cytochrome P450 polymorphisms were genotyped using an amplifier real-time polymerase chain reaction system following standard protocols. RESULTS: Evidence indicating that CYP2D6 polymorphism has a significant (P = 0.046) effect on the pharmacokinetics of olanzapine was obtained, confirming the beneficial effects of therapeutic drug monitoring (TDM) for olanzapine. CONCLUSIONS: TDM should therefore be used as a standard care during olanzapine therapy. TDM is also useful in assessing adherence and may have a role in limiting olanzapine dosage geared at minimizing the risk of long-term toxicity.

Simultaneous Determination of Antipsychotic Drugs and Their Active Metabolites by LC-MS-MS and its Application to Therapeutic Drug Monitoring.

A quantitative method was developed to support therapeutic drug monitoring of eight antipsychotic drugs: chlorpromazine, haloperidol, zuclopenthixol, clozapine, risperidone, quetiapine, aripiprazole or olanzapine and some active metabolites (dehydroaripiprazole, N-desmethylclozapine and 9-hydroxyrisperidone) in human serum. Separation of the compounds was achieved using a Zorbax SB-C18 (150 mm × 4.6 mm, 5 µm) column and mass-spectrometric detection in multiple reaction monitoring mode. Human blood samples were collected in vacutainer tubes and the analytes were extracted with methyl-tert-butyl ether. The lower limits of quantitation were equal 0.5-1 ng/mL for all analytes. The method was applied with success to serum samples from schizophrenic patients undergoing polypharmacy with two or more different antipsychotic drugs. Precision data, accuracy results were satisfactory, and no interference from other psychotropic drugs was found. Hence, the method is suitable for the TDM of the analytes in psychotic patients' serum.

Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration.

BACKGROUND: Haloperidol is used for the treatment of alcohol use disorders in patients with signs of alcohol-related psychosis. Haloperidol therapy poses a high risk of adverse drug reactions (ADR). Contradictory data, which include the effects of genetic polymorphisms in genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate and plasma drug concentration ratio, are described in patients with different genotypes. The primary objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder. METHODS: The study included 69 male patients with alcohol use disorder. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with HPLC-MS using the concentration of endogenous substrate of the enzyme and its urinary metabolites [6-hydroxy-1,2,3,4-tetrahydro-ß-carboline(6-HO-THBC) to pinoline ratio for CYP2D6 and 6-ß-hydroxycortisol to cortisol ratio for CYP3A]. The equilibrium plasma concentration was determined using LC-MS-MS. RESULTS: Results indicated that both C/D indexes and equilibrium concentration levels depend on CYP2D6 genetic polymorphism, but only in patients receiving haloperidol intramuscular injections [0.26 (0.09; 0.48) vs. 0.54 (0.44; 0.74), p=0.037]. CONCLUSIONS: The study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.