Relationship of the 1846G > A Polymorphism of the CYP2D6 Gene to the Equilibrium Concentration Levels of Haloperidol in Patients with Acute Alcoholic Hallucinosis.

Haloperidol is currently used in addictology for the treatment of acute psychotic disorders, including acute alcoholic hallucinosis. The use of haloperidol is often accompanied by the occurrence of adverse drug reactions (ADRs). There is evidence that CYP2D6 isoenzyme is involved in the biotransformation of haloperidol. Aim: The study aimed to evaluate the relationship of 1846G > A polymorphism of the CYP2D6 gene to the equilibrium concentration levels of haloperidol in patients with acute alcoholic hallucinosis. Material and Methods: The study was conducted on 100 male patients with acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile was evaluated using the PANSS (Positive and Negative Syndrome Scale) scale. The safety of therapy was assessed using the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR). Equilibrium plasma concentration levels of haloperidol were investigated using the high-performance liquid chromatography with mass spectrometry (HPLC with MS/MS). Results: No statistically significant results were obtained during the therapy efficacy assessment (dynamics of the PANSS score: GG genotype (-13.00 [-16.00; -16.00; -11.00]), GA genotype (-15.00 [-16.75; -13.00], p = 0.728). There was a statistically significant difference in safety assessment scores (dynamics of the UKU score: GG genotype (8.00 [7.00; 10.00]), GA genotype (15.00 [9.25; 18.00], p < 0.001); dynamics of the SAS score: GG genotype (11.00 [9.00; 14.00]), GA genotype (14.50 [12.00; 18.00], p < 0.001). The pharmacokinetic study results showed a statistically significant difference: GG (3.13 [2.32; 3.95]), GA (3.89 [2.92; 5.26], p = 0.010). Thus, a study conducted on a group of 100 patients with acute alcoholic hallucinosis demonstrated an association between the 1846G > A polymorphism of the CYP2D6 gene (rs3892097) and the safety profile of haloperidol therapy. We also revealed the presence of statistically significant difference in the equilibrium concentration levels of haloperidol in patients with the GG and AG genotypes. Conclusion: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients carrying the GG genotype. It is shown that 1846G > A polymorphism of the CYP2D6 gene (rs3892097) has a statistically significant effect on the equilibrium concentration levels of haloperidol.

Relationship of CYP3A4*1B Single Nucleotide Polymorphism to the Efficiency and Safety Profiles of Haloperidol in Patients Enduring Acute Alcoholic Hallucinosis.

To date, haloperidol has been widely used to treat patients with acute alcoholic hallucinosis. There is strong evidence that haloperidol therapy is commonly associated with adverse drug reactions (ADRs). The 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) is known to affect the metabolism rates of haloperidol; hence it correlates with both therapy efficacy and safety parameters. Objective: The study objective was to investigate the effect of 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) on the efficacy and safety profiles of haloperidol in patients with acute alcoholic hallucinosis. Methods: This study enrolled 100 male patients suffering from acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile of haloperidol was assessed using the PANSS (Positive and Negative Syndrome Scale) validated psychometric scale. The safety profile of therapy was assessed with the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR). Results: There were no statistically significant results for the efficacy rates (dynamics of the PANSS score: AA genotype -14.00 [-16.00; -12.00], AG genotype -13.00 [-14.00; -10.50], p = 0.306). Similarly, there was no statistically significant difference in the safety profiles (dynamics of the UKU score: AA genotype - 9.00 [7.00; 13.00], AG genotype - 8.50 [7.25; 10.50], p = 0.620; dynamics of the SAS score: AA genotype -12.00 [10.00; 16.75], AG genotype - 10.00 [10.00; 12.25], p = 0.321). Conclusion: The study demonstrated that the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) in patients with acute alcoholic hallucinosis does not affect the efficacy and safety rates of haloperidol therapy.

Association of CYP2D6*4 Polymorphism with the Steady-State Concentration of Haloperidol in Patients with Alcohol-Induced Psychotic Disorders.

Background: CYP2D6 subfamily isoenzymes play an important role in the biotransformation of haloperidol, and their activity may influence the efficacy and safety of haloperidol. The use of haloperidol is often associated with the occurrence of adverse drug reactions (ADRs), such as dyskinesia, acute dystonia, and orthostatic hypotension. Previous studies have demonstrated the relationship between the CYP2D6*4 genetic polymorphism and CYP2D6 activity, as well as haloperidol efficacy and safety rates. Purpose: To evaluate the association of CYP2D6*4 genetic polymorphism with the steady-state concentration of haloperidol in patients with acute alcohol-induced psychotic disorders (AIPDs). Material and methods: The study involved 100 male patients with AIPD (average age 41.4 ± 14.4 years) who received haloperidol by injections in a dose of 5-10 mg/day. The efficacy profile was assessed using a validated psychometric PANSS scale (Positive and Negative Syndrome Scale). Therapy safety was assessed using the internationally validated UKU (Side-Effect Rating Scale) and SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scales. Genotyping was performed with the real-time polymerase chain reaction. Results: We revealed the statistically significant results in terms of therapy safety evaluation (dynamics of the UKU scores: (GG) 8.00 [7.00; 10.00], (GA) 15.0 [9.25; 18.0], p < 0.001; dynamics of the SAS scores: (GG) 11.0 [9.0; 14.0], (GA) 14.50 [12.0; 18.0], p < 0.001. Pharmacokinetic study showed a statistically significant difference across the groups with different genotypes: (GG) 3.13 [2.32; 3.95], (GA) 3.89 [2.92; 5.26], p = 0.010. Conclusion: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients who carry the GG genotype. It was shown that CYP2D6*4 genetic polymorphism has a statistically significant effect on the steady-state concentration of haloperidol.

Correlation of 1846G>A Polymorphism of CYP2D6 Gene with Haloperidol Efficacy and Safety in Patients with Alcoholic Hallucinoses.

Background: Previous studies have shown that haloperidol biotransformation occurs with participation of the CYP2D6 isoenzyme. The CYP2D6 gene is highly polymorphic, which may contribute to differences in its activity and in the haloperidol biotransformation rates across different individuals, resulting in variable drug efficacy and safety profiles. Purpose: The study aimed to investigate the correlation of the 1846G> A polymorphism of CYP2D6 gene with the efficacy and safety rates of haloperidol in patients with alcoholic hallucinoses. Material and methods: One hundred male patients received 5-10 mg/day haloperidol by injections for 5 days. The efficacy and safety assessments were performed using the validated psychometric scales PANSS, UKU, and SAS. For genotyping, the real-time polymerase chain reaction was performed. Results: We revealed no statistically significant results in terms of haloperidol efficacy in patients with different genotypes (dynamics of the PANSS scores: (GG) -13.00 [-16.00; -11.00], (GA) -15.00 [-16.75; -13.00], p = 0,728). Our findings revealed the statistically significant results in terms of treatment safety evaluation (dynamics of the UKU scores: (GG) 8.00 [7.00; 10.00], (GA) 15.0 [9.25; 18.0], p < 0.001; dynamics of the SAS scores: (GG) 11.0 [9.0; 14.0], (GA) 14.50 [12.0; 18.0], p < 0.001. Conclusion: These results suggest that genotyping for common CYP3A variants might have the potential to guide benzodiazepine withdrawal treatment. The effect of of the 1846G>A polymorphism of CYP2D6 gene on the safety profile of haloperidol was demonstrated in a group of 100 patients with alcoholic hallucinoses.

Microstructure of Spark Plasma-Sintered Silicon Nitride Ceramics.

The microstructure and phase composition of the high-content Al2O3-Y2O3-doped spark plasma-sintered silicon nitride were investigated. Fully dense silicon nitride ceramics with a typical α-Si3N4 equiaxed structure with average grain size from 200 to 530 nm, high elastic modulus of 288 GPa, and high hardness of 2038 HV were spark plasma sintered (SPSed) at 1550 °C. Silicon nitride with elongated ß-Si3N4 grains, higher hardness of 1800 HV, density of 3.25 g/cm3, and Young's modulus 300 GPa SPSed at 1650 °C was also reviewed.

Microstructure and Phase Composition of Cold Isostatically Pressed and Pressureless Sintered Silicon Nitride.

The microstructure and physical properties of new Y2O3 and Al2O3 oxide-doped silicon nitride ceramics fabricated by cold isostatic pressing and free sintering were investigated. The phase composition of produced material was also studied by X-ray diffraction at room and elevated temperature. The fabricated ceramics featured a microstructure of Si5AlON7 grains with a fine-grained α-Si3N4 with a small amount of Y2SiAlON5. Described ceramics is attractive for many high-temperature structural applications due to beneficial combination of fine-grained structure with improved mechanical properties and small weight loss.

[Development of methods of local hyperthermia to achieve more marked tumor pathomorphism]. / Razvitie metodov lokal'noi gipertermii dlia dostizheniia bolee vyrazhennogo patomorfoza opukholei.

Regular investigations on application of hyperthermia in oncology have been carried out since the second half of the 1950s. The usage of distant tissues heating faces considerable difficulties in maintenance of therapeutic temperature in the whole volume of the tumor. Thus, the use of interstitial hyperthermia is promising, especially, ferromagnetic hyperthermia which causes damage not only to central but also to peripheral zones of tumors. Light and electron microscopies have not revealed specific features of cell damage by which ferromagnetic hyperthermia might differ from other methods of antitumor treatment.