Metabolic Modeling-Based Drug Repurposing in Statin: An Overview of Mechanistic Approaches in the Management of Craniocerebral Trauma

Drug repurposing, known as drug repositioning, is considered a method for redeveloping a compound to utilize in a distinctive illness, which is now becoming a progressively critical procedure for industrial researchers and the scholarly community. A large number of repurposed medicines have been discovered by chance in the lab or through the careful monitoring of drug action in the clinic and retrospective analysis of clinical findings. Additionally, statins are broadly used to treat hyperlipidemia and prevent cardiovascular disease although their application as the neuroprotective agents weakening secondary neurological harm is yet limited in traumatic brain injury (TBI). Their other non-cholesterol-mediated (i.e., pleiotropic) mechanisms of action include upregulating endothelial nitric oxide synthase expression, and enhancing neurogenesis and synaptogenesis, as well as anti-apoptotic effects, increased angiogenesis, and various antioxidant and anti-inflammatory mechanisms. Almost all studies have supported the potential role of statins in neuroprotection, and a few have particularly focused on their effects in traumatic brain injury models. The sulfonylurea receptor 1 (SUR1) protein is a regulatory component linked with pore-forming ion channels. Thus, ATP-sensitive potassium (KATP) channels are created, which can be demonstrated in pancreatic islet cells and certain neurons. Further, transient receptor potential melastatin 4 (TRPM4) is the second pore-forming subunit of SUR1. Upregulating SUR1 and opening SUR1-TRPM4 opening have been observed in the different models related to central nervous system (CNS) injuries such as TBI. Sulfonylurea drugs may prevent neuronal degeneration and improve post-TBI cognitive results by inhibiting the SUR1-TRPM4 channel

Evaluation of the Association between Trough and Area Under the Curve to Minimum Inhibitory Concentration Ratio (AUC24/MIC) of Vancomycin in Infected Patients with Methicillin Resistant Staphylococcus aureus (MRSA)

Background: The recent studies emphasized on the correlation of vancomycin antibacterial effect with pharmacokinetics properties such as the area under the curve/minimum inhibitory concentration (AUC24/MIC) ≥400 and serum trough level 15-20 mg /L in the patients with severe infection with methicillin-resistant Staphylococcus aureus (MRSA). The purpose is to assay the vancomycin pharmacokinetic properties in our population and evaluates the correlation between AUC24/MIC and trough serum level of vancomycin in given patients. Methods: The patients with a positive MRSA culture, treated with vancomycin, were enrolled in this cross-sectional study. Three plasma samples were obtained during the study including 30 min before fourth and the fifth dose as trough levels and 1 hour after the fourth dose as peak level to determine AUC24. E-TEST determined the MIC of vancomycin. Results: Thirty-eight patients with an average age of 48.33±16.44 were enrolled in this study. The mean ± SD of MIC was 0.99±0.30 mg/L. Thirty-four patients reached the adequate therapeutic range of AUC24/MIC ≥ 400 due to the standard vancomycin dosing method. In comparison, only 7 and 10 patients had the first and second trough levels in target intervals of 15-20 mg/L, respectively. Due to the receiver operating characteristic curve test (ROC test), the trough level after the fourth dose had a strong correlation with target AUC24/MIC with a sensitivity of 94.1%and specificity of 75.0%. Conclusion: This study concluded using only a trough level is not appropriate for therapeutic drug monitoring (TDM) of vancomycin. In our population, target AUC24/MIC (≥ 400) had a reasonably strong correlation with the trough level before the fifth dose which achieved with trough level ≥10.81 mg/L and MIC< 1 mg/L

Imatinib Metabolism and Disposition in Isolated Rat Perfused Liver: Imatinib Metabolism and Disposition in Isolated Rat Perfused Liver

Imatinib is an orally administered tyrosine kinase inhibitor which inhibits the Bcr-Abl protein-tyrosine kinase with high selectivity. Imatinib is rapidly absorbed from the gut, after oral intake and has an almost absolute bioavailability of 98%. The metabolism of imatinib is mediated by the cytochrome P450 (CYP) isoenzymes in the liver and gut wall. CGP74588 is a major active metabolite of imatinib. The study was performed on Male Sprague-Dawley rats (250-300 g) housing under artificial light on a 12-h light/dark cycle with free access to standard laboratory chow and water. Re-circulating (at imatinib concentration of 1 and 5 μg/ml) and single-pass (imatinib dose of 1mg) perfusion modes in the presence and absence of BSA were tested. Throughout the experiment, perfusate temperature (37± 0.5 C°), pH (7.4±0.2) and liver viability (ALT and AST) were monitored. The concentrations of imatinib and its main metabolite in perfusion buffer and liver homogenate were determined by a validated HPLC method.No metabolite was detected in outlet perfusate in all conditions. However, negligible amounts of metabolite were found in liver homogenate at 1 and 5 μg/ml imatinib concentrations in re-circulating perfusion mode. The rapid and remarkable disappearance of imatinib from perfusate was related to its accumulation in liver. Statistical moment definition was used to calculate some pharmacokinetic parameters. These calculations also confirmed liver accumulation and slow and sustained dissociation of imatinib from liver

Frequency of Important CYP450 Enzyme Gene Polymorphisms in the Iranian Population in Comparison with Other Major Populations: A Comprehensive Review of the Human Data

Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug dosing, efficacy, and safety. The distribution of cytochrome P450 alleles differs significantly between populations with important implications for personalized drug therapy and healthcare programs. To provide a meta-analysis of CYP allele polymorphisms with clinical importance, we brought together whole-genome and exome sequencing data from 800 unrelated individuals of Iranian population (100 subjects from 8 major ethnics of Iran) and 63,269 unrelated individuals of five major human populations (EUR, AMR, AFR, EAS and SAS). By integrating these datasets with population-specific linkage information, we evolved the frequencies of 140 CYP haplotypes related to 9 important CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) giving a large resource for major genetic determinants of drug metabolism. Furthermore, we evaluated the more frequent Iranian alleles and compared the dataset with the Caucasian race. Finally, the similarity of the Iranian population SNVs with other populations was investigated

Variations in the Frequencies of Polymorphisms in the CYP450s Genes in Eight Major Ethnicities of Iran: A Review of the Human Data

Genetic polymorphisms in cytochrome P450 genes can cause variation in metabolism. Thus, single nucleotide variants significantly impact drug pharmacokinetics, toxicity factors, and efficacy and safety of medicines. The distribution of CYP450 alleles varies drastically across ethnicities, with significant implications for personalized medicine and the healthcare system. We combined whole-genome and exome sequencing data to provide a review of CYP450 allele polymorphisms with clinical importance. Data were collected from 800 unrelated Iranians (100 subjects from 8 major ethnicities of Iran), more than 32,000 unrelated Europeans (other than Caucasian), and four Middle Eastern countries. We analyzed the frequencies and similarities of 17 CYP450 frequent alleles related to nine important CYP450 isoenzymes and homozygous and heterozygous genotypes based on these alleles in eight major Iranian ethnics by integrating these data with population-specific linkage information and compared these datasets with mentioned populations

A repurposed drug screen for regulating metabolic disease: an overview in the management of traumatic brain injury

Introduction & Background: The aim of this study is to review the mechanistic approaches and therapeutic opportunities in the management of traumatic brain injuries. Methods: A large number of repurposed medicines have been discovered by chance in the lab or through the careful monitoring of drug action in the clinic and retrospective analysis of clinical findings. Statins are broadly used to treat hyperlipidemia and prevent cardiovascular disease although their application as the neuroprotective agents weakening secondary neurological harm is yet limited in traumatic brain injury (TBI).Their other non-cholesterol-mediated (i.e., pleiotropic) mechanisms of action include up regulating endothelial nitric oxide synthase expression, enhancing neurogenesis and synaptogenesis, and anti-apoptotic effects, increased angiogenesis, and various antioxidant and anti-inflammatory mechanisms. Results: Almost all studies have supported the potential role of statins in neuroprotection, and a few have mainly focused on their effects in traumatic brain injury models.ATP-sensitive potassium (KATP) channels are created, which can be demonstrated in pancreatic islet cells and certain neurons. Transient receptor potential melastatin 4 (TRPM4) is the second pore-forming subunit of SUR1. Upregulating SUR1 and opening SUR1-TRPM4 opening have been observed in the different models related to central nervous system (CNS) injuries such as TBI. Sulfonylurea drugs may prevent neuronal degeneration and improve post-TBI cognitive results by inhibiting the SUR1-TRPM4 channel. Conclusion: Drug repurposing, known as drug repositioning, is considered a method for redeveloping a compound to utilize in a distinctive illness, which is now becoming a progressively necessary procedure for industrial researchers and the scholarly community.Introducción y antecedentes. El objetivo de este estudio es revisar los enfoques mecanicistas y las oportunidades terapéuticas en el manejo de las lesiones cerebrales traumáticas. Métodos. Se ha descubierto una gran cantidad de medicamentos reutilizados por casualidad en el laboratorio o mediante un seguimiento cuidadoso de la acción del fármaco en la clínica y el análisis retrospectivo de los hallazgos clínicos. Las estatinas se usan ampliamente para tratar la hiperlipidemia y prevenir enfermedades cardiovasculares, aunque su aplicación como agentes neuroprotectores que debilitan el daño neurológico secundario aún es limitada en la lesión cerebral traumática (TBI). Sus otros mecanismos de acción no mediados por el colesterol (es decir, pleiotrópicos) incluyen hasta regula la expresión de la sintasa de óxido nítrico endotelial, mejora la neurogénesis y la sinaptogénesis y los efectos antiapoptóticos, aumenta la angiogénesis y varios mecanismos antioxidantes y antiinflamatorios. Resultados. Casi todos los estudios han respaldado el papel potencial de las estatinas en la neuroprotección, y algunos se han centrado principalmente en sus efectos en modelos de lesiones cerebrales traumáticas. Se crean canales de potasio sensibles al ATP (KATP), que se pueden demostrar en las células de los islotes pancreáticos y en ciertas neuronas. El receptor potencial transitorio de melastatina 4 (TRPM4) es la segunda subunidad formadora de poros de SUR1. Se ha observado la regulación positiva de SUR1 y la apertura de SUR1-TRPM4 en los diferentes modelos relacionados con lesiones del sistema nervioso central (SNC), como TBI. Las sulfonilureas pueden prevenir la degeneración neuronal y mejorar los resultados cognitivos posteriores a una TBI al inhibir el canal SUR1-TRPM4. Conclusión. La reutilización de medicamentos, conocida como reposicionamiento de medicamentos, se considera un método para volver a desarrollar un compuesto para utilizarlo en una enfermedad específica, que ahora se está convirtiendo en un procedimiento cada vez más necesario para los investigadores industriales y la comunidad académica

Impact of obesity and bariatric surgery on metabolic enzymes and p-glycoprotein activity using the Geneva cocktail approach

The inter-individual variability of CYP450s enzyme activity may be reduced by comparing the effects of bariatric surgery on CYP-mediated drug elimination in comparable patients before and after surgery. The current research will use a low-dose phenotyping cocktail to simultaneously evaluate the activities of six CYP isoforms and P-gp. The results showed that following weight reduction after surgery, the activity of all enzymes increased compared to the obese period, which was statistically significant in the case of CYP3A, CYP2B6, CYP2C9, and CYP1A2. Furthermore, the activity of P-gp after surgery decreased without reaching a statistical significance (p-value > 0.05). Obese individuals had decreased CYP3A and CYP2D6 activity compared with the control group, although only CYP3A was statistically important. In addition, there was a trend toward increased activity for CYP1A2, CYP2B6, CYP2C9, and CYP2C19 in obese patients compared to the control group, without reaching statistical insignificance (p-value ≥ 0.05). After six months (at least), all enzymes and the P-gp pump activity were significantly higher than the control group except for CYP2D6. Ultimately, a greater comprehension of phenoconversion can aid in altering the patient's treatment. Further studies are required to confirm the changes in the metabolic ratios of probes after bariatric surgery to demonstrate the findings' clinical application. As a result, the effects of inflammation-induced phenoconversion on medication metabolism may differ greatly across persons and drug CYP pathways. It is essential to apply these results to the clinic to recommend dose adjustments