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

Clinical effects of topical antifungal therapy in chronic rhinosinusitis: a randomized, double-blind, placebo-controlled trial of intranasal fluconazole

Several studies have been in favor of fungi as a possible pathogenesis of chronic rhinosinusitis (CRS); however, to date, there is no scientific consensus about the use of antifungal agents in disease management. The aim of the present study was to investigate the efficacy of intranasal fluconazole in improving disease symptoms and objective outcomes of patients with CRS. A randomized, double-blind, placebo-controlled study was conducted on 54 patients who were diagnosed with CRS and had not been responsive to routine medical treatments. They were randomly assigned to receive either fluconazole nasal drop 0.2 % or placebo in addition to the standard regimen for a duration of 8 weeks. Patients’ outcomes were evaluated according to Sino-Nasal Outcome Test 20 (SNOT-20), endoscopic scores, and Computed Tomography (CT) scores. No statistically significant difference was found in SNOT-20 (p = 0.201), endoscopic (p = 0.283), and CT scores (p = 0.212) of the patients at baseline and after 8-week course of treatment between drug and placebo group. Similar to many studies, the use of topical antifungal treatment for patients with CRS was not shown to be significantly effective. However, further studies are needed to obtain high levels of consistent evidence in order to arrive at a decision whether antifungal therapy is effective in management of CRS or not

Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

Purpose. Tramadol Hydrochloride is a widely-used centrally acting analgesic drug, which has some features of being a P-gp substrate. The present study evaluates the functional involvement of P-gp in CNS distribution of tramadol. Methods. The possibe involvement of P-glycoprotein in brain distribution of tramadol was evaluated using a pharmacokinetic approach in two groups of Pgp-inhibited and control rats. Six male Sprague-Dawley rats were used in each group to collect plasma and brain at 1, 5, 10, and 30 min following two tramadol doses of 1 and 10 mg/kg. Results. The brain uptake clearances of tramadol in Pgp-inhibited and control rats were 2.47±0.56 and 2.34±0.56 ml min-1g-1, respectively, for 1 mg/kg and 3.50±0.60 and 3.14±1.02 mlmin-1g-1, respectively, for 10 mg/kg dose. The brain-to-plasma concentration ratio (Kp,app) of more than 1 in all the time points following both the high and low dose cases (sometimes more than 3) indicated the brain accumulation of the drug. Linear correlation was found between tramadol dose and both corresponding plasma and brain concentrations, but the presence of a dose-dependency was not confirmed by the data obtained for brain-to-plasma concentration ratio. Conclusion. Considering the results of the previous studies and the present research, it seems that the brain accumulation of tramadol is not affected by P-gp inhibition which implies that there may be some other transport mechanisms involved in BBB transport of tramadol. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page

Effect of 3,4-Methylenedioxymethamphetamine on Liver CYP2C19 Enzyme Activity in Isolated Perfused Rat Liver Using Omeprazole Probe

Background and purpose: This study aimed at investigating the effects of 3,4-Methyl​enedioxy​methamphetamine (MDMA) on liver cytochrome 2C19 enzyme activity, which is a major liver enzyme in the metabolism of a wide range of drugs, using omeprazole as a probe of the CYP2C19 activity in isolated perfused rat liver. Materials and methods: This experimental study was done in 20 male Sprague–Dawley (SD) rats (weighing 250–300 g). After isolating the animal liver, omeprazole was administered at 400 μm and the concentration of omeprazole and its metabolite were determined. The liver was then washed with perfusion buffer, and MDMA was transferred at 300 ng/ml unilaterally from the same liver for 30 minutes. After re-washing the liver with perfusion buffer, omeprazole was passed through the liver for second time and the metabolic ratio was determined after exposure to MDMA. This process was also done in a group of animals at 600 ng/ml of MDMA. Results: Analysis of data from three end-time intervals after exposure to liver at 300 and 600 ng/ml of MDMA, showed 26.6% and 20.6% reduction in the activity of CYP2C19. Findings showed that MDMA administration could significantly reduce the activity of CYP2C19. Conclusion: According to this study, liver exposure to MDMA can significantly reduce cytochrome 2C19 activity, but, further studies are needed to examine this issue more closely

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

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

Study the effect of 3,4-Methylenedioxy methamphetamine on cytochrome P450 2E1 activity

Evaluating the effects of ecstasy on CYP2E1 activity is of great concern, mainly due to growing trends in abuse and co-administration of MDMA with ethanol and the dominant role of this isoenzyme on ethanol metabolism. This study aimed to evaluate the effects of MDMA on CYP2E1 activity. A total of 24 male rats were selected and divided into three groups. The first and second groups consisted of 12 rats and were employed to optimize the perfusion method, and the third group was employed for studying the alteration of CYP2E1 activity after liver exposure to MDMA (300 and 600 ng/ml). The amount of chlorzoxazone and 6-hydroxy chlorzoxazone in a sample obtained from liver perfusion before and after exposure to a buffer containing MDMA was determined by HPLC-FL. The enzymatic activity of rat CYP2E1 decreased after liver perfusion with a buffer containing 600 ng/ml of MDMA. However, no significant changes were observed in chlorzoxazone and 6-hydroxy chlorzoxazone concentration in perfusate before and after liver perfusion with a buffer containing 300 ng/ml of MDMA. Our findings suggest that the activity of CYP2E1 in rats might decrease only after administration of MDMA at a lethal dose. However, further animal and human studies are needed to confirm our assumption

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

CLINICAL EFFECTS OF TOPICAL ANTIFUNGAL THERAPY IN CHRONIC RHINOSINUSITIS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF INTRANASAL FLUCONAZOLE

ABSTRACT Several studies have been in favor of fungi as a possible pathogenesis of chronic rhinosinusitis (CRS); however, to date, there is no scientific consensus about the use of antifungal agents in disease management. The aim of the present study was to investigate the efficacy of intranasal fluconazole in improving disease symptoms and objective outcomes of patients with CRS. A randomized, double-blind, placebo-controlled study was conducted on 54 patients who were diagnosed with CRS and had not been responsive to routine medical treatments. They were randomly assigned to receive either fluconazole nasal drop 0.2 % or placebo in addition to the standard regimen for a duration of 8 weeks. Patients' outcomes were evaluated according to Sino-Nasal Outcome Test 20 (SNOT-20), endoscopic scores, and Computed Tomography (CT) scores. No statistically significant difference was found in , endoscopic (p = 0.283), and CT scores (p = 0.212) of the patients at baseline and after 8-week course of treatment between drug and placebo group. Similar to many studies, the use of topical antifungal treatment for patients with CRS was not shown to be significantly effective. However, further studies are needed to obtain high levels of consistent evidence in order to arrive at a decision whether antifungal therapy is effective in management of CRS or not