Pharmacology Research & Perspectives最新文献

There has been scarce research on the potential neuroprotective effects of remifentanil (REM) in septic individuals. We aimed to investigate the role and underlying mechanism of REM in LPS-induced neuroinflammation. Thirty-two rats were randomly divided to control, lipopolysaccharide (LPS), LPS + REM, and REM groups. Depending on the group, 4 h after intraperitoneal administration of LPS or saline, REM or saline was infused intravenously for 40 min. Following the sacrification, blood samples and brain tissues were collected for analysis. Brain tissues (prefrontal cortex, cerebellum, and hippocampus) were stained with hematoxylin and eosin, caspase-3 (Cas-3), and tumor necrosis factor alpha (TNF-α). Quantitative reverse transcription-polymerase chain reaction analysis was used to detect claudin-5 (CLDN5), zonula occludens-1 (ZO-1), phosphatidylinositol 3-kinase (PI3K), serine-threonine protein kinase (AKT), and hypoxia-inducible factor 1 alpha (HIF-1α) gene expression levels. Histopathologic and immunohistochemical analyses showed that REM treatment improved LPS-induced histological changes. REM does not reduce TOS and OSI levels or increase TAS levels, suggesting that it is ineffective through oxidative stress. LPS-induced changes in gene expression levels (PI3K, AKT, HIF-1α, and CLDN5) were also reversed by REM. REM was found to prevent neuroinflammation, and apoptosis by restoring blood-brain barrier, and regulating the PI3K/AKT/HIF-1α pathway. These findings suggest that REM is protective against neuroinflammation.

This study aimed to evaluate the anticonvulsant properties of fenoprofen on the experimental model of pentylenetetrazole (PTZ)-induced epilepsy. Male Wistar rats were randomly grouped into five, and the kindling model was induced by intraperitoneal injection of PTZ 35 (mg/kg) every other day for 1 month. Aside from the control and PTZ groups, three groups received intraperitoneal injections of fenoprofen at doses of 10, 20, and 40 (mg/kg) before each PTZ injection. Rats were challenged with PTZ 70 (mg/kg) 1 week after kindling development. Then rats were subjected to deep anesthesia, and serum and brain samples were prepared. Oxidative stress (OS) markers (malondialdehyde, superoxide dismutase, and glutathione peroxidase) were measured in serum samples. Hippocampal tissue was used to investigate the relative expression of OS-related genes (nuclear factor [erythroid-derived 2]-like 2 (Nrf2)/heme oxygenase 1 (Hmox1)) and histological studies. Seizure behavior was assessed based on Lüttjohann's score. In treated groups, the number of myoclonic jerks and generalized tonic-clonic seizure (GTCS) duration decreased significantly, while myoclonic jerks and GTCS latency increased compared with the PTZ group. The biochemical evaluation revealed the antioxidative effects of fenoprofen. The decreased expression of Nrf2/HO-1 genes in the PTZ group was reversed after fenoprofen administration. The results of the histological study obtained from Nissl staining in the hippocampal tissue also confirmed the protective effect of fenoprofen. The anticonvulsant effects of fenoprofen seem to be through inhibition of OS-related markers, induction of protective effect in hippocampal tissue, and activation of the Nrf2/HO-1 signaling pathway.

Aromatase inhibitors are used for patients with hormone-receptor positive breast cancer. Alzheimer's disease is the most prevalent cause of dementia. Several studies have suggested an association between the use of aromatase inhibitors and the development of Alzheimer's disease. The objective of this study was to identify potential pharmacovigilance signals associated with dementia and Alzheimer's disease and third-generation aromatase inhibitors in menopausal and postmenopausal women. VigiBase, the global database of individual case safety reports of the World Health Organization, was used to investigate this possible association. A disproportionality analysis was performed for women aged 45 years and older. The reporting odds ratio (ROR) and its 95% CI for reporting dementia are exemestane, 2.08 (1.35-3.19); anastrozole, 1.59 (1.09-2.32); and letrozole, 1.43 (1.05-1.95) and for Alzheimer's disease are exemestane, 0.94 (0.30-2.92); anastrozole: 2.63 (1.55-4.45); and letrozole, 1.33 (0.76-2.35). For senile dementia, only letrozole has cases, with an ROR of 6.77 (2.51-18.31). Signals of disproportionate reporting have been observed between the occurrence of dementia, dementia Alzheimer's type, and senile dementia with aromatase inhibitors, which is in line with estrogen functions and aromatase activity, as well as the findings from preclinical studies. Additional research is required to elucidate this intricate matter.

Cachexia is a multifactorial metabolic syndrome characterized by weight and skeletal muscle loss caused by underlying illnesses such as cancer, heart failure, and renal failure. Inflammation, insulin resistance, increased muscle protein degradation, decreased food intake, and anorexia are the primary pathophysiological drivers of cachexia. Cachexia causes physical deterioration and functional impairment, loss of quality of life, lower response to active treatment, and ultimately morbidity and mortality, while the difficulties in tackling cachexia in its advanced phases and the heterogeneity of the syndrome among patients require an individualized and multidisciplinary approach from an early stage. Specifically, strategies combining nutritional and exercise interventions as well as pharmacotherapy that directly affect the pathogenesis of cachexia, such as anti-inflammatory, metabolism-improving, and appetite-stimulating agents, have been proposed, but none of which have demonstrated sufficient evidence to date. Nevertheless, several agents have recently emerged, including anamorelin, a ghrelin receptor agonist, growth differentiation factor 15 neutralization therapy, and melanocortin receptor antagonist, as candidates for ameliorating anorexia associated with cancer cachexia. Therefore, in this review, we outline cancer cachexia-associated anorexia and its pharmacotherapy, including corticosteroids, progesterone analogs, cannabinoids, anti-psychotics, and thalidomide which have been previously explored for their efficacy, in addition to the aforementioned novel agents, along with their mechanisms.

Dersimelagon is a novel investigational orally administered selective agonist of the melanocortin-1 receptor. The drug-drug interaction (DDI) potential of dersimelagon was investigated in both nonclinical (in vitro) and clinical studies. The in vitro inhibition of CYP/UGT isoforms and efflux/uptake transporters by dersimelagon was assessed. The impact of 300-mg dersimelagon on the pharmacokinetics (PK) of substrate drugs and the effect of co-administering verapamil on 100-mg dersimelagon PK (as substrate drug) were investigated in healthy participants in a Phase 1 study. DDIs were assessed based on ratios of C_max and AUC_0-∞ of substrate drug administered alone and with dersimelagon (or verapamil). Relatively potent in vitro inhibition of CYP2C9, CYP3A, UGT1A1, BCRP, P-gp, and OATPs by dersimelagon was observed. In the clinical study, exposures of atorvastatin (CYP3A, P-gp, BCRP, OATP substrate) rosuvastatin (BCRP and OATP substrate), and β-hydroxy simvastatin (metabolite of simvastatin) increased 2- to 3-fold (atorvastatin: C_max LS mean ratio = 198.0%; AUC_0-∞ ratio = 196.6%; rosuvastatin: C_max ratio = 316.5%, AUC_0-∞ ratio = 206.0%) when co-administered with dersimelagon. Midazolam (CYP3A substrate), digoxin (P-gp), pravastatin (OATP), and simvastatin (CYP3A) did not show any clinically relevant DDI effects when co-administered with dersimelagon. Dersimelagon exposure increased ~25% when co-administered with verapamil, an effect not considered clinically relevant. Dersimelagon 300 mg did not elicit major DDIs involving CYP/UGT enzymes and drug transporters; however, dersimelagon may have potential for clinically relevant DDIs with drugs that are substrates for BCRP, such as atorvastatin and rosuvastatin, and caution should be exercised when co-administering 300-mg dersimelagon with these statin drugs. Trial Registration: ClinicalTrials.gov: NCT04793295, NCT04402489, NCT04440592, NCT02834442, NCT03520036, NCT03503266.

The enzyme N-acetyltransferase 2 (NAT2) plays an important role in metabolism and detoxification of xenobiotics, including carcinogens and medications. We aimed to assess the contribution of the NAT2 polymorphism to susceptibility to inflammatory bowel disease (IBD) in the Polish population. The study involved 101 IBD patients and 100 healthy controls. The NAT2 gene mutations at positions 481T, 803G, 590A, and 857A were identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique on peripheral blood DNA samples. Carriers of the NAT2*5 allele had a greater chance of developing Crohn's disease (CD) (OR = 1.73, 95% CI 1.06-2.83). Also, the NAT2*4/5 genotype was more prevalent in CD patients (OR = 2.77, 95% CI 1.17-6.57). When compared to the control group, the prevalence of the NAT2*4/6 genotype in the IBD patient population was significantly lower (10.9% vs. 30.0%, p < 0.01). In the Polish population, polymorphism in the NAT2 gene may potentially alter susceptibility to IBD.

Mathematical models of thrombin generation (TG) that have been developed are based on a systems biology approach. Although this approach provides important information about the coagulation system, its clinical applicability is limited by its complexity and number of input variables required. The aim of this study was to develop a semimechanistic model able to describe TG in trauma and control patients. A dataset containing longitudinal data of TG assays and coagulation factors from 40 trauma patients and 20 control patients was used for model building. The model considered three fundamental processes: the degradation of tissue factor (TF) through a first-order process, the activation of factor II by the TF through a first-order process, and the degradation of thrombin through a first-order process. Model fitting was performed using a nonlinear mixed-effects approach. The condition of the patient (trauma and control) and coagulation factors were modelled as covariates. Model building demonstrated the presence of two additional processes that improved the predictive capacity of the model: the activation of factor II by TF governed by a second-order constant and, a mechanism of factor II activation by TF characterized by a 7-compartment transit chain governed by a second-order constant. In the covariate model only the inclusion of patient condition was significant. Model evaluation demonstrated excellent performance in describing the temporal pattern of TG in trauma and control patients. Thrombin generation can be adequately modelled using a semimechanistic approach. Its application in practice could help to better assess the risk of hemorrhage and/or thrombosis in different settings.

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of heart failure cases globally, and this incidence is increasing due to extended lifespans and accumulating comorbidities. Emerging evidence suggests that Wnt signaling plays a role in cardiomyocyte hypertrophy and cardiac fibrosis, which are key features of HFpEF. Furthermore, Porcupine (PORCN) inhibitors, which negatively regulate Wnt signaling, have shown promising results in improving cardiac function and reducing cardiac hypertrophy and/or fibrosis. This study investigated whether acute oral administration of the PORCN inhibitor, Wnt-c59, alters the maladaptive structural and/or functional features in a mouse model of HFpEF. Male mice were given a high-fat diet and L-NAME (0.5 g L^-1) in drinking water for 5 weeks, followed by a 2-week intervention of orally administered Wnt-c59 (5 mg kg^-1 day^-1). HFpEF mice were characterized by hypertension, cardiac hypertrophy and fibrosis, and diastolic dysfunction, although there was no evidence of activation of Wnt signaling in the heart. Despite this, short-term treatment of HFpEF mice with Wnt-c59 ameliorated adverse cardiac remodeling by increasing the ratio of the more compliant collagen type 3 to that of the more tensile collagen type 1 in the heart. Furthermore, Wnt-c59 also improved diastolic dysfunction, which was associated with the increased cardiac expression of brain natriuretic peptide, a known promoter of ventricular compliance. Our findings demonstrate that even short-term administration of a PORCN inhibitor improves both the structural and functional features of experimental HFpEF.

Post-traumatic epilepsy (PTE) is a life-long complication of traumatic brain injury (TBI). The development of PTE is associated with neurological morbidity and increases the risk of mortality. An aim of EpiBioS4Rx (Epilepsy Bioinformatics Study for Antiepileptogenic Therapy) was to test potential therapies to prevent the development of PTE in the lateral fluid percussion injury (LFPI) rat model of TBI, in which rats were subjected to injury at the left parietal cortex. Sodium selenate has been reported to be antiepileptogenic post-TBI in rodent models by activating protein phosphatase 2A and reducing phosphorylated tau (p-tau) protein. We aimed to characterize the pharmacokinetics (PK) and brain uptake of sodium selenate using naïve control and LFPI rats. Rats received either a single bolus dose or a single bolus dose followed by a 7-day subcutaneous minipump infusion of sodium selenate. Sodium selenate and selenium concentrations in plasma and brain were analyzed and used for PK estimation and brain exposure assessment. Selenium concentrations rapidly increased after sodium selenate administration, demonstrating biotransformation from sodium selenate to selenium. Sodium selenate and selenium PK parameters were estimated using non-compartmental analysis. Sodium selenate clearance (CL/F) and volume of distribution (V_d/F) varied by dose and route of administration, suggesting differences in bioavailability and nonlinear pharmacokinetics at the doses tested. Brain-to-plasma partition coefficients (AUC_brain/AUC_plasma) for sodium selenate and selenium were found to be 0.7-1.3 and 0.1-0.3 following single-dose injection, respectively, indicating active transport of sodium selenate across the blood-brain barrier (BBB).