Pharmacology Research & Perspectives最新文献

Binimetinib is a MEK1/2 inhibitor particularly active in cells harboring activating mutations in the MAP kinase pathway, especially in BRAF and NRAS. Binimetinib, in combination with encorafenib, has received marketing approval in several jurisdictions for the treatment of patients with BRAF V600E or V600K mutant melanoma. The absorption, distribution, metabolism, and excretion of binimetinib were evaluated by administering a carbon 14-labeled binimetinib 45 mg dose (containing 40 μCi of radiolabeled material) to 6 healthy male participants. A total of 62.3% of the radioactivity was eliminated in the feces, while 31.4% was eliminated in the urine. The overall recovery of radioactivity in the excreta for all 6 participants was 93.6% (3.27%), indicating that good mass balance was achieved. The total percentage of the dose in the excreta of all metabolites containing the N-demethylation clearance of binimetinib by CYP1A2 and CYP2C19 was approximately 17.8%. The contribution of direct glucuronidation to the clearance of binimetinib was estimated to be 61.2% and represented the majority of the clearance. Additionally, excretion of unchanged binimetinib into the urine was estimated to have contributed 6.9% to the overall clearance. Based on study results, binimetinib is at least ≈ 50% absorbed, but based on its PK properties and because its glucuronide conjugates are unstable in the GI tract, absorption is thought to be significantly higher.

Oxidation of dopamine can cause various side effects, which ultimately leads to cell death and contributes to Parkinson's disease (PD). To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and α-synuclein in animals with low VMAT2 expression. Conversely, animals that overexpress VMAT2 show better protection for dopamine neurons. Based on these findings, this study used histone deacetylase inhibitors (HDACi) to increase VMAT2 expression, reduce dopamine-induced oxidative stress, and evaluate the resulting behavioral improvements in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. LMK-235 not only increased VMAT2 expression at various concentrations in the SH-SY5Y cell line differentiated into dopaminergic cells but also demonstrated effective cytoprotective properties in several toxicity assays. It significantly raised VMAT2 expression in both the striatum and the ventral tegmental area of an MPTP-induced PD model, supporting its role in reversing behavioral abnormalities linked to PD. In addition to these results, coadministration of LMK-235 with L-DOPA, a standard therapy for PD, restored typical behavioral patterns, highlighting the potential of HDACi in alleviating PD symptoms. The expression of VMAT2 induced by LMK-235, an inhibitor of Class IIa histone deacetylases primarily found in the nervous system, aids in sequestering dopamine into vesicles, potentially enhancing cell survival by inhibiting dopamine oxidation. Additionally, upregulation of VMAT2 has been shown to offer effective protection against MPTP-induced toxicity and significantly improve behavioral abnormalities associated with PD. Coadministration with L-DOPA produced the most notable improvement in behavioral outcomes. Altogether, these findings suggest that the overexpression of VMAT2 may offer a promising strategy for developing treatments for PD by mitigating dopaminergic neuron death resulting from dopamine oxidation.

Medicine repurposing is a strategy to identify new uses for the existing medicines for the purpose of addressing areas of unmet medical need. This paper aims to provide horizon scanning intelligence on repurposed medicines that are evaluated by non-commercial organizations such as academia and highlights opportunities for further research to improve patient health outcomes. A scan of the clinical landscape of non-commercially sponsored repurposed medicines is routinely conducted by the NIHR Innovation Observatory (IO). This ongoing project involves a horizon scan of clinical trial registries and the IO's internal horizon scanning Medicines Innovation Database to identify potential candidate medicines used as monotherapy or in combination to treat new indications outside the scope of their licensed indication. In addition to making these data publicly available, the output also supports the NHS England Medicines Repurposing Programme. The snapshot scan reported here (trials completing April 2020-March 2023) identified a total of 528 technologies (meaning, a single product or combination of medicinal products targeting a specific indication in one or more related trials). The technologies were classified according to their characteristics and targeted therapeutic indications as well as revealing the least treated disease conditions. The candidate medicines identified in this scan could potentially receive tailored support toward adoption into practice and policy. The NIHR IO regularly provides this scan as a source of intelligence on repurposed medicines. This provides valuable insights into innovation trends, gaps, and areas of unmet clinical need.

Laboratory measurements used for safety assessments in clinical trials are subject to the limits of the used laboratory equipment. These limits determine the range of values which the equipment can accurately measure. When observations fall outside the measurable range, this creates a problem in estimating parameters of the normal distribution. It may be tempting to use methods of estimation that are easy to implement, however selecting an incorrect method may lead to biased estimates (under- or overestimation) and change the research outcomes, for example, incorrect result of two-sample test about means when comparing two populations or biased estimation of regression line. In this article, we consider the use of four methods: ignoring unmeasured observations, replacing unmeasured observations with a multiple of the limit, using a truncated normal distribution, and using a normal distribution with censored observations. To compare these methods we designed a simulation study and measured their accuracy in several different situations using relative error $\frac{\hat{\mu }-\mu }{\mu }$ , ratio $\frac{\hat{\sigma }}{\sigma }$ , and mean square errors of both parameters. Based on the results of this simulation study, if the amount of observations outside of measurable range is below 40%, we recommend using a normal distribution with censored observations in practice. These recommendations should be incorporated into guidelines for good statistical practice. If the amount of observations outside of measurable range exceeds 40%, we advise not to use the data for any statistical analysis. To illustrate how the choice of method can affect the estimates, we applied the methods to real-life laboratory data.

The increasing utilization of cannabis products combined with lack of data regarding potential cannabis-prescription drug interactions is concerning. This study aimed to review published case reports and FDA Adverse Event Reporting System (FAERS) spontaneous reports to assess cannabis-drug interactions in persons aged 18 and over. A literature search identified 20 case reports that were each assessed for drug interaction causality using the Drug Interaction Probability Scale. Data collected from the FAERS revealed a greater proportion of reports mentioning serious outcomes, including death, when cannabis was used concomitantly with controlled substances compared to noncontrolled substances. Fisher's exact test showed a statistically significant difference between the controlled and noncontrolled groups (p = 0.043). Overall, these findings emphasize the need for additional research and vigilant monitoring of cannabis use when combined with other medications.

Gold nanoparticles (AuNPs) present with unique physicochemical features and potential for functionalization as anticancer agents. Three-dimensional spheroid models can be used to afford greater tissue representation due to their heterogeneous phenotype and complex molecular architecture. This study developed an A549 alveolar carcinoma spheroid model for cytotoxicity assessment and mechanistic evaluation of functionalized AuNPs. A549 spheroids were generated using an agarose micro-mold and were characterized (morphology, acid phosphatase activity, protein content) over 21 culturing days. The 72-h cytotoxicity of carboxyl-polyethylene glycol- (PCOOH-) and amine-polyethylene glycol- (PNH₂-) functionalized AuNPs against Day 7 spheroids was assessed by determining spheroid morphology, acid phosphatase activity, protein content, caspase-3/7 activity, and cell cycle kinetics. Spheroids remained stable over the experimental period. Although the A549 spheroids' volume increased while remaining viable over the culturing period, structural integrity decreased from Day 14 onwards. The PCOOH-AuNPs lacked cytotoxicity at a maximum concentration of 1.2 × 10¹² nanoparticles/mL with no prominent alteration to the cellular processes investigated, while the PNH₂-AuNPs (at a maximum of 4.5 × 10¹² nanoparticles/mL) displayed dose- and time-dependent cytotoxicity with associated loss of spheroid compactness, debris formation, DNA fragmentation, and a 75% reduction in acid phosphatase activity. Differentiation between cytotoxic and non-cytotoxic AuNPs was achieved, with preliminary elucidation of cytotoxicity endpoints. The PNH₂-AuNPs promote cytotoxicity by modulating cellular kinetics while destabilizing the spheroid ultrastructure. The model serves as a proficient platform for more in-depth elucidation of NP cytotoxicity at the preclinical investigation phase.

The lack of effective treatments for dry age-related macular degeneration (AMD) is in part due to a lack of a preclinical animal model that recapitulates features of the clinical state including macular retinal pigment epithelium (RPE) degeneration, also known as geographic atrophy (GA). A nonhuman primate model of GA was developed and its responsiveness to an approved treatment, avacincaptad pegol (ACP), a complement C5 inhibitor, was evaluated. Intravitreal (ivt) administration of sodium iodate (SI) into one eye of male Macaca fascicularis leads to retinal areas (mm²) of hyper- or hypo-autofluorescence. Qualitative changes to the retinal structure over time were observed with spectral domain optical coherence tomography (OCT). Six days after SI administration, prior to treatment, mean (± SEM) GA of all eyes was 8.2 ± 1.8 mm². Following randomization to treatment groups, either vehicle or ACP was ivt injected and treatment was continued every 4 weeks, for a total of four treatments. Sixteen weeks after SI administration, the GA area in vehicle-treated eyes was 18.9 ± 6.6 mm², whereas GA in ACP-treated eyes was 11.4 ± 4.0 mm², a reduction by about 36%. Increased, followed by decreased, overall macular thickness was observed with OCT over time following SI administration. Treatment with ACP did not change alter macular thickness thinning. Geographic atrophy-like lesions that expand over time are observed following SI administration. The current macaque model could be utilized to further explore the mechanism of dry AMD and to develop more novel therapeutics.

To understand differences in anti-factor-Xa levels produced by two different dosing strategies (conventional and individualized) for therapeutic enoxaparin in a cohort of hospital inpatients. A multicenter, retrospective cohort study over a two- and a half-year period for inpatients with stable renal function and on therapeutic enoxaparin. Anti-factor-Xa levels were taken 3-5 h after enoxaparin administration and a minimum of 48 h of dosing. The final analysis included 278 patients from five hospitals: conventional dosing was used for 141, while 137 were given an unconventional dose, that is, individualized for their renal function and weight. Out-of-range levels were frequent (35% to 40% of all inpatients). After adjustment for age, renal function, and body mass index (BMI), the conventional group was more likely to experience above-range levels (> 1.0 IU/mL; OR 2.50 [95% CI 1.38-4.56], p < 0.003) than the individualized group. Individualized dosing was independently associated with higher odds of a below-range anti-Xa level (< 0.5 IU/mL) compared to conventional dosing (OR 2.27 [95% CI 1.07-4.76], p = 0.03). Within the conventional group, above-range levels were significantly and independently associated with decreasing renal function (OR 0.97, 95% CI 0.96-0.99, p = 0.004) and with increasing BMI (OR 1.06, 95% CI 1.01-1.10, p = 0.02). No such associations were seen with an individualized approach. Clinical event rates were low and not different between groups (p > 0.24). Conventional therapeutic dosing of enoxaparin exposed people with obesity or renal impairment to more frequent above-range anti-factor-Xa levels; individualizing the dose could improve this but might expose people to subtherapeutic levels. More research is needed.

Relugolix is an oral gonadotropin-releasing hormone receptor antagonist that suppresses sex steroid hormones and is approved as monotherapy for prostate cancer and as a fixed-dose combination with estradiol/norethindrone for the treatment of endometriosis and uterine fibroids. The aim of this postmarketing study was to determine the pharmacokinetics and quantify the amount of relugolix excreted into breast milk of healthy lactating women. Following a single, oral dose of 40 mg relugolix, breast milk was sampled over 120 h. Pharmacokinetic parameters were determined, including the cumulative amount of relugolix excreted into breast milk to derive the total infant dose. The safety and tolerability of relugolix were also assessed. Eight healthy lactating women were enrolled and completed the study per protocol. Relugolix was safe and well tolerated based on adverse events and other safety data. It was excreted into breast milk with a median time to peak concentration (t_max) of 5.81 h and a geometric mean peak concentration (C_max) of 15.7 ng/mL, similar to corresponding plasma data from previous clinical studies. The mean cumulative amount of relugolix excreted was 0.0051 mg over 24 h and 0.0067 mg over 120 h, corresponding to 0.0128% and 0.0167% of the maternal dose, respectively. The body weight-adjusted relative daily infant dose of approximately 0.25% suggests a 400-fold lower newborn than maternal relugolix exposure. Relevant effects of relugolix on the breastfed child appear unlikely given its limited excretion into breast milk of lactating women but cannot be fully excluded in the absence of infant safety data.

Drug repurposing provides a cost-effective and time-saving approach to cancer therapy. Aripiprazole (ARI), a third-generation antipsychotic, has shown potential anticancer properties by modulating pathways central to tumor progression and resistance. This scoping review systematically examines evidence on ARI's anticancer effects, mechanisms of action, and translational potential. A systematic search of PubMed, EMBASE, SCOPUS, and Web of Science was conducted following PRISMA-ScR guidelines. Eligible studies included in vitro, in vivo, and clinical investigations. Data on cancer types, pathways, assays, and outcomes were extracted and synthesized to identify trends and gaps. Of 588 screened studies, 23 met inclusion criteria, spanning cancer types such as breast, colorectal, lung, and brain cancers. ARI modulates key pathways like PI3K/AKT/mTOR and Wnt/β-catenin, induces apoptosis through mitochondrial dysfunction and ER stress, and overcomes drug resistance by inhibiting P-glycoprotein activity and expression. It exhibits tumor-suppressive effects in vivo and synergizes with chemotherapy and radiotherapy. Retrospective population studies suggest ARI's prolactin-sparing properties may reduce the risk of hormone-sensitive cancers such as breast and endometrial cancer compared to antipsychotics with stronger dopamine receptor blockade. Additionally, ARI's ability to target multiple Hallmarks of Cancer highlights its promise as a repurposed anticancer agent. However, current evidence is primarily preclinical and observational, with limited clinical validation. Large-scale cohort studies and prospective trials are essential to confirm its efficacy and address translational challenges. By bridging these gaps, ARI could emerge as a valuable adjunctive therapy in oncology, leveraging its safety profile and versatility to address unmet needs in cancer treatment.