European Journal of Pharmaceutical Sciences最新文献

Background

Bilastine is a well-known non-sedating second-generation antihistamine authorised worldwide for the symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria with proven efficacy and good safety and tolerability profile. When the oral route is not suitable or a rapid onset of action is preferred, parenteral formulations represent an effective treatment option. However, the parenteral formulations currently available are sedating antihistamines. The objective of this research was to compare the peripheral anti-H₁ activity of different bilastine formulations (i.v., i.m. and oral) and dexchlorpheniramine among them also versus placebo.

Methods

This was a single-dose, randomized, crossover, double-blind, placebo-controlled, phase I clinical study performed on 25 adult healthy volunteers that compared the peripheral antihistaminic activity of a single dose of bilastine 12 mg i.v., bilastine 12 mg i.m., bilastine 20 mg oral tablets and dexchlorpheniramine 5 mg i.m. among them and versus placebo by inhibiting the histamine-induced wheal and flare (W&F) response. Pharmacokinetics, safety, and tolerability were also evaluated.

Results

All bilastine formulations showed a rapid onset of action (15 min for parenteral and 30 min for the oral formulation), and the maximum effect in both wheal (i.v. 74.44 %; i.m.:74.29 %; oral 70,27 %) and flare area reduction (i.v. and i.m. 80.63 %; oral 77.67 %), was significantly larger compared to dexchlorpheniramine i.m. (25.85 % for wheal and 28.65 % for flare) and placebo (1.35 % for wheal and 4.02 % for flare). A more pronounced reduction in itching score was reached for bilastine oral, followed by i.m. and i.v. formulations. No serious adverse events (SAEs) were reported during the study, and 8 treatment-emergent adverse events (TEAEs) were reported by 5 subjects, all resolved without sequelae. For psychomotor assessments, dexchlorpheniramine i.m. showed a fast onset of drowsiness, as well as decreased attention and coordination when compared to all bilastine formulations and placebo.

Conclusions

All bilastine formulations showed a peripheral H₁-blocking effect inducing a significantly greater inhibition of the wheal and flare response as compared to dexchlorpheniramine i.m. or placebo and provided a greater reduction of the itching sensation score. This study reconfirmed that bilastine has no sedative effect, even in a parenteral formulation. These results suggest that new bilastine parenteral formulation (i.v. or i.m.) may represent a suitable alternative for patients requiring immediate treatment of histamine-mediated type I hypersensitivity reactions, such as acute urticaria, or in those cases where oral administration is not possible.

Background: Species differences in CYP2D6 drug metabolism complicate the extrapolation of in vivo pharmacokinetic data to humans and impact the prediction of drug responses. This study aimed to develop an in vivo model to predict human responses to CYP2D6 metabolized compounds and to evaluate medication risks and disease development.

Methods: We used embryonic stem cell (ES) targeting and CRISPR-Cas9 technology to create a humanized CYP2D6 mouse model by inserting the human wild-type CYP2D6 gene and knocking out the mouse Cyp2d locus. Metoprolol was used as the substrate probe to examine the pharmacokinetic properties of exogenous substances, tissue distribution, and in situ metabolism of CYP2D6. Untargeted and quantitative metabolomics analyses compared endogenous substance metabolism between different species of CYP2D6 enzymes.

Results: No significant differences in CYP2D6 homologous protein distribution and expression of primary metabolic organs were found between humanized CYP2D6 mice and wild-type (WT) mice. The activity and metabolic capacity of CYP2D6 in humanized mice were substantially lower than homologous Cyp2d22 of WT mice in metabolizing metoprolol. The levels of several glycerolipids and glycerophospholipid-related metabolites were down-regulated in humanized CYP2D6 mice. Triglyceride TG (14:0_22:6_22:6) was significantly downregulated in male and female humanized mice, suggesting a strong association with reduced CYP2D6 activity.

Conclusions: This study established a robust animal model to investigate human CYP2D6-mediated metabolic profiles of exogenous and endogenous compounds, predict medication risks, and explore the potential roles of CYP2D6 in organ-specific toxicity and disease development.

Progression-free survival (PFS) is an important clinical metric in oncology and is typically illustrated and evaluated using a survival function. The survival function is often estimated post-hoc using the Kaplan-Meier estimator but more sophisticated techniques, such as population modeling using the nonlinear mixed-effects framework, also exist and are used for predictions. However, depending on the choice of population model PFS will follow different distributions both quantitatively and qualitatively. Hence the choice of model will also affect the predictions of the survival curves.

In this paper, we analyze the distribution of PFS for a frequently used tumor growth inhibition model with and without drug-resistance and highlight the translational implications of this. Moreover, we explore and compare how the PFS distribution for combination therapy differs under the hypotheses of additive and independent-drug action.

Furthermore, we calibrate the model to preclinical data and use a previously calibrated clinical model to show that our analytical conclusions are applicable to real-world setting. Finally, we demonstrate that independent-drug action can effectively describe the tumor dynamics of patient-derived xenografts (PDXs) given certain drug combinations.

Recent advances in understanding Alzheimer's disease (AD) suggest the possibility of an infectious etiology, with Porphyromonas gingivalis emerging as a prime suspect in contributing to AD. P. gingivalis may invade systemic circulation via weakened oral/intestinal barriers and then cross the blood-brain barrier (BBB), reaching the brain and precipitating AD pathology. Based on the proposed links between P. gingivalis and AD, a prospective approach is the development of an oral nanovaccine containing P. gingivalis antigens for mucosal delivery. Targeting the gut-associated lymphoid tissue (GALT), the nanovaccine may elicit both mucosal and systemic immunity, thereby hampering P. gingivalis ability to breach the oral/intestinal barriers and the BBB, respectively.

The present study describes the optimization, characterization, and in vitro evaluation of a candidate chitosan-coated poly(lactic-co-glycolic acid) (PLGA-CS) nanovaccine containing a P. gingivalis antigen extract. The nanocarrier was prepared using the double emulsion solvent evaporation method and optimized for selected experimental factors, e.g. PLGA amount, surfactant concentration, w₁/o phase ratio, applying a d-optimal statistical design to target the desired physicochemical criteria for its intended application. After nanocarrier optimization, the nanovaccine was characterized in terms of particle size, polydispersity index (PdI), ζ-potential, encapsulation efficiency (EE), drug loading (DL), morphology, and in vitro release profile, as well as for mucoadhesivity, stability under simulated gastrointestinal conditions, antigen integrity, in vitro cytotoxicity and uptake using THP-1 macrophages.

The candidate PLGA-CS nanovaccine demonstrated appropriate physicochemical, mucoadhesive, and antigen release properties for oral delivery, along with acceptable levels of EE (55.3 ± 3.5 %) and DL (1.84 ± 0.12 %). The integrity of the encapsulated antigens remained uncompromised throughout NPs production and simulated gastrointestinal exposure, as confirmed by SDS-PAGE and Western blotting analyses. Furthermore, the nanovaccine showed effective in vitro uptake, while exhibiting low cytotoxicity. Taken together, these findings underscore the potential of PLGA-CS NPs as carriers for adequate antigen mucosal delivery, paving the way for further investigations into their applicability as vaccine candidates against P. gingivalis.