Pharmaceutics最新文献

(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK-PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL/kg and CL = 4.5 × 10^-1 mL/h/kg). A precursor-pool PK-PD model (k_in = 6.1 × 10^-3 mg/h, k_p = 8.6 × 10^-4 h^-1 and k_out = 2.7 × 10^-2 h^-1) with a parallel transit chain (k₀ = 1.9 × 10^-1 h^-1) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope₁ = 1.1 × 10^-1 h) and the elimination of MA (Slope₂ = 1.25 h) through the transit chain. Regarding the reference dose (1 mg/kg) of the RIM model, the administration of 4 mg/kg would lead to a mean reduction of 65% (C_max), 80% (C_min), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.

The deformulation stage of original drug products, which includes the quantification of critical excipients, is crucial for the successful development of generic drug products of solid dosage form. Sodium lauryl sulphate (SLS) belongs to the group of critical excipients due to its influence on the bioavailability of drugs, such as metformin. The purpose of this work is to carry out a feasibility study in order to develop a simple, economical, and robust analytical method for the quantification of SLS in metformin-containing tablets after their dissolution in water. Firstly, SLS is extracted with chloroform in acidic conditions, followed by the addition of methylene blue (MB) in order to form a SLS-MB ion pair, which is then measured photometrically at a wavelength of 651 nm. Additionally, interference from matrix components (excipients and APIs) was assessed, and it was found that metformin also forms a blue complex; therefore, this specific extraction method was developed. Other matrix components did not interfere with SLS determination. This method shows a well-estimated precision of 3.3% and accuracy of 5%, a calibration linearity of R² = 0.99990, and a working range of 0.38 µg/mL to 10 µg/mL of SLS in water. The midpoint of the calibration graph corresponds to the concentration of SLS obtained by dissolving a single tablet in 1 L of water. This method seems appropriate for total SLS determination in tablets and can be applicable for deformulation.

Aedes mosquito-borne diseases remain a significant global health threat, necessitating effective control strategies. This study introduces monoterpenes-based nanohydrogels for potential use as repellents against Aedes aegypti, the primary dengue vector worldwide. We formulated hydrogels using cymene- and myrcene-based nanoemulsions with different polymers: chitosan, carboxymethylcellulose (CMC), and carbopol^®. Our evaluations of rheological, texture, and bioadhesive properties identified CMC hydrogel as the most promising gelling agent for topical application, exhibiting sustained monoterpene release over 12 h with low skin permeation and high retention in the stratum corneum. Myrcene-loaded CMC hydrogel achieved a 57% feeding deterrence compared to 47% with cymene hydrogel in the mosquito membrane-feeding model. Molecular docking studies revealed interactions between myrcene and an essential amino acid (Ile116) in the Ae. aegypti odorant-binding protein 22 (AeOBP22), corroborating its higher repellent efficacy. These findings suggest that myrcene-loaded CMC hydrogels offer a promising, minimally invasive strategy for personal protection against Ae. aegypti and warrant further investigation to optimize monoterpene concentrations for vector control.

A lack of strategies for the utilization of harvest residues (HRs) has led to serious environmental problems due to an accumulation of these residues or their burning in the field. In this study, wheat and corn HRs were used as feedstock for the production of microcrystalline cellulose (MCC) by treatment with 2-8% sodium hydroxide, 10% hydrogen peroxide and further hydrolysis with 1-2 M hydrochloric acid. The changes in the FT-IR spectra and PXRD diffractograms after chemical treatment confirmed the removal of most of the lignin, hemicellulose and amorphous fraction of cellulose. A higher degree of crystallinity was observed for MCC obtained from corn HRs, which was attributed to a more efficient removal of lignin and hemicellulose by a higher sodium hydroxide concentration, which facilitates the dissolution of amorphous cellulose during acid hydrolysis. MCC obtained from HRs exhibited lower bulk density and poorer flow properties but similar or better tableting properties compared to commercial MCC (Ceolus^TM PH101). The lower ejection and detachment stress suggests that MCC isolated from HRs requires less lubricant compared to commercial MCC. This study showed that MCC isolated from wheat and corn HRs exhibits comparable tableting behaviour like commercial sample, further supporting this type of agricultural waste utilization.

In the present study with a novel two-chamber setup (TCS) for dustiness investigations, the relationship between pressure differences as well as air velocities and the resulting dust emissions is investigated. The dust emissions of six particle size fractions of acetaminophen at pressure differences between 0 and 12 Pa are examined. The results show that both simulated and measured air velocities increase with increasing pressure difference. Dust emissions decrease significantly with increasing pressure difference and air velocity. Fine particles cause higher dust emissions than coarse particles. A high goodness of fit is obtained with exponential and quadratic functions to describe the relationship between pressure difference and dust emission, indicating that even moderate increases in pressure may lead to a reduction in the emission. Average air velocities within the TCS simulated with Computational Fluid Dynamics are between 0.09 and 0.37 m/s, whereas those measured experimentally are between 0.09 and 0.41 m/s, both ranges corresponding to the recommended values for effective particle separation in containment systems. These results underline the ability of the novel TCS to control pressure and airflow, which is essential for reliable dust emission measurements and thus provide support for further scientific and industrial applications.

Metformin inhibits enhanced secretion of anterior pituitary hormones. Its impact on prolactin and gonadotropin concentrations is absent in individuals with hypovitaminosis D. The aim of this prospective cohort study was to investigate whether vitamin D status determines the effect of metformin on hypothalamic-pituitary-thyroid axis activity in levothyroxine-naïve women. The study included three groups of women of reproductive age with subclinical non-autoimmune hypothyroidism, which were matched for age, thyroid-stimulating hormone (TSH) concentration, and insulin sensitivity: untreated women with vitamin D deficiency/insufficiency (group A), women effectively supplemented with exogenous calciferol (group B), and untreated women with normal 25-hydroxyvitamin D concentrations (25OHD) (group C). Owing to concomitant type 2 diabetes or prediabetes, all subjects were treated with metformin. Concentrations of 25OHD, TSH, total and free thyroid hormones, glucose, insulin, glycated hemoglobin (HbA_1c), prolactin, and peripheral markers of thyroid hormone action were assayed before metformin treatment and six months later. Based on hormone concentration, structure parameters of thyroid homeostasis were calculated. Except for 25OHD concentrations, there were no between-group differences in baseline values of the measured variables. Metformin reduced glucose, the homeostatic model assessment 1 of insulin resistance ratio (HOMA1-IR), and HbA_1c in all study group, but these effects were less pronounced in group A than in the remaining groups. The reduction in TSH and Jostel's index was observed only in groups B and C, and its degree correlated with baseline TSH concentrations, baseline 25OHD concentrations, and the degree of improvement in HOMA1-IR. The drug did not affect circulating levels of 25OHD, free and total thyroid hormones, prolactin, other structure parameters of thyroid homeostasis, and markers of thyroid hormone action. The obtained results allow us to conclude that low vitamin D status in young women mitigates the impact of metformin on thyrotroph secretory function.

3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative with notable psychoactive properties and emerging therapeutic potential, particularly for treating post-traumatic stress disorders (PTSD) and substance use disorders. However, its use remains controversial due to inter-individual variability influenced by both environmental and genetic factors. In this context, pharmacogenomics could play a crucial role in guiding MDMA treatment by identifying individuals with genetic predispositions affecting their response to MDMA. Tailoring treatment plans based on individual's genetic makeup may enhance therapeutic outcomes and minimize adverse effects, leading to safer and more effective use of MDMA in clinical settings. Literature analysis reveals that the influence of genetic variants within genes encoded for enzymes involved in MDMA metabolism and/or pharmacodynamics (PD) targets have been relatively under-investigated in humans. Some studies have pointed out associations between MDMA-induced effects and polymorphisms. For example, the catechol-O-methyltransferase (COMT) Val158Met polymorphism has been associated with cognitive and cardiovascular MDMA-induced effects. Similarly, polymorphisms in the serotonin-linked promoter region (5HTTLPR) have been associated with several MDMA-induced adverse effects including mood disorders. However, despite these findings, only a few associations have been highlighted. Furthermore, some genes encoded for MDMA targets have been only poorly investigated, representing a significant research gap. These observations underscore the need for large-scale, controlled pharmacogenomics studies focusing on a broad panel of genes involved into MDMA pharmacokinetics and PD. Such studies could provide critical insights for optimizing MDMA's therapeutic use and minimizing its risks.

Topical ocular drug delivery faces several challenges due to the eye's unique anatomy and physiology. Physiological barriers, tear turnover, and blinking hinder the penetration of drugs through the ocular mucosa. In this context, nanoparticles offer several advantages over traditional eye drops. Notably, they can improve drug solubility and bioavailability, allow for controlled and sustained drug release, and can be designed to specifically target ocular tissues, thus minimizing systemic exposure. This study successfully designed and optimized PLGA and PCL nanoparticles for delivering baricitinib (BTB) to the eye using a factorial design, specifically a three-factor at five-levels central rotatable composite 2³⁺ star design. The nanoparticles were small in size so that they would not cause discomfort when applied to the eye. They exhibited low polydispersity, had a negative surface charge, and showed high entrapment efficiency in most of the optimized formulations. The Challenge Test assessed the microbiological safety of the nanoparticle formulations. An ex vivo permeation study through porcine cornea demonstrated that the nanoparticles enhanced the permeability coefficient of the drug more than 15-fold compared to a plain solution, resulting in drug retention in the tissue and providing a depot effect. Finally, the in vitro ocular tolerance studies showed no signs of irritancy, which was further confirmed by HET-CAM testing.

Gold-based nanoparticles for surface-enhanced Raman scattering (SERS) imaging show great potential for precise tumor detection and photothermal therapy (PTT). However, the metabolizability of gold nanoparticles (Au NPs) raises big concerns. Herein, we designed a core-shelled nanostructure of copper sulfide (CuS)-coated Au NPs with surface pegylation (PEG-Au@CuS NSs). The excreted Au in the gallbladders at 1 h and 4 h in mice injected with PEG-Au@CuS NSs was 8.2- and 19.1-fold of that with the pegylated Au NPs (PEG-AuNPs) of the same Au particle size, respectively. By loading the Raman reporter 3,3'-Diethylthiatricarbocyanine iodide (DTTC) in the core-shell junction of PEG-Au@CuS NSs, the PEG-Au-DTTC@CuS NSs exhibited the Raman signal-to-noise (S/N) ratio of 4.01 after 24 h of intravenous (IV) injection in the mice bearing an orthotopic CT26-Luc colon tumor. By contrast, the DTTC-coated PEG-AuNPs (PEG-Au-DTTC NPs) achieved an S/N ratio of 2.71. Moreover, PEG-Au-DTTC@CuS NSs exhibited an increased photothermal conversion effect compared with PEG-Au-DTTC NPs excited with an 808-nm laser. PEG-Au-DTTC@CuS NSs enabled intraoperative SERS image-guided photothermal therapy for a complete cure of the colon tumor-bearing mice. Our data demonstrated that the PEG-Au-DTTC@CuS NSs are promising intraoperative Raman image-guided theranostic nanoplatform with enhanced hepatobiliary excretion.

This study reports for the first time the isolation of four diterpenoid compounds: 15-Hydroxy-12-oxo-abietic acid (1), 12α-hydroxyabietic acid (2), (-)-Jolkinolide E (3), and 15-Hydroxydehydroabietic acid (4) from Clinopodium bolivianum (C. bolivianum). The findings demonstrate that both the dichloromethane/methanol (DCMECB) extract of C. bolivianum and the isolated compounds exhibit significant anti-inflammatory (inhibition of NF-κB activation), antibacterial (primarily against Gram-positive bacteria), and anti-biofilm (primarily against Gram-negative bacteria) activities. Among the isolated diterpenes, compounds 3 and 4 showed notable anti-inflammatory effects, with IC₅₀ values of 17.98 μM and 23.96 μM for compound 3, and 10.79 μM and 17.37 μM for compound 4, in the HBEC3-KT and MRC-5 cell lines. Regarding their antibacterial activity, compounds 3 and 4 were particularly effective, with MIC values of 0.53-1.09 μM and 2.06-4.06 μM, respectively, against the S. pneumoniae and S. aureus Gram-positive bacteria. Additionally, these compounds demonstrated significant anti-biofilm and anti-quorum sensing activities, especially against Gram-negative bacteria (H. influenzae and L. pneumophila). We also explain how compound 3 (BIC = 1.50-2.07 μM, Anti-QS = 0.31-0.64 μM) interferes with quorum sensing due to its structural homology with AHLs, while compound 4 (BIC = 4.65-7.15 μM, Anti-QS = 1.21-2.39 μM) destabilises bacterial membranes due to the presence and position of its hydroxyl groups. These results support the traditional use of C. bolivianum against respiratory infections caused by both Gram-positive and Gram-negative bacteria. Furthermore, given the increasing antibiotic resistance and biofilm formation by these bacteria, there is a pressing need for the development of new, more active compounds. In this context, compounds 3 and 4 isolated from C. bolivianum offer promising potential for the development of a library of new, more potent, and selective drugs.