Journal of Pharmaceutical Innovation最新文献

Background

The present study aims to evaluate regulatory frameworks in tackling anti-microbial resistance (AMR) across the US & Europe. It examines the WHO’s Global Action Plan (GAP) on AMR, legislation, clinical trials, and various strategies to combat the rising threat of AMR with a focus on Qualified Infectious Disease Product (QIDP) and PRIME designation approvals.

Objective

This study analyzes regulatory policies, legislation in the US & Europe, and various strategies addressing AMR globally, and provides recommendations to enhance and streamline them, ultimately combating the AMR crisis.

Methods

Data on regulatory policies were sourced from authoritative entities like the FDA (US) and EMA (EU), EU commission. The study also examined national action plans (NAPs) for AMR in these regions and the WHO’s GAP. Information on drug products approved for AMR under the Generating Antibiotic Incentives Now (GAIN) Act was obtained from the US FDA and PRIME designation of EMA, while incentives for tackling AMR were assessed from various legal sites in both countries.

Results

The study reveals a complex regulatory landscape, with varying degrees of implementation and adherence across the US & EU. The WHO’s GAP highlights the need for a unified global approach. The US has initiatives like the GAIN Act. The 24 QIDP-designated drugs approved by the FDA demonstrate the US’s focus on tackling AMR. Alternative strategies show promise but require further research to ensure efficacy and safety. EMA demonstrated a proactive and flexible approach to combating antimicrobial resistance through initiatives like PRIME designation and Stewardship and Access Plans.

Conclusion

AMR is a critical global health issue requiring immediate and coordinated action. Strengthening regulatory frameworks, enforcing legislation, and promoting responsible antimicrobial use are essential. Investment in new treatments and global collaboration is crucial to combat AMR effectively.

Purpose

Irinotecan is widely used in metastatic colorectal cancer, but its clinical utility is limited by gastrointestinal toxicity, particularly intestinal mucositis, for which effective therapies are lacking. This study evaluated the protective effects of pioglitazone, a thiazolidinedione PPAR-γ agonist, against irinotecan-induced mucositis in female Swiss mice.

Methods

Mucositis was induced by irinotecan (75 mg/kg, i.p., for 4 days), followed by pioglitazone treatment (3, 10, and 30 mg/kg orally, or 3 mg/kg intraperitoneally) for 7 days.

Results

Pioglitazone at 30 mg/kg (p.o.) significantly reduced diarrhea score and partially restored leukocyte counts and spleen weight, while also improving duodenal weight. Histological analysis revealed preservation of villus structure, crypt integrity, and goblet cell numbers, with reduced inflammatory infiltration and mucosal vacuolization. At the biochemical level, pioglitazone restored superoxide dismutase (SOD) activity, normalized glutathione S-transferase (GST) activity, and markedly decreased myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) activities, although glutathione (GSH) remained depleted and nitrite levels elevated.

Conclusions

Collectively, these findings demonstrate that pioglitazone at 30 mg/kg (p.o.) attenuates key clinical, histological, and inflammatory alterations and modulates redox-related parameters associated with irinotecan-induced mucositis. Pioglitazone thus emerges as a promising candidate for repurposing as an adjuvant therapy to improve chemotherapy tolerability in colorectal cancer.

Purpose

Velpatasvir, a direct-acting antiviral agent, exhibits poor aqueous solubility that limits absorption and oral bioavailability. This study aimed to augment its dissolution through co-processing with amino acids, particularly arginine, and to evaluate its intestinal absorption when co-perfused with arginine.

Methods

Co-processing was achieved by physical mixing and dry co-grinding at different molar ratios. The formulations were characterized by Fourier Transform Infrared (FTIR) spectroscopy, Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD), and dissolution studies. In-situ intestinal perfusion in duodenum, jejunum, ileum, and colon was conducted with and without arginine.

Results

Dry co-grinding at a 1:1 molar ratio with arginine markedly enhanced dissolution efficiency from 31.27% (unprocessed drug) to 98.14%, attributed to co-amorphization as confirmed by spectroscopic and thermal analyses. In-situ perfusion data revealed insufficient small intestinal absorption, likely due to P-glycoprotein efflux, indicated by negative anatomical reserve length (ARL) values. Absorptive clearance per unit length (PeA/L) values were 0.0034, 0.0027, 0.0029, and 0.039 mL/min·cm in duodenum, jejunum, ileum, and colon, respectively. Co-perfusion with arginine increased absorptive clearance per unit length, producing 5.59-, 4.07-, and 4.14-fold increases in PeA/L in the duodenum, jejunum, and ileum, respectively, with statistical significance observed in the duodenum.

Conclusion

These findings indicate that amino acid co-amorphization enhances dissolution and arginine co-perfusion improves intestinal absorption, optimizing velpatasvir’s therapeutic potential for Hepatitis C.

Purposes

Osteoarthritis is a musculoskeletal disease characterized by cartilage degradation and chronic pain, affecting approximately 7.6% of the global population in 2021. Passiflora edulis leaves contain bioactive compounds with potential for osteoarthritis treatment. Formulating P. edulis extract into chitosan nanoparticles can enhance its absorption, bioavailability, and efficacy. This study aimed to evaluate the anti-inflammatory and anti-osteoarthritis properties of P. edulis leaf nanoparticles (PLEN).

Methods

PLEN was evaluated for its anti-inflammatory activity in LPS-induced RAW 264.7 cells and anti-osteoarthritis effects on monosodium iodoacetate (MIA) induced rat model of osteoarthritis. Furthermore, previously identified P. edulis leaf compounds were subjected to molecular docking against iNOS (PDB ID: 3E6T), TNF-α (PDB ID: 7KP8), IL-6 (PDB ID: 7DC8), and MMP-9 (PDB ID: 4XCT).

Results

PLEN treatment demonstrated anti-inflammatory activity by inhibiting NO production by 43.68–60.58%, reducing iNOS levels by 11.98–38.83%, and decreasing TNF-α levels by 7.74–16.92%. In-vivo evaluation showed that PLEN increased body weight, reduced knee oedema, spleen weight, inflammation, and cartilage degradation. Molecular docking of P. edulis bioactive compounds revealed that cyclopassifloside II exhibited the highest iNOS inhibition with a docking score of -113.083 kcal/mol, N-cis-feruloyltyramine inhibited TNF-α with a docking score of -115.021 kcal/mol, cyclopassifloside XII inhibited IL-6 with a docking score of -116.875 kcal/mol, and luteolin-6-C-fucoside inhibited MMP-9 with a docking score of -122.91 kcal/mol.

Conclusion

This study demonstrated that PLEN exerts anti-inflammatory and anti-osteoarthritis activities, and the results suggest different P. edulis bioactive compounds may target distinct anti-inflammatory and anti-osteoarthritis pathways.

Purpose

Neuroinflammation is a complex response of the central nervous system towards certain stressors, including trauma, infection, and neurodegenerative disorders. While neuroinflammation plays a crucial role in defending the brain against infections, excessive or prolonged inflammation can result in pathological conditions like epilepsy. In the current study, the anti-epileptic and anti-depressant activities of the methanolic extract of Tagetes minuta L. leaves and flowers were evaluated to validate the scientific evidence that has been used traditionally.

Methods

In this study, mice weighing 25–30 g were given pentylenetetrazol (PTZ) 40 mg/kg for 15 days alternatively to induce epilepsy and diazepam (2 mg/kg) was used as reference standard for comparison. Thereafter, subjected to behavioral tests such as the elevated-plus maze test (EPM), the light-dark test (LD), and the forced swim test (FSD). Afterward, T. minuta methanolic extract (TME) was administered at two different doses (150 mg/kg and 250 mg/kg) in the PTZ-induced epileptic model, showing notable antidepressant and antiepileptic effects. The enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were performed to evaluate levels of neuroinflammatory markers. Moreover, GC-MS analysis was performed to determine the presence of phytochemicals in TME that contribute to its bioactivity.

Results

TME caused a reduction in neuroinflammation by upregulating brain-derived neurotropic factors (BDNF) and downregulating inflammatory cytokines, including cyclooxygenase (COX2), p-nuclear factor kappa B (p-NF-κB), tumor necrosis factor (TNF), and interleukin-6 (IL-6). Moreover, GC-MS analysis confirmed the presence of various phytoconstituents that may contribute to its anticonvulsant properties.

Conclusion

Concluding that T. minuta methanolic extract has encouraging potential as an antidepressant and anticonvulsant agent. However, the mechanism of phytochemicals responsible for the medicinal value should be explored individually.

Graphical Abstract

Objectives

Diabetic neuropathy is a severe diabetic complication that causes hyperalgesia, allodynia and vulvodynia in diabetic female patients. Modern-day pharmaceutical therapies, consisting of topical medications, opioids, GABA analogues, and antidepressants, have the disadvantage of causing systemic adverse effects and poor adherence, while providing only partial alleviation from the symptoms of neuropathy. This study was aimed to assess the preclinical efficacy of carbopol-940 based multimodal topical gel combining 3-hydroxyflavone (3-HF), gabapentin, and ketamine in streptozotocin (STZ) induced diabetic neuropathy to fill the therapeutic gap.

Methods

10% Gabapentin gel (GG-10%) and a control gel (CG) were used in contrast to test the effects of a 10% multimodal test gel (MMTG-10%) in female rats. The Flinching Response Threshold (FRT), Paw Withdrawal Threshold (PWT), Flinching Response Latency (FRL), and Paw Withdrawal Latency (PWL) were exploited to assess the responses to pain using von Frey filaments applied to the hind paw and vulva region. Vulvar tissues were subjected to histopathological examination.

Results

The 10% MMTG produced significant changes (rise) in FRT, PWT, FRL, and PWL as compared to gabapentin gel and control gel. A major drop was seen in PWD (***p < 0.001) when treated with 10% MMTG in comparison to the diseased control group (DC) whereas the 10% GG-10% produced less effect in reducing PWD and CG produced no effect in reducing PWD. Histopathological evaluation revealed that there was a reduction in atrophy, desquamation, and hyperkeratosis and restoration of vulvar architecture.

Conclusion

Our findings indicated that the MMTG-10% proves to be a promising therapeutic approach for diabetes-induced neuropathic pain, particularly for vulvodynia, by promoting tissue regeneration and providing additional analgesic efficacy. This approach could lower the healthcare expenses for chronic diabetic problems and makes a patient’s life better.

Lung cancer remains the leading cause of cancer death globally, highlighting an urgent need for therapies that can overcome acquired resistance. The epidermal growth factor receptor (EGFR) is a well-validated target in non-small-cell lung cancer (NSCLC)however, the continuous emergence of resistance mutations necessitates the exploration of chemically diverse scaffolds with potent binding affinity against the drug-resistant T790M mutant. Here, we present a streamlined, hierarchical in silico discovery framework designed to accelerate the identification of novel EGFR inhibitors targeting the T790M/ L858R resistance mutations. By integrating pharmacophore modeling, 3D-QSAR, and AI-driven toxicity assessments, this study demonstrates a cost-effective lead optimization protocol that significantly reduces the experimental burden associated with early-stage drug discovery. Top matches from three optimal pharmacophoric hypotheses were docked into the EGFR structure (PDB: 3IKA) and ranked by predicted binding affinity. Seven chemically diverse lead compounds were identified with docking scores between − 11.015 and − 10.128 kcal·mol⁻¹. All leads satisfied key drug-like filters (molecular weight < 500 Da, fitness score > 0.5, ≤ 7 hydrogen bond donors, ≤ 10 acceptors, and logP between − 2.856 and − 0.084) and showed acceptable in silico ADME/Tox profiles. Molecular dynamics simulations of the top ligand–receptor complexes supported stable binding modes and persistent intermolecular interactions. In silico ADME and toxicity predictions further supported their drug-likeness, indicating good absorption, minimal hepatotoxicity, and low carcinogenic risk. These findings nominate four promising candidates for experimental validation and medicinal chemistry optimization as potential EGFR inhibitors to address T790M-mediated resistance in NSCLC.

Graphical Abstract

The present study aims to formulate and optimized mucoadhesive chitosan-coated alginate microbeads as a guardian; encapsulating amoxicillin trihydrate for site specific H. pylori healing in peptic ulcer therapy. This study investigates a gastroretentive mucoadhesive drug delivery method for eliminating H. pylori at specific sites. Using ionotropic gelation, chitosan-coated alginate beads loaded with amoxicillin were formulated and optimized using Box Behnken design, considering concentration of polymer, drug and coating solution as a formulation variable. The optimized bead formulation exhibited in vitro drug release up to 8 h, following Korsmeyer-Peppas model. Release mechanism follows non-fictional anomalous transport, 86.54% sustained drug release, 91% to 96.42% entrapment efficiency, and 62–68% mucoadhesion was observed. It was observed that H. pylori could be absolutely eradicated in vitro. Both the SEM and EDAX investigations revealed a rough outer surface with chitosan coating and dense spherical beads, as well as full loading of the element composition. In conclusion, the developed chitosan-coated alginate beads, offers revolutionary possibilities for H. pylori treatment as gastroretentive mucoadhesive system for delivery of amoxicillin. Potentially improve the therapeutic efficacy and reducing the frequency of dose and identifies the effective healing treatment for H. pylori associated ulcer.

Graphical Abstract

Purpose

Effective wound healing treatments are essential to prevent infections and in promoting recovery, as wounds can serve as entry points for various pathogens. This study aims to develop and characterize sodium hyaluronate based silver nanoparticle dispersion (SND) -loaded hydrogel for enhanced antimicrobial activity and improvedwound healing efficacy.

Method

Silver Nanoparticles (SNPs) were synthesized by the wet chemical method and stabilized with sodium hyaluronate, serving as a bifunctional excipient. The SNPs were characterized using UV-Visible spectroscopy, TEM (transmission electron microscopy), zeta sizer and ICP-AES (Inductively coupled plasma- atomic emission spectrometry). The optimized SNPs were then incorporated into a Carbopol^® 974p based hydrogel matrix. The formulation was evaluated for in vitro drug release using the franz diffusion apparatus and then compared to a commercially available hydrogel, adhesive force, antimicrobial activity tested against Staphylococcus aureus and in vivo wound healing efficacy evaluated in rats.

Results

The optimized SNPs had an average size of 34 nm with a zeta potential of -13.7 mV, and ICP-AES analysis confirmed SNP concentration of approximately 51.91±1.52μg/ml. The developed hydrogel exhibited a controlled drug release pattern, with 23±0.89% drug diffusion and 77±1.25% retention, compared to 67±1.85% diffusion and 33±1.97% retention in the marketed formulation. Adhesive force was higher (± 1.05 g) than that of the conventional gel ( ± 0.87 g). The zone of inhibition against S. aureus was 23±1.2 mm for the test hydrogel versus 21±0.54 mm for the marketed product at 32ug/ml concentration. In vivo wound contraction reached ~90% by Day 16 with the SND loaded hydrogel (T52), significantly higher than ~75% in the marketed group and ~60% in the placebo. Histopathology confirmed enhanced angiogenesis and collagen formation in the treated group.

Conclusion

The sodium hyaluronate-stabilized SND loaded hydrogel exhibited exhibited superior adhesion, sustained drug release, potent antibacterial activity, and enhanced wound healing compared to conventional formulations. These findings suggest its potential as an effective therapeutic option for managing infected wounds and promoting tissue regeneration.

Graphical Abstract

Fungal and bacterial infections are critical complications in atopic dermatitis (AD), significantly affecting patient quality of life and healthcare outcomes. Luliconazole (LZ), a potent topical broad-spectrum antifungal, inhibits ergosterol biosynthesis but is limited by low water solubility and dermal bioavailability. Metronidazole (MTZ), a nitroimidazole antimicrobial, exhibits robust antibacterial properties and offers potential enhanced antimicrobial benefits when combined with antifungals. This study focuses on the co-crystallization of LZ and MTZ to overcome LZ’s solubility limitations and enhance its therapeutic efficacy in AD. The co-crystals of LZ and MTZ were synthesised and characterized using advanced analytical techniques, including Powder X-ray diffraction (PXRD), Differential Scanning Calorimetry (DSC), and Nuclear Magnetic Resonance (NMR) spectroscopy, confirming successful co-crystal formation. A topical cream was subsequently formulated and evaluated for its physicochemical properties, including pH, spreadability, viscosity, and in-vitro release study. The in vitro antimicrobial activity of the formulation was assessed against Escherichia coli, Staphylococcus aureus, and Candida albicans, pathogens frequently implicated in secondary infections in AD. Results demonstrated that the co-crystal significantly enhanced the solubility of LZ and exhibited enhanced antifungal and antibacterial effects. The topical cream showed favourable physicochemical attributes and superior antimicrobial activity, positioning it as a promising dual-therapy approach for managing fungal and bacterial infections associated with atopic dermatitis. This novel formulation addresses critical challenges in the treatment of AD, offering a potential improvement in clinical outcomes and patient compliance.

Graphical Abstract