Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Oral heat-clearing and detoxifying Chinese patent medicines (CPMs) are frequently added to conventional therapy for pediatric acute upper respiratory tract infection (AURTI), but comparative evidence among products is sparse. Objectives: To compare adjunctive oral CPMs, prioritizing time to fever resolution and to assess total effective rate, cough resolution and adverse events. Methods: Eight databases and grey-literature sources were searched from inception to 31 May 2026. Eighteen studies were synthesized qualitatively; ten studies contributed to quantitative analyses. Two loop-enabling trials were added: One head-to-head comparison of Xiaoer Chiqiao Qingre Granules (CQ) with Lianhua Qingwen Granules (LHQW) and one LHQW-plus-conventional-therapy comparison. Loop-specific direct-versus-indirect inconsistency was assessed. Results: The CT-CQ-LHQW triangle formed one closed loop. No statistically detectable inconsistency was found for total effective rate (inconsistency factor 1.06, 95% CI 0.86-1.31; P=0.583) or adverse events (0.13, 95% CI 0.003-5.27; P=0.283), although the safety interval was very wide. The consistency-model RRs versus conventional therapy were 1.24 (95% CI 1.12-1.38) for LHQW and 1.18 (95% CI 1.07-1.32) for CQ. Pairwise analyses favored adjunctive CPMs for fever and cough resolution, with substantial heterogeneity. Conclusion: A real closed loop permits a limited consistency check, but certainty remains very low because only one loop was available, safety events were sparse and clinical and outcome definitions varied. Product rankings remain exploratory. Registration: The review was not prospectively registered. Funding: None.

Abstract: Background: Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and lacks effective targeted therapy. Traditional Chinese medicine formulas, such as Xinbao Pill, have shown potential cardiovascular benefits; however, their molecular mechanisms are not yet fully understood. Objectives: This study aimed to systematically explore the multi-compound, multi-target mechanism of Xinbao Pill in the treatment of HFpEF using a network pharmacology approach. Methods: Active ingredients of Xinbao Pill were identified from the TCMSP database according to predefined pharmacokinetic criteria. Three GEO datasets (GSE180065, GSE240400 and GSE269053) were analyzed to identify differentially expressed genes associated with HFpEF. Elastic Net regression was used to refine the intersecting targets. Molecular docking and 100 ns all-atom molecular dynamics simulations were used to predict and validate the structural stability of compound-target interactions. Results: A total of 32 active compounds were identified. Differential expression analysis identified 1,368 HFpEF-related genes across the three datasets, including 23 overlapping targets. Elastic Net regression further selected 11 key genes (Clk1, Comt, Drd2, Ephx2, Fgr, Hcn2, Mme, Pparg, Ptgds, Slc27a1, Vdr). Molecular docking predicted strong binding affinities for several compound-target pairs, including Withanolide D-VDR (-12.0 kcal/mol) and 12-Deoxywithastramonolide-EPHX2 (-11.5 kcal/mol). Molecular dynamics simulations confirmed the structural stability of both top-ranked complexes over 100 ns, with low RMSD values and well-defined free energy minima. Conclusions: This in-silico study identified candidate targets and bioactive compounds that may be associated with the potential effects of the Xinbao Pill in HFpEF. The identified key targets and compounds may serve as promising candidates for further experimental validation and therapeutic development.

Abstract: Background: The genus Allium is a chemically diverse source of bioactive secondary metabolites, yet wild populations remain unevenly studied. Wild Allium ampeloprasum L. from Cyprus is underexplored despite evidence that the species contains phenolic, flavonoid and organosulfur constituents with diverse bioactivity. This study provides a locality-specific phytochemical and in-vivo evaluation of its methanolic bulb extract (AAB). Objectives: To characterise AAB and assess its acute toxicity, antinociceptive and local anti-inflammatory activity in Wistar albino rats. Methods: Dried bulb powder (50.0 g) was macerated in methanol, yielding 2.906 g extract (5.812%). Constituents were quantified by LC-MS/MS and screened using SwissADME and ProTox-III. Acute toxicity followed the two-phase Lorke design using 12 rats. Three independent efficacy cohorts (25 rats each; n = 5/group) received distilled water, AAB at 125, 250 or 500 mg/kg, or piroxicam 20 mg/kg. Antinociception was assessed by writhing, hot-plate and formalin tests and local anti-inflammatory activity by formalin-induced paw oedema. Biochemical, haematological, ESR and CRP measurements were performed after the final 5-h paw oedema assessment. Results: Thirteen constituents were quantified, with caffeic acid and trans-ferulic acid showing the highest relative abundances. No mortality occurred up to 5000 mg/kg, although transient clinical signs were observed. AAB reduced writhing by 45.8%, 69.5% and 91.5% at 125, 250 and 500 mg/kg, respectively (adjusted p = 0.0035, p < 0.0001 and p < 0.0001). Hot-plate latency increased significantly only at 500 mg/kg (adjusted p = 0.0067). Paw licking decreased at all concentrations in both formalin phases (adjusted p < 0.0001), with late-phase inhibition of 85.71-95.71%. Paw oedema inhibition at 5-h was 66.67-71.11%. Post-oedema blood analyses showed selected biochemical changes without a consistent concentration-related pattern. Conclusion: AAB demonstrated antinociceptive and local anti-inflammatory activity in rat models. Absence of mortality does not establish safety; further standardisation, mechanistic investigation and longer-duration toxicity studies are required.

Abstract: Pharmaceutical manufacturing remains constrained by legacy paradigms that collapse engineered systems into static legal descriptors and struggle to integrate real‑world evidence. Geopolitical instability, supply‑chain fragility, climate‑driven disruption, declining institutional trust and the accelerating influence of generative artificial intelligence expose that constraint as an epistemic ceiling. This Perspective outlines a professional path for leapfrogging toward a patient‑centric Pharma 5.0 paradigm grounded in ontological honesty and epistemic humility. The argument traces this ceiling across three layers—the individual practitioner, the quality system and the broader ecosystem—and places Deming’s System of Profound Knowledge, Kegan’s orders of consciousness and McGilchrist’s hemispheric account alongside the classical sequence of the nafs and a heart‑centered posture of practice (Dil Se).  Leapfrogging is a knowledge strategy before it is a technology strategy. Recent United States hearings and independent quality‑scoring efforts reveal an ontology capable of detecting divergence yet unable to revise certified reality. Pakistan and the broader Global South live under the same ceiling, shaped by high generic volumes and thin margins. Thailand’s May 2025 registration of a domestically developed trastuzumab biosimilar demonstrates capability‑first sequencing; a subsequent United States draft guidance issued on 29 October 2025—proposing that comparative efficacy studies may be unnecessary when analytical comparability is high—confirms the direction of that sequence rather than authorizing it after the fact. Preparing for Pharma 5.0 requires unlearning certain validated habits, cultivating sovereignty of judgment before sovereign infrastructure and building quality systems capable of revising their own descriptions.

Abstract: Background: Liver fibrosis is a chronic wound healing process of liver injury and gut–liver axis dysregulation has been recently identified as an important contributor to liver fibrosis progression. Quercetin has been reported to have anti-inflammatory activity and microbiota-modulating effects. However, the potential targets of quercetin remain unclear, as does the relationship between quercetin-associated targets and changes in the gut microbiota in liver fibrosis. Objectives: The purpose of this study was to use network pharmacology to predict potential targets of quercetin associated with liver fibrosis and to explore changes in gut microbiota following treatment with quercetin using a CCl₄-induced rat model. Methods: Eighteen male Sprague–Dawley rats were randomized into CON group, MOD group and QR group (n = 6 per group). Liver fibrosis was induced by weekly subcutaneous injection of carbon tetrachloride (CCl₄) for eight weeks. Oral gavage of quercetin (50 mg/kg/day) was performed in QR group. Histopathological changes were assessed by hematoxylin–eosin staining, Masson staining and Ishak scoring. Potential targets of quercetin were screened using network pharmacology, followed by protein–protein interaction (PPI) network construction and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Cecal microbiota composition was determined by 16S rRNA gene sequencing. Parametric or non-parametric tests were used accordingly, including one-way ANOVA or Kruskal–Wallis test. Results: Histopathology revealed significant liver injury and fibrosis in the MOD group relative to the CON group. The QR group showed lower Ishak fibrosis scores and milder histopathological features compared with the MOD group. Network pharmacology analysis identified UBC, UBE2I, RBX1, PSMB7 and UBA1 as hub targets, with KEGG pathways of interest including the TNF signaling pathway, p53 signaling pathway, Toll-like receptor signaling pathway and ubiquitin-mediated proteolysis. Alpha diversity of the cecal microbiota differed significantly among groups, whereas beta diversity did not. Relative abundance of Proteobacteria decreased and Firmicutes increased in the QR group relative to the MOD group. Taxa enrichment analysis identified enrichment of Muribaculaceae and Ligilactobacillus in the QR group. Conclusion: Histopathology and microbiome analyses indicated that quercetin intervention was associated with altered liver histopathological features and shifts in gut microbiota composition in rats with CCl₄-induced liver fibrosis. Network pharmacology predicted several hub targets and pathways potentially linked to these observations. As the present analyses are purely correlational and lack mechanistic validation at the molecular level, no causal relationships are implied between the predicted targets/pathways and the observed histological or microbiome changes. These findings should be regarded as hypothesis-generating and warrant further validation studies.