Mohammad Hailat

The carboxylic acid metabolite of clopidogrel (clopidogrel CA) is the principal circulating species formed after oral administration of the drug and is widely used as a surrogate marker for clopidogrel disposition. This work aimed to develop and validate a simple, rapid and practice-oriented liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for quantifying clopidogrel CA in rat plasma and to apply it to evaluate a potential pharmacokinetic interaction with the antidiabetic agent pioglitazone. Chromatographic separation was achieved on a C18 column using an isocratic mobile phase of acetonitrile and 0.001 M ammonium chloride (80:20, v/v) at a flow rate of 0.45 mL/min, with glimepiride as the internal standard. Detection was performed in positive-ion multiple reaction monitoring mode (m/z 308.1 → 113.2 for clopidogrel CA and 491.5 → 126.3 for glimepiride). The method was linear over the range 0.075–12.0 µg/mL and met the acceptance criteria of the FDA and EMA bioanalytical method validation guidelines for selectivity, linearity, precision, accuracy and recovery. Oral co-administration of pioglitazone (30 mg/kg) with clopidogrel (10 mg/kg) significantly reduced the mean peak plasma concentration (Cmax) of clopidogrel CA from 8.896 to 6.599 µg/mL (p < 0.05), produced a non-significant decrease in AUC0–24 (81.423 vs 73.818 µg·h/mL, p > 0.05) and delayed the time to peak concentration. These findings indicate a measurable pharmacokinetic interaction between pioglitazone and clopidogrel that warrants confirmation using active metabolite and pharmacodynamic endpoints.

Background/Objectives: optimization of the therapeutic efficacy of antidiabetic agents is still a great challenge in the management of type 2 diabetes mellitus (T2DM), and attention is becoming more and more focused on the use of adjunctive agents that help target the drug action beyond the classic glycemic target. This study examined the effect of co-administration of an Artemisia herba-alba Asso (Asteraceae) aqueous extract on the glucose-lowering effect of dapagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor. Methods: qualitative phytochemical screening and total phenolic and total flavonoid content were used to characterize the aqueous preparation. Male Wistar albino rats were divided into eight groups (10 rats each): four healthy and four diabetic rats induced with streptozotocin (STZ). Vehicle control, oral administration of an aqueous A. herba-alba preparation (0.39 g/kg twice daily), dapagliflozin (0.143 mg/kg/day), or a combination of both was given for 30 days. At baseline and days 7, 14, 21, and 30, glycated hemoglobin (HbA1c) was measured by nephelometry. Parallel fasting blood glucose (FBG) was monitored. Results: the diabetic animals treated with the combination regimen showed the greatest and most sustained decrease in HbA1c (from 4.42 ± 0.40% at baseline to 3.44 ± 0.17% at day 30; p < 0.001) and the greatest decrease in FBG (from 186.0 to 122.2 mg/dL). A. herba-alba monotherapy had little effect on HbA1c and had minimal effect on FBG (214.9 to 217.6 mg/dL); dapagliflozin monotherapy had a modest effect on HbA1c. The untreated diabetic controls (n = 10) showed a progressive increase in HbA1c from 4.45 ± 0.60% at 72 h post-induction to 11.90 ± 0.99% by day 30 (p < 0.001), consistent with delayed hemoglobin glycation relative to the rise in blood glucose. The repeated-measures ANOVA showed a highly significant interaction between time and treatment (p < 0.001). Conclusions: this study showed that the phytochemically defined aqueous A. herba-alba preparation is a beneficial adjunct to SGLT2 inhibitor therapy, an effect not observed with either treatment alone.

Background/Objectives: Diabetes mellitus type 2 (T2DM) is often associated with hypertension, necessitating treatment with combinations of medications that address both glycemic control and blood pressure. Whether commonly co-prescribed antihypertensives modify the glycemic efficacy of a sulfonylurea remains insufficiently characterized in controlled preclinical models. Methods: One hundred adult male Wistar rats were allocated to ten parallel groups (n = 10): healthy and diabetic untreated controls; glimepiride, bisoprolol or amlodipine monotherapy (in healthy and diabetic animals); and the diabetic combinations glimepiride+bisoprolol and glimepiride+amlodipine. T2DM was induced with a high-fat diet plus low-dose streptozotocin (35 mg/kg, i.p.) and confirmed by fasting blood glucose ≥ 200 mg/dL. Glycated hemoglobin (HbA1c) was measured weekly for 11 weeks. Non-parametric inference (Kruskal–Wallis, Dunn’s with Bonferroni correction, Mann–Whitney U, Wilcoxon signed-rank) was complemented by Random Forest regression and PCA/K-means clustering. Results: Week-11 HbA1c differed markedly across groups (Kruskal–Wallis H = 94.3, p < 0.001). Glimepiride + bisoprolol achieved near-normal control (4.37% ± 0.15), statistically indistinguishable from healthy groups (p ≥ 0.33), and was the only diabetic regimen with a declining trajectory (−0.66 percentage points; Wilcoxon p = 0.004). Adding either antihypertensive to glimepiride did not worsen glycemic control. Amlodipine monotherapy did not attenuate hyperglycemia (8.47% ± 0.20), approaching that of untreated diabetic controls (9.31% ± 0.18), consistent with the absence of intrinsic glucose-lowering activity. All agents showed pronounced disease-state dependence (healthy–diabetic divergence 2.33–3.13 points). Random Forest prediction was accurate (R² = 0.985), and unsupervised clustering separated effective from ineffective regimens, corroborating the statistical findings. Conclusions: In this model, bisoprolol co-administration enhanced and amlodipine co-administration preserved glimepiride-mediated glycemic control. Glimepiride+bisoprolol emerged as the most effective regimen, supporting cardioselective β-blockade as a metabolically favorable antihypertensive partner for sulfonylurea therapy and warranting clinical confirmation. More broadly, these results provide a preclinical, evidence-based rationale for selecting metabolically favorable antihypertensives in patients with coexisting T2DM and hypertension, with the potential to improve glycemic outcomes and reduce the risk of adverse drug–disease interactions during combination therapy.

Glycemic variability is a stand-alone risk factor for diabetic complications. Background/Objectives: We investigated whether combining quercetin-rich Allium cepa L. (white onion) juice with the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin could reduce glycemic variability beyond that achieved with monotherapy in experimental diabetes. Methods: Wistar rats were made diabetic with streptozotocin (35 mg/kg) and maintained for 60 days in the following groups: vehicle, dapagliflozin (0.1 mg/day), fresh onion juice (5 mL twice daily), and dapagliflozin + fresh onion juice (5 mL twice daily). Diabetic Wistar rats (n = 10/group) were gavaged with vehicle, dapagliflozin (0.1 mg/day), fresh onion juice (5 mL twice daily), or both. The juice was expected to contain phytochemicals (quercetin derivatives and organosulfur compounds) based on published reports on similar A. cepa cultivars. A validated immunoassay was used to measure glycated hemoglobin (HbA1c) every 10 days. All treatments reduced HbA1c to the same level (~7.1–7.2%) as compared to diabetic controls (9.0 ± 0.3%) (p < 0.001), though only the combination treatment reduced glycemic variability (HbA1C coefficient of variation 3.9 ± 0.6% vs. 7.8 ± 1.2% with dapagliflozin and 11.2 ± 1.8% with onion) (p < 0.001). Results: Across the 10-day sampling schedule, the combination kept HbA1c within a narrow 6.8–7.2% band, whereas the monotherapies fluctuated more widely; because intraday and postprandial glucose were not captured, effects on short-term excursions could not be directly assessed. There were no cases of severe hypoglycemia and only infrequent and non-repeated cases of mild hypoglycemia. Conclusions: In this exploratory, hypothesis-generating study, the additive interaction between onion phytochemicals and dapagliflozin was associated with lower glycemic variability via mechanisms proposed in the literature; quercetin-rich A. cepa juice may therefore warrant further investigation as an adjunct in diabetes management, pending batch-specific phytochemical characterization and confirmatory studies.

A novel isocratic reversed-phase high-performance liquid chromatographic (RP-HPLC) procedure was developed and extensively validated for the simultaneous quantitative determination of three structurally related oxicam anti-inflammatory drugs (Tenoxicam sodium, Meloxicam and Piroxicam) in bulk form in pharmaceutical formulations. Chromatographic separation was achieved on a Syncronis C-18 column (250 × 4.5 mm, 5 µm) using a methanol–water mobile phase (70:30, v/v; pH 3.3) delivered at 0.80 mL/min with ultraviolet detection at 248 nm. Following the ICH Q2(R1) guidance, a comprehensive study of the parameters was carried out, which resulted in excellent linear ranges (r² ≥0.997) for all three compounds, a mean recovery of 99–103%, percent RSD values of intraday and interday repeatability of the method that were less than 2.0% and limits of detection and quantification that were adequate. ICH Q1A(R2) facilitates chemical stress testing under acidic, alkaline, oxidative, thermal and photolytic conditions, resulting in chromatographically distinguishable, baseline-resolved peaks for byproducts, confirming the stability-indicating property of the assay. The elution times for the analytes were 3.874 min (Meloxicam), 4.920 min (Piroxicam), and 6.404 min (Tenoxicam sodium). The validated assay provides an accurate and convenient analytical tool for the simultaneous quality assurance and chemical stability assessment of these three oxicam drugs in pharmaceutical development and regulatory environments.

Diabetes mellitus is a condition where there is an increase in blood glucose levels due to either decreased insulin synthesis or decreased insulin use. There are other forms of diabetes mellitus, but type 1 and type 2 are the most common. The goal of insulin therapy is to minimize the risk of hypoglycemia while achieving the greatest possible management of blood glucose levels. Insulin administered subcutaneously has some drawbacks, including pain, allergic reactions, hyperinsulinemia, and poor patient compliance. To address these drawbacks, researchers proposed using smart biodegradable polymer-based devices to regulate insulin levels and circumvent the challenges of administering insulin orally, as this review will demonstrate using a variety of techniques. Specifically, this comprehensive review covers smart stimuli-responsive hydrogels based on poly(N-isopropylacrylamide) (PNIPAAm) copolymers for temperature- and pH-dependent oral insulin delivery, poly(lactic-co-glycolic acid) (PLGA) biodegradable microcapsules designed for sustained subcutaneous insulin release with controlled initial burst, biodegradable insulin-loaded nanoparticles prepared via double emulsion and microfluidic/salting-out methods, insulin-albumin microbeads as implantable long-term delivery systems, and glucose-responsive complex polymeric micelles (CPMs) capable of repeated on–off insulin release.

Catheter-associated urinary tract infections are often caused by biofilm formation on device surfaces. This paper presents an antimicrobial catheter-coating hydrogel comprising p(HEMA) and carboxyl-functionalized p(HEMA-co-MA), loaded with benzalkonium chloride (BAC) to increase hydrophilicity, pH responsiveness, and antibiofilm activity. Hydrogels were prepared by free-radical polymerization, loaded with BAC via swelling, and their physicochemical properties were characterized. Furthermore, microbiological assessment focused on the detection of MIC/MBC/MFC, disk diffusion, biofilm assays, SEM imaging, and RT-qPCR sequencing were used to determine the impact on biofilm-related gene expression to evaluate antimicrobial activity against major catheter-associated urinary tract infection (CAUTI)-associated pathogens and identify the higher BAC loading p(HEMA) and enhanced hydrophilicity and pH-responsive swelling (p(HEMA-co-MA)). The two hydrogels exhibited a wide range of antimicrobial activity and provided lasting inhibition for up to 8 days. It is worth noting that the MA-functionalized hydrogel exhibited a high intrinsic antifouling property, and biofilm development was reduced by more than 85% in BAC-loaded formulations. SEM and gene-expression studies showed reduced microbial adhesion and substantial repression of virulence and biofilm-associated genes. In summary, BAC-loaded p(HEMA) and p(HEMA-co-MA) coatings exhibit strong antimicrobial and antiadhesive properties, and the incorporation of MA results in more effective biofilm suppression, which supports their future use as advanced catheter coatings to prevent the development of device-related infections.

Background/Objectives: Antimicrobial resistance (AMR) is a major global health issue. Since community pharmacists are frontline health officials regarding the provision and management of antibiotics, it is of great importance to study the knowledge, attitudes, and practices (KAPs) of pharmacists with respect to antimicrobial stewardship (AMS) to formulate specific interventions. In Jordan, where dispensing antibiotics without a prescription is a common situation, this study was designed to assess the KAPs of community pharmacists in southern Jordan on AMR and AMS, the gap in the knowledge base and the practice, and the effect of other variables on antimicrobial education and responsible dispensing. Results: Participant pharmacists (n = 383) confirmed a moderate or lack of knowledge in antibiotic choice, resistance mechanisms, and the basis of stewardship. Despite positive attitudes for AMS, important practice gaps occurred: 38.6% infrequently dispensed antibiotics without prescriptions, 67.4% mistakenly believed that antibiotics may cure viral infections (flu/common cold), and only 33.4% firmly rejected non-prescription antibiotic requests. Knowledge scores were significantly higher among bachelor’s degree pharmacists, public university pharmacists, and urban-working pharmacists. Practice scores were better among master’s degree holders and urban practitioners. Conclusions: This work indicates that the AMS knowledge and practices of pharmacists in the southern Jordanian community are lacking in a severe way, with almost 4 out of 10 having poor behaviors including dispensing non-prescription antibiotics.

Microneedle arrays are a simple, noninvasive transdermal delivery system. The technique's preparation, optimization, and scaling up are all active research topics. This paper investigates a simple method for making microneedle molds for inverted-solvent casting preparation of microneedle arrays. The effect of different resins and printing conditions on the geometry of microneedle arrays was investigated using stereolithography 3D printing. Four molds prepared in this study were selected to be filled with candesartan cilexetil in a mixture of polymers that include EMPROVE® and gantrez. The fully formed MNAs were evaluated based on skin perforation, drug release through Franz cells, bending ability, and sterilization. The model drug and the resultant MNAs were evaluated based on the MNA's shape, drug release, and compression resistance. To improve process quality and achieve highly aligned defect-free needles, the surface of the fabricated microneedles was modified with a monolayer of hyaluronic acid. The structure design was optimized using computer-aided design. The molds were tested by producing candesartan cilexetil microneedle array patches for transdermal delivery. This study discovered that hot plate post-treatment and avoiding shear force during mold peeling are critical for fabricating high-quality arrays. Candesartan cilexetil microneedles were successfully prepared, and the release rate was 73.36 ± 7.29% of the loaded candesartan cilexetil amount over 24 hours. The obtained molds can potentially be used to fabricate microneedle arrays successfully.