Future Journal of Pharmaceutical Sciences最新文献

Background

Paclitaxel-induced peripheral neuropathy (PIPN) is one of the most common and debilitating toxicity. Up till now, no treatment or preventive medication is recommended by guidelines. Pentoxifylline has been found to prevent PIPN in animal models. This study aimed to evaluate the tolerability and efficacy of pentoxifylline in preventing PIPN. To our knowledge, this is the first clinical trial to evaluate the potential effect of pentoxifylline on the prevention of PIPN in breast cancer (BC) patients.

Results

A simple-randomized placebo-controlled study was conducted on 60 BC patients receiving weekly paclitaxel and either pentoxifylline 400 mg twice daily (n = 30) or placebo (n = 30) for 12 weeks. Only 55 patients completed the study. The main objective was the evaluation of the effect of pentoxifylline on the incidence of PIPN which revealed no significant difference between the pentoxifylline group (85%) and the placebo group (100%). Secondary objectives included time to develop grade 2 or 3 (TTG 2/3) PIPN, the patient’s quality of life (QOL), serum tumor necrosis factor-α (TNF-α) and malondialdehyde and the tolerability of pentoxifylline. The median TTG 2/3 PIPN was not reached in the pentoxifylline group compared to 77 days (95% confidence interval of 70.91 to 83.07) in the placebo group. However, the difference did not reach significance. The assessment of the impact of PIPN on QOL was performed at baseline and at weeks 4, 8 and 12 using Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) subscale. The magnitude of the worsening in the QOL was significantly lower in the pentoxifylline group than in the placebo group at weeks 4, 8, and 12 (p values = 0.028, 0.003, and 0.018, respectively). Analysis of the serum TNF-α and malondialdehyde revealed no significant differences between the groups. Pentoxifylline was safe, tolerable and did not affect paclitaxel toxicity.

Conclusion

Oral pentoxifylline (400 mg twice daily) did not decrease the incidence of PIPN. However, it improved patients’ QOL significantly.

Trial registration Clinical Trials.gov, NCT05189535. Registered 4 October 2021, https://classic.clinicaltrials.gov/ct2/show/NCT05189535.

Background

Analytical Quality by Design (AQbD) has emerged as a pivotal paradigm in the realm of analytical chemistry, revolutionizing the approach to method development and validation. This innovative strategy integrates principles of Quality by Design (QbD) into analytical procedures, aiming to ensure the quality and robustness of analytical methods. The traditional approach to method development often involves a trial-and-error process, where parameters are adjusted until satisfactory results are obtained. However, this approach can be time-consuming, resource-intensive, and may lack reproducibility. AQbD addresses these challenges by providing a systematic framework for method development that emphasizes understanding the relationship between critical process parameters (CPPs) and critical quality attributes (CQAs).

Discussion

Analytical Quality by design (AQbD) presents an innovative approach to creating and validating analytical procedures, aimed at achieving quality measurements within the method operable design region (MODR). The QbD approach to analytical development is proactive, methodical, and risk-based significantly helps in acquiring an in-depth knowledge of how critical process parameters (CPPs) affect analytical performances, measured by critical quality attributes (CQAs). Experiment design (DoE) is an essential part of QbD, functioning to carry out the response surface analysis and screening process, and ultimately to enable the definition of the multidimensional region of the successful operating ranges of the CPPs, known as the design space (DS). The purpose of this article is to offer a thorough description of the QbD approach's method development process and its implementation in analytical procedure validation, to produce high-quality output, employing statistical analysis in conjunction with other designing tools.

Conclusion

Analytical Quality by design (AQbD) offers a systematic and proactive approach to method development in analytical procedures. By focusing on method resilience and incorporating statistical analysis and experiment design (DoE), AQbD enables the production of high-quality outputs, while minimizing out of trend (OOT) and out of specification (OOS) results. This innovative strategy enhances the reliability and reproducibility of analytical methods, ultimately leading to improved outcomes across various industries.

Background

Cancer is the predominant cause of mortality and a remarkable obstacle to elevating life anticipation in every nation on globe. Hepatocellular carcinoma (HCC), a hyper-vascular tumour, develops and progresses due to angiogenesis, a key feature of malignancy. HCC exhibits high neoangiogenic activity because of the need to generate new blood vessels for tumour growth.

Methods

The present work includes the construction of virtual library of ligands, virtual screening using the Dockthor-VS server, ADMET study using the SwissADME and Osiris property explorer. All the synthesized compounds were characterized by UV, IR, NMR and mass spectroscopic techniques. MTT assay was done to find the IC₅₀ of the synthesized compounds against HepG2 cell line. The more active compound found is subjected to the molecular dynamics simulation study.

Results

The ligands exhibited good docking scores, ADMET profile compared to the reference drugs. The target compounds were obtained with the satisfactory yields of 66–82%. The best activity against the HepG2 cancer cell line is observed with the compound SA-4 with IUPAC name (2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)-N-(5-(3-nitrophenyl)-5H-thiazolo[4,3-b] [1,3,4] thiadiazol-2-yl) acetamide). The experimental results obtained show correlation with the in silico results. MD simulation of the compound SA-4 indicates the moderate stability of the protein-ligand complex in real time environment.

Conclusion

The results obtained suggest that the compound SA-4 has the potential to be a promising anticancer agent effective against the VEGFR-2 and FGFR-4.

Graphical abstract

Background

Hemodialysis (HD) patients often have multiple comorbidities, leading to care from various prescribers and a complex medication regimen. Patients on HD are particularly vulnerable to treatment-related problems (TRPs). This study aimed to evaluate the impact of the lack of clinical pharmacy services on HD care by assessing the types and frequencies of TRPs encountered in HD units.

Patients and methods

This was a prospective observational study. Data were collected from medical records and medication reconciliation of HD patients attending to a large Hospital specialized in Nephrology and Urology at the Minia region in Egypt. The frequencies and percentages of demographic data were calculated. Standard multiple regression analysis was conducted to assess predictors of TRPs.

Results

A total of 103 patients were included. The mean age was 47.6 ± 15.1 years; patients had been on HD for 5.95 ± 5.04 years, had 2.47 ± 0.57 comorbidities and took 7.02 ± 1.35 different medications. Within the included patients, 121 TRPs were identified. The most common TRPs were the need for more frequent monitoring, followed by inappropriate dose/dosing frequency and the need for additional therapy (33.9%, 26.2%, and 15.5%, respectively). We did not identify any predictors of TRP in this study.

Conclusion

In the Minia HD population of Egypt, TRPs affected 75% of the patients. Therefore, involving clinical pharmacy services to tailor the optimal management plan for each patient is crucial to reduce the frequency of TRPs in this vulnerable patient population.

Background

Numerous insect pests attack stored grains causing both qualitative and quantitative losses. The most damaging pest that infests dry stored produce is the red flour beetle, Tribolium castaneum, a secondary pest of stored goods. This pest, especially in its adult stage, exhibits resistance to chemical insecticides, thereby rendering the traditional pesticides ineffective in controlling it. Phyto-derivatives, which are strong insecticides and also ecologically benign, have gained interest as non-chemical solutions for controlling this pest. Hence, the objective of this study was to investigate the potential of Piper longum leaf extract insecticidal action as an environmentally benign insecticide for the first time against the adults of T. castaneum. In this study, P. longum leaf ethanol extract was tested against the adults of T. castaneum by petri dish bioassay method. Ad hoc studies to verify significant mortality for the initial confirmation of adulticidal activity were conducted for 24 h at different dosages of 62.5, 125, 250, 500 and 1000 mg/L of P. longum leaf ethanol extract. Thereafter, dosages set at 10, 20, 30 and 40 mg/L for the fractions of P. longum leaf ethanol extract were conducted. Prior to this, the leaf extract of this plant was subjected to column chromatography for fractionation. The fractions tested for adulticidal activity were subjected to gas chromatography–mass spectroscopy.

Results

Significant adulticidal action with 100% adult mortality was observed in ethanol extract of P. longum leaves. Among the fourteen fractions (F0–F13) obtained tested, only fractions, F5, F10 and F13, demonstrated adulticidal activity, and the remaining fractions displayed poor activity. One hundred per cent morality was noted in T. castaneum adults after 96 h at 40 mg/L in F5 and F10, and in F13 at 20 mg/L, and their respective LD₅₀ values were 17.6, 26.6 and 10.0 mg/L. The fractions F5, F10 and F13 contained fatty acids, viz., hexadecanoic acid, dotriacontane and heptacosane in F5; tetradecanoic acid and nonadecanoic acid in F10; and octadecanoic acid, aspartame and tridecanoic acid in F13, revealed through gas chromatography–mass spectroscopy.

Conclusions

The results of the study showed that P. longum ethanol leaf extract revealed significant adulticidal activity and is a promising toxic agent to the adults of T. castaneum. The fatty acids in the ethanolic leaf extract fractions of P. longum could have caused toxicity to the adults of T. castaneum. According to the current literature survey, this is the first research report on the adulticidal activity of P. longum leaf extracts against the adults of T. castaneum.

Background

Type-2 Diabetes (T2DM) is a long-term medical disorder characterized by Insulin deficiency and high blood glucose levels. Among other medications to cure T2DM, the review of the literature found that various Pyrimidine derivatives act as an agonist for G-protein-coupled receptor 119 (GPR119) was proposed to control blood glucose levels by enhancing the function of pancreatic Beta-cells and its mechanism of action with fewer adverse effects. In the present research work, In-silico investigations were carried out to investigate the potential of the Pyrimidine analog as an agonist to the protein target GPR119 receptor. We performed exhaustive molecular modeling and protein modeling methodologies such as homology modeling, and molecular docking along with various drug designing tools such as 3D-QSAR and Pharmacophore Mapping to ascertain the design of better GPR119 agonists.

Results

Based on in-depth computational studies, we designed new pyrimidine moiety and analyzed them for GPR119 receptor agonist and further explored the ADMET properties. Designed compounds were found to exhibit better-predicted activities as compared to reference compound.

Conclusions

The current research on pyrimidine derivatives, using molecular docking, 3D-QSAR and Pharmacophore mapping demonstrated that the obtained computational model has significant properties and the designed molecules and Dataset from this model, produced antidiabetic compound against the target GPR119 i.e., compound 1S, 1Z and 1D with the docking score of − 11.696, − 9.314 and − 8.721, respectively. The pharmacokinetics and drug-likeness studies revealed that these compounds may be the future candidates for the treatment of diabetes acting via the GPR119 agonist mechanism.

Background

The PI3K signalling pathway regulates the metabolic activity of cells. Disruption by PI3K inhibitors causes an aerobic/anaerobic imbalance that decreases energy production and cell growth. Cancer cells adapt to PI3K inhibitors in order to reduce their effectiveness. Resistance to Apitolisib could be due to intrinsic factors or acquired adaptation. Oncologists often ask whether to discontinue Apitolisib, increase its dose, or use a drug combination.

Methods

We observed the proliferation of resistant cells in (H1975R+) and out (H1975R−) of Apitolisib treatment, cell cycle pattern, energy phenotyping/reprogramming, and the effects of combining Apitolisib with Vorinostat on the acquired proliferation of H1975R− cells.

Results

The Proliferation of H1975R− cells increased, while that of H1975R+ cells remained suppressed. Both conditions showed a 5 × decrease in the number of cells at the Go/G1 phase and doubled at S and G2/M phases (p < 0.0001). Both H1975R− and H1975R+ cells exhibited decreased ECAR, with a stronger effect observed in H1975R+ cells (p < 0.0001). Oxygen consumption (OCR) increased significantly in H1975R− compared with that in H1975P (p = 0.02). The resistant cells became energetically active using mitochondrial respiration in drug-free medium; H1975R+ was hypo-energetic and consumed more free fatty acids (p = 0.0001). Ketone bodies in H1975R+ were increased by 40% and 2 × in BOHB and AcAc levels, respectively, compared to that in H1975P and H1975R− (p < 0.0001). H1975R− cell survival was 80% compared with 20% in H975R+ cells treated with 7 μM Vorinostat. Vorinostat effectively controlled acquired hyperproliferation of H1975R− cells.

Conclusion

If a tumour becomes unresponsive to Apitolisib, it is advisable to continue the inhibitor and consider a combination with non-tyrosine kinase inhibitors.

Background

Coccoloba uvifera L. (Family: Polygonaceae) known as sea grape is natively distributed in middle and south America. The aqueous leaf extract showed inhibitory activities against α-glucosidase and α-amylase in previous reports. Moreover, the hydroalcoholic leaves extract ameliorated hyperglycemia in the oral glucose tolerance test. Despite these promising results, the extracts used in these studies were not standardized, nor was their mechanism of action elucidated. The current study aims to standardize the ethanolic C. uvifera leaves extract (CU) using markers, and assess its ameliorative activity against diabetes and its hepatoprotective activity against diabetic complications.

Results

Standardized leaves’ ethanolic extract contained 0.09 ± 0.00057 and 0.23 ± 0.0011 mg/g gallic acid and rutin, respectively, as estimated by HPLC. Administration of CU (100, 200 and 400 mg/kg) for 6 weeks ameliorated DM manifestations in STZ-induced diabetic rats in a dose-dependent manner. The ethanolic extract reduced fasting blood glucose, increased serum insulin and reduced elevated liver enzymes. CU counteracted oxidative stress, promoted glucose metabolizing enzymes and reduced gluconeogenesis enzymes. The underlying mechanism involved increased expression of IR, IRS-1, IRS-2 and GLUT2 in liver tissue through activation of PI3K/AKT signaling. The histopathological study demonstrated reduced inflammation and hepatocyte degeneration.

Conclusion

CU could be used as a promising antidiabetic drug with hepatoprotective activity in diabetes hepatic complications. The standardized CU ethanolic extract should be further assessed clinically alone or in combination with other antidiabetic remedies.

Background

Wound healing is a natural but complex process that can be delayed by infection. Rosuvastatin calcium (RVS) is an anti-hyperlipidemic that was recently reported to have a wound healing capability. The study aimed to investigate the impact of combining RVS with Levofloxacin (LV) on wound healing. A physically crosslinked polyvinyl alcohol (PVA) film loaded with RVS and LV was formulated as wound dressing. Formulation optimization was carried out using Box–Behnken design. The effect of independent variables (PVA and propylene glycol concentrations and the number of freeze–thaw cycles) on tensile strength (TS), elongation to break (%EB) and in vitro drugs’ release was studied. For simultaneous RVS and LV quantification in the formulations and pure form, three spectrophotometric methods: derivative of ratio spectrophotometry, first derivative and mean centering, were developed. Also, their greenness was evaluated by the Analytical Eco-Scale and the Green Analytical Procedure Index. Then, the wound healing effect of the optimized wound dressing was evaluated in rat models.

Results

The optimized dressing had sufficient mechanical strength (9.45 ± 0.67 MPa), adequate flexibility (112.6 ± 3.8% EB) and suitable drug release (52.3 ± 1.4% for LV and 38.99 ± 1.6% for RVS after 12 h). The proposed methods were validated following ICH guidelines, and greenness assessment suggested their very low environmental effect. The wound healing evaluation showed a higher wound contraction percentage when RVS was combined to LV. A histopathological study confirmed marked improvement in animals treated with combined formula with lowest inflammatory infiltration and optimum epithelialization, compared to other groups.

Conclusion

Study findings suggest that combined LV-RVS dressing would be a beneficial platform with potentiated wound healing capacity.

Graphic abstract

Background

This study investigated the antidiabetic and antioxidant properties of hemp seed oil using various bioanalytical methods. Furthermore, this study determined the suppressive properties of hemp seed oil on α-amylase, acetylcholinesterase and carbonic anhydrase II that purified by the sepharose-4B-L-Tyrosine-sulfanilamide affinity chromatoghraphy, all of which are related to different metabolic diseases. Moreover, the phenolic concentration in the essential oil was quantified through LC–HRMS chromatography. Thirteen distinct phenolic compounds were detected in hemp seed oil. Additionally, both the chemical components and quantity of essential oils within hemp seed oil were assessed through GC–FID and GC/MS analyses.

Results

The predominant essential oils in hemp seed oil included linoleoyl chloride (34.62%), linoleic acid (33.21%), and 2-4-di-tert-butylphenol (5.79%). Hemp seed oil's ability to scavenge radicals was studied through the use of 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) and 1,1-diphenyl-2-picrylhydrazil bioanalytical radical scavenging methods. The results unveiled its potent radical-scavenging properties, with an 46.20 μg/mL for 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) radicals and IC₅₀ of 9.76 μg/mL for 1,1-diphenyl-2-picrylhydrazil radicals. The investigation also extended to explore the reducing capabilities of Fe³⁺-2,4,6-tri(2-pyridyl)-S-triazine, copper (Cu²⁺), and iron (Fe³⁺). Hemp seed oil demonstrated notable inhibitory effect against α-amylase (IC₅₀: 545.66 μg/mL), achethylcholinesterase (IC₅₀: 28.00 μg/mL), and carbonic anhydrase II (IC₅₀: 322.62 μg/mL).

Conclusions

This interdisciplinary research will prove valuable and set the stage for future investigations into the antioxidant characteristics and enzyme inhibition patterns of plants and plants oils that hold medical and industrial significance.