Formulation and Pharmacokinetic Evaluation of Ethyl Cellulose/HPMC-Based Oral Expandable Sustained Release Dosage of Losartan Potassium.

Prolonged retention of losartan potassium in the upper gastrointestinal tract is anticipated to increase its absorption and exposure to CYP450 enzyme subfamilies, undertaking its conversion to more potent (10-40 times) active metabolite, losartan carboxylic acid (LCA). Consistent with this, hydroxypropyl methylcellulose K4M/ethyl cellulose-based novel expandable films (EFs) containing losartan potassium (LP) suitable for prolonged retention in the stomach were developed. The films were prepared by solvent casting method. USP type II dissolution apparatus (0.1 N HCl, 37°C, 100 rpm) was used to perform the dissolution testing (drug release, unfolding behavior, film integrity, erosion, and water uptake) of the films. In vivo pharmacokinetic studies were carried out in rabbits. An HPLC-UV method was used for the quantification of the drug and its active metabolite in plasma. These folded films placed inside hard gelatin capsule shells unfolded to full dimensions in dissolution medium and provided sustained drug release throughout 12 h. The plasma drug concentration-time curves obtained from the in vivo studies were used to determine pharmacokinetic parameters, such as area under the plasma drug concentration-time curve (AUC), area under first moment curve (AUMC), mean residence time (MRT), Cmax, Tmax, t1/2, ke, and Fr in comparison with that of the market formulation, Cozaar®. The novel EFs significantly changed the pharmacokinetic parameters of the drug and its active metabolite. The apparent elimination rate constant (ke) significantly decreased, while MRT and elimination half-life (t1/2) increased in both cases. The relative bioavailabilities (Fr) of both LP and E3174 using the novel formulation were higher than that of Cozaar®.

Optimizing the fabrication of electrospun nanofibers of prochlorperazine for enhanced dissolution and permeation properties.

Despite being an approved antiemetic for more than five decades, the clinical usefulness of prochlorperazine is limited by its low solubility and inconsistent absorption in the gastrointestinal tract, which presents challenges for nanotherapeutic interventions. Here, we report the preparation of a highly soluble and permeable nanofiber formulation of prochlorperazine using the Quality-by-Design approach. The final nanofiber formulation with drug entrapment of 88.02 ± 1.14 % was obtained at 20.0 kV, with a flow rate of 0.5 ml/h and tip-to-collector distance of 19.9 cm. Physio-mechanical properties, such as thickness (0.42 ± 0.02 mm), pH resistance (7.04 ± 0.08), folding endurance (54 ± 5), and tensile strength (0.244 ± 0.02 N.mm-2), were appropriate for packaging and application to oromucosal surfaces. The content uniformity (93.48-106.63 %) and weight variation (<1.8 mg) of the optimal nanofiber formulation were within the permissible limits prescribed for orodispersible films. Microscopical investigations confirm a randomly deposited and dense network of woven nanofibers with an average diameter of 363 ± 5.66 nm. The drug particles were embedded homogeneously on the fiber in the nanoform (4.27 ± 1.34 nm). The spectral analysis using TEM-EDS shows diffraction peaks of sulfur and chlorine, the elemental constituents of prochlorperazine. The drug was amorphized in the nanofiber formulation, as led by the decline of the crystallinity index from 87.25 % to 7.93 % due to electrostatic destabilization and flash evaporation of the solvent. The enthalpy of fusion values of the drug in the nanofiber mat decreased significantly to 23.6 J/g compared to its pristine form, which exhibits a value of 260.7 J/g. The nanofibers were biocompatible with oral mucosal cells, and there were no signs of mucosal irritation compared to 1 % sodium lauryl sulfate. The fiber mats rapidly disintegrated within <1 s and released ≈91.49 ± 2.1 % of the drug within 2 min, almost 2-fold compared to the commercial Stemetil MD® tablets. Similarly, the cumulative amount of the drug permeated across the unit area of the oromucosal membrane was remarkably high (31.28 ± 1.30 µg) compared to 10.17 ± 1.11 µg and 13.10 ± 1.79 µg from the cast film and drug suspension. Our results revealed these nanofiber formulations have the potential to be fast-dissolving oromucosal delivery systems, which can result in enhanced bioavailability with an early onset of action due to rapid disintegration, dissolution, and permeation.

A Rare Incidence of Hepatocellular Carcinoma With Tumor Thrombus Extending to the Right Heart.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths and the sixth most commonly diagnosed cancer worldwide due to several common risk factors, including hepatitis C virus (HCV), hepatitis B virus (HBV), and other causes of cirrhosis. In HCC, intrahepatic vascular invasion and a tumor thrombus are commonly observed. However, the extrahepatic spread of the tumor thrombus to the heart via the portal vein, hepatic vein, and inferior vena cava (IVC) is rarely reported and is considered a poor prognostic factor. In addition, rarely, there is a risk of cor pulmonale and thromboembolism of the pulmonary vessels. Our patient also presented with this rare complication of HCC. Our patient's clinical presentation was bilateral pedal edema, moderate ascites, and abdominal discomfort with raised jugular venous pressure. These signs and symptoms are related to an impairment of the right heart caused by intracardiac tumor thrombus metastasis, leading to diastolic dysfunction. Based on these findings, echocardiography and abdominal computed tomography (CT) scan were performed with the definitive diagnosis of hepatocellular carcinoma with tumor thrombus metastases in the hepatic vein, inferior vena cava, and right atrium. The management team agreed on a conservative treatment plan based on the advanced stage of the disease and the high risk associated with aggressive treatment modalities. Unfortunately, on day 7 of admission, the patient died from a possible pulmonary embolism that led to cardiopulmonary arrest. This case underscores the importance of screening patients with a high HCC tumor burden with abdominal ultrasound and echocardiography for early detection and timely management.

Utilization of Artificial Intelligence in Disease Prevention: Diagnosis, Treatment, and Implications for the Healthcare Workforce.

Artificial intelligence (AI) has been described as one of the extremely effective and promising scientific tools available to mankind. AI and its associated innovations are becoming more popular in industry and culture, and they are starting to show up in healthcare. Numerous facets of healthcare, as well as regulatory procedures within providers, payers, and pharmaceutical companies, may be transformed by these innovations. As a result, the purpose of this review is to identify the potential machine learning applications in the field of infectious diseases and the general healthcare system. The literature on this topic was extracted from various databases, such as Google, Google Scholar, Pubmed, Scopus, and Web of Science. The articles having important information were selected for this review. The most challenging task for AI in such healthcare sectors is to sustain its adoption in daily clinical practice, regardless of whether the programs are scalable enough to be useful. Based on the summarized data, it has been concluded that AI can assist healthcare staff in expanding their knowledge, allowing them to spend more time providing direct patient care and reducing weariness. Overall, we might conclude that the future of "conventional medicine" is closer than we realize, with patients seeing a computer first and subsequently a doctor.

Global Effect of COVID-19 Pandemic on Cancer Patients and its Treatment: A Systematic Review.

Background: At a global level, the COVID-19 disease outbreak has had a major impact on health services and has induced disruption in routine care of health institutions, exposing cancer patients to severe risks. To provide uninterrupted tumor treatment throughout a pandemic lockdown is a major obstacle. Coronavirus disease (COVID-19) and its causative virus, SARS-CoV-2, stance considerable challenges for the management of oncology patients. COVID-19 presents particularly severe respiratory and systemic infection in aging and immunosuppressed individuals, including patients with cancer. Objective: In the present review, we focused on emergent evidence from cancer sufferers that have been contaminated with COVID-19 and cancer patients who were at higher risk of severe COVID-19, and indicates that anticancer treatment may either rise COVID-19 susceptibility or have a duple therapeutic impact on cancer as well as COVID-19; moreover, how SARS-CoV-2 infection impacts cancer cells. Also, to assess the global effect of the COVID-19 disease outbreak on cancer and its treatment. Methods: A literature survey was conducted using PubMed, Web of Science (WOS), Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and VIral Protein domain DataBase (VIP DB) between Dec 1, 2019 and Sep 23, 2021, for studies on anticancer treatments in patients with COVID-19. The characteristics of the patients, treatment types, mortality, and other additional outcomes were extracted and pooled for synthesis. Results: This disease has a huge effect on sufferers who have cancer(s). Sufferers of COVID-19 have a greater percentage of tumor diagnoses than the rest of the population. Likewise, cancer and highest proportion is lung cancer sufferers are more susceptible to COVID-19 constriction than the rest of the population. Conclusion: Sufferers who have both COVID-19 and tumor have a considerably elevated death risk than single COVID-19 positive patients overall. During the COVID-19 pandemic, there was a reduction in the screening of cancer and detection, and also deferral of routine therapies, which may contribute to an increase in cancer mortality there in future.

Multiple-reaction monitoring (MRM) LC-MS/MS quantitation of venlafaxine and its O-desmethyl metabolite for a preclinical pharmacokinetic study in rabbits.

Preclinical pharmacokinetic (PK) studies in animal models during the formulation development phase give preliminary evidence and near clear picture of the PK behavior of drug and/or its dosage forms before clinical studies on humans and help in the tailoring of the dosage form according to the expected and requisite clinical behavior. The present work reports a first of its kind preclinical PK study on extended-release (ER) solid oral dosage forms of venlafaxine (VEN) in New Zealand White rabbits. The VEN is a highly prescribed and one of the safest and most effective therapeutic agents used in the treatment of different types of depression disorders worldwide. The multiple-reaction monitoring (MRM) LC-MS/MS method developed for this purpose demonstrated enough reliability in simultaneously quantitating VEN and its equipotent metabolite O-desmethylvenlafaxine (ODV) in rabbit plasma. The method described uses solid-phase extraction for sample preparation followed by an ultrafast LC-MS/MS analysis. The chromatographic separation was achieved isocratically with a predominantly polar mobile phase by employing RPLC. The triple quadrupole LC/MS/MS system operated in MRM mode used an ESI probe as an ion source in positive polarity. The validation results are within the permissible limits of US FDA recommendations and acceptance criteria for bioanalytical method validation.

Effectiveness and safety profiling of zolpidem and acupressure in CKD associated pruritus: An interventional study.

BACKGROUND: Chronic kidney disease (CKD)-associated pruritus (CKD-aP) contributes to poor quality of life, including reduced sleep quality and poor sleep quality is a source of patient stress and is linked to lower health-related quality of life. This study aimed to investigate the effectiveness of zolpidem 10 mg and acupressure therapy on foot acupoints to improve the sleep quality and overall quality of life among hemodialysis patients suffering from CKD-aP. METHOD: A multicenter, prospective, randomized, parallel-design, open label interventional study to estimate the effectiveness of zolpidem (10 mg) oral tablets versus acupressure on sleep quality and quality of life in patients with CKD-aP on hemodialysis. A total of 58 hemodialysis patients having sleep disturbance due to CKD-aP completed the entire 8-week follow-up. The patients were divided into a control (acupressure) group of 28 patients and an intervention (zolpidem) group of 30 patients. RESULTS: A total of 58 patients having CKD-aP and sleep disturbance were recruited. In the control group there was a reduction in the PSQI score with a mean ±â€ŠSD from 12.28 ±â€Š3.59 to 9.25 ±â€Š3.99, while in the intervention group the reduction in PSQI score with a mean ±â€ŠSD was from 14.73 ±â€Š4.14 to 10.03 ±â€Š4.04 from baseline to endpoint. However, the EQ5D index score and EQ-visual analogue scale (VAS) at baseline for the control group with a mean ±â€ŠSD was 0.49 ±â€Š0.30 and 50.17 ±â€Š8.65, respectively, while for the intervention group the values were 0.62 ±â€Š0.26 and 47.17 ±â€Š5.82, respectively. The mean EQ5D index score in the control group improved from 0.49 ±â€Š0.30 to 0.53 ±â€Š0.30, but in the intervention group there was no statistical improvement in mean EQ5D index score from 0.62 ±â€Š0.26 to 0.62 ±â€Š0.27 from baseline to week 8. The EQ 5D improved in both groups and the EQ-VAS score was 2.67 points higher at week 8 as compared to baseline in the control group, while in the intervention group the score was 3.33 points higher at week 8 as compared to baseline. Comparing with baseline, the PSQI scores were significantly reduced after week 4 and week 8 (P =  < .001). Furthermore, at the end of the study, the PSQI scores were significantly higher in the control as compared to the intervention group (P = .012). CONCLUSION: An improvement in sleep quality and quality of life among CKD-aP patients on hemodialysis has been observed in both the control and intervention groups. Zolpidem and acupressure safety profiling showed no severe adverse effect other that drowsiness, nausea and daytime sleeping already reported in literature of zolpidem.

Protocol for Determining the Induction of Human Embryonic Stem Cells into Myogenic Lineage Using Electrospun Nanofibers.

An efficient method for the development of myogenic differentiation using the stem cells can be beneficial in patients with severely compromised mobility, muscular damage, or degenerative diseases. The stem cells can prove to be excellent clinical source of myogenic progenitor cells due to their ability of self-proliferation, renewal, and differentiation into a specific phenotype. They represent an essential component of tissue engineering along with other factors (e.g., 3D scaffolds, ECM mimicking environment, and growth factors). In this chapter, we describe the experimental protocols for isolation of the embryonic stem cells, their proliferation on nanofiber scaffolds, and finally their differentiation into myogenic cells. Furthermore, this chapter elaborates experimental methods to assess the myogenic fate of embryonic stem cells on the nanofiber scaffolds.

Experimental Protocol for Induction of Transgene Expression in Neural Stem Cells Through Polymeric Nanoparticles.

Therapy based on stem cells utilizes these cells in neurodegeneration, brain/spinal cord injury, and much recently in repairing of severe heart diseases. Owning to their stemness, these cells are the potential source of progenitors that can offer a therapeutic remedy to a variety of diseases and/or disorders. The ability of these cells to regenerate and differentiate into specified phenotypes has great utility in tissue regeneration applications. This chapter provides a detailed account for isolation of neural stem cells from the mice embryo. Furthermore, the fabrication of chitosan-tripolyphosphate/hyaluronic acid-based nanoparticles and evaluating their efficiency in inducing transfection in the isolated neural stem cells as an approach for the treatment of neurodegenerative disorders.

A randomized controlled trial for effectiveness of zolpidem versus acupressure on sleep in hemodialysis patients having chronic kidney disease-associated pruritus.

BACKGROUND: Pruritus adds to the complications of chronic kidney disease (CKD) patient and a well-recognized complication among the CKD patients. Majority of the patients on hemodialysis experience a generalized pruritus and patients reported being moderately to extremely disturbed by at least one of the sleep-related condition. This study aim to investigate the effectiveness of zolpidem 10 mg and acupressure therapy on foot acupoints to improve the sleep quality and overall quality of life among hemodialysis patients suffering from CKD-associated pruritus. METHODS: A multicentered, open-label, parallel group, prospective randomized controlled trial among patients suffering from CKD-associated pruritus with sleep disturbance, after randomization into control, and intervention group to be held at North West General Hospital and Research Center Peshawar, Pakistan and Institute of Kidney Diseases Peshawar, Pakistan. RESULTS: The primary outcome is to investigate the effectiveness of zolpidem 10 mg and acupressure therapy on foot acupoints to improve the sleep quality and overall quality of life among hemodialysis patients suffering from CKD-associated pruritus. After baseline assessment by Urdu version of 5D itch scale and Urdu version of Pittsburgh Sleep Quality Index (PSQI) and Urdu EQ-5D 3L, the intervention group will be given zolpidem 10 mg oral tablets and control group with acupressure on both foots on KI-1 acupoints for total of 6 minutes. Assessment will be done at weeks 4 and 8 from baseline by using Urdu version of 5D itch scale and Urdu version of PSQI and Urdu EQ-5D 3L, whereas safety profiling of zolpidem 10 mg tablet at week 6 from baseline and acupressure acceptability at week 6 from baseline. Analysis of covariance will be used to examine the differences in treatment effects between the intervention and control groups. CONCLUSION: Improvement of sleep quality and quality of life among patients with CKD-associated pruritus requires great importance. This study aims to improve the quality of sleep and quality of life among patients with hemodialysis suffering from CKD-associated pruritus.

Analysis of proteins associated with ozone stress response in soybean cultivars.

Ozone stress induces leaf injuries and yield losses in soybean. To identify the proteins associated with the stress response, ozone tolerant and sensitive cultivars were analyzed by 2D-PAGE. After 11 days of ozone stress unifoliate leaves of tolerant soybean cv. Enrei developed 15% and sensitive cv. Nakasennari developed 52% leaf injury symptoms. Analysis of proteins in the unifoliate leaves identified six proteins in tolerant cv. Enrei and three proteins in sensitive cv. Nakasennari, responded significantly to ozone stress. The significantly responded proteins identified in this study were ATP synthase α-subunit, ATP synthase ß-subunit, phosphoglycerate kinase, aldo/ketoreductase, rubiscoactivase and glutamine synthetase. To understand that the differences in response of ATP synthase proteins were ultimately associated with extracellular ATP signaling response, ozone sensitive cv. Nakasennari was treated with 1 mM ATP. Unifoliate leaves of ATP treated plants have significantly reduced injury symptoms (20%) under ozone stress compare to control plants (47%). This confirms that extracellular ATP signaling in ATP synthase dependent manner is playing a pivotal role in inducing ozone stress tolerance and preventing injuries in soybean cultivars.

Identification of cold-responsive genes in energycane for their use in genetic diversity analysis and future functional marker development.

Breeding for cold tolerance in sugarcane will allow its cultivation as a dedicated biomass crop in cold environments. Development of functional markers to facilitate marker-assisted breeding requires identification of cold stress tolerance genes. Using suppression subtractive hybridization, 465 cold-responsive genes were isolated from the cold-tolerant energycane Ho02-144. Predicted gene interactions network indicated several associated pathways that may coordinately regulate cold tolerance responses in energycane. Expression analysis of a select set of genes, representing signaling and transcription factors, genes involved in polyamine and antioxidant biosynthesis, protein degradation and in the repair of damaged proteins in the cytosol, showed their time-dependent regulation under cold-stress. Comparative expression profiles of these genes between Ho02-144 and a cold-sensitive clone (L79-1002) showed that almost all genes were induced immediately upon imposition of cold stress and maintained their expression in Ho02-144 whereas they were either downregulated or their upregulation was very low in L79-1002. Simple sequence repeat markers derived from 260 cold-responsive genes showed allelic diversity among the cold-sensitive commercial hybrids that were distinct from the Saccharum spontaneum clones. Future efforts will target sequence polymorphism information of these genes in our ongoing QTL and association mapping studies to identify functional markers associated with cold tolerance in sugar/energycane.

Identification of cleistogamy-associated proteins in flower buds of near-isogenic lines of soybean by differential proteomic analysis.

Differential proteomics analyses were performed on flower buds of chasmogamous (CH) and cleistogamous (CL) soybean to identify candidate genes that are associated with cleistogamy which is the production of permanently closed flowers. The proteins were extracted from flower buds of CH cv. Toyosuzu and CL cv. Karafuto-1, and separated by two-dimensional polyacrylamide gel electrophoresis. Of the 640 proteins detected on the gel, nine were differentially expressed in Toyosuzu and nine in Karafuto-1. Among these differentially expressed proteins, those associated with cleistogamy were identified using a pair of near-isogenic lines (NILs). beta-Galactosidase and protein disulfide isomerase were expressed differentially between the NILs for cleistogamy. Furthermore, the mRNA expression pattern of protein disulfide isomerase corresponded to the protein level, whereas that of beta-galactosidase was not consistent with the protein level. These results suggest that the protein disulfide isomerase and beta-galactosidase may be useful markers for achieving a better understanding of the molecular-biological mechanisms of cleistogamy in soybean.

The genus Crataegus: chemical and pharmacological perspectives

Traditional drugs have become a subject of world importance, with both medicinal and economical implications. A regular and widespread use of herbs throughout the world has increased serious concerns over their quality, safety and efficacy. Thus, a proper scientific evidence or assessment has become the criteria for acceptance of traditional health claims. Plants of the genus Crataegus, Rosaceae, are widely distributed and have long been used in folk medicine for the treatment of various ailments such as heart (cardiovascular disorders), central nervous system, immune system, eyes, reproductive system, liver, kidney etc. It also exhibits wide range of cytotoxic, gastroprotective, anti-inflammatory, anti-HIV and antimicrobial activities. Phytochemicals like oligomeric procyanidins, flavonoids, triterpenes, polysaccharides, catecholamines have been identified in the genus and many of these have been evaluated for biological activities. This review presents comprehensive information on the chemistry and pharmacology of the genus together with the traditional uses of many of its plants. In addition, this review discusses the clinical trials and regulatory status of various Crataegus plants along with the scope for future research in this aspect.