Notes

Nonclinical pharmacology associated with daridorexant: a whole new two orexin receptor villain for the treatment of sleeping disorders.
Introduction Although life-threatening if left untreated, visceral leishmaniasis (VL) is still a neglected endemic disease in 98 countries worldwide. The number of drugs available is low and few are in clinical trials. In the last decades, efforts have been made on the development of nanocarriers as drug delivery systems to treat VL. Given the preferential intracellular location of the parasite in the liver and spleen macrophages, the rationale is sturdy. selleckchem In a clinical setting, liposomal amphotericin B displays astonishing cure rates. Areas covered A literature search was performed through PubMed and Google Scholar. We critically reviewed the main literature highlighting the success of nanomedicine in VL. We also reviewed the hurdles and yet unfulfilled promises rising awareness of potential drawbacks of nanomedicine in VL. Expert opinion VL is a disease where nanomedicines successes shine through. However, there are a lot of obstacles on the road to developing more efficient strategies such as targeting functionalization, oral formulations, or combined therapies. And those strategies raise many questions.Background Study to describe the degree of menopausal palpitation distress and its demographic, clinical, symptom, and quality-of-life (QOL) correlates. Analysis of existing, baseline, data from peri- and postmenopausal women, 42 to 62 years of age, who participated in the Menopause Strategies-Finding Lasting Answers for Symptoms and Health (MsFLASH) clinical trials testing interventions for vasomotor symptoms (n = 759). Up to 46.8% of menopausal women report having palpitations, yet the symptom is relatively understudied. Little is known about palpitation distress or its correlates. Materials and Methods Degree of distress from "heart racing or pounding" was self-reported over the past two weeks as "not at all," "a little bit," "moderately," "quite a bit," or "extremely." Other measures included self-report forms, clinic-verified body mass index (BMI), vasomotor symptom diaries, and validated symptom and QOL tools. Results The percentage who reported palpitation distress was 19.6%, 25.2%, and 33.5% in the three trials or 25.0% overall. In multivariate analysis, the odds of reporting palpitation distress was lower in past smokers (odds ratio [OR] = 0.59 [95% confidence interval (CI) 0.38-0.90]) and current smokers (OR = 0.48 [0.27-0.87]) relative to never-smokers and lower with every 5 kg/m2 higher BMI (OR = 0.82 [0.69-0.98]).The odds of reporting palpitation distress was higher with every five point more severe insomnia (OR = 1.28 [1.05-1.54]), five point worse depressive symptoms (OR = 1.47 [1.11-1.95]), five point worse perceived stress (OR = 1.19 [1.01-1.39]), and one point worse menopausal QOL (OR = 1.29 [1.06-1.57]). Conclusions Menopausal palpitation distress is common and associated with demographic, clinical, symptom, and QOL factors. Findings can be used for screening in clinical practice and to justify additional research on this understudied symptom.
Several new biopharmaceutical dosage forms have developed over time, such as lyophilized vial, liquid vial, and liquid prefilled syringe formulations. This review summarizes major pharmaceutical dosage forms and their advantages, disadvantages, and countermeasures against the shortcomings of each formulation. The appropriate combination of active pharmaceutical ingredients, excipients, and containers should be selected for the safe and less burdensome administration to the patients. Finally, we note certain opinions on the future development of not only therapeutic proteins but also gene therapeutics.

This review is to discuss the challenges of the development of dosage forms to improve pharmaceutical stability and how they can be overcome.

Silicone oil-free syringes are highly preferable for minimizing subvisible particles in the drug. It can be proposed that materials with less protein adsorption property are preferable for the suppression of protein aggregation. It is required to minimize adverse effects of biopharmaceuticals through proper quality control of the drug in a container, based on the understating of physicochemical stability of the protein in solution, the physicochemical properties of the container, and their combinations.
Silicone oil-free syringes are highly preferable for minimizing subvisible particles in the drug. It can be proposed that materials with less protein adsorption property are preferable for the suppression of protein aggregation. It is required to minimize adverse effects of biopharmaceuticals through proper quality control of the drug in a container, based on the understating of physicochemical stability of the protein in solution, the physicochemical properties of the container, and their combinations.Objectives Near-Infrared based imaging modalities integrated with thermotherapy can facilitate detection of cancer at early stages and mediate high-resolution image-guided hyperthermia. In this work, fluorescent iron oxide nanoparticles (FIO) have been developed possessing deep tissue penetrable NIR imaging and site-specific magnetic hyperthermia characteristics for the elimination of cancer cells. Methods One-pot synthesis of amine-functionalized superparamagnetic iron oxide nanoparticles (HIO) were achieved using ethylenediamine (EDA) facilitated conjugation of indocyanine green (ICG) mediated by electrostatic interactions. Results EDA acts as a capping and reducing agent to direct the structural growth of hydrophilic Fe3O4 nanocrystals with high saturation magnetization, specific absorption rate, and T2 value of 118 emu/g, 329.8 ± 5.96 W/g, and 40.17 mM-1s-1, respectively. Here, Fe2+/Fe3+ of two was maintained to achieve magnetite nanocrystals contradictory to the gold standard ratio of 0.5 without additives for nucleation and growth. Developed FIO showed excellent cytocompatibility even at higher concentrations and on subjecting to magnetic hyperthermia reduced its survival percentage. FIO biodistribution in mice showed enhanced half-life than free ICG with preferential localization in the brain and liver. Conclusion Developed FIO using a facile technique is a potential clinical alternative for cellular tracking, imaging, and hyperthermia.The hip and pelvis have a complex anatomy and are a common source of pain and injury in the athletic population. The clinical examination of the hip requires a systematic approach to differentially diagnose hip problems with overlapping pain referral patterns. Because of the complex anatomy of the hip, the physical examination is a comprehensive evaluation of the 4 main pain generators of the hip from deep to superficial the osteochondral, capsulolabral, musculotendinous, and neurovascular elements of the hip. The hip examination begins with the standing examination and gait analysis followed by a seated, supine, lateral, and prone examination. A targeted physical examination used in conjunction with a layered understanding of the hip and pelvis can help guide diagnostic testing, distinguish hip-specific diagnoses from similar presenting pathologies, and inform treatment.Although numerous trials have convincingly shown benefits of statin therapy in both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), most showed relative risk reductions of 25-40%, and thus many individuals continue to have ASCVD events despite statin therapy. Substantial progress has been made in developing therapies that address the residual risk for ASCVD despite statin therapy. In this review, we summarize progress of currently available therapies along with therapies under development that further reduce low-density lipoprotein cholesterol and apolipoprotein B-containing lipoproteins, reduce lipoprotein(a), reduce ASCVD events in patients with high triglycerides, and directly target inflammation to reduce ASCVD risk.The substantial increase in life expectancy of men has focused growing attention on quality-of-life issues associated with reproductive aging. Serum total and free testosterone levels in men, after reaching a peak in the second and third decade of life, decline gradually with advancing age. The trajectory of age-related decline is affected by comorbid conditions, adiposity, medications, and genetic factors. Testosterone treatment of older men with low testosterone levels improves overall sexual activity, sexual desire, and erectile function; improves areal and volumetric bone density, as well as estimated bone strength in the spine and the hip; corrects unexplained anemia of aging; increases skeletal muscle mass, strength and power, self-reported mobility, and some measures of physical function; and modestly improves depressive symptoms. The long-term effects of testosterone on major cardiovascular events and prostate cancer risk remain unclear. The Endocrine Society recommends against testosterone therapy of all older men with low testosterone levels but suggests consideration of treatment on an individualized basis in men who have consistently low testosterone levels and symptoms or conditions suggestive of testosterone deficiency.Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with a significant lifetime risk of diffuse gastric cancer (DGC), a malignancy characterized by late clinical presentation and poor prognosis, as well as lobular breast cancer. HDGC is linked to germline pathogenic variants in the E-cadherin gene (CDH1) that are inherited in an autosomal dominant pattern; however, in many families with DGC clustering, no genetic cause has been identified. This review discusses key elements that allow risk assessment of potential inherited DGC susceptibility. We provide a practical overview of the recommendations for surveillance and treatment of individuals at risk and patients with early disease. The review also outlines future research avenues to improve our understanding of the genetic background and natural history of the disease, the endoscopic detection of early lesions, and the outcome of prophylactic surgery in young individuals.Rationale In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results Multiple aberrant immune responses in fatal COVID-19 were found, principally crophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.Aim To investigate the mobile genetic elements harboring blaKPC gene in carbapenem-resistant Klebsiella pneumoniae recovered during a 6-month outbreak in a high-complexity hospital from Ecuador. Results A total of 62 isolates belonging to ST258 pilv-I-positive (n = 45), ST25 serotype K2 (n = 8), ST348 (n = 6), ST42 (n = 1), ST196 (n = 1), and ST1758 (n = 1) were collected from intensive care unit (ICU), neurosurgery, burn unit, internal medicine, pneumology, and neurology. Pulsed-field gel electrophoresis analysis showed two major clusters of ST258 and ST25 related to bloodstream infections and pneumonia circulating in ICU. The PCR assay showed that in non-ST258 isolates, the blaKPC-2 gene were located on the Tn4401a transposon inserted in the transferable pKpQIL-like IncFIIK2 plasmid; the whole-genome sequencing of ST258 clone showed two plasmids, the blaKPC-2 gene was located on nonconjugative IncR plasmid, whereas the IncFIB/IncFII plasmid lacked ß-lactamase genes. We found an IncM plasmid in blaKPC-2-harboring Klebsiella pneumoniae ST1758 clone.
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