Drug Discoveries and Therapeutics最新文献

Anamorelin, a non-peptide ghrelin analog and growth hormone secretagogue, is a novel oral drug used to treat cancer cachexia. Patients with cancer cachexia frequently use several drugs and anamorelin is a substrate of cytochrome P450 (CYP) 3A4; therefore, drug-drug interactions with CYP3A4 inhibitors and inducers pose a clinical problem. In this study, we aimed to determine the concentration of anamorelin in human plasma using a simple high-performance liquid chromatography-ultraviolet (HPLC-UV)-based method. The analysis involved extracting a 200-μL plasma sample and protein precipitation using solid-phase extraction. Anamorelin was isocratically separated using a mobile phase consisting of 0.5% potassium dihydrogen phosphate (pH 4.5) and acetonitrile (61:39, v/v) on a Capcell Pack C18 MG II column (250 mm × 4.6 mm) at a flow rate of 1.0 mL/min and monitored at a detection wavelength of 220 nm. The calibration curve was linear within a plasma concentration range of 12.5-1,500 ng/mL, with a coefficient of determination of 0.9999. The intra- and inter-day coefficients of variation were 0.37-6.71% and 2.05-4.77%, respectively. The accuracy of the assay and recovery were 85.25-112.94% and > 86.58%, respectively. This proposed HPLC-UV method is simple and can be applied in clinical settings.

Drug-resistant bacterial infections have become a substantial problem in various communities. Appropriate antimicrobial use is required because reducing antimicrobial use could reduce the number of resistant bacteria. The inappropriate use of antimicrobials can be prevented by improving the knowledge of patients, physicians, and other healthcare professionals; however, no antimicrobial awareness survey specifically aimed at patients has been conducted yet. Therefore, to promote proper antimicrobial use, mainly by patients, we conducted a survey on the attitudes of patients who brought their antimicrobial prescriptions from insurance pharmacies. The results were based on 858 responses. Awareness of the terms "bacteria, viruses, and antimicrobials" was > 80%, whereas that of "drug-resistant bacteria" was only 37.2%. Only 26.5% of respondents understood what the efficacy of antimicrobial drugs meant. Additionally, 31.5% of the respondents had experienced discontinuation antimicrobials, and approximately 70% of the reasons for discontinuation were self-judged symptom improvement. Furthermore, those who had experienced discontinuation were less aware of the various aspects of antimicrobial use than those who had not. In antimicrobial treatment, avoiding the emergence of drug-resistant bacteria is difficult, is detrimental to patients consuming treatment, and presents a major problem in society. Therefore, healthcare professionals should strive to optimize infectious disease treatment by providing appropriate guidance on the proper use of antimicrobials, significance of taking them, and harmful effects of their discontinuation to patients.

Imatinib is an oral molecular targeted therapy that acts as a tyrosine kinase inhibitor. Silkworms present a promising experimental model for elucidating the pharmacokinetic and toxicity profiles of various compounds. This study aimed to establish an experimental paradigm for investigating the pharmacokinetics of imatinib in silkworms. A comparative analysis of imatinib pharmacokinetic parameters across silkworms, humans, mice, and rats revealed similarities in time to maximum concentration (T_max) and apparent clearance values between silkworms and humans. However, differences in elimination half-life (t_1/2) and apparent volume of distribution between silkworms and humans remained within 5- and 4-fold ranges, respectively. Importantly, mice demonstrated pharmacokinetic parameters closer to those of humans than rats during imatinib studies. Additionally, silkworms and mice exhibit similar T_max and t_1/2 values. This study highlights the potential of silkworms as valuable tools for investigating imatinib metabolism in pharmacokinetic studies. Furthermore, it underscores the applicability of silkworms in elucidating the pharmacokinetic parameters of various molecular-targeted drugs, thus facilitating advancements in drug development and evaluation.

Non-tuberculous mycobacteria (NTM) cause skin infections, respiratory diseases, and disseminated infections. Mycobacterium avium and Mycobacterium intracellulare, which are slow grown Mycobacterium, are main agents of those NTM diseases. A silkworm infection model with Mycobacterium abscessus, a rapidly growing Mycobacterium species, was established to quantitatively evaluate its virulence within a short period. However, a silkworm infection model to quantitatively evaluate the virulence of M. intracellulare has not yet been developed. In this study, we determined the virulence of M. intracellulare subspecies within 4 days using a silkworm infection model. The subspecies of M. intracellulare strains used in this study were estimated by phylogenetic tree analysis using core gene data. The median lethal dose (LD₅₀) values, which are the dose of a pathogen required to kill half of the silkworms in a group, were determined 4 days after infection. The LD₅₀ value of M. intracellulare subsp. chimaera DSM44623 was higher than that of M. intracellulare subsp. intracellulare ATCC13950. These results suggest that the virulence of M. intracellulare subspecies can be compared using a silkworm model within 4 days.

Patients with thrombotic antiphospholipid syndrome (APS) are at high risk for recurrent thrombosis, and indefinite anticoagulation is recommended. Patients with APS merit indefinite anticoagulation, and vitamin K antagonists (VKAs) have historically been the standard treatment. Direct oral anticoagulants (DOACs) present an appealing alternative to VKAs. Due to their pharmacokinetic and pharmacodynamic characteristics, DOACs offer advantages over VKAs, namely the lack of need for laboratory monitoring, the usage of a fixed dosage, and the absence of significant interaction with dietary components and drugs. The efficacy and safety of DOACs in patients with APS have been studied in four phase II/III clinical trials (three with rivaroxaban and one with apixaban). These studies showed DOACs' inferiority compared to VKAs in preventing recurrent thrombosis. Recurrence was significantly greater in patients with arterial thrombotic events and a triple positivity for antiphospholipid antibodies. No differences were observed in the incidence of venous thromboembolism between both groups. Major bleeding was similar in patients treated with DOACs or VKAs. Several observational studies have reported similar results. This review aims to analyse the existing evidence on the efficacy and safety of DOACs for secondary prevention in patients with APS.

This systematic review and meta-analysis aimed to estimate the prevalence of pregnancy- and lactation-associated osteoporosis in postpartum women within 1 year of delivery. We searched MEDLINE via PubMed and Igaku Chuo Zasshi for articles published in English or Japanese from the inception of the database to September 2021. Two researchers independently screened and included observational studies reporting the prevalence of pregnancy- and lactation-associated osteoporosis in postpartum women within 1 year of delivery. Of the 3,425 screened records, 8 articles centered on postpartum women were included in the review. Seven studies used dual-energy X-ray absorptiometry for assessing bone mineral density, while one used a quantitative ultrasound method. In the seven studies that used dual-energy X-ray absorptiometry, the parameters used to define osteoporosis were the T-score (two studies), Z-score (three studies), both T- and Z-scores (one study), and young adult mean (one study). Evaluation timeframes included 1 week (three studies), 1-2 months postpartum (three studies), and 1 week to 12 months postpartum (one study). The estimated prevalence of pregnancy- and lactation-associated osteoporosis defined by dual-energy X-ray absorptiometry was as follows: lumbar spine (six studies), 5% (95% confidence interval [CI], 0-13; heterogeneity [I²] = 99%) and femoral neck (three studies), 12% (95% CI, 0-30; I² = 99%). Pregnancy and lactation were found to elevate the fracture risk in women, underscoring the necessity for a standardized assessment in diagnosing pregnancy- and lactation-associated osteoporosis. This imperative step aims to enable early detection and treatment of bone mineral loss among postpartum women.

Actin rearrangement and phosphorylation-dephosphorylation in the nervous system contribute to plastic alteration of neuronal structure and function. Phosphatase and actin regulator (PHACTR) family members are actin- and protein phosphatase 1 (PP1)-binding proteins. Because some family members act as regulators of neuronal morphology, studying the regulatory mechanisms of PHACTR is valuable for understanding the basis of neuronal circuit formation. Although expression patterns of PHACTR family molecules (PHACTR1-4) vary across distinct brain areas, little is known about the extracellular ligands that influence their mRNA levels. In this study, we focused on an important neurotrophin, brain-derived neurotrophic factor (BDNF), and examined its effect on mRNA expression of PHACTR family member in cortical neurons. PHACTR1-3, but not PHACTR4, were affected by stimulation of primary cultured cortical neurons with BDNF; namely, sustained downregulation of their mRNA levels was observed. The observed downregulation was blocked by an inhibitor of the extracellular signal-regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) pathway, U0126, suggesting that ERK/MAPK plays an inhibitory role for gene induction of PHACTR1-3. These findings aid the elucidation of how BDNF regulates actin- and PP1-related neuronal functions.

The classification system for drug registration and the review and approval process influence the innovation and development of pharmaceuticals. China's previous classification standards for registration of traditional Chinese medicines (TCMs) overly emphasized the material basis while neglecting the clinical value of TCM. Moreover, the review and approval system did not fully consider the characteristics of new TCM drugs, such as the clinical experience already available for many TCM formulations guided by TCM theories. This resulted in suboptimal quality and quantity in the development of new TCM drugs. Since 2019, China has introduced a series of policies and regulations aimed at reforming the classification system for registration of TCMs and establishing a review system tailored to TCM characteristics. The new classification system for registration of TCMs emphasizes that the development of new TCM drugs should be oriented towards clinical value, focusing on meeting unmet clinical needs. The policies and regulations promote the conversion of prescriptions in ancient classics into new drugs and encourages the conversion of preparations from medical facilities into new TCM drugs. Secondary development of already marketed TCM products is encouraged to enhance the advantages of their clinical use. The new review system places importance on the role of TCM theories and clinical experience in supporting the registration of new TCM drugs. These reform measures have paved a path for registration and review of the characteristics of TCMs and will positively promote the development of new TCMs.

Generic medications contain the identical active ingredient in the same concentration as their branded counterparts and are administered in the same manner, aiming to deliver comparable efficacy, dosage, and clinical outcomes. Nevertheless, variations in additives and formulation processes, particularly noticeable in topical medications, can influence factors like ease of use and patient adherence. Therefore, in this study, we aimed to compare the rheological attributes of branded and generic injectable ointments, assessing disparities in formulation performance and their impact on patient care. Posterisan^® Forte and Hemoporison^® ointments were used as the branded and generic versions, respectively, and their viscosity, ductility, and viscoelastic properties were evaluated. Posterisan^® Forte showcased enhanced spread ability, maintaining uniform flow characteristics across varying temperatures, whereas Hemoporison^® displayed pronounced thixotropic properties and stiffness, suggesting potential benefits for applications necessitating reversible viscosity adjustments and heightened rigidity. Despite sharing identical additives, observable differences in physical characteristics highlight the necessity of understanding formulation traits, which could influence ointment behavior. Alterations in fluidity and viscosity may affect how patients perceive and apply the medication, potentially influencing treatment outcomes and the occurrence of adverse effects.

Parkinson's disease (PD) is a complex multisystem neurodegenerative disease, and cognitive impairment is a common symptom in the trajectory of PD. Duzhong Fang (DZF) consists of Eucommia ulmoides, Dendrobium, Rehmanniae Radix, and Dried Ginger. Our previous study showed that DZF improves motor deficits in mice. However, whether DZF can ameliorate cognitive impairment in PD has not been reported. In this study, we established mice models of PD induced by rotenone and examined the effect of DZF on cognitive impairment in Parkinson's disease (PD-CI). The results confirmed that DZF treatment not only significantly improved the motor deficits in PD mice and decreased the loss of dopaminergic neurons, but also had significant effects in improving cognitive impairment. We further integrate serum metabolome and network pharmacology to explore the mechanisms by which DZF improves PD-CI. The results revealed that DZF can treat PD-CI by regulating sphingolipid metabolism to inhibit neuronal apoptotic pathway. In conclusion, preliminary studies confirmed that DZF contributes to the improvement of cognitive ability in PD, and our results provide a potential drug for the clinical treatment of PD and a theoretical foundation for DZF in clinical application.