Basic & Clinical Pharmacology & Toxicology最新文献

Chronic kidney disease (CKD) remains a significant global health burden despite recent advances in pharmacotherapy, including sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists. Renal fibrosis, a central pathological hallmark of CKD progression, is mediated by persistent inflammation and macrophage activation, wherein the kallikrein–kinin system—particularly kinin receptors—plays a critical role. Emerging evidence supports the therapeutic potential of dual kinin receptor antagonism, especially targeting B1R, though the precise molecular mechanisms remain incompletely understood, necessitating further investigation. To elucidate the role of kinin receptors in renal injury, male C57BL/6 mice were subjected to folic acid-induced nephropathy and treated with either the B1R antagonist R715 or the B2R antagonist HOE140. Treatments were administered pre- and postfolic acid injection. Renal function was evaluated via serum creatinine, blood urea nitrogen and urine analyses. Renal tissues underwent histopathological assessment and gene expression profiling to assess injury and fibrotic responses. B2R antagonism (HOE140) failed to attenuate acute tubular injury but ameliorated chronic damage by downregulating proinflammatory mediators and upregulating anti-inflammatory markers. In contrast, B1R blockade (R715) exacerbated acute kidney injury yet mitigated chronic fibrosis, improving renal function and reducing profibrotic gene expression. These findings delineate distinct, time-dependent roles of B1R and B2R in modulating macrophage polarization (M1/M2) and fibrogenesis, identifying potential targets for antifibrotic therapies.

To address challenges in deprescribing, we investigated the feasibility of an intervention consisting of a clinical medication review (CMR) focused on deprescribing, supported by a training programme for healthcare providers (HCPs) among older patients with hyperpolypharmacy (≥ 10 chronic medications) in primary care. A mixed-methods feasibility study was conducted in six Dutch community pharmacies using Bowen's framework. The intervention comprised HCP training and a five-step deprescribing-focused CMR. Within 6 Bowen domains, 18 outcomes were assessed through (patient) questionnaires, interviews (patients, HCPs), process parameters, and medication dispensing data. Five pharmacists conducted CMRs with 24 patients (median age: 84.5 years). The intervention was well accepted by patients and HCPs. However, barriers emerged regarding implementation and practicality. Consultations lacked complete discussion of patient concerns, and pharmacists reported varying levels of confidence in making deprescribing decisions. Time constraints limited the incorporation of deprescribing into CMRs. On average, 1.3 medications per patient were deprescribed. Within a setting of motivated and CMR-experienced HCPs, adding a focus on deprescribing to CMRs for older patients with hyperpolypharmacy was feasible and well received. Feasibility was supported by high acceptability and deprescribing potential, though barriers in implementation and practicality indicate the need for further evaluation in broader primary care settings.

Many patients report being allergic to opioids and/or have allergy warnings documented in their medical records. However, the reasoning behind these warnings is often unclear and frequently lacks clinical validation. Reported reactions may include skin rashes, itching, severe vomiting, fainting or respiratory arrest occurring during postoperative recovery where opioids were administered. In many cases, there is also uncertainty about which specific opioid was used. An allergy warning to one opioid further raises the question of whether the patient can tolerate other opioids. In this review, we address the exceedingly rare IgE-mediated opioid allergy and cross-reactivity between opioids, along with non–immune-mediated histamine release and other adverse effects of opioids that patients or clinicians may mistake for allergic reactions. We propose a simple risk stratification algorithm for the clinical management of patients labelled as opioid allergic—helping to distinguish who should be referred for allergy evaluation and who can safely be treated with opioids with or without antihistamine pre-treatment.