Pharmacological Reports最新文献

Background: The neuropeptide B/W receptor 1 (NPBWR1) system, including its two endogenous ligands, Neuropeptides B and W (NPB and NPW), has garnered interest as a potential target to develop novel analgesics. Behavioral studies were typically conducted with exogenously administered endogenous ligands. In this study, we examined truncated NPB-23 and its peptidomimetic RTIBW-16 in a panel of antinociceptive assays, including the hot plate, carrageenan-induced inflammatory, and paclitaxel chemotherapy-induced peripheral neuropathy (CIPN) pain assays.

Methods: Male and female C57BL/6 mice underwent testing in the hot plate acute nociception assay. After a minimum one-week washout, mice were enrolled in the carrageenan inflammatory pain model, receiving intraplanar carrageenan (0.3% carrageenan in a 20 µL volume). Separate mouse cohorts received a cycle of intraperitoneal paclitaxel injections (cumulative dose 32 mg/kg). The von Frey assay was utilized to assess CIPN and carrageenan-induced allodynia. NPB-23 and RTIBW-16 (0.56-100 µg) were administered via acute intrathecal (it) injections.

Results: Single it doses of NPB-23 and RTIBW-16 evoked dose-dependent antinociception (hotplate) and evoked dose-dependent anti-allodynia in mouse models of CIPN and carrageenan-induced unilateral hind paw inflammation. In the hot plate assay, RTIBW-16 showed an earlier onset but shorter duration of action than NPB-23 with similar maximum peak effects. Both compounds were statistically equipotent in the reversal of mechanical allodynia induced by either paclitaxel or carrageenan. RTIBW-16 maintained a longer duration of action than NPB-23 in the CIPN assay.

Conclusions: Single it doses of both NPBWR1 agonists alleviated acute pain in the hotplate test and mechanical allodynia in the hind paws of a mouse model of inflammatory pain. NPBWRI agonists also evoked anti-allodynia in a mouse model of CIPN. Our findings suggest that NPBWR1 is a promising target for developing analgesics with novel mechanisms.

Breast cancer (BC) is one of the most common malignant tumors in women worldwide, and its treatment faces numerous challenges. Despite the effectiveness of modern treatment methods such as surgery, radiotherapy, chemotherapy, and targeted therapy, issues like recurrence, metastasis, and drug resistance still significantly affect patient prognosis and survival rates. This is particularly true for triple-negative breast cancer (TNBC) and HER2-positive BC, for which treatment outcomes are relatively poor. Withaferin A (WA), a natural plant-derived compound, has shown significant anti-cancer effects in the treatment of BC. WA inhibits the progression of BC through multiple mechanisms, including suppressing cell migration and invasion, inducing tumor cell apoptosis, regulating autophagy and metabolic pathways, and modulating miRNA expression. In combination therapy, WA exhibits a good synergistic effect when used with other anti-cancer drugs such as phenethyl isothiocyanate (PEITC), cisplatin, and sulforaphane, significantly enhancing therapeutic efficacy and reducing drug resistance. This review summarizes the research progress on the mechanisms of WA in combating BC, aiming to provide a foundation for the scientific development and clinical application of WA in BC treatment.

Telmisartan, a well-established antihypertensive drug, has shown promising therapeutic potential for a variety of central nervous system (CNS) disorders. This review outlines the fundamental characteristics of telmisartan, focusing on its dual pharmacological effects as an angiotensin II type 1 receptor (AT1R) antagonist and a peroxisome proliferator-activated receptor (PPAR) γ activator. These mechanisms underpin its neuroprotective and anti-inflammatory effects, which are essential to its therapeutic benefits in CNS diseases. Telmisartan modulates key cellular components of the CNS, including microglia, astrocytes, oligodendrocytes, vascular endothelial cells, and neurons, thereby offering protection against neuroinflammation, oxidative stress, and neuronal damage. We summarize telmisartan's efficacy in addressing a range of neurological conditions, such as stroke, traumatic brain injury, dementia, Parkinson's disease, demyelinating diseases, psychiatric disorders, and gliomas. By targeting multiple pathways involved in these disorders, telmisartan demonstrates potential as both an adjunctive and standalone therapy. Its ability to attenuate neuroinflammation and promote cellular repair highlights its versatility in CNS disease management. This review underscores the potential of telmisartan as a valuable therapeutic option for CNS disorders, warranting continued exploration to optimize its clinical application.

Background: Recently, the antinociceptive effect of LMH-2, a σ1 receptor antagonist, has been reported in diabetic mice with neuropathic pain. However, the mechanism by which this effect is produced is not completely clear. In this study, we explored the involvement of TRPV1 and the MOR-NMDAR complex in the antiallodynic effect of LMH-2 in hyperglycemic mice with neuropathic pain.

Methods: Hyperglycemia was induced in mice by administering streptozotocin-nicotinamide. Four weeks later, once neuropathic pain was established, the antiallodynic effect of LMH-2 (56.2 mg/kg) was evaluated using the up-down method with the von Frey filaments, both in the absence and the presence of capsazepine (8 mg/kg, ip), naloxone (NLX, 1 mg/kg, ip), NMDA (0.4 nM/10 µL, it), or their co-administration (NLX-NMDA). Gabapentin was used as positive control.

Results: Pretreatment with NLX did not alter the antiallodynic effect of LMH-2 in the up-down method with the von Frey filaments in hyperglycemic mice, whereas NMDA significantly reduced it. The addition of NLX to NMDA (NLX-NMDA) did not modify the effect of NMDA alone on the antiallodynic activity of LMH-2. Additionally, capsazepine completely blocked the antinociceptive effect of LMH-2 in hyperglycemic mice. Molecular docking analysis suggested a potential interaction between LMH-2 and TRPV1. Moreover, a higher dose of LMH-2 did not cause mortality or damage in healthy mice.

Conclusion: These results suggest the potential utility of LMH-2 in the treatment of diabetic neuropathy and highlight a key role for TRPV1 in LMH-2's antiallodynic mechanism, along with a possible, albeit limited, interaction with the MOR/NMDA complex.

Background: Bloodstream infection (BSI), defined as bacteraemia accompanied by sepsis or septic shock, is a frequent cause of hospitalization in departments of internal medicine (DIM). This study aimed to characterize the epidemiology, microbiological profile, and antibiotic treatment patterns of BSIs in a DIM setting in 2021-2023 in Polish hospital.

Methods: A three-year, single-centre retrospective analysis was conducted at a DIM in Southern Poland. Medical records from 2021 to 2023 were reviewed for patients diagnosed with sepsis (ICD-10 codes A40-A41) with microbiological confirmation. Antibiotic use was assessed using Days of Therapy (DOT) and Length of Therapy (LOT). Empiric and targeted therapies were classified according to the WHO AWaRe (Access, Watch, Reserve) framework.

Results: A total of 124 BSI cases were identified, with an incidence rate of 5.8%. Community-acquired BSIs accounted for 84.3% of cases, while 15.7% were hospital-acquired. The predominant pathogens were Escherichia coli and Staphylococcus aureus. The median LOT for empiric therapy was 3 days (IQR 2-4), with third-generation cephalosporins being the most frequently used agents (78 patients; 43.3%, 228 DOTs; 43.9%). Targeted therapy had a median LOT of 8 days (IQR 5-10), most commonly involving penicillins (33 patients; 28.4%, 291 DOTs; 34.5%). Access group antibiotics were significantly more prevalent in targeted therapy compared to empiric therapy (p < 0.001).

Conclusions: Microbiological confirmation of BSI facilitates a safe de-escalation from broad-spectrum empiric antibiotics to narrow-spectrum targeted therapy, supporting antimicrobial stewardship in internal medicine settings.

Background: Statin usage has increased significantly in India due to the very high incidence of dyslipidemia, however, approximately 18% of the population is at risk for statin-induced myopathy. Hence, we conducted a population-level screening for pharmacogenetic determinants of statin therapy, particularly Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) and ATP-binding cassette sub-family G member 2 (ABCG2).

Materials and methods: Whole exome sequencing was performed in 2180 subjects, and the variant data were segregated further into diplotypes and phenotypes.

Results: SLCO1B1 normal function was observed in 81% of subjects (diplotypes: 1/*1, *1/*14, *1/*20, *1/*37, and *37/*37). Increased SLCO1B1 function was observed in 8% of the population (diplotypes: *14/*14 and *20/*20). Decreased function of SLCO1B1 (*1/*15) was observed in 5% of the population. Poor function of SLCO1B1 was observed in 6% of the population (diplotypes: *5/*5 and *15/*15). About 81.46% of subjects displayed normal ABCG2 function, while 17.34% had decreased and 1.19% had poor function. Combined SLCO1B1/ABCG2 functional defects were observed in 7.4% of subjects. Two rare SLCO1B1 variants in SLCO1B1 i.e., rs201722521 and rs71581988, were reported to affect the binding affinity of certain statins. The SLCO1B1 C-C-C-A-A-A haplotype was associated with a 2.22-fold risk for hyperbilirubinemia (95% CI: 1.13-4.36, p = 0.02). Rosuvastatin's daily dose of up to 10 mg is well tolerated across the different SLCO1B1 functionality groups.

Conclusions: This study demonstrates that 11% of our population exhibit decreased or poor function of SLCO1B1 and 7.4% exhibit decreased or poor function of both SLCO1B1 and ABCG2, necessitating adjustments in daily statin doses to minimize the risk for statin-induced myopathy.

The temporal stability of ligand-receptor complexes is increasingly acknowledged as a critical factor in drug discovery, influencing both efficacy and pharmacodynamics. Although the relationship between the duration of compound action and complex stability can be traced back to Paul Ehrlich's 19th-century doctrine Corpora non agunt nisi fixata, its significance has gained renewed attention in recent years. This review comprehensively examines the concept of residence time (RT). We first summarize key ligand binding models (lock-and-key, induced-fit, and conformational selection) and delve into various perspectives on how RT impacts functional outcomes. Furthermore, we discuss experimental methods for measuring RT, highlighting both radioligand and non-radioligand approaches. The growing interest in RT has spurred advancements in computational techniques, particularly molecular dynamics simulations, which utilize diverse strategies to observe dissociation events. We outline these molecular dynamics-based methods, their theoretical foundations, and provide examples of their application in assessing RT. Finally, we highlight molecular determinants of prolonged RT, focusing primarily on G protein-coupled receptors (GPCRs) while also incorporating relevant data from other receptor classes.

Background: Recent preclinical studies have shown sex-dependent antidepressant-like responses of cannabidiol in adolescence, which were dependent on biological sex, early-life stress, and dose. In particular, cannabidiol (10 mg/kg) induced acute and sustained antidepressant-like responses in adolescent male rats, while it lacked efficacy in females. This follow-up study aimed at further characterizing cannabidiol's effects in adolescence, in an attempt to overcome female unresponsiveness, while also evaluating its long-term safety profile in adulthood.

Methods: Groups of adolescent rats of both sexes were treated (ip) with cannabidiol (10, 30, 60 mg/kg) or vehicle (1 ml/kg) for 7 days. Acute (30 min post-injection) and repeated (24 h post-treatment) antidepressant-like responses were measured in the forced-swim test. Brains were collected to evaluate several neurochemical correlates in the hippocampus (CBR1, CBR2, BDNF, and cell proliferation) after adolescent cannabidiol exposure (acute and repeated). Some rats were left undisturbed until adulthood, when long-term effects on cognition were measured in the Barnes maze (short- and long-term memory) or affective-like responses in the forced-swim test. Data was analyzed with two-way ANOVAs (independent variables: sex and treatment).

Results: While the dose of 10 mg/kg of cannabidiol induced antidepressant-like effects in adolescent rats, higher doses had no effect in adolescent rats of both sexes. No changes were observed in any of the hippocampal neuroplasticity markers evaluated. Adolescent cannabidiol exposure did not induce long-term changes in cognitive performance or affective-like behavior.

Conclusions: Overall, our data suggest that adolescent cannabidiol treatment produces dose-dependent antidepressant-like effects of moderate magnitude without compromising long-term cognition in rats.