Clinical Pharmacology : Advances and Applications最新文献

Introduction: Peptic ulcer disease represents a worldwide health problem because of its high morbidity, mortality and economic loss. It is a very prevalent condition affecting around 10%-15% of the general population worldwide. Most of the available antiulcer drugs are costly and have an incidence of relapse, drug interactions and several side effects upon chronic usage. Hence, the use of herbal medicine may be safe, economical and effective in such cases when drugs are used for long periods. Ethnobotanical reports showed traditional claims on the use of Cordia africana seeds for the treatment of gastric ulcers. However, the safety and efficacy of these remedies are not well known. The aim of this study is, therefore, to evaluate the antiulcer activity and safety of a crude extract of C. africana seeds in animal models.

Methods: Shade-dried seeds of C. africana were extracted by 80% methanol and dried by the rotator evaporator and lyophilized. The crude extract was used to evaluate antiulcer activity in vivo with pylorus ligation method, on Wistar albino rats weighing 230-250g. Preliminary phytochemical screening was performed using a standard procedure. Acute toxicity study was carried out in Swiss albino mice before antiulcer activity tests.

Results: No sign of toxicity was observed upon the administration of 2000 mg/kg of the crude extract to mice. Single-dose administration of 400 and 600 mg/kg extract showed a significant reduction in the volume of secretion and acidity of the stomach (p <0.01). The doses 400 and 600 mg/kg have reduced the ulcer score by 83.58% and 88%.

Conclusion: The result of this study showed that the hydromethanolic crude extract of C. africana has strong antisecretory and ulcer protective activities against ulcers produced by pylorus ligation.

Aim: Opium addiction is a serious public health concern in the Middle East countries causing various illnesses. Opium use is associated with an increased risk of several cancers; however, the underlying mechanisms are not yet fully elucidated. Altered levels of adiponectin and its related main receptors, Adiponectin receptor 1 and 2 (AdipoR1 and AdipoR2) have been associated with several malignancies. Opium users are at risk of various cancers. All together let us to the hypothesis that probable overexpression of AdipoRs in opium users might be linked to the occurrence of cancer in this population.

Methods: One hundred opium users along with 100 healthy non-opium users were enrolled in the study. Opium users were followed up for 5 years (2014-2019) to evaluate the occurrence of malignancies. AdipoR1 and AdipoR2 expressions were measured using a flow cytometry method.

Results: Expression of AdipoR1 and AdipoR2 was significantly higher in opium users compared with the healthy control group (P=0.0001 and 0.0001, respectively). Eight opium users developed cancer during the follow-up period. Subjects abusing opium developed cancer by 8.6 folds comparing to non-opium users (P=0.034; OR=8.6; 95% CI (1.06-70.1)). Expression of these two receptors was significantly higher in opium users developing cancer compared with cancer-free opium (P=0.001).

Conclusion: Considering the significant overexpression of AdipoR1 and AdipoR2 in opium users and in opium users who developed malignancies and the association between upregulation of these receptors in most cancers affecting opium users and assessment of AdipoRs may serve as an early detection tool of cancer in this population.

Objective: The IL-33/ST2 pathway plays a fundamental role in the cardiovascular system and can be considered as a new therapeutic strategy for the treatment or prevention of cardiovascular diseases. ST2, as an interleukin (IL)-1 receptor family member, has transmembrane (ST2L) and soluble (sST2) isoforms. sST2 neutralizes IL-33 and thereby inhibits the cardioprotective role of IL-33/ST2L signaling pathway. Increase in sST2 level is associated with weak cardiac output and can be a predictor of mortality in heart failure (HF). Thereby, we hypothesized that there may be a relationship between the cardioprotective effects of carvedilol and sST2 and IL-3 in HF patients.

Methods: sST2 and IL-33 were measured in serum of 66 individuals; 22 healthy volunteers and 44 suffering from HF; among whom 25 patients received carvedilol and the other 19 patients did not receive any β-blockers.

Results: Lack of association between serum levels of IL-33 and sST2 was observed between HF patients and healthy individuals (2.4466 ± 0.69 vs 2.6748 ± 0.33 and 3416.6 ± 1089.1 vs 2971.6 ± 792.5, respectively). Our results indicated no significant difference between sST2 and IL-33 levels in HF patients who did not receive beta-blockers and patients receiving carvedilol (P=0.59 and P=0.97).

Conclusion: Our results showed a lack of association between serum levels of IL-33 and sST2 and HF. Moreover, the results do not confirm the cardioprotective mechanism of carvedilol by means of IL-33/sST2 pathway.

Dolutegravir 50 mg (DTG) and rilpivirine 25 mg (RPV) are a newly approved 2-drug regimen for the treatment of HIV in virally suppressed patients. A 2-part study evaluated the relative bioavailability and food effect of five experimental fixed-dose combination (FDC) tablet formulations of DTG/RPV. When given with a moderate- or high-fat meal, the absorption of both DTG and RPV was increased, resulting in higher exposures. As per product labelling, DTG/RPV FDC should be taken with a meal.

Background: High on-treatment ADP platelet reactivity (HPR) measured by VerifyNow P2Y12 assay (VN) is an established risk factor for ischemic events after percutaneous coronary intervention (PCI). We hypothesized that routine use of VN at time of PCI in clinical practice may affect choice of P2Y12 antiplatelet therapy at discharge.

Methods: In a single center retrospective analysis, we examined the influence of VN testing on choice of P2Y12 inhibitor post PCI in routine clinical practice. Assessment of HPR was used routinely in clinical care during the time period of analysis at discretion of clinical providers. Subjects with PRU>208 after the loading dose of clopidogrel or during clopidogrel steady state were switched to alternate P2Y12 inhibitors.

Results: We identified 1001 patients with PCI during the time period specified. A total of 252 subjects underwent VN testing. Among those, 43% were found to have HPR on clopidogrel and were switched to alternate therapies (prasugrel [n=60], ticagrelor [n=48]). Patients who had VN platelet function testing were more likely to be discharged on clopidogrel as compared to those who did not have VN assay done (57% vs. 50%, p=0.039). There was no significant difference in 1-year net-MACE (CVD, MI, stent thrombosis, BARC 2 or higher bleeding) using tailored antiplatelet therapy (VN testing) as compared to standard of care group (adjusted HR:0.92, 95% CI: 0.54-1.5, p=0.74).

Conclusion: Routine use of VN assay in personalized antiplatelet treatment decision-making after PCI is associated with lower likelihood of using novel P2Y12 inhibitors.

Purpose: Trifluridine/tipiracil (FTD/TPI) is approved in Japan, the United States (US), and Europe for metastatic colorectal cancer (mCRC) refractory to standard therapies. This Phase 1b open-label study focused on the pharmacokinetic (PK) and toxicity profiles of FTD/TPI in Chinese patients with solid tumors.

Methods: Patients with definitive histologically or cytologically confirmed advanced/metastatic solid tumors refractory to standard treatments were enrolled. FTD/TPI (35 mg/m²) was administered orally twice daily for five consecutive days, followed by a 2-day recovery. Treatment was repeated for five consecutive days, followed by a 16-day recovery. The primary objective was to assess PK characteristics of FTD, 5-trifluoromethyl-2,4 (1H,3H)-pyrimidinedione (FTY; an inactive form of FTD), and TPI, calculated from plasma concentrations. Additionally, these PK values were compared with those from similar Phase 1 studies in patients from Japan and the US, using Tukey-Kramer's honestly significant difference (HSD) multiple comparison tests. Safety and preliminary efficacy of FTD/TPI were assessed.

Results: Fifteen patients (12 males, three females) were enrolled, most with CRC (87%). Geometric mean analysis showed that maximum plasma concentration (C_max) of FTD increased after multiple administration (from day 1 [3019.5 ng/mL] to day 12 [3693.1 ng/mL]), and the exposure (AUC_0-t) increased 2.4-fold (day 1:7796.6 ng/mL•h; day 12:18,181.3 ng/mL•h). There was no meaningful change in the exposure to FTY and TPI throughout the study. HSD tests showed comparable PK for FTD, FTY, and TPI between Chinese and Japanese patients, and comparable exposure to FTD between Chinese and US patients. Eight patients (53.3%) experienced Grade 3 treatment-emergent adverse events, most frequently anemia and fatigue (13.3%, two events each). Median progression-free survival was 1.9 months.

Conclusion: FTD/TPI had an acceptable safety and efficacy profile and PK characteristics were comparable between Chinese, Japanese, and US patients, suggesting that this treatment may be suitable for Chinese patients with refractory mCRC.

Trial registration: This trial was registered at clinicaltrials.gov as NCT02261532.

Objective: Flurbiprofen 8.75 mg spray and lozenge have a rapid onset of action for sore throat relief, suggesting local action, although tissue penetration and the mechanism of local relief have not been determined. This investigation aimed to quantify the permeation and penetration of flurbiprofen, applied as local pharmaceutical forms, into full-thickness cadaveric human mucosal pharynx tissue, representing the clinical scenario as far as possible.

Methods: A validated high-performance liquid chromatography method quantified the permeation and penetration of flurbiprofen (spray and lozenge formulations) into human cadaveric pharynx tissue using a micro Franz cell model mimicking physiological and anatomical conditions. Full-thickness mucosal pharynx tissue, consisting of oral epithelium, basement membrane, and lamina propria, was utilized to imitate the in vivo setting. Flurbiprofen was analyzed on the surface of the pharynx tissue, within the pharynx tissue and in receiver fluid, over 60 mins.

Results: Flurbiprofen was detected in receiver fluid from 10 mins following spray application and was quantifiable from 20 mins. Flurbiprofen from lozenge was detected from 10 mins and was above the limit of quantitation in receiver fluid from 40 mins. Flurbiprofen recovered from the surface of the pharynx tissue was 24.45% and 8.48% of applied dose for spray and lozenge, respectively. Flurbiprofen recovered within pharynx tissue was 46.50% and 54.65% of applied dose for spray and lozenge, respectively. For flurbiprofen lozenge, recovery within pharynx tissue was 6-fold higher relative to recovery from the pharynx tissue surface.

Conclusion: Flurbiprofen from spray and lozenge formulations penetrated human cadaveric pharynx tissue, indicating that flurbiprofen can reach all layers of the pharynx mucosal tissue, including the underlying lamina propria, which contains blood vessels and nerve fibers that contribute to pain during sore throat. This suggests that flurbiprofen may have a local mechanism of action for sore throat, although this has yet to be determined.