Clinical Pharmacology : Advances and Applications最新文献

Background: Voclosporin, a more potent derivative of cyclosporine, has been studied extensively in patients with immunologic disorders such as psoriasis, organ transplantation, uvetitis and lupus nephritis. Although better tolerated and safer than cyclosporine, voclosporin is inferior to cyclosporine in treating psoriasis, non-inferior to tacrolimus in organ transplantation and efficacious in treating lupus nephritis.

Methods: The pharmacokinetic dispositions of voclosporin and cyclosporine in central and peripheral compartments were analyzed and correlated with their distinct clinical efficacy and safety profiles.

Results: Both drugs demonstrated non-linear pharmacokinetics with increasing doses, more prominently at lower doses of voclosporin than at 10-fold higher doses of cyclosporine. Repeated lower dosing of voclosporin produced preferential calcineurin inhibition in and near blood circulation, leading to relatively lower cardiovascular and renal adverse effects but inferior efficacy for psoriasis compared to cyclosporine. With 10-fold higher plasma levels and deeper tissue penetration, cyclosporine has more prevalent renal and cardiac toxicities but superior efficacy to treat psoriasis.

Conclusion: Although the two drugs are similar in structure and mechanism of action, the high potency and low dose compounded by the non-linear disposition of voclosporin resulted in more systemic versus local calcineurin inhibition than with cyclosporine. The dispositional difference between voclosporin and cyclosporine accounted for the puzzling efficacy and safety observations in different patients and was the basis for their optimal and differential use in treating diverse immunologic disorders.

Introduction: Recent investigations showed that anticholinergic drugs could use for the management of storage symptoms after transurethral resection of the prostate (TURP). The use of intravesical botulinum toxin-A (BTX-A) for the management of overactive bladder is rapidly increasing. In this research, we assess the efficacy of BTX-A vs solifenacin in men suffering from bladder outlet obstruction-over active bladder (BOO-OAB) managed with TURP.

Methods: In this case-control study, 50 men with BOO-OAB randomized into two groups. The control group (A) underwent TURP and subsequently managed by solifenacin 5 mg daily, and the case group (B) underwent TURP and BTX-A injection in the bladder wall in the same session. Treatment success was the primary outcome and defined as post-injection improvement in the storage score of the International Prostate Symptom Score (IPSS) from baseline.

Results: The IPSS, post-void residual volume, frequency, incomplete emptying, nocturia and urgency subscores considerably ameliorated after 12 weeks and 36 weeks for both groups, but it was more significant in the case arm. The quality of life (QoL) scores significantly improved after the treatments in both groups. Intervention group showed significant reductions regarding urgency incontinence compared with the solifenacin group at 12th and 36th weeks.

Conclusion: BTX-A is an effective and well-tolerated treatment in patients with benign prostatic hyperplasia (BPH) who are candidates of TURP and simultaneously suffer from OAB symptoms.

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.