Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza

Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid.     

Attenuated Novel SARS Coronavirus 2 Infection in an Allogeneic Hematopoietic Stem Cell Transplant Patient on Ruxolitinib

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has a high death rate in patients with comorbidities or in an immunocompromised state. We report a mild and attenuated SARS CoV-2 infection in a patient who is 17 months post stem cell transplantation and maintained on the JAK/STAT inhibitor ruxolitinib, a proposed novel therapy for SARS CoV-2 pneumonia.     

生长抑素及其类似物联合质子泵抑制剂应用于急性非静脉曲张性上消化道出血的循证分析

目的 系统评价生长抑素及其类似物联合质子泵抑制剂（proton pump inhibitor，PPI）治疗急性非静脉曲张性上消化道出血（acute non-variceal upper gastrointestinal bleeding，ANVUGIB）的有效性和安全性，并分析其用药经济性。方法 采用循证医学方法搜集生长抑素及其类似物联合PPI治疗ANVUGIB的RCT、队列研究进行meta分析，得到相应的有效性及安全性分析结果，并进行成本-效果分析。结果 最终纳入6个RCT均未接受内镜治疗，共610例受试者。Meta分析结果显示，生长抑素及其类似物联合高、中、低剂量PPI治疗在以下方面均优于单用高、中、低剂量PPI治疗，差异有统计学意义，总有效率[OR=3.34，95%CI（2.03，5.47），P<0.000 01]、止血时间[MD=-9.04，95%CI（-11.69，-6.38），P<0.000 01]、输血量[MD=-1.10，95%CI（-1.46，-0.74），P<0.000 01]；在不良反应发生率方面，2组差异无统计学意义[OR=0.49，95%CI（0.11，2.12），P=0.34]。ANVUGIB患者予生长抑素联合高、中、低剂量奥美拉唑与单用高、中、低剂量奥美拉唑进行成本-效果分析，增量成本效果比分别为172.28，217.26，330.37，敏感性分析后显示结果稳定。而接受内镜治疗后应用生长抑素及其类似物联合PPI治疗仅1个队列研究，研究结果显示内镜治疗成功后联合治疗并不优于PPI单药治疗。结论 现有证据表明，生长抑素及其类似物联合PPI治疗未经内镜治疗的ANVUGIB患者为较有效的方案，两者安全性相当、耐受性较好，从药品直接成本考虑，高剂量PPI组联合治疗较中、低剂量PPI组联合治疗更具有成本效果性。而对于经内镜下止血治疗的患者两者疗效相当，可考虑单用PPI。     

Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

Uterine PEComa with aggressive behavior: A review with an additional case of spontaneous vaginal expulsion

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor originating from perivascular epitheloid cells showing melanocytic and smooth muscle differentiation. The uterus represents the second most common site of origin. A 49 years woman presented to our Hospital for a vaginal spontaneous expulsion of a mass suggestive for malignant mesenchymal tumor. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy and the histopathological report was compliant with a PEComa with aggressive behavior. Medical Literature databases about PEComa were searched. The current literature identified near 90 cases of uterine PEComas and they are categorized as uncertain malignant potential or with aggressive behavior. Primary surgical excision represents the gold-standard treatment. Recently targeted therapy with mTOR inhibitors has been introduced with an important beneficial. In this paper we review the Literature about the uPEComa with aggressive behavior reporting the first case of spontaneous vaginal expulsion.     

沙库巴曲缬沙坦在心力衰竭治疗中的应用

心力衰竭是一种慢性疾病，是心脏无法泵出足够的血液为其他身体器官提供氧气，从而引发呼吸短促、疲劳和水肿等症状。目前其治疗包括病因治疗、一般治疗、药物治疗及非药物治疗等，其中血管紧张素受体脑啡肽酶抑制剂（ARNI）是当前新研发出的一类抗心衰药物，沙库巴曲缬沙坦是其代表药物，具有阻断肾素-血管紧张-醛固酮系统（RAAS）及抑制脑啡肽酶（NEP）的双重作用，新的欧美指南均推荐用于射血分数降低心力衰竭（HFrEF）的治疗。本文现就沙库巴曲缬沙坦在心力衰竭治疗中的作用机理、临床试验、药物安全性作一综述，旨在为该病的临床治疗提供参考。