批准用于奶牛的抗菌药物分析

我国奶牛养殖规模不断扩大,奶业产值比重逐步提高,给奶牛疫病防治带来巨大压力。奶牛乳房炎及细菌性肺炎等呼吸系统疾病和细菌性肠炎等消化系统疾病最为常见,抗菌药物的使用成为主要防治手段。但抗菌药物的不当使用易使细菌产生耐药性,增加临床治疗的成本和难度,危害我国奶牛产业发展。本文对截至2021年7月我国和美国、英国、日本、欧盟批准用于奶牛的抗菌药物产品进行整理、统计与分析,包括抗菌药物的分类、剂型以及适应证等,旨在为我国奶牛用抗菌药物管理、合理用药和新兽药开发提供参考。     

Hepatitis B virus infection reactivation in patients under immunosuppressive therapies: Pathogenesis,screening, prevention and treatment

With a 5.3% of the global population involved, hepatitis B virus (HBV) is a major public health challenge requiring an urgent response. After a possible acute phase, the natural history of HBV infection can progress in chronicity. Patients with overt or occult HBV infection can undergo HBV reactivation (HBVr) in course of immunosuppressive treatments that, apart from oncological and hem-atological diseases, are also used in rheumatologic, gastrointestinal, neurological and dermatological settings, as well as to treat severe acute respiratory syndrome coronavirus 2 infection. The risk of HBV reactivation is related to the immune status of the patient and the baseline HBV infection condition. The aim of the present paper is to investigate the risk of HBVr in those not oncological settings in order to suggest strategies for preventing and treating this occurrence. The main studies about HBVr for patients with occult hepatitis B infection and chronic HBV infection affected by non-oncologic diseases eligible for immunosuppressive treatment have been analyzed. The occurrence of this challenging event can be reduced screening the population eligible for immunosuppressant to assess the best strategies according to any virological status. Further prospective studies are needed to increase data on the risk of HBVr related to newer immunomodulant agents employed in non-oncological setting.     

Matrine,oxymatrine, and compound Kushen injection from the roots of Sophora flavescens: an overview of their anticancer activities

In the present review, we updated current information on the chemistry, contents, and anticancer properties of matrine (MT), oxymatrine (OMT), and compound Kushen injection (CKI). The anticancer properties were focused on lung, breast, and liver cancer cells because they are most susceptible. Sources of information were from Google, Google Scholar, PubMed, PubMed Central, Science Direct, PubChem, J-Stage, Directory of Open Access Journals (DOAJ), and China National Knowledge Infrastructure (CNKI). Reference was also made on botanical websites, such as Flora of China and World Flora Online. MT and OMT are dominant quinolizidine alkaloids from the roots of Sophora flavescens (Kushen) of the family Fabaceae. Against lung, breast, and liver cancer cells, MT and OMT inhibit cell proliferation; induce cell cycle arrest, apoptosis, and autophagy; restrict angiogenesis; and inhibit cell metastasis, invasion, and migration. The processes involve various molecular targets and signaling pathways. CKI is a traditional Chinese medicine (TCM) composed of root extracts of S. flavescens and Smilax glabra (Baituling) of the family Smilacaceae. With MT and OMT as major components, CKI has been approved for the treatment of cancer in China more than 20 years ago. In recent years, systematic reviews and meta-analysis have been undertaken to evaluate the anticancer effects of CKI. When CKI is used alone and in combination with chemotherapy of western medicine, there is much to be learned concerning their interactions besides their individual and integrated efficacy. Some perspectives of MT, OMT, and CKI are discussed, and their suggestions for future research are provided.     

Medicinal nicotine in COVID-19 acute respiratory distress syndrome,the new corticosteroid

The cholinergic anti-inflammatory pathway (CAP) refers to the anti-inflammatory effects mediated by the parasympathetic nervous system. Existence of this pathway was first demonstrated when acetylcholinesterase inhibitors showed benefits in animal models of sepsis. CAP functions via the vagus nerve. The systemic anti-inflammatory effects of CAP converges on the α7 nicotinic acetylcholine receptor on splenic macrophages, leading to suppression of pro-inflammatory cytokines and simultaneous stimulation of anti-inflammatory cytokines, including interleukin 10. CAP offers a novel mechanism to mitigate inflammation. Electrical vagal nerve stimulation has shown benefits in patients suffering from rheumatoid arthritis. Direct agonists like nicotine and GTS-1 have also demonstrated anti-inflammatory properties in models of sepsis and acute respiratory distress syndrome, as have acetylcholinesterase inhibitors like Galantamine and Physostigmine. Experience with coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome indicates that immunomodulators have a protective role in patient outcomes. Dexamethasone is the only medication currently in use that has shown to improve clinical outcomes. This is likely due to the suppression of what is referred to as a cytokine storm, which is implicated in the lethality of viral pneumonia. Nicotine transdermal patch activates CAP and harvests its anti-inflammatory potential by means of an easily administered depot delivery mechanism. It could prove to be a promising, safe and inexpensive additional tool in the currently limited armamentarium at our disposal for management of COVID-19 induced acute hypoxic respiratory failure.     

Phase 0 Study of Vandetanib-Eluting Radiopaque Embolics as a Preoperative Embolization Treatment in Patients with Resectable Liver Malignancies

PurposeTo assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies.Materials and MethodsThe VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7–21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging.ResultsEight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441–404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%–100%). There were no significant changes in perfusion imaging parameters after TACE.ConclusionsBTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.     

Dose optimization with population pharmacokinetics of ritonavir-boosted lopinavir for Thai people living with HIV with and without active tuberculosis

BackgroundPrior to dolutegravir availability, ritonavir-boosted lopinavir (LPV/r) was an alternative recommendation when first-line drugs could not be used. A high concentration of protease inhibitors was observed in the Thai people living with HIV (PLWH). Thus, dose reduction of LPV/r may be possible. However, the pharmacokinetics and dose optimization of LPV/r have never been investigated. This study aimed to develop a population pharmacokinetic model of LPV/r and provide dosage optimization in Thai PLWH.MethodsLPV and RTV trough concentrations from Thai PLWH were combined with intensive data. The data were analyzed by the nonlinear mixed-effects modeling approach. The influence of RTV concentration on LPV oral clearance (CL/F) was investigated.ResultsRifampicin (RIF) use increased LPV and RTV CL/F by 2.16-fold and 1.99-fold, respectively. The reduced dose of 300/75 and 200/150 mg twice daily provided a comparable percentage of patients achieving LPV target trough concentration to the standard dose for PI-naïve patients. For HIV/TB co-infected patients receiving RIF who could not tolerate the recommended dose, the reduced dose of 600/150 mg twice daily was recommended.ConclusionThe population pharmacokinetic model was developed by integrating the interaction between LPV and RTV. The reduced LPV/r dosage offers sufficient LPV exposure for Thai PLWH.     

Orphan drug development: The impact of regulatory and reimbursement frameworks

The enactment of orphan drug-specific legislation pioneered by the USA was subsequently followed by many regions, including the European Union (EU), Australia, Japan, and Taiwan. Here, we discuss the associated regulations established and their impacts in the aforementioned regions, which are among the first with frameworks specific for orphan drugs. Varied scopes of rare diseases or orphan drugs, diverse incentives, and heterogeneous types of reimbursement systems imply the prioritization of the agencies concerned. The numbers of designated and approved drugs reflect the impact of the regulatory and reimbursement frameworks. A comparison of the frameworks and their impact in the respective regions could provide valuable information for developing and improving related frameworks for countries worldwide.     

Metabolism of non-steroidal anti-inflammatory drugs (NSAIDs) by Streptomyces griseolus CYP105A1 and its variants

In the field of drug development, technology for producing human metabolites at a low cost is required. In this study, we explored the possibility of using prokaryotic water-soluble cytochrome P450 (CYP) to produce human metabolites. Streptomyces griseolus CYP105A1 metabolizes various non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, meclofenamic acid, and ibuprofen. CYP105A1 showed 4′-hydroxylation activity towards diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, and meclofenamic acid. It should be noted that this reaction specificity was similar to that of human CYP2C9. In the case of mefenamic acid, another metabolite, 3′-hydroxymethyl mefenamic acid, was detected as a major metabolite. Substitution of Arg at position 73 with Ala in CYP105A1 dramatically reduced the hydroxylation activity toward diclofenac, flufenamic acid, and ibuprofen, indicating that Arg73 is essential for the hydroxylation of these substrates. In contrast, substitution of Arg84 with Ala remarkably increased the hydroxylation activity towards diclofenac, mefenamic acid, and flufenamic acid. Recombinant Rhodococcus erythrocyte cells expressing the CYP105A1 variant R84A/M239A showed complete conversion of diclofenac into 4′-hydroxydiclofenac. These results suggest the usefulness of recombinant R. erythropolis cells expressing actinomycete CYP, such as CYP105A1, for the production of human drug metabolites.