Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: A workshop summary

As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity.     

Locust bean gum safety in neonates and young infants: An integrated review of the toxicological database and clinical evidence

Locust bean gum (LBG) is a galactomannan polysaccharide used as thickener in infant formulas with the therapeutic aim to treat uncomplicated gastroesophageal reflux (GER). Since its use in young infants below 12 weeks of age is not explicitly covered by the current scientific concept of the derivation of health based guidance values, the present integrated safety review aimed to compile all the relevant preclinical toxicological studies and to combine them with substantial evidence gathered from the clinical paediatric use as part of the weight of evidence supporting the safety in young infants below 12 weeks of age. LBG was demonstrated to have very low toxicity in preclinical studies mainly resulting from its indigestible nature leading to negligible systemic bioavailability and only possibly influencing tolerance. A standard therapeutic level of 0.5 g/100 mL in thickened infant formula is shown to confer a sufficiently protective Margin of Safety. LBG was not associated with any adverse toxic or nutritional effects in healthy term infants, while there are limited case-reports of possible adverse effects in preterms receiving the thickener inappropriately. Altogether, it can be concluded that LBG is safe for its intended therapeutic use in term-born infants to treat uncomplicated regurgitation from birth onwards.     

FDA对防滥用阿片类药物研究的要求

阿片类处方药滥用在全球已成为严重的公共卫生问题,防滥用阿片类制剂可不同程度地阻止其滥用。FDA为鼓励、支持和加速研发可遏制滥用的阿片类产品,于2013年公布了“防滥用的阿片类药物——评价和说明书”指导原则（草案）。介绍该指导原则的主要内容,包括上市前的实验室破坏和提取研究、药动学研究、临床滥用可能性研究和上市后研究,希望对我国这方面的研究和审评有帮助。     

The epidemiology of non-alcoholic steatohepatitis (NASH) in the United States between 2010-2020: a population-based study

Introduction and objectivesNon-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that can progress to liver cirrhosis, liver failure and hepatocellular carcinoma. It is the second leading cause of liver transplant in the US. We aim to investigate the prevalence, demographics and risk factors NASH patients in the US.Patients and methodsWe used a large database (Explorys IBM) that aggregates electronic health records from 26 nationwide healthcare systems. We identified adults with NASH between 2010-2020. Demographics including age, gender and race were collected. NASH risk factors including Diabetes Millets (DM), Hyperlipidemia (HLD), Hypertension (HTN) and Obesity were also collected. Cochran-Armitage test was used to assess the statistical significance of year-by-year trend. Univariable and multivariable logistic regression were used to estimate the odds ratio (OR) of risk factors.ResultsNASH annual prevalence rate increased from 1.51% in 2010 to 2.79% in 2020 (p < 0.0001). The proportion of patients with NASH by gender was 54.1% female vs 45.9% male (OR 1.04 [0.91-1.11]). Caucasian had higher odds of NASH than non-Caucasian (OR 1.42 [1.31-1.54]). NASH is strongly associated with DM and obesity (OR 18.61 [17.35-19.94]) and (OR 20.97 [17.87-23.21]), respectively. Other components of metabolic syndrome were associated with NASH to a lesser degree; HTN (OR 3.24 [3.20-3.28]) and HLD (OR 4.93 [4.85-4.01]).ConclusionThe prevalence of NASH has significantly increased in the US in the last decade. This is likely related to the increased prevalence of risk factors as well as increased awareness of the disease.     

Pharmacotherapy Approaches in Nontuberculous Mycobacteria Infections

Nontuberculous mycobacteria (NTM) comprise a heterogeneous group of organisms, with only a small subset known to cause disease in humans. Although NTM infection is not a reportable disease, both the increasing clinical recognition and recent advancements in laboratory diagnostic capabilities of NTM infections in immunocompromised and immunocompetent patients are rapidly evolving. We reviewed antimicrobial agents used to treat the most frequently encountered NTM infections and examined optimized drug dosing strategies, toxicity profiles, drug-drug interactions, and the role of therapeutic drug monitoring. Antimicrobial susceptibility testing and patient monitoring on therapy were also examined. We used PubMed to review the published literature on the management of select NTM pathogens, the common syndromes encountered since 2000, and select pharmacokinetic principles of select antimicrobial agents used since 1990. We included select clinical trials, systematic reviews, published guidelines, and observational studies when applicable. The prolonged duration and the necessity for combination therapy for most forms of NTM disease can be problematic for many patients. A multidisciplinary care team that includes pharmacy engagement may help increase rates of optimal patient tolerability and successful treatment completion.     

美国化学仿制药立项调研及评估

目的 为拟在美国注册申报化学仿制药的中国企业提供立项指导和帮助,从目标产品的初步获得、产品具体信息的调研分析评估,到最终策略的制定,进行系统的介绍。方法 主要采用例证法。结果 获得美国仿制药立项信息收集及评估的途径和方法,形成并明确开发注册策略制定的思路和要素。结论 美国的药品信息比较透明公开,从公共途径基本可以获得产品开发所需要的相关信息。立项评估并不能做到百分百正确无误,企业可以设立自己的立项标准,只要在企业可接受范围内即可进行。     

The Impact of Endogenous Breast Cancer Resistance Protein on Human P-Glycoprotein-Mediated Transport Assays Using LLC-PK1 Cells Transfected With Human P-Glycoprotein

Lilly Laboratories cell porcine kidney 1 (LLC-PK1) cells transfected with human P-glycoprotein (LLC-PK1-P-gp) are widely used in transport assays to identify drug candidates that function as substrates of this efflux transporter. Endogenous transporters expressed in LLC-PK1 cells may complicate the interpretation of findings from P-gp-mediated transport assays. We investigated the impact of porcine breast cancer resistance protein (Bcrp) in P-gp-mediated transport assays in LLC-PK1 cells. Porcine Bcrp mRNA was detected in both LLC-PK1 wildtype (WT) and LLC-PK1-P-gp cells by quantitative RT-PCR. To investigate the activity and impact of porcine Bcrp, we conducted transport assays using 6 typical BCRP substrates in LLC-PK1 cells. Efflux ratios (ER) of the 6 BCRP substrates in LLC-PK1 WT cells were >2, and were reduced in the presence of the BCRP inhibitor Ko143. The efflux activities of the 6 BCRP substrates were confirmed using MDCKII cells transfected with human BCRP. Net ERs of prazosin and fluvastatin, dual substrates of P-gp and BCRP, determined by dividing ERs in LLC-PK1-P-gp cells by those in LLC-PK1 WT cells, were <2, but increased to >2 in the presence of Ko143. These results indicated that endogenous Bcrp in LLC-PK1 cells was involved in the transport of BCRP substrates and may interfere with the identification of P-gp substrates.