Real life juvenile toxicity case studies: the good, the bad and the ugly

With the growing experience in the conduct of juvenile toxicity studies for multiple classes of compound, the 'case-by-case' approach has become under much more pressure. Instead, a general screen or 'standard design' is now commonly expected by regulatory authorities with more routine inclusion of neurological and reproductive assessments. Minor modifications or additions can be made to the design to address specific questions according to the class of drug or intended clinical use. This drift from a 'case-by-case' approach to a 'standard design' approach is present within certain reviewing divisions of the FDA, often requesting by default a rodent and non-rodent juvenile animal study. However, juvenile animal studies should be designed thoughtfully to fulfil a purpose based on scientific rationale, with each endpoint carefully considered in terms of practicality and interpretability of data generated. Only when using the appropriate strategy and design may juvenile studies add value by (1) identifying potential safety or pharmacokinetic issues for drugs intended for paediatric use, (2) suggesting additional clinical endpoints and (3) adding new information to the product label. As the knowledge from juvenile animal studies in various species grows, a better understanding of the significance/relevance of findings will be achieved.     

Pharmaceutical tangents: the good, the bad and the ugly

In this article a "tangent" means a change from the plans or path one has agreed to follow in drug discovery, development, production or marketing. There are positive and negative tangents. It is important for companies to have a method for approving tangents in a systematic way. There are two major issues to consider about tangents: Who is proposing the tangent and what are his or her motives? and What are the "pros" and "cons" of adopting a tangent presented as a fait accompli? Tangents include changes in the major direction or orientation of a project such as pursuing a new indication, a new route of administration or a new patient population. It is important to recognize these and other proposals or recommendations as tangents when they are initially proposed. There are a series of specific issues and questions to address when evaluating tangents and a number of straightforward ways to minimize nonproductive tangents in pharmaceutical companies.     

Radiation hormesis: the good, the bad, and the ugly

Three aspects of hormesis with low doses of ionizing radiation are presented: the good, the bad, and the ugly. The good is acceptance by France, Japan, and China of the thousands of studies showing stimulation and/or benefit, with no harm, from low dose irradiation. This includes thousands of people who live in good health with high background radiation. The bad is the nonacceptance of radiation hormesis by the U. S. and most other governments; their linear no threshold (LNT) concept promulgates fear of all radiation and produces laws which have no basis in mammalian physiology. The LNT concept leads to poor health, unreasonable medicine and oppressed industries. The ugly is decades of deception by medical and radiation committees which refuse to consider valid evidence of radiation hormesis in cancer, other diseases, and health. Specific examples are provided for the good, the bad, and the ugly in radiation hormesis.     

Adverse Drug Reactions: A Retrospective Review of Hospitalized Patients at a State Psychiatric Hospital

Background: There is a paucity of information regarding adverse drug reactions (ADRs) in psychiatric patients. Information on common and preventable ADRs (pADRs) in psychiatric patients will allow for targeted improvement projects.Objective: To characterize reported ADRs and pharmacist interventions to prevent ADRs in an extended-care state psychiatric hospital.Methods: Four years of ADR reports were assessed for probability, reaction severity, pharmacological class of medication involved, preventability, change in therapy, and transfers to a medical facility. The pharmacist intervention database was queried for interventions classified as “prevention of ADR.” The interventions were assessed for type of medication and recommendation acceptance.Results: Medication classes responsible for ADRs included mood stabilizers (30%), typical antipsychotics (25%), atypical antipsychotics (25%), and antidepressants (8%). Nine percent resulted in transfer to a medical facility. Of all ADRs, 34.4% were pADRs; mood stabilizers (41%) and atypical antipsychotics (27%) were the most common pADRs. The most common causes of pADRs were supratherapeutic serum concentrations, drug-drug interactions, and history of reaction. There were 87 pharmacist interventions that were classified as “prevention of ADR,” and the acceptance rate of pharmacists’ recommendations was 96.5%. Mood stabilizers (20%), atypical antipsychotics (17%), and typical antipsychotics (11%) were commonly associated with prevented ADRs. Lithium accounted for 13.8% of prevented ADRs; these ADRs were most often due to a drug–drug interaction with a nonsteroidal anti-inflammatory drug.Conclusions: ADRs were most commonly associated with mood stabilizers and antipsychotics, and pADRs were common. There is an opportunity to provide education to medical staff on therapeutic drug monitoring and drug–drug interactions for these classes, particularly lithium.     

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

Hydrogen sulfide is rapidly gaining ground as a physiological mediator of inflammation, but there is no clear consensus as to its precise role in inflammatory signaling. This article discusses the disparate anti-inflammatory ('the good') and proinflammatory ('the bad') effects of endogenous and pharmacological H(2)S in disparate animal model and cell culture systems. We also discuss 'the ugly', such as problems of using wholly specific inhibitors of enzymatic H(2)S synthesis, and the use of pharmacological donor compounds, which release H(2)S too quickly to be physiologically representative of endogenous H(2)S synthesis. Furthermore, recently developed slow-release H(2)S donors, which offer a more physiological approach to understanding the complex role of H(2)S in acute and chronic inflammation ('the promising') are discussed.     

Reactive oxygen species and insulin resistance: the good, the bad and the ugly

Reactive oxygen species (ROS) contribute to the progression of various human diseases, including type 2 diabetes mellitus (T2DM). ROS can suppress the insulin response and contribute to the development of insulin resistance, a key pathological feature of T2DM. Paradoxically, ROS generated by NADP(H) oxidases at the plasma membrane and endomembranes might also be required for normal intracellular signaling. Growth factors, cytokines and hormones such as insulin promote the generation of ROS for the coordinated inactivation of protein tyrosine phosphatases and the promotion of tyrosine phosphorylation-dependent signaling. A recent study has established the potential of H(2)O(2) to enhance insulin sensitivity in vivo and attenuate the development of insulin resistance. Thus, ROS have the capacity to both promote and attenuate the insulin response. Here I review evidence indicating that ROS promote insulin sensitivity versus insulin resistance and discuss the potential complications associated with the widespread use of antioxidants.     

中成药说明书安全性信息及不良反应监测数据分析

目的 分析中成药说明书安全性信息，结合不良反应监测数据，为临床合理使用中成药提供依据。方法 通过实地收集获取410个中成药品种的说明书，对安全性信息进行统计和分析；检索浙江省的不良反应监测数据，选取重点品种对比说明书与监测数据之间的差异。结果 共收集中成药说明书410份，302个品种[不良反应]项为尚不明确（占73.66%）；262个品种[禁忌]项为尚不明确（占63.90%）；仅3个品种[特殊人群]项有相关规定。重点品种的不良反应监测数据显示中成药的不良反应并不少见，可累及全身多个系统和器官。结论 中成药的安全监测成果还没有彻底落实在说明书安全性信息的修订与完善中。药品生产企业应充分发挥药品安全主体责任，主动补充更新说明书安全性信息。     

Association between prescribing of antimuscarinic drugs and antimuscarinic adverse effects in older people

Many commonly prescribed medications have antimuscarinic side effects. These can be severe and disabling, but it is not always possible to predict which patients will suffer these effects. The development of practical tools that predict the likelihood of adverse drug reactions would aid rational prescribing, thereby improving patient safety and outcomes. Avoiding predictable adverse drug reactions would also make significant cost savings. This paper discusses the current knowledge on the association between the prescribing of antimuscarinic drugs and adverse outcomes, and proposes novel ways to improve trial design, and data collection and interpretation in order to better identify those patients at the highest risk of antimuscarinic side effects.     

IL-27 and autoimmune rheumatologic diseases: The good,the bad,and the ugly

The footprint of cytokines is evident in almost every biological process, such as development, as well as the pathogenesis of the different diseases, immune responses to pathogens, etc. These small proteins are categorized into different functional classes; for instance, they can play a pro-inflammatory or anti-inflammatory role in different situations, or they can confer a polarization to the immune system. Interleukin (IL)-27 is a member of the IL-12 family. Antigen-presenting cells are the primary source of IL-27 production, which exerts its effects by bindings to the IL-27 receptor expressed on the surface of target cells. Interaction of IL-27 and IL-27 receptor leads to activation of the JAK-STAT and p38 MAPK signaling pathways. Most studies focused on the inflammatory effects of this cytokine, but gradually anti-inflammatory effects were also revealed for this cytokine, which changed the traditional perception of the function of this cytokine. The functionality of IL-27 in the pathogenesis of rheumatic diseases has been attributed to a double-blade sword. Hence, novel therapeutic approaches have been devised targeting IL-12 family that has been accompanied with promising results. In this review, we focused on the inflammatory and anti-inflammatory properties of IL-27 in different autoimmune rheumatologic diseases and its plausible therapeutic potentials.     

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant

AIMS: The pharmacokinetics of mycophenolic acid and its glucuronide are complex. This study investigated the pharmacokinetics, pharmacodynamics and protein binding of mycophenolic acid and its glucuronide metabolite, early post-transplant in renal allograft recipients. METHODS: Forty-two de novo renal transplant recipients receiving mycophenolate mofetil and concomitant cyclosporin (n = 32) or tacrolimus (n = 10) participated in the study. Blood samples were taken on day 5 post-transplant for measurement of free and total concentrations of mycophenolic acid, mycophenolic acid glucuronide and relevant biochemistry. Associations between free fraction and biochemistry were investigated. Free and total 6-h area under the concentration-time curve (AUC0-6) of mycophenolic acid was assessed relative to clinical outcomes in the first month post-transplant. RESULTS: Kinetic variability of free and total mycophenolic acid and its glucuronide was greater in patients on cyclosporin (12- to 18-fold variation) than on tacrolimus (four- to fivefold) cotherapy. Cyclosporin-treated patients also had significantly lower predose total mycophenolic acid concentrations than tacrolimus-treated patients (median 0.8 mg l(-1) and 1.6 mg l(-1), respectively, P = 0.002). Mycophenolic acid glucuronide predose concentration correlated positively with mycophenolic acid glucuronide AUC0-6 (r > 0.95). Mycophenolic acid free fraction varied 11-fold, from 1.6% to 18.3%, whilst the glucuronide free fraction varied threefold, from 17.4% to 54.1%. Urea and creatinine concentrations correlated positively (r > 0.46), whilst albumin correlated negatively (r = -0.54) with free fraction of mycophenolic acid. Similar relationships were found for the free fraction of mycophenolic acid glucuronide. Mycophenolic acid free fraction was on average 70% higher in patients with albumin concentrations below a specified albumin cut-off concentration of 31 g l(-1)[free fraction = 7 +/- 4% for lower albumin and 4 +/- 3% for higher albumin, respectively; P = 0.001; 95% confidence interval (CI) for the difference 1.9, 4.2]. Neither free nor total mycophenolic acid AUC0-6 was related to rejection (P > 0.07). Free AUC0-6 was significantly higher in those patients with thrombocytopenic, leukopenic and/or infectious outcomes than in those without (mean +/- SD 1.9 +/- 0.3 mg h(-1) l(-1) and 1.1 +/- 0.1 mg h(-1) l(-1), P = 0.0043; 95% CI for the difference 0.3, 1.4). CONCLUSIONS: The marked variability in mycophenolic acid/glucuronide pharmacokinetics occurring early post-transplant during the current study was greater in cyclosporin (12-18-fold) than in tacrolimus (four- to fivefold) treated patients. Concomitant cyclosporin was associated with total mycophenolic acid concentrations approximately half that of tacrolimus. Patients with marked renal impairment had the highest free fractions reported to date. The exposure to unbound mycophenolic acid was significantly related to infections and haematological toxicity.     

追踪评价新型抗肿瘤药物用药的适宜性、有效性和安全性

目的 追踪评价新型抗肿瘤药物用药的适宜性、有效性和安全性,完善药品供应,保障患者用药的可及性和连续性,促进临床合理用药经验的积累。方法 参考药品使用说明书建立新型抗肿瘤药物用前适应证审核标准;参考《新型抗肿瘤药物临床应用指导原则》和药品说明书建立追踪评价标准;采用追踪方法学评价实施新型抗肿瘤药物用前审核制度以来通过审核的患者用药的适宜性、有效性和安全性。结果 2018年度共审核通过41例新型抗肿瘤药物用药患者,适宜性评价结果为3例不符合用药指征,2例不符合给药方法。有效性评价结果为客观有效率53.7%（22/41）,疾病控制率80.5%（33/41）;追踪时间截至2020年5月,24例无进展生存期>12个月,占比58.5%（24/41）,14例患者死亡,占比34.1%（14/41）。安全性评价结果为7例使用贝伐珠单抗未检测尿常规,4例使用曲妥珠单抗未检查心脏超声;可能由新型抗肿瘤药物引起的不良反应,包括4例使用曲妥珠单抗发生心脏不良反应,2例使用索拉菲尼或奥西替尼发生皮肤及皮下组织不良反应,1例使用贝伐珠单抗发生出血不良反应,不良反应发生率17.1%（7/41）。结论 实施新型抗肿瘤药物用前审核制度可以保障患者用药的可及性和连续性,临床药师应积极实施新型抗肿瘤药物的药物重整、药学监护和用药教育,提高患者用药的适宜性、有效性和安全性。