A benefit/risk approach towards selecting appropriate pharmaceutical dosage forms - An application for paediatric dosage form selection

The design and selection of new pharmaceutical dosage forms involves the careful consideration and balancing of a quality target product profile against technical challenges and development feasibility. Paediatric dosage forms present particular complexity due to the diverse patient population, patient compliance challenges and safety considerations of this vulnerable population. This paper presents a structured framework for assessing the comparative benefits and risks of different pharmaceutical design options against pre-determined criteria relating to (1) efficacy, (2) safety and (3) patient access. This benefit/risk framework has then been applied to three hypothetical, but realistic, scenarios for paediatric dosage forms in order to explore its utility in guiding dosage form design and formulation selection. The approach allows a rigorous, systematic and qualitative assessment of the merits and disadvantages of each dosage form option and helps identify mitigating strategies to modify risk. The application of a weighting and scoring system to the criteria depending on the specific case could further refine the analysis and aid decision-making. In this paper, one case study is scored for illustrative purposes. However, it is acknowledged that in real development scenarios, the generation of actual data considering the very specific situation for the patient/product/developer would come into play to drive decisions on the most appropriate dosage form strategy.     

Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent,Norepinephrine-Independent Processes

The alpha2 adrenergic receptor (α₂-AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of α₂-AR signaling. Recent studies show yohimbine-induced drug-seeking behavior is attenuated by orexin receptor 1 (OX₁R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR₁) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX₁R–dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX₁R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.     

Differences in Perceived Severity of Zika Virus Infection and Dengue Fever and its Influence on Mosquito Control Practices in Malaysia

The aims of this study were to explore the differences in (1) the perception of severity towards ZIKV infection and dengue fever, and (2) mosquito control practices before and after the ZIKV outbreak were declared a Public Health Emergency of International Concern (PHEIC). Data were collected between Feb to May 2016 using a computer-assisted telephone interviewing system. The median scale score for perceived severity of ZIKV was 3 (interquartile range [IQR] 1–5) versus 4 (IQR 3–5) for dengue (P?<?0.001). The scores for mosquito control practices before and after ZIKV was declared a PHEIC were similar, at 4 (IQR 3–5). Multivariate analysis revealed that participants with a higher score for perception of severity of ZIKV were more likely to report greater mosquito control practices after the declaration of the PHEIC (OR 1.822 [95% CI 1.107–2.998]). The emerging ZIKV pandemic requires concerted efforts to enhance mosquito control practices among the Malaysian public. Efforts to improve public mosquito control practices should focus on enhancing the perception of the severity of ZIKV.     

The postmodernist war on evidence-based practice

In this paper, we examine the war of words between those who contend that health care practice, including nursing, should primarily be informed by research (the evidence-based practice movement), and those who argue that there should be no restrictions on the sources of knowledge used by practitioners (the postmodernists). We review the postmodernist interventions of Dave Holmes and his colleagues, observing that the postmodernist style to which they adhere, which includes the use of continental philosophy, metaphors, and acerbic delivery, tends to obscure their substantive arguments. The heated nature of some responses to them has tended to have the same effect. However, the substantive arguments are important. Five main postmodernist charges are identified and discussed. The first argument, that the notion of ‘best evidence’ implies a hierarchical and exclusivist approach to knowledge, is persuasive. However, the contention that this hierarchy is maintained by the combined pressures of capitalism and vested interests within academia and the health services, is less well founded. Nevertheless, postmodernist contentions that the hierarchy embraced by the evidence-based practice movement damages health care because it excludes other forms of evidence that are needed to understand the complexity of care, it marginalizes important aspects of clinical knowledge, and it fails to take account of individuals or their experience, are all seen to be of some merit. However, we do not share the postmodernist conclusion that this adds up to a fascist order. Instead, we characterize evidence-based practice as a necessary but not sufficient component of health care knowledge.     

Treatment choices for the glycaemic management of patients with type 2 diabetes and chronic kidney disease: Analysis of the SAIL patient linked dataset

Aims

Chronic kidney disease (CKD) is common in type 2 diabetes and limits the treatment choices for glycaemic control. Our aim was to examine real-world prescribing for managing hyperglycaemia in the presence of CKD.

Structure theorems and the dynamics of nitrogen catabolite repression in yeast

By using current biological understanding, a conceptually simple, but mathematically complex, model is proposed for the dynamics of the gene circuit responsible for regulating nitrogen catabolite repression (NCR) in yeast. A variety of mathematical "structure" theorems are described that allow one to determine the asymptotic dynamics of complicated systems under very weak hypotheses. It is shown that these theorems apply to several subcircuits of the full NCR circuit, most importantly to the URE2-GLN3 subcircuit that is independent of the other constituents but governs the switching behavior of the full NCR circuit under changes in nitrogen source. Under hypotheses that are fully consistent with biological data, it is proven that the dynamics of this subcircuit is simple periodic behavior in synchrony with the cell cycle. Although the current mathematical structure theorems do not apply to the full NCR circuit, extensive simulations suggest that the dynamics is constrained in much the same way as that of the URE2-GLN3 subcircuit. This finding leads to the proposal that mathematicians study genetic circuits to find new geometries for which structure theorems may exist.     

Experiences of a low-intensity anticoagulation regimen for extended secondary prevention of venous thromboembolism

Extended treatment with vitamin K antagonists for more than 6 months is often used for secondary prevention of venous thromboembolism (VTE) in patients at high or moderate risk for recurrent events. The intensity of anticoagulant therapy is usually maintained at an International Normalized Ratio (INR) of 2-3. An INR of 1.5-2 might also prevent thromboembolic events with less complications of bleeding, but results from randomized trials are not yet available. In a non-prospective, uncontrolled study 40 patients with a history of VTE and an estimated high risk for recurrent events due to several previous events and/or thrombophilic defects were, after a median of 11.5 months on regular intensity anticoagulation (INR 2-3), switched to a low intensity regimen (INR 1.5-2). In six of the patients an estimated high risk for complications of bleeding contributed to this decision. After a median follow-up of 36 months (140 patient-years) recurrent events, complications of bleeding and some basic quality of life measurements regarding the new treatment were registered. No recurrent events, four minor bleedings and no major bleedings were registered. Twenty-six patients preferred an INR of 1.5-2 compared to 2-3. The main reasons for that preference were a lower risk for bleeding (13 patients) and less frequent monitoring of the INR (18 patients). No patient preferred full-dose anticoagulation at INR 2-3. In patients at a high risk for recurrence of VTE an initial period of regular intensity anticoagulation, followed by a low-intensity regimen, may provide effective and safe secondary prophylaxis.