Unraveling the Pharmacokinetic Interaction of Ticagrelor and MEDI2452 (Ticagrelor Antidote) by Mathematical Modeling

The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence

Analysis of the viscosity dependent parameters of couple stress fluid in porous parallel plates

Purpose: This paper aims to present a detailed analysis to explore the various properties of non-Newtonian couple stress lubricants between parallel porous plates. Design/methodology/approach: With reference to the theories based on micro-continuum analysis, a non-linear, non-Newtonian Reynolds type equation is arrived. The closed form solutions obtained clearly indicate the changes in pressure, load bearing capacity and response time because of variation in viscosity of couple stress fluid. Findings: It is observed that the viscosity variation factor greatly influences the change in pressure, load carrying capacity and squeezing time. Originality/value: It is observed that the nature of lubricants with suitable additives greatly helps in overcoming the adverse effect because of porous surface. Reynolds type equation is analysed using appropriate boundary conditions. The expression for pressure distribution arrived at in turn leads to the analysis of load bearing capacity and response time. © 2018, Emerald Publishing Limited

Assessment of role of Porphyromonas gingivalis as an aggravating factor for chronic obstructive pulmonary disease patients with periodontitis

Introduction: Periodontitis is a chronic inflammatory disease associated with a number of lung conditions such as chronic obstructive pulmonary disease (COPD) and pneumonia. Both chronic periodontitis (CP) and COPD share similar risk factor profiles. Thus, recognition of interaction between periodontitis and COPD could lead to establishment of better preventive and therapeutic approaches. The microbial analysis of sputum from COPD patients with CP to detect periodontal pathogen Porphyromonas gingivalis (P. gingivalis) both before and after nonsurgical periodontal therapy. Materials and Methods: The study group comprised 30 individuals diagnosed as COPD with CP. Periodontal indices, lung function test, and P. gingivalis in sputum were assessed before and 6 months after nonsurgical periodontal therapy. Results: A decrease in the count of P. gingivalis and decreased periodontal indices values were observed in COPD patients with periodontitis after nonsurgical periodontal therapy. Lung function test (forced expiratory volume in the first/forced vital capacity) was improved in COPD patients with periodontitis after nonsurgical periodontal therapy. Conclusions: The study results suggest that nonsurgical periodontal therapy can be a part of treatment protocol in COPD patients because it helps in reducing the P. gingivalis count and improving the lung function

Controlling the bioactivity of a peptide hormone in vivo by reversible self-assembly

The use of peptides as therapeutic agents is undergoing a renaissance with the expectation of new drugs with enhanced levels of efficacy and safety. Their clinical potential will be only fully realised once their physicochemical and pharmacokinetic properties have been precisely controlled. Here we demonstrate a reversible peptide self-assembly strategy to control and prolong the bioactivity of a native peptide hormone in vivo. We show that oxyntomodulin, a peptide with potential to treat obesity and diabetes, self-assembles into a stable nanofibril formulation which subsequently dissociates to release active peptide and produces a pharmacological effect in vivo. The subcutaneous administration of the nanofibrils in rats results in greatly prolonged exposure, with a constant oxyntomodulin bioactivity detectable in serum for at least 5 days as compared to free oxyntomodulin which is undetectable after only 4 h. Such an approach is simple, cost-efficient and generic in addressing the limitations of peptide therapeutics