Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist

Aims

Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy.

Methods

An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure−response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose−response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated.

Results

The results suggested that a 20 mg dose of MK-3207 (EC₅₀ of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose−response would be reached around 40–100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial.

Conclusions

The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose−response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.     

Female Migrant Sex Workers in Moscow: Gender and Power Factors and HIV Risk

This study aimed to build formative knowledge regarding HIV risks in female migrant sex workers in Moscow, focusing on gender and power. This was a collaborative ethnographic study, informed by the theory of gender and power, in which researchers conducted minimally structured interviews with 24 female sex workers who were migrants to Moscow and who provided sexual services to male migrant laborers. Overall, the female migrant sex workers engaged in HIV risk behaviors and practiced inadequate HIV protection with their clients. These behaviors were shaped by gender and power factors in the realms of labor, behavior, and cathexis. In the labor realm, because some female migrants were unable to earn enough money to support their families, they were pushed or pulled into sex work providing service to male migrants. In the behavior realm, many female migrant sex workers were intimidated by their male clients, feared violence, and lacked access to women's health care and prevention. In the cathexis realm, many had a sense of shame, social isolation, emotional distress, and lacked basic HIV knowledge and prevention skills. To prevent HIV transmission requires addressing the gender and power factors that shape HIV/AIDS risks among female migrant sex workers through multilevel intervention strategies.     

Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction

Ischemia resulting from myocardial infarction (MI) promotes VEGF expression, leading to vascular permeability (VP) and edema, a process that we show here contributes to tissue injury throughout the ventricle. This permeability/edema can be assessed noninvasively by MRI and can be observed at the ultrastructural level as gaps between adjacent endothelial cells. Many of these gaps contain activated platelets adhering to exposed basement membrane, reducing vessel patency. Following MI, genetic or pharmacological blockade of Src preserves endothelial cell barrier function, suppressing VP and infarct volume, providing long-term improvement in cardiac function, fibrosis, and survival. To our surprise, an intravascular injection of VEGF into healthy animals, but not those deficient in Src, induced similar endothelial gaps, VP, platelet plugs, and some myocyte damage. Mechanistically, we show that quiescent blood vessels contain a complex involving Flk, VE-cadherin, and beta-catenin that is transiently disrupted by VEGF injection. Blockade of Src prevents disassociation of this complex with the same kinetics with which it prevents VEGF-mediated VP/edema. These findings define a molecular mechanism to account for the Src requirement in VEGF-mediated permeability and provide a basis for Src inhibition as a therapeutic option for patients with acute MI.     

Children with seizures exhibit preferences for foods compatible with the ketogenic diet

Although highly effective for the treatment of intractable epilepsy, the ketogenic diet is not always included in the treatment option hierarchy presented to families, in part due to perceptions that children will find the high-fat/low-carbohydrate regimen unpalatable. This study assessed if children with seizures exhibit food preferences compatible with the diet, as well as if caregivers were accurate in predicting preferences. Children aged 2-17, with (n=29) and without (n=30) a history of seizures, participated in a paired choice food preference assessment while parents estimated child preferences verbally. Children with seizures exhibited significantly higher preferences for fat versus carbohydrate foods compared with controls, and parents demonstrated low accuracy. Future studies could use similar assessment methods to prospectively track whether such preferences predict diet compliance and/or efficacy. Research into the underlying metabolic basis for this preference and possible related neurophysiological mechanisms in seizure etiology and treatment is warranted.     

Heat therapy in the management of heart failure

Heart failure remains a health care epidemic, and additional complementary therapies beyond pharmaceuticals and devices are needed. Using heat therapy or topical thermal therapy is an ancient therapeutic approach for the treatment of heart failure. Currently, there are several studies reporting salutary effects of heat therapy in patients with heart failure using either dry heat or water immersion therapies. The authors describe an additional theoretic construct using topically applied heat pads that might be a simple and economic approach to affect heat therapy as an adjunct for many patients. Hopefully future studies will continue to explore heat therapy as adjunctive care for heart failure patients.     

Impact of the Diet on the Formation of Oxidative Stress and Inflammation Induced by Bacterial Biofilm in the Oral Cavity

The diet is related to the diversity of bacteria in the oral cavity, and the less diverse microbiota of the oral cavity may favor the growth of pathogenic bacteria of all bacterial complexes. Literature data indicate that disturbances in the balance of the bacterial flora of the oral cavity seem to contribute to both oral diseases, including periodontitis, and systemic diseases. If left untreated, periodontitis can damage the gums and alveolar bones. Improper modern eating habits have an impact on the oral microbiome and the gut microbiome, which increase the risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease and cancer. The subject of our consideration is the influence of the traditional diet on the formation of oxidative stress and inflammation caused by bacterial biofilm in the oral cavity. Through dental, biomedical and laboratory studies, we wanted to investigate the effect of individual nutrients contained in specific diets on the induction of oxidative stress inducing inflammation of the soft tissues in the oral cavity in the presence of residual supra- and subgingival biofilm. In our research we used different types of diets marked as W, T, B, F and noninvasively collected biological material in the form of bacterial inoculum from volunteers. The analyzed material was grown on complete and selective media against specific strains of all bacterial complexes. Additionally, the zones of growth inhibition were analyzed based on the disc diffusion method. The research was supplemented with dental and periodontological indicators. The research was supplemented by the application of molecular biology methods related to bacterial DNA isolation, PCR reactions and sequencing. Such selected methods constitute an ideal screening test for the analysis of oral bacterial microbiota. The obtained results suggest that certain types of diet can be an effective prophylaxis in the treatment of civilization diseases such as inflammation of the oral cavity along with periodontal tissues and gingival pockets.     

Effect of Portacaval Anastomosis on Glutamine Synthetase Protein and Gene Expression in Brain, Liver and Skeletal Muscle

The effects of chronic liver insufficiency resulting from end-to-side portacaval anastomosis (PCA) on glutamine synthetase (GS) activities, protein and gene expression were studied in brain, liver and skeletal muscle of male adult rats. Four weeks following PCA, activities of GS in cerebral cortex and cerebellum were reduced by 32% and 37% (p<0.05) respectively whereas GS activities in muscle were increased by 52% (p<0.05). GS activities in liver were decreased by up to 90% (p<0.01), a finding which undoubtedly reflects the loss of GS-rich perivenous hepatocytes following portal-systemic shunting. Immunoblotting techniques revealed no change in GS protein content of brain regions or muscle but a significant loss in liver of PCA rats. GS mRNA determined by semi-quantitative RT-PCR was also significantly decreased in the livers of PCA rats compared to sham-operated controls. These findings demonstrate that PCA results in a loss of GS gene expression in the liver and that brain does not show a compensatory induction of enzyme activity, rendering it particularly sensitive to increases in ammonia in chronic liver failure. The finding of a post-translational increase of GS in muscle following portacaval shunting suggests that, in chronic liver failure, muscle becomes the major organ responsible for the removal of excess blood-borne ammonia.