Functional Analysis of TRPA1, TRPM3, and TRPV1 Channels in Human Dermal Arteries and Their Role in Vascular Modulation.

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces "local" changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels' contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries.

Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review.

Background: Neonatal hypoxic ischaemic encephalopathy due to perinatal asphyxia, can result in severe neurodevelopmental disability or mortality. Hypothermia is at present the only proven neuroprotective intervention. During hypothermia, the neonate may need a variety of drugs with their specific pharmacokinetic profile.

Pharmacokinetic Interactions between the Hepatitis C Virus Inhibitors Elbasvir and Grazoprevir and HIV Protease Inhibitors Ritonavir, Atazanavir, Lopinavir, and Darunavir in Healthy Volunteers.

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (= 10) and the potential two-way pharmacokinetic interactions of elbasvir (= 30) or grazoprevir (= 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir.

RVCL-S and CADASIL display distinct impaired vascular function.

Objective: We aimed to evaluate the role of endothelial-dependent and endothelial-independent vascular reactivity in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), both cerebral small vessel diseases are considered models for stroke, vascular dementia, and migraine.

Methods: RVCL-S (n = 18) and CADASIL (n = 23) participants with and mutations, respectively, were compared with controls matched for age, body mass index, and sex (n = 26). Endothelial function was evaluated by flow-mediated vasodilatation, and endothelial-independent vascular reactivity (i.

SLC22A1/OCT1 Genotype Affects O-desmethyltramadol Exposure in Newborn Infants.

Background: This study determined whether the SLC22A1 [encoding the organic cation transporter 1 (OCT1)] genotype could explain, in addition to the postmenstrual age (referring to gestational plus postnatal age) and CYP2D6 genotype, the tramadol (M) pharmacokinetic variability in early infancy.

Methods: Fifty infants, median postmenstrual age 39.5 (interquartile range: 36.

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.

Tramadol and o-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study.

Background And Objectives: We aimed to study the impact of size, maturation and cytochrome P450 2D6 (CYP2D6) genotype activity score as predictors of intravenous tramadol disposition.

Methods: Tramadol and O-desmethyl tramadol (M1) observations in 295 human subjects (postmenstrual age 25 weeks to 84.8 years, weight 0.

The propylene glycol research project to illustrate the feasibility and difficulties to study toxicokinetics in neonates.

This paper aims to describe our propylene glycol (PG) research project to illustrate the feasibility and the difficulties encountered to perform excipient studies in neonates. PG is frequently co-administered excipient. PG accumulation potentially results in hyperosmolarity, lactic acidosis or hepato-renal toxicity in adults, reflecting issues related to pharmacokinetics (PKs) and -dynamics (PDs).

Pharmacokinetics of drugs in neonates: pattern recognition beyond compound specific observations.

Although the principles of drug disposition also apply in neonates, their specific characteristics warrant focussed assessment. Children display maturation in drug disposition, but this is most prominent in the first year of life. Besides maturational aspects of drug absorption and distribution, maturation mainly relates to (renal) elimination and (hepatic) metabolic clearance.

Pharmacokinetics of Drugs in Neonates: Pattern Recognition Beyond Compound Specific Observations.

Although the principles of drug disposition also apply in neonates, their specific characteristics warrant focussed assessment. Children display maturation in drug disposition, but this is most prominent in the first year of life. Besides maturational aspects of drug absorption and distribution, maturation mainly relates to (renal) elimination and (hepatic) metabolic clearance.

Interictal type 1 cannabinoid receptor binding is increased in female migraine patients.

Objective: To compare binding of the type 1 cannabinoid receptor (CB1R) between migraine patients and healthy volunteers.

Background: It has been suggested that endocannabinoid deficiency may play a role in the pathophysiology of migraine. Nonetheless, biochemical studies substantiating this idea remain scarce and are faced with methodological shortcomings partly because of the difficulty to perform measurements of endocannabinoids within the central nervous system itself.

The effects of laropiprant, a selective prostaglandin D₂ receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin.

Laropiprant (LRPT) is being developed in combination with Merck's extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD₂ receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A₂ receptor TP (approximately 190-fold less potent at TP compared with DP1).

The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men.

Aims: To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG).

Methods: Twenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.

Does intravenous paracetamol administration affect body temperature in neonates?

Introduction: Intravenous paracetamol (acetaminophen) has recently been registered for treatment of pain in neonates but the pharmacodynamics, including effects on body temperature, have not been reported.

Methods: A pooled analysis on body temperature recordings in neonates exposed to intravenous paracetamol was performed. Body temperature was recorded by skin probe and registered before and every 2 h following initiation of single or repeated intravenous paracetamol administration (up to 48 h).

Endothelial function in migraine: a cross-sectional study.

Background: Migraine has been associated with cardiovascular disorders. Endothelial dysfunction may be a mechanism underlying this association. The present study tested the hypothesis that endothelium-dependent vasodilation, basal endothelial nitric oxide release and endothelial fibrinolytic capacity are impaired in migraine patients.

No arguments for increased endothelial nitric oxide synthase activity in migraine based on peripheral biomarkers.

Objectives: To assess whether migraine patients display a chronic nitric oxide synthase (NOS) hyperactivity by comparing the nitric oxide (NO) production before and following a loading dose of L-arginine between migraine patients (interictally) and matched healthy control subjects. In addition, we evaluated whether a loading dose of L-arginine triggers an acute migraine headache in migraineurs.

Subjects And Methods: Twenty healthy subjects and 20 migraine patients participated in a 2-period, randomised, double-blind, placebo-controlled study.

Altered arterial function in migraine of recent onset.

Objective: Migraine is associated with cardiovascular disorders but the underlying mechanisms are unknown. Arterial structure and function are important determinants of cardiovascular morbidity and mortality. The aim of the present study was to assess arterial properties in patients with migraine of recent onset.

Acute effects of sumatriptan on aortic blood pressure, stiffness, and pressure waveform.

Background And Objectives: Sumatriptan, a 5-hydroxytryptamine (HT)(1B/1D) receptor agonist, is an effective acute antimigraine drug. Because of its vasoconstrictor activity, it is contraindicated in patients at high risk for adverse cardiovascular events. Acute antimigraine drugs without vasoconstrictor effects are currently being developed, and sensitive, noninvasive techniques by which to detect drug-induced vascular effects would facilitate their clinical development.

Calcitonin gene-related peptide-induced vasodilation in the human forearm is antagonized by CGRP8-37: evaluation of a human in vivo pharmacodynamic model.

Objectives: The aims of this study were to assess the potential of CGRP8-37, the C-terminal fragment of calcitonin gene-related peptide (CGRP), to inhibit CGRP-induced vasodilation in the human forearm and to evaluate a pharmacodynamic model to aid the clinical development of novel CGRP-receptor antagonists.

Methods: Forearm blood flow (FBF) responses to intra-arterial CGRP infusions were measured via venous occlusion plethysmography in 21 healthy subjects. Dose response to CGRP was assessed during graded infusion of CGRP (1, 3, and 10 ng.

Reproducibility of forearm vasodilator response to intra-arterial infusion of calcitonin gene-related peptide assessed by venous occlusion plethysmography.

Aims: To assess the reproducibility of the forearm blood flow (FBF) response to intra-arterial infusion of calcitonin-gene related peptide (CGRP), measured by venous occlusion plethysmography. In addition, to compare different ways of expressing the FBF response and perform sample size calculations.

Methods: On two separate visits, CGRP (10 ng min(-1) dl(-1) forearm) was infused for 45 min into the brachial artery of six healthy subjects.

Calcitonin gene-related peptide: exploring its vasodilating mechanism of action in humans.

Objective: In vitro studies suggest that the vasodilator mechanism of action of calcitonin gene-related peptide (CGRP) involves various endothelium-dependent and endothelium-independent mechanisms. An in vivo analysis of the contribution of nitric oxide, prostaglandins, calcium-sensitive potassium channels (K(+)(Ca) channels), and adenosine triphosphate (ATP)-sensitive potassium channels (K(+)(ATP) channels) to CGRP-induced vasodilation in humans was performed.

Methods: CGRP (3, 10, and 30 ng x min(-1) x dL(-1) forearm) was infused into the brachial artery of 40 healthy subjects.