Improved method for analysis of cysteinyldopa in human serum

5‐S‐l‐Cysteinyl‐l‐dopa is a well‐known pigment intermediate and analysis of its serum concentration is well suited for evaluation of treatment and follow‐up of stage III and IV malignant melanoma. A simplified analytical method is described using organic extraction followed by clean‐up on a boronate gel to capture the compound containing vicinal hydroxyls. Weak acid solution elutes the 5‐S‐cysteinyldopa suitable for high‐performance liquid chromatography (HPLC). The absolute recoveries of cysteinyldopa and its diastereomer 5‐S‐D‐cysteinyl‐l‐dopa (used as an internal standard) were 81.5±2.8% and 81.3±2.7%, respectively, and use of the internal standard for the whole procedure gave an analytical recovery of 101±0.8%. The limit of quantitation was 1.5?nmol/L and the imprecision of the method was <5.0% over the analytical range 1.5–500?nmol/L. The method is cheap and easy to perform and compares well with other described techniques. The use of the method is illustrated by results obtained during treatment of a patient with metastatic malignant melanoma.     

Kynurenate Derivative Attenuates the Nitroglycerin‐Induced CamKIIα and CGRP Expression Changes

(Headache 2010;50:834‐843) Objective.— To examine the efficacy of L‐kynurenine and a novel kynurenic acid derivative on the nitroglycerin‐induced calmodulin‐dependent protein kinase II alpha (CamKIIα) and calcitonin gene‐related peptide (CGRP) expression changes in the rat caudal trigeminal nucleus. Background.— Systemic administration of the nitric oxide donor nitroglycerin can trigger an attack in migraineurs. In the rat, nitroglycerin activates second‐order neurons in the caudal trigeminal nucleus, and increases expression of the CamKIIα and decreases that of the CGRP there. As glutamatergic mechanisms may be crucial in trigeminal pain processing, the aim of our study was to examine the effects of L‐kynurenine, a metabolic precursor of the N‐methyl D‐aspartate receptor antagonist kynurenic acid, on the nitroglycerin‐induced changes in CamKIIα and CGRP immunoreactivity. Methods.— One hour before the nitroglycerin (10 mg/kg bodyweight, s.c.) injection, the animals were pretreated with L‐kynurenine (300 mg/kg bodyweight, i.p.) or 2‐(2‐N,N‐dimethylaminoethylamine‐1‐carbonyl)‐1H‐quinolin‐4‐one hydrochloride (300 mg/kg bodyweight, i.p.), a novel kynurenic acid derivative. Four hours later, the rats were perfused transcardially and the cervical spinal cord segments were removed for immunohistochemistry. Results.— L‐kynurenine and 2‐(2‐N,N‐dimethylaminoethylamine‐1‐carbonyl)‐1H‐quinolin‐4‐one hydrochloride pretreatment attenuated the nitroglycerin‐induced changes in CamKIIα and CGRP immunoreactivity in the rat caudal trigeminal nucleus. Conclusions.— These findings suggest a mechanism by which the inhibition of the excitatory amino acid receptors by kynurenic acid and its derivatives can alter trigeminal nociception.     

Involvement of AMPA Receptors in CSD‐Induced Impairment of LTP in the Hippocampus

Objective.— To investigate the alteration of hippocampal long‐term plasticity and basal synaptic transmission induced by repetitive cortical spreading depressions (CSDs). Background.— There is a relationship between migraine aura and amnesia attack. CSD, a state underlying migraine attacks, may be responsible for hippocampus‐related symptoms. However, the precise role of CSD on hippocampal activity has not been investigated. Methods.— Male Wistar rats were divided into CSD and control groups. Repetitive CSDs were induced in vivo by topical application of solid KCl. Forty‐five minutes later, the ipsilateral hippocampus was removed, and hippocampal slices were prepared for a series of electrophysiological studies. Results.— Repetitive CSDs led to a decrease in the magnitude of long‐term potentiation in the hippocampus. CSD also reduced hippocampal synaptic efficacy, as shown by a reduction in post‐synaptic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor responses. In contrast, the post‐synaptic N‐methyl‐d ‐aspartate receptor responses remained unchanged. In addition, there were no changes in paired‐pulse profiles between the groups, indicating that CSD did not induce any presynaptic alterations. Conclusion.— These findings suggest that a reduction of post‐synaptic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor responses is the mechanism responsible for impaired hippocampal long‐term potentiation induced by CSD.     

Comparison of behavioral,neuroprotective, and proinflammatory cytokine modulating effects exercised by (+)‐cis‐EC and (−)‐cis‐EC stereoisomers in a PTZ‐induced kindling test in mice

Epoxy‐carvone (EC) has chiral centers that allow generation of stereoisomers, including (+)‐cis‐EC and (?)‐cis‐EC, whose effects in the kindling tests have never been studied. Accordingly, this study aims to comparatively investigate the effect of stereoisomers (+)‐cis‐epoxy‐carvone and (?)‐cis‐epoxy‐carvone on behavioral changes measured in scores, in the levels of cytokines (IL‐1β, IL‐6, and TNFα) and neuronal protection in the face of continuous treatment with pentylenetetrazol. Swiss mice were divided into five groups (n = 10), receiving vehicle, (+) – cis‐EC, (?) – cis‐EC (both at the dose of 30 mg/kg), and diazepam (4 mg/kg). Thirty minutes after the respective treatment was administered to the animals one subconvulsive dose of PTZ (35 mg/kg). Seven subconvulsives treatments were made on alternate days, in which each treatment several parameters were recorded. In the eighth treatment, the animals receiving the highest dose of PTZ (75 mg/kg) and were sacrificed for quantification of cytokines and histopathologic analysis. All drugs were administered by intraperitoneal route. In the kindling test, (+)‐cis‐EC and (?)‐cis‐EC reduced the average scores. The stereoisomer (+)‐cis‐EC decreased levels of proinflammatory cytokines IL‐1β, IL‐6, and TNFα, whereas comparatively (?)‐cis‐EC did not reduce IL‐1β levels. Histopathological analysis of the mice hippocampi undergoing this methodology showed neural protection for treated with (+)‐cis‐EC. The results suggest that the anticonvulsant effect of (+)‐cis‐EC possibly takes place due to reduction of proinflammatory cytokines involved in the epileptogenic process, besides neuronal protection, yet further investigation of the mechanisms involved is required.     

Activation of PAR‐2 Elicits NO‐Dependent and CGRP‐Independent Dilation of the Dural Artery

(Headache 2010;50:1017‐1030) Objectives.— The goal of this study was to determine the vascular effects of protease‐activated receptor‐2 (PAR‐2) activation in the rat cranial vasculature. Background.— The role of PAR‐2 in pain and inflammatory conditions has been established but the information available on its effects and receptor distribution in the trigeminal vascular axis is limited. We studied the dilatory function and expression of PAR‐2 in the neuro‐vascular circuit, critical in migraine pathogenesis. We also investigated the interaction of PAR‐2 with calcitonin gene‐related peptide (CGRP) and dural mast cells. Methods.— We used an improved model of intravital microscopy on the closed cranial window in rats to study the vascular effects of PAR‐2 activating peptides (PAR‐2 APs; SLIGRL‐NH₂, 2‐Furoyl‐LIGRLO‐NH₂) in the dural vasculature. Measurement of immunoreactive CGRP in skull halves and in trigeminal nucleus caudalis was done by using an enzyme‐linked immunosorbent assay. We also analyzed the presence of PAR‐2 in different migraine relevant tissues by quantitative real‐time PCR and Western blot analysis. Results.— PAR‐2 APs and trypsin induced a dose‐dependent increase in dural artery diameter. The topical application of a nonspecific nitric oxide synthase (NOS) inhibitor, L‐N^G‐Nitroarginine methyl ester, attenuated SLIGRL‐NH₂ responses. Olcegepant, a CGRP receptor antagonist, did not a have significant effect on the SLIGRL‐NH₂ responses, though exogenous CGRP responses were completely blocked. There was no significant release of CGRP from skull halves incubated with SLIGRL‐NH₂ as compared with those incubated with the corresponding negative peptide. Chronic mast cell degranulation did not change the vascular effects of PAR‐2 APs. mRNA and protein expression of PAR‐2 were found throughout trigeminovasuclar axis. Conclusion.— PAR‐2 activation leads to vasodilation of dural arteries and these responses are partially mediated by nitric oxide. As PAR‐2 is present throughout trigeminovasuclar axis, it may have a role in migraine pathogenesis, independent of CGRP and mast cell mediated mechanism.     

Outcome of patients hospitalized for COVID‐19 and exposure to angiotensin‐converting enzyme inhibitors and angiotensin‐receptor blockers in France: results of the ACE‐CoV study

Data are lacking on the impact of ACEI/ARB exposure on unfavorable outcome in the population of patients hospitalized for COVID‐19 with hypertension/cardiovascular disease, particularly in Europe. The ACE‐CoV study was designed to assess this question. The study was conducted in the Covid‐Clinic‐Toul cohort, which contains data about all patients hospitalized at Toulouse University hospital, France with a SARS‐CoV‐2 infection since March, 2020. We selected the patients with a history of cardiovascular disease (heart failure or coronary disease) and/or arterial hypertension. We conducted a subgroup analysis in patients with arterial hypertension. ACEI/ARB exposures at admission were assessed. The outcome was composite: admission to intensive care unit, need of mechanical ventilation or death during the 14 days after admission to hospital. We used logistic regression models with propensity scores (PS) weighted by overlap weighting (OW) and inverse probability of treatment weighting (IPTW). Between March 2020 and April 20, 2020, the Covid‐Clinic‐Toul included 263 patients. Among them, 111 were included in the ACE‐CoV study population. In OW‐PS‐adjusted analyses, the association of exposure to ACEIs or ARBs with outcome occurrence was OR: 1.56 (95% CI: 0.73–3.33). It was 0.99 (95% CI: 0.68–1.45) for ACEIs and 1.64 (95% CI: 0.77–3.50) for ARBs. Analyses with weighting by the IPTW‐PS method gave similar results. Results were similar when considering the subgroup of patients with arterial hypertension. The ACE‐CoV study found no association between exposure to ACEIs or ARBs and unfavorable outcome in hospitalized patients for COVID‐19 with a history of cardiovascular disease/arterial hypertension.     

Improving opioid effectiveness: from ideas to evidence.

Opioid effectiveness can be improved by individualizing dosing, route of administration and the drug. Particularly in the treatment of chronic non-cancer pain, careful patient selection is essential. The current review concentrates on new ideas about improving opioid effectiveness by increasing efficacy or reducing adverse effects by combining other drugs that modulate opioid receptor mediated effects. These pharmacological "oipioid adjuvants" include e.g. alpha(2)-adrenergic agonists, non-steroidal anti-flammatory analgesics, NMDA-receptor antagonists, CCK-antagonists, gabapentinoids and NK-1 receptor antagonists. The theoretical background and the clinical evidence of these combinations will be discussed.     

Long‐Term Care Quality‐of‐Life Scale utility in community home care

This study aimed to test the utility of the Long‐Term Care Quality‐of‐Life assessment scale within community home care contexts and to compare the scale against the World Health Organization Quality‐of‐Life scale in terms of reliability and validity. Both scales were administered concurrently to 109 older adults receiving home care. Analysis revealed the Long‐Term Care Quality‐of‐Life scale to have good test–retest reliability, modest but acceptable internal consistency, and pairwise comparison between the Long‐Term Care Quality‐of‐Life and World Health Organization Quality‐of‐Life scales' scores suggesting moderate‐to‐strong correlation of criterion validity and comparability between scales. The results showed that the assessment of individual perceptions of life quality within home care contexts can be monitored and recorded, and that Long‐Term Care Quality‐of‐Life scale monitoring in home and residential care can identify opportunities for quality‐of‐life support and care continuity, even with transitions between care services and systems. The implications of the present study lie in having access to a validated quality‐of‐life assessment scale that can be used across care contexts to support evidence‐based practice, continuity of care, and acknowledgement of individual circumstances in services and care planning.     

The recent outbreaks of human coronaviruses: A medicinal chemistry perspective

Coronaviruses (CoVs) infect both humans and animals. In humans, CoVs can cause respiratory, kidney, heart, brain, and intestinal infections that can range from mild to lethal. Since the start of the 21st century, three β‐coronaviruses have crossed the species barrier to infect humans: severe‐acute respiratory syndrome (SARS)‐CoV‐1, Middle East respiratory syndrome (MERS)‐CoV, and SARS‐CoV‐2 (2019‐nCoV). These viruses are dangerous and can easily be transmitted from human to human. Therefore, the development of anticoronaviral therapies is urgently needed. However, to date, no approved vaccines or drugs against CoV infections are available. In this review, we focus on the medicinal chemistry efforts toward the development of antiviral agents against SARS‐CoV‐1, MERS‐CoV, SARS‐CoV‐2, targeting biochemical events important for viral replication and its life cycle. These targets include the spike glycoprotein and its host‐receptors for viral entry, proteases that are essential for cleaving polyproteins to produce functional proteins, and RNA‐dependent RNA polymerase for viral RNA replication.