Pharmacological characterization of abediterol, a novel inhaled ß(2)-adrenoceptor agonist with long duration of action and a favorable safety profile in preclinical models.

Abediterol is a novel potent, long-acting inhaled ß(2)-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human ß(2)-adrenoceptor and a functional selectivity over ß(1)-adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human ß(2)-adrenoceptor (E(max) = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC(50) = 1.9 ± 0.4 nM; t½ onset = 7-10 min) is not significantly different from that of formoterol, but its duration of action (t½ ∼ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t½ = 36 h) than salmeterol (t½ = 6 h) and formoterol (t½ = 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile.

Femitags for feminist connected crowds in Latin America and Spain.

In recent years, women are acting all over the world against gender violence and femicide. This new wave of feminist claims is characterized by the intensive use of social media to spread consciousness and amplify influence. For this research, we analyse three femitags (i.e., feminist hashtags) from Twitter that have been relevant in different crucial mobilizations in Argentina, Spain, and Mexico. These are three hashtags with different functions for activism that have shown special relevance due to their continuity or their intensity in the Spanish-speaking area between 2015 and 2020 (before the confinement due to the COVID-19 pandemic). #NiUnaMenos (#NotASingleWomanLess) started in Argentina in 2015 and called to massive mobilizations on the streets. #Cuéntalo (#TellIt) was initiated in Spain in 2018 for sexual abuse disclosure. #NiUnaMas (#NotASingleWomanMore) trended in México around 2020 to denounce every new victim of rape or femicide. We analyse how those hashtags have spread in the Spanish-speaking region, what kind of social actors have been involved and what has been the role of opinion leaders. All data were collected with academic access to the Twitter API during December 2021. We have found that the most influential actors in the conversation are contingent and circumstantial, the leadership structure tends towards horizontality, and opinion leaders with large numbers of followers are only important in very specific moments. In all cases, femitags serve as a toolbox for action and build up an archive of grievances with a transnational dimension. Furthermore, all of them point out that structural violence against women leads to feminicide.1.

Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile.

Aclidinium bromide is a novel potent, long-acting inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease. Aclidinium showed subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)). [(3)H]Aclidinium dissociated slightly faster from M(2) and M(3) receptors than [(3)H]tiotropium but much more slowly than [(3)H]ipratropium. Its association rate for the M(3) receptor was similar to [(3)H]ipratropium and 2.6 times faster than [(3)H]tiotropium. Residence half-life of [(3)H]aclidinium at the M(2) receptor was shorter than at the M(3) receptor, demonstrating kinetic selectivity for the M(3) receptor. In isolated guinea pig trachea, aclidinium showed comparable potency to ipratropium and tiotropium, faster onset of action than tiotropium, and duration of action similar to tiotropium and significantly longer than ipratropium. Nebulized aclidinium inhibited bronchoconstriction induced by acetylcholine in guinea pigs in a concentration-dependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t(1/2) = 29 h) was much longer than ipratropium (8 h) but shorter than tiotropium (64 h). In dogs, aclidinium induced a smaller and more transient increase in heart rate than tiotropium at comparable supratherapeutic doses. Therefore, under these conditions, aclidinium showed a greater therapeutic index than tiotropium (4.2 versus 1.6). These results indicate that aclidinium is a potent muscarinic antagonist with a fast onset of action, a long duration of effect, and a favorable cardiovascular safety profile.

Synthesis and structure-activity relationships of novel histamine H1 antagonists: indolylpiperidinyl benzoic acid derivatives.

A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.

Respuesta: La vigilancia de la salud y la valoración de la aptitud para trabajar: deconstruir, reconceptualizar y consensuar para mejorar / Response: Health surveillance and fitness for duty: deconstruct, reconceptualize and finding consensus on how to improve

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La aptitud laboral y la aptitud psicofísica en las profesiones de riesgo / No disponible

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Aclidinium bromide, a novel long-acting muscarinic antagonist for COPD with improved preclinical renal and urinary safety profile.

AIMS: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist currently in registration phase for the treatment of chronic obstructive pulmonary disease. Since urinary difficulty and retention have been reported for anticholinergic agents such as tiotropium and ipratropium, it is important to examine the preclinical urinary and renal safety profile of aclidinium. MAIN METHODS: The effect of aclidinium on urine and electrolyte excretion, renal function and voiding cystometry was analysed in conscious water-loaded Wistar rats (10-1000 µg/kg, s.c.), anaesthetised Beagle dogs (1000 µg/kg, i.v.) and anaesthetised guinea pigs (3-100µg/kg, intratracheally), respectively. Aclidinium plasma levels were determined in an independent study. Active comparators were tiotropium (all studies) and ipratropium (cystometry only). KEY FINDINGS: Aclidinium 1000 µg/kg had no effect on urine excretion in rats, in contrast to tiotropium 100 µg/kg which significantly decreased this parameter (p<0.05). Aclidinium 1000 µg/kg also had no effect on renal function in Beagle dogs. In guinea pigs, aclidinium 3-100 µg/kg had no effect on urinary bladder function, whereas tiotropium and ipratropium 100 µg/kg decreased the peak micturition pressure (p<0.05), increased the volume of urine retained in the bladder (p<0.01) and showed a trend to decrease the volume of urine excreted. SIGNIFICANCE: Aclidinium had no significant effect on urinary and renal function in the animal models studied. These results, together with the rapid plasma clearance of aclidinium reported previously, suggest a lower propensity to induce urinary retention in humans than tiotropium and ipratropium.

Icatibant for hereditary angioedema.

Hereditary angioedema (HAE) is an autosomal dominant, potentially life-threatening disease, characterized by recurrent self-limiting bouts of edema mainly involving the extremities, genitalia, face, intestines and airways. The prevalence of HAE in the general population has been estimated to be in the range of 1:10,000 to 1:150,000. Currently, acute attacks of HAE are treated mainly symptomatically, with poor outcomes. Recently, it has been demonstrated that bradykinin (BK) is responsible for most of the symptoms of HAE. Icatibant (Firazyr, HOE 140, JE049) is a potent, specific and selective B2 BK receptor antagonist that has recently been approved by the EMEA for the treatment of HAE. In phase III clinical trials, 30 mg of subcutaneous icatibant demonstrated rapid and stable relief from symptoms in cutaneous, abdominal or laryngeal HAE attacks. Local site reactions after subcutaneous injection of icatibant were observed, however, these reactions were mild to moderate in severity and resolved spontaneously and quickly. Icatibant is a new, safe and effective treatment for acute attacks of HAE.

Comparative antiallergic effects of second-generation H1-antihistamines ebastine, cetirizine and loratadine in preclinical models.

Ebastine (CAS 90729-43-4), cetirizine (CAS 83881-51-0) and loratadine (CAS 79794-75-5) are second generation H1-antihistamines of proven efficacy for treating allergy. Recent clinical studies have found ebastine to be more effective than cetirizine or loratadine in alleviating the symptoms of seasonal allergic rhinitis. The objective of this study was to compare the efficacy of these compounds in three guinea-pig modeles of bronchoconstriction, elicited either by histamine, allergen or leukotriene C4 in order to shed light onto the mechanisms that might explain differences found in clinical studies. In the present experiments, ebastine and cetirizine were equipotent against aerosol histamine-induced bronchospasm in guinea pigs (ED50 115 and 100 micrograms/kg p.o., respectively), while loratadine was three-fold less potent. In the same model the effects of ebastine, loratadine and cetirizine lasted 21, 19 and 15 h, respectively. Ebastine (ED50 334 micrograms/kg p.o.) was the most potent compound in inhibiting allergen-induced bronchospasm in conscious guinea pigs. In vitro studies in tracheally perfused guinea pig lungs demonstrated that ebastine and loratadine inhibited with equal potency the bronchoconstriction induced by leukotriene C4 whilst cetirizine was significantly less potent. Finally, in another in vivo study, ebastine reverted the changes in pulmonary resistance induced by leukotriene C4 in anaesthetised guinea pigs, whereas cetirizine and loratadine were devoid of activity in this model. In accordance with the clinical data, ebastine proved to be the substance with the widest range of application in animal experiments, too.

Almotriptan, a new anti-migraine agent: a review.

Almotriptan is a new anti-migraine agent with nanomolar affinity for human 5-HT(1B), 5-HT(1D), and 5-HT(1F) receptors, weak affinity for 5-HT(1A) and 5-HT(7) receptors and no significant affinity for more than 20 other pharmacological receptors. Almotriptan was effective in animal models predictive of anti-migraine activity in humans and had a good safety profile in animal studies. From the toxicological point of view, almotriptan has a profile similar to that of other marketed triptans. In animal studies, at levels substantially higher than required for therapeutic activity in humans, almotriptan was devoid of any oncogenic, genotoxic or teratogenic effects. Almotriptan is well absorbed orally; its absolute bioavailability in humans is 70%. Its peak plasma levels are reached at 1 to 3 h after its administration; its elimination half-life is 3 to 4 h. Almotriptan is metabolized by monoamine oxidase-mediated oxidative deamination and cytochrome P450-mediated oxidation as the major metabolic route and by flavin monooxygenase as the minor route. No dose adjustment is required for gender or age, and only in the case of severe renal impairment the dose should not exceed 12.5 mg over a 24-h period. There was no significant interaction between a single dose of almotriptan and propranolol, fluoxetine or verapamil, at multiple doses. The efficacy of almotriptan in the treatment of acute migraine was demonstrated in clinical trials on more than 3000 patients with migraine. At two h after oral administration of almotriptan, 12.5 mg, the percentages of patients showing pain relief and a pain-free score were 64 and 36%, respectively. The effects of almotriptan were significantly better than those of placebo. When almotriptan was administered in the early phase of migraine, the percentage of pain-free patients at 2 h rose to 84%. In a phase III, double-blind and placebo-controlled study, the incidence of adverse events with almotriptan was not statistically different from that of placebo. Based on the available data, it appears that almotriptan is the triptan of choice when good efficacy and high tolerability are desired.