Once-daily glycopyrronium via the Breezhaler® device for the treatment of COPD: pharmacological and clinical profile

In the management of chronic obstructive pulmonary disease (COPD), there is an unmet medical need for effective bronchodilator treatments that not only have a fast onset of action, but also a long duration of action and are delivered using a simple, easy-to-use device. Long-acting muscarinic antagonists such as glycopyrronium and tiotropium, along with long-acting beta-2 agonists such as indacaterol, formoterol and salmeterol are the pillars of pharmacological therapy for the long-term management of patients with COPD. Glycopyrronium, the quaternary ammonium ion of glycopyrronium bromide, acts as a competitive antagonist by selectively binding to the muscarinic receptors in the bronchial smooth musculature, thus inhibiting acetylcholine-mediated bronchoconstriction. Glycopyrronium is an inhaled once-daily long-acting muscarinic antagonist recently approved for the maintenance treatment of patients with COPD. Glycopyrronium is administered by a single-dose, dry-powder inhaler, the Breezhaler® device, designed specifically to have a low internal resistance, be easy to use and confirm efficient drug delivery in patients with a wide range of COPD severities, irrespective of the age. Glycopyrronium has been shown to provide rapid and sustained improvements in lung function, dyspnea, health status, exercise endurance and exacerbation risk and an acceptable safety and tolerability profile.     

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

β₃-Adrenoceptor agonists are an emerging drug class for the treatment of the overactive bladder syndrome, and clinical proof-of-concept data have been obtained for three representatives of this class, mirabegron, ritobegron, and solabegron. We review here the pharmacological profile of these three drugs and discuss the potential clinical relevance of differences between them. In the absence of direct comparative studies, it appears that all three are strong agonists selective for β₃- vs. β₁- and β₂-adrenoceptors in studies with cloned receptor subtypes. The potency of these agonists may be species-dependent, with all three having high potency in the human detrusor. All three agonists were effective in one or more animal models of bladder dysfunction, which typically involved reductions of micturition frequency. Agonist doses effective for bladder function lowered blood pressure in some cases, but the relevance of this for clinical use is difficult to determine due to species differences in the importance of cardiovascular β₃-adrenoceptors. While limited effects on other organ systems are expected for β₃-adrenoceptor agonists, this requires further investigation.     

Pharmacological profile of a 17β-heteroaryl-substituted neuroactive steroid

Rationale

In order to improve upon the pharmacological properties of the neuroactive steroid ganaxolone, it was used as the starting point in the design of novel neurosteroids that replace the 17β-acetyl side chain with an isoxazole bioisostere.

Objectives

UCI-50027 (3-[3α-hydroxy-3β-methyl-5α-androstan-17β-yl]-5-(hydroxymethyl)isoxazole) was designed as an orally active neuroactive steroid specifically targeted at the gamma-aminobutyric acid(A) receptor (GABA_AR).

Methods

UCI-50027 was tested in vitro in Xenopus oocytes expressing human GABA_ARs and in vivo as an anticonvulsant, for ataxic effects and for anxiolytic activity.

Results

In vitro, UCI-50027 dose-dependently enhanced the activity of GABA at human α₁β₂γ_2L, α₂β₁γ_2L, and α₄β₃δ GABA_ARs. Consistent with its action as a positive allosteric modulator (PAM), it had no direct activity in the absence of GABA. UCI-50027 protected against acute pentylenetetrazol (PTZ)-induced convulsions with an ED₅₀ of 6 mg/kg p.o. In the rotarod (RR) paradigm in mice, the AD₅₀ (the ataxic dose where half of the animals fail the RR test) was found to be 38 mg/kg p.o., giving a therapeutic index (TI = RR AD₅₀/PTZ ED₅₀)～6 versus 2.8 for ganaxolone. In the mouse-elevated plus maze (EPM) model for anxiety, UCI-50027 showed a minimum effective dose (MED) ≤0.3 mg/kg p.o. Thus, the TI (TI = RR AD₅₀/EPM MED) for the compound as an anxiolytic is ≥127 versus 3.3 for ganaxolone.

Conclusions

UCI-50027 is an orally active neuroactive steroid with pharmacological activity consistent with a GABA_AR PAM that has an improved separation between anticonvulsant/anxiolytic and rotarod effects, potent activity as an anticonvulsant and anxiolytic when compared to ganaxolone.     

Pharmacological properties of Myrtacine® and its potential value in acne treatment

This study aimed at evaluating the antiproliferative, antibacterial, and anti-inflammatory properties of an ethanolic myrtle extract (Myrtacine?) in vitro, characterising its potential active compounds (myrtucommulones A and B') by structural analysis, and evaluating their biological activity. Antiproliferative activity was assessed by the BrdU incorporation assay in HaCat keratinocytes and inhibitory and bactericidal activities against P. ACNES strains by measuring the minimal inhibitory concentration (MIC) and D value. Anti-inflammatory effect was evaluated by measuring 6-keto-prostaglandin F1 α and [3H]-arachidonic acid metabolite production in keratinocytes stimulated for inflammation. Myrtacine? inhibited keratinocyte proliferation by 27?% and 76?% at 1 and 3?μg/mL, respectively (p?相似文献   

Pharmacological profile of a new potent and specific α2-adrenoceptor antagonist,L-657,743

Summary L-657,743, (2S,12bS)1,3-dimethylspiro (1, 3,4,5, 6,6, 7,12 b-octahydro-2-H-benzo[b]furo[2,3-a]quinolizine)-2, 4- pyrimidin-2-one, was tested in several in vitro and in vivo models for ₂-adrenoceptor antagonism. L-657,743 exhibited a high affinity ( 1 nM) for ₂-adrenoceptors labelled by [³H] rauwolscine or [3H]clonidine with a 240-fold selectivity versus ₁-adrenoceptors labelled by [³H]prazosin. L-657,743 was a potent, selective, and competitive ₂-adrenoceptor antagonist in the rat isolated vas deferens (pA₂ = 9.3 vs clonidine; pA₂ = 7.1 vs methoxamine). In vivo, L-657,743 potently blocked clonidine-induced mydriasis in the rat and stimulated cerebrocortical norepinephrine synthesis, two indices of central ₂-adrenoceptor antagonism. L-657,743 exhibited a comparatively low affinity for several monoamine receptor subtypes (D₁, D₂, 5-HT₁, 5-HT₂) in radioligand binding assays in vitro and a comparatively low potency to alter the synthesis of brain DA and 5-HT in vivo indicating a marked ₂-specificity versus other monoamine receptor mechanisms. Compared to yohimbine, L-657,743 had considerably higher ₂-antagonist potency and ₂/₁ selectivity and was significantly more ₂-specific (i.e., vs. DA, 5-HT receptors). Send of fprint requests to : D. J. Pettibone at the above address     

Resolution of a1-Adrenoceptor Antagonist (±)-DDPH and Pharmacological Activity of (-)-DDPH

本文将ａ１受体拮抗剂（±）－ＤＤＰＨ用（＋）－酒石酸和（－）－二苯甲酰酒石酸为拆分剂拆分为（＋）－ＤＤＰＨ体和（－）－ＤＤＰＨ。（－）－ＤＤＰＨ和（±）－ＤＤＰＨ拮抗ａ１受体激动剂苯肾上腺素作用强度相近，ＰＡ２值分别为７．６９和７．５５。