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Uli Hacksell - One of the best experts on this subject based on the ideXlab platform.
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amide urea and carbamate analogues of the Muscarinic Agent 4 n 3 chlorophenyl carbamoyl oxy 2 butynyl trimethylammonium chloride
Journal of Medicinal Chemistry, 1992Co-Authors: Bjoern M. Nilsson, Hugo M. Vargas, Uli HacksellAbstract:A series of amide, urea, and carbamate analogues of the Muscarinic (M1) ganglionic stimulant [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride (McN-A-343; 1) was prepared. The C1-methyl-substituted carbamates 8-11 were resolved into the enantiomers. In order to investigate the ganglionic stimulant activity and affinity of the new compounds we studied their ability to increase mean arterial blood pressure (MAP) in the pithed rat and their ability to displace the M1 receptor selective antagonist [3H]pirenzepine from rabbit sympathetic ganglia. The quaternary ammonium derivatives of 1, but not their corresponding tertiary amines, displayed ganglionic stimulant properties. The urea derivative 14 and the acetamide derivative 18 were almost equipotent to 1 as ganglionic agonists. In addition, 14 and 18 showed only 2- to 3-fold less affinity to ganglionic Muscarinic receptors than 1. Introduction of a methyl group in the 1 position of the butynyl chain of 1 and its 4-chlorophenyl analogue increased ganglionic stimulant potency. The resulting (+/-)-9 and (+/-)-11 were the most potent analogues in this study. They were found to be partial agonists and showed 5- and 16-fold higher potency than 1, respectively, in increasing the MAP. They also displayed 6- and 18-fold higher affinity than 1 for ganglionic M1 receptors. The (S)-enantiomers of 9 and 11 were 1.5- and 4.9-fold more potent, respectively, than their antipodes as ganglionic Muscarinic stimulants. The C1-methyl-substituted urea and acetamide derivatives (15 and 19) were 1.5- and 3-fold less potent than 1 and displayed several-fold lower affinity for ganglionic M1 receptors. The new quaternary analogues retained the selectivity for ganglionic Muscarinic receptors since they produced weak partial agonist effects on the guinea pig ileum and showed several-fold lower nicotinic activity than 1 in the frog rectus abdominis assay.
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Analogues of the Muscarinic Agent 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane]: synthesis and pharmacology.
Journal of medicinal chemistry, 1992Co-Authors: Gunnar Nordvall, Staffan Sundquist, Gunilla Glas, Lisbeth Nilvebrant, Adolf Gogoll, Uli HacksellAbstract:A number of tetrahydrofuran analogues of 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane] (1) have been prepared with the aim to obtain information about the relative importance of each of the oxygens in 1 for efficacy and for selectivity. In addition, the dimethyl and desmethyl analogues of 1 were prepared. The new compounds were compared to cis- and trans-1 with regard to their ability to displace (-)-[3H]-3-quinuclidinyl benzilate ((-)-[3H]QNB) from Muscarinic receptors in cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs. Functional studies were made on isolated guinea pig bladder and ileum. The new compounds exhibited both lower affinity and efficacy than cis-1. A conformational study was performed, and the effects of steric and electronic factors on the biological activity of the compounds are discussed.
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Phenyl-substituted analogues of oxotremorine as Muscarinic antagonists.
Journal of medicinal chemistry, 1992Co-Authors: Bjoern M. Nilsson, Hugo M. Vargas, Bjoern Ringdahl, Uli HacksellAbstract:A series of phenyl-substituted analogues of the Muscarinic Agent oxotremorine (1) have been prepared. The new compounds (3b-11b and 9c) were assayed for antiMuscarinic activity on the isolated guinea pig ileum and in intact mice. They were also evaluated for ability to inhibit the binding of the Muscarinic antagonist (-)-[3H]-N-methylscopolamine to homogenates of the rat cerebral cortex. The phenyl-substituted derivatives were devoid of intrinsic Muscarinic activity. Instead, they behaved as competitive Muscarinic antagonists in these assays with similar or lower affinity for Muscarinic receptors than the corresponding methyl-substituted analogues. The succinimide (8b) and the pyrrolidone (3b) derivatives of 1 substituted with a phenyl group at position 1 of the butynyl chain showed the highest antiMuscarinic potency with dissociation constants (KD) of 0.10 and 0.20 microM, respectively, in the ileum assay. The phenyl-substituted analogues showed an approximately 10-fold lower in vivo antiMuscarinic potency than their corresponding methyl-substituted positional isomers. A correlation was observed between in vitro and in vivo potency within subsets consisting of methyl- and phenyl-substituted derivatives.
Nitin V Vanjare - One of the best experts on this subject based on the ideXlab platform.
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Does roflumilast induce phagocytic activity in COPD patients
International journal of chronic obstructive pulmonary disease, 2015Co-Authors: Baishakhi Ghosh, Nitin V VanjareAbstract:Dear editor We read the article by Porpodis et al1 with great interest. In this study, the authors have evaluated the effect of roflumilast on the phagocytic activity of systemic phagocytes in severe and very severe COPD patients by measuring the oxidative burst post-bacterial stimulation. The study group for this study involved 21 severe or very severe COPD patients who were administered roflumilast in addition to other COPD treatments such as long-acting beta-adrenoceptor agonists (LABA) + inhaled corticosteroids (ICS) + long-acting anti-Muscarinic Agent (LAMA) or ICS + LABA. Prior animal studies have reported that ICS impairs Klebsiella pneumoniae phagocytosis and decreases oxidative stress post-infection with bacteria.2 It would have been interesting to know the phagocytic efficacy of roflumilast in combination with other therapeutic drugs for instance, whether the phagocytic efficacy of the combination of roflumilast and ICS is more as compared to other combinations. This could have been possibly achieved by dividing the study group into subgroups such as ICS + roflumilast or LABA + roflumilast or LAMA + roflumilast or ICS + LABA + roflumilast. Porpodis et al1 also reported that roflumilast increases phagocytic activity, and this anti-inflammatory effect contributes toward increase in lung function parameters among COPD subjects.3 Previous studies have reported that ICS + LABA or ICS + LABA + LAMA improves the lung function. However, in this study there is no control group (group without roflumilast treatment) therefore, the improvement seen in lung function could be a combined effect of ICS + LABA, ICS + LABA + LAMA and roflumilast and not roflumilast alone. Additionally, it would have been interesting to know whether increase in phagocytosis by roflumilast can contribute toward improvement of exacerbations. It has been reported by Calverley et al4 that roflumilast decreases exacerbations among mild to moderate COPD patients, but there are no data available with reference to severe COPD patients. Lastly, the authors should have presented the lung function data in terms of actual values along with the percent predicted format, this would have made the results easy to comprehend.
L. Olbe - One of the best experts on this subject based on the ideXlab platform.
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Cephalic Phase of Pancreatic-Polypeptide Secretion Studied by Sham Feeding in Man
Scandinavian Journal of Gastroenterology, 2010Co-Authors: Thue W. Schwartz, Bo Stenquist, L. OlbeAbstract:The effect of sham feeding on pancreatic-polypeptide (PP) secretion was studied in 26 duodenal ulcer (DU) patients and in 8 healthy subjects. Modified sham feeding (MSF) by the ‘chew and spit’ technique induced a rapid increase in plasma concentrations of PP both in DU patients, 56 (2–138) pmol/1, and in the healthy subjects, 24 (2–45) pmol/1, median peak-increment and range. Four out of 26 DU patients and 2 out of 8 healthy subjects did not show any PP response to MSF. The PP response to MSF was abolished by pretreatment with atropine, or benzilonium, a quarternary anti-Muscarinic Agent with minimal cerebral actions. The PP response to MSF was not dependent on the gastric acid response, since a PP response to sham feeding was found in 13 out of 17 patients with selectively denervated parietal cell area, and thus, without acid response. During adequate sham feeding, in which the food is also swallowed but does not reach the stomach, the PP increment, 100 (81–129) pmol/1, was larger than during MSF in the ...
Mario Cazzola - One of the best experts on this subject based on the ideXlab platform.
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New perspectives on the role of Muscarinic antagonists in asthma therapy.
Expert review of respiratory medicine, 2020Co-Authors: Maria Gabriella Matera, Carmela Belardo, Michele Rinaldi, Barbara Rinaldi, Mario CazzolaAbstract:Introduction: There is increasing evidence that tiotropium, a long-acting Muscarinic Agent (LAMA), is useful in the presence of severe-uncontrolled asthma despite the optimization of therapy with i...
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Safety Considerations with Dual Bronchodilator Therapy in COPD: An Update
Drug Safety, 2016Co-Authors: Maria Gabriella Matera, Paola Rogliani, Luigino Calzetta, Mario CazzolaAbstract:Combining a long-acting β_2-agonist (LABA) with a long-acting anti-Muscarinic Agent (LAMA) provides synergistic benefit on airway smooth muscle relaxation, which may have major implications for the use of LABA/LAMA combinations in the treatment of chronic obstructive pulmonary disease (COPD). There are four different approved LAMA/LABA fixed-dose combinations (FDCs)—glycopyrronium/indacaterol, umeclidinium/vilanterol, tiotropium/olodaterol, and aclidinium/formoterol—and another, glycopyrronium/formoterol, that is still under clinical development. Many pivotal trials have shown that all of these FDCs are more effective than monotherapies in inducing bronchodilation and do not amplify the possible adverse events (AEs) that are characteristic of LAMAs and LABAs when used as monotherapy. Unfortunately, these clinical trials have included a very small and highly selected fraction of the COPD patient population. Therefore, it is questionable whether such data can be extrapolated to a larger, ‘real-life’ population of patients with COPD, especially given that COPD patients with co-morbidities are often excluded from clinical trials, COPD is a major risk factor for most cardiovascular diseases, and both LAMAs and LABAs have a high potential to impact cardiac activities. All clinical trials have been conducted under widely varying conditions and, consequently, AE rates of a drug observed in a clinical trial cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Head-to-head studies comparing the different LAMA/LABA FDCs that will include the true patients that we meet in our everyday practice are absolutely essential if we wish to make a therapeutic choice that is not purely empirical.
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Pharmacological interaction between LABAs and LAMAs in the airways: optimizing synergy.
European Journal of Pharmacology, 2015Co-Authors: Luigino Calzetta, Maria Gabriella Matera, Mario CazzolaAbstract:Nowadays there is solid clinical information for combining β2-agonists and anti-Muscarinic Agents, although the nature (additive or synergistic) of the net clinical result obtained by co-administration of these two classes of bronchodilators is not completely elucidated from a pharmacological point of view. Recent preclinical studies demonstrated that combining a long-acting β2-agonist (LABA) with a long-acting anti-Muscarinic Agent (LAMA) provides synergistic benefit on airway smooth muscle relaxation, which may have major implications for the use of LABA/LAMA combinations in the treatment COPD. Indeed, the LABA/LAMA synergism has been proved also in patients with moderate-to-severe COPD. Nevertheless, there is still a strong medical need for dose-finding clinical trials designed to identify the most favourable doses of LABA/LAMA combinations able to induce a real synergism. We strongly believe that the Bliss Independence theory represents an effective model for investigating the cross-talk between β2-adrenoreceptor and the Muscarinic pathways leading to the synergistic interaction between β2-agonists and anti-Muscarinic Agents. In any case, the possibility of eliciting a synergistic bronchodilator effect when combining a LABA and a LAMA suggests that the therapeutic approach proposed by GOLD recommendations to only use LABA/LAMA combination in more severe COPD patients who are not controlled by a single bronchodilator should be reconsidered. We support the possibility of an early intervention with low doses of LABA/LAMA combination to optimize bronchodilation and reduce the risk of adverse events that characterize both LABAs and LAMAs, especially when administered at the full doses currently approved for the treatment of COPD.
Baishakhi Ghosh - One of the best experts on this subject based on the ideXlab platform.
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Does roflumilast induce phagocytic activity in COPD patients
International journal of chronic obstructive pulmonary disease, 2015Co-Authors: Baishakhi Ghosh, Nitin V VanjareAbstract:Dear editor We read the article by Porpodis et al1 with great interest. In this study, the authors have evaluated the effect of roflumilast on the phagocytic activity of systemic phagocytes in severe and very severe COPD patients by measuring the oxidative burst post-bacterial stimulation. The study group for this study involved 21 severe or very severe COPD patients who were administered roflumilast in addition to other COPD treatments such as long-acting beta-adrenoceptor agonists (LABA) + inhaled corticosteroids (ICS) + long-acting anti-Muscarinic Agent (LAMA) or ICS + LABA. Prior animal studies have reported that ICS impairs Klebsiella pneumoniae phagocytosis and decreases oxidative stress post-infection with bacteria.2 It would have been interesting to know the phagocytic efficacy of roflumilast in combination with other therapeutic drugs for instance, whether the phagocytic efficacy of the combination of roflumilast and ICS is more as compared to other combinations. This could have been possibly achieved by dividing the study group into subgroups such as ICS + roflumilast or LABA + roflumilast or LAMA + roflumilast or ICS + LABA + roflumilast. Porpodis et al1 also reported that roflumilast increases phagocytic activity, and this anti-inflammatory effect contributes toward increase in lung function parameters among COPD subjects.3 Previous studies have reported that ICS + LABA or ICS + LABA + LAMA improves the lung function. However, in this study there is no control group (group without roflumilast treatment) therefore, the improvement seen in lung function could be a combined effect of ICS + LABA, ICS + LABA + LAMA and roflumilast and not roflumilast alone. Additionally, it would have been interesting to know whether increase in phagocytosis by roflumilast can contribute toward improvement of exacerbations. It has been reported by Calverley et al4 that roflumilast decreases exacerbations among mild to moderate COPD patients, but there are no data available with reference to severe COPD patients. Lastly, the authors should have presented the lung function data in terms of actual values along with the percent predicted format, this would have made the results easy to comprehend.
