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1
Folkow, L. P. "Adrenergic vasomotor responses in nasal mucosa of hooded seals." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 263, no. 6 (December 1, 1992): R1291—R1297. http://dx.doi.org/10.1152/ajpregu.1992.263.6.r1291.
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In seals respiratory heat and water losses are restricted through nasal heat exchange. The heat exchange efficiency is apparently controlled through adjustments in the nasal mucosal blood flow rate and/or pattern. In this study the adrenergic mechanisms involved in regulation of mucosal blood flow were investigated. The nasal mucosal vasculature of 14 newly killed hooded seal (Cystophora cristata) pups was perfused by a constant-flow peristaltic pump with 37 degrees C oxygenated modified Krebs solution via the sphenopalatine arteries. The effects of single-dose injections of various drugs on resistance to flow were monitored with a pressure transducer. Epinephrine, norepinephrine, alpha 1-adrenoceptor agonist phenylephrine, alpha 2-agonist clonidine, beta 1-agonist dobutamine, and beta 2-agonist terbutaline caused transient pressure increases that were blocked by alpha-adrenoceptor antagonists. Papaverine and vasoactive intestinal polypeptide induced vasodilatation, showing that some basal vascular tone was present. Nevertheless, the beta 1- and beta 2-agonist isoproterenol had no effect on resistance, and none of the beta-agonists attenuated the pressor responses to alpha-agonists. In conclusion, adrenergic control of nasal mucosal blood flow in seals is essentially exerted through alpha-adrenoceptor-mediated arteriolar constriction, whereas beta-adrenoceptor-mediated dilatation seems to be of little importance. It is suggested that such sympathoadrenergic vascular mechanisms contribute to control nasal heat exchange efficiency in seals.
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Tavernier, G., J. Galitzky, P. Valet, A. Remaury, A. Bouloumie, M. Lafontan, and D. Langin. "Molecular mechanisms underlying regional variations of catecholamine-induced lipolysis in rat adipocytes." American Journal of Physiology-Endocrinology and Metabolism 268, no. 6 (June 1, 1995): E1135—E1142. http://dx.doi.org/10.1152/ajpendo.1995.268.6.e1135.
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The mechanisms underlying catecholamine control of lipolysis were studied in rat white adipocytes from epididymal, retroperitoneal, and subcutaneous fat depots. Sensitivity of subcutaneous adipocytes to selective beta 3-adrenoceptor agonists was lower than that of internal adipocytes. beta 3-Adrenoceptor mRNA levels were lower in subcutaneous adipocytes. A decreased beta 1/beta 2-adrenoceptor-mediated lipolysis was also observed in these adipocytes, and the number of beta 1/beta 2-adrenoceptors was lower than in the internal adipocytes. The number of alpha 2-adrenoceptors was higher in subcutaneous adipocytes without a marked difference in alpha 2-adrenoceptor-mediated antilipolysis between the depots. Subcutaneous adipocytes were also characterized by a lower maximal lipolytic response to drugs acting at different levels of the lipolytic cascade, suggesting differences at the postreceptor level. Lower hormone-sensitive lipase activity and mRNA levels in subcutaneous adipocytes were in agreement with the lipolysis data. These results suggest that the pattern of expression of the genes of the lipolytic pathway varies with the anatomic location of the fat depot.
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Lofdahl, CG, and KF Chung. "Long-acting beta 2-adrenoceptor agonists: a new perspective in the treatment of asthma." European Respiratory Journal 4, no. 2 (February 1, 1991): 218–26. http://dx.doi.org/10.1183/09031936.93.04020218.
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New long-acting beta 2-adrenoceptor agonists, formoterol and salmeterol, may soon appear in several European countries for treatment of asthma. This review examines currently available information and compares the basic pharmacology and describes the clinical effects of these new drugs. The long duration of bronchodilation seen in clinical studies seems to be similar, whereas in isolated tissues there might be a difference in the binding characteristics to the beta 2-adrenoceptor. Long-acting beta 2-agonists could have an inhibitory effect on inflammatory events related to asthma, but the clinical relevance of these effects is not clear at present. Long-term studies up to one year with both new drugs have not shown any unexpected side-effects, and no tachyphylaxis to beta-adrenoceptor stimulation has been reported. Patients appear to strongly prefer the new drugs compared to the short-acting beta 2-agonists. The potential place for these drugs in the treatment of asthma is discussed and some pitfalls pointed out. It is likely that the long-acting beta 2-agonists will be beneficial to many asthmatic patients.
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Ulrik, CS, and A. Kok-Jensen. "Different bronchodilating effect of salmeterol and formoterol in an adult asthmatic." European Respiratory Journal 7, no. 5 (May 1, 1994): 1003–5. http://dx.doi.org/10.1183/09031936.94.07051003.
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New long-acting beta 2-adrenoceptor agonists, salmeterol and formoterol, have recently been marketed for treatment of asthma, but studies comparing the clinical efficacy of the two drugs have not been published. We report on an asthmatic patient who had a striking difference in bronchodilating effect of the two drugs, formoterol being more effective than salmeterol both in immediate response and during long-term treatment. Although, both formoterol and salmeterol are highly selective for the beta 2-adrenoceptors (comparable to salbutamol and terbutaline), differences in their chemical structure suggest differences in their mechanisms of action or receptor specificity. The clinical implication of our observation appears to be that a less favourable response in an individual patient to one of the long-acting beta 2-agonists should not preclude a trial with another. Future studies comparing the clinical efficacy of formoterol and salmeterol should probably also address the question of responders and nonresponders to these drugs; and furthermore, seek to explore a possible relationship to inherited variance in beta 2-receptors.
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al-Damluji, S., and D. Francis. "Activation of central alpha 1-adrenoceptors in humans stimulates secretion of prolactin and TSH, as well as ACTH." American Journal of Physiology-Endocrinology and Metabolism 264, no. 2 (February 1, 1993): E208—E214. http://dx.doi.org/10.1152/ajpendo.1993.264.2.e208.
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In normal male volunteers, intravenous infusions of the alpha 1-adrenergic agonist methoxamine stimulated the secretion of prolactin, thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH), and the effects were abolished by pretreatment with the alpha 1-antagonist prazosin. To investigate the site of action of methoxamine, its effects were compared with those of equipotent doses of norepinephrine, an alpha 1-agonist that reaches the pituitary gland and the median eminence after an intravenous infusion but, unlike methoxamine, does not cross the blood-brain barrier. Norepinephrine did not stimulate secretion of prolactin, TSH, or ACTH, suggesting that the stimulant alpha 1-adrenoceptors are located in the central nervous system and not directly on the pituitary gland or in the periphery. The alpha 2- and beta-adrenoceptor agonist properties of norepinephrine could not account for the differences from methoxamine, as pretreatment with prazosin did not modify hormone concentrations after norepinephrine. Methoxamine had no behavioral stimulant effects, as judged by visual analog scales that were sensitive to physiological changes in behavioral arousal. In four patients with hypothalamic dysfunction but responsive pituitary corticotrophs, methoxamine had no stimulant effect on the secretion of ACTH, confirming that the alpha 1-adrenoceptors that stimulate ACTH secretion are not located directly on the pituitary. None of the drugs had an effect on the secretion of growth hormone or the gonadotrophins.
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Moore, N. G., G. G. Pegg, and M. N. Sillence. "Anabolic effects of the beta 2-adrenoceptor agonist salmeterol are dependent on route of administration." American Journal of Physiology-Endocrinology and Metabolism 267, no. 3 (September 1, 1994): E475—E484. http://dx.doi.org/10.1152/ajpendo.1994.267.3.e475.
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It is reported that a long duration of action is required for beta 2-adrenoceptor agonists to evoke an anabolic response. In the present study, we compare the potency of clenbuterol with that of the new long-acting compound salmeterol, when given at equimolar doses to female Wistar rats by different routes of administration. Given orally for 10 days, salmeterol had no effect on growth at a dose of 120 micrograms/day, whereas at 2.4 mg/day the drug caused significant increases in body and carcass weight and in the mass of the mixed-fiber gastrocnemius/plantaris and tibialis anterior muscles, but there were no increases in the slow-twitch soleus muscles. A similar growth response was seen when clenbuterol was given orally at a dose of only 97 micrograms/day, with an additional response seen in soleus muscle at 1.9 mg/day. Thus clenbuterol was more potent than salmeterol when given by this route of administration. When the drugs were infused by osmotic minipump, both salmeterol (130 micrograms/day) and clenbuterol (100 micrograms/day) caused increases in body weight gain and in the weights of the mixed-fiber muscles, with the most dramatic effect of infusion being to greatly increase the anabolic effect of salmeterol in soleus muscle. A single intraperitoneal injection of salmeterol (53 micrograms) or clenbuterol (40 micrograms) caused a similar rapid increase in the concentration of adenosine 3',5'-cyclic monophosphate in gastrocnemius muscle. These results indicate that the potency of salmeterol in vivo is dependent on its route of administration and that slow-twitch muscles are less sensitive than mixed-fiber muscles to the anabolic effects of beta 2-adrenoceptor agonists.
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García-Lunar, Inés, Daniel Pereda, Borja Ibanez, and Ana García-Álvarez. "Neurohormonal Modulation as a Therapeutic Target in Pulmonary Hypertension." Cells 9, no. 11 (November 22, 2020): 2521. http://dx.doi.org/10.3390/cells9112521.
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The autonomic nervous system (ANS) and renin-angiotensin-aldosterone system (RAAS) are involved in many cardiovascular disorders, including pulmonary hypertension (PH). The current review focuses on the role of the ANS and RAAS activation in PH and updated evidence of potential therapies targeting both systems in this condition, particularly in Groups 1 and 2. State of the art knowledge in preclinical and clinical use of pharmacologic drugs (beta-blockers, beta-three adrenoceptor agonists, or renin-angiotensin-aldosterone signaling drugs) and invasive procedures, such as pulmonary artery denervation, is provided.
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Janson, C., J. Boe, G. Boman, B. Mossberg, and N. Svedmyr. "Bronchodilator intake and plasma levels on admission for severe acute asthma." European Respiratory Journal 5, no. 1 (January 1, 1992): 80–85. http://dx.doi.org/10.1183/09031936.93.05010080.
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We have measured the plasma levels of salbutamol, terbutaline and theophylline in 140 patients (70 men, mean age 57 yrs) arriving for emergency treatment with severe acute asthma. The aim of the study was to investigate how the measured plasma levels correlated with the reported bronchodilator intake and whether the pretreatment beta 2-agonist levels influenced the effect of emergency salbutamol treatment. We found a highly significant correlation between the reported 24 h dose and the measured plasma concentrations for all three drugs. A plasma concentration less than 40 mumol.l-1 was found in 63 of the 107 patients who had taken theophylline, while no patient had a plasma concentration greater than 110 mumol.l-1. A plasma concentration above the suggested therapeutic range was found in 23 of the 95 patients who had taken terbutaline (greater than 30 nmol.l-1) and in 12 of the 98 patients who had taken salbutamol (greater than 60 nmol.l-1). A significant negative correlation was found between the initial plasma beta 2-agonist levels and the bronchodilation after i.v. salbutamol treatment (5 micrograms.kg-1), while there was no clear indication that high plasma beta 2-agonist levels reduced the bronchodilator effect of a high dose of inhaled salbutamol (0.15 mg.kg-1 x 2). We conclude that some patients arriving with acute asthma have high blood concentrations of beta 2-agonists, which possibly limit the response to i.v. beta 2-agonist treatment, while the effect of high-dose inhaled beta 2-agonists appears to be related to a lesser degree to the drug concentration on arrival. In this study overtreatment with theophylline appears to be uncommon.
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Lammers, JW, ME Muller, HT Folgering, and CL van Herwaarden. "Effects of terbutaline and atenolol on large and small airways in asthmatic patients." European Respiratory Journal 1, no. 5 (May 1, 1988): 453–57. http://dx.doi.org/10.1183/09031936.93.01050453.
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In order to localize the main site of action of the beta 2-adrenoceptor selective agonist terbutaline and the beta 1-adrenoceptor selective antagonist atenolol in the airways of asthmatic patients, we compared the effects of these drugs on maximal expiratory flow-volume (MEFV) curves when breathing air and when breathing a helium-oxygen (HeO2) mixture. To investigate whether a shift in localization of the bronchodilator effect occurs when terbutaline is inhaled repeatedly, dose-response curves with terbutaline were performed for parameters derived from MEFV curves when breathing air and for density dependence of expiratory airflow. By measurement of MEFV curves when the patients were breathing air alone, it was not possible to determine whether there is a difference in the bronchoconstrictor effect of atenolol between large and small airways. Inhalation of terbutaline to a cumulative dose of 2.0 mg induced a stepwise improvement in expiratory airflow parameters for large and small airways function when breathing air. Doubling the dose of inhaled terbutaline to 4 mg did not result in any further improvement of lung function. Neither atenolol nor terbutaline induced significant mean changes in density dependence of expiratory airflow. This was partly due to large inter- and intra-individual variations of this parameter. Another possibility is that atenolol and terbutaline effect large and small airways function equally.
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Naline, E., Y. Zhang, Y. Qian, N. Mairon, GP Anderson, B. Grandordy, and C. Advenier. "Relaxant effects and durations of action of formoterol and salmeterol on the isolated human bronchus." European Respiratory Journal 7, no. 5 (May 1, 1994): 914–20. http://dx.doi.org/10.1183/09031936.94.07050914.
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The objective of this study was to evaluate the potency and efficacy (intrinsic activity) of formoterol and salmeterol and their duration of action in comparison with other beta-adrenoceptor agonists in isolated human bronchi. Human bronchi were obtained at thoracotomy from patients with lung cancer. Potency (-log of the concentration of drug inducing 50% of maximal relaxation (-log EC50)) and efficacy (maximal effect (Emax), % of response to theophylline 3 x 10(-3) mol.l-1) were determined by analysis of cumulative isometric concentration-response curves to beta 2-adrenoceptor agonists in bronchial rings at resting tone or contracted maximally with acetylcholine 10(-3) mol.l-1 to induce functional antagonism. The onset and duration of action of beta-adrenoceptor agonists were measured by assessing the relaxant activity of drugs on the basal tone of isolated bronchi. In terms of potency, the rank order of the substances studied was formoterol > fenoterol > or = salmeterol > or = isoprenaline > or = salbutamol > or = adrenaline > or = terbutaline. Formoterol was 150-200 times more potent than isoprenaline. On preparations contracted with acetylcholine 10(-3) mol.l-1 the intrinsic activity (IA) of salbutamol, terbutaline and salmeterol compared with that of isoprenaline ranged 0.62-0.66. Intrinsic activity was higher with formoterol (0.84) and fenoterol (0.75). The onset of action of formoterol (2.14 +/- 0.55 min, n = 11) was not significantly different from that of salbutamol (1.90 +/- 0.24 min, n = 8) but shorter than that of salmeterol (6.40 +/- 1.40 min, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)
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S., Narendra Babu, Vinoth Kumar C., and Nandini R. "Comparative study of adverse drug reaction pattern of two anti-asthma groups of drugs in a tertiary care hospital." International Journal of Basic & Clinical Pharmacology 8, no. 4 (March 23, 2019): 788. http://dx.doi.org/10.18203/2319-2003.ijbcp20191118.
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Background: Bronchial Asthma is one of the worldwide health problems associated with increased morbidity and also mortality. Bronchial Asthma is a disease of airways that is characterized by increased responsiveness of the trachea-bronchial tree. Anti asthmatic drugs are associated with adverse effects which can affect the compliance and course of treatment. Monitoring adverse drug reactions in asthma will play a vital role in alerting physicians about the possibility and circumstances of such events, thereby protecting the user population from avoidable harm.Methods: The study was conducted in 500 bronchial asthma patients (250 patients in Beta 2 agonist group (Salbutamol) and 250 patients in Methylxanthine group (Deriphyllin) who fulfilled the study criteria and were observed for three months at Madras Medical College and Rajiv Gandhi Government General Hospital, Chennai. Their prescriptions were collected and analysed. Adverse drug reactions(ADRs) in each group were collected and evaluated. The causality assessment was done by WHO-UMC assessment scale and severity by using Modified Hartwig-Seigel severity assessment scale.Results: Total 38% of patients taking anti-asthma drugs were encountered adverse drug reactions and were more common in elderly females (61 to 70 years). Adverse Drug Reactions were more common in Methylxanthine group (48%) compared to Beta 2 agonist group (28%). Headache (38%) was the commonest ADR in Methylxanthine group and Tremors (31%) in Beta 2 agonist group. Most of ADRs were mild (95 %), manageable and comes under possible (60 %) category of WHO causality assessment scale.Conclusions: Treatment of Bronchial Asthma is mainly based on Beta 2 agonist and Methylxanthine group. So, occurrence of ADR is much common. Our study offers a representative idea of the ADR profile of anti asthmatic drugs. Constant vigil in detecting ADRs and subsequent dose adjustments can make therapy with anti asthmatic drugs safer and more effective. This, in turn, will improve compliance.
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Pascali, Francesco D., Michael Ippolito, Emily Wolfe, Konstantin E. Komolov, Nathan Hopfinger, Douglas Lemenze, Nicholas Kim, et al. "LBMON186 Beta-agonist Profiling Reveals Novel Biased Signaling Phenotypes For The Beta 2-adrenergic Receptor With Implications In The Treatment Of Asthma." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A587—A588. http://dx.doi.org/10.1210/jendso/bvac150.1217.
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Abstract Asthma involves chronic airway inflammation and airway smooth muscle (ASM) cell contraction. Treatment include agonists of the beta 2-AR, a GPCR that induces the Gs/cAMP pathway leading to ASM relaxation. These agonists can also promote severe side effects which have been correlated with beta-arrestins (barr) activation. Therefore, biased ligands selective for the Gs/cAMP pathway over the barr-induced side effects should be beneficial. To test this, we have used high-throughput screening to identify Gs-biased agonists. The initial lead candidates were further analyzed for their ability to modulate Gs and Gi interaction, cAMP production, and barr interaction. We identified three compounds which showed minimal barr recruitment as well as decreased barr-mediated outputs including receptor internalization and ERK activation. They also showed reduced GRK-mediated phosphorylation of the receptor as well as decreased agonist-promoted receptor desensitization in human ASM cells. These Gs-biased agonists may contribute to develop more effective drugs for asthma and may help to determine the structure determinants of receptor mediated biased signaling. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
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Teo, K. K., J. OʼRiordan, H. Webb, and J. Horgan. "Training response in patients with coronary artery disease receiving beta-adrenoceptor blocking drugs, with and without partial agonist activity." International Journal of Rehabilitation Research 8 (September 1985): 46. http://dx.doi.org/10.1097/00004356-198509001-00081.
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Konyshko, N. A., T. E. Morozova, and A. S. Konyshko. "Pharmacotherapy for pregnant women with arterial hypertension considering pathogenetic factors during the SARS-CoV-2 pandemic." Voprosy ginekologii, akušerstva i perinatologii 21, no. 4 (2022): 29–39. http://dx.doi.org/10.20953/1726-1678-2022-4-29-39.
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Objective. To analyze and present current scientific data and the results of our own research on the features of pharmacotherapy for pregnant women with arterial hypertension (AH) under present conditions. Materials and methods. A comprehensive analysis of the available up-to-date scientific sources over the past decade was carried out in the Scopus, PubMed.com, and E-library databases. Physicians (n = 100) and pregnant women with AH (n = 164) were interviewed about the use of antihypertensive agents between 2009 and 2021. Conclusions. The general principles of pharmacotherapy for AH in pregnant women include: maximum efficacy for the mother; fetal safety; therapy according to blood pressure (BP) levels, maternal and fetal risk factors; initiation of treatment with minimal doses of one drug; switching to another class of drugs and combination therapy when the first-line drugs are not effective or poorly tolerated; preference to dynamic, remote and “hard” control of hemodynamic parameters aimed at target systolic BP of 140 mm Hg and diastolic BP of 85 mm Hg. The antihypertensives of choice with proven efficacy and safety in the gestational period are a centrally acting α-adrenoceptor agonist α-methyldopa, a calcium channel blocker nifedipine, and beta-blockers. All interviewed specialists in the Central Federal District are sufficiently competent and informed about the pharmacological control of AH in pregnant women. Key words: pregnant women, arterial hypertension, SARS-CoV-2, antihypertensive agents
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Harding, S. E., S. M. Jones, P. O'Gara, G. Vescovo, and P. A. Poole-Wilson. "Reduced beta-agonist sensitivity in single atrial cells from failing human hearts." American Journal of Physiology-Heart and Circulatory Physiology 259, no. 4 (October 1, 1990): H1009—H1014. http://dx.doi.org/10.1152/ajpheart.1990.259.4.h1009.
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Human myocytes were isolated from right atrial appendage, and contractile responses to inotropic agents were studied. Responses to inotropic agents of cells isolated from patients with mild heart disease [New York Heart Association (NYHA) classes I and II] were compared with those of myocytes from rabbit atria. Maximally effective concentrations of calcium, forskolin, and isoproterenol increased contraction amplitude to a similar extent (11.9, 11.5, and 11.3% change in cell length, respectively), but histamine produced a smaller effect (7.1%). The maximum responses of rabbit atrial cells to calcium (18.5%) and isoproterenol (15.0%) were significantly greater than human. In human cells, the velocity of contraction or relaxation was accelerated more by isoproterenol (P less than 0.05) or forskolin (P less than 0.01) than by high calcium. Only relaxation velocity was increased by isoproterenol in rabbit cells (P less than 0.05). Rabbit myocytes contracted and relaxed 10-30% faster than human (P less than 0.05). Cells from the atria of patients with New York Heart Association (NYHA) heart failure class III or IV were less responsive to isoproterenol than those from class I or II (P less than 0.01). Omitting data from patients who had been taking calcium-channel blockers or beta-adrenoceptor agonist or antagonist drugs did not affect the conclusions. Analysis of variance revealed a significantly greater between-patient than within-patient variation (P less than 0.001), indicating that cells from the same patient have a tendency to respond in a similar way. Responses to high calcium did not differ among NYHA classes. The effect of forskolin was not reduced in NYHA class III, although there was a decreased response in cells from two patients in NYHA class IV.(ABSTRACT TRUNCATED AT 250 WORDS)
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Apolikhina, I. A., A. S. Chochueva, A. S. Saidova, and E. A. Gorbunova. "MODERN POSSIBILITIES OF MEDICAL TREATMENT OF OVERACTIVE BLADDER IN WOMEN." Medical Council, no. 2 (December 30, 2017): 122–27. http://dx.doi.org/10.21518/2079-701x-2017-2-122-127.
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Overactive bladder (OAB) is a serious urination disorder which affects at least 17% of the population above 40 years old, of which 56% are women and 44% are men. M-cholinoblockers are the first line therapy and the main treatment for OAB. However, their side effects, along with low efficacy, force women to stop taking the drugs. Activation of beta-3-adrenergic receptors is known toreduce the tone of detrusor muscle in the bladder. This resulted in the invention of mirabegron (Mirabegron, Betmiga, Astellas Pharma Europe, Netherlands), the first drug of a new pharmacologic group (beta-3 adrenergic agonists) for the treatment of OAB. A selective beta-3 agonist, mirabegron has no side effects such as dry mouth, increased intraocular pressure or constipation. Numerous clinical studies demonstrated a reduction in the number of episodes of urinary incontinence and frequent urination in the mirabegron group compared to the placebo group.
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Hassan, J. Abu, S. Saadiah, H. Roslan, and Bmz Zainudin. "Bronchodilator response to inhaled beta-2 agonist and anticholinergic drugs in patients with bronchiectasis." Respirology 4, no. 4 (December 1999): 423–26. http://dx.doi.org/10.1046/j.1440-1843.1999.00215.x.
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Tyurenkov, Ivan N., Denis V. Kurkin, Dmitry A. Bakulin, Elena V. Volotova, Aleksej V. Smirnov, Dmitry S. Mednikov, and Mikhail A. Shafeev. "Influence of novel GPR119 receptor agonist on plasma glucose and insulin level, as well as structural changes of pancreas islets in rats with experimental type 2 diabetes." Problems of Endocrinology 62, no. 4 (June 10, 2016): 32–37. http://dx.doi.org/10.14341/probl201662432-37.
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Background. GPR119 receptor is a promising target for novel antidiabetic drugs development because of its agonists in addition to hypoglycemic effects have cytoprotective effect on beta cells.Aim — to assess the effect of the novel GPR119 receptor agonist and sitagliptin on carbohydrate metabolism and morphological structure of the pancreas in animals with experimental type 2 diabetes.Material and methods. The study was performed in Wistar rats with streptozotocin-nicotinamide-induced diabetes. Serum insulin was determined by ELISA (Rat Insulin, (INS) ELISA Kit, 96 CSB). Immunohistochemical studies were performed using mouse monoclonal antibodies to insulin (clone 1G4, GeneTex) with determination of the absolute and relative area of immunopositive material (beta-cells) of the pancreatic islets.Results. 28-day treatment of animals with diabetes by GPR119 receptor agonist — ZB-16 (dipiaron) (1 mg/kg, per os, daily) and an inhibitor of the DPP-4 (sitagliptin) led to a reduction of fasting hyperglycemia and improve its glucose tolerance and enhance basal and stimulated insulin secretion relative to the control without treatment. Morphometric assessment of islets revealed that animals treated with the ZB-16 and sitagliptin have significantly higher absolute and relative islets area, as well as the perimeter of the insulin-positive material compared to islets of rats without treatment.Conclusion. Course administration of GPR119 receptor agonist to animals with streptozotocin-nicotinamide-induced diabetes has a pronounced antidiabetic effect consists in reducing fasting plasma glucose, improve glucose utilization, increase basal and stimulated insulin secretion, as well as increasing the area of the insulin-positive material in islets. Antidiabetic action of novel GPR119 receptor agonist, was comparable to that of sitagliptin.
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Fukushima, T., K. Sekizawa, Y. Jin, M. Yamaya, H. Sasaki, and T. Takishima. "Effects of beta-adrenergic receptor activation on alveolar macrophage cytoplasmic motility." American Journal of Physiology-Lung Cellular and Molecular Physiology 265, no. 1 (July 1, 1993): L67—L72. http://dx.doi.org/10.1152/ajplung.1993.265.1.l67.
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We studied the effects of fenoterol, a beta-adrenoceptor agonist, on the cytoplasmic motility of alveolar macrophages (AM) from dog lungs in vitro. Four days after the instillation of Fe3O4 particles (3 mg/kg) into the lower lobe bronchus, AM were harvested by bronchoalveolar lavage. Remanent field strength (RFS) from the AM containing Fe3O4 particles (5 x 10(6) cells) was measured immediately after magnetization. RFS decreased with time due to particle rotation (relaxation), which is related to cytoplasmic motility of AM. Fenoterol (10(-9) M to 10(-5) M) decreased the relaxation rate (lambda 0; min-1) in a concentration-dependent fashion with the maximum effect at 10(-6) M. Both forskolin (10(-6) M to 10(-4) M) and dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) (10(-3) M) mimicked fenoterol-induced inhibitory effects on lambda 0. Fenoterol and forskolin concentration-dependently increased intracellular levels of cAMP, which were parallel to decreases in lambda 0 induced by these drugs. KT 5720 (10(-5) M), a specific inhibitor of protein kinase A, significantly inhibited fenoterol (10(-6) M)-induced inhibitory effects on lambda 0 (P < 0.01). These results imply that beta-adrenergic receptor activation inhibits cytoplasmic motility of AM via increases in intracellular levels of cAMP, which may be coupled with activation of a cAMP-dependent protein kinase.
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Sakai, M., R. S. Danziger, R. P. Xiao, H. A. Spurgeon, and E. G. Lakatta. "Contractile response of individual cardiac myocytes to norepinephrine declines with senescence." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 1 (January 1, 1992): H184—H189. http://dx.doi.org/10.1152/ajpheart.1992.262.1.h184.
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The present study utilized individual isolated left ventricular cardiac myocytes from hearts of animals of a broad age range to evaluate the response to norepinephrine and to other stimuli that augment myocardial cell contractile performance. During electrical stimulation before drugs neither the amplitude nor the velocity of shortening normalized for resting cell length differed among cells isolated from 2-, 6- to 8-, or 24-mo-old animals. Norepinephrine augmented twitch amplitude and velocity about fourfold in cells from 2-mo-old hearts but only by 2.5-fold in cells from 24-mo-old hearts (age effect, P less than 0.001). In contrast, the contractile response to increases in bathing [Ca2+] or to the addition of the calcium channel agonist BAY K 8644 or of 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT cAMP) did not vary with age. These results indicate that the age-associated contractile deficit during beta-adrenergic stimulation is specific to the beta-adrenergic pathway and an age-associated deficit in the net production of cAMP. This can be attributed to a diminished cardiac myocyte response to beta-adrenergic agonists, in contrast to modulation of the beta-adrenergic response by other receptor agonists, which are present in intact tissue but absent under the conditions of the present study.
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Ahn, Seungkirl, Alem W. Kahsai, Biswaranjan Pani, Qin-Ting Wang, Shuai Zhao, Alissa L. Wall, Ryan T. Strachan, et al. "Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library." Proceedings of the National Academy of Sciences 114, no. 7 (January 27, 2017): 1708–13. http://dx.doi.org/10.1073/pnas.1620645114.
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The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein–coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human β2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the β2AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the β2AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the β2AR. In cell-signaling studies, 15 inhibits cAMP production through the β2AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits β-arrestin recruitment to the activated β2AR. This study presents an allosteric small-molecule ligand for the β2AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.
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Stuhmeier, Klaus-Dieter, Bernd Mainzer, Jochen Cierpka, Wilhelm Sandmann, and Jorg Tarnow. "Small, Oral Dose of Clonidine Reduces the Incidence of Intraoperative Myocardial Ischemia in Patients Having Vascular Surgery." Anesthesiology 85, no. 4 (October 1, 1996): 706–12. http://dx.doi.org/10.1097/00000542-199610000-00004.
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Background Most new perioperative myocardial ischemic episodes occur in the absence of hypertension or tachycardia. The ability of alpha 2-adrenoceptor agonists to inhibit central sympathetic outflow may benefit patients with coronary artery disease by increasing the myocardial oxygen supply and -demand ratio. Methods A randomized double-blind study design was used in 297 patients scheduled to have elective vascular surgical procedures to evaluate the effects of 2 micrograms/kg-1 oral clonidine (n = 145) or placebo (n = 152) on the incidence of perioperative myocardial ischemic episodes, myocardial infarction, and cardiac death. Continuous real-time S-T segment trend analysis (lead II and V5) was performed during anesthesia and surgery and correlated with arterial blood pressure and heart rate before and during ischemic events. Dose requirements for vasoactive and antiischemic drugs to control blood pressure and heart rate as well as episodes of myocardial ischemia (i.e., catecholamines, beta-adrenoceptor antagonists, nitrates, and systemic vasodilators) and fluid volume load were recorded. Results Administration of clonidine reduced the incidence of perioperative myocardial ischemic episodes from 39% (59 of 152) to 24% (35 of 145) (P < 0.01). Hemodynamic patterns, percentage of ischemic time, and the number of ischemic episodes per patient did not differ. Nonfatal myocardial infarction developed after operation in four patients receiving placebo compared with none receiving clonidine (day 2 to 21; P = 0.07). The incidence of fatal cardiac events (1 vs. 2) was not different. Dose requirements for vasoactive and antiischemic drugs did not differ between the groups, but the amount of presurgical fluid volume was slightly greater in patients receiving clonidine (951 +/- 388 vs. 867 +/- 381 ml; P < 0.03). Conclusion A small oral dose of clonidine, given prophylactically, can reduce the incidence of perioperative myocardial ischemic episodes without affecting hemodynamic stability in patients with suspected or documented coronary artery disease.
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Padro, Caroline, and Virginia Sanders. "Cleavage of CD23 by ADAM proteins is regulated by beta-2 adrenergic receptor engagement on primed B cells (55.11)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 55.11. http://dx.doi.org/10.4049/jimmunol.186.supp.55.11.
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Abstract Allergic asthma severity may be associated with IgE levels. We have shown that beta-2 adrenergic receptor (β2AR) engagement on CD40L/IL-4-primed B cells increases the level of IgE produced per cell, without affecting class switch recombination. β2AR agonists alleviate bronchoconstriction by targeting the β2AR expressed on bronchiolar smooth muscle cells to trigger airway relaxation, but these drugs also target the β2AR on primed B cells, potentially producing an IgE effect that may be counterproductive to the drugs intended use. We reported that surface CD23 expression remained constant on primed B cells exposed to a β2AR agonist, while CD23 mRNA, total CD23 protein, and soluble CD23 (sCD23) increased. Thus, if sCD23 positively regulates IgE production, an increase due to β2AR engagement may worsen bronchoconstriction, albeit relieving it in the short term. We hypothesized that the primary sheddase of CD23, ADAM10, is regulated by β2AR engagement on a primed B cell. Although we found that β2AR engagement was unable to affect the level of ADAM10 protein or mRNA produced compared to primed cells alone, our recent data indicated that the β2AR-induced increase in CD23 shedding may be mediated by increased localization of mature ADAM10 with CD23. Thus, ADAM10 may be a molecular target that can be blocked during β2AR drug therapy to prevent increased sCD23 and IgE, which may counteract the therapeutic bronchorelaxation.
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Diab, Alsarah Mutwakil Abbas, Eman MutwakilAhmedAlmostafa Suliman, AyatAbdallah Hassan Abdallah, Mohamed AbdelhadiElzubair Dyab, Tanzeel Omer Elamin Awadalla, Naila Mubarak Kirkisawi, and Nazik Elmalaika Obaid Seid Ahmed Husain. "Association between Exposure to Beta 2 Agonists and Corticosteroids and Acquiring Benign Joint Hypermobility Syndrome among Asthmatic Patients: a Case-Control Study." Sudan Journal of Medical Sciences 12, no. 4 (December 28, 2017): 215. http://dx.doi.org/10.18502/sjms.v12i4.1353.
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Background:Beta2 (β2) agonists as relievers and corticosteroids as controllers are the mainstay drugs for asthma treatment. Benign Joint Hypermobility Syndrome (BJHS) is a connective tissue disorder with musculoskeletal symptoms.We had examined the possible association between the use of β2 agonists and corticosteroids and acquiring BJHS in asthmatic patients.Methods:This was a case-control, hospital-based study including a group of asthmatics who had BJHS (cases), compared with a matched group of asthmatics without BJHS (controls) for the β2 agonists and corticosteroids past and current pattern of use. Information was collected by face-to-face interview and clinical examination and from subjects’ medical records using pre-structured questionnaire. BJHS diagnosis was based on the revised Brighton criteria. Asthma severity was reflected by a score, which was calculated from the asthma questionnaire. Comparison of exposure was done by Calculation of Odds Ratio.Results:Development of BJHS was found to be significantly associated with chronicity of asthma of average duration of 13.2 years, and hence to prolonged use of β2 agonists and/or corticosteroids (OR 1.019; 95% CI 0.999 - 1.039, P=0.006)Exposure to β2 agonist and corticosteroid (87 and 79 cases and controls respectively P=0.05)high asthma score (42.9 ± 9.8 and 40.4 ± 8.3 among cases and controls respectively, P=0.011) were significantly associated with the development of BJHS.
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Vuksanović, Aleksandar. "Lower urinary tract symptoms (LUTS): The role of medications in improvement of quality of life." Galenika Medical Journal 1, no. 3 (2022): 99–105. http://dx.doi.org/10.5937/galmed2203100v.
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The treatment of patients with lower urinary tract symptoms (LUTS) is a significant part of everyday clinical practice, not only for urologists but also for general practitioners. Symptoms of the lower urinary tract include symptoms of urine storage, emptying (bladder) and post-micturition symptoms. Almost half of the men at the beginning of the 6th decade of life have, more or less pronounced, symptoms of bladder emptying disorders. These symptoms significantly affect the quality of life, not only of the patient, but also of his family and often significantly disrupt daily work activities. The causes of their occurrence can be numerous, from prostate enlargement and histological changes in the prostate to various neurological diseases. The diagnostic procedures that are performed are aimed at determining the cause of their occurrence. The most common cause is - the prostate and contrary to the patient's opinion, there is no absolute correlation between prostate size and the severity of symptoms. LUTS therapy is aimed at improving the quality of life, preventing the occurrence of complications of the disease and reducing the risk of the need for surgical treatment. The number of surgical interventions, in order to treat LUTS, has significantly decreased compared to the period 2-3 decades ago. The reason is the available drug therapy, which has significantly fulfilled the goals of treatment. There are several groups of drugs that are used: Phyto preparations - Alpha 1 blockers (a1 adrenoceptor antagonists), 5 Alpha-reductase inhibitors (5-ARI inhibitors), muscarinic receptor antagonists, 5 phosphodiesterase inhibitors (PDE 5 inhibitors), beta 3 agonist. Today, in the treatment of LUTS, combination therapy is most often used. It involves the use of two, and sometimes more drugs, which are given in a targeted manner depending on the predominant symptoms.
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Rickles, Richard J., Winnie F. Tam, Antoaneta Necheva, Thomas Giordano, Alexis A. Borisy, and Margaret S. Lee. "Adenosine A2A and Beta-2 Adrenergic Receptor Agonist Synergy in B-Cell Malignancies: Selectivity, Breadth of Activity and Effects of Chronic Exposure." Blood 114, no. 22 (November 20, 2009): 3762. http://dx.doi.org/10.1182/blood.v114.22.3762.3762.
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Abstract Abstract 3762 Poster Board III-698 By using a high throughput combination screening strategy, we made the surprising discovery that adenosine A2A and beta-2 adrenergic receptor (b2AR) agonists have synergistic anti-proliferative activity in combination with dexamethasone, melphalan, lenalidomide, bortezomib and doxorubicin in preclinical multiple myeloma (MM) models. Both A2A and b2AR agonists are highly selective and demonstrate no single agent activity or synergy in normal cell types including human PBMCs, AoSMCs, HUVECs or HCAECs at concentrations 2-3 orders of magnitude greater than the IC50 in MM cell lines. To further examine the selectivity and breadth we have evaluated A2A and b2AR agonist combinations in a panel of 83 cell lines including solid tumor types and hematological malignancies. Single agents and combinations with dexamethasone and melphalan were systematically studied at multiple ratios of clinically relevant concentrations. Using a quantitative synergy score based on the Loewe model (Lehar et al. Nat Biotech 2009), we observe that combination activity for A2A or b2AR agonists is highly selective for hematologic malignancies with synergy observed most frequently in multiple myeloma and DLBCL cell lines. Synergy is also observed with the B-cell lines JM-1 (pre B-ALL) and GA-10 (Burkitt's lymphoma). Using a relative synergy cut-off (synergy score >1), we find that 13 of the 18 MM cell lines tested demonstrate a synergistic interaction between the A2A agonist CGS-21680 and dexamethasone and 11 demonstrate a synergistic interaction between CGS-21680 and melphalan. Using this same measure, 9 of 18 MM cell lines demonstrate synergy with combinations of the b2AR agonist salmeterol with either dexamethasone or melphalan. Nine and ten of the cell lines in this MM panel are insensitive or respond weakly to dexamethasone and melphalan as single agents respectively. All cell lines were treated with the same concentrations of dexamethasone or melphalan, pointing to A2A agonists having a higher breadth of activity across the MM cell line panel. An interesting observation is the strong synergy observed for A2A or b2AR agonists with dexamethasone in the glucocorticoid-insensitive cell lines EJM and ANBL-6, which suggests that these agents may help restore steroid sensitivity in refractory patients. In general, drug resistance is a recurrent problem for cancer drugs and development of resistance after chronic exposure can reduce drug efficacy and promote refractory disease. We therefore examined the effects of chronic exposure to either A2A or b2AR agonists in the MM.1S cell line. Exposure of cells to CGS-21680 or salmeterol for one month reduced single agent sensitivity >80%. Surprisingly, combinations of either agent with dexamethasone maintained similar amounts of synergy and cell killing as found with naïve untreated cells. As determined by Western blot analysis, the reduction in single agent activity after chronic exposure is not accompanied by a reduction in receptor levels. These data demonstrate that synergistic combinations of A2A and b2AR agonists are highly selective for B-cell malignancies and support the notion that synergistic drug combinations improve therapeutically relevant selectivity and circumvent drug resistance. This work further supports the rationalefor investigation of A2A and b2AR agonists in the treatment of B-cell malignancies and in particular, patients who have MM. Disclosures: Rickles: CombinatoRx, Inc.: Employment. Tam:CombinatoRx, Inc.: Employment. Necheva:CombinatoRx, Inc.: Employment. Giordano:CombinatoRx, Inc.: Employment. Borisy:CombinatoRx, Inc.: Employment. Lee:CombinatoRx, Inc.: Employment.
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Fassakhov, R. S. "Mild asthma: from paradoxes to therapy optimization." Medical Council, no. 15 (October 12, 2018): 38–42. http://dx.doi.org/10.21518/2079-701x-2018-15-38-42.
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Exacerbations of bronchial asthma are specific not only for severe, but also for mild disease course. Analysis of the causes revealed paradoxes in the treatment that contribute to the uncontrolled course of mild asthma. A promising direction is the use of combination drugs containing a early-onset beta-2-agonist and inhaled glucocorticosteroid, which can significantly improve adherence to treatment and significantly improve control and reduce the number of exacerbations. The review discusses in detail the merits of the combination drug SabaComb, its place in the recommendations for the treatment of mild asthma.
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Burroughs, SF, and GJ Johnson. "Beta-lactam antibiotic-induced platelet dysfunction: evidence for irreversible inhibition of platelet activation in vitro and in vivo after prolonged exposure to penicillin." Blood 75, no. 7 (April 1, 1990): 1473–80. http://dx.doi.org/10.1182/blood.v75.7.1473.1473.
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Abstract beta-Lactam antibiotics cause platelet dysfunction with bleeding complications. Previous in vitro studies documented reversible inhibition of agonist-receptor interaction. This mechanism is inadequate to explain the effect of beta-lactam antibiotics in vivo. Platelet function does not return to normal immediately after drug treatment, implying irreversible inhibition of platelet function. We report here evidence of irreversible platelet functional and biochemical abnormalities after in vitro and in vivo exposure to beta-lactam antibiotics. Irreversible binding of [14C]-penicillin (Pen) occurred in vitro. After 24 hours' in vitro incubation with 10 to 20 mmol/L Pen, or ex vivo after antibiotic treatment, irreversible functional impairment occurred; but no irreversible inhibition of alpha 2 adrenergic receptors, measured with [3H]-yohimbine, or high-affinity thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptors, measured with agonist [3H]-U46619 and antagonist [3H]-SQ29548, occurred. However, low- affinity platelet TXA2/PGH2 receptors were decreased 40% after Pen exposure in vitro or in vivo, indicating irreversible membrane alteration. Two postreceptor biochemical events were irreversibly inhibited in platelets incubated with Pen for 24 hours in vitro or ex vivo after antibiotic treatment. Thromboxane synthesis was inhibited 28.3% to 81.7%. Agonist-induced rises in cytosolic calcium ([Ca2+]i) were inhibited 40.1% to 67.5% in vitro and 26.6% to 52.2% ex vivo. Therefore, Pen binds to platelets after prolonged exposure, resulting in irreversible dysfunction attributable to inhibition of TXA2 synthesis and impairment of the rise in [Ca2+]i. The loss of low- affinity TXA2/PGH2 receptors suggests that the primary site of action of these drugs is on the platelet membrane.
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Burroughs, SF, and GJ Johnson. "Beta-lactam antibiotic-induced platelet dysfunction: evidence for irreversible inhibition of platelet activation in vitro and in vivo after prolonged exposure to penicillin." Blood 75, no. 7 (April 1, 1990): 1473–80. http://dx.doi.org/10.1182/blood.v75.7.1473.bloodjournal7571473.
Full textAbstract:
beta-Lactam antibiotics cause platelet dysfunction with bleeding complications. Previous in vitro studies documented reversible inhibition of agonist-receptor interaction. This mechanism is inadequate to explain the effect of beta-lactam antibiotics in vivo. Platelet function does not return to normal immediately after drug treatment, implying irreversible inhibition of platelet function. We report here evidence of irreversible platelet functional and biochemical abnormalities after in vitro and in vivo exposure to beta-lactam antibiotics. Irreversible binding of [14C]-penicillin (Pen) occurred in vitro. After 24 hours' in vitro incubation with 10 to 20 mmol/L Pen, or ex vivo after antibiotic treatment, irreversible functional impairment occurred; but no irreversible inhibition of alpha 2 adrenergic receptors, measured with [3H]-yohimbine, or high-affinity thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptors, measured with agonist [3H]-U46619 and antagonist [3H]-SQ29548, occurred. However, low- affinity platelet TXA2/PGH2 receptors were decreased 40% after Pen exposure in vitro or in vivo, indicating irreversible membrane alteration. Two postreceptor biochemical events were irreversibly inhibited in platelets incubated with Pen for 24 hours in vitro or ex vivo after antibiotic treatment. Thromboxane synthesis was inhibited 28.3% to 81.7%. Agonist-induced rises in cytosolic calcium ([Ca2+]i) were inhibited 40.1% to 67.5% in vitro and 26.6% to 52.2% ex vivo. Therefore, Pen binds to platelets after prolonged exposure, resulting in irreversible dysfunction attributable to inhibition of TXA2 synthesis and impairment of the rise in [Ca2+]i. The loss of low- affinity TXA2/PGH2 receptors suggests that the primary site of action of these drugs is on the platelet membrane.
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Rickles, Richard J., Laura Pierce, Thomas Giordano, Winnie F. Tam, William Avery, Melissa Farwell, David Crowe, et al. "Adenosine A2A and Beta-2 Adrenergic Receptor Agonism: Novel Selective and Synergistic Multiple Myeloma Targets Discovered through Systematic Combination Screening." Blood 112, no. 11 (November 16, 2008): 384. http://dx.doi.org/10.1182/blood.v112.11.384.384.
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Abstract Using a high throughput combination screening strategy, we have discovered that agonism of either adenosine A2A receptors (A2A) or beta-2 adrenergic receptors (bAR) demonstrate significant, synergistic, anti-proliferative effects in preclinical Multiple Myeloma (MM) models. Using quantitative synergy analysis, we observe that A2A and bAR agonists have significant anti-proliferative effects in a broad panel of 10 MM cell lines when combined with each other or with standard MM agents. Individual A2A agonists CGS-21680 and HE-NECA inhibited proliferation 25–80% with EC50s ranging from 2–20 nM. Individual bAR agonists salmeterol and formoterol inhibited proliferation 35–75% with EC50s ranging from 10–30 pM. Potent, highly synergistic, inhibition of proliferation, up to 95%, was demonstrated with combinations of A2A or bAR agonists and multiple agents including dexamethasone, lenalidomide, bortezomib, melphalan, doxorubicin, HDAC inhibitors and HSP90 inhibitors at clinically relevant concentrations. These combinations exceeded Loewe additivity, and demonstrated both substantial increases in efficacy over maximal single agent levels as well as significant potency shifting with many combination indices (CIs) in the range of 0.1 to 0.3. Synergistic anti-proliferative effects were observed broadly across several MM cell lines and when using cell lines unresponsive to standard MM drugs, e.g. A2A agonists CGS-21680 and HE-NECA in combination with dexamethasone inhibited 75–85% of the proliferation of EJM, and MOLP-8 dexamethasone-insensitive cell lines as compared to 35–60% for the single agent A2A agonists. The selective A2A antagonist SCH58261 but not A1, A2B and A3 selective antagonists DPCPX, MRS1754 and MRS1523 blocked the synergy and antiproliferative activity of HE-NECA, demonstrating that the effect is mediated via the A2A receptor. siRNA directed against adenosine and adrenergic receptor isoforms, caused a concomitant reduction in the antiproliferative effects of HE-NECA and salmeterol. Synergy (CI<0.4) observed between A2A and bAR agonists suggested that while both these targets signal through Gs coupled signaling pathways, the two targets contribute to the antiproliferative effect via distinct molecular mechanisms. Anti-proliferative effects occurred through a synergistic induction of apoptosis. Combinations of either agonist with dexamethasone demonstrate 50–75% Annexin V positive MM.1S cells after 24 hours treatment whereas single agents show less than 10%. The activity, synergy and selectivity of A2A and bAR combinations were observed in xenograft models of MM. SCID CB17 mice received subcutaneous inoculation of RPMI-8226 cells and once tumors were palpable, mice were treated with vehicle, bortezomib (0.5 mg/kg IV Q3D), salmeterol (10 mg/kg s.c QD) or the combination of both agents. After 19 days of treatment, the combination showed significantly greater reduction in tumor volume than either of the single agents alone (70% vs. 34%; p<0.05, ANOVA). High throughput combination screening facilitated the discovery of two novel and related classes of drug targets with highly synergistic and selective anti-tumor activity in MM. These preclinical data provide a strong rationale for the investigation of A2A and bAR agonists in the treatment of MM.
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Tam, Winnie F., Richard J. Rickles, Thomas Giordano, Alexis Borisy, and Margaret S. Lee. "A2A or Beta-2 Adrenergic Receptor Agonist Synergies Induce Distinct Patterns of Gene Expression Relevant to Multiple Myeloma Cell Survival." Blood 114, no. 22 (November 20, 2009): 3831. http://dx.doi.org/10.1182/blood.v114.22.3831.3831.
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Abstract Abstract 3831 Poster Board III-767 Using a high-throughput combination screening strategy, we have demonstrated that adenosine A2A receptors (A2AR) or beta-2 adrenergic receptors (bAR) agonists, in low nano-molar range, exhibit highly synergistic anti-proliferative activity when combined with Multiple Myeloma drugs, such as dexamethasone, lenalidomide, bortezomib, melphalan and doxorubicin at clinically relevant concentrations. Synergy and selectivity have been observed in multiple myeloma (MM) cell lines and ex vivo using patient tumor cells. To understand this synergistic mechanism, we employed the Affymetrix U133 plus 2.0 cDNA microarray to investigate the differentially expressed genes in a multiple myeloma MM1.S cell line treated with A2AR agonists, bAR agonists, dexamethasone, or in combinations (A2AR/ bAR agonists and dex) for six hours. Using conventional hierarchical clustering, unsupervised analyses clearly separate the A2AR/ bAR agonists or the dexamethosone groups from the combination groups, suggesting a unique mechanism underlying the combination treatments. With SAM (Significance Analysis of Microarrays), we found 314 and 309 genes that showed statistically significant up-regulation or down-regulation respectively in the combination groups compared to the untreated control, with a false discovery rate=<1%. Interestingly, only a few genes were statistically different between A2AR agonists with dex and bAR agonists with dex, indicating that they may function with a similar mechanism. To further investigate the genes that are coordinately expressed, we performed gene set enrichment analyses (GESA) with the published or curated gene sets available from Board Institute (Cambridge, MA) or GeneGo pathway analysis software (Encinitas, CA). We found that the cells treated with drug combinations were enriched in genes involved in multiple cancer relevant pathways including TGF-beta receptor signaling, WNT signaling, MAPK/Erk signaling, PKA signaling, IGF-RI signaling, the stress response pathway and the myc pathway. Bim1 is one of the genes upregulated by single agent and combination drug treatment and is important for cell killing as siRNA targeting Bim1 reduces single agent and combination effects. Down-regulation of IRF4 by combination treatments is particularly interesting. High levels of IRF-4 expression have been suggested as an independent risk factor for poor survival in multiple myeloma patients (Heintel D et. al., Leukemia 2008). Moreover, IRF4 has recently been shown to be critical for proliferation and/or survival in a number of multiple myleoma cell lines (Shaffer et al., Nature 2008). Consistent with these observations, flow cytometric analysis of annexinV/PI stained MM1.S cells transfected with siRNA against IRF4 confirms that IRF-4 is important for MM.1S survival. Furthermore, direct or indirect downstream targets of IRF4 (e.g. MYC, HK2, PDK1, and SUB1) are coordinately down-regulated in MM1.S cells when IRF4 expression is reduced by A2AR / bAR agonists with dex. These data suggest that A2A and bAR agonist combinations coordinately down-regulate both myc and IRF4, which form a positive autoregulatory loop important for MM proliferation/survival and further underscore the utility of systematic combination screening in the identification of pathway and chemical interactions relevant to disease. Disclosures: Tam: CombinatoRx, Inc.: Employment. Rickles:CombinatoRx, Inc.: Employment. Giordano:CombinatoRx, Inc.: Employment. Borisy:CombinatoRx, Inc.: Employment. Lee:CombinatoRx, Inc.: Employment.
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Jun, Ikhyun, Young Joon Choi, Bo-Rahm Kim, Kyoung Yul Seo, and Tae-im Kim. "Activation of ADRB2/PKA Signaling Pathway Facilitates Lipid Synthesis in Meibocytes, and Beta-Blocker Glaucoma Drug Impedes PKA-Induced Lipid Synthesis by Inhibiting ADRB2." International Journal of Molecular Sciences 23, no. 16 (August 22, 2022): 9478. http://dx.doi.org/10.3390/ijms23169478.
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Meibomian gland dysfunction is one of the main causes of dry eye disease and has limited therapeutic options. In this study, we investigated the biological function of the beta 2-adrenergic receptor (ADRB2)/protein kinase A (PKA) pathway in lipid synthesis and its underlying mechanisms in human meibomian gland epithelial cells (HMGECs). HMGECs were cultured in differentiation media with or without forskolin (an activator of adenylate cyclase), salbutamol (an ADRB2 agonist), or timolol (an ADRB2 antagonist) for up to 4 days. The phosphorylation of the cAMP-response element-binding protein (CREB) and the expression of peroxisome proliferator activator receptor (PPAR)γ and sterol regulatory element-binding protein (SREBP)-1 were measured by immunoblotting and quantitative PCR. Lipid synthesis was examined by LipidTOX immunostaining, AdipoRed assay, and Oil Red O staining. PKA pathway activation enhanced PPARγ expression and lipid synthesis in differentiated HMGECs. When treated with agonists of ADBR2 (upstream of the PKA signaling system), PPARγ expression and lipid synthesis were enhanced in HMGECs. The ADRB2 antagonist timolol showed the opposite effect. The activation of the ADRB2/PKA signaling pathway enhances lipid synthesis in HMGECs. These results provide a potential mechanism and therapeutic target for meibomian gland dysfunction, particularly in cases induced by beta-blocker glaucoma drugs.
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KAMEDA, HARUKO, YOSHIO MONMA, and TSUNEYOSHI TANABE. "A comparison of the .BETA.-adrenoceptor agonist potency of labetalol with those of sympathomimetic drugs, and the role of .ALPHA.-receptors in pharmacological actions of these drugs on tracheal smooth muscles in guinea pigs." CHEMICAL & PHARMACEUTICAL BULLETIN 34, no. 11 (1986): 4797–804. http://dx.doi.org/10.1248/cpb.34.4797.
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Manuel, ST, M. Kundabaka, N. Shetty, and A. Parolia. "Asthma and dental erosion." Kathmandu University Medical Journal 6, no. 3 (April 6, 2009): 370–74. http://dx.doi.org/10.3126/kumj.v6i3.1714.
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Asthma is a chronic inflammatory condition of the airway, characterised by the presence of airflow obstruction which is variable over short periods of time, or is reversible with treatment. Medication comprises of bronchodilators, corticosteroids and anticholinergic drugs. Most asthma drugs are inhaled using various forms of inhalers or nebulizers. Inhaled drugs must be used regularly. The effects of these drugs on the dentition such as tooth decay and erosion have been a subject of debate among dental practitioners. Asthmatic medications can place the patient at risk of dental erosion by reducing salivary protection against extrinsic or intrinsic acids. Asthmatic individuals are one of the higher risk groups suffering from dental erosion. Therefore patients with bronchial asthma should receive special prophylactic attention. This article presents a case of an asthmatic with dental manifestations and reviews the possible causes and management of the same. Key words: Asthma, dry powder inhalers, beta-2 agonist, gastro-esophageal reflux, dental erosion. doi: 10.3126/kumj.v6i3.1714 Kathmandu University Medical Journal (2008), Vol. 6, No. 3, Issue 23, 370-374
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Yang, Shaobin, Yaqin Du, Xiaoqian Zhao, Qi Tang, Wei Su, Yuemeng Hu, and Peng Yu. "Cannabidiol Enhances Microglial Beta-Amyloid Peptide Phagocytosis and Clearance via Vanilloid Family Type 2 Channel Activation." International Journal of Molecular Sciences 23, no. 10 (May 11, 2022): 5367. http://dx.doi.org/10.3390/ijms23105367.
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Alzheimer’s disease (AD) is associated with the accumulation and aggregation of amyloid in the brain. The cation channel TRPV2 may mediate the pathological changes in mild cognitive impairment. A high-affinity agonist of TRPV2 named cannabidiol is one of the candidate drugs for AD. However, the molecular mechanism of cannabidiol via TRPV2 in AD remains unknown. The present study investigated whether cannabidiol enhances the phagocytosis and clearance of microglial Aβ via the TRPV2 channel. We used a human dataset, mouse primary neuron and microglia cultures, and AD model mice to evaluate TRPV2 expression and the ability of microglial amyloid-β phagocytosis in vivo and in vitro. The results revealed that TRPV2 expression was reduced in the cortex and hippocampus of AD model mice and AD patients. Cannabidiol enhanced microglial amyloid-β phagocytosis through TRPV2 activation, which increased the mRNA expression of the phagocytosis-related receptors, but knockdown of TRPV2 or Trem2 rescued the expression. TRPV2-mediated effects were also dependent on PDK1/Akt signaling, a pathway in which autophagy was indispensable. Furthermore, cannabidiol treatment successfully attenuated neuroinflammation while simultaneously improving mitochondrial function and ATP production via TRPV2 activation. Therefore, TRPV2 is proposed as a potential therapeutic target in AD, while CBD is a promising drug candidate for AD.
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Cavallo, Martyn J., Hugh B. Dorman, Francis G. Spinale, and Raymond C. Roy. "Myocyte Contractile Responsiveness after Hypothermic, Hyperkalemic Cardioplegic Arrest." Anesthesiology 82, no. 4 (April 1, 1995): 926–39. http://dx.doi.org/10.1097/00000542-199504000-00016.
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Background Acute left ventricular dysfunction is commonly encountered after hypothermic, hyperkalemic cardioplegic arrest (HHCA) and often requires inotropic intervention for successful separation from cardiopulmonary bypass. However, the basic mechanisms involved in depressed left ventricular function and the cellular basis for the differential effects of inotropic drugs after HHCA are unknown. Accordingly, the goal of this study was to determine the effects of calcium (Ca2+) and beta-adrenergic receptor agonists (beta AR) stimulation on isolated myocyte contractile function after HHCA. Methods Myocytes were isolated from the left ventricle of nine pigs and randomly assigned to one of the following treatment groups: (1) normothermic, control: incubation in oxygenated cell culture media for 2 h at 37 degrees C; and (2) cardioplegia: incubation in 4 degrees C crystalloid cardioplegia for 2 h, followed by rewarming. Steady-state myocyte contractile function was measured after pulse stimulation at baseline, in the presence of extracellular Ca2+ (3-10 mM), and in the presence of the beta AR agonist isoproterenol (2-100 nM). Myocyte profile surface area was measured for both normothermic myocytes and myocytes after HHCA. In a separate set of experiments, myocyte contractile function also was documented after 2 h of hypoxic conditions with both normothermic incubation and HHCA, in the presence and absence of beta AR stimulation. Results Baseline myocyte contractile function was significantly less in the cardioplegia group compared to control. Extracellular Ca2+ produced a dose-dependent significant increase in myocyte contractile function in the normothermic control group, whereas increased extracellular Ca2+ only minimally increased myocyte contractile function in the cardioplegia group. A dose-dependent, significant increase in myocyte contractile function was observed in both groups after beta AR stimulation by isoproterenol; however, myocyte contractile function in the cardioplegia group was decreased compared to the control group. Hypoxia under normothermic conditions significantly reduced myocyte contractile function, myocyte relaxation, and beta-adrenergic responsiveness. Hypoxia in combination with cardioplegic arrest compounded the negative effects on contractile processes but did not further impair beta-adrenergic responsiveness. Myocyte profile surface area was significantly increased after HHCA. Conclusions The minimal improvement in myocyte contractile function after HHCA with increased extracellular Ca2+ suggests that Ca2+ depletion is not the primary mechanism for depressed myocyte contractility after HHCA. On the other hand, because beta AR administration improved myocyte contractile function after HHCA, the cellular basis for the effects of beta AR stimulation after HHCA is probably not increased myocyte Ca2+ but rather alternative mechanisms, such as changes in myofilament sensitivity to Ca2+. These results also suggest that the abnormalities in left ventricular function after HHCA result from the direct effects of hyperkalemic induced electromechanical uncoupling as well as relative hypoxic conditions.
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Sibille, Brigitte, Isabelle Mothe-Satney, Gwenaëlle Le Menn, Doriane Lepouse, Sébastien Le Garf, Elodie Baudoin, Joseph Murdaca, et al. "Gene Doping with Peroxisome-Proliferator-Activated Receptor Beta/Delta Agonists Alters Immunity but Exercise Training Mitigates the Detection of Effects in Blood Samples." International Journal of Molecular Sciences 22, no. 21 (October 25, 2021): 11497. http://dx.doi.org/10.3390/ijms222111497.
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Synthetic ligands of peroxisome-proliferator-activated receptor beta/delta (PPARβ/δ) are being used as performance-enhancing drugs by athletes. Since we previously showed that PPARβ/δ activation affects T cell biology, we wanted to investigate whether a specific blood T cell signature could be employed as a method to detect the use of PPARβ/δ agonists. We analyzed in primary human T cells the in vitro effect of PPARβ/δ activation on fatty acid oxidation (FAO) and on their differentiation into regulatory T cells (Tregs). Furthermore, we conducted studies in mice assigned to groups according to an 8-week exercise training program and/or a 6-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist, in order to (1) determine the immune impact of the treatment on secondary lymphoid organs and to (2) validate a blood signature. Our results show that PPARβ/δ activation increases FAO potential in human and mouse T cells and mouse secondary lymphoid organs. This was accompanied by increased Treg polarization of human primary T cells. Moreover, Treg prevalence in mouse lymph nodes was increased when PPARβ/δ activation was combined with exercise training. Lastly, PPARβ/δ activation increased FAO potential in mouse blood T cells. Unfortunately, this signature was masked by training in mice. In conclusion, beyond the fact that it is unlikely that this signature could be used as a doping-control strategy, our results suggest that the use of PPARβ/δ agonists could have potential detrimental immune effects that may not be detectable in blood samples.
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Samir, Ahmed, Hesham Salem, and Mohammed Abdelkawy. "Optimization of two charge transfer reactions for colorimetric determination of two beta 2 agonist drugs, salmeterol xinafoate and salbutamol, in pharmaceutical and biological samples." Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 269 (March 2022): 120747. http://dx.doi.org/10.1016/j.saa.2021.120747.
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Wood, AM, AT Dinh Xuan, G. Cremona, A. Lockhart, and TW Higenbottam. "The alpha 1-adrenergic agonist methoxamine and the "loop" diuretic frusemide reduce nasal potential difference." European Respiratory Journal 4, no. 7 (July 1, 1991): 802–6. http://dx.doi.org/10.1183/09031936.93.04070802.
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Pretreatment by inhalation with the alpha 1-adrenergic agonist methoxamine and the "loop" diuretic frusemide reduces the bronchial response to certain airway challenges in asthma. To test whether these drugs may act by altering airway epithelial ion and water transport, their effect on nasal potential difference (PD) when applied topically in eight normal volunteers was measured. For comparison, the effect of the Na(+)-channel blocking drug amiloride and the beta 2-adrenergic agonist salbutamol was also tested. Both methoxamine and frusemide significantly reduced PD: at the highest concentration given (10(-3) mol.l-1), there was a mean drop in PD from baseline of 39.5% following methoxamine treatment (p less than 0.05) and a mean drop of 30.2% following frusemide (p less than 0.05). Neither drug was as effective as amiloride, which caused a mean drop in PD of 27.5% from baseline at 10(-6) mol.l-1 and a drop of 71.6% at 10(-3) mol.l-1 (p less than 0.01 for each concentration). Salbutamol had no significant effect on PD (p greater than 0.05). We conclude that methoxamine and frusemide may derive their protective effect on some bronchial challenge, at least in part, from their effect on airway epithelial ion flux.
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Haskó, G., C. Szabó, Z. H. Németh, V. Kvetan, S. M. Pastores, and E. S. Vizi. "Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice." Journal of Immunology 157, no. 10 (November 15, 1996): 4634–40. http://dx.doi.org/10.4049/jimmunol.157.10.4634.
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Abstract Adenosine released into the extracellular space by immunologic and nonimmunologic stimuli has been shown to regulate various immune functions. In this study we report that i.p. pretreatment of mice with CGS-21680 HCl (CGS), a selective agonist of A2 adenosine receptors, at 0.2 to 2 mg/kg caused an augmentation of plasma IL-10 levels induced by i.p. injection of LPS, but decreased plasma levels of LPS-induced TNF-alpha. 2-Chloro-N6-cyclopentyladenosine (CCPA), an agonist of A1 adenosine receptors, at 0.5 mg/kg diminished LPS-induced plasma TNF-alpha concentrations, but enhanced LPS-induced IL-10 levels only at the highest dose used (2 mg/kg). The specific A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-beta- D-ribofuranuronamide, at 0.2 and 0.5 mg/kg potentiated LPS-stimulated IL-10 production and inhibited LPS-induced TNF-alpha production. LPS-induced plasma nitrite and nitrate levels (the breakdown products of nitric oxide (NO)) were suppressed by CGS and CCPA. In the RAW 264.7 macrophage cell line, pretreatment of the cells with both CGS and CCPA inhibited LPS-induced IL-10, TNF-alpha, and NO production, each in a concentration-dependent manner. The inhibitory effect of these drugs on cytokine and NO production was associated with improved mitochondrial respiration. Neither CGS nor CCPA affected the LPS-induced nuclear translocation of transcription factor nuclear factor-kappaB in these cells. These results demonstrate that adenosine receptor stimulation differentially modulates the LPS-induced production of IL-10, TNF-alpha, and NO in vitro and in vivo. The increase in LPS-induced IL-10 production and suppression of LPS-induced TNF-alpha and NO production caused by adenosine receptor activation may explain some of the immunomodulatory actions of adenosine released in excess during inflammatory and/or ischemic insult.
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Alzamami, Ahmad, Norah A. Alturki, Youssef Saeed Alghamdi, Shaban Ahmad, Saleh Alshamrani, Saeed A. Asiri, and Mutaib M. Mashraqi. "Hemi-Babim and Fenoterol as Potential Inhibitors of MPro and Papain-like Protease against SARS-CoV-2: An In-Silico Study." Medicina 58, no. 4 (April 5, 2022): 515. http://dx.doi.org/10.3390/medicina58040515.
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The coronaviruses belong to the Coronaviridae family, and one such member, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is causing significant destruction around the world in the form of a global pandemic. Although vaccines have been developed, their effectiveness and level of protection is still a major concern, even after emergency approval from the World Health Organisation (WHO). At the community level, no natural medicine is currently available as a cure. In this study, we screened the vast library from Drug Bank and identified Hemi-Babim and Fenoterol as agents that can work against SARS-CoV-2. Furthermore, we performed molecular dynamics (MD) simulation for both compounds with their respective proteins, providing evidence that the said drugs can work against the MPro and papain-like protease, which are the main drug targets. Inhibiting the action of these targets may lead to retaining the virus. Fenoterol is a beta-2 adrenergic agonist used for the symptomatic treatment of asthma as a bronchodilator and tocolytic. In this study, Hemi-Babim and Fenoterol showed good docking scores of −7.09 and −7.14, respectively, and performed well in molecular dynamics simulation studies. Re-purposing the above medications has huge potential, as their effects are already well-proven and under public utilisation for asthma-related problems. Hence, after the comprehensive pipeline of molecular docking, MMGBSA, and MD simulation studies, these drugs can be tested in-vivo for further human utilisation.
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Jaionen, Jouko, Markku Hynynen, Anne Kuitunen, Hannu Heikkila, Juha Perttila, Markku Salmenpera, Mika Valtonen, Riku Aantaa, and Antero Kallio. "Dexmedetomidine as an Anesthetic Adjunct in Coronary Artery Bypass Grafting." Anesthesiology 86, no. 2 (February 1, 1997): 331–45. http://dx.doi.org/10.1097/00000542-199702000-00009.
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Background Alpha 2-adrenergic agonists decrease sympathetic tone with ensuing attenuation of neuroendocrine and hemodynamic responses to anesthesia and surgery. The effects of dexmedetomidine, a highly specific alpha 2-adrenergic agonist, on these responses have not been reported in patients undergoing coronary artery bypass grafting. Methods Eighty patients scheduled for elective coronary artery bypass grafting received, in a double-blind manner, either a saline placebo or a dexmedetomidine infusion, initially 50 ng.kg-1.min-1 for 30 min before induction of anesthesia with fentanyl, and then 7 ng.kg-1.min-1 unit the end of surgery. Filling pressures, blood pressure, and heart rate were controlled by intravenous fluid and by supplemental anesthetics and vasoactive drugs. Results Compared with placebo, dexmedetomidine decreased plasma norepinephrine concentrations by 90%, attenuated the increase of blood pressure during anesthesia (3 vs. 24 mmHg) and surgery (2 vs. 14 mmHg), but increased slightly the need for intravenous fluid challenge (29 vs. 20 patients) and induced more hypotension during cardiopulmonary bypass (9 vs. 0 patients). Dexmedetomidine decreased the incidence of intraoperative (2 vs. 13 patients) and postoperative (5 vs. 16 patients) tachycardia. Dexmedetomidine also decreased the need for additional doses of fentanyl (3.1 vs. 5.4), the increments of enflurane (4.4 vs. 5.6), the need for beta blockers (3 vs. 11 patients), and the incidence of fentanyl-induced muscle rigidity (15 vs. 33 patients) and postoperative shivering (13 vs. 23 patients). Conclusions Intraoperative intravenous infusion of dexmedetomidine to patients undergoing coronary artery revascularization decreased intraoperative sympathetic tone and attenuated hyperdynamic responses to anesthesia and surgery but increased the propensity toward hypotension.
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Awad, E. W., and M. Anctil. "IDENTIFICATION OF beta-LIKE ADRENOCEPTORS ASSOCIATED WITH BIOLUMINESCENCE IN THE SEA PANSY RENILLA KOELLIKERI." Journal of Experimental Biology 177, no. 1 (April 1, 1993): 181–200. http://dx.doi.org/10.1242/jeb.177.1.181.
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Previous studies have reported pharmacological and biochemical evidence for the involvement of adrenergic substances in the regulation of neuroeffector activities in the bioluminescent cnidarian Renilla koellikeri (Cnidaria, Anthozoa). Therefore, direct radiobinding assays were developed to identify and characterize beta-adrenergic binding in membrane preparations from this species, using the two beta-antagonists [3H]dihydroalprenolol and [3H]CGP12177 as tracers. In addition, the effect of various beta-adrenergic agents on luminescence was examined. Binding of the radioligands at 25°C was rapid, reversible, saturable and specific. Saturation studies revealed the presence of two different and independent classes of binding site, site1 and site2, in the body of the colony (rachis). In contrast, homogeneous populations of binding sites corresponding to site1 were detected in autozooid polyps and to site2 in the peduncle. The pharmacological profile of beta-adrenergic binding in R. koellikeri membrane preparations displayed properties consistent with the presence of two sites and followed a pattern similar to beta2- and beta1-adrenergic receptor subtypes for site1 and site2, respectively. Bioluminescence in polyps was induced by beta-agonists as well as by one beta1-selective antagonist, atenolol, and was blocked by several beta-blockers including (+/−)CGP12177. The specificity pattern of the physiological effect of beta-adrenergic drugs on luminescence mirrors that of the radioligand interaction with site1. This suggests that radioligand binding to site1 represents binding to the receptor that mediates luminescence excitation in R. koellikeri. Blockade of the luminescent responses to site1 agonists by isotonic MgCl2 indicates that this beta-adrenergic mechanism must rely on interneuronal transmission. Collectively, these results suggest the evolutionary conservation of beta-adrenoceptors and of their dual character from coelenterates to higher vertebrates.
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Nikulina, N. N., S. V. Seleznev, M. B. Chernysheva, and S. S. Yаkushin. "Drug-induced bradycardia as a medical and social problem: data from the Cardiac Drug Overdoses Hospital Registry (STORM)." Russian Journal of Cardiology 25, no. 7 (August 15, 2020): 3918. http://dx.doi.org/10.15829/1560-4071-2020-3918.
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Aim. To analyze hospitalizations due to drug-induced bradyarrhythmia (DIB) over a 5-year period (2014-2018), its clinical characteristics, causes and outcomes.Material and methods. The analysis included all hospitalizations due to DIB at the Ryazan Regional Vascular Center in 2017 and 2018 and retrospectively in 2014.Results. A total of 325 cases of DIB were included in the analysis (age 76,0 [68.0; 82.0] years; men — 26,1%). The proportion of DIB as a hospitalization cause in 2017 increased by 4,3 times compared to 2014 (p<0,001), in 2018 compared to 2014 — by 6,3 times (p<0,001) and compared to 2017 — by 46,2% (p=0,001). We recorded the following manifestations of DIB: bradycardia (<40 bpm — 51,4%), atrioventricular (31,7%) and sinoatrial (29,2%) block, syncope (36,0%), Frederick’s syndrome (8,6%), pauses >3 s (5,9%). Management in intensive care was required in 42,2% of patients, temporary cardiac pacing — in 7,7%, permanent pacemaker — in 6,2%. Mortality rate was 6,2%. Before hospitalization, patients took beta-blockers (65,1%), antiarrhythmic agents (39,6%), cardiac glycosides (23,0%), ^-imidazoline receptor agonist moxonidine (13,5%, its prescription rate increased 8,9 times over 5 years, p=0,004), nondihydropyridine calcium channel blockers (7,9%), and other drugs (15,4%). In 60,1% of patients, ≥2 drugs with bradycardic action were used, in 22,0% — ≥3, in 8,1% — ≥4, in 10,6% — with an excessive single/daily dose.Conclusion. The medical and social significance of DIB have been demonstrated. DIB due to exceeding the recommended dose was associated with independent try of patients to manage the deterioration. In other cases, DIB was due to the summation/ potentiation of several drugs’ action, the comorbidities contributing to the development of bradyarrhythmia and/or changes in pharmacokinetic properties of drugs.
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Chung, Bo Young, Ji Young Um, Jin Cheol Kim, Seok Young Kang, Min Je Jung, Hye One Kim, and Chun Wook Park. "Anaphylaxis: Five Years’ Experience in the Emergency Rooms of Five University Hospitals in Korea." Medicina 56, no. 12 (December 14, 2020): 695. http://dx.doi.org/10.3390/medicina56120695.
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Background: Anaphylaxis is an allergic disease that requires special handling due to its potential fatality. Recent epidemiological data indicate that the incidence of anaphylaxis is rising. However, actual data on the prevalence or causes of anaphylaxis in Korea are limited. Methods: The emergency room attendees diagnosed with anaphylaxis between 2011 and 2015 in five university hospitals were included. Medical records were reviewed retrospectively. Results: During the 5 years, a total of 505 subjects were diagnosed with anaphylaxis. Respiratory presentations were more common in children than in adults, while adults presented more frequently with cardiovascular symptoms. Intraoral angioedema was more often observed in the countryside than in the city. Insect stings/bites were more common in the countryside than in the city. Drugs were much more common in adults than in children. In the countryside, the frequency of anaphylaxis was higher in summer and autumn than in spring and winter. The use of corticosteroids was less common in children than in adults, while children more frequently got treatment with inhaled beta 2 agonist. Conclusions: The principal causes of anaphylaxis in Korean patients were food, drugs, and stings/bites. The cause, clinical features and management of anaphylaxis were significantly different depending on age and region. These real-world data on anaphylaxis could be helpful to deepen that understanding of this condition for physicians and patients.
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Schifano, Fabrizio, Stefania Chiappini, John Corkery, and Amira Guirguis. "Abuse of Prescription Drugs in the Context of Novel Psychoactive Substances (NPS): A Systematic Review." Brain Sciences 8, no. 4 (April 22, 2018): 73. http://dx.doi.org/10.3390/brainsci8040073.
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Recently, a range of prescription and over-the-counter drugs have been reportedly used as Novel Psychoactive Substances (NPS), due to their potential for abuse resulting from their high dosage/idiosyncratic methods of self-administration. This paper provides a systematic review of the topic, focusing on a range of medications which have emerged as being used recreationally, either on their own or in combination with NPS. Among gabapentinoids, pregabalin may present with higher addictive liability levels than gabapentin, with pregabalin being mostly identified in the context of opioid, polydrug intake. For antidepressants, their dopaminergic, stimulant-like, bupropion activities may explain their recreational value and diversion from the therapeutic intended use. In some vulnerable clients, a high dosage of venlafaxine (‘baby ecstasy’) is ingested for recreational purposes, whilst the occurrence of a clinically-relevant withdrawal syndrome may be a significant issue for all venlafaxine-treated patients. Considering second generation antipsychotics, olanzapine appears to be ingested at very large dosages as an ‘ideal trip terminator’, whilst the immediate-release quetiapine formulation may possess proper abuse liability levels. Within the image- and performance- enhancing drugs (IPEDs) group, the beta-2 agonist clenbuterol (‘size zero pill’) is reported to be self-administered for aggressive slimming purposes. Finally, high/very high dosage ingestion of the antidiarrhoeal loperamide has shown recent increasing levels of popularity due to its central recreational, anti-withdrawal, opiatergic effects. The emerging abuse of prescription drugs within the context of a rapidly modifying drug scenario represents a challenge for psychiatry, public health and drug-control policies.
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Clark, Michael T., Adeboye Adejare, Gamal Shams, Dennis R. Feller, and Duane D. Miller. "5-Fluoro- and 8-fluorotrimetoquinol: selective .beta.2-adrenoceptor agonists." Journal of Medicinal Chemistry 30, no. 1 (January 1987): 86–90. http://dx.doi.org/10.1021/jm00384a015.
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Patessio, A., A. Podda, M. Carone, N. Trombetta, and CF Donner. "Protective effect and duration of action of formoterol aerosol on exercise-induced asthma." European Respiratory Journal 4, no. 3 (March 1, 1991): 296–300. http://dx.doi.org/10.1183/09031936.93.04030296.
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The short-term protective effect on exercise-induced asthma (EIA) and the duration of action of formoterol, given by metered dose aerosol at a dose of 24 micrograms, were compared with salbutamol (200 micrograms) and placebo in twelve asthmatic EIA-positive patients in a double-blind, placebo-controlled, three period cross-over study. On each treatment day the patients were given one of the drugs or placebo and two exercise tests were performed at the second and at the eighth hour after dosing. Using a standard procedure, exercise was performed by treadmill in well-controlled environmental conditions. In the first test at 2 h a significant difference relative to placebo (p less than 0.001) at each incremental time after exercise (i.e. 5, 10, 15, 20, 30 min) was obtained with both formoterol and salbutamol, without any significant difference between formoterol and salbutamol. After the eighth hour test formoterol still protected against EIA in comparison to both salbutamol and placebo. The effect of salbutamol at this time was not different from placebo. No adverse effects were reported in any treatment group. Formoterol has a long duration of action in protecting against EIA that persisted for eight hours, removing the need to dose with beta 2-agonist before every exercise.
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Berger, Geraint, Nipun Arora, Ian Burkovskiy, Yanfang Xia, Anu Chinnadurai, Robert Westhofen, Georg Hagn, et al. "Experimental Cannabinoid 2 Receptor Activation by Phyto-Derived and Synthetic Cannabinoid Ligands in LPS-Induced Interstitial Cystitis in Mice." Molecules 24, no. 23 (November 21, 2019): 4239. http://dx.doi.org/10.3390/molecules24234239.
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Interstitial cystitis (IC) is a chronic bladder disorder with unclear etiology. The endocannabinoid system has been identified as a key regulator of immune function, with experimental evidence for the involvement of cannabinoid receptors in bladder inflammation. This study used intravital microscopy (IVM) and behavioral testing in lipopolysaccharide-induced IC, to investigate the anti-inflammatory analgesic effects of a natural dietary sesquiterpenoid, beta-caryophyllene (BCP), which is present in cannabis among other plants, and has reported agonist actions at the cannabinoid 2 receptor (CB2R). BCP’s anti-inflammatory actions were compared to the synthetic CB2R-selective cannabinoid, HU308, and to an FDA-approved clinical treatment (dimethyl sulfoxide: DMSO). IVM data revealed that intravesical instillation of BCP and/or HU308 significantly reduces the number of adhering leukocytes in submucosal bladder venules and improves bladder capillary perfusion. The effects of BCP were found to be comparable to that of the selective CB2R synthetic cannabinoid, HU308, and superior to intravesical DMSO treatment. Oral treatment with BCP was also able to reduce bladder inflammation and significantly reduced mechanical allodynia in experimental IC. Based on our findings, we believe that CB2R activation may represent a viable therapeutic target for IC, and that drugs that activate CB2R, such as the generally regarded as safe (GRAS) dietary sesquiterpenoid, BCP, may serve as an adjunct and/or alternative treatment option for alleviating symptoms of inflammation and pain in the management of IC.
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Mutiah, Roihatul, Alif Firman Firdausy, Yen Yen Ari Indrawijaya, and Hibbatullah Hibbbatullah. "In Silico Prediction of Heliannuol A, B, C, D, and E Compounds on Estrogen Receptor β Agonists." Indonesian Journal of Cancer Chemoprevention 12, no. 1 (March 29, 2021): 37. http://dx.doi.org/10.14499/indonesianjcanchemoprev12iss1pp37-45.
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Heliannuols has a benzoxepine ring that produces anticancer activity by the inhibition mechanism of phosphoinositide 3 kinases (PI3K). Heliannuols are a compound that can be found in the leaves of sunflower (Helianthus annuus L.). The purpose of this study is to predict interactions, toxicity, physicochemical, and pharmacokinetics of Heliannuol A, B, C, D, and E based in silico as candidate anticancer drugs. Estrogen receptor beta (ERβ) is a new potential therapy for glioma with an antiproliferative effect. Ligands agonist ERβ have the potential activity to inhibit the proliferation of glioma cells and the discovery of this ligand has opened new therapy through the ERβ to prolong survival in cancer patients. Prediction of physicochemical properties based on Lipinski rules and penetrate in the blood-brain barrier. Receptor validation shows that 2I0G(A) has a smaller RMSD value than 2I0G(B), receptor validation is valid if the RMSD value less than 2. The result of molecular docking shows that Heliannuols comply with Lipinski rules and have low toxicity. Heliannuols also have a similar amino acid with Erteberel, but the rerank score of Erteberel still lower than Heliannuols.Keywords: Helianthus annuus, Heliannuols, estrogen receptor β (ERβ), in silico, toxicity.