Short-acting Agonist Research Articles

Стан вивчення поліморфізму окремих генів у виникненні бронхіальної астми

The study of the polymorphism of individual genes is the basis of both preventive medicine and is used in the selection of adequate therapy. Polymorphism of individual candidate genes in bronchial asthma (BA) is studied taking into account many personal characteristics and the influence of environmental factors. Aim - to analyze the status of the study of the role of polymorphism of β2-adrenoceptors (ADRβ2) in the pathogenesis of bronchial asthma in children and to compare them with our own findings. Materials and methods. The results of research on polymorphism of individual genes in children with BA, which includes the PubMed database, were analyzed. An in-depth study of the anamnesis data (disease, life, hereditary), a complex clinical and laboratory examination of children (n=101) of school age with BA was carried out (the average age was: for boys 11.15±0.48 years; for girls - 10.63±0.7 years). Patients were diagnosed with BA in accordance with the GINA recommendations of the current revision. Determination of the Arg16Gly polymorphism of the ADRβ2 gene (rs 1042713) was performed by the polymerase chain reaction method followed by restriction enzyme analysis. The obtained data were processed in the Statsoft STATISTICA software package. Mean values were given as (M±m), Student's test was used for comparison. Results. The assessment of the frequency of polymorphism of the Arg16Gly gene in BA established that two variants prevailed in boys: Arg16Gly and Gly16Gly; at that time, the Gly16Gly genotype prevailed among girls, which, according to individual studies, is associated with good effectiveness of the applied therapy (nebulization of salbutamol). Mutations in the ADRβ2 gene in patients with BA were twice as frequent in the Arg16Gly genotype and three times as frequent in the Gln27Glu genotype, in contrast to healthy children. Such a polymorphism affects the functional activity of ADRβ2, the occurrence and course of BA. Conclusions. The Arg16Gly polymorphism of the ADRβ2 gene in children with BA largely determines the sensitivity of ADRβ2 to the applied exacerbation therapy and the effectiveness of basic treatment. In patients with the Gly16Gly genotype, most researchers note the good clinical effectiveness of both fast broncholytic drugs (β2 short-acting agonists) and basic anti-inflammatory drugs. The diagnosed homozygous Arg16Arg genotype of the ADRβ2 gene mostly accompanies the uncontrolled (or partially controlled) course of asthma in children. The revealed features of the Arg16Gly polymorphism of the ADRβ2 gene will help the doctor to draw up an adequate treatment plan, which is based on the genetically determined sensitivity of ADRβ2 receptors to medical preparations. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the author.

Curcumin and Tulsi For Pulmonary Disorders In Pandemic Century

Asthma, a chronic respiratory disorder, is witnessing an increasing global incidence, necessitating exploration of alternative treatments beyond conventional therapies. This study reviews the therapeutic potential of natural products, namely curcumin and tulsi, in managing asthma, juxtaposed against the backdrop of conventional pharmaceuticals. Adverse effects and limitations of current medications such as short-acting agonists, inhaled corticosteroids, and monoclonal antibodies are highlighted. Moreover, embryonic risks associated with these drugs further underscore the need for safer alternatives. Experimental findings suggest the efficacy of curcumin in reducing airway obstruction and inflammation, backed by its safety profile. Tulsi (holy basil), a mainstay in Ayurvedic treatment, also demonstrates promising effects in alleviating asthma symptoms. Future research will expand on this foundation to provide a holistic, natural treatment approach to asthma management.

Transition From Methadone to Buprenorphine Using a Short-acting Agonist Bridge in the Inpatient Setting: A Case Study.

: Methadone and buprenorphine are the most common medications for opioid use disorder. Buprenorphine is often the preferred medication because of fewer drug-drug interactions and fewer regulatory barriers. For these reasons, patients often desire to transition from methadone to buprenorphine, but this can be difficult because of the risk of precipitated withdrawal. There are protocols designed to minimize withdrawal; however, these can be time-consuming or infeasible due to formulation and dosage availability of buprenorphine. We describe an inpatient transition from methadone to buprenorphine using a hydromorphone bridge over a 7-day period. This method used commonly available dosages and formulations of buprenorphine. To our knowledge, this is the first time a method has been described that transitions a patient from methadone to buprenorphine using a short-acting opioid agonist bridge and readily available opioid dosages and formulations. This case provides a viable alternative for rapidly transitioning a patient from methadone to buprenorphine that can be used as a template for an alternative method to transitions between these medications.

β2-Adrenergic receptor (β2-AR) agonist formoterol suppresses differentiation of L6 myogenic cells by blocking PI3K–AKT pathway

ABSTRACTβ2-Adrenergic receptor (β2-AR) is implicated in muscle metabolic activities such as glycogen metabolism, glucose uptake, lipolysis and muscle growth. However, the functional role of β2-AR in the differentiation of skeletal muscle is largely unknown. Here, we examined the functional role of β2-AR in L6 myoblast differentiation using the long-term-acting β2-AR-specific agonist formoterol. We observed that formoterol treatment strongly suppressed L6 myoblast differentiation and the expression of myosin heavy chain (MHC) in a dose- and time-dependent manner. Showing that both long-acting agonist (formoterol) and short-acting agonist (terbutaline) inhibited the induction of MHC protein, whereas β2-AR antagonist (ICI-118,551) upregulated MHC expression, we clearly demonstrated that β2-AR is involved in L6 myoblast differentiation. Furthermore, our pharmacological inhibition study revealed that the PI3K–AKT pathway is the main signaling pathway for myotube formation. Formoterol inhibited the activation of PI3K–AKT signaling, but not that of ERK signaling. Moreover, formoterol selectively inhibited AKT activation by IGF-I, but not by insulin. Collectively, our findings reveal a previously undocumented role of β2-AR activation in modulating the differentiation of L6 myoblasts.

Gastrointestinal actions of glucagon‐like peptide‐1‐based therapies: glycaemic control beyond the pancreas

The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose-lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP-1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorized as short- or long-acting, with each having unique islet-cell and gastrointestinal effects that lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long-acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual β-cell function.

Long-Acting Beta Agonists Enhance Allergic Airway Disease.

Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6.

Salbutamol misuse or abuse with fatal outcome: A case-report

Salbutamol is a short-acting agonist of the β(2) adrenergic receptors sometimes misused or abused, which can result in various cardiovascular adverse effects. We report one case of fatal salbutamol misuse or abuse in a 36-year-old poorly controlled female asthmatic patient with a past medical history of alcoholism and a recent smoking cessation. She died shortly after hospital admission following acute dyspnea and sudden collapse at home. Toxicological analyses evidenced salbutamol overdose, and necropsy showed acute lung edema and marked dysplasia of the right ventricle and revealed the patient was pregnant. The involvement of an initial disorder of the ventricular rhythm leading to cardiac failure is suggested by the presence of several combined pro-arrhythmogenic factors, such as arrhythmogenic right ventricle dysplasia, hypoxemia related to bronchospasm and salbutamol overdose.

Pharmacotherapeutic management of COPD patients in Greece – adherence to international guidelines

International guidelines for Chronic Obstructive Pulmonary Disease (COPD) propose the most cost-effective management of the disease. However, the management of COPD differs between countries and between clinics within the same country. To examine prescription trends for COPD by Lung Specialists (LS) and Primary Care Physicians (PCP) in Greece and to study prescription adherence to international guidelines. A retrospective analysis of COPD prescriptions, obtained from pharmacies located all over the country, was performed between 1997 and the beginning of 2003. The data collected were compared with those of other European countries. A subgroup analysis was carried out for prescriptions issued by PCP and LS. Between 1997 and 2003, LS and PCP used different pharmacological interventions for the management of COPD. Only the LS prescriptions showed a tendency to guideline adherence. Differences in preferences for different pharmacological drug classes were noted. Thus, LSs were found to generally prefer inhaled corticosteroids (ICSs), followed by anticholinergic drug + a beta(2)-short-acting agonist combinations, long-acting beta(2)-agonists, xanthines, short-acting beta(2)-agonists and expectorants. In contrast, PCPs used mostly short-acting beta(2)-agonists followed by xanthines, ICSs, expectorants, anticholinergic drug + beta(2)-short-acting agonist combinations and long-acting beta(2)-agonists. It appears that compliance to international COPD management-guidelines in force at the time of the study increased between 1997 and 2003 only for LSs but not for PCPs.

Proliferative aspects of airway smooth muscle

Increased airway smooth muscle (ASM) mass is perhaps the most important component of the airway wall remodeling process in asthma. Known mediators of ASM proliferation in cell culture models fall into 2 categories: those that activate receptors with intrinsic receptor tyrosine kinase activity and those that have their effects through receptors linked to heterotrimeric guanosine triphosphate–binding proteins. The major candidate signaling pathways activated by ASM mitogens are those dependent on extracellular signal-regulated kinase and phosphoinositide 3′-kinase. Increases in ASM mass may also involve ASM migration, and in culture, the key signaling mechanisms have been identified as the p38 mitogen-activated protein kinase and the p21-activated kinase 1 pathways. New evidence from an in vivo rat model indicates that primed CD4 + T cells are sufficient to trigger ASM and epithelial remodeling after allergen challenge. Hyperplasia has been observed in an equine model of asthma and may account for the increase in ASM mass. Reduction in the rate of apoptosis may also play a role. β 2-Adrenergic receptor agonists and glucocorticoids have antiproliferative activity against a broad spectrum of mitogens, although it has become apparent that mitogens are differentially sensitive. Culture of ASM on collagen type I has been shown to enhance proliferative activity and prevent the inhibitory effect of glucocorticoids, whereas β 2-agonists are minimally affected. There is no evidence that long-acting β 2-agonists are more effective than short-acting agonists, but persistent stimulation of the β 2-adrenergic receptor probably helps suppress growth responses. The maximum response of fluticasone propionate against thrombin-induced proliferation is increased when it is combined with salmeterol.

Efficacy and safety of long-acting GnRH agonists in in vitro fertilization and embryo transfer

The introduction of gonadotrophin-releasing hormone (GnRH) agonists combined with gonadotrophins is considered to be one of the most significant events in the development of in vitro fertilization and embryo transfer (IVF-ET) programmes. This article reviews the use of GnRH agonists in IVF-ET programmes and the efficacy and safety of long-acting GnRH agonists. The use of agonists results in higher clinical pregnancy rates, more supernumerary embryos for cryopreservation and allows convenient programming of oocyte recovery. There are different types of agonist and ovarian stimulation protocol available for clinical use. Recent meta-analysis of the Cochrane database has demonstrated the superiority of the long protocols over the short and ultra-short protocols for GnRH agonist use in IVF and GIFT. The depot injection offers increased clinical and patient compliance and improves efficacy of pituitary downregulation. However, compared with short-acting agonists, the depot preparations are associated with a longer period of stimulation and higher doses of gonadotrophins. To date, there is no evidence of an increased risk of pregnancy wastages or teratogenicity in human pregnancies exposed to long-acting agonists.

Brain Endothelium Lack One of Two Pathways of P-Selectin–Mediated Neutrophil Adhesion

P-selectin, an endothelial leukocyte adhesion receptor, is rapidly translocated to the cell surface upon release from storage granules called Weibel-Palade bodies and is also transcriptionally upregulated upon cytokine stimulation of endothelial cells (ECs). These two pathways of surface expression are coincident with the rapid and cytokine-inducible pathway of neutrophil adhesion to ECs. Constitutive P-selectin expression is largely absent in cultured murine brain microvascular EC (BMEC) monolayers, but interleukin-1beta and tumor necrosis factor-alpha stimulation for 4 hours leads to dramatic P-selectin upregulation. The functional relevance of differential P-selectin expression in these cells was examined by studying BMECs derived from wild-type mice and P-selectin-deficient mice. We show that P-selectin deficiency does not affect Weibel-Palade body formation or their release in response to short-acting agonists. However, in the absence of P-selectin, the brain endothelium is unable to support neutrophil adhesion after stimulation with these agonists, which may contribute to the immune privilege status of the brain. We show that P-selectin does play a major role in supporting neutrophil adhesion in the cytokine-induced pathway in BMECs in the context of other cytokine-inducible endothelial-leukocyte adhesion receptors, E-selectin, ICAM-1, and VCAM-1.

The effects of long-term treatment with salmeterol and salbutamol on the flow rate and composition of whole saliva in the rat

The effect of long-acting β 2-radrenoceptor agonists on salivary glands and saliva secretion has not been studied before. Sprague-Dawley rats were given either the long-acting β 2- agonist salmeterol, 1 mg/kg body wt per day or the short-acting agonist salbutamol, 5 mg/kg per day. Saline solution was used as control. After 18 days pilocarpine-stimulated saliva was collected, and after 21 days saliva was collected after stimulation with isoproterol and pilocarpine in combination. The saliva was analysed for total protein, amylase, hexosamine, sialic acid, sodium, potassium and calcium. At day 25 the salivary glands were extirpated and weighed. The weight of the parotid glands increased significantly after both salmeterol and salbutamol treatment, approx. 40%; the submandibular gland weights were not affected by either β 2- agonist treatment. Pilocarpine-stimulated salivary flow rate was increased in the salbutamol, but not in the salmeterol, group. In the salmeterol group the concentration of sialic acid was increased and that of calcium was decreased. In saliva stimulated with pilocarpine and isoproterenol in combination, the concentrations of total protein, amylase and calcium were decreased after salmeterol. In the salbutamol group, total protein and potassium were decreased. The ratio sialic acid: total protein was increased at both saliva collections in both β 2-agonist groups. It is concluded that rats treated chronically with the long-acting β 2 adrenoceptor agonist salmeterol have an impaired secretion of salivary proteins and calcium and that the effect resembles that of salbutamol.

Beta endorphin levels during heroin, methadone, buprenorphine, and naloxone challenges: Preliminary findings

Beta endorphin (BE) is a polypeptide agonist for the brain's endogenous opioid system. Levels of BE are elevated by opioid antagonists such as naloxone and depressed by short-acting agonists such as heroin and morphine; they become normalized during steady-state methadone. Buprenorphine (BUP) is a partial opioid agonist whose effects on BE levels were examined in six former heroin addicts and 14 methadone-maintained patients before and after being switched to sublingual BUP 2 mg daily for 1 month. In six former methadone-treated subjects BE levels also were measured after stopping BUP and after naloxone challenge. Levels of BE were not significantly lower in subjects started on BUP after stopping heroin (n = 6) (8.0 versus 8.1 ng/ml) or in subjects started on BUP after stopping methadone (n = 14) (11.6 vs 15.6 ng/ml). However, BE levels were lower on BUP than after naloxone challenge (n = 6) (7.0 versus 34.9 ng/ml). Levels of BE did not significantly change between the first 2 weeks (“early”) and “later,” although BE levels on methadone significantly correlated with BE levels on BUP in the “early” but not the “later” phase. The BE levels on BUP also did not differ from BE levels of unmedicated normals.

Naloxone benzoylhydrazone, a κ 3 opioid agonist, stimulates food intake in rats

Naloxone benzoylhydrazone (NalBzoH) is a selective, short-acting agonist at theκ 3 opioid receptor and a slowly dissociating potent antagonist at the mu opioid receptor. Given the important role of κ receptors in the opioid control of food intake, the present study examined the central and peripheral effects of NalBzoH upon food intake. Central administration of NalBzoH (1–20 μg, i.c.v.) significantly increased food intake for up to 12 h, but failed to alter intake or body weight after 24 or 48 . The 12 h duration of NalBzoH-mediated effects may be due to either persistentκ 3 receptor occupancy, and/or activation of an ingestive system which maintains its activity. Peripheral administration of NalBzoH (20 mg/kg, s.c.) significantly increased food intake for up to 1 h. To distinguishκ 1 (U50, 488H) andκ 3 (NalBzoH) hyperphagic effects, these agonist effects were compared following pretreatment with either naltrexone or theκ 1 antagonist, nor-binaltorphamine (Nor-BNI). Whereas naltrexone significantly reduced both U50, 448H and NalBzoH hyperphagia, Nor-BNI blocked U50, 448H, but not NalBzoH hyperphagia. These data indicate a distinct role for theκ 3 receptor in ingestive behavior separable from thatofκ 1 effects.

Ingestive behavior following central [D-Ala 2, Leu 5, Cys 6]-Enkephalin (DALCE), a short-acting agonist and long-acting antagonist at the delta opioid receptor

DALCE (1–40 μg, ICV), a short-acting agonist and long-acting antagonist at the delta opioid receptor, was examined for its effects upon food intake in rats under spontaneous, deprivation,glucoprivic and palatable conditions. DALCE (10 μgt) significantly stimulated free feeding for up to 10 h but only minimally decreased (40 μg) food intake and body weight after 24–72 h. DALCE, administered prior to food deprivation (24 h), failed to affect subsequent 24-h intake and sporadically decreased intake and body weight change after 48–72 h. 2-Deoxy-D-glucose (650 mg/kg, IP) hyperphagia was transiently (2 h) decreased by long-term DALCE (10 μg) pretreatment. Hyperphagia following exposure to a high-fat diet was significantly potentiated by long-term DALCE (1 μg) pretreatment. DALCE (10 μg) hyperphagia (2–10 h) was eliminated by central pretreatment with either naltrexone (20 μg) or the kappa antagonist, nor-binaltorphamine (20 μg) but was minimally affected by central pretreatment with the mu antagonist, beta-funaltrexamine (20 μg) or long-term DALCE (40 μg). The general inability of the antagonist actions of DALCE to alter these forms of feeding argues againts a role for the delta opioid receptor in these responses.

Increased feeding in response to decreased glucose utilization in the rat and monkey.

SMITH, GERARD P., AND ALAN N. EPSTEIN. Increased feeding in response to decreased glucose utili<ation ilz the rat and monkey. Am. J Physiol. 217(4) : 1083-1087. 1969.-The glucostatic hypothesis for the control of food intake predicts that decreased glucose utilization leads to increased food intake. Since the glucose analogue, 2-deoxy-D-glucose (Z-DG), produces decreased intracellular glucose utilization of most tissues and particularly of brain, the injection of 2-DG into 5 monkeys and 28 rats provided an explicit test of the predicted relationship. Both monkeys and rats ate more after 2-DG. The most effective systemic doses of Z-DG were 300 mg/kg (iv) in monkeys and 750 mg/kg (ip) in rats. Larger doses ( < 1,000 mg/kg) produced drowsiness, stupor, ataxia, or retching, but not convulsions. When separate groups of rats were tested with either insulin (6 U Iletin) or 2-DG (750 mg/kg), they increased their mean food intake to approximately the same amount, but the rats treated with Z-DG ate sooner. Shorter latency of feeding with 2-DG is interpreted as resulting from the fact that 2-DG produces decreased glucose utilization of brain directly, whereas insulin reduces cerebral glucose utilization indirectly as a consequence of hypoglycemia. Since Z-DG produced marked hyperglycemia during the period of increased feeding, these results show that the abrupt onset of decreased glucose utilization, not hypoglycemia, is a sufficient condition for feeding in mammals.