Actions of a picomolar short-acting S1P? agonist in S1P?-eGFP knock-in mice.
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ABSTRACT:
SUBMITTER: Cahalan SM
PROVIDER: S-EPMC3430385 | biostudies-literature | 2011 May
REPOSITORIES: biostudies-literature
Publications
Actions of a picomolar short-acting S1P₁ agonist in S1P₁-eGFP knock-in mice.
Cahalan Stuart M SM Gonzalez-Cabrera Pedro J PJ Sarkisyan Gor G Nguyen Nhan N Schaeffer Marie-Therese MT Huang Liming L Yeager Adam A Clemons Bryan B Scott Fiona F Rosen Hugh H
Nature chemical biology 20110327 5
Sphingosine 1-phosphate receptor 1 (S1P(1)) is critical for lymphocyte recirculation and is a clinical target for treatment of multiple sclerosis. By generating a short-duration S1P(1) agonist and mice in which fluorescently tagged S1P(1) replaces wild-type receptor, we elucidate physiological and agonist-perturbed changes in expression of S1P(1) at a subcellular level in vivo. We demonstrate differential downregulation of S1P(1) on lymphocytes and endothelia after agonist treatment. ...[more]
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Project description:BACKGROUND Asthma is a common disease in the U.S. POPULATION:Initial therapy in the stepwise approach for asthma management is short-acting ??-agonist (SABA) therapy as needed for symptom control. However, a significant adverse event that can occur with administration is bronchospasm. Here, we report a case of paradoxical bronchospasm with administration of SABAs during multiple pulmonary function tests (PFTs). CASE REPORT A 25-year-old, non-smoking, African American male with a history of moderate asthma and allergic rhinitis treated with fluticasone/salmeterol diskus, albuterol hydrofluoroalkane (HFA) inhaler, and montelukast presented to our clinic complaining of recurrent episodes of acute shortness of breath immediately following each administration of albuterol for 4 weeks. PFTs were performed with levalbuterol (Xopenex) and albuterol (ProAir), yielding significant decrease in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). Nebulized albuterol and ipratropium bromide also improved FEV1 and FVC. He was successfully transitioned to an ipratropium rescue inhaler for asthma exacerbations. CONCLUSIONS Paradoxical bronchoconstriction is the unexpected constriction of smooth muscle walls of the bronchi that occurs in the setting of an expected bronchodilatory response. This phenomenon has been observed with ??-agonist-containing inhaler formulations and is an under-recognized adverse event. Theories suggest that the formulation excipients can trigger airway hyperresponsiveness in patients with allergically inflamed airways. Removal of excipients or use of anticholinergic inhalers improved respiratory function. Clinicians should be aware of paradoxical bronchospasm as an adverse effect with common inhaler formulations containing ??-agonists and counsel patients accordingly in the appropriate clinical setting.
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Project description:Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting ?(2)-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the non-charged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid-sensitive disposition mechanism for cationic long-acting ?(2)-agonist bronchodilators in the airway. Potency rank order and other 'classical' features of anti-inflammatory effects do not apply to inhaled corticosteroids' rapid drug transport actions.
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Project description:BackgroundUS national guidelines recommend assessing short-acting beta-agonist (SABA) medication use as a marker of asthma severity and control. However, the relationship between recent SABA use and asthma exacerbations is not currently known.ObjectiveTo evaluate the proximal relationship between the type and frequency of SABA use and asthma-related outcomes.MethodsWe evaluated SABA use among patients with asthma ages 5 to 56 years who were members of a large health maintenance organization in southeast Michigan. Frequency of use was estimated from pharmacy data assessing the timing and amount of SABA fills. Cox proportional hazards models were used to examine the prospective relationship between average daily SABA use for 3 months and outcomes associated with poor asthma control (ie, oral corticosteroids use, asthma-related emergency department visits, and asthma-related hospitalizations). We separately accounted for SABA metered-dose inhaler (MDI) and SABA nebulizer use.ResultsOf the 2,056 patients who met study criteria, 1,569 (76.3%) had used a SABA medication in their baseline year. After adjusting for potential confounders, SABA nebulizer use was associated with asthma-related emergency department visits (adjusted hazard ratio [aHR], 6.32; 95% confidence interval [CI], 2.38 to 16.80) and asthma-related hospitalizations (aHR, 21.62; 95% CI, 3.17 to 147.57). In contrast, frequency of SABA MDI use was not associated with these outcomes.ConclusionsFrequency of SABA use during a 3-month period was associated with poor asthma outcomes. The relationship with poor asthma outcomes was strongest for SABA nebulizer use, suggesting that the type of SABA used is also of prognostic importance.
| S-EPMC2646829 | biostudies-literature
Project description:BackgroundOne goal of guideline-based asthma therapy is minimal use of short-acting β₂ agonist (SABA) medications. Inner-city children with asthma are known to have high SABA use.ObjectiveTo examine factors associated with high SABA use in inner-city children with asthma.MethodsOne hundred inner-city children with persistent asthma were enrolled into a randomized controlled trial of an emergency department (ED) and home intervention. All children underwent serologic allergen specific IgE and salivary cotinine testing at the ED enrollment visit. Pharmacy records for the past 12 months were obtained. Number of SABA fills during the past 12 months was categorized into low- to moderate- vs high-use groups. SABA groups were compared by the number of symptom days and nights, allergen sensitization, and exposures. Regression models were used to predict high SABA use.ResultsMean number of SABA fills over 12 months was 3.12. Unadjusted bivariate analysis showed that high SABA users were more than 5 times more likely to have an asthma hospitalization, almost 3 times more likely to have an asthma intensive care unit admission, and more than 3 times more likely to have prior specialty asthma care or positive cockroach sensitization than low to moderate SABA users. In the final regression model, for every additional inhaled corticosteroid fill, a child was 1.4 times more likely and a child with positive cockroach sensitization was almost 7 times more likely to have high SABA use when controlling for prior intensive care unit admission, receipt of specialty care, child age, and income.ConclusionProviders should closely monitor SABA and controller medication use, allergen sensitization, and exposures in children with persistent asthma.Trial registrationClinicalTrials.gov, identifier NCT01981564.
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Project description:BackgroundCatecholamine infusion elicits an increase in clotting factors and this increase has been attributed to stimulation of ?2-adrenorecptors (?2AR). Accordingly, we tested the hypothesis that inhalation of a short-acting selective ?2AR agonist can induce a procoagulant state in healthy individuals.MethodsWe recruited 23 healthy volunteers (nine females; mean age: 26±0.8 years; body mass index: 24.7±0.5 kg/m2) and randomly allocated them into two groups, the ?2AR arm (seventeen subjects) and the saline arm (six subjects). Hemodynamics, plasma norepinephrine concentration, and procoagulant, anticoagulant, and fibrinolytic profiles of each participant were determined using specific assays before and after inhalation of either 2 mL nebulized normal saline or a mixture of 1 mL saline and 1 mL of salbutamol (5 mg salbutamol sulfate), a selective ?2AR agonist, which were delivered by a nebulizer over ten minutes.ResultsSaline inhalation had no effect on the procoagulant, anticoagulant and fibrinolytic profiles of the six healthy volunteer in the study's saline arm. Salbutamol inhalation caused (a) a significant increase in the activity or levels of the procoagulant factors; FVIII increased by 11±3% (p = 0.04), von Willebrand factor increased by 7±1% (p = 0.03), and (b) a significant decrease in the activated partial prothrombin time from 27.4±0.4 seconds to 25.5 ±0.5 seconds (p<0.001) in the 17 volunteers in the study's ?2AR arm. D-dimer and prothrombin fragments F1+2 were elevated by 200 ±90% and 505.0 ±300.0%, respectively. In addition, the activity of the anticoagulant protein C pathway (demonstrated by the protein C Global assay) decreased from 1.0±0.08 to 0.82±0.06 (p<0.001). Although plasma levels of tissue plasminogen activator decreased, all other indices of the fibrinolytic system did not change following salbutamol inhalation.ConclusionWe found that a single inhalation of salbutamol, a short-acting ?2AR agonist, activates the clotting system without affecting the fibrinolytic system. This induction of a procoagulant state in healthy subjects warrants further investigation in patients treated with these agents.
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Project description:Short-acting β2-agonist (SABA) use is known to be lower in Korean patients with asthma than in those from other countries, while the rate of asthma exacerbations in Korea is higher than in other countries. Thus, an epidemiologic study on SABA use and the relationship between SABA overuse and treatment outcomes in asthma is needed in Korea. We performed a cross-sectional study using the National Health Insurance Service-National Sample Cohort 2002-2012 database. We evaluated the trend of annual SABA use and overuse (prescription of 3 or more SABA canisters/year) and the impact of SABA overuse on mortality. During the study period, the proportion of asthmatic patients who used SABA was approximately 8%-11%, with no significant change in trend. The mean annual SABA use in asthmatic patients was 0.15-0.22 canisters/patient/year and 1.93-2.05 canisters/patient/year in those who used SABA in 12 months. SABA overuse was observed in about 2%-4% of asthmatic patients during the study period. SABA overuse generally tended to increase as the age of patients increased, with triple peaks in the late 20s (3.3%), late 40s (3.1%), and late 70s (3.6%). SABA overuse was associated with mortality (adjusted odds ratio, 1.72; 95% confidence interval, 1.61-1.84). The rate of SABA use was very low in Korean asthmatic patients between 2002-2012. SABA overuse was found in 2%-4% of patients in Korea. SABA overuse was associated with an increased risk of mortality.
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Project description:The aim of the study was to compare the efficacy of half-dose, long-acting GnRH analogue (Diphereline) with Suprefact in IVF/ICSI (in vitro fertilization/intracytoplasmic sperm injection) cycles.In this randomized clinical trial performed in Royan Institute, 126 infertile women who were first time candidates for IVF/ICSI were enrolled. Patients were randomly divided into two groups by using a random number table. In one group, 62 patients received a single half dose, 1.87 mg Diphereline, in mid-luteal phase. In the other group, 64 cases were treated with buserelin from the previous mid-luteal phase. P value less than 0.05 was considered significant.The mean age of patients in the Diphereline and Suprefact groups was 27.9 ±3.6 and 29.6 ±3.5 years, respectively (p = 0.01). In the Diphereline group, the mean number of used gonadotropins was 25.6 ±12.1 ampoules, while in the second group it was 25.9 ±8.5 ampoules. Numbers of retrieved and MII oocytes were significantly higher in the Diphereline group (12.1 ±6.3 and 9.6 ±5.5) in comparison to the Suprefact group (9.4 ±6.4 and 7.2 ±5.1). Although the number of developed embryos in the Diphereline group was statistically higher than in the Suprefact group (6.1 ±3.9 vs. 4.7 ±3.4, p = 0.04) there was no significant difference in pregnancy rate (37.1%, 95% CI [26.16-49.54] vs. 37.5%, 95% CI [26.67-49.75]).A half-dose, long-acting GnRH agonist can be successfully used in ovarian stimulation and produces a higher number of MII oocytes and embryos. The pregnancy rates with this method are acceptable.
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Project description:Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (-)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability.
| S-EPMC2843818 | biostudies-literature
Project description:To identify the potential interaction partners of PRSS37, three testis lysates of Prss37E/+ mice (PRSS37-EGFP knock-in heterozygous mice) and three testis lysates of pAcr-EGFP transgenic mice were immunoprecipitated using anti-GFP mAb magnetic beads. The GFP-IP products of six samples from two groups were subsequently analyzed by mass spectrometry (MS) to identify differentially immmunoprecipitated proteins (DIPs) in the PRSS37-EGFP group. Proteins detected in pAcr-EGFP group were used as negative controls to exclude the endogenous proteins and polypeptides that interact nonspecifically with the anti-GFP mAb magnetic beads.
2021-05-06 | PXD024833 | Pride
Project description:BackgroundRecent years have seen a rise in the diversity and use of synthetic cannabinoids. The present study evaluated the behavioral effects of the third-generation indazole-3-carboxamide-type synthetic cannabinoid, AB-FUBINACA.MethodsAdult male and female C57BL/6J mice were treated with AB-FUBINACA (0-3 mg/kg, i.p.) and tested repeatedly in the tetrad battery measuring catalepsy, antinociception, hypothermia, and locomotor activity. Mice treated with AB-FUBINACA (≥2 mg/kg, i.p.) displayed classic cannabinoid effects in the tetrad that were blocked by the CB1 receptor selective antagonist rimonabant. To address tolerance and withdrawal effects, a second group of mice was injected with AB-FUBINACA (3 mg/kg, s.c.) or vehicle consisting of 5% ethanol, 5% Kolliphor EL, and 90 % saline every 12 h and tested daily in modified tetrad over the course of 5 days. On the 6th day, withdrawal was precipitated using rimonabant (3 mg/kg, s.c.), and somatic signs of withdrawal (i.e., head twitches and paw tremors) were quantified.ResultsAlthough mice did not develop tolerance to AB-FUBINACA or cross-tolerance to Δ9-tetrahydrocannabinol (THC; 50 mg/kg, i.p.), somatic precipitated withdrawal signs were observed. Repeated tetrad testing up to 48 h post injection indicated that AB-FUBINACA effects are relatively short-lived, as compared with THC. Brain levels of AB-FUBINACA, as quantified by UHPLC-MS/MS, were undetectable 4 h post injection.ConclusionsThese data indicate that the cannabinoid effects of AB-FUBINACA are relatively short-lived, yet sufficient to induce dependence in mice.
| S-EPMC7461724 | biostudies-literature