Receptor Agonist Drugs Research Articles

Human Somatostatin SST4 Receptor Transgenic Mice: Construction and Brain Expression Pattern Characterization.

Somatostatin receptor subtype 4 (SST4) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST4 receptor expression and function between humans and mice, we generated an SST4 humanized mouse line to serve as a translational animal model for preclinical research. A transposon vector containing the hSSTR4 and reporter gene construct driven by the hSSTR4 regulatory elements were created. The vector was randomly inserted in Sstr4-deficient mice. hSSTR4 expression was detected by bioluminescent in vivo imaging of the luciferase reporter predominantly in the brain. RT-qPCR confirmed the expression of the human gene in the brain and various peripheral tissues consistent with the in vivo imaging. RNAscope in situ hybridization revealed the presence of hSSTR4 transcripts in glutamatergic excitatory neurons in the CA1 and CA2 regions of the hippocampus; in the GABAergic interneurons in the granular layer of the olfactory bulb and in both types of neurons in the primary somatosensory cortex, piriform cortex, prelimbic cortex and amygdala. This novel SST4 humanized mouse line might enable us to investigate the differences of human and mouse SST4 receptor expression and function and assess the effects of SST4 receptor agonist drug candidates.

Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study.

Semaglutide, a glucagon‐like peptide‐1 (GLP‐1) analogue, has been coformulated in a tablet with the absorption enhancer, sodium N‐(8‐[2‐hydroxybenzoyl] amino) caprylate (SNAC). We investigated tablet erosion and the pharmacokinetics of oral semaglutide administered with 2 different water volumes and evaluated the relationships between these parameters. In a randomized, single‐center (Quotient Sciences, UK), open‐label, 2‐period crossover trial, 26 healthy men received single doses of 10 mg oral semaglutide with 50 or 240 mL water while fasting. Tablet erosion and gastrointestinal transit were assessed by gamma scintigraphy. Semaglutide and SNAC plasma concentrations were measured until 24 and 6 hours, respectively, after administration. Complete tablet erosion (CTE) occurred in the stomach irrespective of water volume administered with the tablet (primary end point). Mean time to CTE was 85 versus 57 minutes with 50 versus 240 mL water (ratio 50/240 mL, 1.51; 95% confidence interval, 0.96‐2.37; P = .072). Area under the semaglutide concentration‐time curve from 0 to 24 hours (AUC0‐24h,semaglutide) and maximum semaglutide concentration (Cmax,semaglutide) were ∼70% higher with 50 versus 240 mL water (P = .056 and P = .048, respectively). Median time to maximum semaglutide concentration (tmax,semaglutide) was 1.5 hours independent of water volume with dosing. Higher AUC0‐24h,semaglutide and Cmax,semaglutide and longer tmax,semaglutide were significantly correlated with longer time to CTE and later gastric emptying of tablet and water (all P < .05). The safety profile was as expected for the GLP‐1 receptor agonist drug class. In conclusion, the oral semaglutide tablet erodes in the stomach irrespective of water volume with dosing. Slower tablet erosion in the stomach results in higher semaglutide plasma exposure.

El papel de los estimulantes de trombopoyetina (eltrombopag y romiplostim) en trombocitopenia inmune secundaria a Lupus Eritematoso Sistémico (LES)

Introduction: Immune thrombocytopenia is a frequent hematologic manifestation in systemic lupus erythematosus (SLE). Corticosteroids are the first line of treatment for moderate to severe thrombocytopenia in this disease, in conjunction with antimalarials or other immunosuppressants. In particular cases where the response to initial interventions is not achieved, second-line therapies with different mechanisms of action re available. Objective: This narrative review will focus on two thrombopoietin receptor agonist drugs (TPO-RA): eltrombopag and romiplostim, and their role in immune thrombocytopenia secondary to SLE. In addition, its pharmacological profile, dose and indications will be reviewed in the context of this disease. Methods: A literature search was conducted in different databases; scientific articles and guidelines were nalyzed, both for SLE and immune thrombocytopenia. With the purpose of answering different clinical questions that constantly arise in the scene of daily practice. Results and conclusions: The use of TPO-RA stimulants is a therapeutic alternative for particular scenarios in patients with SLE and immune thrombocytopenia, however studies focused on this particular population are necessary to be able to make strong recommendations about its utility. Current data are extrapolated from primary immune thrombocytopenia.

(Invited) Near Infrared Nanosensors to Image Brain Neurochemistry

Neurons communicate through chemical neurotransmitter signals that either terminate at the postsynaptic process (“wired transmission”) or diffuse beyond the synaptic cleft to modulate the activity of larger neuronal networks (“volume transmission”). Molecules such as dopamine belong to the latter class of neurotransmitters, and have been the pharmacological targets of antidepressants and antipsychotics for decades. Owing to the central role of dopamine over a range of behaviors and psychiatric disorders, real-time imaging of the signal’s spatial propagation would constitute a valuable advance in neurochemical imaging. To this end, we present a nanoscale near-infrared fluorescent nanosensor for dopamine and demonstrate its efficacy for imaging dopamine volume transmission in the extracellular space of the brain striatum and prefrontal cortex (Beyene et al. ACS Chem. Neuro. 2017). The sensor is developed from polymers pinned to the surface of single wall carbon nanotubes (SWNT) in which the surface-adsorbed polymer is the recognition moiety and the carbon nanotube the fluorescence transduction element. Excitonic transitions in functionalized SWNT yield up to ΔF/F = 4500% near-infrared fluorescence emission in the presence of dopamine (Beyene et al. Nano Letters 2018). We next demonstrate imaging of evoked dopamine release in acute striatal slices, and show altered dopamine reuptake kinetics when brain tissue is exposed to dopamine receptor agonist and antagonist drugs (Beyene et al. Science Advances 2019). Lastly, we discuss how to evolve synthetic molecular recognition for other neuromodulators of interest, such as serotonin (Jeong et al. Science Advances 2019). We characterize our findings in the context of their utility for high spatial and temporal neuromodulator imaging in the brain, describe nanosensor exciton behavior from a molecular dynamics (MD) perspective, and validate nanosensor for use to elucidate dopaminergic signaling variability with disease or pharmacological perturbations at a synaptic scale.

Drug Design of GLP-1 Receptor Agonists: Importance of In Silico Methods.

Drug design based on degradation-resistant, long-acting Glucagon-like peptide-1 receptor (GLP-1R) agonists for treating type 2 diabetes is attracting a lot of attention. Here, the authors have examined in detail how in silico drug design is aiding in developing novel GLP-1 receptor agonist drugs. Their pharmacotherapy and adverse effects have also been summarized. After the analysis of currently available information on this topic, the authors feel that in silico method is a great auxiliary tool in almost all the experimental studies on GLP-1 receptors and is highly efficient in identifying novel drug molecules that can act as GLP-1 receptor agonists.

Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials.

An association between Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA) and risk of pancreatitis and pancreatic cancer has been suggested. Since its first description, several new trials (including three cardiovascular outcome trials) have been published, substantially increasing the available data set. This suggests the need for an update of the previous meta analysis. A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials, with duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. The endpoints were pancreatitis, pancreatic cancer reported as serious adverse events. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above, on an intention-to-treat basis. A total of 43 trials fulfilling inclusion criteria (all reporting data on pancreatitis and pancreatic cancer) was identified. GLP-1 RA showed no association with pancreatitis (MH-OR 1.24 [0.94, 1.64]; p=0,13) and pancreatic cancer (MH-OR 1.28 [0.87, 1.89]; p=0,20). No clear evidence of risk for pancreatitis was observed, whereas data on pancreatic cancer are too scarce to draw any conclusion.

The Role of the Cannabinoid System in Opioid Analgesia and Tolerance.

Opioid receptor agonist drugs, such as morphine, are very effective for treating chronic and severe pain; but, tolerance can develop with long-term use. Although there is a lot of information about the pathophysiological mechanisms of opioid tolerance, it is still not fully clarified. Suggested mechanisms for opioid tolerance include opioid receptor desensitisation, reduction of sensitivity G-proteins, activation of Mitogen-Activated Protein Kinase (MAPK), altered intracellular signaling pathway including nitric oxide, and activation of mammalian Target of Rapamycin (mTOR). One way to reduce opioid tolerance and increase the analgesic potential is to use low doses. Combination of cannabinoids with opioids has been shown to manifest the reduction of the opioid dose. Experimental studies revealed an interaction of the endocannabinoid system and opioid antinociception. Cannabinoid and opioid receptor systems use common pathways in the formation of analgesic effect and demonstrate their activity via G Protein Coupled Receptors (GPCR). Cannabinoid drugs modulate opioid analgesic activity at a number of distinct levels within the cell, ranging from direct receptor associations to post-receptor interactions through shared signal transduction pathways. This review summarizes the data indicating that with combining cannabinoids and opioids drugs may be able to produce long-term analgesic effects, while preventing the opioid analgesic tolerance.

Major cardiovascular events, heart failure, and atrial fibrillation in patients treated with glucagon-like peptide-1 receptor agonists: An updated meta-analysis of randomized controlled trials

Background and aimsGlucagon-like Peptide 1 Receptor Agonists (GLP1-RA) has been associated with a reduction of major cardiovascular events (MACE) and mortality on the basis of the results of cardiovascular outcome trials (CVOT). Several meta-analyses on this issue have been recently published; however, they were all restricted to CVOT, with the exclusion of all studies designed for other endpoints; moreover, other cardiovascular endpoints, such as atrial fibrillation and heart failure have not been fully explored. Methods and resultsA Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. We included 43 trials, enrolling 63,134 patients. A significant reduction of MACE (MH-OR 0.87 [0.83, 0.92]), all-cause mortality (MH-OR 0.89 [0.83, 0.96]), and a nonstatistical trend toward reduction of heart failure (MH-OR 0.93 [0.85, 1.01]) was observed – GLP1-RA did not increase the risk of atrial fibrillation (MH-OR 0.94 [0.84, 1.04]). ConclusionThe present meta-analysis confirms the favorable effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events, cardiovascular and all-cause mortality, stroke, and possibly myocardial infarction. Conversely, the effects on heart failure remain uncertain. Available data on atrial fibrillation seems to exclude any major safety issues in this respect. Registration number (PROSPERO)CRD42018115577.

Side effects of mirabegron studied on ants as models

The overactive bladder syndrome (OAB) affects the quality of life. It is most often treated with anticholinergic drugs, but at the cost of many unwanted effects. In the last decade to date, mirabegron, an adrenergic receptor agonist drug used to relieve OAB has appeared in the pharmacopoeia. It works through a different mechanism than antimuscarinic drugs, with apparently fewer side effects. In the same way that we have examined the adverse effects of the anticholinergic oxybutynin on the ant Myrmica sabuleti used as a biological model, here we examine the side effects of mirabegron. Unlike oxybutynin, mirabegron had no adverse effect on ants, except that it increased their meat consumption, reduced their sugar water intake and decreased their general activity. No adaptation was observed for this last- mentioned effect, which may correspond to the tiredness reported in humans. The ants did not become dependent on the consumption of mirabegron, whose effect on general activity decreased very slowly and disappeared about 52 hours after weaning. Patients are advised to take mirabegron daily though its elimination half-life is 50 hours, and fatigue is one of the side effects of the treatment. In the event that patients under mirabegron medication show a decrease in activity over their treatment, it would be careful to space out the medication or to add an appropriate stimulant or to alternate mirabegron with an anticholinergic drug that does not affect the patient’s level of activity. The kind of antimuscarinic drug that could be used together with mirabegron, the respective dosage and the timing of each drug should be defined depending on their combined efficacy and side effects, and taking into account their elimination time.

Side effects of mirabegron studied on ants as models

The overactive bladder syndrome (OAB) affects the quality of life. It is most often treated with anticholinergic drugs, but at the cost of many unwanted effects. In the last decade to date, mirabegron, an adrenergic receptor agonist drug used to relieve OAB has appeared in the pharmacopoeia. It works through a different mechanism than antimuscarinic drugs, with apparently fewer side effects. In the same way that we have examined the adverse effects of the anticholinergic oxybutynin on the ant Myrmica sabuleti used as a biological model, here we examine the side effects of mirabegron. Unlike oxybutynin, mirabegron had no adverse effect on ants, except that it increased their meat consumption, reduced their sugar water intake and decreased their general activity. No adaptation was observed for this last- mentioned effect, which may correspond to the tiredness reported in humans. The ants did not become dependent on the consumption of mirabegron, whose effect on general activity decreased very slowly and disappeared about 52 hours after weaning. Patients are advised to take mirabegron daily though its elimination half-life is 50 hours, and fatigue is one of the side effects of the treatment. In the event that patients under mirabegron medication show a decrease in activity over their treatment, it would be careful to space out the medication or to add an appropriate stimulant or to alternate mirabegron with an anticholinergic drug that does not affect the patient’s level of activity. The kind of antimuscarinic drug that could be used together with mirabegron, the respective dosage and the timing of each drug should be defined depending on their combined efficacy and side effects, and taking into account their elimination time.

Dexmedetomidine modulates transient receptor potential vanilloid subtype 1

Dexmedetomidine, a highly selective alpha-2 adrenergic receptor agonist and novel sedative drug with minimal respiratory suppression, have shown anti-nociceptive activity in various pain models by poorly understood mechanisms. Because alpha-2 adrenergic receptor is co-localized with TRPV1 polymodal nociceptive receptor in dorsal root ganglion neurons and up-regulated in neuropathic pain animal models, the analgesic activity might be mediated through inhibition of TRPV1 in the peripheral nervous system. In an effort to elucidate whether modulatory effect of dexmedetomidine on TRPV1 activity could be the potential peripheral mechanism underlying the antinociceptive effect of dexmedetomidine, intracellular calcium concentration after capsaicin application was investigated in mice dorsal root ganglion (DRG) neurons, with and without pretreatment of dexmedetomidine. Dexmedetomidine (10 μM) reduced capsaicin-induced calcium responses by 29.7 ± 7.39% (n = 34, p < 0.0001), in dose-dependent manner. Higher level of inhibition was observed with increased dose of dexmedetomidine (50 μM, 45.1 ± 8.58%, n = 15, p = 0.0002), and lower inhibition by decreased dose (1 μM, 18.8 ± 1.48%, n = 148, p = 0.004). RT-PCR analysis revealed expression of TRPV1 and alpha-2A, alpha-2B and alpha-2C subtypes of adrenergic receptor in mice DRG neurons, and immunocytochemical analysis revealed co-expression of TRPV1 and alpha-2A receptors in primary cultured DRG neurons. In summary, these results suggested the inhibition of TRPV1 expressed in the primary sensory neurons as a potential mechanism that contributes to the anti-nociceptive action of dexmedetomidine.

Encapsulation of Leflunomide (LFD) in a novel niosomal formulation facilitated its delivery to THP-1 monocytic cells and enhanced Aryl hydrocarbon receptor (AhR) nuclear translocation and activation.

Leflunomide (LFD) is an Aryl hydrocarbon receptor (AhR) agonist and immunomodulatory drug with several side effects. Niosomes are novel drug delivery systems used to reduce the unfavorable effects of drugs by enhancing their bioavailability, controlling their release and targeting specific sites. Here, we prepared niosomal formulations of LFD, evaluated their properties and delivered to THP-1 monocytic cells to study the activation and nuclear translocation of AhR. Four types of non-ionic surfactants were utilized to formulate niosomes by thin film hydration (TFH) method. Entrapment efficiency (EE %) of niosomes were quantified and dynamic light scattering (DLS) was performed. Transmission electron microscopy (TEM) was used to identify the morphology of LFD niosomes. Dialysis method was used to measure LFD release rate. MTS assay was adopted to examine the viability of the cells upon each treatment. The nuclear transfer of AhR was investigated by Immunocytochemistry (ICC). The mRNA expression of IL1β and CYP1A1 were evaluated using quantitative RT-PCR. Span 60: cholesterol (1:1) showed the highest EE% (70.00 ± 6.24), largest particles (419.00 ± 4.16nm) and the best uniformity with the lowest PDI (0.291 ± 0.007). TEM micrographs of Span 60 (1:1) nanoparticles showed conventional spherical vesicles with internal aqueous spaces. The release rate of LFD from Span 60 (1:1) vesicles was slower. Although the viability of LFD niosome-treated THP-1 cells was decreased, they were associated with lower cytotoxic effects compared with the free LFD counterparts. Both free and niosomal LFD treatments intensified the nuclear translocation of AhR. The mRNA expression of CYP1A1 was overexpressed while IL1β was downregulated in both free and niosomal LFD treated combinations. LFD encapsulation in Span 60: cholesterol (1:1) niosomal formulation could be introduced as a suitable vehicle of transferring LFD to THP-1 cells, with minimal cytotoxic effects, enhancing the AhR nuclear translocation and activation and inducing immunomodulatory properties. Graphical abstract The Graphical abstract; it demonstrates the workflow of the study and summary of results in brief.

Review of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus in patients with chronic kidney disease and their renal effects.

Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD), and when it causes CKD it is collectively referred to as diabetic kidney disease. One of the newer therapies for managing hyperglycemia is the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) drug class. This review summarizes the effects of GLP‐1RAs in patients with T2DM with CKD and evidence for renoprotection with GLP‐1RAs using data from observational studies, prospective clinical trials, post hoc analyses, and meta‐analyses. Evidence from some preclinical studies was also reviewed. Taken together, subgroup analyses of patients with varying degrees of renal function demonstrated that glycemic control with GLP‐1RAs was not markedly less effective in patients with mild or moderate renal impairment vs that in patients with normal function. GLP‐1RAs were associated with improvements in some cardiorenal risk factors, including systolic blood pressure and body weight. Furthermore, several large cardiovascular outcome studies showed reduced risks of composite renal outcomes, mostly driven by a reduction in macroalbuminuria, suggesting potential renoprotective effects of GLP‐1RAs. In conclusion, GLP‐1RAs effectively reduced hyperglycemia in patients with mild or moderately impaired kidney function in the limited number of studies to date. GLP‐1RAs may be considered in combination with other glucose‐lowering medications because of their ability to lower glucose in a glucose‐dependent manner, lowering their risk for hypoglycemia, while improving some cardiorenal risk factors. Potential renoprotective effects of GLP‐1RAs, and their renal mechanisms of action, warrant further investigation.

Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes.

Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP‑1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials. In a single-dose, first-in-human trial, 135 healthy males received oral semaglutide (2-20mg semaglutide co-formulated with 150-600mg SNAC) or placebo with SNAC. In a 10-week, once-daily, multiple-dose trial, 84 healthy males received 20 or 40mg oral semaglutide (with 300mg SNAC), placebo, or placebo with SNAC, and 23 males with type 2 diabetes (T2D) received 40mg oral semaglutide (with 300mg SNAC), placebo, or placebo with SNAC. Oral semaglutide was safe and well-tolerated in both trials. The majority of adverse events (AEs) were mild, with the most common AEs being gastrointestinal disorders. In the single-dose trial, semaglutide exposure was highest when co-formulated with 300 mg SNAC. In the multiple-dose trial, semaglutide exposure was approximately twofold higher with 40 versus 20mg oral semaglutide in healthy males, in accordance with dose proportionality, and was similar between healthy males and males with T2D. The half-life of semaglutide was approximately 1week in all groups. The safety profile of oral semaglutide was as expected for the GLP-1 receptor agonist drug class. Oral semaglutide co-formulated with 300mg SNAC was chosen for further clinical development. The pharmacokinetic results supported that oral semaglutide is suitable for once-daily dosing. CLINICALTRIALS. NCT01037582, NCT01686945.

Comparative efficacy of prucalopride and tegaserod in patients with predominantly constipated irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) affects 5-20% of all individuals aroun d the world. In Mexico (Veracruz), a prevalence of 16.9% has been documented. Its diagnosis is based on the Rome III criteria, and its treatment has different approaches; within the pharmacological options are the serotonin receptor agonist drugs (5-HT4). The effectiveness of tegaserod has been established in patients with IBS with constipation (IBS-C), considering prucalopride as a drug with therapeutic potential for this condition, since it shows greater affi nity for the 5-HT4 receptor than tegaserod, and accelerates colonic transit. However, more data from randomized controlled trials that prove this are required. Objective: To compare the efficacy of prucalopride versus tegaserod in the treatment of irritable bowel with constipation, by means of the Bristol scale, the global scale of symptoms and associated symptoms. Material and methods: Two groups of patients were established (A and B) in a randomized manner: men and women between 18 and 50 years of age with Rome criteria III for IBS-C; all were given the same diet. In group A, Prucalopride was administered at a dose of 2 mg orally every 24 hours for two weeks. In group B, 6 mg of tegaserod were administered every 12 hours for two weeks. The clinical evolution of each patient was assessed each week during the two weeks of the study period, including the assessments of the adapted and validated Bristol scale, and the global scale of symptoms and associated symptoms. Results: Twenty-two patients were included, 21 (95.5%) female, with a 1:21 ratio; the average age was 37.27 years; 11 (50%) received prucalopride, and the rest, tegaserod. To evaluate the association between the treatment given and the symptoms of «rectal fullness, evacuation effort and evacuation urgency», Fisher’s exact test was used, being not statistically significant (p &gt; 0.05); for «abdominal distension, abdominal movements and Bristol scale», Mann-Whitney U was used, being not statistically signifi cant (p &gt; 0.05); however, for «abdominal pain», with the same test, a statistically signifi cant difference was found (p &lt; 0.05). Of those treated with prucalopride, one (9%) had diarrhea, three (27%) headache, and one (9%) headache and nausea; with tegaserod, two (18%) had diarrhea, two (18%) headache, and one (9%) headache and nausea. Conclusions: Both, prucalopride and tegaserod improve to some degree all the symptoms evaluated for IBS-C, but prucalopride signifi cantly and more promptly improves the symptom of «abdominal pain». It was evidenced that the diarrea event implied change of treatment in both groups.

Reciprocal modulation of helper Th1 and Th17 cells by the β2-adrenergic receptor agonist drug terbutaline.

Catecholamine hormones are powerful regulators of the immune system produced by the sympathetic nervous system (SNS). They regulate the adaptive immune system by altering T-cell differentiation into T helper (Th) 1 and Th2 cell subsets, but the effect on Th17 cells is not known. Th17 cells, defined, in part, by chemokine receptor CCR6 and cytokine interleukin (IL)-17A, are crucial for mediating certain pathogen-specific responses and are linked with several autoimmune diseases. We demonstrated that a proportion of human Th17 cells express beta 2-adrenergic receptor (β2AR), a G protein-coupled receptor that responds to catecholamines. Activation of peripheral blood mononuclear cells, which were obtained from venous blood drawn from healthy volunteers, with anti-cluster of differentiation 3 (CD3) and anti-CD28 and with a β2-agonist drug, terbutaline (TERB), augmented IL-17A levels (P<0.01) in the majority of samples. TERB reduced interferon gamma (IFNγ) indicating that IL-17A and IFNγ are reciprocally regulated. Similar reciprocal regulation was observed with dbcAMP. Proliferation of Th cells was monitored by carboxyfluorescein diacetate N-succinimidyl ester labeling and flow cytometry with antibody staining for CD3 and CD4. TERB increased proliferation by a small but significant margin (P<0.001). Next, Th17 cells (CD4+ CXCR3- CCR6+ ) were purified using an immunomagnetic positive selection kit, which removes all other mononuclear cells. TERB increased IL-17A from purified Th17 cells, which argues that TERB acts directly on Th17 cells. Thus, hormone signals from the SNS maintain a balance of Th cells subtypes through the β2AR.

Microvascular effects of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized controlled trials.

Results with GLP1-receptor agonists (GLP-1RA) on microvascular complications of diabetes are contrasting. In trials designed for cardiovascular outcomes, both liraglutide and semaglutide were associated with a relevant reduction in the incidence and progression of nephropathy. On the other hand, in the same trials, semaglutide was associated with an increased progression of retinopathy, and a similar trend was observed for liraglutide. This meta-analysis is aimed at assessing the effects of GLP-1RA on retinopathy and nephropathy. A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration >11weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. Of the 113 trials fulfilling the inclusion criteria, 78 and 62 did not report information on retinopathy and nephropathy, respectively. Treatment with GLP1-RA was not associated with a significant increase in the incidence of retinopathy (MH-OR [95% CI] 0.92 [0.74-1.16]. p=0.49). In subgroup analyses, GLP1-RA were associated with a lower risk of retinopathy in comparison with sulfonylureas. Cases of macular edema were reported only in nine trials with no sign of increased risk. GLP1-RA reduced the incidence of nephropathy with respect to comparators (MH-OR [95% CI] 0.74 [0.60-0.92]. p=0.005). This difference was significant versus placebo, but not versus any class of active comparators. GLP1-RA appear to reduce the incidence and/or progression of nephropathy and to have no specific effect on retinopathy-with the notable exception of semaglutide, which could have a negative impact on the retina.

Antinociceptive and respiratory effects following application of transdermal fentanyl patches and assessment of brain μ-opioid receptor mRNA expression in ball pythons.

OBJECTIVE To quantify plasma fentanyl concentrations (PFCs) and evaluate antinociceptive and respiratory effects following application of transdermal fentanyl patches (TFPs) and assess cerebrospinal μ-opioid receptor mRNA expression in ball pythons (compared with findings in turtles). ANIMALS 44 ball pythons (Python regius) and 10 turtles (Trachemys scripta elegans). PROCEDURES To administer 3 or 12 μg of fentanyl/h, a quarter or whole TFP (TFP-3 and TFP-12, respectively) was used. At intervals after TFP-12 application in snakes, PFCs were measured by reverse-phase high-pressure liquid chromatography. Infrared heat stimuli were applied to the rostroventral surface of snakes to determine thermal withdrawal latencies after treatments with no TFP (control [n = 16]) and TFP-3 (8) or TFP-12 (9). Breathing frequency was measured in unrestrained controls and TFP-12-treated snakes. μ-Opioid receptor mRNA expression in brain and spinal cord tissue samples from snakes and turtles (which are responsive to μ-opioid receptor agonist drugs) were quantified with a reverse transcription PCR assay. RESULTS Mean PFCs were 79, 238, and 111 ng/mL at 6, 24, and 48 hours after TFP-12 application, respectively. At 3 to 48 hours after TFP-3 or TFP-12 application, thermal withdrawal latencies did not differ from pretreatment values or control treatment findings. For TFP-12-treated snakes, mean breathing frequency significantly decreased from the pretreatment value by 23% and 41% at the 24- and 48-hour time points, respectively. Brain and spinal cord tissue μ-opioid receptor mRNA expressions in snakes and turtles did not differ. CONCLUSIONS AND CLINICAL RELEVANCE In ball pythons, TFP-12 application resulted in high PFCs, but there was no change in thermal antinociception, indicating resistance to μ-opioid-dependent antinociception in this species.

Effects of glucagon-like peptide-1 receptor agonists on mortality and cardiovascular events: A comprehensive meta-analysis of randomized controlled trials

IntroductionThe publication of the results of LEADER and SUSTAIN-6 trials suggested a possible beneficial effect of the class of GLP-1 receptor agonists on cardiovascular morbidity and mortality. The aim of the present meta-analysis is to collect and synthetize all available evidence on the effect of GLP-1 receptor agonists on cardiovascular events and mortality. MethodsA Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration >11weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. The principal outcome of this analysis was the effect of GLP-1 receptor agonists on all-cause and cardiovascular mortality, overall (fatal plus nonfatal) myocardial infarction, stroke, and heart failure. ResultsOut of 113 trials fulfilling inclusion criteria (mean duration 41.7±38.2weeks), 32, 25, 48, 43 and 32 reported at least one event for all-cause and cardiovascular mortality, overall (fatal plus nonfatal) myocardial infarction, stroke, and heart failure, respectively. In GLP-1 receptor agonist-treated patients, all-cause mortality, cardiovascular mortality, and myocardial infarction were significantly lower than in comparators (MH-OR [95% CI] 0.88 [0.79–0.97], p=0.015, 0.84 [0.74–0.96], p=0.009, and 0.90 [0.80–1.00], p=0.050, respectively), whereas no beneficial effect was observed for stroke and heart failure (MH-OR [95% CI] 0.90 [0.81–1.00]. p=0.059. 0.89 [0.76–1.04]. p=0.15. and 0.92 [0.81–1.06]. p=0.25. respectively). ConclusionsOverall, the agents of this class appear to reduce all-cause mortality, cardiovascular mortality, and the incidence of myocardial infarction at mid-term follow up.

Systematic Design of Trypsin Cleavage Site Mutated Exendin4-Cysteine 1, an Orally Bioavailable Glucagon-Like Peptide-1 Receptor Agonist.

Exendin-4 is a strong therapeutic candidate for the treatment of metabolic syndrome. Related receptor agonist drugs have been on the market since 2005. However, technical limitations and the pain caused by subcutaneous injection have severely limited patient compliance. The goal of the study is to investigate a biologically active exendin-4 analog could be administered orally. Using intraperitoneal glucose tolerance tests, we discovered that exendin4-cysteine administered by oral gavage had a distinct hypoglycemic effect in C57BL/6J mice. Using Rosetta Design and Amber, we designed and screened a series of exendin4-cysteine analogs to identify those that retained biological activity while resisting trypsin digestion. Trypsin Cleavage Site Mutated Exendin4-cysteine 1 (TSME-1), an analog whose bioactivity was similar to exendin-4 and was almost completely resistant to trypsin, was screened out. In addition, TSME-1 significantly normalized the blood glucose levels and the availability of TSME-1 was significantly higher than that of exendin-4 and exendin4-cysteine. Collectively orally administered TSME-1, a trypsin-resistant exendin-4 analog obtained by the system, is a strong candidate for future treatments of type 2 diabetes.