Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease.

KW-6356 is a selective antagonist and inverse agonist of the adenosine A2A receptor. The primary aim of the present analysis was to characterize the pharmacokinetics (PK) of KW-6356 and its active metabolite M6 in healthy subjects and patients with Parkinson's disease (PD). We pooled concentration-time data from healthy subjects and patients with PD who were administered KW-6356. Using these data, we developed a population PK model by sequentially fitting the KW-6356 parameters followed by the M6 parameters. A first-order absorption with a 1-compartment model for KW-6356 and a 1-compartment model for M6 best described the profiles. The covariates included in the final models were food status (fed/fasted/unknown) on first-order absorption rate constant, baseline serum albumin level on apparent clearance of KW-6356, and baseline body weight on apparent volume of distribution of KW-6356 and apparent clearance of M6. No covariate had a clinically meaningful impact on KW-6356 or M6 exposure.

Activation of central adenosine A2B receptors mediate brain ghrelin-induced improvement of intestinal barrier function through the vagus nerve in rats.

Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelin-induced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-d-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.

Polydeoxyribonucleotide Exerts Protective Effect Against CCl4-Induced Acute Liver Injury Through Inactivation of NF-κB/MAPK Signaling Pathway in Mice.

Acute liver injury (ALI) causes life-threatening clinical problem, and its underlying etiology includes inflammation and apoptosis. An adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), exhibits anti-inflammatory and anti-apoptotic effects by inhibiting the secretion of pro-inflammatory cytokines. In the current study, the protective effect of PDRN against carbon tetrachloride (CCl4)-induced ALI was investigated using mice. For the induction of ALI, mice received intraperitoneal injection of CCl4 twice over seven days. Mice from the PDRN-treated groups received an intraperitoneal injection of 200 µL saline containing PDRN (8 mg/kg), once a day for seven days, starting on day 1 after the first CCl4 injection. In order to confirm that the action of PDRN occurs through the adenosine A2A receptor, 8 mg/kg 3,7-dimethyl-1-propargylxanthine (DMPX), an adenosine A2A receptor antagonist, was treated with PDRN. Administration of CCl4 impaired liver tissue and increased the liver index and histopathologic score. The expression of pro-inflammatory cytokines was increased, and apoptosis was induced by the administration of CCl4. Administration of CCl4 activated nuclear factor-kappa B (NF-κB) and facilitated phosphorylation of signaling factors in mitogen-activated protein kinase (MAPK). In contrast, PDRN treatment suppressed the secretion of pro-inflammatory cytokines and inhibited apoptosis. PDRN treatment inactivated NF-κB and suppressed phosphorylation of signaling factors in MAPK. As a result, liver index and histopathologic score were reduced by PDRN treatment. When PDRN was treated with DMPX, the anti-inflammatory and anti-apoptotic effect of PDRN disappeared. Therefore, PDRN can be used as an effective therapeutic agent for acute liver damage.

Regadenoson administration and QT interval prolongation during pharmacological radionuclide myocardial perfusion imaging.

The objective of our study is to assess change in QTc interval with Regadenoson administration during myocardial perfusion imaging (MPI). We conducted a retrospective, observational analysis of 1497 consecutive patients who underwent pharmacological radionuclide MPI. On multivariate logistic regression analyses, there was no statistical significance of QTc prolongation when adjusted for ischemia/fixed perfusion defect on MPI and QT prolonging medications being taken prior to stress testing. However, a positive stress ECG after Regadenoson injection had a statistical significance (p value 0.0004). Regadenoson is a safe drug for use in MPI with little, if any, side effects of major clinical significance.

Reduction of repetitive behavior by co-administration of adenosine receptor agonists in C58 mice.

Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.

Neuroprotective effect of pharmacological postconditioning on cerebral ischaemia-reperfusion-induced injury in mice.

OBJECTIVES: To investigate the mechanism of neuroprotection rendered via pharmacological postconditioning in cerebral ischaemia-reperfusion-induced injury in mice. METHODS: Pharmacological postconditioning is strategy which either involves hindering deleterious pathway or inducing modest stress level which triggers intracellular defence pathway to sustain more vigorous insult leading to conditioning. Hence, in current research we explored the potentiality of CGS21680 (0.5 mg/kg; i.p), an adenosine A2 A receptor agonist and PTEN inhibitor, SF1670 (3 mg/kg; i.p.) to trigger postconditioning after inducing cerebral global ischaemia (17 min) and reperfusion (24 h)-induced injury via occlusion of both carotid arteries. Mice were also given treatment with LY294002 (1.5 mg/kg; i.p.), a PI3K inhibitor and adenosine A2 A receptor antagonist, Istradefylline (2 mg/kg; i.p.), to establish the precise mechanism of postconditioning. Various biochemical and behavioural parameters were assessed to examine the effect of pharmacological postconditioning. KEY FINDINGS: Pharmacological postconditioning induced with CGS21680 and SF1670 attenuated the infarction along with improved behavioural and biochemical parameters in comparison with ischaemia-reperfusion control group. The outcome of postconditioning with CGS21680 and SF1670 was significantly reversed by LY294002 and Istradefylline, respectively. CONCLUSIONS: The neuroprotective effects of CGS21680 and SF1670 postconditioning on cerebral ischaemia-reperfusion injury may be due to PI3K/Akt pathway activation.

Effects of intra-accumbal or intra-prefrontal cortex microinjections of adenosine 2A receptor ligands on responses to cocaine reward and seeking in rats.

RATIONALE AND OBJECTIVES: Many studies indicated that adenosine via its A2A receptors influences the behavioral effects of cocaine by modulating dopamine neurotransmission. The hypothesis was tested that A2A receptors in the nucleus accumbens (NAc) or the prefrontral cortex (PFc) may modulate cocaine reward and/or cocaine seeking behavior in rats. METHODS: The effects of local bilateral microinjections of the selective A2A receptor agonist CGS 21680 or the A2A receptor antagonists KW 6002 and SCH 58261 were investigated on cocaine self-administration on reinstatement of cocaine seeking. RESULTS: The intra-NAc shell, but not intra-infralimbic PFc, administration of CGS 21680 significantly reduced the number of active lever presses and the number of cocaine (0.25 mg/kg) infusions. However, tonic activation of A2A receptors located in the NAc or PFc did not play a role in modulating the rewarding actions of cocaine since neither KW 6002 nor SCH 58261 microinjections altered the cocaine (0.5 mg/kg) infusions. The intra-NAc but not intra-PFc microinjections of CGS 21680 dose- dependently attenuated the reinstatement of active lever presses induced by cocaine (10 mg/kg, i.p.) and the drug-associated combined conditioned stimuli using the subthreshold dose of cocaine (2.5 mg/kg, i.p.). On the other hand, the intra-NAc pretreatment with SCH 58261, but not with KW 6002, given alone evoked reinstatement of cocaine seeking behavior. CONCLUSION: The results strongly support the involvement of accumbal shell A2A receptors as a target, the activation of which exerts an inhibitory control over cocaine reward and cocaine seeking.

Intravenous regadenoson with aminophylline reversal is safe and equivalent to intravenous adenosine infusion for fractional flow reserve measurements.

BACKGROUND: Small studies have shown that adenosine is equivalent to regadenoson when obtaining coronary fractional flow reserve (FFR) measurements. A study that also evaluates time and safety of aminophylline reversal of regadenoson effects has not been presented. HYPOTHESIS: Reversal of regadenoson with aminophylline is safe and equivalent to adenosine for FFR measurements. METHODS: Forty-six consecutive patients who underwent clinically indicated FFRs at the time of coronary angiography were enrolled between 4/2012 and 5/2014. Each patient had FFR measured using adenosine 140 mcg/kg/min IV, and following return to baseline, FFR was measured using regadenoson 400 mcg IV, which then was reversed with aminophylline 150 mg IV. Time to baseline hemodynamics was measured. Agreement between the two assessments was compared using linear regression. RESULTS: FFR results were similar with both agents (R2 = 0.935, P < 0.0001). Also, using the 0.80 cutoff for significantly depressed FFR, there was no divergence regarding studies' significance. After aminophylline reversal of regadenoson, hemodynamics returned to baseline in 111 ± 71 seconds. There were no unexpected side effects or complications. CONCLUSIONS: For FFR measurement, regadenoson and adenosine are equivalent hyperemic agents. Regadenoson with aminophylline reversal may be considered as an alternative to adenosine for FFR measurements.

Caffeine Delays Light-entrained Activity and Potentiates Circadian Photic Phase-resetting in Mice.

Caffeine is widely used to reduce sedation and increase alertness. However, long-term caffeine use may disrupt circadian (daily, 24-h) rhythms and thereby negatively affect health. Here, we examined the effect of caffeine on photic regulation of circadian activity rhythms in mice. We found that entrainment to a standard 12-h light, 12-h dark (LD) photocycle was delayed during oral self-administration of caffeine. Both acute, high-dose caffeine and chronic, oral caffeine exposure potentiated photic phase-delays in mice, suggesting a possible mechanism by which entrainment to LD was delayed. The effect of caffeine on photic phase-resetting was mimicked by administration of adenosine A1, but not A2A, receptor antagonist in mice. Our results support the hypothesis that caffeine interferes with the ability of the circadian clock to respond normally to light.

Image-guided chemotherapy with specifically tuned blood brain barrier permeability in glioma margins.

Blood-brain barrier (BBB) disruption is frequently observed in the glioma region. However, the tumor uptake of drugs is still too low to meet the threshold of therapeutic purpose. Method: A tumor vasculature-targeted nanoagonist was developed. Glioma targeting specificity of the nanoagonist was evaluated by in vivo optical imaging. BBB permeability at the glioma margin was quantitatively measured by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Single-photon emission computed tomography imaging/computed tomography (SPECT/CT) quantitatively determined the glioma uptake of the radiolabeled model drug. T2-weighted MRI monitored the tumor volume. Results: Immunostaining studies demonstrated that the BBB remained partially intact in the invasive margin of patients' gliomas regardless of their malignancies. DCE-MRI showed that vascular permeability in the glioma margin reached its maximum at 45 min post nanoagonist administration. In vivo optical imaging indicated the high glioma targeting specificity of the nanoagonist. SPECT/CT showed the significantly enhanced glioma uptake of the model drug after pre-treatment with the nanoagonist. Image-guided paclitaxel injection after nanoagonist-mediated BBB modulation more efficiently attenuated tumor growth and extended survival than in animal models treated with paclitaxel or temozolomide alone. Conclusion: Thus, image-guided drug delivery following BBB permeability modulation holds promise to enhance the efficacy of chemotherapeutics to glioma.

Myocardial Stress Perfusion MRI: Experience in Pediatric and Young-Adult Patients Following Arterial Switch Operation Utilizing Regadenoson.

Dextro-transposition of the great arteries (D-TGA) is one of the most common cyanotic heart lesions. The arterial switch operation (ASO) is the preferred surgical palliation for D-TGA. One of the primary concerns following the ASO is complications arising from the coronary artery transfer. There is a need for myocardial perfusion assessment within ASO patients. There is no report on the utility of regadenoson as a stress agent in children following ASO. Our objective was to observe the safety and feasibility of regadenoson as a pharmacologic stressor for perfusion cardiac MR in a pilot cohort of pediatric and young-adult patients who have undergone ASO. We reviewed our initial experience with regadenoson stress cardiac MR in 36 pediatric and young-adult patients 15.1 ± 4.5 years (range 0.2-22 years) with history of ASO. The weight was 61.6 ± 21.5 kg (range 3.8-93 kg). All patients underwent cardiac MR because of concern for ischemia. Subjects' heart rate and blood pressure were monitored and pharmacologic stress was induced by injection of regadenoson. We evaluated their hemodynamic response and adverse effects using changes in vital signs and onset of symptoms. A pediatric cardiologist and radiologist qualitatively assessed myocardial perfusion and viability images. All stress cardiac MR examinations were completed without adverse events. Resting heart rate was 72 ± 13 beats per minute (bpm) and rose to peak of 120 ± 17 bpm (95 ± 50% increase, p < 0.005) with regadenoson. Image quality was considered good or diagnostic in all cases. A total of 11/36 (31%) patients had a perfusion defect on the stress FPP images. 14 of the 36 patients (39%) underwent cardiac catheterization within 6 months of the CMR and the findings showed excellent agreement. Regadenoson may be a useful coronary hyperemia agent to utilize for pediatric patients following arterial switch procedure when there is concern for ischemia. The ability to administer as a single bolus with one IV makes it advantageous in pediatrics. In a limited number of cases, regadenoson stress perfusion showed excellent agreement with cardiac catheterization.

Nanolayered hybrid mediates synergistic co-delivery of ligand and ligation activator for inducing stem cell differentiation and tissue healing.

Cellular behaviors, such as differentiation, are regulated by complex ligation processes involving cell surface receptors, which can be activated by various divalent metal cations. The design of nanoparticle for co-delivery of ligand and ligation activator can offer a novel strategy to synergistically stimulate ligation processes in vivo. Here, we present a novel layered double hydroxide (LDH)-based nanohybrid (MgFe-Ado-LDH), composed of layered MgFe hydroxide nanocarriers sandwiching the adenosine cargo molecule, maintained through an electrostatic balance, to co-deliver the adenosine (Ado) ligand from the interlayer spacing and the Mg2+ ion (ligation activator) through the dissolution of the MgFe nanocarrier itself. Our findings demonstrate that the MgFe-Ado-LDH nanohybrid promoted osteogenic differentiation of stem cells through the synergistic activation of adenosine A2b receptor (A2bR) by the dual delivery of adenosine and Mg2+ ions, outperforming direct supplementation of adenosine alone. Furthermore, the injection of the MgFe-Ado-LDH nanohybrid and stem cells embedded within hydrogels promoted the healing of rat tibial bone defects through the rapid formation of fully integrated neo-bone tissue through the activation of A2bR. The newly formed bone tissue displayed the key features of native bone, including calcification, mature tissue morphology, and vascularization. This study demonstrates a novel and effective strategy of bifunctional nanocarrier-mediated delivery of ligand (cargo molecule) and activation of its ligation to receptor by the nanocarrier itself for synergistically inducing stem cell differentiation and tissue healing in vivo, thus offering novel design of biomaterials for regenerative medicine.

Influence of body mass index and type of low-level exercise on the side effect profile of regadenoson.

PURPOSE: Regadenoson, an A2A adenosine receptor pharmacologic stress agent for radionuclide myocardial perfusion imaging (MPI), is administered as a single, fixed dose. We studied the side effect profile of regadenoson combined with two types of low-level exercise, according to body mass index (BMI). METHODS: Three hundred and fifty-six patients (46.1% men, mean age 67.7±10.7 years, range 31-90 years) underwent regadenoson stress testing combined with low-level exercise. Subjects were classified according to BMI as normal, overweight, or obese, and the type of low-level exercise performed as walking on the treadmill (TE group, n=190) or forcefully swinging legs while sitting (SS group, n=166). Patients' demographics, medical history, clinical symptoms during stress, changes in ECG, oxygen saturation (SatO2), systolic blood pressure (SBP), and heart rate (HR) were evaluated. RESULTS: Groups were comparable (p=ns) with regard to cardiovascular risks factors. The incidence of side effects was similar across BMI (p=ns), although the TE patients showed improved profiles over those with SS exercise, with a significantly lower incidence of flushing, dizziness and nausea/gastrointestinal discomfort (12.9% vs. 28.4%; 19.9% vs. 33.4%; 11.4% vs. 19.2%, respectively; all p<0.05). Regarding the hemodynamic response, we did not observe significant changes in SBP and HR after regadenoson administration across BMI categories. Comparing the TE and SS groups, no significant changes were observed in SBP, but there was a higher increase in HR in the TE group (p<0.05). CONCLUSIONS: Regadenoson in combination with low-level exercise is safe and well tolerated over a wide range of BMI, with TE exercise showing a better side effect profile than SS.

Adenosine A2A receptors are up-regulated and control the activation of human alveolar macrophages.

Chronic inflammatory lung diseases remain a health concern and new anti-inflammatory treatments are needed. Targeting adenosine A2A receptors (A2AR) affords robust anti-inflammatory effects in animal models, but the translation of this promising strategy to humans has been challenging, possibly due to interspecies differences in receptor distribution and effects. Thus, we now assessed the efficiency of a selective A2AR agonist to control the activation of fresh human alveolar inflammatory cells. We collected bronchoalveolar lavage fluid from patients with interstitial lung disease and loaded alveolar cells with the intracellular free calcium probe FURA-2/AM. Calcium transients were then recorded in response to superfusion with a proinflammatory peptide (N-formylmethionyl-leucyl-phenylalanine - FMLP), in the absence or presence of the selective A2AR agonist CGS21680. In a second experiment, cells were continuously exposed to FMLP and A2AR density was assessed by immunocytochemistry. Sixteen patients were included, nine for analysis of calcium transients, and seven for immunocytochemistry. When alveolar macrophages were exposed to 100 nM FMLP for 120 s, a peak elevation of intracellular free calcium levels (97.0% over baseline) was recorded; CGS21680 (100 and 300 mM) significantly reduced this peak to 89.5% and 81.5%, respectively. The immunofluorescence analysis revealed a time-dependent increase of A2AR density in alveolar macrophage upon exposure to 1 µM FMLP, up to 148% of control at 6 h. These results show that pro-inflammatory stimuli up-regulate A2AR and their activation dampens the impact of pro-inflammatory stimuli. This supports that targeting A2AR is a promising therapy for human lung inflammatory diseases, especially for diseases with a strong inflammatory component.

Adenosine A2A receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction.

BACKGROUND: This work evaluated the hypothesis that 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), an agonist of adenosine A2A receptor, could be beneficial for preventing cardiac dysfunction due to hypertension associated with myocardial infarction (MI). METHODS: Male spontaneously hypertensive rats (SHR) were randomly divided into four groups (six animals per group): sham-operation (SHR-Sham), and myocardial infarction rats (SHR-MI) were treated orally either with vehicle or LASSBio-294 (10 and 20 mg.kg-1.d-1) for 4 weeks. Echocardiography and in vivo hemodynamic parameters measured left ventricle (LV) structure and function. Exercise tolerance was evaluated using a treadmill test. Cardiac remodeling was accessed by LV collagen deposition and tumor necrosis factor α expression. RESULTS: Early mitral inflow velocity was significantly reduced in the SHR-MI group, and there was significant recovery in a dose-dependent manner after treatment with LASSBio-294. Exercise intolerance observed in the SHR-MI group was prevented by 10 mg.kg-1.d-1 of LASS-Bio-294, and exercise tolerance exceeded that of the SHR-Sham group at 20 mg.kg-1.d-1. LV end-diastolic pressure increased after MI, and this was prevented by 10 and 20 mg.kg-1.d-1 of LASSBio-294. Sarcoplasmic reticulum Ca2+ ATPase levels were restored in a dose-dependent manner after treatment with LASSBio-294. Fibrosis and inflammatory processes were also counteracted by LASSBio-294, with reductions in LV collagen deposition and tumor necrosis factor α expression. CONCLUSION: In summary, oral administration of LASSBio-294 after MI in a dose-dependent manner prevented the development of cardiac dysfunction, demonstrating this compound's potential as an alternative treatment for heart failure in the setting of ischemic heart disease with superimposed chronic hypertension.

Common genetic polymorphisms of adenosine A2A receptor do not influence response to regadenoson.

AIM: Hemodynamic response to regadenoson varies greatly, and underlying mechanisms for variability are poorly understood. We hypothesized that five common variants of adenosine A2A receptor (ADORA2A) are associated with altered response to regadenoson. METHODS: Consecutive subjects (n = 357) undergoing resting regadenoson nuclear stress imaging were enrolled. Genotyping was performed using Taqman-based assays for rs5751862, rs2298383, rs3761422, rs2267076 and rs5751876. RESULTS: There was no significant difference in heart rate or blood pressure between different genotypes following regadenoson administration. There was also no significant difference in myocardial ischemia detected by nuclear perfusion imaging as defined by summed difference score, or in self-reported side effects among the genotypes tested. CONCLUSION: The common A2A variants studied are not associated with variability in hemodynamic response to regadenoson or variability in detection of ischemia with nuclear perfusion stress imaging.

Nanoagonist-mediated endothelial tight junction opening: A strategy for safely increasing brain drug delivery in mice.

Even though opening endothelial tight junctions is an efficient way to up-regulate brain drug delivery, the extravasation of blood-borne components from the compromised tight junctions can result in adverse consequences such as edema and neuronal injuries. In this work, we developed a nanoagonist that temporarily opened tight junctions by signaling adenosine 2A receptor, a type of G protein-coupled receptor expressed on brain capillary endothelial cells. Magnetic resonance imaging demonstrated remarkable blood-brain barrier permeability enhancements and significantly increased brain uptakes of both small molecular and macromolecular paramagnetic agents after nanoagonist administration. Gamma ray imaging and transmission electron microscope observed tight junction opening followed by spontaneous recovery after nanoagonist treatment. Immunofluorescence staining showed the unspoiled basal membrane, pericytes and astrocyte endfeet that enwrapped the vascular endothelium. Importantly, edema, apoptosis and neuronal injuries observed after hypertonic agent mediated tight junction-opening were not observed after nanoagonist intervention. The uncompromised neurovascular units may prevent the leakage of blood-borne constituents into brain parenchyma and accelerate tight junction recovery. Considering blood-brain barrier impermeability is a major obstacle in the treatment of central nervous system diseases, nanoagonist-mediated tight junction opening provides a promising strategy to enhance brain drug delivery with minimized adverse effects.

Myocardial stress perfusion magnetic resonance: initial experience in a pediatric and young adult population using regadenoson.

BACKGROUND: Dipyridamole and adenosine are traditional pharmacological stressors for myocardial perfusion. Regadenoson, a selective adenosine A2A agonist, has a lower side effect profile with lower incidence of bronchospasm and bradycardia. There is a growing need for myocardial perfusion assessment within pediatrics. There is no report on the utility of regadenoson as a stress agent in children. OBJECTIVE: To observe the safety and feasibility of regadenoson as a pharmacologic stressor for perfusion cardiac MR in a pilot cohort of pediatric patients weighing more than 40 kg who have congenital heart disease and pediatric acquired heart disease. MATERIALS AND METHODS: We reviewed our initial experience with regadenoson stress cardiac MR in 31 pediatric patients 15.8 ± 1.7 years (range 12-22 years) with congenital heart disease and acquired heart disease. Mean patient weight was 60 ± 15 kg (range of 40-93 kg). All patients underwent cardiac MR because of concern for ischemia. The cohort included a heterogeneous group of patients at a pediatric institution with potential risk for ischemia. Subjects' heart rate and blood pressure were monitored and pharmacologic stress was induced by injection of 400 mcg of regadenoson. We evaluated their hemodynamic response and adverse effects using changes in vital signs and onset of symptoms. A pediatric cardiologist and radiologist qualitatively assessed myocardial perfusion and viability images. RESULTS: One child was unable to complete the stress perfusion portion of the examination, but did complete the remaining portion of the CMR. Resting heart rate was 72 ± 14 beats per minute (bpm) and rose to peak of 124 ± 17 bpm (95 ± 50% increase, P < 0.005) with regadenoson. Image quality was considered good or diagnostic in all cases. Three patients had irreversible perfusion defects. Four patients had reversible perfusion defects. Nine of the patients underwent cardiac catheterization with angiography and the findings showed excellent agreement. CONCLUSION: Regadenoson might be a safe and feasible pharmacologic stress agent for use in cardiac MR in older pediatric patients with congenital heart disease and acquired heart disease. The ease of use as a bolus and the advantage of a prolonged hyperemia make its use appealing in pediatrics. In a limited number of cases, regadenoson stress perfusion showed excellent agreement with cardiac catheterization. Regadenoson might be a viable pharmacologic stress agent in this population.

[The regulative effcets of A2a adenosine receptor on expression of SOCS-3 in rats of hypoxic pulmonary hypertension].

OBJECTIVE: To study the regulative effects and mechanism of A2aAR on expression of suppressor of cytokinesignaling-3(SOCS-3) in hypoxic pulmonary hypertension rats. METHODS: Sprague-Daeley rats were randomly divided into 3 groups: a normal control group, a hypoxia group, and a hypoxia with selective agonists of A2aAR group. Animals in the hypoxia groups were housed in a chamber with 8%- 11% O2 and 1%-3% CO2 for 8 hours (8: 00 AM to 4: 00 PM) daily for 28 days. They were treated intraperitoneally with either 4 ml/kg weight of normal saline or 0.2 mg/kg weight of CGS-21680 30 minutes before exposure to hypoxia. Four weeks later, mean pulmonary artery pressure (mPAP), mean carotid arterial pressure (mCAP) and right ventricular rate [RV/(LV+ S)] were measured. The expression of A2aAR and SOCS-3 in pulmonary arterioles was measured by immunohistochemistry. The expression of A2aAR mRNA and SOCS-3 mRNA in lung tissues were measured by real time RT-PCR. The expression of A2aAR protein and SOCS-3 protein in lung tissues were measured by Western blot. RESULTS: The mPAP in the hypoxia group was [(20.9±3.9)mmHg, 1 mmHg=0.133 kPa], significantly higher than the normal control group [(12.6±6.6)mmHg](P<0.01). The mPAP in CGS-21680 group was [ (14.8±3.8)mmHg], significantly lower than the hypoxia group(P<0.01). RV/(LV+ S) in the hypoxia group was [(35.2±2.0)%] , significantly higher than the normal control group [(29.6±2.7)%] (P<0.01). RV/(LV+ S) in the CGS-21680 group was [(28.3±8.8)%], significantly lower than the hypoxia group(P<0.01). WA/TA in the hypoxia group was (73±5, P<0.01), significantly higher than the normal control group. WA/TA in CGS21680 group was (54±3, P<0.01), significantly lower than the hypoxia group. A2aAR and SOCS-3 expressions on pulmonary arterioles in the hypoxia group were (0.134±0.034) and (0.119±0.011), both significantly higher than the normal group(P<0.01); and CGS-21680 treatment further increased their expressions. The mRNA expression of both molecules showed a 1.5-fold increase after 28-day hypoxia exposure. A2aAR activation by CGS-21680 treatment in hypoxia-exposed rats further increased the expression levels of A2aAR and SOCS-3 to about 2-fold higher than the normal controls. Furthermore, protein levels of A2aAR and SOCS-3 in the lung tissue were determined using Western blot. A similar increase was observed in hypoxia-induced pulmonary hypertension, and CGS-21680 treatment group showed the highest levels of these 2 proteins. CONCLUSION: A2aAR activation prevents hypoxia-induced pulmonary hypertension, and its mechanisms are related to the activation of A2aAR SOCS-3 signaling pathway.