Biomedical subjects

J M Rieger

Publications and source records attributed to J M Rieger.

14 recordsLinked to original sources

PubMed2006

Mouse spinal cord compression injury is reduced by either activation of the adenosine A2A receptor on bone marrow-derived cells or deletion of the A2A receptor on non-bone marrow-derived cells.

Activation of the adenosine A(2A) receptor (A(2A)R) at the time of reperfusion has been shown to reduce ischemia-reperfusion injury in peripheral tissues and spinal cord. In this study we show that treating mice with the A(2A)R agonist, 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid methyl ester for four days beginning before or just after the onset of reperfusion after compression-induced spinal cord injury rapidly (within 1 day) and persistently (>42 days) reduces locomotor dysfunction and spinal cord demyelination. Protection is abolished in knockout/wild type bone marrow chimera mice selectively lacking the A(2A)R only on bone marrow-derived cells but retaining receptors on other tissues including blood vessels. Paradoxically, reduced spinal cord injury is also noted in A(2A)R -/- mice, and in wild type/knockout bone marrow chimera mice selectively lacking the A(2A)R on non-bone marrow-derived cells, or in mice treated with the A(2A) antagonist, 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol. The greatest protection is seen in knockout/wild type bone marrow chimera mice treated with 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid methyl ester, i.e. by activating the A(2A)R in mice expressing the receptor only in bone marrow-derived cells. The data suggest that inflammatory bone marrow-derived cells are the primary targets of A(2A) agonist-mediated protection. We conclude that A(2A) agonists or other interventions that inhibit inflammation during and after spinal cord ischemia may be effective in reducing spinal cord injury in patients, but excessive or prolonged stimulation of the A(2A)R may be counterproductive. It may be possible to devise strategies to produce optimal spinal cord protection by exploiting temporal differences in A(2A)R-mediated responses.

Adenosine A2 Receptor Agonists↗

PubMed2006

Functional outcomes after organ preservation treatment in head and neck cancer: a critical review of the literature.

The use of radiation therapy and/or chemotherapy in advanced head and neck cancer is increasing in popularity, driven by the notion that sparing the organs of speech and swallowing from surgical resection will also spare function. This critical review of the literature considered functional outcomes after organ preservation to assess the impact of such treatment on speech, swallowing and quality of life in patients with head and neck cancer. Literature searches were conducted on several library databases. A total of 50 relevant articles were identified and found to meet the inclusion criteria specified a priori. The majority of reports suggested that organ preservation techniques have the potential to result in swallowing disorders, often related to dysmotility of the oropharyngeal and laryngeal structures, and resulting in frequent episodes of aspiration. This may lead to the need for enteral feeding in the short term for some patients while, in others, this need is life long. Speech does not appear to be affected to the same degree as swallowing. These results suggest that organ preservation does not translate into function preservation for all patients with head and neck cancer.

Adolescent↗

PubMed2006

Effect of novel A2A adenosine receptor agonist ATL 313 on Clostridium difficile toxin A-induced murine ileal enteritis.

Clostridium difficile is a spore-forming, anaerobic, gram-positive bacillus that releases two main virulence factors: toxins A and B. Toxin A plays an important pathogenic role in antibiotic-induced diarrhea and pseudomembranous colitis, a condition characterized by intense mucosal inflammation and secretion. Agonist activity at A2A adenosine receptors attenuates inflammation and damage in many tissues. This study evaluated the effects of a new selective A2A adenosine receptor agonist (ATL 313) on toxin A-induced injury in murine ileal loops. ATL 313 (0.5 to 5 nM) and/or the A2A adenosine receptor antagonist (ZM241385; 5 nM) or phosphate-buffered saline (PBS) were injected into ileal loops immediately prior to challenge with toxin A (1 to 10 microg/loop) or PBS. Intestinal fluid volume/length and weight/length ratios were calculated 3 h later. Ileal tissues were collected for the measurement of myeloperoxidase, adenosine deaminase activity, tumor necrosis factor alpha (TNF-alpha) production, histopathology, and detection of cell death by the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) method. Toxin A significantly increased volume/length and weight/length ratios in a dose-dependent fashion. ATL 313 treatment significantly (P < 0.05) reduced toxin A-induced secretion and edema, prevented mucosal disruption, and neutrophil infiltration as measured by myeloperoxidase activity. ATL 313 also reduced the toxin A-induced TNF-alpha production and adenosine deaminase activity and prevented toxin A-induced cell death. These protective effects of ATL 313 were reversed by ZM241385. In conclusion, the A2A adenosine receptor agonist, ATL 313, reduces tissue injury and inflammation in mice with toxin A-induced enteritis. The finding of increased ileal adenosine deaminase activity following the administration of toxin A is new and might contribute to the pathogenesis of the toxin A-induced enteritis by deaminating endogenous adenosine.

Adenosine A2 Receptor Agonists↗

PubMed2001

Pharmacological stress myocardial perfusion imaging with the potent and selective A(2A) adenosine receptor agonists ATL193 and ATL146e administered by either intravenous infusion or bolus injection.

BACKGROUND: Adenosine (Ado) and dipyridamole are alternatives to exercise stress for myocardial perfusion imaging. Though generally safe, side effects frequently occur that cause patient discomfort and sometimes lead to premature termination of the study or require aminophylline administration. Recently, a new class of A(2A) Ado receptor agonists was synthesized. ATL193 and ATL146e are 2-propynylcyclohexyl-5'-N-ethylcarboxamido derivatives of Ado. The study goals were to evaluate the potency and selectivity of these new compounds on recombinant canine Ado receptors and to evaluate their hemodynamic properties in dogs to assess their usefulness as vasodilators for myocardial perfusion imaging. METHODS AND RESULTS: In assays of recombinant canine Ado receptors, ATL-193 and ATL-146e were highly selective for the A(2A) over the A(1) and A(3) receptors and were more potent than MRE-0470 and CGS-21680. In 16 anesthetized dogs, the agonists were administered by infusion (ATL-193; n=7 normal) or bolus injection (ATL-146e; n=9 critical left anterior descending coronary artery stenosis), and hemodynamic responses were compared with those of Ado. Both agonists produced dose-dependent coronary flow (CF) elevation without provoking the hypotension observed with Ado. After an ATL-146e bolus, the CF increase was sustained for several minutes, providing ample time for injection and myocardial uptake of (99m)Tc-sestamibi, and CF returned to baseline within 20 minutes. The CF increase was completely blocked by the selective A(2A) antagonist ZM241385 (3 microgram. kg(-1). min(-1)). CONCLUSIONS: ATL-193 and ATL-146e are highly potent and selective Ado A(2A) receptor agonists with excellent potential for use as vasodilators for myocardial perfusion imaging. An important advantage of ATL-146e is the ability to administer it by bolus injection.

Adenosine↗

PubMed2001

Design, synthesis, and evaluation of novel A2A adenosine receptor agonists.

We have been interested in the design, synthesis, and evaluation of novel adenosine A2A agonists. Through the use of comparative molecular field analysis (CoMFA) we have generated a training model that includes 78 structurally diverse A2A agonists and correlated their affinity for isolated rat brain receptors with differences in their structural and electrostatic properties. We validated this model by predicting the activity of a test set that included 24 additional A2A agonists. Our CoMFA model, which incorporates the physiochemical property of dipole and selects against A1 receptor activity, generated a correlated final model (r2 = 0.891) that provides for enhanced A2A selectivity and predictability. Synthesis, pharmacological evaluation, and modeling of four novel ligands further validate the utility and predictive power (r2 = 0.626) of the CoMFA model.

Alkynes↗

PubMed2001

Systemic adenosine A2A agonist ameliorates ischemic reperfusion injury in the rabbit spinal cord.

BACKGROUND: The adenosine A2A agonist ATL-146e (4-[3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxytetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester) has been shown to prevent reperfusion injury in multiple organ systems through inhibition of activated leukocyte-endothelial interaction. We hypothesized that systemic ATL-146e could reduce spinal cord reperfusion injury after aortic clamping. METHODS: Twenty-six rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group received intravenous ATL-146e for 3 hours during reperfusion. A second cohort received only vehicle and served as controls. Animals were assessed at 24 and 48 hours using the Tarlov (0 to 5) scoring system for hind limb function. To evaluate neuronal attrition, immunostaining of lumbar spinal cord sections was performed using anti-SMI 33 antibody against neurofilament. RESULTS: Systemic ATL-146e was tolerated without hemodynamic lability. Animals that received ATL-146e had significantly improved neurologic outcomes 24 and 48 hours after spinal cord ischemia (p < 0.001). There was preservation of neuronal architecture in the ventral horn of spinal cord sections from animals receiving ATL-146e compared with control animals. CONCLUSIONS: Intravenous ATL-146e given during reperfusion is tolerated without hemodynamic lability, and results in substantially improved spinal cord function after ischemia by preservation of ventral horn neurons.

Animals↗

PubMed2001

Cyclic AMP-dependent inhibition of human neutrophil oxidative activity by substituted 2-propynylcyclohexyl adenosine A(2A) receptor agonists.

Novel 2-propynylcyclohexyl-5'-N:-ehtylcarboxamidoadenosines, trans-substituted in the 4-position of the cyclohexyl ring, were evaluated in binding assays to the four subtypes of adenosine receptors (ARs). Two esters, 4-(3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl)-cyclohexanecarboxylic acid methyl ester (ATL146e) and acetic acid 4-(3-[6-amino-9-(5-ethylcarbamoyl-3, 4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl] -prop-2-ynyl)-cyclohexylmethyl ester (ATL193) were >50 x more potent than 2-[4-(2-carboxyethyl)phenethylamino]-5'-N:-ethylcarboxamidoadenosine (CGS21680) for human A(2A) AR binding. Human A(2A) AR affinity for substituted cyclohexyl-propynyladenosine analogues was inversely correlated with the polarity of the cyclohexyl side chain. There was a comparable order of potency for A(2A) AR agonist stimulation of human neutrophil [cyclic AMP](i), and inhibition of the neutrophil oxidative burst. ATL146e and CGS21680 were approximately equipotent agonists of human A(3) ARs. We measured the effects of selective AR antagonists on agonist stimulated neutrophil [cyclic AMP](i) and the effect of PKA inhibition on A(2A) AR agonist activity. ATL193-stimulated neutrophil [cyclic AMP](i) was blocked by antagonists with the potency order: ZM241385 (A(2A)-selective)>MRS1220 (A(3)-selective)>>N-(4-Cyano-phenyl)-2-[4-(2,6-dioxo-1,3-dipropyl-2,3,4,5,6,7-hexahydro-1H-purin-8-yl)-phenoxy]-acetamide (MRS1754; A(2B)-selective) approximately 8-(N-methylisopropyl)amino-N(6)-(5'-endohydroxy-endonorbornyl)-9-methyladenine (WRC0571; A(1)-selective). The type IV phosphodiesterase inhibitor, rolipram (100 nM) potentiated ATL193 inhibition of the oxidative burst, and inhibition by ATL193 was counteracted by the PKA inhibitor H-89. The data indicate that activation of A(2A)ARs inhibits neutrophil oxidative activity by activating [cyclic AMP](i)/PKA.

Adenosine↗

PubMed2001

Adenosine analogue reduces spinal cord reperfusion injury in a time-dependent fashion.

BACKGROUND: We hypothesized that inflammation during spinal cord reperfusion worsens ischemic injury. ATL-146e, an adenosine A(2A) agonist with known anti-inflammatory properties, was used to test this hypothesis at varied intervals to determine the time course of reperfusion injury. METHODS: Forty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group (n = 14 animals) received 0.06 microg/kg/min systemic ATL-146e over 3 hours, beginning after 30 minutes of ischemic time. A second group (n = 6 animals) received ATL-146e over 1.5 hours. A third group (n = 3 animals) received ATL-146e over 1 hour, and a fourth group (n = 17 animals) received saline solution. All animals were assessed at 48 hours for hind limb motor function (Tarlov scale, 0-5). RESULTS: Animals that received ATL-146e for 3 hours (Tarlov score, 4.3 +/- 0.22; P <.001) or 1.5 hours (Tarlov score, 2.7 +/- 0.6; P <.05) had improved neurologic outcomes compared with rabbits that received saline solution (Tarlov score, 0.6 +/- 0.29). Animals that received ATL-146e for 1 hour (Tarlov score, 0.7 +/- 0.8) were not significantly different from those animals that received saline solution. CONCLUSIONS: Systemic ATL-146e, given during reperfusion, results in time-dependent improvement in spinal cord function after ischemia. This implies that the mechanism of spinal reperfusion injury includes leukocyte-mediated inflammation at a critical post-ischemic time interval.

Adenosine↗

PubMed2001

An adenosine A2A agonist, ATL-146e, reduces paralysis and apoptosis during rabbit spinal cord reperfusion.

BACKGROUND: We hypothesized that systemic ATL-146e, an adenosine A(2A) agonist, would decrease spinal cord reperfusion inflammatory stress and inhibit apoptosis and that these effects would correlate with improved neurologic functional outcome. METHODS: Thirty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group of animals (n = 14) received 0.06 microg/kg per minute of ATL-146e infused intravenously for 3 hours, beginning 15 minutes before reperfusion. A second group of animals (n = 16) underwent spinal cord ischemia with saline vehicle alone and served as ischemic controls. Animals (n = 9, 11) from each group survived for 48 hours and assessed for neurologic impairment with the Tarlov (0-5) scoring system. Four animals from each group were humanely killed at the end of the 3-hour treatment period, and the remainder killed after 48 hours' survival. In all animals, lumbar spinal cord tissue specimens were frozen for subsequent Western blot analysis of heat shock protein 70 (HSP 70), and for the p85 fragment of poly (ADP-ribose) polymerase (PARP). Neuronal viability indices were determined at 48 hours with hematoxylin and eosin staining. RESULTS: There was improvement in neurologic function in rabbits receiving ATL-146e (P <.001) compared with ischemic controls. At the end of the 3-hour treatment period there was a 46% (P <.05) decrease in HSP 70 expression in the ATL-146e group compared with the control group, but no difference in PARP expression. At 48 hours, there was no difference between control and ATL-146e groups in HSP 70 expression, but there was a 65% (P <.05) reduction in PARP in the spinal cords of animals that had received ATL-146e. There was a significant improvement in neuronal viability indices in animals receiving ATL-146e compared with ischemic controls (P <.05). CONCLUSIONS: Systemic ATL-146e infusion during reperfusion after spinal cord ischemia results in preservation of hindlimb motor function. There is evidence of decreased spinal cord inflammatory stress immediately after treatment with ATL-146e as indicated by reduced HSP 70 induction. Treatment with ATL-146e is associated with a reduction in neuronal apoptosis as suggested by a substantial decrease in the fragmentation of PARP at 48 hours. These results suggest that inflammation during reperfusion and subsequent apoptosis contribute to paralysis after restoration of blood flow to the ischemic spinal cord.

Animals↗

PubMed2001

Selective A(2A) adenosine receptor activation reduces skin pressure ulcer formation and inflammation.

Activation of A(2A) adenosine receptors (A(2A)-AR) by ATL-146e (formerly DWH-146e) prevents inflammatory cell activation and adhesion. Recurrent ischemia-reperfusion (I/R) of the skin results in pressure ulcer formation, a major clinical problem. ATL-146e was evaluated in a novel reproducible rat model of pressure ulcer. A 9-cm(2) region of dorsal rat skin was cyclically compressed at 50 mmHg using a surgically implanted metal plate and an overlying magnet to generate reproducible tissue necrosis. Osmotic minipumps were implanted into 24 rats divided into four equal groups to infuse vehicle (control), ATL-146e (0.004 microg x kg(-1) x min(-1)), ATL-146e plus an equimolar concentration of A(2A) antagonist, ZM-241385, or ZM-241385 alone. Each group received 10 I/R cycles. In non-I/R-treated skin, ATL-146e has no effect on blood flow. I/R-treated skin of the ATL-146e group compared with the vehicle group had 65% less necrotic area, 31% less inhibition of average skin blood flow, and fewer extravasated leukocytes (23 +/- 3 vs. 49 +/- 6 per 500 microm(2)). These data suggest that ATL-146e, acting via an A(2A)-AR, reduces leukocyte infiltration and is a potent prophylactic for I/R injury in skin.

Animals↗

PubMed2001

Adenosine A(2A) receptor stimulation reduces inflammation and neointimal growth in a murine carotid ligation model.

Endothelial activation and leukocyte recruitment are early events in atherosclerosis and the vascular response to injury. Adenosine has anti-inflammatory effects on leukocytes and endothelial cells mediated through its A(2A) receptor. We tested the hypothesis that A(2A) activation would reduce inflammation and neointimal formation in a murine carotid ligation model. Before injury, mice were randomized to a 7-day subcutaneous infusion of a specific A(2A) receptor agonist (ATL-146e, 0.004 microg/kg per minute), vehicle control, ATL-146e plus ZM241385 (a selective A(2A) antagonist), or ZM241385 alone. Leukocyte recruitment and adhesion molecule expression were assessed at early time points, and the neointimal area was measured at 14 and 28 days after injury. Compared with control mice, ATL-146e-treated mice had significantly less neutrophil and macrophage recruitment and vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and P-selectin expression in the first 7 days after injury. Neointimal area was markedly and persistently reduced by 80% at 14 and 28 days, despite termination of ATL infusion at 7 days. ATL-146e+ZM241385-treated and ZM241385-treated animals had neointimal areas similar to those of control animals, confirming that the observed effects of ATL-146e were mediated specifically by the A(2A) receptor. These data demonstrate that novel stimulation of adenosine A(2A) receptors can inhibit early inflammatory processes that are important in neointimal formation after vascular injury.

Animals↗

PubMed2000

Comparative molecular field analysis of colchicine inhibition and tubulin polymerization for combretastatins binding to the colchicine binding site on beta-tubulin.

A molecular modeling study using Comparative Molecular Field Analysis (CoMFA) was undertaken to develop a predictive model for combretastatin binding to the colchicine binding site of tubulin. Furthermore, we examined the potential contribution of lipophilicity (log P) and molecular dipole moment and were unable to correlate these properties to the observed biological data. In this study we first confirmed that tubulin polymerization inhibition (IC50) correlated (R2 = 0.92) with [3H]colchicine displacement. Although these data correlated quite well, we developed two independent models for each set of data to quantify structural features that may contribute to each biological property independently. To develop our predictive model we first examined a series of molecular alignments for the training set and ultimately found that overlaying the respective trimethoxyphenyl rings (A ring) of the analogues generated the best correlated model. The CoMFA yielded a cross-validated R2 = 0.41 (optimum number of components equal to 5) for the tubulin polymerization model and an R2 = 0.38 (optimum number of components equal to 5) for [3H]colchicine inhibition. Final non-cross-validation generated models for tubulin polymerization (R2 of 0.93) and colchicine inhibition (R2 of 0.91). These models were validated by predicting both biological properties for compounds not used in the training set. These models accurately predicted the IC50 for tubulin polymerization with an R2 of 0.88 (n = 6) and those of [3H]colchicine displacement with an R2 of 0.80 (n = 7). This study represents the first predictive model for the colchicine binding site over a wide range of combretastatin analogues.

Bibenzyls↗

PubMed2000

A(2A) adenosine receptor-mediated inhibition of renal injury and neutrophil adhesion.

We sought to determine the mechanisms responsible for the reduced renal tissue injury by agonists of A(2A) adenosine receptors (A(2A)-ARs) in models of ischemia-reperfusion (I/R) injury. DWH-146e, a selective A(2A)-AR agonist, was administered subcutaneously to Sprague-Dawley rats and C57BL/6 mice via osmotic minipumps, and animals were subjected to I/R. I/R led to an increase in plasma creatinine and kidney neutrophil infiltration. Infusion of DWH-146e at 10 ng. kg(-1). min(-1) produced a 70% reduction in plasma creatinine as well as a decrease in neutrophil density in outer medulla and cortex and myeloperoxidase activity in the reperfused kidney. Myeloperoxidase activity in kidney correlated with the degree of renal injury. P-selectin and intercellular adhesion molecule 1 (ICAM-1) immunoreactivity were most prominent in endothelial cells of peritubular capillaries and interlobular arteries of cortex and outer and inner medulla of vehicle-treated mice whose kidneys were subjected to I/R. DWH-146e treatment led to a pronounced decrease in P-selectin- and ICAM-1-like immunoreactivity. These data are consistent with our hypothesis that A(2A)-AR agonists limit I/R injury due to an inhibitory effect on neutrophil adhesion.

Acute Kidney Injury↗

PubMedDate not supplied

The effect of automatic speech recognition systems on speaking workload and task efficiency.

PURPOSE: This investigation explored the speech-production behaviors associated with the use of automatic speech recognition (ASR) software for dictation of spontaneous and scripted material by individuals with and without spinal cord injury (SCI). The variables of interest in determining speaking workload and efficiency included syllables per breath group, frequency of breath groups, frequency of apnea, time needed for dictation and number of words spoken during a dictation task. METHOD: Twelve individuals participated, six with SCI and six able-bodied cohorts matched for age, sex and height. Subjects dictated with continuous-speech ASR, discrete-word ASR and no ASR in a spontaneous-speaking situation, as well as in a scripted speaking situation. RESULTS: For all variables, differences amongst dictation conditions were significant. No significant differences were found between speaker groups. Dictation with both discrete-word and continuous-speech ASR resulted in a decrease in the number of syllables produced per breath group, increases in the frequency of breath groups and apnea, with differences from normal being greater for dictation with discrete-word ASR. In addition, when participants dictated with either type of ASR, the amount of time and number of words produced were significantly greater than that associated with production of the same message without ASR, requiring 'more work' on the part of the speaker and ultimately reducing the efficiency with which a message was produced. CONCLUSIONS: From a human factors perspective, these results suggest that ASR software, especially discrete-word ASR, has the potential to increase energy expenditure during dictation over a prolonged period of time, thereby increasing speech workloads and the potential for overuse of the laryngeal system.

Adult↗