Pharmacodynamic efficacy, clinical safety, and outcomes after prolonged platelet Glycoprotein IIb/IIIa receptor blockade with oral xemilofiban: results of a multicenter, placebo-controlled, randomized trial

BACKGROUND: Parenteral administration of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers can reduce ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers may allow more sustained receptor antagonism with the potential for long-term secondary prevention. The pharmacodynamic efficacy, clinical safety, and outcomes after prolonged receptor blockade with an orally active GP IIb/IIIa antagonist are not known. The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) Trial is a multicenter, placebo-controlled, randomized trial of xemilofiban, an oral platelet GP IIb/IIIa blocking agent, administered to patients after percutaneous coronary intervention. METHODS AND RESULTS: After successful elective percutaneous coronary intervention, 549 patients were randomized to receive either placebo or xemilofiban in a dose of 15 or 20 mg. Stented patients randomized to placebo also received ticlopidine 250 mg orally BID for 4 weeks. Patients who received abciximab during the coronary intervention and who were randomized to receive xemilofiban were administered a reduced dosage (10 mg TID for 2 weeks) followed by the randomized maintenance dose of 15 or 20 mg BID for 2 more weeks. All patients received 325 mg aspirin PO QD. Ex vivo platelet aggregation in response to 20 micromol/L ADP and 4 microg/mL collagen was measured over time after the initial dose of study drug and at days 14 and 28 of long-term therapy in 230 patients. All patients were followed clinically for 90 days. Xemilofiban inhibited platelet aggregation to both ADP and collagen with peak levels of inhibition that were similar at 14 and 28 days of long-term oral therapy. Plasma levels of xemilofiban correlated with the degree of platelet inhibition. Peak platelet inhibition on day 1 correlated with the subsequent occurrence of insignificant or mild bleeding events. Although this study was not powered to evaluate differences in clinical outcomes, a trend (P=0.04) was observed for reduction of cardiovascular events at 3 months in patients not treated with abciximab who received the highest dose (20 mg) of xemilofiban studied. CONCLUSIONS: Xemilofiban inhibited platelet aggregation and was well tolerated during 28 days of long-term oral therapy. The observed trend in reduction of cardiovascular events in follow-up awaits confirmation in the larger-scale phase III study (EXCITE trial) currently in progress.     

A nitric oxide synthesis inhibitor (L-NAME) reduces licking behavior and Fos-labeling in the spinal cord of rats during formalin-induced inflammation

Formalin injected subcutaneously into the hindpaw of the rat produces an animal model of inflammation that exhibits a phasic component and a tonic component of pain. We evaluated the effects of a nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), on a formalin-induced behavior, hindpaw licking, and on Fos-labeling of nuclei in the fifth lumbar spinal segment. Our results demonstrated that pretreatment with intrathecal doses of 0.3 and 1.0 mg of L-NAME significantly reduced licking behavior associated with injection of formalin into the left hindpaw of the rat. In addition, these same doses of L-NAME reduced formalin-induced Fos-labeling in the ipsilateral dorsal gray matter (as compared to the contralateral gray matter). Qualitative assessment suggested that the reduction in labeling occurred primarily in the superficial dorsal horn. The stereoisomer, D-NAME, administered at the same doses had little to no effect on either formalin-induced licking or Fos-labeling. Finally, our results revealed that total licking time was related to Fos-labeling. Rats that spent less time licking the hindpaw exhibited a smaller increase in Fos-labeling. Our results suggest that the production of nitric oxide is associated with licking behavior resulting from formalin injection into the hindpaw of rats. Our results also suggest that the production of nitric oxide and Fos are associated. Indeed, these substances may be involved in spinal pathways associated with nociception.     

Professionalism in emergency medicine. SAEM Ethics Committee. Society for Academic Emergency Medicine

INTRODUCTION: F-16 pilots have a high incidence of minor neck injuries. It was hypothesized that pilots who did neck strengthening exercises and pilots who used other preventive strategies would have fewer injuries. METHOD: We surveyed 268 U.S. Air Force F-16 pilots. Subjects were divided into two groups. Group I, the Early Intervention Group, performed an intervention, or not, from the start of their F-16 careers. Outcomes were measured as a percent of pilots reporting an injury during their F-16 careers. Group II, the Midstream Intervention Group, initiated an intervention after sustaining an injury. Injuries before and after the intervention were compared as a median injury rate per 100 h F-16 time. RESULTS: The 1 -yr prevalence of neck injury was 56.6% and for an F-16 career was 85.4%. For every 100 h in the F-16, the risk of injury increased by 6.9%. Only 26.9% of the pilots routinely did neck strengthening exercises. For the Early Intervention Group, fewer injuries were associated with neck strengthening exercises and placing the head against the seat prior to loading +Gz. For the Midstream Intervention Group, a lower median injury rate was associated with neck strengthening exercises, placing the head against the seat prior to loading, warming up with stretching or isometrics, prepositioning the head prior to loading, and unloading prior to moving the head. Interventions not associated with fewer injuries included body exercises and placing the head against the canopy. CONCLUSION: Certain strategies may prevent neck injuries. Prospective research is needed to confirm these results.     

Insulin-like growth factor (IGF)-I but not IGF-II promotes lean growth and feed efficiency in broiler chickens

The efficacy of exogenous IGFs to stimulate growth and modulate protein and fat deposition was examined in a number of broiler chicken lines. From around 600 g body weight the chickens received a continuous infusion of vehicle (0.1 M acetic acid), human recombinant IGF-I or [Gly1]IGF-II at 300 microg/kg body weight per day, or a combined infusion of 150 microg/kg/day of each IGF for 2 weeks. Experiment 1 used commercial broiler female chickens and included measurements of nitrogen balance, Ntau-methylhistidine excretion and muscle protein synthesis rates. In Experiment 2 the same treatments were applied to three experimental lines of chickens selected for high food consumption (relatively fat), high food utilisation efficiency (relatively lean), or at random (control). IGF-I, but not IGF-II, significantly increased growth rate and food utilisation efficiency by around 10-15% in each experiment, an effect which was consistent across all genotypes. Nitrogen balance was significantly increased by IGF-I in Experiment 1 as was carcass nitrogen content in Experiment 2, indicating that the increased growth was in lean tissue. Carcass fat was consistently reduced in chickens receiving IGF-I and was related to the levels of circulating IGF-I (r2 = 0.30, P < 0.01) but not triiodothyronine. Protein synthesis rates were unaffected by treatment and could not account for increased growth rate. However, there was a significant reduction in Ntau-methylhistidine excretion indicating a reduced rate of muscle protein breakdown in IGF-I-treated chickens (1. 56%/day vs 2.05%/day for IGF-I-treated vs controls, P < 0.05). The efficiency of feed utilisation was inversely related to the rate of protein breakdown (r2 = 0.25, P < 0.01). In conclusion, these experiments are the first to report an enhancement of growth and food utilisation efficiency by broiler chickens receiving exogenous IGF-I. Our results show that IGF-I may be important in controlling the growth and efficiency of food utilisation of young chickens at least in part by modulating the rates of protein breakdown.     

Oxytocin and addiction: a review

Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released at the posterior pituitary, also is released in the central nervous system (CNS). OXT acts within the CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin was potently decreased by OXT treatment. In relation to cocaine abuse, OXT dose-dependently decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT. OXT receptors in the CNS--mainly those located in limbic and basal forebrain structures--are responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism. Dopaminergic neurotransmission--primarily in basal forebrain structures--is another important biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g. hypothermia-inducing effect of ethanol) also was inhibited by OXT.     

Multiparameter flow cytometric analysis of polymorphonuclear leucocytes in whole blood from patients with adult rapidly progressive periodontitis reveals low expression of the adhesion molecule L-selectin (Cd62L)

In order to assess the nephrotoxic potential of antibiotics, various aminoglycosides and cephalosporins were tested for their potency to alter the excretion of tubular marker proteins (and brush border antigens) or to change the normal pattern of serumproteinuria as analyzed by SDS polyacrylamidgel gradient electrophoresis. After aminoglycosides, especially after gentamicin injection, a cumulative highly significant increase in the urinary output of marker proteins emerged (healthy volunteer model). In contrast, cephalosporins exhibited practically no nephrotoxic effect on proximal tubule cells. Excretion of tubular marker proteins was enhanced under combined administration of cephalosporins and aminoglycosides mainly due to the aminoglycoside component. There was no nephrotoxic synergy of both drugs. Image analysis of rat kidney sections after injection of aminoglycosides revealed that increased shedding of tubular membrane components under the toxic challenge is followed by rapid inductive repair processes (overshoot protein synthesis) of tubular cells. After a limited acute toxic damage tubular cells may recover within one week.     

The effect of stimulatory electrode placement on F-wave latency measurements

BACKGROUND AND PURPOSE: The purpose of this study was to compare the effects of two commonly used stimulating electrode placements on F-wave latency. SUBJECTS: Fifty healthy subjects aged 20 to 47 years were tested. METHODS: F-waves were obtained from median and ulnar nerves bilaterally. A total of 200 nerves were tested. RESULTS: A paired t-test indicated a statistically significant difference in F-wave latency between the two stimulating electrode placements. Stepwise linear regression equations demonstrated that our results were consistent with previously published studies. CONCLUSION AND DISCUSSION: Although a statistically significant difference exists between the two techniques, the magnitude of the difference is not likely to be clinically important. Therefore, the most important factor may be to use a consistent technique when investigating potential neuropathies.