Drug and Alcohol Rehabilitation: Gestational Naltrexone Ameliorates Fetal Ethanol Exposures Enhancing Effect on the Postnatal Behavioral and Neural Response to Ethanol.
Gestational naltrexone ameliorates fetal ethanol exposures enhancing effect on the postnatal behavioral and neural response to ethanol.
Filed under: Drug and Alcohol Rehabilitation
Exp Biol Med (Maywood). 2012 Oct 8;
Youngentob SL, Kent PF, Youngentob LM
The association between gestational exposure to ethanol and adolescent ethanol abuse is well established. Recent animal studies support the role of fetal ethanol experience-induced chemosensory plasticity as contributing to this observation. Previously, we established that fetal ethanol exposure, delivered through a dam’s diet throughout gestation, tuned the neural response of the peripheral olfactory system of early postnatal rats to the odor of ethanol. This occurred in conjunction with a loss of responsiveness to other odorants. The instinctive behavioral response to the odor of ethanol was also enhanced. Importantly, there was a significant contributory link between the altered response to the odor of ethanol and increased ethanol avidity when assessed in the same animals. Here, we tested whether the neural and behavioral olfactory plasticity, and their relationship to enhanced ethanol intake, is a result of the mere exposure to ethanol or whether it requires the animal to associate ethanol’s reinforcing properties with its odor attributes. In this later respect, the opioid system is important in the mediation (or modulation) of the reinforcing aspects of ethanol. To block endogenous opiates during prenatal life, pregnant rats received daily intraperitoneal administration of the opiate antagonist naltrexone from gestational day 6-21 jointly with ethanol delivered via diet. Relative to control progeny, we found that gestational exposure to naltrexone ameliorated the enhanced postnatal behavioral response to the odor of ethanol and postnatal drug avidity. Our findings support the proposition that in utero ethanol-induced olfactory plasticity (and its relationship to postnatal intake) requires, at least in part, the associative pairing between ethanol’s odor quality and its reinforcing aspects. We also found suggestive evidence that fetal naltrexone ameliorated the untoward effects of gestational ethanol exposure on the neural response to non-fetal-exposure odorants. Thus, gestational naltrexone may also have a neuroprotective and/or neuroproliferative impact on olfactory development.
HubMed – drug
Prolonged nerve blockade delays the onset of neuropathic pain.
Filed under: Drug and Alcohol Rehabilitation
Proc Natl Acad Sci U S A. 2012 Oct 8;
Shankarappa SA, Tsui JH, Kim KN, Reznor G, Dohlman JC, Langer R, Kohane DS
Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain. Pharmacological blockade of that activity has been shown to mitigate the onset of associated molecular events in the nervous system. However, results in preventing onset of pain behaviors by providing prolonged nerve blockade have been mixed. Furthermore, the experimental techniques used to date to provide that blockade were limited in clinical potential in that they would require surgical implantation. To address these issues, we have used liposomes (SDLs) containing saxitoxin (STX), a site 1 sodium channel blocker, and the glucocorticoid agonist dexamethasone to provide nerve blocks lasting ?1 wk from a single injection. This formulation is easily injected percutaneously. Animals undergoing spared nerve injury (SNI) developed mechanical allodynia in 1 wk; nerve blockade with a single dose of SDLs (duration of block 6.9 ± 1.2 d) delayed the onset of allodynia by 2 d. Treatment with three sequential SDL injections resulting in a nerve block duration of 18.1 ± 3.4 d delayed the onset of allodynia by 1 mo. This very prolonged blockade decreased activation of astrocytes in the lumbar dorsal horn of the spinal cord due to SNI. Changes in expression of injury-related genes due to SNI in the dorsal root ganglia were not affected by SDLs. These findings suggest that formulations of this kind, which could be easy to apply clinically, can mitigate the development of neuropathic pain.
HubMed – drug
Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system.
Filed under: Drug and Alcohol Rehabilitation
Proc Natl Acad Sci U S A. 2012 Oct 8;
Kirkby NS, Lundberg MH, Harrington LS, Leadbeater PD, Milne GL, Potter CM, Al-Yamani M, Adeyemi O, Warner TD, Mitchell JA
Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.
HubMed – drug
A Phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection.
Filed under: Drug and Alcohol Rehabilitation
J Infect Dis. 2012 Oct 8;
Moss RB, Hansen C, Sanders RL, Hawley S, Li T, Steigbigel RT
Background.?DAS181, a novel host directed antiviral in development for influenza treatment, was assessed in this Phase II clinical trial.Methods.?This study was a double blind, placebo controlled Phase II clinical trial assessing influenza viral load and patient safety in otherwise healthy influenza infected subjects. Subjects were randomized to a single-dose, multiple-dose or placebo group, and were followed for safety and virologic outcomes.Results.?A total of 177 laboratory confirmed influenza infected subjects were enrolled in the trial encompassing 3 influenza seasons from 2009-2011 in both the Northern and Southern Hemisphere. Thirty seven percent of subjects had confirmed infection with influenza B, 33% seasonal H3N2, 29% Pandemic 2009 H1N1, and 1 subject was positive for both influenza B and Pandemic 2009 H1N1. Significant effects were observed in regard to decreased change from baseline viral load and viral shedding in the multiple-dose group compared to placebo as measured by quantitative PCR (P<0.05). No instances of H274Y were observed among viral isolates from this trial. Overall, the drug was generally well tolerated.Conclusions.?DAS181 significantly reduced viral load in subjects infected with influenza, thus warranting future clinical development of this novel host-directed therapy. HubMed – drug
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