Pretreatment with hydromorphone, a mu-opioid agonist, does not alter the acute behavioral and physiological effects of ethanol in humans

BACKGROUND: Endogenous opioid systems are thought to mediate at least some of the behavioral effects of ethanol. Opioid antagonists, like naloxone and naltrexone, decrease ethanol self-administration under a variety of conditions in different species of laboratory animals (e.g., rodents and nonhuman primates). Opioid agonists, like morphine, also alter ethanol consumption. However, the dose-response functions for opioid agonists are complex in that low doses increase ethanol self-administration, whereas moderate to high doses decrease ethanol self-administration. The results of prospective human laboratory studies that assessed the behavioral effects of ethanol after pretreatment with an opioid antagonist are mixed. The aim of the present study was to assess the acute subject-rated effects of ethanol (0, 0.5, and 1 g/kg) after pretreatment with hydromorphone, a mu-opioid agonist. METHODS: In the present experiment, the acute subject-rated, performance-impairing, and physiological effects of ethanol (0, 0.5, and 1 g/kg) were examined after pretreatment with hydromorphone (0, 1, and 2 mg), a mu-opioid agonist, in nine healthy volunteers. Volunteers received one of the nine possible ethanolhydromorphone combinations during each of nine experimental sessions. RESULTS: Ethanol produced prototypical subject-rated drug effects (e.g., dose dependently increased ratings of "high"), impaired performance, and increased heart rate. Hydromorphone pretreatment generally did not significantly alter the subject-rated, performance-impairing, or physiological effects of ethanol. CONCLUSIONS: The results of the present experiment suggest that hydromorphone pretreatment does not significantly affect the subject-rated effects of ethanol. Future human laboratory studies should test higher doses of hydromorphone. Future studies also might use more sophisticated behavioral procedures like self-administration, or perhaps drug discrimination, to determine if opioid agonists can modulate the behavioral effects of ethanol in humans.     

Strengthening clinical effectiveness trials: equipoise-stratified randomization.

As psychiatric practice patterns evolve to take advantage of the growing list of treatments with proven efficacy, research studies with broader aims will become increasingly important. Randomized trials may need to accommodate multiple treatment options. In completely randomized designs, patients are assigned at random to one of the options, requiring that patients and clinicians find each of the options acceptable. In "clinician's choice" designs, patients are randomized to a small number of broad strategies and the choice of specific option within the broad strategy is left up to the clinician. The clinician's choice design permits some scope to patient and clinician preferences, but sacrifices the ability to make randomization-based comparisons of specific options. We describe a new approach, which we call the "equipoise stratified" design, that merges the advantages and avoids the disadvantages of the other two designs for clinical trials. The three designs are contrasted, using the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression trial as an example.     

Quantitation of allograft fibrosis and chronic allograft nephropathy

Despite improvements in the prevention and treatment of acute renal allograft rejection, the long-term survival of renal transplants has not increased. Immunologic and non-immunologic factors contribute to the gradual deterioration of graft function and to the histologic lesion characterized by vascular and interstitial fibrosis ('chronic rejection'). Quantitation of this process has been attempted using various invasive and non-invasive methods. These methods, performed at different times post-transplant, are reviewed in this article. In particular, pathology scoring systems and the potential of using computerized image analysis of biopsy material are discussed.     

Opposing effects of retinoic acid and dexamethasone on cellular retinol-binding protein ribonucleic acid levels in the rat.

Cellular retinol-binding protein (CRBP) is a potential mediator of vitamin A action. To determine whether retinoic acid and dexamethasone administration, alone and in combination, influence CRBP gene expression, adult female vitamin A-sufficient Sprague-Dawley rats randomly received 1) all-trans retinoic acid (100 micrograms) by intragastric intubation, 2) dexamethasone (2 micrograms/g BW) by ip injection, or 3) both all-trans retinoic acid and dexamethasone in the same doses. Control animals received either cottonseed oil by intragastric intubation or saline by ip injection. Six hours after treatment, lung and liver tissue were collected for Northern blot analysis with the radiolabeled cDNA specific for rat CRBP. Retinoic acid administration increased the amount of lung CRBP mRNA only, whereas dexamethasone decreased both lung and liver CRBP mRNA abundance. In animals treated with both retinoic acid and dexamethasone, CRBP mRNA abundance was also reduced. We conclude that CRBP gene expression can be modulated by both retinoic acid and dexamethasone in the vitamin A-sufficient animal. In the whole animal, our findings indicate that dexamethasone not only represses CRBP gene expression, but also opposes the effect of retinoic acid.     

Effect of ciliary neuronotrophic factor on somatostatin expression in chick ciliary ganglion neurons

The normal development of somatostatin (SOM) expression in neurons of the chick ciliary ganglion and the effects of ciliary neuronotrophic factor (CNTF) on SOM induction in cultured ciliary ganglion neurons, were studied by immunocytochemical techniques. SOM immunoreactivity was first detectable in some neurons of the ganglion at embryonic day (E)8 and between E14 to hatch, 44–46% of the neuronal population contained the peptide. It was inferred that essentially all choroid neurons, which constitute 50% of the neuronal population, contain SOM. Culture studies indicated that CNTF supported both the SOM positive choroid neurons and the SOM negative ciliary neurons. Although CNTF was necessary for the survival and maturation of cultured ciliary ganglion neurons, it did not influence either the induction or maintenance of SOM expression in these neurons. CNTF may instead act as a permissive factor, allowing the induction of SOM in neurons of the ciliary ganglion by other, more specific, factors.     

Hyperalphalipoproteinaemic activity of BRL 26314--I. Enhanced cholesterol turnover in rats

Administration of BRL 26314 [N-(4-chlorobenzyl)-L-phenylalanine] raises circulating high-density lipoprotein (HDL) cholesterol and lowers total triglyceride levels in rats whether maintained on stock or semi-synthetic diets. HDL is also elevated by BRL 26314 in hypothyroid rats and in rats with pre-existing hyperlipidaemia where aortic total cholesterol concentration is decreased. BRL 26314 promotes the excretion of a dose of radiolabelled cholesterol as faecal sterols and bile acids, and decreases the extent of cholesterol-radiolabelling in tissue pools, particularly the aorta and adipose tissue. The increase in cholesterol and bile acid (cholic acid) turnover distinguishes BRL 26314 from a cholestatic agent such as 1-naphthyl isothiocyanate where a superficially similar change in HDL concentration disguises an impaired cholesterol transport. BRL 26314 is not a general protein inducer but part of the mechanism of action may involve enhancement of white adipose tissue lipoprotein lipase activity.