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Biomedical subjects

R Z Litten

Publications and source records attributed to R Z Litten.

At least 37 records · Page 2Linked to original sources

Disulfiram (antabuse) contracts in treatment of alcoholism.

Although studies repeatedly demonstrate that alcoholics who consistently take disulfiram experience more favorable drinking outcomes, serious problems with compliance among the majority of alcoholic patients have reduced the effectiveness of disulfiram as a therapeutic adjunct. In general, alcoholism counseling with disulfiram simply prescribed seems no more effective than counseling without disulfiram (Fuller et al. 1986). Problems with compliance as well as problems with acceptance by patients and likely by clinical staff reduce the utility of disulfiram in the treatment of alcoholism. Implants, incentives, and various forms of observed or supervised disulfiram have been studied as possible solutions to the problems with compliance. Disulfiram implants appear largely ineffective due to failure to release adequate levels of disulfiram and risks of surgical complications and rejection. Newer techniques (see Allen and Litten 1992) may ultimately lead to a more effective implant. Incentives with personally relevant and obvious reinforcement value such as money, avoidance of incarceration, remaining employed, and continuation of methadone for opiate addicts, have been used effectively. Enhancement strategies with less tangible incentives also show promise. Among these are feedback on results of biochemical measures of disulfiram compliance and continuation in a familiar treatment program. Although each of the studies of incentives suffers from specific methodological limitations, the findings uniformly demonstrate better disulfiram compliance, less drinking, and better clinical outcomes for those who received a meaningful incentive for taking disulfiram. External monitoring of the patient taking disulfiram to assure compliance is typically used in studies evaluating incentives for taking the medication. Observed or supervised disulfiram in its own right and without tangible incentives also has received increasing attention as a method for enhancing compliance. Incorporation of such a strategy would seem to have potential for wide applicability in alcoholism treatment programs. Three forms of supervised disulfiram have been studied: (1) a written disulfiram contract, such as in BMT, with instructions about the benefits of the disulfiram contract and methods to establish disulfiram use as a daily habit and specifying that the alcoholic will take disulfiram daily while the spouse observes, that the couple will mutually thank each other, and that they will refrain from arguments or discussions about the alcoholic's drinking; (2) the disulfiram contract used in CRA, which is identical in form to the BMT contract except that talk about drinking is not prohibited; and (3) supervised disulfiram without a written contract, special instructions, or explicit verbal thanking. Studies of these three forms of observed disulfiram have been among the better controlled studies. Each approach has produced very promising results. A disulfiram contract with BMT produced less short-term drinking than disulfiram accompanied either by couples or individual counseling. Unfortunately, the superior BMT drinking results eroded because many couples discontinued their disulfiram contract after treatment ended (O'Farrell et al. 1985, 1992). Adding couples RP sessions after BMT led to better fulfillment of the disulfiram contract and better drinking and marital outcomes than BMT alone. These better RP outcomes persisted for 18 to 24 months after BMT for the entire sample and throughout the entire 30-month followup after BMT for those with more severe drinking and marital problems (O'Farrell et al. 1993). Thus, disulfiram contracts used with BMT are associated with less drinking and greater disulfiram compliance, while the specific contribution of disulfiram contracts to BMT remains to be investigated.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcohol Deterrents↗

NIDA-NIAAA workshop: efficacy of therapies in drug and alcohol addiction. Strategies for treatment of alcohol problems.

Well-controlled clinical trials have been performed to determine efficacy of alternative alcoholism treatment strategies. Six effective treatment approaches are discussed, and a research project example demonstrates the benefits of each. The treatments considered are: brief intervention, behavioral contracting, naltrexone, social skills training, the community reinforcement approach, and patient-treatment matching.

Alcoholism↗

Carbohydrate-deficient transferrin as a measure of immoderate drinking: remaining issues.

A growing body of investigations demonstrate that elevated levels of carbohydrate-deficient transferrin (CDT) effectively distinguishes alcoholics recently consuming large amounts of alcohol from light social drinkers or teetotalers. Nevertheless, important questions still remain concerning the value of CDT as a more generalized marker of alcohol consumption. Most important, the nature of the drinking pattern, including quantity and frequency, necessary to raise levels of CDT significantly remains unclear. Neither has research convincingly demonstrated that CDT is as accurate a marker for women, young adults, or non-Caucasian ethnic groups as for White, middle-aged men. Whereas CDT might serve as a useful outcome measure in trials of alcoholism treatment effectiveness, current research suggests that CDT is of limited value in identifying problematic drinking in general medical or community settings in which a broad continuum of drinkers is represented. Combining CDT with other biochemical or self-report screening measures may, however, improve sensitivity in these contexts. At present, the most accurate laboratory technique to detect CDT seems to be isoelectric focusing. Additional research, however, is needed to resolve the issue of whether CDT is best quantitated as a simple value or if its ratio to total transferrin or non-CDT results in higher predictive validity.

Alcoholism↗

Reducing the desire to drink. Pharmacology and neurobiology.

The past decade has witnessed major advances in understanding of neural functioning and neurobiological bases of alcohol consumption. Concurrent with this, a range of exciting investigations have been conducted on pharmacologic agents that may curb drinking behavior. Research is reviewed on several promising medications influencing neurotransmitter and endocrine systems with particular attention to the serotonergic and opioid systems. Following this overview, recommendations are offered regarding research methodology to support future pharmacotherapy trials.

Alcohol Deterrents↗

Techniques to enhance compliance with disulfiram.

Pharmacodynamic benefits of disulfiram in the treatment of alcoholism have yet to be clearly demonstrated. Nevertheless, research does suggest that disulfiram may well have positive effects on drinking if medicational compliance procedures are employed. This paper reviews research on four strategies for enhancing disulfiram compliance: implants, incentives, contracts, and patient information. Generalizations about the strategies are drawn and needs for future research are briefly addressed.

Alcoholism↗

Pharmacotherapies for alcoholism: promising agents and clinical issues.

The past 10 years have witnessed important advances in research on pharmacotherapy for alcoholism. Promising drugs are discussed under six headings: agents to treat alcohol withdrawal; anticraving agents; agents that make drinking an aversive experience; agents to alleviate concomitant psychiatric problems; agents to treat concurrent drug abuse; and amethystic ("sobering-up") agents. Research on the drug classes is summarized and clinical issues surrounding specific agents and alcoholism pharmacotherapy in general are discussed. Finally, long-range therapeutic implications of recent findings on the actions of alcohol on basic mechanisms of the brain are offered.

Alcohol Deterrents↗

Effects of irradiation and semistarvation on rat thyrotropin beta subunit messenger ribonucleic acid, pituitary thyrotropin content, and thyroid hormone levels.

The effect of radiation-induced anorexia on serum thyrotropin (TSH), pituitary TSH-beta mRNA, pituitary TSH content, serum thyroxine (T4), and serum 3,5,3'-triiodothyronine (T3) was investigated using feed-matched controls. Rats received 10 Gy gamma whole-body irradiation and were examined 1-3 days postirradiation. Feed-matched and untreated controls were also studied. The average food intake of the irradiated and feed-matched groups was approximately 18% of the untreated controls. Over the three day period both the irradiated and feed-matched groups lost a significant amount of body weight. The serum T4 levels of both the irradiated and feed-matched groups were not significantly different from each other, but were significantly depressed when compared to the untreated control group. The serum TSH and T3 were, however, significantly greater in the irradiated than the feed-matched groups at day 3 posttreatment. To determine if the difference in the serum TSH level between the two groups was due to a pretranslational alteration in TSH production, we measured the TSH-beta mRNA using an RNA blot hybridization assay. We found that the TSH-beta mRNA level was the same in the irradiated and feed-matched groups, suggesting that the mechanism responsible for the radiation-induced increase in the serum TSH level is posttranscriptional. Pituitary TSH content in the irradiated rats was significantly less than in pair-fed controls, suggesting that irradiation may permit enhanced secretion of stored hormone.

Animals↗

Alterations in rat cardiac myosin isozymes induced by whole-body irradiation are prevented by 3,5,3'-L-triiodothyronine.

Changes in cardiac myosin isozymes and serum thyroid hormone levels were investigated in rats following 10 Gy whole-body gamma irradiation. The percent beta-myosin heavy chain increased from 21.3 +/- 1.8 to 28.1 +/- 6.8 (NS) at 3-day postirradiation, 37.7 +/- 1.9 (P less than .001) at 6-day postirradiation, and 43.8 +/- 3.3 (P less than .001) at 9-day postirradiation. Along with the change in myosin isozymes was a significant 53% decrease (P less than .001) in the serum thyroxine (T4) level by day 3 postirradiation, remaining depressed through day 9 postirradiation. The serum 3,5,3'-triiodothyronine (T3) level, however, was normal until day 9, when significant depression was also observed. In contrast, the thyroid-stimulating hormone (TSH) level was significantly increased by fourfold at day 3, returning to near normal values by day 9 postirradiation. Daily injections of physiological doses of T3 (0.3 microgram/100 g body weight) prevented the change in the myosin isozymes following whole-body irradiation. Daily pharmacological injections of T3 (3.0 micrograms/100 g body weight) to the irradiated rats produced a further decrease in the percent beta-myosin heavy chain (below control values) indicating tissue hyperthyroidism. Thus, this study suggests that the change in myosin isozymes following whole-body irradiation is caused by an alteration in thyroid hormone activity.

Animals↗

Norepinephrine-induced phosphorylation of a 25 kd phosphoprotein in rat aorta is altered in intraperitoneal sepsis.

An attenuation of the contractile response to norepinephrine (NE) has been previously demonstrated in rat aorta during intraperitoneal sepsis and endotoxemia. In this study, we determined whether NE-induced protein phosphorylation is altered in septic rat aorta as compared to control rat aorta. We found that the NE-induced phosphorylation of a 25 kd phosphoprotein was decreased. NE increased phosphorylation of the 25 kd band by 54% (P less than .01) in the control aorta but only 12% (not significant) in the septic aorta. Pyrophosphate gel purification of phosphorylated myosin showed that this 25 kd band was not related to the myosin-phosphorylated (P) light chain. Two-dimensional polyacrylamide gel electrophoresis analysis revealed that this 25 kd band represents two proteins with distinct isoelectric points of 6.5 and 6.2. These results further document that intrinsic alterations occur in the NE-mediated signal transduction system in rat aorta during sepsis and that such alterations could contribute to depressed aortic contractility.

Animals↗

Efficiency and capacity of protein synthesis are increased in pressure overload cardiac hypertrophy.

We measured the rate of protein synthesis and total RNA content in the right ventricle (RV) at day 2 and day 4 after pulmonary artery constriction to determine the contributions of changes in capacity and efficiency of in vivo protein synthesis to pressure overload (PO) cardiac hypertrophy. A significant increase in the proportion of RV weight to total heart weight was observed at day 2 and day 4 when compared with untreated controls. The rate of protein synthesis was significantly higher at day 2 post-PO (0.31 +/- 0.06 day-1 or 30 +/- 5 mg.g RV-1.day-1, means +/- SD, P less than 0.05) as well as at day 4 (0.25 +/- 0.05 day-1 or 28 +/- 9 mg.g RV-1.day-1, P less than 0.05) than for untreated rabbits (0.15 +/- 0.03 day-1 or 17 +/- 4 mg.g RV-1.day-1). RNA content was significantly higher at day 2 (1.47 +/- 0.17 mg/g RV, P less than 0.05) than in controls (1.16 +/- 0.14 mg/g RV), whereas there was a slight but nonsignificant increase at day 4 (1.36 +/- 0.21 mg/g RV, P less than 0.1). The efficiency of protein synthesis (synthesis/RNA) per gram RV was significantly increased both at day 2 (20.5 +/- 2.2 g protein.g RNA-1.day-1, P less than 0.05) and day 4 (19.8 +/- 3.5 g protein.g RNA-1.day-1, P less than 0.05) compared with control (14.6 +/- 2.3 g protein.g RNA-1.day-1). The increase in efficiency appeared to be caused by pressure overload itself based on a comparison of 0-4 day data vs. data obtained from sham animals (P less than 0.05).

Animals↗

Alterations in bidirectional transmembrane calcium flux occur without changes in protein kinase C levels in rat aorta during sepsis.

A depression in aortic contractility has been previously demonstrated in rat intraperitoneal sepsis and during endotoxemia. In this study, we determined whether the mobilization of extracellular calcium (using 45Ca) and the release of intracellular calcium are altered in septic rat aorta when compared to sham-operated controls. The concentration of protein kinase C was also determined by using [3H] phorbol-12,13-dibutyrate (PDBu). We found that calcium influx was unaltered under basal conditions but that the ability of norepinephrine (NE) to augment influx was significantly depressed (P less than .05; [control vs. septic, 572 +/- 54 [SE] vs. 428 +/- 30 mumol Ca2+/kg dry wt. aorta]). Calcium influx stimulated by high K+ was unchanged in aortae between control and septic animals. In the presence of NE, calcium efflux (an indirect measurement of intracellular calcium release) was significantly diminished (P less than .001) in aortae from septic rats. The concentration of aortic protein kinase C as assessed by PDBu binding sites was unaltered in septic rats when compared with controls. In conclusion, we found that during sepsis alpha 1-adrenergic receptor activation of both calcium influx and efflux by NE is decreased; these alterations could be related to the depressed aortic contractility observed in sepsis.

Animals↗

Alterations in rat aortic alpha 1-adrenoceptors and alpha 1-adrenergic stimulated phosphoinositide hydrolysis in intraperitoneal sepsis.

We investigated the alterations of rat aortic alpha 1-adrenoceptors and alpha 1-adrenergic stimulated phosphoinositide (PI) metabolism in intraperitoneal sepsis. An analysis of [125I]-hydroxyethylaminotetralone (HEAT) binding to alpha 1-adrenoceptors on rat aortic membranes revealed decreased numbers of receptors without changes in affinity. The maximum number of binding sites decreased from 349 +/- 35 fmol/mg to 146 +/- 16 fmol/mg (P less than 0.05 vs. control). PI metabolism was similarly attenuated in aortae from septic rats. The norepinephrine-stimulated hydrolysis of [32P]-phosphatidylinositol-4,5-bisphosphate was significantly decreased in aortae from septic rats as was the alpha 1-adrenoceptor stimulated accumulation of [3H]-inositol monophosphate. Finally, the basal labeling of [32P]-phosphatidylinositol-4,5-bisphosphate but not of [32P]-phosphatidylinositol or [32P]-phosphatidic acid was significantly diminished. These results imply that signal transduction induced by alpha 1-adrenoceptor agonists in rat aorta is significantly altered in intraperitoneal sepsis. These findings may help define the mechanisms of depressed aortic contractility in models of sepsis and endotoxic shock.

Animals↗

Effects of a phorbol ester on rat aortic contraction and calcium influx in the presence and absence of BAY k 8644.

Phorbol esters like phorbol-12,13-dibutyrate (PDB) exert potent contractile effects on rat aorta. In the present study, we determined whether phorbol esters alter contraction by augmenting calcium influx through calcium channels. Isometric tensions and calcium influx (using 45Ca) were measured in rat aortic rings exposed to PDB in the presence and absence of BAY k 8644, a calcium channel agonist. We found that PDB alone caused significant increases in isometric tension. The addition of 100 nM BAY k 8644 enhanced the PDB-induced rat aortic contraction which was inhibited as well as reversed by the calcium channel antagonist, nitrendipine. In the presence of PDB alone, calcium influx was significantly increased only after an extended time (30 min) of isometric contraction. In the presence of BAY k 8644, however, PDB caused a significant increase in calcium influx during shorter periods (10 min) of isometric contraction. We also found that the biologically inactive phorbol, 4-alpha-phorbol, did not potentiate the effects of BAY k 8644 on either contraction or calcium influx. These results indicate that PDB may induce rat aortic contraction via activation of protein kinase C which in the presence of a calcium channel agonist can potentiate the mobilization of calcium through nitrendipine-sensitive calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Myosin isozyme synthesis and mRNA levels in pressure-overloaded rabbit hearts.

The in vivo synthesis rates of myosin isozyme heavy chains beta and alpha were measured in right ventricular (RV) muscle at 2 and 4 days following pulmonary artery constriction in rabbits, together with measurements of their relative mRNA levels. The synthesis rate of beta-myosin heavy chains was elevated in 2-day (0.27 +/- 0.06 day-1 or 2.5 +/- 0.7 mg/g RV/day, mean +/- SD) and in 4-day (0.25 +/- 0.08 day-1 or 2.8 +/- 1.0 mg/g RV/day) pressure overload, when compared to untreated rabbits (0.15 +/- 0.04 day-1 or 1.5 +/- 0.4 mg/g RV/day). However, the synthesis rates of alpha-myosin heavy chains in the same hearts were not altered significantly. There was a differential increase in the fractional synthesis rate of beta vs. alpha heavy chains in 2-day and 4-day pressure overload and in 2-day shams, suggesting switching toward beta heavy chain synthesis had occurred at these time points. beta heavy chain synthesis, as a proportion of total (alpha + beta) heavy chain synthesis, was significantly higher in 4-day pressure overload (78 +/- 9%) than in 4-day sham rabbits (63 +/- 6%). This increase in relative beta-synthesis was associated with a significant increase in the relative proportion of beta heavy chain mRNA level (76 +/- 13% vs. 56 +/- 7%). Furthermore, relative beta-synthesis and the beta-mRNA levels correlated linearly with each other in all experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The economy of isometric force development, myosin isoenzyme pattern and myofibrillar ATPase activity in normal and hypothyroid rat myocardium.

Hypothyroidism was induced in Wistar-Kyoto rats by adding propylthiouracil to the drinking water (0.8 mg/ml). Initial heat, total activity-related heat, and resting heat rate were measured in left ventricular papillary muscle preparations of propylthiouracil-treated and control rats contracting isometrically at 12 beats/min (21 degrees C), using Hill type, planar vacuum-deposited bismuth and antimony thermopiles. In the propylthiouracil preparations, relative to control, time-to-peak tension increased from 288 +/- 27 (mean +/- SD) to 411 +/- 25 msec (P less than 0.001), dp/dtmax decreased from 38.3 +/- 9.5 to 20.4 +/- 3.5 g X mm-2/sec (P less than 0.001), and peak developed tension decreased from 6.11 +/- 1.75 to 4.64 +/- 0.89 g X mm-2 (P less than 0.05). In the propylthiouracil preparations, initial heat was significantly (P less than 0.001) reduced by 27 or 43% when normalized to peak twitch tension or tension-time integral, respectively. In experiments where the papillary muscles were tetanized, the slope of the linear function of total activity-related heat versus tension-time integral was decreased by 43% (P less than 0.001) in the propylthiouracil preparations, indicating an improved economy of isometric tension maintenance. The predominant myosin isoenzyme of the left ventricular wall, as well as the papillary muscle myocardium, was the V3 variety in the propylthiouracil animals, in contrast to V1 in the controls. Myofibrillar actomyosin calcium-magnesium-stimulated adenosine triphosphatase activity was significantly (P less than 0.02) decreased from 55 +/- 18 (control) to 31 +/- 8 nmol inorganic phosphate ion/mg X min (propylthiouracil).(ABSTRACT TRUNCATED AT 250 WORDS)

Actomyosin↗