Alcohol use as a mediator of the effect of two alcohol reduction interventions on mental health symptoms of ART clients in Vietnam.

We aimed to examine the mediating role of alcohol use in the pathway from the interventions to depression and anxiety symptoms using data from a randomized controlled trial among people living with HIV (PWH) with hazardous alcohol use (n = 440) in Thai Nguyen, Vietnam. Participants were randomized into either a combined intervention (CoI), a brief intervention (BI) and a standard of care arm. Both interventions were based on cognitive behavioral therapy and motivational enhancement therapy. Alcohol use was measured as the percentage of days abstinent from alcohol in the last 30 days. Symptoms of depression and anxiety were measured with the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 scales. Alcohol use was a significant mediator of the effects of two alcohol interventions on depression symptoms, but not anxiety symptoms. There were significant indirect effects via alcohol use of both interventions on depression symptoms at 12 months (CoI: mean difference (MD) = -0.134; 95%CI: -0.251, -0.035); (BI: MD = -0.141; 95%CI: -0.261, -0.038). There were no significant direct or total effects of the interventions on either symptoms at 12 months. Interventions with a dual focus on mental health and alcohol disorders are needed to determine optimal ways to tackle these common comorbidities among PWH.

"I refused to drink but they still forced me": A mixed-methods approach to understanding the pathways to reduce alcohol use among Vietnamese people with HIV.

AIMS: This study explores the effects of two evidence-based alcohol reduction counseling interventions on readiness to change, alcohol abstinence self-efficacy, social support, and alcohol abstinence stigma among people with HIV (PWH) who have hazardous alcohol use in Vietnam. METHODS: PWH receiving antiretroviral therapy (ART) were screened for hazardous drinking and randomized to one of three study arms: combined intervention (CoI), brief intervention (BI), and standard of care (SOC). A quantitative survey was conducted at baseline (N = 440) and 3-month post-intervention (N = 405), while in-depth interviews were conducted with a subset of BI and CoI participants at baseline (N = 14) and 3 months (N = 14). Data was collected from March 2016 to August 2017. A concurrent mixed-methods model was used to triangulate quantitative and qualitative data to cross-validate findings. RESULTS: At 3 months, receiving the BI and CoI arms was associated with 2.64 and 3.50 points higher in mean readiness to change scores, respectively, compared to the SOC group (BI: ß = 2.64, 95% CI: 1.17-4.12; CoI: ß = 3.50, 95% CI 2.02-4.98). Mean alcohol abstinence self-efficacy scores were 4.03 and 3.93 points higher among the BI and CoI arm at 3 months, compared to SOC (BI: ß = 4.03, 95% CI: 0.17-7.89; CoI: ß = 3.93, 95% CI: 0.05-7.81). The impacts of the interventions on social support and alcohol abstinence stigma were not significant. Perceived challenges to refusing drinks at social events remained due to strong alcohol abstinence stigma and perceived negative support from family and friends who encouraged participants to drink posed additional barriers to reducing alcohol use. CONCLUSIONS: Both the CoI and BI were effective in improving readiness to change and alcohol abstinence self-efficacy among PWH. Yet, participants still faced significant barriers to reducing their drinking due to social influences and pressure to drink. Interventions at different levels addressing social support and alcohol abstinence stigma are warranted.

Effects of Two Alcohol Reduction Interventions on Depression and Anxiety Symptoms of ART Clients in Vietnam.

Little is known about the potential mental health impacts of cognitive behavioral therapy and motivational interviewing interventions that focus on alcohol reduction among people with HIV (PWH). Our study aimed to assess the impact of two evidence-based alcohol reduction interventions on depression and anxiety symptoms of antiretroviral therapy (ART) clients with hazardous alcohol use. We conducted a secondary data analysis of data from a three-arm randomized controlled trial among ART clients in Thai Nguyen, Vietnam that evaluated the impacts of two alcohol reduction interventions in Vietnam. ART clients 18 years old or more with hazardous alcohol use (based on the Alcohol Use Disorders Identification Test-Consumption) were enrolled and randomized into one of three arms: Combined intervention, Brief intervention, and Standard of care (SOC). Symptoms of depression, measured with the Patient Health Questionnaire-9, and anxiety, measured with the Generalized Anxiety Disorder-7 scale, were assessed at baseline and 3, 6, and 12 months post-intervention. Generalized estimating equations were used to evaluate the effects of the interventions on depression and anxiety symptoms. The prevalence of depression and anxiety symptoms at baseline was 25.1% and 16.1%, respectively. Decreases in depression and anxiety symptoms were observed in all three arms from baseline to 12-month follow-up. There were no significant differences in depression and anxiety symptoms among participants receiving either intervention, relative to the SOC. Interventions with a dual focus on alcohol and mental health are needed to achieve more pronounced and sustainable improvements in depression and anxiety symptoms for PWH with hazardous alcohol use.

Social support modifies the association between hazardous drinking and depression symptoms among ART clients in Vietnam.

INTRODUCTION: Hazardous drinking is widespread among people with HIV (PWH). PWH are also vulnerable to depression due to HIV-related social stigma, and social support can play an important role in improving mental health for this population. No studies have explored whether social support modifies the association of hazardous drinking and depressive symptoms among PWH. METHODS: We used baseline data from a randomized controlled trial of two evidence-based alcohol reduction interventions among antiretroviral therapy clients in Vietnam. Hazardous alcohol use was defined as having a score ≥8 for men and ≥ 7 for women on the Alcohol Use Disorders Identification Test. The presence of depression symptoms was defined as a score ≥ 5 on the Patient Health Questionnaire-9. Social support was measured with a 5-question modified version of the Medical Outcomes Study Social Support Instrument. Crude (CPRs) and adjusted prevalence ratios (aPRs) of the association were presented. RESULTS: Hazardous drinking was significantly associated with increased likelihood of having depressive symptoms (aPR = 1.26;95%CI 1.04-1.52). Hazardous drinking and depression symptoms were not associated among those with high social support (aPR = 1.01;95%CI 0.76-1.35), but were associated among those with medium (aPR = 1.24;95%CI 0.92-1.69) and low social support (aPR = 1.71;95%CI 1.25-2.34). CONCLUSIONS: Social support significantly modified the association between hazardous drinking and depression symptoms among ART clients in Vietnam. Interventions to decrease hazardous alcohol use are broadly indicated for PWH in Vietnam and other low-resource settings, but special attention or modifications may be needed to support mental health among those with lower levels of social support.

The relationship between health-related variables and increases in smoking among recently diagnosed HIV+ people who inject drugs in Vietnam.

BACKGROUND: In Vietnam tobacco smoking is prevalent among people living with HIV (PLHIV) and causes excess mortality in this population. Injection drug use is a driver of HIV infections in Vietnam. Changes in HIV disease state may correlate to changes in smoking among PLHIV. This study investigates the relationship between increases in smoking and health-related variables among recently diagnosed HIV+ people who inject drugs (PWID) in Vietnam. METHODS: We analyzed longitudinal data from 323 recently diagnosed HIV+ PWID in a randomized controlled trial from 2009 to 2013 in Thai Nguyen province, Vietnam. The outcome was an increase of >one cigarette/day from baseline visit cigarette smoking. A generalized estimating equation for repeated measures was used to estimate bivariable and multivariable associations between participant characteristics and smoking increases. We collected qualitative data to enhance our understanding of quantitative results, from 16 HIV+ PWID who smoke. RESULTS: Ninety three point 5% of participants reported some smoking at baseline. Smoking fewer cigarettes, higher health related quality of life (QOL), and higher CD4 counts were predictive of increases in smoking at future visits in a multivariable model. Qualitative data showed smoking increases were tied to improved perceived health, and counseling during respiratory illnesses may increase intention to quit. CONCLUSION: HIV+ PWID in Vietnam smoke at a very high rate. Increases in their smoking are correlated to increases in heath-related QOL, and increases in perceptions of health. Any tobacco-use intervention should account for internal tobacco use triggers faced by HIV+ PWID.

Characteristics of persons who inject drugs and who witness opioid overdoses in Vietnam: a cross-sectional analysis to inform future overdose prevention programs.

BACKGROUND: Persons who use opioids have a high risk of overdose and associated mortality. In Vietnam, little is known about the characteristics of this population and the persons who are witness to those overdoses. One approach to combatting fatal overdose has been the use of peer interventions in which a friend or injecting partner administers overdose reversal medication, but availability in Vietnam of these medications is limited to pilot programs with aims to expand in the future (Le Minh and V.F. Go, Personal Communication, 2016). The primary objective of this paper is to explore the characteristics associated with witnessing three or more overdoses in a lifetime. METHODS: This cross-sectional analysis used baseline data from a four-arm randomized control trial conducted in Thai Nguyen, Vietnam, known as the Prevention for Positives project. One thousand six hundred seventy-three PWID were included in the analysis. We conducted bivariable and multivariable logistic regression to identify characteristics associated with witnessing three or more overdoses in a lifetime. Characteristics explored included education, employment, marital status, risky drug use behaviors, locations for accessing syringes, recent overdose, history of incarceration, drug treatment, and having slept outside in the past 3 months. RESULTS: Seventy-two percent (n = 1203) of participants had witnessed at least one overdose in their lifetime, and 46% had witnessed three or more overdoses (n = 765). In the multivariable model, having less than secondary education (AOR 0.70; 95% CI 0.57, 0.86), having slept outside in the past 3 months (AOR 1.77; 95% CI 1.31, 2.40), having a history of incarceration (AOR 1.33; 95% CI 1.07, 1.65), having a history of drug treatment (AOR 1.41; 95% CI 1.12, 1.77), experiencing a recent non-fatal overdose (AOR 3.84; 95% CI 2.36, 6.25), injecting drugs daily (AOR 1.79; 95% CI 1.45, 2.20), receptive needle sharing (AOR 1.30; 95% CI 1.04, 1.63), and number of years injecting (AOR 1.04; 95% CI 1.02, 1.07) were significantly associated with witnessing three or more overdoses. CONCLUSIONS: Targeted interventions are needed to train persons witnessing an overdose to administer overdose-reversal medication. This includes targeting persons prior to release from prisons, drug treatment centers, and those accessing syringe exchange programs. Additional research should assess the burden of witnessing an overdose as well as locations for medication distribution. Assessments of the training capacity and needs for implementing these programs among drug using peers in Vietnam are of the utmost importance.

Suicide seasonality and antidepressants: a register-based study in Sweden.

OBJECTIVE: Seasonality of completed suicides with a peak in spring and early summer is a well-documented finding. The circannual serotonergic functioning is hypothesized to be central in this phenomenon. Antidepressant medications exert their pharmacological action mainly by regulating serotonin. Our aim is to study the amplitude of the seasonal effect among suicide victims positive for different classes of antidepressants or without any antidepressants at the time of death. METHOD: By using Swedish Registers, 12 448 suicides with forensic data for antidepressive medication and information on in-patient-treated mental disorder were identified during 1992-2003. Seasonality was estimated with a Poisson regression variant of the circular normal distribution of completed suicides. RESULTS: Higher suicide seasonality was found for individuals treated with selective serotonin reuptake inhibitor (SSRIs) compared to those with other antidepressant treatment or without any antidepressant treatment. The finding is more evident for men and violent suicide methods and those without history of in-patient treatment. CONCLUSION: Our results provide preliminary support for the serotonergic hypothesis of suicide seasonality and raise the question of a possible accentuation of the natural suicide seasonality in patients treated with SSRIs, a hypothesis that warrants further investigation.

Return to post-test counselling by out-of-treatment injecting drug users participating in a cross-sectional survey in north Vietnam.

Return to post-test counselling is essential for optimal individual and public health impact of voluntary counselling and testing (VCT) services. Our study assessed factors associated with return to post-test counselling among 309 out-of-treatment injecting drug users who underwent VCT as part of a cross-sectional survey in Bac Ninh, Vietnam during August and September 2003. The overall return rate to post-test counselling was 54% (n=167). While participants in the rural study district were significantly less likely (chi2=5.8; p<0.05) to return compared with participants in the town centre (42.7 versus 58.1%), return rates did not significantly vary by age, perception of personal HIV risk, HIV serostatus diagnosed by the study, counsellor, history of HIV testing or prior knowledge of HIV status. In a multivariate analysis, higher return rate was associated with residence in Bac Ninh town centre (adjusted OR=1.9; CI=1.1-3.1). Of HIV-positive participants (n=131), 45% (n=59) did not return to collect test results. In view of the findings it is crucial to address risk perception and benefits of collecting test results during pre-test counselling sessions in order to maximize the desired impact of community-based VCT services targeting IDUs in Vietnam.

The relationship of excess body weight and health-related quality of life: evidence from a population study in Taiwan.

OBJECTIVE: Excess body weight is related to significant morbidity and mortality. However, less is known about the relationship of body weight to health-related quality of life (HRQOL), especially for Asian populations. We examined the relationship of excess weight and HRQOL in a general population sample from Taiwan. RESEARCH METHODS AND PROCEDURES: This cross-sectional study used a national representative sample (n = 14,221) from the 2001 Taiwan National Health Interview Survey. Body weight was categorized using body mass index (BMI in kg/m2) as normal (18.5-24.9), overweight (25-29.9), and obese (> or = 30). HRQOL was measured using the Taiwan version of the SF-36. We compared the body weight-HRQOL relationships by age, gender, and status of chronic condition, respectively. We especially used the Generalized Estimating Equations (GEE) to examine the relationships of BMI and HRQOL by taking into account the correlations of HRQOL within households. Four models were developed to adjust sequentially for sets of covariates: Model 1 with no adjustment; Model 2 adjusting for sociodemographic variables; Model 3 adding chronic conditions; Model 4 further adding smoking status. RESULTS: Unadjusted physical HRQOL was best for normal weight, worse for overweight, and worst for obese individuals. For unadjusted mental HRQOL, overweight subjects had at least as good mental domain scores of HRQOL as those with normal weight or obesity, depending on the subscales. As age increased, excess weight was associated with worse physical, but not mental HRQOL. Compared to men, women with excess weight showed a greater deficit in physical HRQOL. Multivariable analyses suggested that obesity was associated with worse physical HRQOL compared to overweight, which, in turn, was worse or comparable to normal weight. Specifically, in the model adjusting for demographic variables, the deficit in physical functioning and physical component scores for the obese vs normal weight were statistical significant (P < 0.05) and clinically important difference (effect size > or = 0.3). Both obesity and overweight were associated with higher mental component scores than normal weight, but the effect size was < 0.3. CONCLUSION: In Taiwan, excess weight was related to worse physical, but not mental HRQOL. The lack of impact of increased body weight on mental health status presents a potential challenge to preventing the increases in obesity. More research is needed to elucidate the mechanisms by which excess weight affects specific domains of HRQOL, and to develop effective prevention strategies.

Compliance subsampling designs for comparative research: estimation and optimal planning.

For studies with treatment noncompliance, analyses have been developed recently to better estimate treatment efficacy. However, the advantage and cost of measuring compliance data have implications on the study design that have not been as systematically explored. In order to estimate better treatment efficacy with lower cost, we propose a new class of compliance subsampling (CSS) designs where, after subjects are assigned treatment, compliance behavior is measured for only subgroups of subjects. The sizes of the subsamples are allowed to relate to the treatment assignment, the assignment probability, the total sample size, the anticipated distributions of outcome and compliance, and the cost parameters of the study. The CSS design methods relate to prior work (i) on two-phase designs in which a covariate is subsampled and (ii) on causal inference because the subsampled postrandomization compliance behavior is not the true covariate of interest. For each CSS design, we develop efficient estimation of treatment efficacy under binary outcome and all-or-none observed compliance. Then we derive a minimal cost CSS design that achieves a required precision for estimating treatment efficacy. We compare the properties of the CSS design to those of conventional protocols in a study of patient choices for medical care at the end of life.

Addressing an idiosyncrasy in estimating survival curves using double sampling in the presence of self-selected right censoring.

We investigate the use of follow-up samples of individuals to estimate survival curves from studies that are subject to right censoring from two sources: (i) early termination of the study, namely, administrative censoring, or (ii) censoring due to lost data prior to administrative censoring, so-called dropout. We assume that, for the full cohort of individuals, administrative censoring times are independent of the subjects' inherent characteristics, including survival time. To address the loss to censoring due to dropout, which we allow to be possibly selective, we consider an intensive second phase of the study where a representative sample of the originally lost subjects is subsequently followed and their data recorded. As with double-sampling designs in survey methodology, the objective is to provide data on a representative subset of the dropouts. Despite assumed full response from the follow-up sample, we show that, in general in our setting, administrative censoring times are not independent of survival times within the two subgroups, nondropouts and sampled dropouts. As a result, the stratified Kaplan-Meier estimator is not appropriate for the cohort survival curve. Moreover, using the concept of potential outcomes, as opposed to observed outcomes, and thereby explicitly formulating the problem as a missing data problem, reveals and addresses these complications. We present an estimation method based on the likelihood of an easily observed subset of the data and study its properties analytically for large samples. We evaluate our method in a realistic situation by simulating data that match published margins on survival and dropout from an actual hip-replacement study. Limitations and extensions of our design and analytic method are discussed.

Adolescents in high-risk trajectory: clustering of risky behavior and the origins of socioeconomic health differentials.

BACKGROUND: We have evaluated high-risk behavior of adolescents 12 to 17 years of age on the basis of seven binomial psychosocial variables in order to assess whether there is a tendency of these variables to cluster in the same individuals and to identify socioeconomic covariates of risky behavior. METHODS: Study participants were 547 adolescents from four high schools in Greece: two in rural areas, one in an upper-medium socioeconomic class areas, and one in a low-to-medium socioeconomic class area of Athens. Clustering was assessed by evaluating concordance of high-risk attributes examined in pairs, and was expressed as a series of odds ratios (ORs) as well as by factor analysis. RESULTS: All but one OR were higher than the null value, but they were particularly high with respect to smoking and nonuse of safety belts (OR = 3.2, P < 10(-4)), smoking and binge drinking (OR = 3.3, P < 10(-4)), smoking and riding with a drunk driver (OR = 5.3, P = 10(-4)), smoking and driving under the influence of alcohol (OR = 9.7, P < 10(-4)), nonuse of oral contraceptives and riding a car with a drunk driver (OR = 15.4, P = 0.002), and driving under the influence of alcohol and riding with a drunk driver (OR = 18.6, P < 10(-4)). Factor analysis indicated that risky behavior could be explained in terms of two component factors, namely carelessness in the context of self interest and irresponsible sexual behavior. A composite index integrating information of all seven high-risk indicators regressed on sociodemographic characteristics showed that risky behavior increased sharply with age and was concentrated strongly in the low-education families and the lower income areas. CONCLUSIONS: Several aspects of high-risk behavior tend to aggregate in the same individuals, and the clustering pattern has already been developed by late adolescence, mostly among the less privileged families and population groups. It appears that socioeconomic class health differentials may have strong roots in late adolescence.

Defective glucose-dependent endoplasmic reticulum Ca2+ sequestration in diabetic mouse islets of Langerhans.

Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease associated with abnormal insulin secretion, the underlying mechanisms of which are unknown. Glucose-dependent signal transduction pathways were investigated in pancreatic islets derived from the db/db mouse, an animal model of NIDDM. After stimulation with glucose (4-12 mM), the changes in intracellular Ca2+ concentration ([Ca2+]i) were different; unlike control islets, db/db islets lacked an initial reduction of [Ca2+]i and the subsequent [Ca2+]i oscillations following stimulation with 12 mM glucose. The severity of these defects in Ca2+ signaling correlated with the age-dependent development of hyperglycemia. Similarly defective glucose-induced Ca2+ signaling were reproduced in control islets by pre-exposure to thapsigargin, a selective inhibitor of endoplasmic reticulum (ER) Ca(2+)-ATPase. Estimation of ATPase activities from rates of ATP hydrolysis and by immunoblot hybridization with an antiserum directed against the sarco/endoplasmic reticulum Ca(2+)-ATPase both demonstrated that the ER Ca(2+)-ATPase was almost entirely absent from db/db islets. The effects of inhibition of ER Ca(2+)-ATPase on insulin secretion were also examined; a 4-day exposure of control islets to 1 microM thapsigargin resulted in basal and glucose-stimulated insulin secretion levels similar to those found in db/db islets. These results suggest that aberrant ER Ca2+ sequestration underlies the impaired glucose responses in the db/db mouse and may play a role in defective insulin secretion associated with NIDDM.

The inhibition of long-chain fatty acyl-CoA synthetase by enoximone in rat heart mitochondria.

The mechanism by which enoximone, a reported phosphodiesterase inhibitor, inhibits the oxidation of long-chain fatty acids was studied in isolated rat heart mitochondria using a series of 14C-labeled substrates. Enoximone decreased palmitate oxidation in a time- and concentration-dependent manner. Fifty percent inhibition of palmitate oxidation was achieved with 250 microM of enoximone. In contrast to its effect on palmitate, enoximone (250 microM) increased octanoate oxidation by 30%, whereas pyruvate oxidation was unaffected by enoximone. At that dose there was no effect on the oxidation of palmitoyl-CoA and palmitoyl carnitine. The degree of palmitate oxidation inhibited by enoximone was parallel to the inhibition of acyl-CoA synthetase in both rat heart mitochondria and microsomes. These results suggest that enoximone is a reversible inhibitor of long-chain fatty acyl-CoA synthetase. Moreover, the reaction, which is catalyzed by this enzyme, is a rate-limiting step in the pathway of fatty acid oxidation in rat heart mitochondria.

Selective inhibition of hepatic peroxisomal fatty acid beta-oxidation by enoximone.

Although beta-oxidation of fatty acids occurs in both peroxisomes and mitochondria, beta-oxidizing enzymes in these organelles have distinct differences in their specifity and sensitivity to inhibitors. In this study, the effects of the phosphodiesterase inhibitor enoximone on hepatic peroxisomal and mitochondrial beta-oxidation were investigated. In liver homogenates from control rats, cyanide-insensitive peroxisomal beta-oxidation of palmitoyl-CoA was inhibited progressively by increasing concentrations of enoximone. Similar results were obtained in liver homogenates from rats pretreated with the known peroxisomal proliferator diethylhexylphthalate. In contrast, mitochondrial beta-oxidation of palmitoyl-CoA was not inhibited by enoximone. These data show that enoximone selectively inhibits basal as well as induced peroxisomal, but not mitochondrial, beta-oxidation of the CoA thioester of long-chain fatty acids. The availability of specific inhibitors of peroxisomal beta-oxidation should prove useful in elucidating regulatory mechanisms operative in this pathway in normal as well as in proliferated peroxisomes.

Stimulation of fatty acid oxidation by phosphodiesterase III inhibitors in rat myocytes.

In order to study the regulation of fatty acid oxidation in the heart, the effects of some phosphodiesterase III inhibitors, such as enoximone and milrinone, on the oxidation of [1-14C]palmitic acid, [1-14C]octanoic acid, and [2-14C]pyruvate were studied in adult rat myocytes. Enoximone and milrinone, at a concentration of 0.25 mM, increased palmitate oxidation significantly, by 70 and 40%, respectively. Also, enoximone increased octanoate oxidation by 45%. In contrast, pyruvate oxidation was decreased by 60% by enoximone. To investigate the effects of enoximone or milrinone on the pathway of fatty acid oxidation, their effects on the oxidation of either [1-14C]palmitoyl-CoA or [1-14C]palmitoylcarnitine were studied with rat heart homogenates. Neither enoximone nor milrinone had any effects on the oxidation of these compounds. Compounds known to elevate intracellular [Ca2+] or cyclic AMP, such as the calcium ionophore A23187, ionomycin, dibutyryl cyclic AMP, or isoproterenol, had no effect on palmitate oxidation. Enoximone, at a concentration of 0.25 mM, increased palmitate uptake by 40% in rat myocytes. These results suggest that enoximone and milrinone increase fatty acid oxidation in myocytes by increasing their cellular transport, and they also show the usefulness of these compounds as a tool to study the regulation of this vital pathway in heart.

Stimulation of polyunsaturated fatty acid oxidation in myocytes by regulating its cellular uptake. On the rate limiting step of polyunsaturated fatty acid oxidation in heart.

In order to investigate the regulation of polyunsaturated fatty acid oxidation in the heart, the effect of the phosphodiesterase inhibitor enoximone on the oxidation of [1-14C] arachidonic acid, and [1-14C] arachidonyl-CoA, were studied in adult rat myocytes, and isolated rat heart mitochondria. Enoximone stimulated arachidonate oxidation by 94%, at a concentration of 0.25 mM. The apparent Vmax value of arachidonate oxidation in the presence of enoximone (6.98 nmol/mg protein/30 min), was approximately 75% higher than the value observed with the control (4.0 nmol/mg protein/30 min) in isolated myocytes. Also, enoximone stimulated arachidonate uptake by 27% at a concentration of 0.25 mM. On the other hand, enoximone had no effect on the oxidation of [1-14C] arachidonyl-CoA in isolated rat heart mitochondria. These results suggest that the oxidation of polyunsaturated fatty acids in myocytes is regulated by the rate of uptake of these acids across sarcolemmal membranes.

Stimulation of fatty acid oxidation in myocytes by phosphodiesterase inhibitors and adenosine analogues.

The effect of various phosphodiesterase inhibitors, and adenosine analogues on palmitate oxidation, were studied in isolated rat myocytes. Enoximone, milrinone, and dipyridamole, at a concentration of 250 microM, stimulated palmitate oxidation by 78%, 40%, and 43%, respectively. The specific A1-agonist, N6-cyclopentyladenosine, increased palmitate oxidation by 56%, at a concentration of 250 microM. Moreover, the nucleoside transport inhibitor, S-(P-Nitrobenzyl-)6-thioinosine, increased palmitate oxidation by 40%, at a concentration of 100 microM. These data suggest that the stimulation of palmitate oxidation by enoximone and adenosine analogues may be mediated via the inhibition of the uptake and/or the oxidation of glucose in myocytes.

The role of cyclic AMP and the dihydropyridine-sensitive channels on the mechanism of action of milrinone (Corotrope).

Milrinone (Corotrope) increased cyclic AMP levels in dog guinea pig and rat cardiac muscle. A correlation between the increase in contractile force and cyclic AMP levels in dog ventricular trabeculae was obtained when measurements were made 60-70 s after the addition of milrinone. When cyclic AMP levels were determined at the time of maximal contractile response, only concentrations of milrinone 200-300 times the inotropic dose had any effects in elevating cyclic nucleotide levels. In dog Purkinje tissue and rat cardiac muscle, milrinone had minimal or no effects on contractile force but increased cardiac cyclic AMP levels. Sequential doses of milrinone to perfused guinea pig hearts resulted in severe tachyphylaxis to the inotropic activity of milrinone. However, under these conditions, milrinone was found to elevate cardiac cyclic AMP upon each administration. Furthermore, in this preparation, cross-tachyphylaxis between Bay K 8644 and milrinone was demonstrated. The mechanism of action of Bay K 8644, which acts on sarcolemmal Ca2+, is not mediated by increases in cyclic AMP. Following development of tachyphylaxis to Bay K 8644, in the guinea pig hearts, addition of milrinone results in no increases in contractile force but a significant increase in cyclic AMP levels. In all of the instances of tachyphylaxis, isoproterenol increased both contractile force and cyclic AMP. The data are discussed and we put forth the hypothesis that increased cardiac force due to milrinone is in part due to a direct or indirect action on sarcolemmal Ca2+ channels.