Long-term adjunctive lacosamide treatment in patients with partial-onset seizures.

OBJECTIVE: To evaluate long-term (up to 5.5 years) safety, seizure reduction, and maintenance of efficacy of the antiepileptic drug (AED) lacosamide as adjunctive treatment in an open-label extension trial (SP774; ClinicalTrials.gov: NCT00515619). METHODS: Three hundred and seventy-six adults with partial-onset seizures taking 1-3 AEDs enrolled following completion of a double-blind trial of adjunctive lacosamide. During open-label treatment, dosage of lacosamide (100-800 mg/day) and/or concomitant AEDs could be adjusted to optimize tolerability and seizure control. RESULTS: Kaplan-Meier estimates of patient retention were 74.5% at 12 months, 52.9% at 36 months, and 40.6% at 60 months; median open-label treatment duration was 1183 days (~3.2 years). The most frequently reported treatment-emergent adverse events were dizziness (24.2%), headache (14.4%), diplopia (13.8%), and nasopharyngitis (13.8%); 9.0% of patients discontinued due to adverse events, most commonly dizziness (1.3%). Median percent reduction in 28-day seizure frequency from baseline of the double-blind trial was 49.9% overall, 55.4% for 1-year completers, and 62.3% for 3-year completers. Overall, 50.0% of patients were considered ≥50% responders (achieved ≥50% reduction in 28-day seizure frequency); 55.9% of 1-year completers and 63.0% of 3-year completers were ≥50% responders. CONCLUSION: In eligible patients who entered the open-label extension trial, lacosamide was generally well tolerated. For most patients within each yearly completer cohort, seizure reduction was maintained over time.

Lacosamide cardiac safety: clinical trials in patients with partial-onset seizures.

OBJECTIVE: To evaluate the cardiac safety of adjunctive lacosamide in a large pool of adults with partial-onset seizures (POS). METHODS: Post-randomization changes from baseline for electrocardiographic (ECG) measurements, diagnostic findings, and relevant adverse events (AEs) were compared for pooled data from three randomized, placebo-controlled trials of adjunctive lacosamide for the treatment of POS. RESULTS: Lacosamide did not prolong the QTc interval or affect heart rate as determined by an analysis of data from patients randomized to lacosamide 200, 400, or 600 mg/day (n = 944) compared with placebo (n = 364). After 12-week maintenance treatment, mean changes from baseline for QRS duration were similar between the placebo and lacosamide 200 and 400 mg/day groups (0.0, -0.2, and 0.4 ms), but slightly increased for lacosamide 600 mg/day (2.3 ms). A small, dose-related mean increase in PR interval was observed (-0.3, 1.4, 4.4, and 6.6 ms for the placebo and lacosamide 200, 400, and 600 mg/day groups, respectively). First-degree atrioventricular (AV) block was reported as a non-serious AE in 0.0%, 0.7%, 0.2%, and 0.5% of patients in the same respective groups. Second- or higher degree AV block was not observed. There was no evidence of a PR-interval-related pharmacodynamic interaction of lacosamide with either carbamazepine or lamotrigine. CONCLUSIONS: Evaluation of the pooled cardiac safety data from patients with POS showed that adjunctive lacosamide at the maximum recommended dose (400 mg/day) was not clearly associated with any cardiac effect other than a small, dose-related increase in PR interval that had no evident symptomatic consequence.

The impact of female caregivers' employment status on patterns of formal and informal eldercare.

This article uses data from the 1989 National Long-Term Care Survey and its companion Informal Caregivers Survey to investigate how the employment of female primary caregivers (FPCGs) affects hours of care received by disabled elderly care recipients (CRs). Multivariage analyses controlling for key FPCG and CR characteristics indicate that when FPCGs are employed they provide significantly fewer hours of care personally; however, their CRs also receive significantly more hours of help from other sources. When FPCGs work more than 17 hours per week, their CRs receive significantly fewer total weekly hours of care than would otherwise be the case.

Effects of expectancies on subjective responses to oral delta9-tetrahydrocannabinol.

The effects of expectancies on subjective responses to oral delta9-tetrahydrocannabinol (delta9-THC) were examined. Thirty-five regular marijuana users were assigned to one of two groups: one group was told that they may receive a cannabinoid or placebo and a second group was told that they may receive a drug from one of several classes of drugs (e.g., stimulant, sedative, antiemetic) or placebo. Regardless of the group to which they were assigned, subjects received each of two oral doses of delta9-THC (7.5 and 15 mg) and placebo, one dose per session, for a total of three sessions. Measures of subjective effects, including visual analog scales and the Addiction Research Center Inventory (ARCI), were administered at 0.5-h intervals throughout each session. Consistent with previous research using other drugs, subjects in the current experiment who expected to receive a cannabinoid reported greater pleasurable effects than subjects who did not have this expectancy. The results have implications for understanding the effects of cannabinoids when used in both recreational and clinical settings.

Behavioral responses to ethanol in light and moderate social drinkers following naltrexone pretreatment.

The opioid antagonist naltrexone has been shown to be effective in the treatment of alcoholism, possibly by dampening the subjective effects of ethanol. However, naltrexone does not consistently attenuate the effects of ethanol in social drinkers in laboratory-based challenge studies. In the present study, 25 healthy volunteers, who were either light drinkers (mean = 3 drinks per week) or moderate drinkers (mean = 16 drinks per week), participated in six evening sessions. At each session, subjects ingested a capsule containing naltrexone (25 or 50 mg) or placebo, and 1 hr later they consumed a beverage containing ethanol (0.25 g/kg, equivalent to about two standard alcoholic drinks) or placebo. Subjects received all combinations of pretreatments and beverages. They completed self-report mood questionnaires and psychomotor tests at regular intervals. This low dose of ethanol produced modest but significant effects on self-report measures such as ratings of feeling a drug effect and of liking the drug effect. However, naltrexone (25 or 50 mg) pretreatment had no dampening effect on subjects' responses to ethanol. These results indicate that acute doses of naltrexone that are effective when administered chronically to alcoholics do not attenuate the acute effects of a low dose of ethanol in non-problem drinkers.

Consumer-directed models of personal care: lessons from Medicaid.

"Consumer-directed" models of financing and services delivery are compared with models that emphasize professional control and accountability within the context of Medicaid-financed personal care services (PCS). The Medicaid PCS benefit finances aide or attendant services for low-income persons with functional disabilities to assist them with daily living tasks. Consumer-directed modes of service provision permit service recipients themselves to have greater choice and control over all aspects of service provision. Client surveys in three states found that clients were most satisfied with the program elements of Medicaid PCS services that gave them more choice and control. Case studies of how Medicaid PCS programs in particular states are administered indicate that the use of aides who are independent providers, unattached to a home health or home care agency, is a critical aspect of consumer direction. By itself, however, this factor does not guarantee consumer direction because other Medicaid PCS rules and regulations may restrict client choice and control.

Effects of naltrexone pretreatment on the subjective and performance effects of ethanol in social drinkers.

Clinical trials suggest that opioid antagonists may be effective in the treatment of alcoholism. For example, two recent clinical trials reported that alcoholics treated with the opioid antagonist naltrexone exhibited higher abstinence rates, decreased craving and a decrease in the amount of alcohol consumed if drinking occurred. The present study examined the hypothesis that naltrexone pretreatment would attenuate the behavioral responses to an acute dose of ethanol in normal, healthy social drinkers. Thirteen healthy male and female social drinkers participated in a six-session, double-blind, placebo-controlled, crossover design study. On each session, subjects ingested a capsule containing naltrexone (25 or 50mg) or placebo and one hour later consumed a beverage containing ethanol (0.5g/kg) or placebo. For three hours after the beverage was consumed, breath alcohol levels were measured and subjects completed standardized subjective effects questionnaires and performance tasks at regular intervals. Ethanol alone produced its prototypic effects, including positive subjective responses such as euphoria and increased ratings of overall liking, as well as increased ratings of confusion. Ethanol also impaired performance on a verbal recall task. Naltrexone alone produced few subjective effects and did not impair psychomotor or verbal recall performance. Contrary to our hypothesis, pretreatment with naltrexone did not alter the positive subjective effects, or any other effects, of ethanol. Further research is needed to determine the influence of factors such as baseline level of ethanol consumption or duration of naltrexone treatment on the interaction between ethanol and the endogenous opioid system.

Effect of setting on the reinforcing and subjective effects of ethanol in social drinkers.

The reinforcing and subjective effects of two doses of ethanol [0.5 g/kg (LOW) and 0.8 g/kg (HIGH)] were evaluated under two conditions, a social condition (SOC), in which subjects were tested with two or three other subjects, and a socially isolated condition (ISO), in which subjects were tested alone. Forty-one social drinkers participated in a double-blind, seven-session choice procedure. Subjects were randomly assigned to one of four experimental groups: SOC-LOW, SOC-HIGH, ISO-LOW, or ISO-HIGH. On the first four sessions, subjects sampled ethanol (0.5 or 0.8 g/kg) on two occasions and placebo on the other two occasions. On the three remaining sessions, subjects selected and consumed whichever of the two previously sampled substances they preferred. The number of sessions on which they chose ethanol was the primary measure of the reinforcing effects of ethanol. Standardized self-report questionnaires and a psychomotor test were used to measure subjective and objective drug effects. Subjects in the SOC condition chose ethanol over placebo on significantly more sessions than subjects in the ISO condition. Ethanol produced positive subjective effects (e.g., increased ratings of drug liking and euphoria) for subjects in the SOC condition, but for subjects in the ISO condition, it produced apparently negative effects (e.g., increased ratings of dysphoria). These results extend previous reports that the behavioral effects of ethanol depend upon the social condition in which it is consumed.

Preference for ethanol and diazepam in light and moderate social drinkers: a within-subjects study.

Preference for ethanol (versus placebo) and diazepam (versus placebo) was assessed in light and moderate social drinkers. The study was designed to investigate the relationship of habitual alcohol use to the subjective and behavioral effects of the two drugs. A secondary purpose of the study was to investigate relationships within subjects in their responses to ethanol and diazepam. Light drinkers (n = 13) who consumed one to five drinks per week and moderate drinkers (n = 14) who consumed seven or more drinks per week participated in two seven-session choice experiments, one assessing preference for 0.5 g/kg ethanol versus placebo and the other assessing preference for 20 mg diazepam versus placebo. Drugs were administered double-blind and double-dummy, and the order of participation in the two experiments was counterbalanced. Sessions were conducted during the evenings in a comfortable laboratory environment. The primary dependent measure was the number of times each subject chose the drug (i.e., ethanol or diazepam) over placebo. Subjective and objective measures of the drugs' effects were obtained using standardized self-report questionnaires and psychomotor tests. Whereas both groups preferred the ethanol over placebo (i.e., 63% and 83% ethanol choice for light and moderate drinkers, respectively), only the moderate drinkers preferred the diazepam over placebo (i.e., 40% and 73% diazepam choice for light and moderate drinkers, respectively). Subjective responses to the drugs were generally similar across the groups, although on some measures the light drinkers reported more marked drug effects. The number of times each subject chose ethanol was positively correlated with the number of times he or she chose diazepam (r = 0.57), and on subjective measures, responses to ethanol and diazepam were positively correlated. Thus, subjective and behavioral responses to diazepam and ethanol were related to habitual alcohol consumption, and most notably, moderate drinkers were more likely than light drinkers to prefer diazepam over a placebo.

Effects of ondansetron pretreatment on acute responses to ethanol in social drinkers.

Laboratory animal and clinical studies suggest that the 5-HT(3) receptor subtype may mediate some of the CNS effects of ethanol. Two experiments were conducted to evaluate the effects of the 5-HT(3) receptor antagonist, ondansetron, on the acute responses of social drinkers to a moderate dose of ethanol. In Experiment 1, two doses of ondansetron (0.15 and 0.30mg) or placebo were tested in combination with ethanol (0.5g/kg) or placebo. In Experiment 2, three higher doses of ondansetron (1.0, 3.0 and 10.0mg) or placebo were tested in combination with ethanol (0.5g/kg) or placebo. Sessions were conducted one or two evenings per week from 16.00h until 20.45h. Separate groups of subjects participated in the two placebo-controlled, double-blind experiments (Experiment 1: n = 13; Experiment 2: n = 6). The order of drug administration was counterbalanced across subjects. In each study, subjects were given an intravenous infusion of ondansetron and 5min later consumed an ethanol or placebo beverage. For 3h after the beverage was consumed, physiological, subjective effects and performance measures were taken at regular intervals. Across a wide range of doses, the effects of ondansetron alone did not differ significantly from placebo. Ethanol alone produced prototypic effects on several measures (e.g., increased ratings of "positive" subjective effects and impaired memory performance). Furthermore, ondansetron pretreatment did not modify physiological, subjective or performance effects of ethanol. These findings do not support the hypothesis that the 5-HT(3), receptor/channel complex mediates the positive subjective effects, or any other subjective or performance effects, of ethanol.

Discriminative stimulus effects of phencyclidine: pharmacologically specific interactions with delta 9- and delta 8-tetrahydrocannabinol.

Rats were trained to discriminate a dose of 1.75 mg/kg phencyclidine (PCP) from saline. During substitution tests, both PCP (0.3-10.0 mg/kg) and the non-competitive NMDA antagonist, MK-801 (0.01-0.3 mg/kg) substituted for the PCP stimulus in a dose-dependent manner. In contrast, delta 9-tetrahydrocannabinol (delta 9-THC, 0.1-5.6 mg/kg) and delta 8-tetrahydrocannabinol (delta 8-THC, 0.3-5.6 mg/kg) failed to substitute for the PCP stimulus, up to doses that substantially decreased rate of responding. However, both delta 9-THC and delta 8-THC partially attenuated the discriminative stimulus effects of the PCP training dose. Furthermore, a dose of 3.0 mg/kg delta 9-THC shifted the PCP dose-effect curve for discriminative stimulus effects to the right and shifted the PCP dose-effect curve for rate of responding to the left. The attenuation of the PCP stimulus by delta 9-THC lacked a strong dose-dependent relationship and was observed both at doses which did not alter rate of responding, as well as at doses which substantially decreased rate. In contrast to the effects observed with delta 9-THC and delta 8-THC, morphine, d-amphetamine and chlordiazepoxide failed to attenuate the discriminative stimulus effects of PCP, even at doses that markedly decreased rate of responding. The present findings suggest that delta 9-THC and delta 8-THC alter the discriminative stimulus effects of PCP in a pharmacologically specific manner.

International long-term care reform: A demographic, economic, and policy overview.

Advanced industrial countries around the world are making or contemplating major reforms of their systems for financing and organizing long-term care for the elderly. The paper describes major reform efforts including: the pursuit of cost efficiencies from further differentiation of the acute and long-term care delivery systems, promotion of home and community-based care alternatives to traditional institutions, and 'systems integration' involving consolidation of responsibility for long-term care at one level of government. The paper concludes by discussing the special relevance to the longterm care reform debate in the U.S. of recent British and German decisions to, respectively, decentralize versus centralize responsibility for long-term care.

Delta 9-tetrahydrocannabinol interactions with phencyclidine and ethanol: effects on accuracy and rate of responding.

The effects of delta 9-tetrahydrocannabinol (delta 9-THC) in combination with phencyclidine (PCP) or ethanol were examined in rats responding under a fixed-consecutive-number schedule of food presentation. Under this schedule, a minimum of 13 consecutive responses on one lever followed by one response on another lever produced food. When administered alone, PCP (0.1-10.0 mg/kg) and delta 9-THC (0.1-5.6 mg/kg), but not ethanol (0.3-1.7 g/kg), decreased accuracy. PCP, delta 9-THC, and ethanol alone all produced dose-dependent decreases in rate of responding. A dose-effect curve for PCP or ethanol was then redetermined in combination with selected doses of delta 9-THC (0.125-1.75 mg/kg) and the data were analyzed according to the effect-addition and dose-addition models of additivity. When administered in combination, delta 9-THC produced dose-dependent leftward shifts in the PCP dose-effect curves for both accuracy and rate of responding. The interactions for PCP + delta 9-THC combinations were effect-additive for accuracy. In contrast, the type of interaction obtained for PCP + delta 9-THC combinations on rate of responding depended upon the particular doses combined, as well as on the model used to analyze the interactions. According to the effect-addition model, these interactions were additive at low doses of delta 9-THC and supraadditive at the highest dose. However, according to the dose-addition model the interactions at the higher doses of delta 9-THC were infraadditive. Delta 9-THC also shifted the ethanol dose-effect curve for rate of responding to the left but did not alter the ethanol dose-effect curve for accuracy. The interactions for ethanol + delta 9-THC combinations were effect-additive for accuracy and both effect- and dose-additive for rate of responding. The present investigation clearly illustrates the importance of examining an extensive range of dose combinations on different behavioral measures, as well as the use of appropriate analyses in studies designed to evaluate the interactions between drugs.

Discriminative stimulus properties of cocaine, alone and in combination with buprenorphine, morphine and naltrexone.

Rats were trained to discriminate a dose of 10.0 mg/kg cocaine from saline. During substitution tests, both cocaine (5.6-10.0 mg/kg) and d-amphetamine (1.0-3.0 mg/kg) produced greater than 80% responding on the cocaine-appropriate level. In contrast, buprenorphine (0.03-0.56 mg/kg), morphine (0.3-10.0 mg/kg) and naltrexone (1.0-10.0 mg/kg) failed to substitute for the cocaine stimulus, up to doses that substantially decreased rate of responding. When the cocaine dose-effect curve was redetermined in the presence of selected doses of buprenorphine, the amount of cocaine-appropriate responding following a low dose of cocaine (1.0 mg/kg) was increased slightly whereas cocaine-appropriate responding following higher doses of cocaine (3.0 and 5.6 mg/kg) was reduced slightly. Responding following the training dose of cocaine (10.0 mg/kg) was not changed. These results indicate that buprenorphine produced only small alterations in cocaine's discriminative stimulus effects and that the nature of these alterations differed depending on the dose of cocaine examined.

Discriminative stimulus properties of U50,488 and morphine: effects of training dose on stimulus substitution patterns produced by mu and kappa opioid agonists.

By using a two-lever drug discrimination task, four groups of rats were trained to discriminate either a low (3.0 mg/kg) and a high (5.6 mg/kg) training dose of the kappa opioid agonist U50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl] benzeneacetamine methanesulfonate hydrate] or a low (3.0 mg/kg) and a high (10 mg/kg) training dose of the mu opioid agonist morphine from water. The stimulus effects of the high training dose of U50,488 were shared by the kappa agonists bremazocine and ethylketocyclazocine (i.e., these drugs produced at least 80% drug-appropriate responding), but not by the mu agonists morphine, fentanyl and l-methadone or the nonopioid compounds d-amphetamine, pentobarbital and phencyclidine. Conversely, the stimulus effects of the high training dose of morphine were shared by other mu agonists, but not by the kappa agonists or the nonopioid compounds examined. Similarities in the stimulus effects of morphine and U50,488 occurred, however, when mu and kappa agonists were examined in rats trained to discriminate relatively low training doses of morphine or U50,488 from water. At the low training dose of morphine, complete substitution was obtained with the mu agonists tested as well as the kappa agonist ketocyclazocine. In these rats, intermediate (approximately 70% drug-appropriate responding) levels of substitution were obtained with the kappa agonists bremazocine and ethyylketocyclazocine. Similarly, at the low training dose of U50,488 both the mu and kappa agonists examined substituted completely. Asymmetrical substitution occurred between U50,488 and morphine at the low training doses, with morphine substituting completely for the low training dose of U50,488 and U50,488 failing to substitute for the low training dose of morphine. The rank order of potency for naloxone as an antagonist of the stimulus effects of morphine and U50,488 was; 3.0 mg/kg of morphine greater than 10 mg/kg of morphine greater than 3.0 mg/kg of U50,488 = 5.6 mg/kg of U50,488. The present results indicate that training dose is an important determinant of the different levels of cross-substitution obtained between mu and kappa agonists, and that a greater pharmacological specificity of drug-induced discriminative stimuli can be obtained when relatively high training doses of mu and kappa opioid agonists are used to establish the discrimination.

Medicaid spenddown in nursing homes.

This paper employs information from nationally representative surveys to examine the incidence and causes of Medicaid spenddown among disabled elderly persons. About 10% of nursing home discharges experience "asset spenddown," the process of converting from private pay to Medicaid. In contrast, over 50% of nursing home patients remain private pay throughout their stays. In addition, becoming a Medicaid patient is more common among community residents than among nursing home residents. Implications of findings for health care policies are discussed.

Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation.

The effects of various mu and kappa opioid agonists were evaluated in three squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation before, during and after a regimen of chronic morphine administration. Initially, dose-effect curves for the mu opioid agonists morphine and l-methadone, the kappa opioid agonists U50,488 and tifluadom, the mixed mu/kappa opioid agonist ethylketocyclazocine, and the non-opioid compound pentobarbital were determined in non-tolerant squirrel monkeys. Subsequently, monkeys were administered up to 3.0 mg/kg of morphine twice daily for 8-9 weeks, which resulted in a 1/2 to 3/4 log unit shift to the right of the morphine dose-effect curve relative to its prechronic position. During the chronic morphine regimen, the l-methadone dose-effect curve shifted to the right approximately 3/4 log unit, while the U50,488 and pentobarbital dose-effect curves did not change. In contrast, the ethylketocyclazocine and tifluadom dose-effect curves shifted to the left approximately 1/4 and 3/4 log unit, respectively. The lack of cross-tolerance between mu and kappa agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of mu and kappa agonists. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with kappa agonist activity during the regimen of chronic morphine administration suggests that morphine tolerance modulates their