Treatment advances for cocaine-induced ischemic stroke: focus on dihydropyridine-class calcium channel antagonists.

OBJECTIVE: The authors reviewed the pathogenesis of cocaine-related cerebral ischemia, appraised current knowledge of its sequelae, and assessed the role of putative therapeutic agents, particularly dihydropyridine-class calcium channel antagonists. METHOD: The authors performed an OVID-based literature review of all indexed journals between 1966 and 2000. RESULTS: Cocaine abuse significantly increases the risk of ischemic stroke. The principal mechanism of cocaine-induced cerebral ischemia is vasospasm of large cranial arteries or within the cortical microvasculature. Increased levels of extracellular monoamines, particularly dopamine, mediate vasospasm. Neuroanatomical and labeling studies also have shown that dopamine-innervated neurons may regulate cerebral blood flow. Indeed, dopamine-rich brain regions appear to be relatively specific targets for cocaine-induced cerebral ischemia. Neuroimaging studies show that cocaine-induced hypoperfusion can persist even after 6 months of abstinence. Hypoperfusion can result in deficits on complex and simple psychomotor tasks but perhaps not on memory or attention. Severe cerebral ischemia can directly precipitate neuronal death and degradation, a condition exacerbated by liberation of the excitatory amino acid glutamate. Dihydropyridine-class calcium channel antagonists inhibit cocaine-mediated dopamine release on neurons involved in vasospasm and the control of cortical circulation. Other causes of cerebral ischemia include thrombogenesis and vasculitis. Although antithrombotic agents have potential in alleviating cocaine's neurotoxic effects, their use may be limited by the risk of spontaneous hemorrhage. CONCLUSIONS: Cocaine abuse can result in stroke, neuroischemia, and cognitive deficits that can persist even after prolonged abstinence. Dihydropyridine-class calcium channel antagonists, such as isradipine, show promise as therapeutic agents for preventing cocaine-induced cerebral ischemia.

Combining ondansetron and naltrexone treats biological alcoholics: corroboration of self-reported drinking by serum carbohydrate deficient transferrin, a biomarker.

BACKGROUND: Recently, we showed by using self-report that combining ondansetron (4 microg/kg twice a day) and naltrexone (25 mg twice a day) was effective at reducing drinking and increasing abstinence among early-onset alcoholics (EOAs), who are characterized by a range of antisocial behaviors and high biological and familial disease predisposition. Here, we investigated whether the self-reported differences in drinking would be corroborated by measurements of serum carbohydrate-deficient transferrin (CDT) level, a sensitive, reliable, and well-validated marker of transient alcohol consumption. METHOD: An 8-week double-blind clinical trial was performed in which 20 EOAs were randomized to receive ondansetron (4 microg/kg twice a day) and naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized cognitive behavioral therapy. Serum CDT was assessed at weeks 0 (baseline), 4, and 8. RESULTS: Log serum CDT was significantly lower in the ondansetron and naltrexone group (group mean, 1.44 +/- 0.076) compared with the placebo group (group mean, 1.82 +/- 0.113), as evidenced by a main effect of group [F(1,15) = 7.2, p = 0.017; effect size = 0.32], visit [F(1,16) = 11.2, p = 0.004; effect size = 0.41], and an interaction between group and visit [F(1,16) = 27.54, p < 0.001; effect size = 0.63]. CONCLUSIONS: The combination of ondansetron plus naltrexone was superior to placebo at reducing serum CDT. This corroborated our self-reported drinking data and demonstrated that the medication combination is an effective treatment for EOAs.

Combining ondansetron and naltrexone reduces craving among biologically predisposed alcoholics: preliminary clinical evidence.

RATIONALE: Previously, we have reported that the combination of ondansetron (a 5-HT3 antagonist) and naltrexone (a mu opioid antagonist) appears to act synergistically at improving the drinking outcomes of early onset alcoholics (EOA). a subtype of alcoholic characterized by developing problem-drinking earlier, antisocial behaviors, high familial loading, and biological disease predisposition. Presumably, this medication combination counteracts the interaction between activated central 5-HT3 receptors and the endogenous opioid system during the mediation of alcohol-induced reward. We now hypothesize further that an important mechanism by which the combination diminishes alcohol consumption is through a reduction in craving. OBJECTIVE: To determine whether the combination of naltrexone and ondansetron is superior to a placebo at reducing craving among EOA, and the relationship between craving and drinking behavior in both treatment groups. METHODS: We conducted an 8-week double-blind placebo-controlled clinical trial in which 10 EOA were randomized to receive ondansetron (4 microg/kg b.i.d.) + naltrexone (25 mg b.i.d.) and 10 EOA had a placebo (total n=20) as an adjunct to weekly standardized group cognitive behavioral therapy. Craving was measured by using the obsessive compulsive drinking scale (OCDS). RESULTS: Craving ratings were scored on four subscales which where derived empirically by principal component structure analysis of the OCDS. EOA who received the medication combination, compared with the placebo, had significantly lower scores on "automaticity of drinking" and "alcohol consumption ". Reduction in automaticity of drinking was correlated with self-reported drinking for only the medication combination group. CONCLUSIONS: By reducing automaticity of drinking, the medication combination presumably decreased drinking salience and intensity. Larger scale studies testing these medications, both alone and together, among alcoholic subtypes are needed to establish and extend these promising findings.

Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: A randomized controlled trial.

CONTEXT: Early-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent. OBJECTIVE: To test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT(3) (serotonin) antagonist ondansetron. DESIGN: Double-blind, randomized, placebo-controlled clinical trial. SETTINGS: University of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999). PARTICIPANTS: A total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization. INTERVENTIONS: After 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 microg/kg (n = 67), 4 microg/kg (n = 77), or 16 microg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy. MAIN OUTCOME MEASURES: Self-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption. RESULTS: Patients with early-onset alcoholism who received ondansetron (1, 4, and 16 microg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P =.03, P =.01, and P =.02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P =.03, P =.004, and P =.03, respectively). Ondansetron, 4 microg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P =.02) and total days abstinent per study week (6.74 vs 5.92; P =.03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 microg/kg twice per day) compared with those who received the placebo (-0.17 and -0.19 vs 0.12; P =.03 and P =.01, respectively). CONCLUSION: Our results suggest that ondansetron (particularly the 4 microg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality. JAMA. 2000;284:963-971

Combining ondansetron and naltrexone effectively treats biologically predisposed alcoholics: from hypotheses to preliminary clinical evidence.

BACKGROUND: Individuals considered to be early onset alcoholics (EOA) are characterized by an early onset age, a broad range of antisocial behaviors, high familial loading, and presumed biological disease predisposition. Ondansetron, a 5-HT3 antagonist, improves drinking outcomes and increases abstinence rates among EOA. Individuals with high familial loading for developing alcoholism have lower levels of beta-endorphin and demonstrate a more pronounced increase in beta-endorphin levels in response to alcohol administration compared with individuals who do not have alcoholic relatives. The propensity for naltrexone (a mu opioid antagonist) to reduce alcohol's rewarding effects and drinking in humans is greatest in individuals with high familial loading. Predicated on the added knowledge that 5-HT3 receptors may themselves mediate alcohol reward via activation of the endogenous opioid system, we hypothesized that the combination of ondansetron and naltrexone would act synergistically and would be an effective treatment in EOA. METHODS: We conducted an 8-week double-blind placebo controlled clinical trial in which 20 EOA were randomized to receive ondansetron (4 microg/kg twice a day) + naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized group Cognitive Behavioral Therapy. RESULTS: At endpoint, subjects who received ondansetron + naltrexone (n = 10), compared with those who received placebo (n = 10), had fewer drinks/day (covariate adjusted mean 0.99 +/- 0.60 vs. 3.68 +/- 0.63; F1, 16 = 9.35,p = 0.008; effect size = 1.42), drinks/drinking day (covariate adjusted mean 3.14 +/- 0.87 vs. 6.76 +/- 0.71; F1, 13 = 10.45, p = 0.007; effect size = 1.71), and a trend toward increased percent days abstinent (covariate adjusted mean 69.76 +/- 8.64 vs. 48.24 +/- 9.12; F1, 16 = 3.58, p = 0.08; effect size = 0.88). CONCLUSIONS: Ondansetron plus naltrexone seems to synergistically improve the drinking outcomes of EOA. Larger scale studies that test these medications, both alone and together, among various alcoholic subtypes are needed to establish and extend these promising findings.

Neuropharmacological treatments for alcoholism: scientific basis and clinical findings.

Preclinical studies have exploded our knowledge about the behavioral and biological underpinnings of alcoholism. These studies suggest that certain neurotransmitters, particularly those interacting with the opioid, N-methyl-D-aspartate, and monoamine systems, may play a critical role in the expression of alcohol-drinking and other behaviors associated with its abuse liability. Built upon this foundation, important advances have been made in the development of therapeutic medications for the treatment of alcoholism. Of the medications reviewed, acamprosate's potential appears to be the most widely established. In the USA, naltrexone was approved by the Food and Drug Administration in 1995 for the treatment of alcoholism; however, the results of some studies have been less encouraging. Naltrexone's reliance on high compliance rates for efficacy may, eventually, limit its potential in clinical settings offering generic treatment for alcoholism. The relative paucity of dose-response studies on naltrexone's effects in treating alcoholics is an important gap in the literature. Recent data from a large clinical trial suggests that ondansetron, a serotonin3 antagonist, offers new hope for the treatment of early onset alcoholics; a type of alcoholism most difficult to manage with psychosocial measures alone. Different subtypes of alcoholic may, therefore, have varying treatment responses to serotonergic agents. Matching subtypes of alcoholic to effective treatment medications based upon their different biologies remains an important therapeutic goal. Combinations of effective pharmacological agents need exploration as they may prove to be synergistic, and could shepherd in a new era of treatments aimed at multiple neurotransmitter targets associated with the alcoholism disease. The coming decade promises more powerful tools for characterizing drug effects on alcohol drinking, thereby closing the gap between animal models of addiction and the human condition.

Effects of isradipine, a dihydropyridine-class calcium channel antagonist, on D-methamphetamine-induced cognitive and physiological changes in humans.

D-methamphetamine is abused for its euphoric effects and stimulatory action on cognitive function. Its abuse can, however, be associated with massive hypertension resulting in strokes, ruptured aneurysms, or myocardial infarction. We examined the utility of isradipine, a dihydropyridine-class calcium channel antagonist, in treating d-methamphetamine induced hypertension and evaluated its effects on cognitive function, both of which are mediated by dopaminergic mechanisms. D-methamphetamine dose-dependently increased all vital signs (systolic, diastolic, and mean arterial pressure, and pulse rate) parameters. Isradipine significantly reduced d-methamphetamine-induced increases in diastolic and mean arterial pressure; however, this potentially beneficial therapeutic effect was offset by a significant reflex rise in pulse rate. D-methamphetamine also improved attention, accuracy of reasoning ability, and performance on computerized cognitive function tasks. D-methamphetamine's cognitive improving effects were not altered significantly by isradipine. Isradipine increased the false responding rate but was without significant effect on any other attentional task, or on reasoning ability, or performance. Isradipine does not appear to enhance cognitive function in healthy humans.

Effects of isradipine, a dihydropyridine-class calcium channel antagonist, on d-methamphetamine-induced reduction in hunger.

1. The authors studied the effects of isradipine, a dihydropyridine-class calcium channel antagonist, on d-methamphetamine-induced changes in somatic and psychological perceptions of hunger state using a placebo-controlled, double-blind, Latin Square, cross-over design in 18 healthy volunteers. 2. D-methamphetamine significantly decreased these subjective ratings of hunger, presumably by increasing monoaminergic turnover. 3. Effects on hunger are hypothesized to be mediated by norepinephrine primarily, while dopamine plays only a modest role. Isradipine alone, an inhibitor of dopamine release, had no significant effect on the hunger measures. Additionally, isradipine pretreatment did not significantly alter d-methamphetamine's anorexic effects. 4. Isradipine may, therefore, not significantly modify the control of hunger in humans.

Isradipine, a dihydropyridine-class calcium channel antagonist, attenuates some of d-methamphetamine's positive subjective effects: a preliminary study.

RATIONALE: Dopamine (DA) pathways in the midbrain mediate d-methamphetamine's rewarding effects associated with its abuse liability. Isradipine, a dihydropyridine-class calcium channel antagonist, reduces the rewarding effects of psychostimulants such as cocaine and d-amphetamine, presumably by antagonizing these central DA pathways. This is the first experiment to test the hypothesis that the rewarding effects of d-methamphetamine, like other psychostimulants, can be reduced by isradipine. OBJECTIVE: We studied the effects of high dose isradipine (0.21 mg/kg orally), on the positive subjective effects associated with the abuse liability of low and high dose d-methamphetamine (0.21 mg/kg and 0.42 mg/kg orally, respectively). METHODS: Using a double-blind, double-dummy, placebo-controlled, Latin-Square, cross-over design, 18 healthy male and female volunteers received each of the following six treatments separated by a rest period of 2-7 days: a) placebo+placebo; b) low-dose d-methamphetamine+placebo); c) high-dose d-methamphetamine+placebo; d) high dose isradipine+placebo); e) low-dose d-methamphetamine+high dose isradipine, and f) high-dose d-methamphetamine+high dose isradipine. RESULTS: d-Methamphetamine produced orderly increases in positive subjective measures of both stimulation and mood. Pre-treatment with isradipine significantly reduced some of these positive subjective effects and craving for d-methamphetamine. CONCLUSION: Isradipine as an anti-reward or craving reducing medication is a promising therapeutic agent for the treatment of d-methamphetamine dependence.

Medications to treat alcoholism.

Advances in neurobiology support the development of medications to treat alcoholism by modifying the activity of specific chemical messengers (i.e., neurotransmitters) in the brain. Among the most promising new medications is acamprosate, which appears to decrease the intensity of craving after a person has stopped drinking. Naltrexone (ReVia) has been shown to decrease alcohol consumption, although its practical effectiveness may be compromised by poor patient compliance and other factors. Ondansetron shows promise for decreasing drinking and increasing abstinence rates among early onset alcoholics, who respond poorly to psychosocial treatment alone. Researchers are investigating whether the use of specific medications in combination can further enhance their effectiveness. Additional research is needed to determine how medications interact with different psychosocial factors and treatments.