A controlled trial of naltrexone in obese humans

Based on reports that opiate antagonists can curtail short-term eating in several species including humans, the efficacy of naltrexone in promoting weight loss by obese subjects was examined. Naltrexone, a long-acting oral opiate antagonist, was studied in a randomized parallel double-blind placebo controlled ten week trial in 27 females and 14 males who were 30-100 percent overweight. Subjects on naltrexone lost an average of 1.8 kg and placebo subjects lost 1.5 kg, with no significant difference between groups. Three subjects who took naltrexone had elevations of liver transaminases, two times higher than normal. In the present study naltrexone at a daily dosage of 200 mg did not appear to have efficacy in producing weight loss after eight weeks of treatment. Studies of the effects of naltrexone at higher dosage or for longer periods should monitor hepatic function.     

Interactions Between Alcohol- and Opioid-Induced Suppression of Rat Testicular Steroidogenesis In Vivo

To examine interactions between alcohol and endogenous opioids in their suppressive effects on rat testicular function, the opioid antagonist naltrexone or the opioid agonist morphine was administered to adult male rats alone or in combination with alcohol. Serum testosterone, testicular interstitial fluid (TIF) testosterone, and TIF volumes were measured to assess testicular function. Naltrexone induced dose-dependent increases in serum and TIF testosterone levels without changes in TIF volume. Alcohol (0.5 g/kg) inhibited naltrex-one-induced stimulation of testosterone secretion and shifted the naltrexone dose-response curve to the right. Conversely, naltrexone (0.05 mg/kg) inhibited alcohol-induced suppression of testosterone secretion and shifted the alcohol dose-response curve to the right. Relatively high doses of naltrexone (5 to 30 mg/kg) were needed to stimulate testosterone secretion maximally in rats treated with a low dose of alcohol (0.5 g/kg) and to stimulate normal levels of testosterone secretion in rats treated with a high dose of alcohol (2 g/kg). In addition, combined treatment with 1 and 30 mg/kg of naltrexone and 0.5 to 2 g/kg of alcohol did not alter blood alcohol concentrations significantly, suggesting that the interactions between alcohol and naltrexone were unrelated to gross changes in alcohol metabolism or bioavailability factors. Simultaneous treatments with a low dose of alcohol (0.3 g/kg), near the threshold of efficacy, and low-moderate doses of morphine (0.3 to 3 mg/kg) were not additive in suppressing testosterone secretion, compared with either agent alone. These results support the hypothesis that opioid antagonists can reverse the suppressive effect of alcohol on testicular steroidogenesis, but the results also suggest that endogenous opioids do not exclusively mediate alcohol's effects on testosterone secretion.     

Serum 6-beta-naltrexol levels are related to alcohol responses in heavy drinkers

BACKGROUND: There is strong evidence for the role of the endogenous opioid system in alcohol reinforcement and consumption; however, recent human laboratory studies and clinical trials have reported mixed effects of naltrexone (a nonselective opioid antagonist) on alcohol-related behaviors. This paper reports a secondary data analysis of a human laboratory study that examines the relationship between serum levels of 6-beta-naltrexol, the major, biologically active metabolite of naltrexone, and subjective effects of alcohol. METHODS: The study used a within-subjects design to examine the effects of naltrexone (0, 50, and 100 mg/day) on subjective responses to alcohol (none, moderate, and high dose) in heavy drinkers (n = 23). Each subject received three doses of naltrexone in random order; each naltrexone dose was administered over an 8 day period on an inpatient unit, with a 1 week outpatient washout between doses. After stabilization at each of the naltrexone doses, subjects participated in three alcohol challenge sessions (none, moderate, and high dose) in random order; thus, each subject participated in a total of nine alcohol administration sessions. RESULTS: Doubling the naltrexone dose (50 vs. 100 mg/day) doubled the mean serum 6-beta-naltrexol levels. At each naltrexone dose, there was a 4-fold range in 6-beta-naltrexol levels across subjects. Before alcohol administration, higher 6-beta-naltrexol levels were associated with higher ratings of sedation. After high-dose alcohol administration, higher 6-beta-naltrexol levels were associated with significantly lower ratings of liking and best effects. CONCLUSIONS: These findings provide further evidence of the involvement of the opioid system in the modulation of alcohol effects and suggest that serum 6-beta-naltrexol concentrations may be important in predicting therapeutic response to naltrexone.     

Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin.

AIMS: This double-blind, parallel-group study was conducted to assess the pharmacodynamics, pharmacokinetics, and safety of AZD6140, the first oral, reversible adenosine diphosphate (ADP) receptor antagonist. METHODS AND RESULTS: Patients (n = 200) with atherosclerosis were randomized to receive AZD6140 50, 100, or 200 mg twice daily (bid) or 400 mg daily (qd) or clopidogrel 75 mg qd for 28 days. All groups received aspirin 75-100 mg qd. AZD6140 (100 and 200 mg bid, 400 mg qd) rapidly and nearly completely inhibited ADP-induced platelet aggregation after initial dosing (day 1) and at day 28. On day 1, peak final-extent inhibition of platelet aggregation (IPA) was observed 2-4 h post-dose with AZD6140, whereas clopidogrel minimally inhibited platelet aggregation (mean percentage IPA < 20%, all time points). Four hour post-dose at steady state, the three higher doses of AZD6140 produced comparable final-extent mean percentage IPA (approximately 90-95%), which exceeded that with AZD6140 50 mg bid or clopidogrel (approximately 60%). AZD6140 was generally well tolerated. All bleeding events, except one in a patient receiving 400 mg qd, were minor and of mild-to-moderate severity. CONCLUSION: AZD6140 100 and 200 mg bid were well tolerated and were superior to AZD6140 50 mg bid and clopidogrel 75 mg qd with regard to antiplatelet efficacy.     

Evaluation of tamoxifen dose in advanced breast cancer: a progress report.

The results of an ongoing trial randomizing patients with progressive, metastatic breast carcinoma between tamoxifen (Tam, NSC-180973) and Tam plus fluoxymesterone (Flu) (7 mg/m2 bid) are reported. Each patient received a single dose level of Tam in the range of 2-100 mg/m2 bid. The combination had a higher response rate overall (45% vs 28%) and when only the patients' soft tissue sites were analyzed (54% vs 9%, P=0.04). The time to treatment failure was longer for the combination among those patients with a response or disease stabilization (P=0.08). Response rates with Tam doses less than 12 mg/m2 bid were also higher than with doses greater than or equal to 12 mg/m2 for all patients in the study (62% vs 30%, P=0.025) and for those where only soft tissue sites were evaluable (43% vs 29%, P=0.07). Side effects were mild and consisted primarily of transient hematologic suppression, nausea, masculinization, hepatic enzyme elevations, and edema. The latter three were observed only with the Flu regimen. Leukopenia and thrombocytopenia were more frequent at Tam doses less than 12 mg/m2 bid whereas nausea was more common at higher doses. Tam doses as high as 100 mg/m2 bid were well tolerated. Tam amy be more effective at low doses, has only mild side effects, and is well tolerated at doses up to 100 mg/m2 bid. Combining Tam with Flu appears to enhance the therapeutic effectiveness.     

A Double-Blind, Placebo-Controlled, 6-Day Evaluation of Two Doses of Misoprostol in Gastroduodenal Mucosal Protection against Damage from Aspirin and Effect on Bowel Habits

Ninety-one normal, healthy volunteers participated in a single-center, double-blind, placebo-controlled, randomized, parallel group study: 1) to compare the prostaglandin E1 analog, misoprostol, given at a dose of 200 micrograms bid, with the recommended dose of 200 micrograms qid in protecting the gastroduodenal mucosa against injury due to anti-inflammatory doses of aspirin (3900 mg/day); and 2) to determine whether the reduced dose was associated with a lesser incidence of gastrointestinal (GI) side effects, particularly diarrhea. All subjects received 975 mg of aspirin qid with meals and at bedtime. They were concurrently administered either misoprostol 200 micrograms qid, misoprostol 200 micrograms bid and placebo bid, or placebo qid. All subjects were endoscopically normal at the onset of the study and were re-endoscoped on the morning of the 7th day of therapy, 2 h after the morning dose of medications. Gastric and duodenal mucosa were assessed separately on a 0-7 scale which gave a greater weight to erosions than to hemorrhages. GI symptoms, especially bowel habits, were assessed by means of diary cards. Subjects in both misoprostol groups had significantly less gastric and duodenal mucosal injury than subjects who received placebo (p less than 0.007 for each pairwise comparison). There was no statistically significant difference between the two misoprostol groups (p less than 0.093). Subjects in the misoprostol 200 micrograms qid group had significantly more loose and watery bowel movements than the subjects in the misoprostol 200 micrograms bid group (p less than 0.013), whereas there were no significant differences in bowel habits between the misoprostol 200 micrograms bid and placebo groups (p less than 0.122). More subjects in the misoprostol 200 micrograms qid group reported abdominal pain, loose stools, watery stools, flatulence, dyspepsia, and nausea than in the misoprostol 200 micrograms bid and placebo groups. In conclusion, the adverse events in the misoprostol 200 micrograms bid group were not significantly different from those in the placebo group, and were significantly better than in the misoprostol 200 micrograms qid group. The lower dose retained mucosal protective activity that was statistically indistinguishable from that of misoprostol 200 micrograms qid.     

Hepatotoxicity associated with antiretroviral therapy containing HIV-1 protease inhibitors

Human immunodeficiency virus 1 (HIV-1) protease inhibitors are important components of highly active antiretroviral therapy and have had a profound impact on the natural history of HIV and AIDS. However, in the era of highly active antiretroviral therapy (HAART), drug-induced hepatotoxicity or liver injury has emerged as an important potential complication of combination antiretroviral therapy, particularly those regimens containing protease inhibitors (PIs). Liver injury has been associated each of the six PIs currently approved by the U. S. Food and Drug Administration (FDA), most commonly with administration of full dose ritonavir (600 mg bid or 400 mg bid with saquinavir). However, this regimen has been largely replaced by the use of low-dose ritonavir (相似文献   

Hepatic safety of once-monthly injectable extended-release naltrexone administered to actively drinking alcoholics

Background:  Hepatoxicity has been reported with oral naltrexone. Hepatic safety data were examined from a 6-month study evaluating the efficacy and safety of a now available extended-release formulation of naltrexone (XR-NTX) in patients with alcohol dependence.
Methods:  In all, 624 patients (68% male; median age of 44 years) were randomly assigned to XR-NTX 380 mg ( n  = 205), XR-NTX 190 mg ( n  = 210), or placebo ( n  = 209).
Results:  There were no significant differences in alanine aminotrasferase, aspartate aminotransferase, or bilirubin levels between the study groups at study initiation or at subsequent assessments. Gamma-glutamyltransferase in the XR-NTX 380 mg group was lower compared with placebo at weeks 4, 8, 12, and 20. Both high (>3 times the upper limit of normal) liver chemistry tests (LCTs) and hepatic-related adverse events were infrequent in all study groups. In patients who were drinking heavily throughout the study, obese subjects, or those taking nonsteroidal anti-inflammatory drugs, there was no increase in frequency of high LCTs or hepatic-related adverse events in patients receiving XR-NTX (either dose) compared with placebo.
Conclusion:  Extended-release formulation of naltrexone does not appear to be hepatotoxic when taken at the recommended clinical doses in actively drinking alcohol-dependent patients.     

Evaluation of the pharmacokinetics and pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers

The results of two independent, randomized, two-period crossover, single-center studies, conducted to assess the pharmacokinetics of ticagrelor?±?aspirin, inhibition of platelet aggregation (IPA) with ticagrelor/aspirin vs. clopidogrel/aspirin, and safety, tolerability, and bleeding times are reported here. In Study A (open-label), 16 volunteers received ticagrelor (50?mg bid Days 1–5; 200?mg bid Days 6–9; one 200?mg dose on Day 10)?±?300?mg qd aspirin (Days 1–10). In Study B (double-blind, double-dummy), 16 volunteers received aspirin (300?mg loading dose/75?mg qd Days 2–9) with either ticagrelor (200?mg bid Days 4–8, one 200?mg dose on Day 9) or clopidogrel (300?mg loading dose Day 4, 75?mg qd Days 5–9). At steady-state ticagrelor (50?mg bid, or 200?mg bid), concomitant aspirin (300?mg qd) had no effect on mean maximum plasma concentration (C_max), median time to C_max (t_max), or mean area under the plasma concentration-time curve for the dosing interval (AUC_0–τ) for ticagrelor and its primary metabolite, AR-C124910XX. Following 200?mg bid ticagrelor, mean C_max and AUC_0–τ for both parent and metabolite were comparable with co-administration of aspirin at 75?mg and 300?mg qd. Aspirin (300?mg qd) had no effect on IPA (ADP-induced) by ticagrelor. However, aspirin and ticagrelor had an additive effect on IPA (collagen-induced). Ticagrelor/aspirin increased bleeding times vs. baseline. Ticagrelor/aspirin co-administration was well tolerated at all dose combinations evaluated. In summary, the findings of this study demonstrate that co-administration of aspirin (300?mg qd) with ticagrelor (50?mg bid, or 200?mg bid) had no effect on ticagrelor pharmacokinetics or IPA (ADP-induced) by ticagrelor.     

Naltrexone and cognitive behavioral coping skills therapy for the treatment of alcohol drinking and eating disorder features in alcohol-dependent women: a randomized controlled trial

BACKGROUND: Despite important gender differences in drinking patterns, physiological effects of alcohol, and co-occurring psychiatric conditions, relatively little is known about the efficacy of naltrexone for the treatment of alcohol dependence in women. This study investigated the safety and efficacy of naltrexone in combination with Cognitive Behavioral Coping Skills Therapy (CBCST) in a sample of alcohol-dependent women, some with comorbid eating pathology. METHODS: One hundred three women meeting DSM-IV criteria for alcohol dependence (29 with comorbid eating disturbances) were randomized to receive either naltrexone 50 mg or placebo for 12 weeks in addition to weekly group CBCST. Subjects were enrolled between October 1995 and December 2000 at an outpatient research clinic. RESULTS: No significant differences were observed on the primary outcomes of time to first drinking day, time to first day of heavy drinking, or the percentage of participants who continued to meet the criteria for alcohol dependence. Secondary analyses revealed that naltrexone significantly delayed the time to the second (chi2=5.37, p=0.02) and third (chi2=4.35, p=0.04) drinking days among subjects who did not maintain abstinence from alcohol. Among those with eating disturbances, symptoms of eating pathology improved during treatment, but the effects did not differ according to medication condition. CONCLUSION: When used in conjunction with CBCST, naltrexone did not significantly improve drinking outcomes in the overall sample of alcohol-dependent women. However, naltrexone may be of benefit to women who are unable to maintain total abstinence from alcohol. For women with concurrent eating pathology, participation in treatment for alcoholism may be associated with improvements in eating pathology.     

Endogenous opioids modulate hepatocyte apoptosis in a rat model of chronic cholestasis: the role of oxidative stress.

AIMS/BACKGROUND: There are increasing number of evidences indicating the contribution of endogenous opioids in the pathophysiology of cholestatic liver disease. The aim of the present study was to determine the role of the endogenous-opioid system in the modulation of hepatocytes apoptosis and liver oxidant/anti-oxidant balance during chronic cholestasis in rats. METHODS: We induced cholestasis in rats by bile duct ligation (BDL). Naltrexone, an opioid antagonist, was administered at different doses (2.5, 5, 10, 20 and 40 mg/kg/day) to cholestatic animals for 5 weeks. RESULTS: Naltrexone prevented the cholestasis-induced decrease of hepatic glutathione levels at higher doses (20 and 40 mg/kg/day). In the next phase of the study, we evaluated the effects of 20 mg/kg/day naltrexone treatment on hepatic damage indices and liver oxidant/anti-oxidant balance in 5-week BDL rats. There was a marked increase in the number of apoptotic hepatocytes as well as serum liver enzymes and hepatic lipid peroxidation levels in cholestatic rats compared with sham-operated animals 5 weeks after the operation. Liver anti-oxidant enzyme activities were significantly reduced in cholestatic rats compared with controls. Chronic treatment with naltrexone significantly improved all the aforementioned indices in comparison with saline-treated cholestatic rats. CONCLUSION: Our findings demonstrate that the administration of opioid antagonist is protective against hepatic damage in a rat model of chronic cholestasis. We suggest that increased levels of endogenous opioids contribute to hepatocytes apoptosis in cholestasis, possibly through downregulation of liver anti-oxidant defense.     

以雷贝拉唑与加替沙星为基础的三联疗法治疗幽门螺杆菌感染的疗效观察

目的 研究以雷贝拉唑与加替沙星为基础的三联疗法根除幽门螺杆菌(Hp)的疗效、不良反应和药品的费用,以探讨临床更佳的根除Hp方案.方法 选择符合条件的300例患者,随机分为A、B、C 3组.A组:雷贝拉唑10mg bid,甲磺酸加替沙星200 mg bid,甲硝唑100 mg tid.B组:雷贝拉唑10 mg bid,甲磺酸加替沙星200 mg bid,阿莫西林500 mg tid.C组(对照组):雷贝拉唑10 mg bid,甲硝唑100 mg tid,阿莫西林500 mg tid.以上3组疗程均为2周.停药4周后复查胃镜或14C-UBT.结果 A组、B组、C组Hp根除率分别为91%、92%及87%,3组相比,差异无统计学意义(P＞0.05),未见发生严重不良反应者,A、B、C 3组的治疗费用分别为200.13元、210.76元和149.60元.结论 以雷贝拉唑与加替沙星为基础的三联疗法能有效、安全地根除Hp且能节省费用.     

Effects of ranolazine on exercise tolerance and angina frequency in patients with severe chronic angina receiving maximally-tolerated background therapy: analysis from the Combination Assessment of Ranolazine In Stable Angina (CARISA) randomized trial

Background: Ranolazine has been previously shown to improve exercise capacity and symptoms in patients with severe chronic angina treated with standard doses of beta-blockers and calcium-channel blockers, without a significant effect on heart rate or blood pressure. Objective: The purpose of this study was to assess whether the benefit of ranolazine extends to the subgroup of angina patients treated with maximally-tolerated doses of beta-blockers or calcium blockers. Methods and results: In this post-hoc analysis, 258 patients from the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial were considered as treated with maximally-tolerated doses of beta-blockers or calcium-channel blockers (systolic blood pressure (SBP) ≤100?mm?Hg, and/or a resting heart rate ≤60 beats per minute, and/or an ECG PR interval ≥200?msec). Change from baseline in total exercise duration after 12 weeks compared to placebo were 34.5 (95% CI 0.8; 68.1) sec (p?=?0.045) with ranolazine (750/1000?mg bid) at trough drug levels and 46.3 (13.5; 79.1) (p?=?0.006) at peak drug levels. The number of angina attacks per week compared to baseline were reduced compared to placebo (-2.3?±?0.3 vs -0.9?±?0.6 (p?相似文献   

Elevation of pentylenetetrazole-induced seizure threshold in cholestatic mice: Interaction between opioid and cannabinoid systems

Background and Aim:  Several studies have reported that endogenous opioid and cannabinoid systems may be involved in some pathophysiological changes occurring in cholestatic liver disease. It is well known that endogenous opioids and cannabinoids alter the susceptibility of experimental animals to different models of seizure.
Methods:  The alterations in pentylenetetrazole-induced clonic seizure thresholds were evaluated from 1 to 6 days after bile duct ligation in mice. Whether the pretreatment of cholestatic mice with different doses of opioid receptor antagonist naltrexone or cannabinoid CB₁ receptor antagonist AM251 (AM251) would have changed the clonic seizure threshold was also examined.
Results:  Although the clonic seizure threshold was similar between sham-operated and unoperated mice, there was a time-dependent increase in the threshold in cholestatic mice, reaching a peak on day 3 after bile duct ligation and declining partially after day 4. Chronic pretreatment with naltrexone (2, 5, and 10 mg/kg) reversed the increased threshold in cholestatic mice on day 3 after operation in a dose-dependent manner with the highest doses used restoring the threshold to that of the control animals. A similar reversal of the increased threshold was observed after acute (0.5, 0.75, and 1 mg/kg) or chronic (0.5 mg/kg for 4 days) pretreatment with AM251. Moreover, concurrent administration of doses of AM251 and naltrexone that each separately induced a partial reversal of increased seizure threshold in cholestasis caused a complete restoring of the threshold to the control level.
Conclusions:  Both opioid and cannabinoid CB₁ receptors may be involved in the dramatic increase in pentylenetetrazole-induced seizure threshold in cholestasis.     

Pharmacologic Dissociation Between Impulsivity and Alcohol Drinking in High Alcohol Preferring Mice

Background: Impulsivity is genetically correlated with, and precedes, addictive behaviors and alcoholism. If impulsivity or attention is causally related to addiction, certain pharmacological manipulations of impulsivity and/or attention may affect alcohol drinking, and vice versa. The current studies were designed to explore the relationship among impulsivity, drinking, and vigilance in selectively bred High Alcohol Preferring (HAP) mice, a line that has previously demonstrated both high impulsivity and high alcohol consumption. Amphetamine, naltrexone, and memantine were tested in a delay discounting (DD) task for their effects on impulsivity and vigilance. The same drugs and doses were also assessed for effects on alcohol drinking in a 2‐bottle choice test. Methods: HAP mice were subjected to a modified version of adjusting amount DD using 0.5‐second and 10‐second delays to detect decreases and increases, respectively, in impulsive responding. In 2 experiments, mice were given amphetamine (0.4, 0.8, or 1.2 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) before DD testing. Another pair of studies used scheduled access, 2‐bottle choice drinking to assess effects of amphetamine (0.4, 1.2, or 3.0 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) on alcohol consumption. Results: Amphetamine dose‐dependently reduced impulsivity and vigilance decrement in DD, but similar doses left alcohol drinking unaffected. Naltrexone and memantine decreased alcohol intake at doses that did not affect water drinking but had no effects on impulsivity or vigilance decrement in the DD task. Conclusions: Contrary to our hypothesis, none of the drugs tested here, while effective on either alcohol drinking or impulsivity, decreased both behaviors. These findings suggest that the genetic association between drinking and impulsivity observed in this population is mediated by mechanisms other than those targeted by the drugs tested in these studies.     

Clinical Utility of Rapid Clonidine-naltrcxone Detoxification for Opioid Abusers

Clonidine hydrochloride (an alpha-2 adrenergic agonist) and naltrexone hydrochloride (an opioid antagonist), given in combination, provide a safe and effective treatment of abrupt opioid withdrawal over 4 or 5 days in an outpatient/day setting. Following a naloxone challenge test to verify and quantify opioid dependence, 14 of 17 (82%) heroin users successfully withdrew from opioids and attained maintenance levels of naltrexone. Eight of 9 (89%) successfully completed the 4-day study in which naltrexone therapy was begun on day I. Three to 5 days of clonidine hydrochloride treatment with a peak mean dose of 0.6 mg/day on day 2 for the patients in the S-day study, and 0.5 mg on days 1 and 2 for patients in the 4-day study, attenuated the withdrawal inducing effects of naltrexone. Both groups received naltrexone in single morning doses which were rapidly increased from 12.5 mg on the first day of naltrexone therapy to SO mg on the third day. Clonidine significantly decreased blood pressure in both groups without producing clinical problems. This study has improved the availability of the clonidine-naltrexone combination by developing a single dose per day naltrexone regimen with naltrexone doses generally available to any opioid treatment facility.     

Sarpogrelate, a 5-hT2A receptor antagonist in intermittent claudication. A phase II European study

This was a multinational, multicentre, double-blind Phase II study in Europe to evaluate the efficacy and safety of two dose regimens (200 mg bid and 200 mg tid) of sarpogrelate (MCI-9042, 5-HT2A receptor antagonist) compared to placebo in patients with stable, moderately severe intermittent claudication. Following a single-blind placebo run-in period of 6 weeks, 364 (309 male and 55 female) patients (59.2 +/- 8.4 years, mean +/- SD) were randomized to receive sarpogrelate 200 mg bid, 200 mg tid or placebo for 24 weeks with a follow-up of 8 weeks. The primary objective was the increase of absolute claudication distance (ACD) at the end of treatment (week 24) compared to placebo. Analysis of covariance (ANCOVA) was performed on the log-transformed percentage of baseline ACD: loge(ACD/baseline). A responder analysis (defined as a > or = 50% improvement in ACD) was also performed. There was a marked training/placebo effect on the ACD which persisted up to 16 weeks. At 24 weeks the primary objective did not reach statistical significance (200mg bid vs placebo, p = 0.225; 200mg tid vs placebo, p = 0.580). In the responder analysis, 200 mg bid showed a statistically significant difference vs placebo (p = 0.035). In the exploratory analysis with completers (patients completing all treadmill tests), there was a statistical difference in ACD/baseline change for 200 mg bid (p = 0.035) and in the responder analysis for 200 mg tid (p = 0.044) at 24 weeks compared to placebo. Both treatments showed a carry-over effect for ACD during the 8-week follow-up (weeks 28-32). The treatment was well tolerated and no clinically significant safety concerns were reported. In conclusion, the study results confirm that sarpogrelate is well tolerated and although the primary endpoint failed to reach statistical significance, the responder analysis showed an increased absolute walking distance, which makes a further trial warranted, including a larger population, and possibly also a longer treatment period.     

A Randomized, Double-Blind, Placebo-Controlled Pilot Study of Naltrexone in Outpatients With Bipolar Disorder and Alcohol Dependence

Background:  Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment nonadherence, violence, increased hospitalization, and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence.
Methods:  Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/d) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed.
Results:  The 2 groups were similar in baseline and demographic characteristics. Naltrexone showed trends ( p  < 0.10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the 2 groups. Response to naltrexone was significantly related to medication adherence.
Conclusions:  Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy.     

Evaluation of two equivalent regimens (BID,QID) of cimetidine to raise intragastric pH over a 24-hour period in patients with duodenal ulcer

We evaluated two equivalent regimens of cimetidine to raise intragastric pH over a 24-hr period, using a glass pH electrode in five patients with duodenal ulcer. Each patient received the following drug in a randomized fashion: (1) cimetidine 200 mg after each meal and at bedtime (200 mg qid), (2) cimetidine 400 mg after breakfast and at bedtime (400 mg bid), or (3) placebo tablets (control). Mean intragastric acidity for 24 hr was suppressed by 44.0% in 200 mg qid, and by 73.7% in 400 mg bid of control. In particular, nocturnal gastric acidity was suppressed by 63.1% and 91.3% in 200 mg qid and 400 mg bid, respectively. Thus, 400 mg bid was more effective in lowering gastric acidity than 200 mg qid, although the total daily dose of cimetidine in the two regimens was the same.A part of this work was supported by a grant from the Japanese Ministry of Welfare. This report was presented at the 84th Annual Meeting of the American Gastroenterological Association, Washington, D.C., May 21–27, 1983.