Evaluation of Therapeutics for Advanced-Stage Heart Failure and Other Severely-Debilitating or Life-Threatening Diseases.

Severely-debilitating or life-threatening (SDLT) diseases include conditions in which life expectancy is short or quality of life is greatly diminished despite available therapies. As such, the medical context for SDLT diseases is comparable to advanced cancer and the benefit vs. risk assessment and development of SDLT disease therapeutics should be similar to that of advanced cancer therapeutics. A streamlined development approach would allow patients with SDLT conditions earlier access to therapeutics and increase the speed of progression through development. In addition, this will likely increase the SDLT disease therapeutic pipeline, directly benefiting patients and reducing the economic and societal burden of SDLT conditions. Using advanced-stage heart failure (HF) as an example that illustrates the concepts applicable to other SDLT indications, this article proposes a streamlined development paradigm for SDLT disease therapeutics and recommends development of aligned global regulatory guidance.

The in utero passage of meconium by very low birth weight infants: a marker for adverse outcomes.

OBJECTIVES: To determine the incidence of in utero meconium passage and the rate of associated complications among VLBW infants. STUDY DESIGN: Retrospective review of medical records and prospective evaluation of placental samples from 431 VLBW infants who survived >24 h. Cases with histologic evidence of meconium were re-examined and hemosiderin excluded by a negative iron stain. Statistical analysis included chi2, logistic regression, Student's t-test and Kruskal-Wallis. RESULTS: The 70 infants (16.2%) who had placental evidence of in utero meconium passage were younger, weighed less, and more likely to be delivered by C-section (P = 0.006), intubated in the delivery room (P = 0.02), receive chest compressions (P = 0.003), require volume resuscitation (P = 0.001) and develop grade III-IV intraventricular hemorrhages (P = 0.011) than were control infants. CONCLUSION: Microscopic evaluation of the placental membranes reveals that the in utero passage of meconium occurs in about 16% of premature infants and is associated with adverse perinatal outcomes, including the need for resuscitation at delivery and an increased risk for grade III-IV intraventricular hemorrhages.

Influenza vaccine for patients with chronic obstructive pulmonary disease.

BACKGROUND: Influenza vaccinations are currently recommended in the care of people with COPD, but these recommendations are based largely on evidence from observational studies with very few randomised controlled trials (RCTs) reported. Influenza infection causes excess morbidity and mortality in COPD patients but there is also the potential for influenza vaccination to cause adverse effects or not to be cost effective. OBJECTIVES: To evaluate the evidence from RCTs for a treatment effect of influenza vaccination in COPD subjects. Outcomes of interest were exacerbation rates, hospitalisations, mortality, lung function and adverse effects. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials, and reference lists of articles. References were also provided by a number of drug companies we contacted. SELECTION CRITERIA: RCTs that compared live or inactivated virus vaccines with placebo, either alone or with another vaccine in persons with COPD. Studies of people with asthma were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data. All entries were double checked. Study authors and drug companies were contacted for missing information. MAIN RESULTS: Eleven trials were included but only six of these were specifically performed in COPD patients. The others were conducted on elderly and high-risk individuals, some of whom had chronic lung disease. Inactivated vaccine in COPD patients resulted in a significant reduction in the total number of exacerbations per vaccinated subject compared with those who received placebo (weighted mean difference (WMD) -0.37, 95% confidence interval -0.64 to -0.11, P = 0.006). This was due to the reduction in "late" exacerbations occurring after three or four weeks (WMD -0.39, 95% CI -0.61 to -0.18, P = 0.0004). In Howells 1961, the number of patients experiencing late exacerbations was also significantly less (odds ratio 0.13, 95% CI 0.04 to 0.45, P = 0.002). Both Howells 1961 and Wongsurakiat 2004 found that inactivated influenza vaccination reduced influenza -related respiratory infections (WMD 0.19, 95% CI 0.07 to 0.48, P = 0.0005). In both COPD patient and in elderly patients (only a minority of whom had COPD), there was a significant increase in the occurrence of local adverse reactions in vaccinees, but the effects were generally mild and transient. There was no evidence of an effect of intranasal live attenuated virus when this was added to inactivated intramuscular vaccination. The studies are too small to have detected any effect on mortality. An updated search conducted in September 2001 did not yield any further studies. A search in 2003 yielded two further reports of the same eligible study Gorse 2003. A search in 2004 yielded two reports of the another eligible study Wongsurakiat 2004. The author informed us of another report of the same study Wongsurakiat 2004/2. AUTHORS' CONCLUSIONS: It appears, from the limited number of studies performed, that inactivated vaccine reduces exacerbations in COPD patients. The size of effect was similar to that seen in large observational studies, and was due to a reduction in exacerbations occurring three or more weeks after vaccination, and due to influenza. There is a mild increase in transient local adverse effects with vaccination, but no evidence of an increase in early exacerbations.

Constraint-induced movement therapy for hemiplegic children with acquired brain injuries.

OBJECTIVE: To evaluate the feasibility and efficacy of constraint-induced movement therapy (CIMT) for impaired upper extremity (UE) function in children with acquired brain injury (ABI). DESIGN: Multiple case studies. SETTING: Inpatient pediatric rehabilitation. PARTICIPANTS: Seven consecutive ABI rehabilitation admissions with hemiparesis were recruited without regard to injury etiology, age, or cognitive capacities. MAIN OUTCOME MEASURE: The actual amount of use test (AAUT) was used to evaluate change in UE function. AAUT amount of use (AOU) and quality of movement (QOM) scales were obtained at baseline and follow-up. RESULTS: AOU and QOM item improvements were significant, as were changes in activities of daily living. The effect sizes for these changes were large. CONCLUSIONS: Stringent CIMT training, previously only implemented with adults, can be used effectively with children when everyday elements of a child's life are integrated into adult protocols. The use of child-friendly UE shaping exercises, "pushed into" activities by professional therapists as well as trained teachers, paraprofessionals, and parents, was supported. Effects of impairment, injury, and behavior on outcomes are discussed. Larger controlled studies with additional outcome measures are indicated.

Acute behavioral and physiological effects of modafinil in drug abusers.

Modafinil, a novel stimulant, is effective in the treatment of excessive daytime sleepiness associated with narcolepsy. It is biochemically and pharmacologically distinct from prototypical stimulants such as D-amphetamine, cocaine, and methylphenidate. The present experiment was designed to assess the acute behavioral effects of oral modafinil, cocaine, and placebo in participants (n=9) with recent histories of cocaine use (i.e. positive urine for cocaine or benzoylecgonine during the initial screening interview). Drug effects were assessed with a battery of self-reported drug-effect questionnaires, performance measures, and physiological indices. Cocaine, but not modafinil, produced stimulant-like self-reported drug effects (e.g. increased ratings of High and Stimulated). Modafinil and cocaine dose-dependently increased heart rate and blood pressure. The results of the present study suggest that modafinil has minimal abuse potential, but should be viewed cautiously because of the relatively small sample size. Future studies should further characterize the abuse potential of modafinil using other behavioral arrangements, such as drug discrimination or drug self-administration. A full characterization of the abuse potential of modafinil will become important as the use of this drug increases.

A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data.

OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.

Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison.

BACKGROUND: Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia, questions remain regarding its efficacy for primary negative symptoms, comparison with a moderate dose of a first-generation antipsychotic, and adverse effects during a longer-term trial. This study examined its efficacy in partially responsive, community-based patients, compared clozapine with moderate-dose haloperidol, and extended treatment to 6 months. METHODS: Randomized, double-blind, 29-week trial comparing clozapine (n = 37) with haloperidol (n = 34). Subjects with schizophrenia who were being treated in community settings at 3 collaborating clinical facilities were enrolled. RESULTS: Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an a priori criterion of improvement (57%) compared with haloperidol-treated subjects (25%). Significantly greater improvement was seen in symptoms of psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance, and total score measured on the Brief Psychiatric Rating Scale. No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms. Subjects treated with clozapine experienced more excess salivation, dizziness, and sweating and less dry mouth and decreased appetite than those treated with haloperidol. CONCLUSIONS: Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.

Behavioral pharmacological similarities between methylphenidate and cocaine in cocaine abusers.

Six human participants with recent histories of cocaine use were trained to discriminate 200 mg oral cocaine hydrochloride. A range of doses of oral cocaine (50-300 mg), methylphenidate (15-90 mg), triazolam (0.125-0.75 mg), and placebo were then tested to determine whether they shared discriminative-stimulus and participant-rated effects with 200 mg cocaine. Cocaine and methylphenidate dose-dependently increased cocaine-appropriate responding, produced prototypical stimulant-like participant-rated drug effects (e.g., increased participant ratings of Drug Liking), and increased heart rate and blood pressure. Triazolam produced low levels of cocaine-appropriate responding and impaired performance. Thus, consistent with previous studies, humans can reliably discriminate oral cocaine. Consistent with in vivo behavioral neuropharmacological data, the discriminative-stimulus, participant-rated, and physiological effects of oral cocaine and methylphenidate were similar.

Differential actions of dopamine receptor antagonism in rats upon food intake elicited by either mercaptoacetate or exposure to a palatable high-fat diet.

Selective dopamine receptor antagonists have been shown to reduce food intake of rats under such regulatory challenge conditions as food deprivation and 2-deoxy-D-glucose-induced glucoprivation, and under such palatable conditions as acute exposure to sucrose solutions. Food intake is increased following either pretreatment with the free fatty acid oxidation inhibitor, mercaptoacetate (MA), or acute exposure to a palatable high-fat source. The present study examined whether equimolar doses (50-800 nmol/kg, s.c.) of either the selective D(1) receptor antagonist, SCH23390, or the selective D(2) receptor antagonist, raclopride, would alter food intake elicited by either MA (70 mg/kg, i.p.) or acute exposure to a high-fat diet (67% ground rat chow, 33% vegetable shortening). SCH23390 significantly and dose-dependently reduced MA-induced feeding with the two higher (400 and 800 nmol/kg) doses eliminating this response after the first 2 h and the two lower (50 and 200 nmol/kg) doses preventing the occurrence of significant MA-induced feeding. Raclopride eliminated MA-induced feeding at the highest dose, and produced dose-dependent reductions at lower doses. A different pattern of dopamine antagonist effects emerged for high-fat intake. The identical dose range of SCH23390 failed to alter high-fat intake. In contrast, whereas the highest (800 nmol/kg) dose of raclopride significantly reduced high-fat intake after 1 h, the middle (200 and 400 nmol/kg) doses of raclopride significantly increased high-fat intake after 2 h. These data are discussed in terms of the modulatory actions of dopamine upon food intake, of the differential actions of dopamine receptor subtypes upon intake under challenge and palatable conditions, and of the potential participation of presynaptic and postsynaptic receptor populations in these responses.

Reinforcing and subject-rated effects of methylphenidate and d-amphetamine in non-drug-abusing humans.

The reinforcing effects of methylphenidate (20-40 mg), d-amphetamine (10-20 mg), and placebo were assessed in eight healthy, non-sleep-deprived, non-drug-abusing outpatient volunteers. A modified progressive-ratio schedule was used to assess drug reinforcement in which a sampling session always preceded a self-administration session. During sampling sessions, volunteers received a drug dose to acquaint them with the drug effects. Drug doses were administered in eight identical capsules (i.e., each capsule contained 12.5% of the total dose). During self-administration sessions, which generally were conducted the next day, volunteers were given eight opportunities to work on a computer and could earn all, or some, of the capsules that were administered the previous day. To earn the first capsule, volunteers had to click a computer mouse 50 times. The number of clicks required to earn each additional capsule doubled (i.e., 100, 200, 400, 800, 1,600, 3,200, and 6,400 clicks). The dependent measure on this task was the break point (i.e., the last ratio completed). To characterize more fully the behavioral effects of methylphenidate and d-amphetamine, a battery of subject-rated drug-effect questionnaires, performance tasks, and physiologic measures was also used. Both doses of d-amphetamine increased the break point significantly above placebo levels, whereas only the high dose of methylphenidate did so. Break-point values for the doses of methylphenidate and d-amphetamine that maintained the greatest responding did not differ significantly. Methylphenidate and d-amphetamine produced some stimulantlike subject-rated drug effects (e.g., increased ratings of "drug liking"). These data suggest that methylphenidate, like d-amphetamine, can function as a reinforcer under a modified progressive-ratio schedule and, by inference, has at least some abuse potential in healthy, non-sleep-deprived, non-drug-abusing volunteers.

Increased cortisol: cortisone ratio in acute pulmonary tuberculosis.

To evaluate a possible role for altered cortisol metabolism in mediating the immunoparesis associated with progressive tuberculosis (TB), we have studied the hypothalamic-pituitary-adrenal axis, and the activities of the 11beta-hydroxysteroid dehydrogenases (11-HSDs) that interconvert active cortisol and inactive cortisone. In active pulmonary tuberculosis (PTB), the ratio of cortisol/cortisone metabolites in 24-h urine showed a shift towards active cortisol (ratio, 1.19 +/- 0.1, n = 16 versus 0. 89 +/- 0.05 in cured pulmonary tuberculosis (CTB), n = 13, p < 0. 01; and 0.78 +/- 0.04 healthy volunteers (HV), n = 11, p < 0.005). Conversion of cortisone (administered as 25 mg orally) to cortisol in peripheral plasma was higher in PTB (peak 1,157 +/- 55 nM, n = 14 versus 862 +/- 50 nM in CTB, n = 10, p < 0.005, and 882 +/- 73 nM in HV, n = 10; p < 0.005). Cortisol/cortisone ratio was increased in bronchoalveolar lavage fluid in PTB (7.73 +/- 1.48, mean +/- SE, n = 13) compared with HV (4.05 +/- 0.38, n = 11, p < 0.05) but was not different in plasma (PTB, 3.25 +/- 0.68; HV, 4.01 +/- 0.92). Responses of plasma cortisol to dexamethasone, CRH stimulation, and multidose ACTH stimulation were not different. These data suggest that in pulmonary tuberculosis, central control of glucocorticoid production is normal but that peripheral metabolism, in particular in the lung, is deviated in favor of the active metabolite cortisol. This offers a possible mechanism to explain the immunoparesis observed in progressive pulmonary tuberculosis.

The use of D-dimers in the diagnosis of occult pulmonary emboli in HIV pulmonary disease--two case reports.

Pulmonary thromboembolism is not considered a common cause of morbidity in HIV disease. Although anti-phospholipid antibodies are often seen in HIV disease, they are not associated with an increased thrombotic risk. Computed tomographic (CT) pulmonary angiography has been described as the imaging modality of first choice, as abnormal baseline chest X-rays may reduce the diagnostic utility of ventilation perfusion (VIQ) scanning. In HIV-negative individuals D-dimer testing has been shown to be a good screening tool in suspected pulmonary embolism. We present 2 cases where the diagnosis of pulmonary embolus was established using tests for the clotting degradation products D-dimers.

Influenza vaccine for patients with chronic obstructive pulmonary disease.

BACKGROUND: Influenza vaccinations are currently recommended in the care of people with COPD, but these recommendations are based largely on evidence from observational studies with very few randomised controlled trials (RCTs) reported. Influenza infection causes excess morbidity and mortality in COPD patients but there is also the potential for influenza vaccination to cause adverse effects or not to be cost effective. OBJECTIVES: To evaluate the evidence from RCTs for a treatment effect of influenza vaccination in COPD subjects. Outcomes of interest were exacerbation rates, hospitalisations, mortality, lung function and adverse effects. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and reference lists of articles. References were also provided by a number of drug companies we contacted. SELECTION CRITERIA: RCTs that compared live or inactivated virus vaccines with placebo, either alone or with another vaccine in persons with COPD. Studies of people with asthma were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data. All entries were double checked. Study authors and drug companies were contacted for missing information. MAIN RESULTS: Nine trials were included but only four of these were specifically performed in COPD patients. The others were conducted on elderly and high-risk individuals, some of whom had chronic lung disease. In one study of inactivated vaccine in COPD patients there was a significant reduction in the total number of exacerbations per vaccinated subject compared with those who received placebo (weighted mean difference (WMD) -0.45, 95% confidence interval -0.75 to -0.15, p = 0.004). This difference was mainly due to the reduction in exacerbations occurring after 3 weeks (WMD -0.44, (95% CI -0.68 to -0.20, p<0.001). The number of patients experiencing late exacerbations was also significantly less (OR= 0.13, 95%CI 0.04 to 0.45, p=0.002). There was no evidence of an effect of intranasal live attenuated virus when this was added to inactivated intramuscular vaccination. In studies in elderly patients (only a minority of whom had COPD), there was a significant increase in the occurrence of local adverse reactions in vaccinees, but the effects were generally mild and transient. REVIEWER'S CONCLUSIONS: It appears, from the limited number of studies performed, that inactivated vaccine may reduce exacerbations in COPD patients. The size of effect was similar to that seen in large observational studies, and was due to a reduction in exacerbations occurring three or more weeks after vaccination. In elderly, high risk patients there was an increase in adverse effects with vaccination, but these are seen early and are usually mild and transient.

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

Six non-drug-abusing humans were trained to discriminate 15 mg zolpidem in the present experiment. After participants acquired discrimination, a range of doses of zolpidem (2.5-15.0 mg), triazolam (0.0625-0.3750 mg), pentobarbital (25-150 mg), caffeine (100-600 mg), and placebo were tested to determine whether they shared discriminative-stimulus effects with 15 mg zolpidem. The participant-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital, and caffeine were assessed concurrently. Triazolam and pentobarbital dose dependently increased zolpidem-appropriate responding. Caffeine occasioned low levels of zolpidem-appropriate responding. Zolpidem, triazolam, and pentobarbital, but not caffeine, generally produced a similar constellation of participant-rated drug effects (e.g., increased scores for the Pentobarbital, Chlorpromazine, and Alcohol Group subscale on the Addiction Research Center Inventory) and dose dependently impaired performance. These results suggest that humans can reliably discriminate zolpidem. Despite its unique benzodiazepine-receptor binding profile, the discriminative-stimulus, participant-rated, and performance-impairing effects of zolpidem are similar to those of the barbiturates and benzodiazepines.

The characteristics of false negative cervical smears--implications for the UK cervical cancer screening programme.

OBJECTIVE: To accurately determine whether there are any features of an abnormal cervical smear that predispose to the production of a false negative report, in order to gain insight into why false negative reports are issued, and to establish whether there are steps that can be taken to reduce them. DESIGN: A quantitative retrospective analysis using the AxioHOME microscope of the number, size, and spatial distribution of abnormal cells in a set of 50 slides comprising a mixture of false negative and true positive cervical smears. SETTING: Five different cytology laboratories in the United Kingdom. RESULTS: False negative smears were found to be quantitatively different from true positive smears. They contained significantly fewer abnormal cells (median number of abnormal cells for false negatives = 173, median number of abnormal cells for true positives = 1712; p < 0.004), and these were more likely to be unevenly distributed on the slide. It was possible to predict with a high degree of accuracy whether a smear was a false negative by analysing number and distribution alone (kappa = 0.57). CONCLUSIONS: False negatives are quantitatively different from true positive cervical smears. This has important implications for quality assurance in the UK cervical screening programme. More consideration needs to be given to the effectiveness of existing quality assurance measures, which need to be tailored to the preferential detection of this type of abnormal cervical smear.

Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans.

The present study examined the acute behavioral effects and abuse potential of three drugs commonly used to treat sleep disorders, trazodone, zolpidem and triazolam, and placebo in ten male volunteers with histories of alcohol and drug abuse. Trazodone (100, 200 and 300 mg), a triazolopyridine antidepressant, was included because antidepressants are being used more frequently to treat sleep disorders, but it is unclear whether they have a distinct behavioral pharmacologic profile relative to benzodiazepine hypnotics. Zolpidem (15, 30 and 45 mg), an imidazopyridine hypnotic, was tested because it is the most commonly prescribed hypnotic and purportedly has a unique benzodiazepine-receptor binding profile. Triazolam (0.25, 0.5 and 0.75 mg), a triazolobenzodiazepine hypnotic, was included as the standard component because previous laboratory studies have demonstrated that it has at least some abuse potential. Trazodone, zolpidem and triazolam generally produced comparable dose-related increases in scores on the PCAG scale of the ARCI, which suggests the doses tested were equivalent on some behavioral dimension. The effects of trazodone on subject-rated items thought to measure abuse potential (e.g., subject ratings of Willing to Take Again) were less than those observed with triazolam. Zolpidem and triazolam produced comparable effects on these measures. The highest dose of zolpidem, but not triazolam, increased ratings of Like Drug, Happy, Good Effects, Friendly, Elated, Carefree and Bad Effects. Triazolam and zolpidem produced dose-dependent impairment on all of the performance tasks. Trazodone impaired performance on some, but not all, of these tasks. Consistent with the pharmacokinetics of these compounds, the time-action functions of trazodone, zolpidem and triazolam were similar on these measures. These data suggest that trazodone has less abuse potential than triazolam, and may be a viable alternative to benzodiazepine hypnotics in individuals with histories of alcohol or drug abuse. By contrast, despite its unique neuropharmacological profile, the acute behavioral effects and abuse potential of zolpidem are comparable to those of triazolam.

Risperidone use at a state hospital: a clinical audit 2 years after the first wave of risperidone prescriptions.

BACKGROUND: In spite of some inherent limitations, naturalistic data can provide information on populations that have greater heterogeneity than can controlled clinical trials and on functional outcomes that may be especially important in clinical practice. In the present retrospective naturalistic study, we evaluated key clinical outcomes among the first wave of risperidone-treated patients at a state psychiatric hospital. METHOD: Outcome data were extracted from the charts of 142 patients 2 years after initiation of treatment with risperidone. Their diagnoses included DSM-III-R schizophrenia (57%), schizoaffective disorder (22%), dementia and other organic conditions (7%), bipolar disorder (5%), and other psychiatric disorders (9%). RESULTS: During the 2-year period, 92 of 142 patients were discharged from the hospital: 61 (43%) were discharged on risperidone treatment and 31 (22%) were discharged on treatment with other drugs. At the time of the study, 50 of 142 patients were still in the hospital: of these, 18 (13%) were still receiving risperidone. The modal maximum daily dose of risperidone was 4.1 mg in patients discharged on risperidone treatment and 7.5 mg in patients still in the hospital. All groups were granted more ward privileges after starting risperidone, the most being granted to patients discharged from the hospital on risperidone treatment (p<.05 versus patients discharged on treatment with other drugs) and those still receiving risperidone in the hospital. Significantly fewer patients discharged on risperidone treatment than on treatment with other drugs were readmitted to the hospital within 2 years after discharge (p<.01). CONCLUSION: Improved privilege levels and a reduced readmission rate indicate that risperidone was an effective antipsychotic agent among a heterogeneous patient population in a state hospital. These factors may be especially important to justify use of this agent in the current fiscal climate.

Acute physiological and behavioral effects of oral cocaine in humans: a dose-response analysis.

The present study was designed to assess the acute physiological and behavioral effects of a wide range of doses of oral cocaine HCL (placebo, 50, 100, 200, and 300 mg). Nine volunteers (eight males and one female) with recent histories of cocaine use resided on a general inpatient psychiatry unit while they participated. Drug doses were administered in a double-blind fashion under medical supervision, but for safety purposes, they were administered in ascending order. The physiological, subject-rated, and performance effects of oral cocaine HCL were assessed before drug administration and periodically afterwards for 5 h. Oral cocaine HCL increased heart rate and blood pressure as a graded function of dose, but the magnitude of these effects were not clinically significant. Oral cocaine HCL produced positive subject-rated drug effects (e.g. increased ratings of good effects, like drug, and willing to take again), but did not affect performance. Consistent with the pharmacokinetics of oral cocaine HCL, drug effects were generally discernible from placebo 0.5-1 h after administration, peaked approximately 1 h after administration, and progressively abated during the remainder of the experimental session. The results of this experiment demonstrate that across a six-fold range of doses oral cocaine HCL is well tolerated by individuals with recent histories of cocaine use and can be safely administered under controlled laboratory and medical conditions.

Clozapine withdrawal-emergent dystonias and dyskinesias: a case series.

BACKGROUND: Severe psychotic decompensation during clozapine withdrawal has been reported previously. Less attention has been paid to movement disorders following abrupt clozapine withdrawal. This report describes 4 subjects who experienced severe dystonias and dyskinesias upon abrupt clozapine withdrawal. METHOD: Current and past medical records of 4 subjects with DSM-IV schizophrenia or schizo-affective disorder were reviewed. RESULTS: All subjects had a history of neuroleptic-induced extrapyramidal symptoms, 1 had a history of severe dystonias, and 1 had neuroleptic malignant syndrome. All had mild orolingual tardive dyskinesia prior to clozapine treatment. All subjects had received clozapine for several months, and 3 of the 4 subjects stopped clozapine abruptly. Two subjects experienced cholinergic rebound symptoms within hours, which resolved quickly. These subjects had severe limb-axial and neck dystonias and dyskinesias 5 to 14 days after clozapine withdrawal. Two subjects were unable to ambulate, and 1 had a lurching gait. Two gagged while eating or drinking. Two subjects were returned to clozapine, 1 was started on low-dose risperidone treatment, and 1 was started on olanzapine treatment. All experienced significant improvements in their mental state and movement disorders. CONCLUSION: Severe movement disorders, which may be worse than the movements prior to clozapine treatment, and cholinergic rebound symptoms may occur upon abrupt clozapine withdrawal and must be recognized in addition to the severe psychotic decompensation noted in some patients. Patients, families, and caregivers must be alerted to this possibility. Where possible, a slow clozapine taper, the use of anticholinergic agents, and symptomatic treatment may help minimize these withdrawal symptoms, and reintroduction of clozapine or treatment with the newer atypical agents can help in the clinical management of these symptoms.

Hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria occurring early in clozapine treatment.

This report describes a 48-year-old caucasian male with schizophrenia who developed hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria early in clozapine treatment which resolved on drug discontinuation. The literature on similar cases is reviewed.