The catechol-O-methyltransferase inhibitor tolcapone was compared with the dopamine agonist bromocriptine in an open-label, randomized trial involving 146 levodopa-treated parkinsonian patients with end-of-dose deterioration of efficacy. Tolcapone was given at a dosage of 200 mg three times daily; bromocriptine was titrated from 1.25 mg once daily at baseline to, at most, 10 mg three times daily by day 24 (mean final dose 22.4 mg/day). After 8 weeks, the tolcapone group had a significant reduction in daily levodopa dose compared with the bromocriptine group (p < 0.05). No significant differences in the "on/off" time and motor disability were seen between the tolcapone and bromocriptine treatment groups. Bromocriptine induced more hallucinations, orthostatic hypotension, and nausea, whereas tolcapone therapy was associated with more muscle cramps and dystonia. These results suggest that when added to levodopa therapy, the two drugs have a different side effect profile, with the advantages for tolcapone being absence of titration and quicker efficacy.

In this double-blind, placebo-controlled trial, we investigated the effect of the catechol-O-methyltransferase inhibitor tolcapone 100 or 200 mg three times daily on activities of daily living and motor function in 298 patients with parkinsonism receiving levodopa but without motor fluctuations. At 6 months, both dosages of tolcapone produced significant reductions in the Unified Parkinson's Disease Rating Scale scores for activities of daily living (Subscale II) and motor function (Subscale III) and in the total score for Subscales I to III. These improvements were maintained up to the 12-month assessment. At 6 months, both tolcapone groups had changes in levodopa dosage that were significantly different from placebo: the tolcapone groups had decreases in mean total daily dose of levodopa, whereas the placebo group had a mean increase. Tolcapone was well tolerated. The principal adverse events were levodopa-related, but these were generally mild or moderate. Diarrhea was the most frequent nondopaminergic adverse event. Tolcapone appears to be beneficial in the treatment of patients with parkinsonism who have not yet developed motor fluctuations.

Pomara, Nunzio MD; Tun, Hla MD; Deptula, Dennis PhD; Greenblatt, David J. MD Author Information

We havepn%ouslyreportedthatacutehighandlowdosesof alprazohrm (ALP,0.25mg,0.5mg)and lorazepam(LOR,0.5mg, lmg), whichare thoughtobeequivalent inanxiolyticeffects, impairedmemoryperformance ona verballist learningtask(Buschke’sSeIectiveRemindingTask).These findings,however,werebasedon thecumulativerecallof 7 learning trials (totalmall). In the presentanalysis,we examinedthe acuteand chronic effects of these drugs on recall across the 7 trials. Acute effects were examinedbothbeforeandafterchronicb.i.d.treatmentin a doubleblind placebo-control, parallelstudyinhealthyelderly.Initialacutechallengewith singlehighdosesofbothdrugsresultedinsi@lcantdmg x trialinteractions in whichthe dreg-inducedimpairmentsbecamegreateroverthe courseof successivetrialsat i and 2.5 hourspost-drug. No sigMcant drugx kid interactionswerefoundduringchronictreatment.Afterchronictreatment, only acute techallengewith the single high dose of LOR resultedin increasedimpairment acrossthe7 trialsrelativetoplaceboat2.5hours(drug x trkdinteraction). RerhalIengewiththehighdoseofALPno longercaused such increasedimpairment.This suggeststhat toleranceto the adverse effectsof acuterechallengeon recallacrossthe 7 trialsis momlikelyto developas a resultof chronictreatmentwiththe highdoseof ALP.Low dosesof thetwodrugsproducednosignificant drngxtrialinteractions either in theinitialacutechallengeorrechailengeinspiteofsigMcant impairment in totrdredl.

We examined the acute performance and sedative effects of single high and low doses of alprazolam and lorazepam, both before and after chronic, 3-week b.i.d. treatment in elderly adults. The effects of chronic treatment also were examined in this parallel, double-blind, placebo-controlled study. Initial acute low doses significantly impaired total recall and increased intrusion errors. High doses also impaired delayed recall and critical flicker fusion threshold (CFF). Only chronic treatment with high-dose alprazolam increased intrusions and self-rated sedation. Single-dose rechallenge after chronic treatment was associated with significantly less impairment than the initial challenge in memory tasks but not in the discriminant reaction time (DRAT) task. For most memory measures, the development of tolerance was only partial; rechallenge still produced significant deficits in relation to placebo. The development of tolerance was task-specific and depended on drug type and dosage. Despite impairments in various memory functions, CFF, and DRAT, volunteers did not report significant drug-induced changes in sedation.

Animals or human subjects receiving brain stimulation in the dorsal periaqueductal gray matter (dPAG) show sudden fear-suggestive behavioral reactions and physical signs of autonomic activation which are reminiscent of the symptom profile characterizing a panic attack. An experimental situation in rats measuring dPAG stimulation self-interruption thresholds has been validated as realistically simulating several aspects of panic anxiety with objective signs of symptomatic and predictive validity using established antipanic and panicogenic agents; it was utilized here to evaluate the effects of various cholecystokinin B receptor ligands. A dose-dependent increase in self-interruption thresholds (antipanic-like effect) was recorded following injection of L-365,260 (3.2, 10 and 32 mg/kg i.p.), a CCKB receptor antagonist with good brain penetration, whereas no significant changes in thresholds were recorded following CI-988 (3.2, 10 and 32 mg/kg i.p.), a dipeptoid CCKB receptor antagonist with poor brain penetration. Latencies for self-interruption were not modified, suggesting that motor functions remained intact. No significant changes in self-interruption thresholds were recorded following peripheral administration of the CCKB receptor agonists CCK4 (0.03 to 0.32 mg/kg i.v.; 0.01 to 3.2 mg/kg i.p.) or the metabolically stabilized analog Boc-CCK4 (0.1 to 10 mg/kg i.p.). Systemic administration of the panicogenic compounds caffeine and yohimbine enhance acute anxiety in this model. These data indicate that, in the dPAG simulation of panic anxiety, central CCKB receptor blockade by L-365,260 induces antiaversive effects analogous to those observed following benzodiazepine receptor activation by clonazepam or alprazolam. Potency and efficacy of L-365,260 were lower than those of clonazepam or alprazolam, suggesting modest, but nonetheless authentic, antiaversive properties for this CCKB receptor antagonist. Lack of effects observed following peripheral administration of the agonists CCK4 and Boc-CCK4 or of the dipeptoid antagonist CI-988 is likely to reflect restricted brain penetration of those compounds in rats; it furthermore excludes a contribution of peripheral gastrin and CCKA receptors to the antipanic-like properties of selective CCKB receptor antagonists such as L-365,260.

Objective: To assess the efficacy and tolerability of the catechol-O-methyltransferase inhibitor tolcapone in reducing "off/on" fluctuations in levodopa-treated parkinsonian patients.Design: A randomized, double-blind, placebo-controlled, parallel-group study.Setting: Fifteen Parkinson disease clinics.Patients: Two hundred fifteen referred outpatients with Parkinson disease who showed predictable end-of-dose motor fluctuations that were not controlled by a stable levodopa-carbidopa (Sinemet) regimen of at least 4 weeks' duration.Interventions: In addition to their usual levodopa-carbidopa regimen, patients received placebo or tolcapone, 100 or 200 mg, 3 times daily orally for 6 weeks.Primary Outcome Measure: Change in daily off/on time.Results: Tolcapone, 100 and 200 mg 3 times daily, reduced off time by 2.0 and 2.5 hours per day, respectively, and increased on time by 2.1 and 2.3 hours per day, respectively (P < .001 vs placebo). Investigators' global measures of disease severity indicated that significantly more tolcapone-treated patients had reduced wearing off and symptom severity (P < .001 vs placebo). No significant change in quality-of-life measures occurred. Clinical improvements occurred despite a reduction in total daily levodopa dose of 185.5 mg (23%) in the tolcapone, 100 mg 3 times daily, group and 251.5 mg (29%) in the 200 mg 3 times daily group. Principal adverse events (mainly dyskinesia and nausea) were levodopa related, were not treatment limiting, and were seldom reported as reasons for withdrawal. The frequency of withdrawals because of adverse events was similar in all groups (3% to 7%).Conclusions: Tolcapone was well tolerated and substantially increased on time and reduced off time in patients with fluctuating Parkinson disease. Additionally, levodopa requirements were significantly decreased.

Benzodiazepines with shorter elimination half-lives are widely prescribed In the elderly and generally thought to produce less cognitive toxicity than agents with longer half-lives such as diazepam. However, there are few stud• ies that have examined the cognitive effects of these agents In the elderly. This study assessed the acute and chronic effects on task perfonnance of high and low equivalent doses of alprazolam and lorazepam, two benzo• diazepines with relatively short half-lives. The relationship of these effects to age, plasma drug levels and duration of treatment was also examined. Eighty subjects (ages~7 yrs) participated In an NIMH-sponsored 3-week double-blind, placebo-controlled, parallel group study comparing low(0.25 mg bid) and hlgh-close (0.5 mg bid) alprazolam versus low(0.5 mg bid) and high-dose (1.0 mg bid) lorazepam. Both low and high doses of alprazolam and lorazepam produced significant impairments in the Buschke total recall in the Initial acute challenge. Chronic treatment was associated with minimal next-day effects. Acute rechallenge with high doses of alprazolam and 10• razepam after 3 weeks of chronic treatment was associated with significant less impairment than that observed In the Initial acute challenge, consistent with the development of tolerance. Nevertheless, rechallenge with low doses of lorazepam and alprazolam and high doses of lorazepam still produced significant Impairment compared to placebo. These findings suggest caution In the use of these medications In the elderly.