Peripheral and central nervous system inhibition of 11ß-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384.

ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-(2)H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1-50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ≥2 mg daily maintained peripheral HSD-1 inhibition ≥88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ≥81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ≥2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers.

Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [C(max)], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean C(max), 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding C(max) CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.

Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients.

A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226-90, and compared drug exposure between patch and capsule administrations. This was an open-label, parallel-group study in Alzheimer's disease patients randomized to receive either capsule (1.5-6 mg Q12H, i.e., 3-12 mg/day) or patch (5-20 cm2) in ascending doses through four 14-day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8-fold at 20 cm2, 345 versus 191 ng x h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day).

Multiple-dose plasma pharmacokinetic and safety study of LY450108 and LY451395 (AMPA receptor potentiators) and their concentration in cerebrospinal fluid in healthy human subjects.

The objective of this study was to measure the steady-state cerebrospinal fluid (CSF) concentration of LY450108 and LY451395 (positive modulators of AMPA receptors) in healthy subjects after the administration of 1 mg and 5 mg. Secondary objectives included the evaluation of safety, pharmacokinetics, and steady-state ratio of plasma:CSF concentrations of LY450108 and LY451395 after multiple dosing. This study was an open-label, multiple oral dose study evaluating 1 mg and 5 mg LY450108 and 1 mg and 5 mg LY451395 in 12 (3 subjects per dosing group) healthy subjects, aged 18 to 49 years. Twelve healthy male subjects completed the study. LY450108 and LY451395 were quantifiable in CSF after 1-mg and 5-mg multiple-dose administrations with plasma:CSF ratio of 82:1 and 44:1, respectively. LY450108 and LY451395 1 mg and 5 mg were measured in the CSF. Single and multiple oral doses of LY450108 and LY451395 were determined to be safe and well tolerated in healthy subjects.

First clinical evaluation of ganstigmine in patients with probable Alzheimer's disease.

The objective of this study was to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of five fixed doses of ganstigmine (CHF 2819) in patients with probable Alzheimer's disease (AD). This randomized, double-blind, placebo-controlled trial evaluated five dose levels (5, 7.5, 10, 12.5, and 15 mg) administered orally once daily for 7 days. Adverse events and continuous telemetry were collected on successive panels of six patients (five active, one placebo). Acetylcholinesterase, butyrylcholinesterase, and plasma drug levels were measured. A total of 29 patients were randomized and 18 completed the study. A total of seven patients, including five of five in the 12.5-mg panel, discontinued because of adverse events. Four patients were withdrawn administratively from the first panel while an episode of atrial fibrillation (the only serious adverse event) was investigated. This panel was then repeated. Mild, transient headache or nausea were the most commonly reported adverse events. Multiple moderate adverse events in the 12.5-mg panel (including nausea, vomiting, and anorexia) led to the decision not to proceed with a 15-mg panel. Ten milligrams was determined to be the maximum tolerated dose. Ganstigmine exhibited nonlinear pharmacokinetics, was absorbed rapidly, and reached peak concentrations within 1 hour. Acetylcholinesterase inhibition was dose dependent and lasted as long as 24 hours. Ganstigmine, a novel cholinesterase inhibitor, was well tolerated within a dosing range of 5 to 10 mg. Once-daily dosing is supported by data on acetylcholinesterase inhibition.

Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease.

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics-pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose-disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of 256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half-life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114-666 concentration of about 5.4 microg/L required for half-maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK-PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.

Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review.

The current approach to antimigraine therapy comprises potent serotonin 5-HT1B/1D receptor agonists collectively termed triptans. Sumatriptan was the first of these compounds to be developed, and offered improved efficacy and tolerability over ergot-derived compounds. The development of sumatriptan was quickly followed by a number of 'second generation' triptan compounds, characterised by improved pharmacokinetic properties and/or tolerability profiles. Triptans are believed to effect migraine relief by binding to serotonin (5-hydroxy-tryptamine) receptors in the brain, where they act to induce vasoconstriction of extracerebral blood vessels and also reduce neurogenic inflammation. Although the pharmacological mechanism of the triptans is similar, their pharmacokinetic properties are distinct. For example, bioavailability of oral formulations ranges between 14% (sumatriptan) and 74% (naratriptan), and their elimination half-life ranges from 2 hours (sumatriptan and rizatriptan) to 25 hours (frovatriptan). Clearly, such diverse pharmacokinetic properties will influence the effectiveness of the compounds and favour the prescription of one over another in different patient populations. This article reviews the pharmacological properties of the triptans (time to peak plasma concentration, half-life, bioavailability and receptor binding) and relates these properties to efficacy and time of onset. It also considers the effects of concomitant medication, food, age and disease on the pharmacokinetics of the compounds. In addition, the relative merits, such as headache recurrence, tolerability and route of administration, are discussed. Finally, the performance of the triptans is considered in the context of direct head-to-head comparative trials that have assessed the efficacy profile of the compounds.

A double-blind, randomized, crossover assessment of blood pressure following administration of avitriptan, sumatriptan, or placebo to patients with mild to moderate hypertension.

We examined the effects of avitriptan, a 5-hydroxytryptamine 1-like (5HT1) receptor agonist for the treatment of migraine, in patients with medicated, controlled, mild to moderate hypertension relative to placebo and sumatriptan. The study was randomized, double-blinded, placebo-controlled, and 4-way crossover in design. Twenty patients (12M, 8F) participated. As required by protocol, all were stable on medications for mild to moderate hypertension, with a supine diastolic blood pressure of < 95 mmHg. Qualified subjects were randomized to receive oral administration of either 75 or 150 mg of avitriptan, 100 mg sumatriptan or placebo during the four treatment visits. Supine blood pressure and pulse rates were recorded up to 24 h after drug administration. Avitriptan 150 mg significantly increased peak diastolic and systolic blood pressure, and mean arterial pressure compared to placebo and sumatriptan 100 mg (p < 0.05). Only those hypertensive patients receiving medication for hypertension should receive anti-migraine medications, such as avitriptan, which are 5HT1-like receptor agonists.

NXX-066 in patients with Alzheimer's disease: a bridging study.

Reduced cholinergic transmission is a key neurotransmitter dysfunction in Alzheimer's Disease (AD). NXX-066, a physostigmine analog and acetylcholinesterase (AChE) inhibitor, has demonstrated activity in animal models of memory function, and was well tolerated in healthy subjects up to a single dose of 64 mg and multiple doses of 60 mg QD for seven days. Since AChE inhibitors are often tolerated differently in AD patients than in healthy volunteers, a randomized, placebo-controlled, double-blind, single-center, inpatient bridging study was conducted to determine the maximum tolerated dose (MTD) of NXX-066 in the target patient population. Seven consecutive panels of eight AD patients each (6 active, 2 placebo) received fixed oral doses of NXX-066 (20, 30, 40, 50, 60, 70, or 80 mg BID) for seven days. Initiation of each subsequent panel (dose group) was contingent upon the tolerability of lower dose levels. The MTD was determined to be 70 mg BID when four of six patients receiving 80 mg BID were prematurely discontinued from the study due to nausea and/or vomiting, accompanied in some patients by mild to moderate dizziness, headache, asthenia, and gastric symptoms. Wide variability in plasma levels of NXX-066 was observed in all dose panels. AChE inhibition in whole blood correlated with both maximum plasma concentration and dose; however, AChE inhibition was not predictive of adverse events. In this study, AD patients tolerated larger daily doses of NXX-066 on a BID regimen than healthy normal subjects had tolerated with QD dosing. Further studies are warranted to examine whether differing tolerability between patients and healthy subjects or the reduced dosing interval explains these findings.

Pharmacokinetics of rizatriptan tablets during and between migraine attacks.

Gastric stasis during migraine attacks results in delayed absorption of several orally administered antimigraine agents. This study, as part of a larger trial, was conducted to examine the pharmacokinetics of rizatriptan tablets during and between migraine attacks. Participating patients met IHS criteria for migraine with or without aura, and suffered between one and eight migraines per month for the previous 6 months. In part 1 of the study, 21 patients were randomized to receive a single 5-mg tablet of rizatriptan or placebo in the migraine-free state. In part 2, the same patients were treated during migraine with rizatriptan 5-mg tablets (n=18) or placebo (n=3). Blood samples were obtained before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after dosing. The plasma concentration profile (ie, AUC((0-infinity)), C(max), T(max)) of rizatriptan 5-mg tablets administered during and between migraine attacks were comparable. The median T(max) for rizatriptan between and during attacks was 1 hour, indicating rapid absorption even during a migraine attack. Rizatriptan 5 mg was well tolerated and 67% of the patients experienced headache relief 2 hours postdose.

Pharmacokinetics and pharmacodynamics of avitriptan in patients with migraine after oral dosing.

Avitriptan (BMS-180048) is a 5-HT1-like receptor agonist for the treatment of migraine. This double-blind, placebo-controlled, randomized, parallel-group study evaluated the pharmacokinetics, safety, and preliminary efficacy of avitriptan in patients with migraine during migrainous and pain-free states. Patients met the IHS criteria for migraine with or without aura and suffered one to six migraines per month for at least 1 year. Patients in a clinic experiencing a migraine headache received avitriptan 75 mg, 150 mg, or 200 mg or matching placebo capsules. Blood samples were obtained before and 0.25, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours after dosing. Headache intensity was rated before and up to 6 hours after dosing. Seven to 30 days after the inclinic treatment, patients returned in a pain-free state for the same study medication. All pharmacokinetic and safety measures were repeated. Forty-eight patients (9 men and 39 women) participated. Peak plasma concentrations of avitriptan were achieved 1 to 2 hours following dosing in migraine and pain-free states for all doses. The pharmacokinetics of avitriptan were proportional to dose during a migraine attack over the 75- to 200-mg dose range. The 150- and 200-mg doses of avitriptan demonstrated a greater decrease in headache intensity scores at 2 hours postdose. The most common adverse event was paresthesia. Thus, avitriptan was rapidly absorbed, well tolerated, and demonstrated preliminary efficacy in this population.

Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer's disease.

INTRODUCTION: This study evaluates the activity of SDZ ENA 713, a centrally-selective acetylcholinesterase (AChE) inhibitor, in the cerebral spinal fluid (CSF) of patients with Alzheimer's disease (AD), and its relationship to central and peripheral pharmacokinetic parameters. METHODS: Eighteen AD patients were enrolled in this open-label, multiple-dose study. Patients were titrated in 1 mg bid/week increments to target doses of 1, 2, 3, 4, 5, or 6 mg bid SDZ ENA 713. After patients had been maintained at their target dose for at least 3 days, continuous CSF samples were obtained via a lumbar catheter for 12.5 h, beginning 0.5 h prior to the final dose of SDZ ENA 713. RESULTS: Dose-dependent inhibition of CSF AChE was significantly correlated (P < 0.05) with plasma drug and metabolite concentrations. The 6 mg bid treatment group showed a maximum mean inhibition of 62% at 5.6 h post-dose. CONCLUSION: Rapid, sustained, dose-dependent inhibition of CSF AChE suggests that SDZ ENA 713 has therapeutic potential in AD patients.

Initial safety, tolerability pharmacodynamics, and pharmacokinetics of CI-1007 in patients with schizophrenia.

CI-1007 is a novel dopamine autoreceptor agonist and partial dopamine D2/D3 agonist that is currently under development for the treatment of schizophrenia. This single-blind, rising, multiple-dose, inpatient bridging study was designed to evaluate the safety and tolerability of CI-1007 in consecutive panels of patients with schizophrenia. Following a 4-day placebo washout period, 16 patients (4 per panel) were assigned to receive one of four fixed-dosage regimens of CI-1007 (5, 10, 15, or 20 mg q12h for 9 doses). CI-1007 was generally well tolerated over the dose range evaluated. Adverse events, including mild to moderate sporadic orthostatic hypotension and/or nausea and vomiting, were most commonly observed after the initial drug dose and decreased after repeated dosing. Serum concentrations of growth hormone (GH) increased following the administration of CI-1007, confirming its central dopamine agonist activity. Changes in serum prolactin were not related to dose. The pharmacokinetics of CI-1007 and its active metabolite appear linearly related to dose. The results of this study suggest that patients with schizophrenia tolerate slightly higher initial doses of CI-1007 than do healthy subjects.

Safety and tolerability of metrifonate in patients with Alzheimer's disease: results of a maximum tolerated dose study.

Metrifonate, a pro-drug that is transformed non-enzymatically into a potent inhibitor of acetylcholinesterase (AChE), has been used in the tropics for over 30 years for the treatment of schistosomiasis. A pilot study, and Phase I and Phase II studies of metrifonate in Alzheimer's disease (AD) patients conducted prior to the current study showed benign, dose-dependent adverse event profiles consisting primarily of gastrointestinal events, optimal daily dosing with a loading phase (in the absence of a loading dose phase, 6-8 weeks were required to attain steady-state AChE inhibition levels), and an improvement in Alzheimer's Disease Assessment Scale (ADAS) scores. The current open-label study was designed to evaluate the safety and tolerability of relatively high loading doses, followed by lower maintenance doses of metrifonate in the same patient population, and to determine the maximum tolerated dose (MTD) of metrifonate. Accordingly, the first cohort of 8 probable AD patients (per National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria) were administered once-daily loading doses of 2.5 mg/kg (125-225 mg) for 14 days, followed by 4.0 mg/kg (200-360 mg) for an additional 3 days. These patients were maintained on once-daily doses of 2.0 mg/kg (100-180 mg) for 14 days. AChE inhibition for this cohort ranged from 88% to 94%. On Day 28 of 31, this cohort was discontinued due to moderate to severe side effects in 6 patients; consequently, the second cohort of 8 probable AD patients received a once-daily loading dose of 2.5 mg/kg (125-225 mg) for 14 days followed by a once-daily maintenance dose of 1.5 mg/kg (75-135 mg) for 35 days. This maintenance dose yielded an AChE inhibition level ranging from 89% to 91%. In spite of an AChE inhibition level comparable to that achieved with the higher dose, the reduced dose was associated with a more favorable adverse event profile which was mainly gastrointestinal and musculoskeletal in nature. The maximum tolerated dose was established at 1.5 mg/kg/day (75-135 mg/day) for maintenance dosing in AD patients.

A bridging study of LU 25-109 in patients with probable Alzheimer's disease.

Lu 25-109 is a functionally selective partial M1 agonist with M2/M3 antagonist properties. This double-blind, placebo-controlled, two-part, inpatient bridging study was designed to evaluate the safety and tolerability of multiple oral doses of Lu 25-109 in patients with Alzheimer's Disease(AD), and to determine the maximum tolerated dose (MTD) in this population. In the first part of the study, the fixed-dose MTD was to be determined in five consecutive panels of 6 patients each (4 Lu 25-109/2 placebo). Doses for the five panels were 100, 125, 150, 200, and 225 mg tid for 7 days. Cholinergic adverse events such as increased salivation, dizziness, and gastrointestinal symptoms were observed at all doses studied. The dosing of fixed-dose panels was discontinued after 3 days at 200 mg tid due to unacceptable gastrointestinal adverse events. Thus, 150 mg tid was defined as the fixed-dose MTD. The second part of the study, conducted in a single panel of 8 patients (6 Lu 25-109/2 placebo), was designed to determine if patients could tolerate higher doses of Lu 25-109 when administered on a titration regimen. Patients were to receive doses that were 50%, 75%, 100%, 125%, and 150% of the fixed dose MTD, with dose increases every five days. The first dose, 75 mg tid, was very well-tolerated; however, as in the first phase of the study, patients did not tolerate the 200 mg tid dose. Thus, the titration regimen employed did not improve the overall tolerability of Lu 25-109.

Monitoring of acute migraine attacks: placebo response and safety data.

In the course of evaluating the safety and efficacy of an investigational compound for acute migraine headaches, a large number of patients received placebo at a single site, offering the opportunity to characterize subjective and clinical physiologic responses of migraine patients to placebo in a controlled environment. In a single-site, double-blind, placebo-controlled study, 67 patients reported to the clinic while suffering a moderate to severe acute migraine headache and received oral placebo. For 6 hours after treatment, a continuous electrocardiogram (ECG) was performed, and headache severity, adverse events, and vital signs were recorded. Patients returned and repeated the procedure when free from pain. A headache was considered to be improved if its severity dropped to "mild" or "none." Twenty-five patients (37%; 95% CI: 26% to 50%) experienced headache improvement within 2 hours of receiving placebo, and 32 patients (48%: 36% to 60%) improved within 4 hours. There were no clinically important ECG changes during the migraine visit, and there were no clinically relevant differences in vital signs between the migraine and pain-free visits. Thus, a substantial placebo response occurs in migraine headache. Hemodynamic and ECG parameters are unchanged between migraine and pain-free states.

A bridging study of fananserin in schizophrenic patients.

Fananserin is a potential antipsychotic compound with high affinity for both D4 and 5-HT2A receptors, and negligible affinity for D2 receptors. Because the tolerance for antipsychotic compounds often differs between schizophrenic patients and healthy subjects, this bridging study was designed to evaluate the tolerability of fananserin, to define the slow titration maximum tolerated dose in the target population, and to identify the most rapid well-tolerated rate of titration for this compound. Three rates of titration regimens were examined in a total of 26 schizophrenic patients in a parallel group design, following a 3-day placebo washout period from previous antipsychotic medication. The slow rate of titration (reaching the maximum dose of 600 mg/day in 16 days with 100-mg increases every 3 days) was well tolerated, but a rapid titration schedule (reaching 600 mg/day in 8 days with 200-mg increases every 3 days) resulted in hypotension in 3 of 6 patients and termination of the group on Day 10. An intermediate rate of titration (reaching 600 mg/day in 10 days with 100-mg increases every 2 days) was then examined and was well tolerated, with transient episodes of mild hypotension reported in 2 of 10 patients. Thus, although hypotension was identified as the dose-limiting adverse event in this study, a reduction in the titration rate was effective in reducing the incidence and severity of this side effect. In this study, schizophrenic patients administered multiple doses of fananserin tolerated doses 400 percent greater than the maximum tolerated single dose in healthy volunteers.

Two rapid-dose titrations of sertindole in patients with schizophrenia.

The novel antipsychotic sertindole has demonstrated efficacy in psychosis with an extrapyramidal syndrome profile indistinguishable from placebo. Prior trials of sertindole have increased the dose by 4 mg every third day, whereas the present study evaluated the safety and tolerability of two, previously untested, more rapid dose escalation regimens. Sixteen schizophrenic inpatients entered a 4-day, single-blind placebo washout period in two consecutive groups. All patients received sertindole in 4-mg dose increments up to a maximum dose of 24 mg, which was maintained for 5 days. Dose increases were every other day for group 1 (N = 8) and daily for group 2 (N = 8). Adverse events, electrocardiograms, routine laboratory tests, and plasma sertindole concentrations were recorded. No patient was discontinued because of adverse events. The most frequent adverse events were tachycardia upon orthostatic challenge, nasal congestion, dry mouth, and headache; except for dry mouth, the incidence of these was greater in group 2. All cases of tachycardia were asymptomatic. No clinically significant laboratory abnormalities were detected in either group. In conclusion, 4-mg increases of sertindole every other day seems to be safe. Daily titration was, in general, not well tolerated.

Penetration of trovafloxacin into cerebrospinal fluid in humans following intravenous infusion of alatrofloxacin.

A single-dose study was conducted to determine concentrations of trovafloxacin (CP-99,219) achieved in the cerebrospinal fluid (CSF) relative to those in the serum of healthy subjects after intravenous infusion of alatrofloxacin (CP-116,517), the alanyl-alanyl prodrug of trovafloxacin. Twelve healthy subjects were administered single doses of alatrofloxacin at a trovafloxacin equivalent of 300 mg as an intravenous infusion over 1.0 h. CSF samples were taken by lumbar puncture at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 24 h after the start of the infusion; each subject was sampled at only one time point. Serum samples were taken from each subject at the time of CSF collection. A mean concentration of 5.8 microg of trovafloxacin per ml was present in serum 1.0 h after the start of the infusion. CSF/serum ratios ranged from 0.14 to 0.33 in the postdistribution phase (5 to 24 h postinfusion), with a mean ratio of 0.25. The most common adverse events were dizziness, nausea, and rash and were mild or moderate in intensity. The potency of trovafloxacin against susceptible organisms, coupled with its rapid penetration of CSF following the intravenous administration of alatrofloxacin, suggests that it may be useful in the treatment of bacterial meningitis in humans.

Establishing the maximum tolerated dose of lesopitron in patients with generalized anxiety disorder: a bridging study.

Lesopitron, a 5-hydroxytryptamine 1A agonist, is a new potential anxiolytic of the azapirone class. It has greater potency in animal models of anxiety than buspirone, gepirone, or ipsapirone, and it lacks the antidopaminergic effects associated with buspirone. Lesopitron has been tolerated at single doses up to 50 mg and repeated dosages of 45 mg/day in healthy volunteers. Forty-two patients with generalized anxiety disorder (GAD) were enrolled in this double-blind bridging study to determine the safety and tolerability of fixed doses of lesopitron (20, 25, 30, 40, 45, 50, and 60 mg two times a day) over a 6 1/2-day inpatient administration period. Each of the seven panels included six patients (four drug/two placebo). One patient in the 25-mg, two-times-a-day panel voluntarily withdrew because of increased anxiety symptoms. One patient experienced severe orthostatic hypotension at 60 mg two times a day, and moderate to severe adverse events (dizziness, lightheadedness, nausea, headache) occurred in two other patients at this dosage. The most commonly reported adverse events in all the panels were headache, dizziness, and nausea. Lesopitron is rapidly absorbed in patients, having a time to maximum concentration (Tmax) ranging from 0.5 to 1 hour, and its elimination half-life ranged from 1.1 to 5.6 hours. Peak plasma concentrations showed high interindividual variability for lesopitron, but increased linearly with dose for the main metabolite, 5-hydroxylesopitron. We defined the maximum tolerated dose in GAD patients as 50 mg two times a day, twice as high as the highest dose tested in healthy volunteers.