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.

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.

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.

Placebo-controlled evaluation of three doses of a controlled-onset, extended-release formulation of verapamil in the treatment of stable angina pectoris.

This double-blind, placebo-controlled, parallel-group, multicenter study was designed to evaluate the safety and efficacy of a new controlled-onset, extended-release formulation of verapamil hydrochloride called physiologic pattern release (PPR) verapamil. The study was conducted at 24 sites (13 United States, 5 Canada, 6 overseas; see Appendix). Following a 1- to 3-week single-blind placebo lead-in period, 278 patients with chronic stable angina pectoris (247 males, 31 females, mean age 60.8 years, range 32 to 78) were randomly assigned to 1 of 4 once-daily, fixed-dose treatment groups: verapamil 180, 360, or 540 mg, or placebo. PPR verapamil at all doses significantly increased (p < 0.05) time to moderate angina and symptom-limited exercise duration, and verapamil 360 mg significantly increased (p < 0.05) time to > or = 1 mm ST-segment depression, after 4 weeks of treatment when assessed 24 hour after the previous dose. Larger doses of verapamil were associated with proportionately greater improvements in exercise tolerance. Frequency of anginal attacks was also reduced by verapamil. The most frequently observed adverse events were dizziness, headache, constipation, and nausea. The incidence of constipation was high (20.9%) within the 540 mg treatment group. This verapamil formulation can be clinically titrated within a 180 to 540 mg dosing range, permitting effective once-daily administration for the treatment of chronic stable angina.

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.

Pharmacoeconomics of piperacillin/tazobactam and imipenem/cilastatin in the treatment of patients with intra-abdominal infections.

Costs involved in using piperacillin 4 g/tazobactam 500 mg, given as intermittent intravenous infusions every 8 hours, were compared with those for imipenem/cilastatin 500 mg, given as intermittent intravenous infusions every 6 hours, for the treatment of patients with gangrenous or perforated appendicitis. A total of 88 patients were included in our cost analyses: 42 patients in the piperacillin/tazobactam group and 46 patients in the imipenem/cilastatin group. Durations (mean +/- SD) of antibiotic therapies were 7.8 +/- 3.3 days and 7.1 +/- 2.6 days for the piperacillin/tazobactam and imipenem/cilastatin groups, respectively. No statistical significance was found for the difference in duration of therapy (P = 0.376). Total drug treatment costs were $538.83 +/- $385.33 for the piperacillin/tazobactam group and $687.66 +/- $345.37 for the imipenem/cilastatin group. This difference in treatment cost was statistically significant (P = 0.0001). The need for laboratory tests and the use of other medications were not different between the two groups. Total hospital-days charges were higher for the piperacillin/tazobactam group ($18,339.76 +/- $6090.38) compared with the imipenem/cilastatin group ($16,150.00 +/- $5088.60) (P = 0.052). These findings suggest that length of hospital stay should be the economic focus of antibiotic therapy.

Piperacillin-tazobactam pharmacokinetics in patients with intraabdominal infections.

STUDY OBJECTIVE: To determine the appropriate compartmental and noncompartmental pharmacokinetic parameters for intravenous piperacillin and tazobactam. DESIGN: Sequential selection of patients entered into a randomized, open-label clinical efficacy trial. SETTING: Los Angeles County-University of Southern California Medical Center. PARTICIPANTS: Sequential sample of 18 patients admitted for intraabdominal infections and consented into a comparative antibiotic trial. INTERVENTIONS: Patients received piperacillin 4 g plus tazobactam 500 mg by intravenous intermittent infusion every 8 hours. MEASUREMENTS AND MAIN RESULTS: The estimated noncompartmental pharmacokinetic parameters (mean +/- SD) for piperacillin and tazobactam, respectively, were as follows: maximum concentration in plasma 218.7 +/- 48.9 micrograms/ml and 27.8 +/- 9.1 micrograms/ml; half-life 1.07 +/- 0.22 hours and 1.00 +/- 0.27 hours; elimination rate constant 0.67 +/- 0.13 hr-1 and 0.73 +/- 0.18 hr-1; area under the concentration-time curve from zero hour to infinity 288.5 +/- 71.25 mg.hr/L and 36.3 +/- 9.55 mg.hr/L; total plasma clearance 14.75 +/- 3.93 L/hour and 14.78 +/- 4.39 L/hour; renal clearance 5.69 +/- 1.94 L/hour and 7.85 +/- 3.37 L/hour; volume of distribution at steady state 21.00 +/- 4.18 L and 22.47 +/- 8.27 L; and mean residence time 1.72 +/- 0.29 hours and 1.79 +/- 0.35 hours. CONCLUSION: Our findings were similar to those in other surgical patient models. The two-compartmental model best described piperacillin and tazobactam disposition in our patients. Bayesian analyses of the two-compartment models of piperacillin and tazobactam were able to predict trough, peak, and 2-hour postadministration levels without bias.

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.

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.

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.

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.

Evaluation of cycloserine in the treatment of Alzheimer's disease.

This multicenter study evaluated the efficacy and safety of cycloserine and measured its effects on explicit and implicit memory tests in patients with Alzheimer's disease (AD). Four hundred ten patients with AD, aged 50 years or older, were enrolled in this parallel-group, double-blind, placebo-controlled, randomized trial of 5, 15, or 50 mg cycloserine or placebo twice daily, and 403 entered the double-blind treatment phase. Two hundred sixty-five patients completed the entire 26-week treatment phase. There were no baseline differences among the four treatment groups. Cognitive Drug Research (CDR) efficacy assessments showed no differences between active treatments and placebo from baseline to study weeks 2, 6, 14, or 26. Patients receiving 15 mg of cycloserine improved significantly on one section of an implicit memory test. No differences among treatments were observed for any other assessment scales evaluated. The incidence and severity of adverse events were similar across treatment groups. Cycloserine was well tolerated but did not demonstrate consistent evidence of efficacy during the course of therapy. Higher doses may be necessary to achieve efficacy in the AD population and do not appear to be precluded by the adverse event profile seen in this study.

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.

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.

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).

Comparison of aminoglycoside pharmacokinetics in Asian, Hispanic, and Caucasian patients by using population pharmacokinetic methods.

A population pharmacokinetic model for aminoglycosides was developed from 24 Hispanic, 16 Asian, and 22 Caucasian patients. A nonparametric expectation maximization algorithm for population modeling was used. With this one-compartment model, the parameters were the slope of the apparent volume of distribution versus weight (VS) and the slope of the elimination rate constant versus the creatinine clearance rate (KS). The mean VS (+/- standard deviation) was not different at 0.264 (+/- 0.05), 0.248 (+/- 0.055), and 0.260 (+/- 0.080) liter/kg of body weight for Asian, Hispanic, and Caucasian populations, respectively (P > 0.10). The KS means +/- standard deviations were 0.00424 +/- 0.00129, 0.00404 +/- 0.00160 and 0.00394 0.00103 [h(ml/min/1.73 m2)]-1 +/- for Hispanic, Asian, and Caucasian populations, respectively. Again, there was no statistical difference among the groups (P > 0.10). In conclusion, there are no differences in aminoglycoside pharmacokinetics among Asian, Hispanic, and Caucasian patients.

Orthostasis in Alzheimer disease: a retrospective analysis.

Vitiello et al. (1993) recently reported statistically significant decreases in systolic blood pressure upon standing in patients with Alzheimer disease (AD) (n = 60) as compared with healthy elderly controls (n = 20), which would suggest a possible autonomic dysfunction associated with AD. To investigate this issue, we conducted a retrospective analysis of blood pressures and heart rates of 31 patients 55-85 years of age (mean 69.6) who met National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association criteria for probable AD. The patients were selected from a pool of placebo-treated patients with AD in five inpatient phase I clinical trials. All patients met rigorous entrance criteria and thus were in excellent physical health except for AD. Blood pressure and pulse were assessed after 3-5 min of lying down and after 1-3 min of standing. Systolic and diastolic blood pressures showed decreases upon standing of 12 mm Hg (8.6%) and 6 mm Hg (8.2%), respectively, on day 1 and decreases of 10 mm Hg (7.6%) and 4 mm Hg (5.7%), respectively, on day 7 of hospitalization (p < 0.05). Pulse rates increased upon standing by 17% and 13% on days 1 and 7, respectively (p < 0.05). Our data support the finding of Vitiello et al. of significant postural decreases in systolic blood pressure in patients with AD. Well-controlled, prospective studies of orthostasis in AD and healthy elderly subjects should be conducted to determine its prevalence in both populations and to determine whether the orthostatic changes seen in AD differ from those in normal aging.

Stability of piperacillin sodium-tazobactam sodium and ranitidine hydrochloride in 0.9% sodium chloride injection during simulated Y-site administration.

The stability of piperacillin sodium plus tazobactam sodium and ranitidine hydrochloride in 0.9% sodium chloride injection during simulated Y-site administration was studied. Triplicate test solutions of piperacillin 40 mg/mL plus tazobactam 5 mg/mL (as the sodium salts) or piperacillin 80 mg/mL plus tazobactam 10 mg/mL (as the sodium salts) were mixed 1:1 with ranitidine 0.5 and 2.0 mg/mL (as the hydrochloride salt). The solutions were stored at 23 degrees C, and samples were removed at zero, one, two, and four hours for measurement of drug concentration by stability-indicating high-performance liquid chromatography. At the time of sampling and before any dilution, each sample was visually inspected for color and precipitation, and pH was determined. At all sampling times, the concentrations of piperacillin, tazobactam, and ranitidine were > 90% of initial concentrations. There were no substantial changes in pH or color. Tazobactam 5 mg/mL (as the sodium salt) and ranitidine 0.5 and 2 mg/mL (as the hydrochloride salt) in 0.9% sodium chloride injection were stable for up to four hours during simulated Y-site administration. Piperacillin 80 mg/mL plus tazobactam 10 mg/mL (as the sodium salts) and ranitidine 0.5 and 2 mg/mL (as the hydrochloride salt) were stable for up to four hours during simulated Y-site administration.

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.

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.