Associations Between MMPI-2-RF Internalizing RC Scales and Positive Characteristics.

Past studies indicate that the low scores on the MMPI and MMPI-2 Clinical and Content Scales can reflect positive characteristics. It is currently unclear, however, whether scales on the MMPI-2-Restructured Form (MMPI-2-RF) have that ability. Accordingly, we examined whether low scores on Restructured Clinical (RC) Scales assessing internalizing difficulties (i.

Measuring Positive Health Behaviors and Outcomes with Low Scores on MMPI-2-RF Somatic Scales.

Previous empirical studies have established that poor mental and physical health often cooccur. However, positive health behaviors and outcomes have been demonstrated to buffer against psychological dysfunction. Thus, the ability to assess for positive health behaviors and outcomes with instruments commonly used in practice, such as the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF), is important.

Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week.

Functional neurotoxicity evaluation of noribogaine using video-EEG in cynomolgus monkeys.

Introduction: Continuous video-electroencephalographic (EEG) monitoring remains the gold standard for seizure liability assessments in preclinical drug safety assessments. EEG monitored by telemetry was used to assess the behavioral and EEG effects of noribogaine hydrochloride (noribogaine) in cynomolgus monkeys. Noribogaine is an iboga alkaloid being studied for the treatment of opioid dependence.

Switching Opioid-Dependent Patients From Methadone to Morphine: Safety, Tolerability, and Methadone Pharmacokinetics.

The aim of this study was to switch patients established on methadone opioid substitution therapy (OST) to morphine over 1 week. Subjects established on daily methadone OST (mean dose 60 mg/day) were switched to morphine slow-release capsules, dosed at 4× the previous total daily methadone dose, for 6 days, then given morphine syrup dosed q3h. All 27 subjects enrolled in this study completed the switch from methadone to morphine.

Lost interest for existing compounds: New boosts.

Development of new drugs is typically thought of as a bottom-up endeavor where basic science identifies a target, various strategies are used to generate drugs that stimulate or inhibit the target, the drugs are first tested for safety and efficacy in animals and finally efficacy and safety are evaluated in a well defined clinical development process. However, this is not the only way that new drug products are developed. Many new products come from re-initiating development of discontinued drugs, finding new uses for existing drugs, creating a new product by obtaining marketing approval in expanded territories, obtaining approvals for new formulations or a single isomer of a previously approved racemic drug, converting products from prescription to over-the- counter use or converting folk medicines or vitamins to modern pharmaceuticals.

Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists.

Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities.

Conventional chemotherapy not only kills tumor cells but also changes gene expression in treatment-damaged tissues, inducing production of multiple tumor-supporting secreted factors. This secretory phenotype was found here to be mediated in part by a damage-inducible cell-cycle inhibitor p21 (CDKN1A). We developed small-molecule compounds that inhibit damage-induced transcription downstream of p21.

Phenserine efficacy in Alzheimer's disease.

To gather preliminary evidence in Alzheimer's disease (AD) for the efficacy of phenserine, a non-competitive acetylcholinesterase inhibitor that has independent modulatory effects on amyloid-β generation, a 12-week comparison of patients receiving phenserine (10 and 15 mg BID) or placebo was conducted under double-blind conditions. Patients who completed 12 weeks of the double-blind before others were continued in the double-blind to determine longer-term treatment effects. At 12 weeks, mean ADAS-cog (AD assessment scale-cognitive) changes from baseline were -2.

Pharmacokinetics and dose proportionality of extended-release metformin following administration of 1000, 1500, 2000 and 2500 mg in healthy volunteers.

The pharmacokinetics and dose-exposure relationship of an extended-release formulation of metformin (ER-metformin) was investigated in a randomized, single-dose, four-period crossover study in 24 healthy male volunteers. During each study period, subjects received a randomly assigned dose containing 1000, 1500, 2000 or 2500 mg metformin. Blood samples were drawn 0-72 h after dosing for pharmacokinetic and dose-proportionality assessment.

Efficacy of once-daily extended-release lovastatin as compared to immediate-release lovastatin in patients with hypercholesterolemia.

Objective: to compare the efficacy and safety of 20 mg of lovastatin when administered once daily as an extended-release (ER) tablet or as an immediate-release (IR) tablet.

Research Design And Methods: Male or female patients aged 21-70 years with hypercholesterolemia who provided written informed consent and met the inclusion criteria were screened. A total of 179 patients were enrolled: 100 male and 79 female; 153 were Caucasian, eight Black and 18 other races; the mean age was 56 years.

Cholesterol depletion with physiological concentrations of a statin decreases the formation of the Alzheimer amyloid Abeta peptide.

Epidemiological studies have demonstrated that hypercholsterolemia is a significant risk factor for Alzheimer's disease (AD). The mechanism by which increased cholesterol may contribute to AD is unknown. However, as the generation and accumulation of the amyloid Abeta peptide in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels can regulate Abeta formation and/or clearance.

Pharmacokinetics of lovastatin extended-release dosage form (Lovastatin XL) in healthy volunteers.

The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended-release dosage form (ER-lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER-lovastatin either 10, 20 or 40 mg in a three-way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period.

Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients.

Epidemiological studies demonstrate that hypercholesterolemia is a risk factor for Alzheimer's disease (AD). As the generation and accumulation of the beta-amyloid peptide (Abeta) in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels regulate Abeta formation and/or clearance. To test the effects of altering cholesterol on Abeta formation, we incubated cells with or without lovastatin acid, the active metabolite of the HMG-CoA reductase inhibitor lovastatin, and measured the fraction of Abeta formed from its precursor under each condition.

A multiple-dose pharmacodynamic, safety, and pharmacokinetic comparison of extended- and immediate-release formulations of lovastatin.

Background: Because lovastatin is efficiently extracted by the liver and because its administration in divided doses is associated with increased efficacy, an extended-release (ER) formulation may have the potential for a dose-sparing advantage relative to the immediate-release (IR) formulation in the treatment of hypercholesterolemia.

Objective: This study compared the short-term pharmacodynamics, safety, and pharmacokinetics of multiple doses of lovastatin ER with those of lovastatin IR in patients with fasting low-density lipoprotein cholesterol (LDL-C) levels between 130 and 250 mg/dL and fasting triglyceride levels < 350 mg/dL.

Methods: The study had a randomized, single-blind, positive-controlled, 2-way crossover design, with a 4-week diet/placebo run-in period and two 4-week active-treatment periods.

Comparative pharmacokinetics of lovastatin extended-release tablets and lovastatin immediate-release tablets in humans.

The pharmacokinetics of lovastatin and its active metabolite lovastatin acid was evaluated in 9 healthy subjects in a three-period crossover study following a single oral dose of lovastatin extended-release (ER) tablets and lovastatin immediate-release (IR) tablets. Participants were dosed with lovastatin IR 40 mg tablets following a standard breakfast, lovastatin ER 40 mg tablets following a standard breakfast, and lovastatin ER 40 mg tablets underfasting conditions. Serial plasma samples were collected for up to 48 hours postdose and assayed for lovastatin and lovastatin acid using a liquid chromatography/mass spectroscopy/mass spectroscopy method.

Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide.

The deposition of beta-amyloid (A beta) in neuronal plaques is believed to be crucial for the initiation and progression of Alzheimer's disease (AD). Studies in vitro have shown that inhibiting cholesterol metabolism with lovastatin, or its active metabolite lovastatin acid, lowers A beta production. To examine the effects of lovastatin on A beta in vivo, human subjects who had elevated low-density lipoprotein cholesterol were treated during a double-blind, randomized, placebo-controlled study with 10, 20, 40 or 60 mg once-daily doses of a controlled-release formulation of lovastatin, or matching placebo.

A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia.

Background: Endotoxin (lipopolysaccharide [LPS]) has been associated with sepsis and the high mortality rate seen in septic shock. The administration of a small amount of LPS to healthy subjects produces a mild syndrome qualitatively similar to that seen in clinical sepsis. We used this model to test the efficacy of an endotoxin antagonist, E5531, in blocking this LPS-induced syndrome.

The effects of donepezil in Alzheimer's disease - results from a multinational trial.

Donepezil has been shown to be well tolerated and to improve cognition and global function in patients with mild to moderately severe Alzheimer's disease (AD). The current trial was undertaken to investigate further the efficacy and safety of donepezil, in a multinational setting, in patients with mild to moderately severe AD. This 30-week, placebo-controlled, parallel-group study consisted of a 24-week, double-blind treatment phase followed by a 6-week, single-blind, placebo washout.

An evaluation of the pharmacokinetics of donepezil HCl in patients with moderately to severely impaired renal function.

Aim: The aim of this study was to evaluate the pharmacokinetics of donepezil HCl (5 mg) in patients with moderately to severely impaired renal function (creatinine clearance: <30 ml min(-1) 1.73 m(-2)), following the administration of single oral doses.

Methods: This was an open-label, non-randomized study in patients with compromised renal function (n=11), and in age- and gender-matched healthy controls (n =11).

An evaluation of the pharmacokinetics of donepezil HCl in patients with impaired hepatic function.

Aim: The aim of this study was to evaluate the pharmacokinetic profile of donepezil HCl (5 mg) in patients with impaired hepatic function, following the administration of single oral doses.

Methods: This was an open-label, non-randomized study comparing the pharmacokinetic profile of donepezil in male volunteers with chronic compensated cirrhosis of the liver (n = 10) to that in healthy age- and sex-matched controls (n = 10). Each subject received a single 5 mg oral dose of donepezil.

The effect of multiple doses of donepezil HCl on the pharmacokinetic and pharmacodynamic profile of warfarin.

Aim: The aim of the study was to examine the pharmacokinetic and pharmacodynamic profiles of single doses of warfarin (25 mg) following administration alone, and in combination with multiple doses of donepezil HCl (10 mg day(-1)) in healthy volunteers.

Methods: This was an open-label, two-period crossover study in 12 healthy male volunteers, aged 18-55 years, who were randomized to one of the following treatment groups: (A) donepezil administered for 19 consecutive days with a single dose of warfarin administered on day 14. On day 20, there was a 21-day washout period after which a single dose of warfarin was again administered, and (B) an initial 13-day period with no medication, then a single dose of warfarin administered alone on day 14, followed by a 14-day washout period.

Concurrent administration of donepezil HCl and digoxin: assessment of pharmacokinetic changes.

Aim: The aim of this study was to examine the pharmacokinetics of donepezil HCl and digoxin separately, and in combination, following administration of single oral doses. Changes in cardiac conduction parameters following drug administration were also assessed.

Methods: This was an open-label, randomized, three-period crossover study in healthy male volunteers (n=12).