The pharmacokinetics of continuous subcutaneous levodopa/carbidopa infusion: Findings from the ND0612 clinical development program.

Background: While treatment with levodopa remains the cornerstone of Parkinson's disease (PD) management, chronic oral therapy is often associated with the development of motor complications, that correlate to fluctuating levodopa plasma concentrations, limiting its clinical utility. Continuous infusion is considered to be the optimal delivery route for treating PD patients with motor fluctuations, but current infusion systems require invasive surgery. Subcutaneous infusion of (SC) levodopa has the potential to provide a better tolerated and more convenient route of continuous levodopa delivery.

Population Pharmacokinetic Modeling and Simulation of TV-46000: A Long-Acting Injectable Formulation of Risperidone.

TV-46000 is a long-acting subcutaneous antipsychotic that uses a novel copolymer drug delivery technology in combination with a well-characterized molecule, risperidone, that is in clinical development as a treatment for schizophrenia. A population pharmacokinetic (PPK) modeling and simulation approach was implemented to identify TV-46000 doses and dosing schedules for clinical development that would provide the best balance between clinical efficacy and safety. The PPK model was created by applying pharmacokinetic data from a phase 1 study of 97 patients with a diagnosis of schizophrenia or schizoaffective disorder who received either single or repeated doses of TV-46000.

ND0701, A Novel Formulation of Apomorphine for Subcutaneous Infusion, in Comparison to a Commercial Apomorphine Formulation: 28-Day Pharmacokinetic Study in Minipigs and a Phase I Study in Healthy Volunteers to Assess the Safety, Tolerability, Pharmacokinetics and Relative Bioavailability.

Background: Subcutaneous apomorphine is used for the treatment of Parkinson's disease (PD); however, infusion site reactions are a common adverse event (AE), which can lead to treatment discontinuation. Apomorphine formulations that are more tolerable and convenient for use are needed.

Objective: Our aim was to compare the toxicity and bioavailability of ND0701, a new concentrated formulation of apomorphine free base, with one of the commercially available apomorphine HCl formulations (APO-go, Britannia Pharmaceuticals Ltd).

Reversal of apixaban anticoagulation by four-factor prothrombin complex concentrates in healthy subjects: a randomized three-period crossover study.

Unlabelled: Essentials Prothrombin complex concentrates (PCCs) may reverse the effect of factor Xa (FXa) inhibitors. We conducted an open-label, randomized, placebo-controlled, three-period crossover study in 15 subjects. Both PCCs rapidly reversed apixaban-mediated decreases in mean endogenous thrombin potential.

Relative Bioavailability of Apixaban Solution or Crushed Tablet Formulations Administered by Mouth or Nasogastric Tube in Healthy Subjects.

Purpose: Crushed tablet and solution formulations of apixaban administered orally or via a nasogastric tube (NGT) may be useful in patients unable to swallow solid dose formulations. It is important to understand whether new formulations and/or methods of administration impact apixaban bioavailability and pharmacokinetic properties. These studies evaluated the relative bioavailability (Frel) of apixaban solution administered orally; oral solution administered via NGT flushed with either 5% dextrose in water (D5W) or with infant formula; oral solution via NGT with a nutritional supplement; and crushed tablet suspended in D5W and administered via NGT.

Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes.

Aims: Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, has been shown to lower glycated hemoglobin (HbA1c), weight, blood pressure and serum uric acid in clinical trials. Plasma lipids were also evaluated as exploratory variables. The goal of this study was to estimate the long-term cardiovascular (CV) and microvascular outcomes of dapagliflozin added to the standard of care (SOC) versus SOC using simulation methodology.

The use of clinical utility assessments in early clinical development.

A quickly realizable benefit of model-based drug development is in reducing uncertainty in risk/benefit, comprising individually of safety and effectiveness, two key attributes of a product evaluated for regulatory approval, marketing, and use. In this review, we investigate gaps and opportunities in using fundamental decision analytic principles in drug development and present a quantitative clinical pharmacology framework for the application of such aids for early clinical development decision making. We anticipate that implementation of such emerging tools will enable sufficient scientific understanding of the two attributes to facilitate the early termination of compounds with less than desirable risk/benefit profiles and continuance of compounds with acceptable risk/benefit profiles.

Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist.

Objective: Exercise increases fatty acid oxidation (FAO), improves serum high density lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)delta expression. In parallel, PPARdelta agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metabolism, as suggested in preclinical models.

Methods And Results: Healthy volunteers were allocated placebo (n=6) or PPARdelta agonist (GW501516) at 2.

Posttranslational control of a cardiac ion channel transgene in vivo: clarithromycin-hMiRP1-Q9E interactions.

The present study investigates a novel gene therapy approach for atrial arrhythmias, using a clarithromycin-responsive ion channel subunit mutation, hMiRP1-Q9E, cloned into an expression plasmid; wild-type expression plasmids encoding human minK-related protein 1 (hMiRP1) were also used as controls. In a series of pig studies, right atrial myocardium was injected at one site with hMiRP1-Q9E plasmid DNA; a separate site in the same right atrium was injected with wild-type plasmid or was sham injected. Two weeks after transfection intravenous clarithromycin administration resulted in a site-specific, dose-dependent prolongation of the repolarization phase of the right atrial epicardial monophasic action potential (MAP) only at the hMiRPQ9E sites, but not at sham or wild-type sites.

DNA delivery from an intravascular stent with a denatured collagen-polylactic-polyglycolic acid-controlled release coating: mechanisms of enhanced transfection.

We previously demonstrated that DNA-polylactic-polyglycolic acid (PLGA)-coated stents can deliver genes to the arterial wall with reporter expression involving 1% of neointimal cells. The present study investigated a novel formulation utilizing denatured collagen in DNA-stent coatings; denatured collagen was hypothesized to enhance gene transfer due to adhesion molecule interactions and actin-related mechanisms. Arterial smooth muscle cells (SMCs) cultivated on denatured collagen had significantly greater plasmid DNA (beta-galactosidase) transfection than SMC grown on native collagen (18.

The incorporation of an ion channel gene mutation associated with the long QT syndrome (Q9E-hMiRP1) in a plasmid vector for site-specific arrhythmia gene therapy: in vitro and in vivo feasibility studies.

The present studies investigated the cardiac potassium channel missense mutation, Q9E-hMiRP1, for potential use as a gene therapy construct for cardiac arrhythmias. This gene abnormality is one of a number of mutations that can cause the long QT syndrome (LQTS), a hereditary arrhythmia disorder that is associated with sudden death. However, individuals who carry the Q9E-hMiRP1 variant are predisposed to developing the LQTS only after clarithromycin administration.

A signal transduction pharmacodynamic model of the kinetics of the parasympathomimetic activity of low-dose scopolamine and atropine in rats.

We used a novel pharmacokinetic-pharmacodynamic (PK-PD) approach that had been applied for signal transduction kinetics to investigate the kinetics of the parasympathomimetic effect of scopolamine and atropine in rats. The parasympathetic tone was assessed by continuous measurement of the power of the high frequency band (HF) of electrocardiogram (ECG) R-R intervals obtained by power spectral analysis (PSA) of heart rate variability (HRV). To overcome the inherent noise of the HRV-HF data and to quantitatively identify temporal changes in the autonomic tone, a new approach of stepwise regression of the cumulative HF data was applied.

Scaling vs. nonscaling methods of assessing autonomic tone in streptozotocin-induced diabetic rats.

We studied heart rate variability in rats by power scaling spectral analysis (PSSA), autoregressive modeling (AR), and detrended fluctuation analysis (DFA), assessed stability by coefficient of variation between consecutive 6-h epochs, and then compared cross-correlation among techniques. These same parameters were checked from baseline conditions through acute and chronic disease states (streptozotocin-induced diabetes) followed by therapeutic intervention (insulin). Cross-correlation between methods over the entire time period was r = 0.

Power spectral analysis of heart rate variability in rats as a quantitative tool in the PK-PD analysis of the parasympatholytic activity of atropine.

Purpose: To utilize power spectral analysis (PSA) of heart rate variability (HRV) as a pharmacodynamic (PD) measure of atropine parasympathetic effect, and to model the kinetics of action.

Methods: Heart rate data was collected following atropine administration to rats and was analyzed off-line for high frequency peaks by PSA of HRV as a measure of parasympathetic tone. A temporal cumulative approach (TCA) detected transient changes in parasympathetic activity.

Cumulative plot of heart rate variability spectrum assesses kinetics of action of cholinergic drugs in rats.

A new approach to assess autonomic nervous system (ANS) activity and its response to drug action is presented. Our approach is based on the use of a cumulative plot of data obtained by power spectral analysis of heart rate variability, in defined frequency bands, during short time epochs (e.g.

The effect of cimetidine on the pharmacodynamics of theophylline-induced seizures and ethanol hypnotic activity.

Due to its availability as an over-the-counter drug, the use of cimetidine is increasing, thus adverse interactions with other commonly used agents may also increase. The aim of this study was to investigate whether acute administration of cimetidine could alter the pharmacodynamics of theophylline neurotoxicity and the hypnotic action of ethanol. To examine these questions, rats received a dose of 77 mg/kg cimetidine followed by a constant infusion of either theophylline (1.

The anticonvulsant effect of deprenyl on pentylenetetrazol-induced seizures in Lewis rats.

There is recent evidence that deprenyl may have anticonvulsant action in a rat kindling model of epilepsy as well as in a maximal electroshock model. We therefore investigated the effect of deprenyl on the brain sensitivity threshold to pentylenetetrazol (PTZ)-induced maximal seizures in Lewis rats, in a model that provides pharmacodynamic information free of pharmacokinetic interference. The novel finding of this investigation was the anticonvulsant effect of deprenyl following repetitive administration whereas a single deprenyl dose did not affect the PTZ concentrations required to induce maximal seizures.

The aging thyroid. II. An immunocytochemical analysis of the age-associated lesions.

This study utilizing immunocytochemical techniques consists of two segments, 1) an analysis of the changes with age in the hormone content of normal, involuting, macro- and microfollicles, as well as calcitonin (C) cells, and 2) an analysis of the components of the lesion characteristic of lymphocytic thyroiditis. Involuting and macro- (cystic) follicles show a decline in hormone content with age, while microfollicles show a variable pattern with some showing a high and others a low content, as well as some showing an absence of hormone. There also appears to be an increase with age in hormone-containing C cell micronodules, but we were unable to demonstrate a decline in hormone content of individual C cells.

The aging thyroid. I. A description of lesions and an analysis of their age and sex distribution.

Two types of follicular change in the thyroid are described. The first represents an involutional change in which colloid cysts (macrofollicles) are often found. The second represents a hyperplastic-dysplastic (microfollicular) lesion.

Thyroid hormone levels during glucose tolerance test in euthyroid subjects.

Twelve normal, healthy, clinically and biochemically proven euthyroid volunteer subjects (age 19-35) were administered a standard glucose tolerance test (100 g glucose orally) and thyroxine (T4), triiodothyronine (T3) and reverse triiodothyronine (rT3) levels were determined by specific radioimmunoassays to determine the acute effect of glucose and insulin on peripheral monodeiodination of thyroxine. The fasting levels of T4, T3, rT3 and free thyroxine were 82.4 nmol/l, 1.

Effect of pregnancy on thyroxine binding globulin (TBG) in partial TBG deficiency.

An unusual opportunity was afforded to study the effect of endogenous increase in estrogen on thyroxine binding globulin (TBG) throughout pregnancy in a partially TBG-deficient female who conceived subsequent to initial examination. TBG binding of 125I-thyroxine (T4) before and up to four months of pregnancy was low in comparison to normal. Starting from six months and up to the end of pregnancy, TBG activity showed a definite increase although still below normal.

Studies on obesity. III. effect of triiodothyronine (T3) on thyroglobulin autoantibodies in euthyroid obese subjects.

Effect of T3 therapy on tanned red cell agglutinating thyroglobulin (TRC-TG) antibodies in 10 obese subjects without apparent thyroid disease was investigated. Six other obese subjects without thyroid dysfunction and of approximately the same mean age who also had circulating TRC-TG antibodies served as control subjects and were untreated. In vitro thyroid tests (TSH, total and free T4) performed before T3 therapy, as well as clinical examination, showed thyroid function to be normal in all subjects, and there was no evidence of thyroiditis.