PURPOSE: Dabigatran etexilate is an oral, reversible, direct thrombin inhibitor licensed for the prevention of venous thromboembolism and stroke prevention in patients with atrial fibrillation. The aim of this study was to investigate whether, and to what extent, a switch from enoxparin to dabigatran etexilate affects the pharmacokinetic (PK) and ...

Objectives: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis. Methods: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy (1H-MRS) measurements were performed prior to initiation and following three months of treatment in ...

Peripheral aromatic amino acid decarboxylase (AADC) inhibitors, such as benserazide, are routinely used to potentiate the effects of L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease (PD) and in experimental models of PD. However, there is little information available on the optimal dose or the timing of administration relative to L-DOPA treatment. We ...

RATIONALE: Preclinical evidence indicates that D(1) dopamine receptor full agonists have potential as therapeutic agents for a variety of neurological conditions. Dihydrexidine (DHX) was the first high potency selective D(1) dopamine receptor full agonist and has been studied as a possible treatment for Parkinson's disease (PD). Recently, we discovered doxanthrine ...

Since peripheral sensory neuropathy is the major, clinically relevant side effect of sagopilone we investigated the general and peripheral neurotoxicity of sagopilone administered intravenously with different doses (1.2 and 2.4 mg/kg) and schedules in 48 Wistar rats and we performed in parallel a pharmacokinetic/pharmacodynamic (PK/PD) study. A trend toward a different ...

Background and purpose:  Catechol-O-methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levodopa/carbidopa intestinal gel infusion dose can be reduced by 20% without worsening of motor fluctuations and levodopa concentration stability when oral catechol-O-methyltransferase inhibitors are added. Methods:  A short-term, randomized, partly blinded, ...

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Current treatments for PD focus on dopaminergic therapies, including L-dopa and dopamine receptor agonists. However, these treatments induce neuropsychiatric side effects. Psychosis, characterized by delusions and hallucinations, is one of the most serious such side effects. ...

BACKGROUND: Intermittent peritoneal dialysis (IPD) is an old strategy that has generally been eclipsed, in the home setting, by daily peritoneal therapies. However, for a select group of patients with exhausted vascular access or inability to receive PD at home, in-center IPD may remain an option or may serve as ...

Vallé, M., Schneider, M., Galland, D., Giboin, H., Woehrlé, F. Pharmacokinetic and pharmacodynamic testing of marbofloxacin administered as a single injection for the treatment of bovine respiratory disease. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365-2885.2011.01350.x. New approaches in Pharmacokinetic/Pharmacodynamic (PK/PD) integration suggested that marbofloxacin, a fluoroquinolone already licensed for the treatment ...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Cisatracurium is a non-depolarising neuromuscular blocking drug used in anaesthesia and Intensive Care. Cisatracurium degrades at physiological pH via Hofmann elimination. Therefore, the elimination of cisatracurium may be from both plasma and tissues. Critically ill patients may have or develop resistance to non-depolarising ...

PURPOSE: To identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the first-in-class, oral CDK4/6 inhibitor PD 0332991 administered once daily (QD) for 21 of 28 days (3/1 Schedule) in patients with retinoblastoma protein (Rb)-positive advanced solid tumors, and to describe pharmacokinetic-pharmacodynamic relationships relative to drug effects.EXPERIMENTAL DESIGN: ...

PURPOSE: The pharmacokinetic (PK)-pharmacodynamic (PD) relationship of amrubicin and its active metabolite, amrubicinol, has only been evaluated using trough levels of these agents since the full PK profiles not yet been clarified so far. This study was performed to analyze the full PK profiles of amrubicin and amrubicinol and to ...

ABSTRACT: INTRODUCTION: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the humanized anti-CD4 monoclonal antibody MTRX1011A in a randomized, double-blind placebo-controlled Phase 1 study in patients with rheumatoid arthritis (RA). METHODS: In the single ascending dose (SAD) portion of the study, patients received single doses of placebo ...

BACKGROUND: The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)-approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen. OBJECTIVES: The primary study objective was to predict the ...

What is already known about the subject: - The concentration-effect relationship of rituximab in follicular lymphoma (FL) was previously described using pharmacokinetic-pharmacodynamic (PK-PD) modelling. - The influence of genetic polymorphism of FCGR3A on rituximab efficacy in FL patients was included in this PK-PD model. - Previous studies suggest that increasing ...

Objective  To evaluate the changes in intraocular pressure (IOP) and pupil size in 12 Beagles with inherited glaucoma after instillations of 0.033, 0.0033, 0.001, 0.00033, and 0.0001% travoprost (Travatan®-Alcon Laboratories, Inc., Ft Worth, TX, USA) in multiple single-dose studies. Procedures  Intraocular pressure and pupil diameter (PD) measurements were obtained at ...

It is known that β(2) -microglobulin (β(2) -MG) concentration in peritoneal dialysis (PD) patients is inversely correlated to the residual renal function (RRF). With decreasing RRF, some PD patients may necessarily be treated with hemodialysis (HD) once a week, not only for removing excess water and small solutes, but also ...

INTRODUCTION: Epidemiologic studies consistently find an inverse association between caffeine use and PD. Numerous explanations exist, but are difficult to evaluate as caffeine's symptomatic effect and tolerability in PD are unknown. PATIENTS AND METHODS: We designed an open-label, 6-week dose-escalation study of caffeine to establish dose tolerability and evaluate potential ...

Safinamide is an α-aminoamide with both dopaminergic and nondopaminergic mechanisms of action evaluated as an add-on to dopamine agonist (DA) therapy in early-stage PD. In this 24-week, double-blind study, patients with early PD receiving a stable dose of a single DA were randomized to once-daily safinamide 100 mg, safinamide 200 ...

BACKGROUND: Darbepoetin alfa (KRN321) is a recombinant protein that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its longer half-life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. The efficacy and safety ...

Pramipexole extended release (ER) is a new once-daily formulation of pramipexole, a nonergot dopamine agonist, which is available in five dosage strengths: 0.26 (0.375) mg, 0.52 (0.75) mg, 1.05 (1.5) mg, 2.1 (3) mg and 3.15 (4.5) mg (all doses are expressed in terms of pramipexole base and the corresponding ...

Background: Parkinson's disease (PD) is associated with autonomic dysfunction and chronic levodopa therapy has been reported to impair the autonomic control of heart rate. Aim: Our aim was to assess the immediate effect of a single dose of levodopa on heart rate variability (HRV) in idiopathic PD. Materials and Methods: ...

Background:To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacokinetics (PK) and pharmacodynamics (PD) of higher doses of erlotinib.Methods:Patients ...

The pharmacokinetics-pharmacodynamics (PK-PD) breakpoint of piperacillin/tazobactam (PIPC/TAZ) for hospital-acquired pneumonia (HAP) and Pseudomonas aeruginosa-induced bacteremia is controversial, since the susceptibility of P. aeruginosa to PIPC/TAZ is known to be lower than that set by the Clinical Laboratory Standards Institute (CLSI), ≤64 mg/L. The association between MIC levels and bacterial eradication after ...

PURPOSE: Garenoxacin, a novel des-F(6)-quinolone, possesses potent antibacterial activity against infectious pathogens in the respiratory tract. Population pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte Carlo simulations were used to optimize garenoxacin dosage regimens. METHODS: At the end of phase II stage, the clinical dose of garenoxacin was predicted to be 400 mg once ...

Beta-lactam antibiotics display time-dependant pharmacodynamics whereby constant antibiotic concentrations rather than high peak concentrations are most likely to result in effective treatment of infections caused by susceptible bacteria. Continuous administration has been suggested as an alternative strategy, to conventional intermittent dosing, to optimise beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) properties. With the availability ...

Pramipexole is a nonergolinic dopamine agonist, with high affinity for the D2 subfamily of dopamine receptors. Pramipexole is efficacious for the symptomatic treatment of early Parkinson's Disease (PD) and its early use, before that of levodopa can delay the emergence of levodopa-related motor complication. Dosage should be increased gradually from ...

Aims: To find out the pharmacokinetic (PK) and pharmacodynamic (PD) parameters for assessing the bioequivalence of three marketed products. To study the relationship between the pharmacokinetics of gliclazide and pharmacodynamic effect in healthy male volunteers. Methods: This was an open label, balanced, randomized, 3-treatment, 3-sequence, 3 period, single-dose, cross-over bioavailability ...

PURPOSE: To determine the recommended phase II dose and evaluate the safety and toxicity profile, pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P - an inhibitor of tubulin polymerization that has vascular disrupting and anti-proliferative effects.EXPERIMENTAL DESIGN: BNC105P was administered as a 10 minute (min) infusion on Days 1 and ...

Human interferon beta (IFN beta) has well-established beneficial effects in treating relapsing forms of multiple sclerosis (MS) patients, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20 kDa polyethylene glycol conjugated IFN beta-1a (PEG-IFN beta-1a) is being developed to decrease the frequency of administration and ...

Recent analyses of autopsied brains from subjects previously administered AAV2-neurturin (NRTN) gene transfer argues that optimizing the effects of neurotrophic factors in Parkinson's disease (PD) likely requires delivery to both the degenerating cell bodies (in substantia nigra) and their terminals (in striatum). Prior to implementing this novel dosing paradigm in ...

BACKGROUND: Secretin-stimulated magnetic resonance cholangiopancreatography (MRCP) is used for the diagnosis of sphincter of Oddi dysfunction (SOD), but it does not correlate well with sphincter of Oddi manometry. Serial MRCP following morphine-neostigmine provocation may be of value in the assessment of SOD, but the effects of these pharmacological agents on ...

Summary.  Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti-human FVIIa antibodies develop (∼2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over-expressed by gene transfer in haemophilia dogs, has provided long-term haemostasis (>2 years). ...

Abstract Objective: To examine the pharmacokinetics (PKs) and pharmacodynamics (PDs) of OROS(®) methylphenidate (OROS MPH) dosed once daily (QD) versus an early standard regimen (immediate-release [IR] MPH dosed three times daily [TID]) under various breakfast conditions. Methods: This single-center, double-blind, double-dummy, randomized, crossover study of OROS MPH (NCT00269815) in children ...

Rasagiline is an irreversible monoamine oxidase type B (MAO-B) inhibitor indicated for the treatment of the signs and symptoms of idiopathic Parkinson disease as initial monotherapy and as adjunct therapy to levodopa. Pharmacologic inhibition of monoamine oxidase type A (MAO-A), but not MAO-B, poses a risk of the "cheese effect," ...

PURPOSE: Vismodegib (GDC-0449) is a potent and selective inhibitor of the Hedgehog (Hh) pathway that shows anti-tumor activity in preclinical models driven by mutational or ligand-dependent activation of the Hh pathway. We wished to characterize the pharmacokinetic-pharmacodynamic relationship of vismodegib in both model systems to guide optimal dose and schedule ...

This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo. A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for ...

The purpose of this investigation was to study the effects of renal function on the pharmacokinetics and pharmacodynamics (PK-PD) of free cefazolin administered prophylactically in cardiothoracic surgery. Patients received an initial 2-g dose of cefazolin, followed by 1-g doses 6, 12, 18 and 24 h after the first dose. In patients ...

Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 ...

OBJECTIVE: To determine the efficacy of standard levodopa combined with controlled release levodopa and entacapone in controlling end-of-dose symptoms in Parkinson's disease. METHODS: A single-blind cross over design was used to compare the duration of action for three pharmacological combinations: standard levodopa (L/DDC); standard levodopa combined with entacapone (L/DDC/E); and ...

INTRODUCTION: Two randomized, double-blind, placebo-controlled studies in acute and chronic pain treatment, powered to assess noninferiority of the efficacy of tapentadol immediate release (IR) (50 mg, 75 mg) versus oxycodone hydrochloride (HCl) IR (10 mg), established comparable efficacy of tapentadol IR with oxycodone HCl IR, and suggested tapentadol IR's improved ...

Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the ...

The mammalian target of rapamycin (mTOR) pathway is hyperactivated through oncogenic transformation in many human malignancies. Ridaforolimus (AP23573; MK-8669) is a novel rapamycin analog that selectively targets mTOR and is currently under clinical evaluation. In this study, we investigated the mechanistic basis for the antitumor activity of ridaforolimus in a ...

Background: PREPARED was a randomized, parallel-group, double-blind, multicenter study to evaluate the efficacy of adjunctive ropinirole prolonged release (PR) versus immediate release (IR) in patients with advanced Parkinson's disease (PD). Methods: Patients received once-daily PR (2-24 mg/d; n = 177) or three-times-daily IR (0.75-24 mg/d; n = 173) for 24 ...

Rapamycin has been reported to inhibit hepatic fibrosis, lung fibrosis, renal fibrosis and subglottic stenosis. Fibrosis is also involved in urethral stricture. Therefore we investigated the effect of rapamycin on the inhibition of urethral stricture formation in a rabbit model. Firstly, models of urethral stricture were successfully established by electrocoagulation ...

mTOR inhibitor rapamycin and its analogs are lipophilic, demonstrate blood-brain barrier penetration, and have shown promising antitumor effects in several types of refractory tumors. We thus try to explore the therapeutic effects of mTOR inhibitors on brain metastasis models. We examined the effects of different dose of mTOR inhibitors (rapamycin, ...

: Several randomized trials have demonstrated a biochemical control advantage to an increase from the "conventional" 66 to 70 Gy range to the "high-dose" 75 to 81 Gy range; these trials have also, however, demonstrated a toxicity disadvantage. Our objective was to perform a toxicity analysis of a minor dose ...

: To investigate the change in creatinine clearance (CrCl) over time following upper abdominal radiation utilizing a dose-volume histogram (DVH) multivariate analysis. : The study population included 125 patients with gastrointestinal malignancy treated with abdominal radiation therapy at our institution between 1994 and 2006, with available creatinine and DVH information. ...

The objective of this study was to determine whether season and total rainfall during the breeding season, sheep parity, and/or litter size affect the interval from the introduction of rams to estrus (IRE) in hair Saint Croix sheep in northeastern Mexico. An analysis was made of 874 services performed during ...

The efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the individual beneficial and adverse effects, in two acromegaly ...