Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor.

AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine (5-HT1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months.

The high-cost, type 2 diabetes mellitus patient: an analysis of managed care administrative data.

Background: Type 2 diabetes mellitus (T2DM) affects 25.8 million individuals in the United States and exerts a substantial economic burden on patients, health care systems, and society. Few studies have categorized costs and resource use at the patient level.

An acute rat in vivo screening model to predict compounds that alter blood glucose and/or insulin regulation.

Introduction: Drug-induced glucose dysregulation and insulin resistance have been associated with weight gain and potential induction and/or exacerbation of diabetes mellitus in the clinic suggesting they may be safety biomarkers when developing antipsychotics. Glucose and insulin have also been suggested as potential efficacy biomarkers for some oncology compounds. The objective of this study was to qualify a medium throughput rat in vivo acute Intravenous Glucose Tolerance Test (IVGTT) for predicting compounds that will induce altered blood glucose and/or insulin levels.

A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers.

Purpose: Ticagrelor is a reversibly binding P2Y12 receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between digoxin, a P-glycoprotein substrate, and ticagrelor by evaluating the pharmacokinetics, safety, and tolerability.

Saxagliptin efficacy and safety in patients with type 2 diabetes mellitus and cardiovascular disease history or cardiovascular risk factors: results of a pooled analysis of phase 3 clinical trials.

Objective: This post hoc analysis sought to assess the efficacy, safety, and tolerability of saxagliptin in patients with type 2 diabetes mellitus and cardiovascular (CV) risk factors or disease (CVD).

Methods: Data from 5 randomized controlled trials were pooled to compare saxagliptin 5 mg with placebo: 2 studies of saxagliptin as monotherapy in drug-naïve patients and 1 each of saxagliptin as add-on therapy to metformin, glyburide, or a thiazolidinedione. Analysis was performed according to the following baseline/trial entry criteria: 1) history/no history of CVD; 2) ≥ 2 versus 0 to 1 CV risk factors; 3) statin use versus no statin use; and 4) hypertension versus no hypertension.

A rapid alternative to X-ray crystallography for chiral determination: case studies of vibrational circular dichroism (VCD) to advance drug discovery projects.

The absolute stereochemistry of chiral drugs is usually established via X-ray crystallography. However, vibrational circular dichroism (VCD) spectroscopy coupled with quantum mechanics simulations offers a rapid alternative to crystallography and is readily applied to both crystalline and non-crystalline samples. VCD is an effective complement to X-ray analysis of drug candidates, and it can be used as a high-throughput means of assessing absolute stereochemistry at all phases of the discovery process (hundreds of assignments per year).

Pharmacokinetic profile of the extended-release formulation of quetiapine fumarate (quetiapine XR): clinical implications.

Objectives: A series of studies were conducted to guide the development and characterise the pharmacokinetics of extended-release quetiapine fumarate (quetiapine XR), a once-daily formulation to control the release of the drug.

Methods: Data from these studies are described and discussed herein.

Results: Once-daily quetiapine XR produced a similar area under the plasma concentration-time curve (AUC), minimum plasma concentration (Cmin) and a slightly lower maximum plasma concentration (Cmax) than the equivalent dose of immediate-release quetiapine (quetiapine IR) given twice daily.

Effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease patients.

Background: Ticagrelor is a direct-acting, reversibly binding, oral P2Y12 platelet inhibitor that reduces thrombotic cardiovascular events in patients with acute coronary syndrome. Dyspnea is one of the most commonly reported adverse events associated with ticagrelor.

Objective: To determine the effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease (COPD) patients.

Evaluation of the pharmacokinetic interaction between ticagrelor and tolbutamide, a cytochrome P450 2C9 substrate, in healthy volunteers.

Objectives: To assess the effect of ticagrelor on the pharmacokinetics of tolbutamide (a CYP2C9 substrate), and the effect of tolbutamide on ticagrelor pharmacokinetics.

Methods: In this randomized, double-blind, two-period, crossover study, 23 healthy volunteers received either placebo or ticagrelor 180 mg twice daily (b.i.

Renal biomarker changes associated with hyaline droplet nephropathy in rats are time and potentially compound dependent.

Alpha 2u-globulin mediated hyaline droplet nephropathy (HDN) is a male rat specific lesion induced when a compound or metabolite binds to alpha 2u-globulin. The objective of this study was to investigate if the newer and more sensitive renal biomarkers would be altered with HDN as well as be able to distinguish between HDN and oxidative stress-induced kidney injury. Rats were dosed orally for 7 days to determine (1) if HDN (induced by 2-propanol or D-limonene) altered the newer renal biomarkers and not BUN or creatinine, (2) if renal biomarkers could distinguish between HDN and oxidative stress-induced kidney injury (induced by potassium bromate), (3) sensitivity of HDN-induced renal biomarker changes relative to D-limonene dose, and (4) reversibility of HDN and renal biomarkers, using vehicle or 300 mg/kg/day D-limonene with 7 days of dosing and necropsies scheduled over the period of Days 8-85.

Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects.

Purpose: Ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, is predominantly metabolized by cytochrome P450 3A and both the parent compound and its active metabolite AR-C124910XX are substrates of P-glycoprotein. Rifampicin was used to assess the effects of CYP3A and P-glycoprotein induction on the single-dose pharmacokinetics and pharmacodynamics of ticagrelor.

Methods: Healthy volunteers received a single 180 mg oral dose of ticagrelor on days 1 and 15, and a once-daily 600 mg dose of rifampicin on days 4-17.

Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers.

Purpose: Interactions between ticagrelor and atorvastatin or simvastatin were investigated in two-way crossover studies.

Methods: Both studies were open-label for statin; the atorvastatin study was placebo-controlled for ticagrelor. For atorvastatin, volunteers (n = 24) received ticagrelor (loading dose 270 mg; 90 mg twice daily, 7 days) or placebo, plus atorvastatin calcium (80 mg; day 5).

Hemoglobin A1c outcomes and health care resource use in type 2 diabetes mellitus patients treated with combination oral antidiabetic drugs through step therapy and loose-dose and fixed-dose combinations.

Purpose: To compare outcomes of type 2 diabetes mellitus (T2DM) patients initiating therapy with FDC vs. those with loose-dose combination (LDC) or step therapy (ST) in a managed care population.

Design: A retrospective claims database analysis.

Esomeprazole formulary exclusion: impact on total health care services use and costs.

Esomeprazole was excluded from the United Healthcare formulary for all commercial health plan members January 1, 2007. A retrospective analysis of the Ingenix LabRx database (September 1, 2005, through June 30, 2007) evaluated the effect of this exclusion on health care utilization and costs in a real-world setting. Total medical care services, including pharmacy claims, were examined for 6 months before and after the esomeprazole exclusion.

Association of Self-Reported Weight Change and Quality of Life, and Exercise and Weight Management Behaviors Among Adults with Type 2 Diabetes Mellitus: The SHIELD Study.

Purpose. This study examined the association between self-reported weight change and quality of life, and exercise and weight management behaviors among individuals with type 2 diabetes mellitus (T2DM). Methods.

Evidence for the nitric oxide pathway as a potential mode of action in fenoldopam-induced vascular injury.

Fenoldopam, a dopaminergic DA1 agonist, induces vasodilatation via nitric oxide (NO), and this may be associated with mesenteric arterial injury. NO is produced from the enzymatic action of nitric oxide synthase (NOS), which is regulated by the shear-stress mediating protein caveolin-1. Profound vasodilatation and accompanied decreased shear are early events that could initiate vascular injury.

Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor.

Acute coronary syndromes (ACS) remain life-threatening disorders associated with high morbidity and mortality, despite advances in treatment over the last decade. Adenosine diphosphate-induced platelet activation via P2Y(12) receptors plays a pivotal role in the pathophysiology of ACS. The current standard of treatment involves dual antiplatelet therapy with aspirin (acetylsalicylic acid) and the thienopyridine clopidogrel.

Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals.

Purpose: The aim of this study was to assess age and gender effects on ticagrelor pharmacokinetics and pharmacodynamics (PK/PD).

Methods: Forty healthy individuals [18-45 years (young); ≥ 65 years (elderly); ten men, ten women per age group) received 200 mg ticagrelor.

Results: Ticagrelor was rapidly absorbed [time to maximum concentration (C(max)) (t(max)) 2.

Incidence of peptic ulcer bleeding in the US pediatric population.

Objectives: The aim of the present study was to determine the incidence of peptic ulcer bleeding (PUB) in pediatric patients.

Methods: A hospital inpatient database, Premier Perspective, and an insurance claims database, MarketScan, were analyzed to estimate upper and lower limits for the annual incidence of PUB in the US pediatric population.

Results: Using data from the Premier Perspective database and database-specific projection methodology, the total number of cases of hospitalization of pediatric patients for PUB in the United States in 2008 was estimated to be between 378 and 652.

Multiparameter exploration of piperazine derivatives as δ-opioid receptor agonists for CNS indications.

A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as δ-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifically microsomal clearance, permeability, and hERG channel inhibition.

4-Piperidin-4-ylidenemethyl-benzamides as δ-opioid receptor agonists for CNS indications: identifying clinical candidates.

A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.

Evaluation of the effect of dapagliflozin on cardiac repolarization: a thorough QT/QTc study.

Introduction: Dapagliflozin is a first-in-class sodium-glucose transporter 2 (SGLT2) inhibitor under investigation for the treatment of type 2 diabetes mellitus. A thorough QTc study was conducted, according to International Conference on Harmonization E14 guidelines, to characterize the effect of dapagliflozin on cardiac repolarization.

Methods: The present study was a double-blind, four-period, placebo-controlled crossover study at a single-center inpatient clinical pharmacology unit.

A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABA(A) receptor modulator - an in vitro and in vivo comparison.

What Is Already Known About This Subject: • AZD7325 is an orally administered, potent, selective gamma-amino-butyric acid (GABA(A) ) α2,3 receptor modulator intended for the treatment of anxiety. • The induction effects of AZD7325 on CYP1A2 and CYP3A4 have not been systematically studied.

What This Study Adds: • The in vitro studies showed that AZD7325 was a moderate CYP1A2 inducer and potent CYP3A4 inducer.

Lack of significant food effect on the pharmacokinetics of ticagrelor in healthy volunteers.

What Is Known And Objective: Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist and has been approved in the European Union and the USA for the reduction of clinical thrombotic events in patients with acute coronary syndromes. This study aimed to assess the effect of food on ticagrelor pharmacokinetics.

Methods: The study was an open-label, randomized, 2-period crossover single-centre trial; 26 healthy volunteers received a single 270 mg (3×90 mg tablets) ticagrelor dose orally following: (i) a 10-h overnight fast; and (ii) after a standard high-fat, high-calorie breakfast.

Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment.

Ticagrelor, a P2Y(12) receptor antagonist, is approved in the European Union and the US for the prevention of thrombotic events in patients with acute coronary syndromes. Renal dysfunction potentially affects drug disposition. Ticagrelor pharmacokinetics, pharmacodynamics, and safety in renal impairment were assessed.