Social isolation and oxytocin antagonism increase emotion-related behaviors and heart rate in female prairie voles.

Social isolation influences depression- and anxiety-related disorders and cardiac function. Oxytocin may mediate these conditions through interactions with social behavior, emotion, and cardiovascular function, via central and/or peripheral mechanisms. The present study investigated the influence of oxytocin antagonism using L-368,899, a selective oxytocin receptor antagonist that crosses the blood-brain barrier, on depression- and anxiety-related behaviors and heart rate in prairie voles.

Behavioral and neuroendocrine consequences of disrupting a long-term monogamous social bond in aging prairie voles.

Social support from a spouse, long-term partner, or someone who provides emotional or instrumental support may protect against consequences of aging, including mediating behavioral stress reactivity and altering neurobiological process that underlie short-term stress responses. Therefore, long-term social bonding may have behavioral and neurobiological benefits. The socially monogamous prairie vole provides a valuable experimental model for investigating the benefits of long-term social bonds on short-term stress reactivity in aging animals, given their unique social structure of forming enduring opposite-sex bonds, living in family groups, and bi-parental rearing strategies.

Protective neuroendocrine effects of environmental enrichment and voluntary exercise against social isolation: evidence for mediation by limbic structures.

Previous research indicates that loneliness and social isolation may contribute to behavioral disorders and neurobiological dysfunction. Environmental enrichment (EE), including both cognitive and physical stimulation, may prevent some behavioral, endocrine, and cardiovascular consequences of social isolation; however, specific neural mechanisms for these benefits are still unclear. Therefore, this study examined potential neuroendocrine protective effects of both EE and exercise.

Wheel access has opposing effects on stress physiology depending on social environment in female prairie voles (Microtus ochrogaster).

Physical exercise and chronic social stress are both known to impact general health and hypothalamic-pituitary-adrenal (HPA) axis function, albeit typically in opposing directions. Therefore, the question we investigated in this study was how these two factors - physical exercise and chronic social isolation - would interact when presented simultaneously in a female rodent model. Adult female prairie voles were separated into four experimental groups: (1) isolated without wheel access, (2) isolated with wheel access, (3) paired without wheel access, and (4) paired with wheel access.

Clinical pharmacokinetics of thalidomide.

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions is being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively.

Biomarkers, validation and pharmacokinetic-pharmacodynamic modelling.

Four elements are crucial to successful pharmacokinetic-pharmacodynamic (PK/PD) modelling and simulation for efficient and effective rational drug development: (i) mechanism-based biomarker selection and correlation to clinical endpoints; (ii) quantification of drug and/or metabolites in biological fluids under good laboratory practices (GLP); (iii) GLP-like biomarker method validation and measurements and; (iv) mechanism-based PK/PD modelling and validation. Biomarkers can provide great predictive value in early drug development if they reflect the mechanism of action for the intervention even if they do not become surrogate endpoints. PK/PD modelling and simulation can play a critical role in this process.

Biomarkers in drug discovery and development: from target identification through drug marketing.

Biomarkers of disease play an important role in medicine and have begun to assume a greater role in drug discovery and development. The challenge for biomarkers is to allow earlier, more robust drug safety and efficacy measurements. Their role in drug development will continue to grow for the foreseeable future.

Lymph node status combined with lymphovascular invasion creates a more powerful tool for predicting outcome in patients with invasive breast cancer.

Background: Multiple clinical, biologic, and pathologic factors are known to correlate with outcome in patients with invasive breast cancer. The utility of lymphovascular invasion as an additional useful prognostic indicator has been heretofore ill defined. The purpose of the current study was to determine whether the presence or absence of peritumoral lymphovascular invasion (LVI) contribute further significant information in assessing survival.

The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil.

Aims: To investigate the effects of age and renal and hepatic impairment on the pharmacokinetics, tolerability and safety of sildenafil (single 50-mg oral dose) and its major circulating N-desmethyl metabolite, UK-103,320.

Methods: Three open-label, parallel-group studies were conducted. The first study compared sildenafil pharmacokinetics, safety and toleration in 15 healthy young male subjects (mean age 30 years; range 19--45 years) to 15 healthy elderly male subjects (mean age 70 years; range 65--81 years).

Thalidomide dose proportionality assessment following single doses to healthy subjects.

Thalidomide is approved in the United States for treating erythema nodosum leprosum, a complication of leprosy. The present study determined the single-dose oral pharmacokinetics and dose proportionality from 50 to 400 mg of Celgene's commercial Thalomid thalidomide formulation in an open-label, single-dose, three-way crossover study. Fifteen healthy subjects were given 50, 200, and 400 mg of thalidomide on three occasions, and blood samples were collected over 48 hours.

Quantitative nuclear morphometry by image analysis for prediction of recurrence of ductal carcinoma in situ of the breast.

Clinical management of ductal carcinoma in situ (DCIS) remains a challenge because significant proportions of patients experience recurrence after conservative surgical treatment. Unfortunately, it is difficult to prospectively identify, using objective criteria, patients who are at high risk of recurrence and might benefit from additional treatment. We conducted a multi-institutional, collaborative case-control study to identify nuclear morphometric features that would be useful for identifying women with DCIS at the highest risk of recurrence.

Absolute bioavailability and dose proportionality of oral ganciclovir after ascending multiple doses in human immunodeficiency virus (HIV)-positive patients.

This study was designed to determine the bioavailability and dose linearity and proportionality of ganciclovir after multiple oral administrations of 3,000 mg to 6,000 mg per day. In an open-label, randomized, four-treatment crossover design, 24 patients seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) received in random order multiple oral doses of ganciclovir 1,000 mg every 3 hours (six times a day), 1,000 mg four times a day, and 1,000 mg three times a day and a single 5-mg/kg intravenous infusion (over 1 hour) of ganciclovir. Blood samples for pharmacokinetic determinations were obtained on day 3 of each oral regimen and on the day of the intravenous infusion over a 24-hour time interval.

Optimizing the use of biomarkers, surrogate endpoints, and clinical endpoints for more efficient drug development.

Biomarkers and surrogate endpoints are critical to the future of efficient drug development. Definitions, a conceptual model, and a conceptual framework for validating and bridging biomarkers to clinical endpoints are provided in this presentation. In addition, a few examples are provided to support the development concept.

Pharmacokinetic/pharmacodynamic modeling in drug research and development.

The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology.

Hemoglobin and methemoglobin concentrations after large-dose infusions of diaspirin cross-linked hemoglobin.

Unlabelled: Diaspirin cross-linked hemoglobin (DCLHb) solution is a purified human hemoglobin product chemically stabilized to deliver oxygen to tissues. We determined the peak plasma hemoglobin concentration and assessed changes in methemoglobin concentration after the infusion of 1 g/kg DCLHb in large blood loss surgical patients. This prospective, randomized study included 26 surgical patients who were either infused with up to three 250-mL units of 10% DCLHb or transfused with up to three units of packed red blood cells during the study infusion period.

Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women.

The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.

An evolution of drug development and clinical pharmacology during the 20th century.

The current state of clinical pharmacology and drug development did not just happen. Clinical pharmacology and the drug development process were born, evolved, and have come to the fore during the past 100 years. The past century has been one of accelerating progress in science and medicine.

Single- and multiple-dose pharmacokinetics of ziprasidone in healthy young and elderly volunteers.

Aims: To compare the pharmacokinetics of ziprasidone in healthy young (18-45 years) men and women, and healthy elderly (> or = 65 years) men and women.

Methods: Eight young men, 11 young women, 8 elderly men and 8 elderly women were given oral ziprasidone 40 mg day(-1), in two evenly divided daily doses, for 7 days, followed by a single 20 mg dose on day 8. Serum samples were collected immediately before the morning dose on days 1-8, for up to 12 h after dosing on day 1 and for up to 96 h after dosing on day 8.

Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers.

Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study determined the bioequivalence and pharmacokinetics of Celgene's commercial and clinical trial thalidomide formulations and the Brazilian Tortuga formulation in an open-label, single-dose, three-way crossover design. Seventeen healthy subjects were given 200 mg of thalidomide on three occasions, and blood samples were collected over 48 hours.

Bioequivalence of 1 and 5 mg tacrolimus capsules using a replicate study design.

Tacrolimus (FK506, Prograf) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. A previously conducted, randomized, 24-subject, crossover bioavailability study of 1 and 5 mg capsules (one period each) failed to demonstrate bioequivalence. A single-dose, four-period, four-sequence, randomized, crossover, replicate study (N = 32) was therefore used to evaluate the bioequivalence of the marketed 1 and 5 mg capsules in healthy volunteers.

Thalidomide does not alter estrogen-progesterone hormone single dose pharmacokinetics.

Objectives: To determine the single- and multiple-dose pharmacokinetics of oral thalidomide (200 mg/day, administered for 21 days) and to assess the effects of steady-state plasma concentrations of thalidomide on the single-dose pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone).

Methods: A randomized, 2-period crossover study was performed in 10 healthy premenopausal female volunteers. The pharmacokinetic profiles of plasma concentrations of thalidomide were evaluated with both noncompartmental and compartmental methods, whereas those of ethinyl estradiol and norethindrone were calculated with noncompartmental methods.

The influence of margin width on local control of ductal carcinoma in situ of the breast.

Background: Ductal carcinoma in situ is a non-invasive carcinoma that is unlikely to recur if completely excised. Margin width, the distance between the boundary of the lesion and the edge of the excised specimen, may be an important determinant of local recurrence.

Methods: Margin widths, determined by direct measurement or ocular micrometry, and standardized evaluation of the tumor for nuclear grade, comedonecrosis, and size were performed on 469 specimens of ductal carcinoma in situ from patients who had been treated with breast-conserving surgery with or without postoperative radiation therapy, according to the choice of the patient or her physician.

Interobserver reproducibility of the Lagios nuclear grading system for ductal carcinoma in situ.

Several studies have shown an association between high nuclear grade or necrosis of ductal carcinoma in situ (DCIS) lesions and the risk of local disease recurrence in patients with DCIS treated surgically with less than mastectomy. Although criteria for separating low from high nuclear grade lesions have been published, no information exists regarding interobserver reproducibility (IR). To assess IR in the classification of DCIS, six surgical pathologists from four institutions used the Lagios grading system to grade 125 DCIS lesions.