Investigating CNS distribution of PF-05212377, a P-glycoprotein substrate, by translation of 5-HT receptor occupancy from non-human primates to humans.

PF-05212377 (SAM760) is a potent and selective 5-HT antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (C /C ) of 0.

The Bioequivalence of Tafamidis 61-mg Free Acid Capsules and Tafamidis Meglumine 4 × 20-mg Capsules in Healthy Volunteers.

Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults.

The Economic Impact of New Therapeutic Interventions on Neuropsychiatric Inventory (NPI) Symptom Scores in Patients with Alzheimer Disease.

Background/aims: Few studies have modeled individual Neuropsychiatric Inventory (NPI) symptom scores for Alzheimer disease (AD) patients and assessed the value of therapeutic interventions that can potentially impact them. The main objective of this study was to evaluate the impact of new AD symptomatic treatments on relevant health economic outcomes via their potential effects on cognition and neuropsychiatric symptoms such as depression, irritability, anxiety, and sleep disorder.

Methods: We enhanced the previously published AHEAD model (Assessment of Health Economics in Alzheimer's Disease) by including new variables and functional relations to capture the NPI's individual neuropsychiatric symptoms in addition to the total NPI score.

Metabolism of a 5HT Antagonist, 2-Methyl-1-(Phenylsulfonyl)-4-(Piperazin-1-yl)-1H-Benzo[d]imidazole (SAM-760): Impact of Sulfonamide Metabolism on Diminution of a Ketoconazole-Mediated Clinical Drug-Drug Interaction.

SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (∼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed.

A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer's disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil.

Background: Symptomatic benefits have been reported for 5-HT receptor antagonists in Alzheimer's disease (AD) trials. SAM-760 is a potent and selective 5-HT receptor antagonist that has demonstrated central 5-HT receptor saturation in humans at a dose of 30 mg.

Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD.

The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women.

Background: Limited data exist on the presence of pregabalin in human breast milk of nursing mothers.

Objectives: This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (≥ 12 weeks postpartum).

Methods: In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals.

Quantitative prediction of renal transporter-mediated clinical drug-drug interactions.

Kidney plays a critical role in the elimination of xenobiotics. Drug-drug interactions (DDIs) via inhibition of renal organic anion (OAT) and organic cation (OCT) transporters have been observed in the clinic. This study examined the quantitative predictability of renal transporter-mediated clinical DDIs based on basic and mechanistic models.

The availability and mobility of arsenic and antimony in an acid sulfate soil pasture system.

The Macleay floodplain on the north coast of New South Wales, Australia, has surface soil concentrations of up to 40 mg kg(-1) arsenic (As) and antimony (Sb), due to historical mining practices in the upper catchment. The floodplain also contains areas of active and potential acid sulfate soils (ASS). Some of these areas are purposely re-flooded to halt oxidation processes, but the effect of this management on the metalloid mobility and phytoavailability of the metalloids present is unknown.

Effects of nutrient and lime additions in mine site rehabilitation strategies on the accumulation of antimony and arsenic by native Australian plants.

The effects of nutrient and lime additions on antimony (Sb) and arsenic (As) accumulation by native Australian and naturalised plants growing in two contaminated mine site soils (2,735 mg kg(-1) and 4,517 mg kg(-1) Sb; 826 mg kg(-1) and 1606 As mgkg(-1)) was investigated using a glasshouse pot experiment. The results indicated an increase in soil solution concentrations with nutrient addition in both soils and also with nutrient+lime addition for Sb in one soil. Metalloid concentrations in plant roots were significantly greater than concentrations in above ground plant parts.

Short-term effects of organic amendments on properties of a Vertisol.

Application of organic waste products as amendments has been proposed as a management option whereby soil quality of Vertisols could be improved. An incubation experiment was, therefore, conducted for 4 weeks under controlled temperature conditions (30 degrees C) to identify those potential organic amendments that might improve the quality of a Vertisol. Twelve organic amendments were investigated: cotton gin trash from three sources, cattle manure from two sources, green waste compost, chicken manure from three sources including a commercial product, biosolids and two commercial liquefied vermicomposts.

The chemistry and behaviour of antimony in the soil environment with comparisons to arsenic: a critical review.

This article provides a critical review of the environmental chemistry of inorganic antimony (Sb) in soils, comparing and contrasting findings with those of arsenic (As). Characteristics of the Sb soil system are reviewed, with an emphasis on speciation, sorption and phase associations, identifying differences between Sb and As behaviour. Knowledge gaps in environmentally relevant Sb data for soils are identified and discussed in terms of the limitations this imposes on understanding the fate, behaviour and risks associated with Sb in environmental soil systems, with particular reference to mobility and bioavailability.

Relative uptake of minoxidil into appendages and stratum corneum and permeation through human skin in vitro.

We examined uptake of the model therapeutic agent, minoxidil, into appendages, stratum corneum (SC), and through human skin, under the influence of different vehicles. Quantitative estimation of therapeutic drug deposition into all three areas has not previously been reported. Finite doses of minoxidil (2%, w/v) in formulations containing varying amounts of ethanol, propylene glycol (PG), and water (60:20:20, 80:20:0, and 0:80:20 by volume, respectively) were used.

Comparison of methods for measuring soil microbial activity using cotton strips and a respirometer.

In order to develop a method of measuring the level of microbial activity in soil that is suitable for use by farmers, land managers, and other non-scientists, a simple method for determining soil microbial activity was evaluated and compared with two standard techniques. Soils sampled from vegetable farms in south east Queensland were incubated in the laboratory under controlled moisture and temperature conditions. Three methods were used to measure soil microbial activity, a respirometry method and two methods using the cotton strip assay (CSA) technique (image analysis and tensometer).

Application of clinical trial simulation to compare proof-of-concept study designs for drugs with a slow onset of effect; an example in Alzheimer's disease.

Objective: Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200-400 AD patients would be used to establish drug effect relative to placebo (i.e.

Adsorption of antimony(V) by floodplain soils, amorphous iron(III) hydroxide and humic acid.

Antimony (Sb) emissions to the environment are increasing, and there is a dearth of knowledge regarding Sb fate and behaviour in natural systems. In particular, there is a lack of understanding of sorption of the oxidised Sb(V) species onto soils and soil phases. In this study sorption of Sb(V) by two organic rich soils with high levels of oxalate extractable Fe was examined over the pH range of 2.

How modeling and simulation have enhanced decision making in new drug development.

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds.

The use of clinical trial simulation to support dose selection: application to development of a new treatment for chronic neuropathic pain.

Purpose: Pregabalin is being evaluated for the treatment of neuropathic pain. Two phase 2 studies were simulated to determine how precisely the dose that caused a one-point reduction in the pain score could be estimated. The likelihood of demonstrating at least a one-point change for each available dose strength was also calculated.