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The use of additive manufacturing (AM) technology is growing rapidly for offshore use, whilst established production technologies such as powder metallurgy near-net-shape (PM-NNS) continue to be used. New standards are being introduced and many of the oil and gas majors are now developing supply chains to ensure rapid supply of high-quality complex parts. Environmental concerns are helping to drive this with use of near-net-shape technologies to reduce carbon dioxide emissions through more efficient designs and metal forming methods. Hot isostatic pressing (HIP) has been used to remove shrinkage porosity and internal defects in cast products for many years, predominantly to improve mechanical properties and fatigue resistance. Recently, there has been an increasing focus on AM processes for demanding applications where localized corrosion and similar internal defects and porosity are a concern. HIP technology is being used to either produce PM-NNS parts, or for the post processing of AM produced components to ensure defect free material prior to service in demanding environments. This paper will present a broad overview in the use of HIP equipment to produce parts and components to the offshore industry.

Adaptive Servo Ventilation (ASV) devices mimic tidal breathing to eliminate various forms of sleep disordered breathing. ASV is a particurlarly effective treatment for central/complex sleep apnoea. The authors reviewed data from 44 patients either using or previously using ASV at Nottingham University Hospitals. Resmed S9 CSA and Aircurve10 CS pace wave devices were used. Of the 44 patients, 31 were male and 13 were female. Ages ranged between 31 - 87 years, diagnoses included: obstructive sleep apnoea, central sleep apnoea, motor neurone disease and cheyne stokes respiration. 30 patients initially used another form of device and were switched to ASV if their original treatment was sup-optimal and there was evidence of a complex sleep disorder, 27 of these patients were originally using CPAP and 3 were using bi-level. 14 patients only ever used ASV. Results showed that for all patients: baseline (no treatment) AHI = 35.7, ODI = 29.5 and mean SpO2= 92.7%. AHI on original device = 16 and average use on original device = 6.1 hours. In comparison to AHI on ASV = 1.9, ODI on ASV = 3.4 and average use on ASV = 5.8 hours. The 27 patients on no form of opiate: baseline (no treatment) AHI = 38, ODI = 34 and mean SpO2 = 92%. AHI on original device = 18 and AHI on ASV = 2. The 17 patients were on some form of opiate: baseline (no treatment) AHI = 33 events per hour, ODI = 23 and mean SpO2 = 94%. AHI on original device = 13 and AHI on ASV = 1. ASV was a more effective form of treatment for complex sleep disorders, patients also indicated a preference for ASV. identifying these patients at an earlier treatment stage will be beneficial for patients and healthcare providers. Patients on opiate based medication in particular should be considered for ASV.

The prevalence of chronic kidney disease (CKD) related to type 2 diabetes is increasing worldwide. In addition to standard of care, treatment with anti-inflammatory and antifibrotic agents such as CTP-499, a novel oral, multisubtype selective inhibitor of phosphodiesterases, may be important in CKD treatment. A phase 1b randomized, double-blind, placebo-controlled clinical trial of CTP-499 in CKD patients (25 active, 8 placebo) with an estimated glomerular filtration rate of 30-59 mL/min/1.73 m(2) was conducted to assess safety and tolerability. Secondary outcomes included pharmacokinetics and exploratory effects on inflammatory and hematology markers. Patients received 600 mg CTP-499 or matching placebo tablets orally once daily for 2 weeks, then twice daily for 2 additional weeks. CTP-499 was well tolerated with no serious or severe adverse events, or adverse events leading to discontinuation. CTP-499 was rapidly absorbed and produced acceptable interpatient variability. Of the 5 metabolites (M1-M5), M5 was the most abundant in plasma and urine. Exposure to CTP-499 and metabolites was higher in CKD patients than previously reported in healthy volunteers. No statistically significant differences were detected between the CTP-499- and placebo-treated groups for any of the biomarkers tested. This study provides data supporting further evaluation of CTP-499 in CKD patients.

To determine maximum tolerated dose and food effect for CTP-499, a novel agent being studied for the treatment of diabetic kidney disease. CTP-499 has demonstrated anti-inflammatory, anti-fibrotic and anti-oxidative activities in vitro as well as anti-inflammatory and renoprotective effects in a diabetic nephropathy (DN) model. Two studies were performed. Study 1 was a single-dose escalation study with 600, 1200, 1800, and 2400 mg doses of controlled-release (CR) CTP-499 and a 400 mg immediate release dose to aid in the development of prototype formulations of CTP-499. Study 2 was a food-effect study. Plasma concentrations of CTP-499 and its metabolites were measured to determine pharmacokinetic parameters in each study. Safety was assessed to determine tolerability. Doses up to and including 1800 mg were well tolerated. Cmax was either equivalent (CTP-499) or slightly lower (metabolites) for the fed condition, while overall exposure was equivalent (CTP-499) or slightly higher (metabolites) for the fed condition. The range of tolerated doses of CTP-499 and the effects of food on exposure were identified, contributing to selection of the dose for Phase II development.

Overactive bladder is a common disorder that affects approximately 34 million adults in the United States. Anticholinergic (antimuscarinic) agents are the most widely used pharmacological option for overactive bladder.This study set out to identify and characterize the influence of a number of intrinsic characteristics on the pharmacokinetics of the anticholinergic agent trospium chloride (Sanctura(®)) 60 mg extended release (XR), and to evaluate the correlation between trospium chloride exposure and key efficacy and safety outcomes in subjects and patients.Pharmacokinetic data were obtained from three studies in which a total of 349 subjects received trospium chloride XR for up to 12 weeks. Plasma trospium chloride concentration data were pooled and a population pharmacokinetic model was derived using non-linear mixed-effects modelling. Demographic factors were assessed for influence on the model. The correlation between trospium chloride exposure and key efficacy variables was evaluated. Correlations between exposure and safety outcomes were also assessed.Trospium chloride XR 60 mg once daily for 10 days in healthy volunteers or trospium chloride 60 mg XR once daily for either 2 weeks or 12 weeks in patients with overactive bladder.The best population pharmacokinetic model was determined to be a two-compartment model with zero-order release into the depot compartment and first-order absorption. Body surface area (BSA) was the only covariate to significantly (P0.05) impact trospium chloride 60 mg XR pharmacokinetics. Significant relationships (P0.05) were observed between exposure [maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve from time zero to 24 h (AUC(24))] and efficacy outcomes in the65-year age group for change in average number of voids/day, change in number of incontinence episodes, and change in urgency severity, and in the ≥65-year age group statistical significance (P0.05) was achieved for C(max), but not for AUC(24), for these same three efficacy measures. Statistically significant relationships (P0.004) were also observed between exposure and both dry mouth and constipation, with increased benefit and increased incidence of adverse events (AEs) associated with higher concentrations; the correlation coefficients were low against the aggregate of AEs of interest (0.19 for AUC(24) and 0.18 for C(max)), indicating only mild strength of association.This population pharmacokinetic analysis demonstrated that the only demographic characteristic associated with trospium chloride pharmacokinetics was BSA. Thus, treatment of most patients with overactive bladder with once-daily trospium chloride 60 mg XR should not require consideration of key intrinsic demographic parameters. Furthermore, while efficacy and tolerability outcomes were found to be correlated with trospium chloride exposure, the strength of the association was modest in this study.

The objective of this study is to characterize the steady-state pharmacokinetics and compare the relative bioavailability of the extended-release capsule formulation of the antimuscarinic trospium chloride, developed for once-daily administration, and trospium chloride immediate-release tablets. This is a single-center, multidose, randomized, open-label, 2-period, 2-arm crossover, bioavailability study in healthy adult male and female subjects who are within 20% of their ideal body weight. Subjects receive trospium 60-mg extended-release capsules once daily and trospium 20-mg tablets twice daily for 10 days, each in a crossover manner. Twenty-four subjects are enrolled in the study. With multiple dosing of trospium 60 mg extended-release once daily versus 20 mg twice daily, lower geometric least squares mean area under the concentration-time curve from 0 to 24 hours (17 360 vs 28 590 pg.h/mL; ratio 61%; 90% confidence interval, 51-72) and maximum plasma concentration (1517 vs 2502 pg/mL; 61%; 90% confidence interval, 49-75) are observed. Furthermore, with trospium 60 mg extended-release versus 20 mg, median time to maximum plasma concentration is later (5.0 vs 4.5 hours) and half-life is longer (35.8 vs 27.2 hours). Trospium exposure is lower with multiple dosing of trospium 60 mg extended-release compared with trospium 20 mg twice daily. Thus, with the extended-release formulation, trospium concentrations are less likely to reach the threshold where adverse events may sometimes occur.

The authors studied a potential drug-drug interaction via findings from in vitro and in vivo studies, to assess whether the in vitro system was predictive of in vivo clinical pharmacokinetic outcomes. An in vitro experiment and a clinical study were performed to assess the potential for interaction. The effect of trospium chloride on human P-glycoprotein-mediated transport of [3H]-digoxin was determined in vitro. A randomized, crossover clinical trial in 40 subjects was performed to evaluate the effect of trospium on the pharmacokinetics of digoxin in vivo. The findings from the studies were then compared. The in vitro findings in this study were corroborated by the clinical study via assessment of inhibition and impact on pharmacokinetic parameters. The in vitro system for assessment of a potential interaction of 2 drugs excreted primarily through the kidney was predictive of the pharmacokinetic outcomes obtained from a clinical setting.

Amplitude and phase characteristics of the two most audible combination tones (2f1 − f2) and (f2 − f1) were measured psychoacoustically on four subjects using the cancellation method. Digital stimulus generation allowed for exact phase control and continuous phase shifting. For equal level stimulus tones (f1 and f2) in cosine phase, the results generally corroborate earlier findings. That is, the amplitude of (2f1 − f2) and (f2 − f1) both decrease with increasing f2/f1 with slight changes as a function of stimulus level; (f2 − f1) phase remains relatively constant with respect to stimulus phase as a function of f2/f1, while (2f1 − f2) phase increases dramatically with increasing f2/f1. The present study covers a wide range of primary frequencies and frequency ratios; it also presents data for both (2f1 − f2) and (f2 − f1) from the same subject. Previously unreported combination‐tone pitch shift as a function of cancellation‐tone phase is also described.