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Transthyretin amyloidosis is largely caused by synthesis of mutant transthyretin in the liver and deposition of transthyretin in other organs. A therapeutic approach mediated by RNA interference resulted in reduced transthyretin levels in affected patients and in controls. Transthyretin amyloidosis is a life-threatening disorder caused by the deposition of hepatocyte-derived transthyretin amyloid in various tissues and organs. 1 , 2 Circulating transthyretin is derived from the liver 3 and can form amyloid deposits in peripheral nerves and in the gastrointestinal tract, heart, and kidneys. Transthyretin is also synthesized by the retina and choroid plexus, 4 , 5 which can lead to vitreal and leptomeningeal deposits. More than 100 genetic variants of the gene encoding transthyretin ( TTR ) are associated with autosomal dominant forms of the disease, known as familial amyloidotic polyneuropathy 6 – 8 and familial amyloidotic cardiomyopathy. 9 – 11 The most common mutation associated . . .

Background and Objectives: Pitavastatin is a highly effective lipid-lowering drug (approved dose range 1-4 mg/day) with a distinctive metabolic pathway that has a low potential for drug interactions. The efficacy and safety of pitavastatin have been characterized in a broad clinical development programme conducted initially in Japanese patients. The objectives of the present study were to evaluate the pharmacokinetic bioequivalence of the European (EU) and Japanese (JP) formulations of pitavastatin 2 mg in healthy Japanese and Caucasian men, and to assess whether the bioavailability of each formulation was similar in the two ethnic groups. Methods: In this open-label, single-dose, two-way crossover pharmacokinetic study, healthy men aged 18-45 years were randomized to receive: the JP formulation of pitavastatin 2 mg followed by the EU formulation; or the EU formulation of pitavastatin 2 mg followed by the JP formulation. The main outcome measures were maximum plasma concentration (C max), area under the plasma concentration-time curve (AUC) during a dosage interval (τ) [AUCτ] and AUC from time zero to infinity (AUC∞) for pitavastatin and its main (inactive) metabolite pitavastatin lactone. Plasma concentrations of pitavastatin and pitavastatin lactone were determined using a validated liquid chromatography-tandem mass spectrometry method. Results: Forty-eight Caucasian and 12 Japanese men completed the study. Compared with the Japanese men, the Caucasian men were of greater mean body weight (76.1 vs 58.9 kg), height (180.8 vs 170.8 cm) and body mass index (23.2 vs 20.2 kg/m2). Geometric mean ratios (GMRs) of the pharmacokinetic parameters of pitavastatin demonstrated bioequivalence of the EU and JP formulations: GMRs and 90% confidence intervals (CIs) fell within the range 80-125% in Caucasian men and in Caucasian and Japanese groups combined for pitavastatin C max (combined analysis: GMR 103.1% [90% CI 96.0, 110.6]), AUCτ (GMR 99.6% [90% CI 95.5, 104.0]), and AUC∞ (GMR 104.2% [90% CI 96.2, 112.8]). After adjusting for age and body weight in the pooled formulation analysis, bioequivalence between the Caucasian and Japanese groups was similarly demonstrated for pitavastatin Cmax (GMR 96.8% [90% CI 90.2, 103.8]), AUCτ (GMR 98.3% [90% CI 94.2, 102.7]) and AUC∞ (GMR 85.9% [90% CI 81.1, 91.0]). Conclusion: The EU and JP formulations of pitavastatin showed pharmacokinetic bioequivalence, and there were no clinically relevant differences in exposure to pitavastatin between Caucasian and Japanese participants when differences in body weight were taken into account. [PUBLICATION ABSTRACT]

To compare antisecretory effects of single doses of rabeprazole and esomeprazole. Open, randomised, 2-way crossover, clinical pharmacology study. 24 healthy subjects (10 men; mean age 26.2 y) received a single dose of rabeprazole 20 mg or esomeprazole 40 mg, with a 14-day 'washout'. Intragastric pH was recorded continuously from 24 h before to 24 h after dosing. Mean intragastric pH was higher after esomeprazole than rabeprazole during 0-5 h after dosing (P=0.0001); the reverse was true from 14-24 h (P=0.0002). Mean % time pH>3 and >4 was greater after esomeprazole than rabeprazole during 0-14 h (P=0.041 and 0.044), but the reverse was true during 14-24 h (P=0.0005 and 0.001). In the 0-24 h interval as a whole, there was no difference between treatments in mean pH or % time pH>3 or >4. Single-dose rabeprazole 20 mg was as effective as esomeprazole 40 mg in increasing intragastric pH and maintaining pH>3 and >4, despite the 2-fold difference in dose.

Purpose Hypergastrinaemia induced by proton pump inhibitor (PPI) therapy may cause ECL-cell and parietal-cell hyperplasia and rebound hyperacidity and dyspepsia after PPI withdrawal. The aim of the study was to assess the effect of different dosage-regimens of netazepide, a gastrin/CCK 2 receptor antagonist, on PPI-induced hypergastrinaemia and elevated chromogranin A (CgA). Methods Six groups of eight healthy subjects participated in a randomised, double-blind study of esomeprazole 40 mg daily for 28 days, in combination with netazepide 1, 5 or 25 mg or placebo, daily, during the last 14 days of esomeprazole or during 14 days after treatment withdrawal. Fasting serum gastrin and plasma CgA were measured during treatment and after withdrawal, as biomarkers of acid suppression and ECL-cell activity, respectively. Dyspepsia was monitored throughout the study. Results Esomeprazole increased gastrin and CgA. Netazepide increased gastrin, but not CgA, and inhibited dose dependently the CgA response to esomeprazole. Gastrin and CgA returned to baseline within 2–3 days of esomeprazole withdrawal; netazepide did not shorten that time. There was no rebound dyspepsia after esomeprazole withdrawal. Conclusions Esomeprazole and netazepide each increase gastrin, consistent with a secondary effect of gastric acid suppression, but by different mechanisms. Esomeprazole-induced hypergastrinaemia stimulates ECL cells and thereby increases CgA. Netazepide-induced hypergastrinaemia does not increase CgA, because netazepide blocks gastrin/CCK 2 receptors on ECL cells. Co-administration of netazepide 5 mg abolishes the effect of esomeprazole-induced hypergastrinaemia on ECL cells. The quick return to baseline of gastrin and CgA and absence of dyspepsia after esomeprazole withdrawal do not support the concept of rebound hyperacidity.

Interferon beta-1a (IFNβ-1a) 30 μg weekly by intramuscular (IM) injection is used to treat relapsing forms of multiple sclerosis. We assessed if it can be given safely by inhalation. Twenty-one healthy volunteers inhaled IFNβ-1a 300 μg, formulated for deep delivery to the lungs, in a randomized, parallel-group, repeat-dose trial. Comparators were room air and placebo. The primary outcome measure was carbon monoxide transfer factor corrected for hemoglobin (TLCOc), which measures the CO transfer from inspired gas to pulmonary capillary blood. After 3 and 4 once-weekly doses, IFNβ-1a significantly reduced TLCOc compared with room air: after the third dose, mean standard deviation (SD) change in percent predicted TLCOc was−10.9 (2.8), and after the fourth dose was−12.1 (2.7). After 2, 3, and 4 doses, IFNβ-1a significantly reduced TLCOc compared with placebo: after the second dose, mean (SD) change in percent predicted TLCOc was−8.8 (5.5), after the third dose was−10.9 (2.8), and after the fourth dose was−12.1 (2.7). Circulating IFNβ-1a concentrations were about one-third those of the intramuscular dose regimen. Tolerability of IFNβ-1a and the comparators was equally good. In conclusion, IFNβ-1a reduced TLCOc, whereas placebo and room air did not. A dose of IFNβ-1a 300 μg by inhalation may not be safe for general use.

Purpose Hypergastrinemia induced by proton pump inhibitor (PPI) therapy may cause ECL-cell and parietal-cell hyperplasia and rebound hyperacidity and dyspepsia after PPI withdrawal. The aim of the study was to assess the effect of different dosage-regimens of netazepide, a gastrin/CCK2 receptor antagonist, on PPI-induced hypergastrinemia and elevated chromogranin A (CgA). Methods Six groups of eight healthy subjects participated in a randomized, double-blind study of esomeprazole 40 mg daily for 28 days, in combination with netazepide 1, 5 or 25 mg or placebo, daily, during the last 14 days of esomeprazole or during 14 days after treatment withdrawal. Fasting serum gastrin and plasma CgA were measured during treatment and after withdrawal, as biomarkers of acid suppression and ECL-cell activity, respectively. Dyspepsia was monitored throughout the study. Results Esomeprazole increased gastrin and CgA. Netazepide increased gastrin, but not CgA, and inhibited dose dependently the CgA response to esomeprazole. Gastrin and CgA returned to baseline within 2-3 days of esomeprazole withdrawal; netazepide did not shorten that time. There was no rebound dyspepsia after esomeprazole withdrawal. Conclusions Esomeprazole and netazepide each increase gastrin, consistent with a secondary effect of gastric acid suppression, but by different mechanisms. Esomeprazole-induced hypergastrinemia stimulates ECL cells and thereby increases CgA. Netazepide-induced hypergastrinemia does not increase CgA, because netazepide blocks gastrin/CCK2 receptors on ECL cells. Co-administration of netazepide 5 mg abolishes the effect of esomeprazole-induced hypergastrinemia on ECL cells. The quick return to baseline of gastrin and CgA and absence of dyspepsia after esomeprazole withdrawal do not support the concept of rebound hyperacidity.

Background and Objectives: Pitavastatin is a highly effective lipid-lowering drug (approved dose range 1–4 mg/day) with a distinctive metabolic pathway that has a low potential for drug interactions. The efficacy and safety of pitavastatin have been characterized in a broad clinical development programme conducted initially in Japanese patients. The objectives of the present study were to evaluate the pharmacokinetic bioequivalence of the European (EU) and Japanese (JP) formulations of pitavastatin 2mg in healthy Japanese and Caucasian men, and to assess whether the bioavailability of each formulation was similar in the two ethnic groups. Methods: In this open-label, single-dose, two-way crossover pharmacokinetic study, healthy men aged 18–45 years were randomized to receive: the JP formulation of pitavastatin 2 mg followed by the EU formulation; or the EU formulation of pitavastatin 2mg followed by the JP formulation. The main outcome measures were maximum plasma concentration (C max ), area under the plasma concentration-time curve (AUC) during a dosage interval (τ) [AUC τ ] and AUC from time zero to infinity (AUC ∞ ) for pitavastatin and its main (inactive) metabolite pitavastatin lactone. Plasma concentrations of pitavastatin and pitavastatin lactone were determined using a validated liquid chromatography-tandem mass spectrometry method. Results: Forty-eight Caucasian and 12 Japanese men completed the study. Compared with the Japanese men, the Caucasian men were of greater mean body weight (76.1 vs 58.9 kg), height (180.8 vs 170.8 cm) and body mass index (23.2 vs 20.2 kg/m 2 ). Geometric mean ratios (GMRs) of the pharmacokinetic parameters of pitavastatin demonstrated bioequivalence of the EU and JP formulations: GMRs and 90% confidence intervals (CIs) fell within the range 80–125% in Caucasian men and in Caucasian and Japanese groups combined for pitavastatin C max (combined analysis: GMR 103.1% [90% CI 96.0, 110.6]), AUC τ (GMR 99.6% [90% CI 95.5, 104.0]), and AUC ∞ (GMR 104.2% [90% CI 96.2, 112.8]). After adjusting for age and body weight in the pooled formulation analysis, bioequivalence between the Caucasian and Japanese groups was similarly demonstrated for pitavastatin C max (GMR 96.8% [90% CI 90.2, 103.8]), AUC τ (GMR 98.3% [90% CI 94.2, 102.7]) and AUC ∞ (GMR 85.9% [90% CI 81.1, 91.0]). Conclusion: The EU and JP formulations of pitavastatin showed pharmacokinetic bioequivalence, and there were no clinically relevant differences in exposure to pitavastatin between Caucasian and Japanese participants when differences in body weight were taken into account.