Real world clinical experience with a new formulation of levothyroxine engineered to meet new and stricter regulatory requirements.

Objectives: A new LT4 formulation (Euthyrox [LT4 NF]) was developed to meet new regulatory standards, and has replaced the older formulation (LT4 OF) in a number of countries. We evaluated the possibility of tolerability/safety concerns associated with the switch by analysing spontaneous adverse event (AE) reports before and after switching.

Methods: We examined spontaneous reports of adverse events (AE) from 18 countries generated from individual case safety reports (ICSRs) submitted to the pharmaceutical sponsor's global safety database, over one year before/one year after the switch.

Automatic detection of adverse events to predict drug label changes using text and data mining techniques.

Purpose: The aim of this study was to assess the impact of automatically detected adverse event signals from text and open-source data on the prediction of drug label changes.

Methods: Open-source adverse effect data were collected from FAERS, Yellow Cards and SIDER databases. A shallow linguistic relation extraction system (JSRE) was applied for extraction of adverse effects from MEDLINE case reports.

Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria.

Objective: The combination of chloroquine and methylene blue is potentially effective for the treatment of chloroquine-resistant malaria caused by Plasmodium falciparum. The aim of this study was to investigate whether methylene blue influences the pharmacokinetics of chloroquine.

Methods: In a randomized, placebo-controlled, parallel group design, a 3-day course of therapeutic oral doses of chloroquine (total 2.

Dose individualisation in patients with renal insufficiency: does drug labelling support optimal management?

Objective: An important information source for pharmacotherapy in populations at risk is drug labelling. We compared the recommendations for patients with renal insufficiency included in German drug labellings with evidence from the literature.

Methods: From the 120 drugs with the highest turnover in a large university hospital, all drugs with pharmacokinetics independent of renal function (n=48) and those with substantial accumulation in renal failure (n=28) were identified.

Assessment of levothyroxine sodium bioavailability: recommendations for an improved methodology based on the pooled analysis of eight identically designed trials with 396 drug exposures.

Background: Assessment of dosage form performance in delivering endogenous compounds, such as hormones, in vivo requires a specific approach.

Objectives: Assessment of relative bioavailability of levothyroxine sodium (L-T4) from eight solid preparations, compared with a liquid formulation, by using pharmacological doses, and critical evaluation of trial methodology based on the pooled analysis of individual data.

Design: Eight open-label, randomised, single-dose, crossover phase I studies using eight solid L-T4 dosage forms (25, 50, 75, 100, 125, 150, 175, 200 microg per tablet; administered total doses 600, 625 or 700 microg) and a liquid formulation; assessment of relative bioavailability by 90% confidence intervals for the relative area under the concentration-time curve (AUC) of total thyroxine (TT4), i.

Reduction of saquinavir exposure by coadministration of loperamide: a two-way pharmacokinetic interaction.

Objective: To assess any pharmacokinetic interactions between loperamide and saquinavir.

Design: Double-blind, double-dummy, randomised, placebo-controlled, three-way crossover trial.

Participants: Twelve healthy male and female volunteers, aged 24-46 years.

Endothelial venodilator response in carriers of genetic polymorphisms involved in NO synthesis and degradation.

Aims: Polymorphisms of the NOSIII gene and of the CYBA gene have been associated with a number of pathological conditions such as arterial hypertension, coronary artery disease, and myocardial infarction. Because endothelium-dependent vasodilation is impaired in these disorders, we hypothesized that polymorphisms of NOSIII or CYBA might modulate endothelial function of venous capacitance vessels already before cardiovascular disease becomes overt.

Methods: Endothelium-dependent and -independent venodilation was assessed by measuring local vascular responses to bradykinin and sodium nitroprusside in the dorsal hand vein after preconstriction with phenylephrine in 72 healthy male Caucasians after careful exclusion of cardiovascular risk factors.

Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers.

Background: Ritonavir is a potent in vitro inhibitor of several cytochrome P450 isozymes and ABC transporters including the efflux pump P-glycoprotein (P-gp). This study assessed the effect of repetitive ritonavir administration on digoxin distribution and total and renal digoxin clearance as a marker for P-gp activity in vivo.

Methods: In a randomized, placebo-controlled crossover study, 12 healthy male participants received oral ritonavir (300 mg twice daily) for 11 days.

Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40.

Background: The pharmacokinetics of digoxin is modulated by the efflux pump P-glycoprotein. Cremophor EL (BASF Aktiengesellschaft, Ludwigshafen, Germany) (polyoxyl 35 castor oil), a castor oil derivative used to improve the solubilization of drugs and vitamins, has been shown to inhibit this membrane transporter in vitro and in vivo. So far, no study in humans has evaluated the effect of Cremophor RH40 (BASF Aktiengesellschaft) (polyoxyl 40 hydrogenated castor oil) on P-glycoprotein.

Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement.

Background: The antidiarrheal drug loperamide is frequently used to treat ritonavir-associated diarrhea in patients with human immunodeficiency virus. The absence of marked central opioid effects has been attributed to its low bioavailability and its poor penetration of the blood-brain barrier, both of which might be altered by ritonavir, a potent P-glycoprotein and cytochrome P4503A inhibitor.

Methods: A 16-mg dose of loperamide was administered to 12 healthy male and female volunteers together with either 600 mg of ritonavir or placebo.