In vitro and in vivo immunogenicity assessment of protein aggregate characteristics.

The immunogenicity risk of therapeutic protein aggregates has been extensively investigated over the past decades. While it is established that not all aggregates are equally immunogenic, the specific aggregate characteristics, which are most likely to induce an immune response, remain ambiguous. The aim of this study was to perform comprehensive in vitro and in vivo immunogenicity assessment of human insulin aggregates varying in size, structure and chemical modifications, while keeping other morphological characteristics constant.

The effect of fatty diacid acylation of human PYY on Y receptor potency and half-life in minipigs.

Peptides are notoriously known to display very short in vivo half-lives often measured in minutes which in many cases greatly reduces or eliminates sufficient in vivo efficacy. To obtain long half-lives allowing for up to once-weekly dosing regimen, fatty acid acylation (lipidation) have been used to non-covalently associate the peptide to serum albumin thus serving as a circulating depot. This approach is generally considered in the scientific and patent community as a standard approach to protract almost any given peptide.

Metabolism of peptide YY 3-36 in Göttingen mini-pig and rhesus monkey.

Peptide YY 3-36-amide (PYY3-36) is a peptide hormone, which is known to decrease appetite and food-intake by activation of the Y2 receptor. The current studies were designed to identify the metabolites of PYY3-36 in mini-pig and rhesus monkey. Plasma samples were analyzed by high resolution LC-MS (and MS/MS) in order to unambiguously identify the metabolites of PYY3-36.

Comparison of the pharmacokinetics of three concentrations of insulin aspart during continuous subcutaneous insulin infusion (CSII) in a pig model.

Objectives: The aim of the study was to investigate the pharmacokinetic properties of insulin aspart (IAsp) in three different concentrations given as a continuous subcutaneous insulin infusion (CSII).

Methods: A randomized cross-over study was performed in pigs, where IAsp U200, U100 or U20 was given for 8 h with the same total dose. Six pigs were included and blood was sampled during the CSII and 3 h after.

Clinical studies with oral lipid based formulations of poorly soluble compounds.

This work is an attempt to give an overview of the clinical data available on lipid based formulations. Lipid and surfactant based formulations are recognized as a feasible approach to improve bioavailability of poorly soluble compounds. However not many clinical studies have been published so far.

In vitro-in vivo correlations of self-emulsifying drug delivery systems combining the dynamic lipolysis model and neuro-fuzzy networks.

The aim of the current study was to evaluate the potential of the dynamic lipolysis model to simulate the absorption of a poorly soluble model drug compound, probucol, from three lipid-based formulations and to predict the in vitro-in vivo correlation (IVIVC) using neuro-fuzzy networks. An oil solution and two self-micro and nano-emulsifying drug delivery systems were tested in the lipolysis model. The release of probucol to the aqueous (micellar) phase was monitored during the progress of lipolysis.

Bioavailability of probucol from lipid and surfactant based formulations in minipigs: influence of droplet size and dietary state.

The influence of droplet size on the absorption from lipid and surfactant based formulations was evaluated from two self-emulsifying formulations, a surfactant solution, and an oil solution. The self-emulsifying formulations was a self-emulsifying (SEDDS) and a self-nanoemulsifying (SNEDDS) formulation containing equal lipid and surfactant load, but exhibiting a large difference (approx 100 times) in the mean particle diameter of the resultant emulsion. The formulations were evaluated in a bioavailability study in fasted and fed Göttingen minipigs using probucol as model drug.

Using biorelevant dissolution to obtain IVIVC of solid dosage forms containing a poorly-soluble model compound.

The usefulness of selected biorelevant dissolution media (BDM) to predict in vivo drug absorption was studied. Dissolution profiles of solid formulations of a poorly soluble model compound were compared in BDM simulating fasted and two levels of fed state. A non-physiologically relevant medium containing the cationic surfactant, cetrimide, was also investigated.

Predictors of mortality in patients with type 2 diabetes with or without diabetic nephropathy: a follow-up study.

Objective: To evaluate the prognostic significance of cardiovascular risk factors including 24-h ambulatory blood pressure level and rhythm for all-cause mortality in type 2 diabetic patients.

Methods: In a prospective observational study, 104 patients with type 2 diabetes were followed: 51 patients with diabetic nephropathy and 53 patients with persistent normoalbuminuria. At baseline, 24-h ambulatory blood pressure, left ventricular hypertrophy, glomerular filtration rate and cardiac autonomic neuropathy were measured.

Structural development of self nano emulsifying drug delivery systems (SNEDDS) during in vitro lipid digestion monitored by small-angle X-ray scattering.

Purpose: To investigate the structural development of the colloid phases generated during lipolysis of a lipid-based formulation in an in vitro lipolysis model, which simulates digestion in the small intestine.

Materials And Methods: Small-Angle X-Ray scattering (SAXS) coupled with the in vitro lipolysis model which accurately reproduces the solubilizing environment in the gastrointestinal tract and simulates gastrointestinal lipid digestion through the use of bile and pancreatic extracts. The combined method was used to follow the intermediate digestion products of a self nano emulsified drug delivery system (SNEDDS) under fasted conditions.

Characterization of prototype self-nanoemulsifying formulations of lipophilic compounds.

This study describes the evaluation and characterization of a self-nanoemulsifying drug delivery system (SNEDDS) consisting of a nonionic surfactant (Cremophor RH40), a mixture of long chain mono-, di-, and triacylglycerides (Maisine 35-1 and Sesame oil) and ethanol. Compositions containing 10% (w/w) ethanol, 40%-60% (w/w) lipid content, and 30%-50% (w/w) Cremophor RH40 were identified as pharmaceutically relevant, robust, and self-nanoemulsifying when dispersed in aqueous media. The influence of adding three different lipophilic model drug compounds (danazol, halofantrine, and probucol) to the SNEDDS was evaluated.

Myocardial perfusion in type 2 diabetes with left ventricular hypertrophy: normalisation by acute angiotensin-converting enzyme inhibition.

The purpose of this study was to assess whether acute angiotensin-converting enzyme (ACE) inhibition would improve myocardial perfusion and perfusion reserve in a subpopulation of normotensive patients with diabetes and left ventricular hypertrophy (LVH), both independent risk factors of coronary disease. Using positron emission tomography (PET), we investigated the response of regional myocardial perfusion to acute ACE inhibition with i.v.

Dipyridamole, cold pressor test, and demonstration of endothelial dysfunction: a PET study of myocardial perfusion in diabetes.

Unlabelled: Much evidence suggests endothelial dysfunction to be present in non-insulin-dependent diabetes mellitus (NIDDM) and to be important for the development of myocardial ischemia. Endothelial function in the coronary vessels may be studied in various ways. We compared the effect of cold pressor testing (CPT) with that of dipyridamole, a pharmacologic vasodilator, on coronary blood flow (CBF) measured by PET in NIDDM patients and healthy volunteers.