Clinical testing of three novel transient receptor potential cation channel subfamily V member 1 antagonists in a pharmacodynamic intradermal capsaicin model.

Background: The transient receptor potential cation channel subfamily V 1 (TRPV1) is involved in nociception and has thus been of interest for drug developers, as a target for novel analgesics. However, several oral TRPV1 antagonists have failed in development, and novel approaches to target TRPV1 with innovative chemistry are needed.

Method: This work describes an intradermal microdosing approach in humans for pharmacodynamic deductions and pharmacological profiling of compounds.

Preclinical characterization of three transient receptor potential vanilloid receptor 1 antagonists for early use in human intradermal microdose analgesic studies.

Background: The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel involved in the mediation of peripheral pain to the central nervous system. As such, the TRPV1 is an accessible molecular target that lends itself well to the understanding of nociceptive signalling. This study encompasses preclinical investigations of three molecules with the prospect to establish them as suitable analgesic model compounds in human intradermal pain relief studies.

Chemometric evaluation of the combined effect of temperature, pressure, and co-solvent fractions on the chiral separation of basic pharmaceuticals using actual vs set operational conditions.

The need to determine the actual operational conditions, instead of merely using the set operational conditions, was investigated for in packed supercritical fluid chromatography (SFC) by design of experiments (DoE) using a most important type of compounds, pharmaceutical basics, as models. The actual values of temperature, pressure, and methanol levels were recorded and calculated from external sensors, while the responses in the DoE were the retention factors and selectivity. A Kromasil CelluCoat column was used as the stationary phase, carbon dioxide containing varying methanol contents as the mobile phase, and the six racemates of alprenolol, atenolol, metoprolol, propranolol, clenbuterol, and mianserin were selected as model solutes.

Assessment of Free Drug Concentration in Cyclodextrin Formulations Is Essential to Determine Drug Potency in Functional In Vitro Assays.

Cyclodextrins (CD) have the ability to form inclusion complexes with drugs and can be used as excipients to enhance solubility of poorly soluble drugs. To make accurate estimations of the potency of the drug, knowledge of the free drug concentration is important. The aim of this study was to evaluate the applicability of calculated free drug concentrations toward response measurements in a transient receptor potential vanilloid receptor-1 cell-based in vitro assay.

Structure-interaction relationships between the bile acid GCA and pharmaceuticals using multivariate data analysis and capillary electrophoresis.

Capillary electrophoresis (CE) has been used in an interaction study of 66 pharmaceutical compounds with the bile acid glycocholate (GCA). The developed method proved to have a high precision in its ability to determine the mobility of drugs in buffer and buffer bile acids solutions. The relationship between solute structure and interaction with GCA was studied using two-dimensional descriptors with the in-house software SELMA and a three-dimensional model (quantum mechanical descriptors) in combination with the experimental CE-interaction data.