An Investigation into Drug Partitioning Behaviour in Simulated Pulmonary Surfactant Monolayers with Associated Molecular Modelling

Drug delivery to the body via the inhaled route is dependent upon patient status, device use and respirable formulation characteristics. Further to inhalation, drug-containing particles interact and dissolve within pulmonary fluid leading to the desired pharmacological response. Pulmonary surfactant stabilises the alveolar air-liquid interface and permits optimal respiratory mechanics. This material represents the initial contacting surface for all inhaled matter. On dissolution, the fate of a drug substance can include receptor activation, membrane partitioning and cellular penetration. Here, we consider the partitioning behaviour of salbutamol when located in proximity to a simulated pulmonary surfactant monolayer at pH 7. The administration of salbutamol to the underside of the surfactant film resulted in an expanded character for the two-dimensional ensemble and a decrease in the compressibility term. The rate of drug partitioning was greater when the monolayer was in the expanded state (i.e. inhalation end-point), which was ascribed to more accessible areas for molecular insertion. Quantum mechanics protocols, executed via Gaussian 09, indicated that constructive interactions between salbutamol and integral components of the model surfactant film took the form of electrostatic and hydrophobic associations. The favourable interactions are thought to promote drug insertion into the monolayer structure leading to the observed expanded character. The data presented herein confirm that drug partitioning into pulmonary surfactant monolayers is a likely prospect further to the inhalation of respirable formulations. As such, this process holds potential to reduce drug-receptor activation and / or increase the residence time of drug within the pulmonary space

Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors

Major depressive disorder (MDD) is increasingly viewed as interplay of environmental stressors and genetic predisposition, and recent data suggest that the disease affects not only the brain, but the entire body. As a result, we aimed at determining whether patients with major depression have aberrant molecular responses to stress in peripheral tissues. We examined the effects of two metabolic stressors, galactose (GAL) or reduced lipids (RL), on the transcriptome and miRNome of human fibroblasts from 16 pairs of patients with MDD and matched healthy controls (CNTR). Our results demonstrate that both MDD and CNTR fibroblasts had a robust molecular response to GAL and RL challenges. Most importantly, a significant part (messenger RNAs (mRNAs): 26-33%; microRNAs (miRNAs): 81-90%) of the molecular response was only observed in MDD, but not in CNTR fibroblasts. The applied metabolic challenges uncovered mRNA and miRNA signatures, identifying responses to each stressor characteristic for the MDD fibroblasts. The distinct responses of MDD fibroblasts to GAL and RL revealed an aberrant engagement of molecular pathways, such as apoptosis, regulation of cell cycle, cell migration, metabolic control and energy production. In conclusion, the metabolic challenges evoked by GAL or RL in dermal fibroblasts exposed adaptive dysfunctions on mRNA and miRNA levels that are characteristic for MDD. This finding underscores the need to challenge biological systems to bring out disease-specific deficits, which otherwise might remain hidden under resting conditions

Fluorometric determination of drug-protein association constants : binding of thiopurines by bovine serum albumin

The binding constants and the number of binding sites for the binding sites for the binding of six thiopurines to bovine serum albumin were determined using a fluorescence probe method. The protein molecules appeared to have an average of two binding sites for these compounds under the experimental conditions. The association constants were calculated by means of the Klotz equation. The mechanism of binding for these substances can be hydrophobic and electrostatic in nature

La pression d’affaissement des couches superficielles mixtes, de cholestérol, et de lécithine avec des acides biliaires

La pression d’affaissement des films monomoléculaires mixtes de cholestérol et de lécithine avec les acides biliaires (acide désoxycholique, lithocholique et cholanique) ont été étudié à partir des résultats expérimentaux obtenus antérieurement. On en a conclu à une immiscibilité partielle ou totale pour des films mixtes de cholestérol avec les acides désoxycholique et lithocholique respectivement. Pour les autres systèmes étudiés (cholestérol acide cholanique et lécithine avec l’acide désoxycholique, lithocholique et cholanique) un écart par rapport au comportement idéal fut obtenu, démontrant une interaction. Ce comportement non idéal fut décrit en admettant un comportement régulier du mélange superficiel, d’où on a pu déduire un paramètre d’interaction. Ce paramètre d’interaction est intimement lié à la différence de l’énergie d’interaction potentielle suivant Lennard-Jones. Pour tous les systèmes étudiés il y a accord entre la méthode décrite et celle des aires moléculaire moyennes à une pression superficielle choisie