The empirically calculated parameter LogP(o/w), the log(10) of the coefficient for solvent partitioning between 1-octanol and water, has been used to provide the key data for a unique non-covalent interaction force field called HINT (Hydropathic INTeractions). This experimentally-derived force field encodes entropic as well as enthalpic information and also includes some representation of solvation and desolvation energetics in biomolecular associations. The theoretical basis for the HINT model is discussed. This review includes: 1) discussion of calculational representation of the hydrophobic effect, 2) the rationale for describing the experimental LogP(o/w) based descriptors used in the HINT force field and model as free energy-like, 3) the relationship between hydrophobic fragment constants and partial group electrostatic charge, and 4) the implications of structurally-conserved water molecules on free energy of molecular association. Several recent applications of HINT in structure-based and ligand-based drug discovery are reviewed. Finally, future directions in the HINT model development are proposed.

1-Octanol↗

PubMedDate not supplied

Serological assessment of type I collagen burden in scleroderma spectrum disorders: a systematic review.

RATIONALE: The aim of the study was to evaluate the validity of collagen type I metabolites as markers of disease activity in scleroderma (SSc), through a systematic review of the literature and by validating the results by measuring collagen type I metabolites in well characterized patients with scleroderma spectrum disorders and in Raynaud's phenomenon. METHODS: A systematic review was performed of studies of collagen type I metabolites in scleroderma spectrum disorders published from 1980 to 2003. The collected results from the literature were compared with our own measurements of collagen type I metabolites (PINP and ICTP) in a small number of well characterized patients within the scleroderma spectrum and in patients with primary and "autoimmune" Raynaud's phenomenon. Peptide concentrations from all sources, including the present study, were compared. Reported correlations between peptide concentrations and clinical variables were also analysed. RESULTS: Of 19 papers identified by an extensive Medline search, 12 were eligible for systematic analysis. There was a considerable heterogeneity in the results with a wide range of metabolite concentrations. Values from disease groups and healthy controls overlapped. These findings were confirmed by our study where, similarly, there was a large range of values in all groups, but particularly in the diffuse SSc subset. When the correlation between peptide levels and clinical variables was assessed, large discordance between the studies was observed. CONCLUSIONS: We have not found sufficient evidence to support the use of serum markers of collagen turnover in the assessment of scleroderma activity and severity, in view of their low specificity and the heterogeneity of the results of various studies. Lack of standardized routine evaluation of SSc patients in clinical studies might have accounted for the variability of the findings. However, due to the small sizes of most published studies, demonstration of no effect should come from large-scale randomised trials. Longitudinal serial analysis of these molecules in individual patients may play a future role in the evaluation of the response to fibroblast-targeting therapeutic strategies in scleroderma patients.

Biomarkers↗

PubMedDate not supplied

3,4-Dichlorobenzyloxyacetic acid is extensively metabolized to a taurine conjugate in rats.

The metabolism of the antisickling agent 3,4-dichlorobenzyloxyacetic acid (3,4-DCBAA) was examined after ip administration to rats. Within 5 days after administration of radiolabeled 3,4-DCBAA, 77.4 +/- 4.6% of the dose was recovered in the urine and only 3.2 +/- 0.5% was recovered in the feces. Metabolites in the urine were isolated and characterized by HPLC, electron impact MS, and LC/MS, and their identities were confirmed by comparing their spectra with those of synthetic standards. Quantitation of these urinary metabolites revealed that the majority of the radioactive dose was excreted as a taurine conjugate (60.1 +/- 4.4%), while lesser amounts were excreted as 3,4-dichlorohippurate, unchanged 3,4-DCBAA, the glycine conjugate of 3,4-DCBAA, and a polar unknown which is believed to be glycolic acid. A pathway involving an initial O-dealkylation at the benzyl carbon of 3,4-DCBAA and proceeding through the glycine conjugation of 3,4-dichlorobenzoic acid has been proposed to explain the formation of 3,4-dichlorohippurate and the polar unknown. The extensive conjugation of 3,4-DCBAA with taurine is an unprecedented observation in rats, which usually utilize glycine for amino acid conjugation reactions. Further studies with 3,4-DCBAA may provide insight into the enzymatic mechanisms of taurine conjugation, which are not well defined at this time.

Anemia, Sickle Cell↗

PubMedDate not supplied

Oral ketoconazole in Keratomycosis.

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Administration, Oral↗