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B Testa

Publications and source records attributed to B Testa.

At least 19 recordsLinked to original sources
PubMed1992

Influence of palmitate and benzoate on the unidirectional chiral inversion of ibuprofen in isolated rat hepatocytes.

The influence of benzoic acid, a typical substrate of medium-chain acyl-CoA synthetase, and of palmitic acid, a substrate of long-chain acyl-CoA synthetase, on the metabolic chiral inversion of ibuprofen was investigated in freshly isolated hepatocytes. It was shown that the conjugation of benzoid to hippuric acid does not influence the chiral inversion of ibuprofen. In contrast, palmitic acid inhibited markedly the R-to-S inversion of ibuprofen. It was concluded that this inhibition is due to competition between (R)-ibuprofen and palmitic acid for long-chain acyl-CoA synthetases.

Animals↗
PubMed1992

Nicotinate esters: their binding to and hydrolysis by human serum albumin.

Nicotinate esters were studied for their binding to, and hydrolysis by, human serum albumin. Some esters (ethyl, isopropyl, t-butyl, cyclohexyl, benzyl) were bound but not hydrolysed, while others (2-chloroethyl, 2-butoxyethyl) displayed the opposite behaviour; 1-carbamoylethyl ester was neither bound nor readily hydrolysed. Only p-methoxyphenyl nicotinate was both a ligand and a substrate, and its rate constants of binding and hydrolysis were calculated in a stepwise procedure using a kinetic model.

Chromatography, High Pressure Liquid↗
PubMed1992

Immunoglobulin E distribution in atopic nasal mucosa.

The distribution of B lymphocytes and immunoglobulins G, A, M, and E in nasal mucosa was studied in frozen biopsy sections of nasal turbinate from 16 allergic patients and 8 controls. The immunoperoxidase technique was used with monoclonal and polyclonal antibodies. Comparative analyses of serum immunoglobulin levels were also performed. Few B lymphocytes were observed in the nasal mucosa linings in specimens from allergic and non-allergic patients. In both groups, high positivity for IgG and IgA was observed in the nasal mucosa linings in the specimens. IgM concentration was minimal in both groups. IgE was absent in the nasal turbinate specimens of nonallergic subjects, but was present discontinuously in low concentrations in 7 of the 16 allergic patients. There was no significant difference between allergic and nonallergic patients in the tissue and serum IgG, IgA, and IgM concentrations found. IgE was detected slightly in the nasal mucosa of patients with high IgE serum concentrations (greater than 1000 IU/mL) as well as in patients with very low IgE serum concentration readings. This result raises some doubt on the hypothesis concerning the local production of IgE.

Adolescent↗
PubMed1992

Enzymic hydrolysis of nicotinate esters: comparison between plasma and liver catalysis.

1. The enzymic hydrolysis of a wide series of nicotinic acid esters was investigated using human and rat plasma, and purified hog liver carboxylesterase, and compared with previously published data from rat liver microsomes. Esterase activities were always found to obey Michaelis-Menten kinetics. 2. Rat liver microsomal and plasma enzyme velocities were six orders of magnitude smaller than those of purified hog liver carboxylesterase, and three orders smaller than human plasma activities, but the Km values were of the same magnitude. 3. The binding of nicotinate esters to human plasma esterases, and purified hog liver carboxylesterase, appears to depend mainly on hydrophobic and steric factors.

Animals↗
PubMed1992

Stereophilia.

Explore the source record for details and available documents.

Molecular Structure↗
PubMed1991

pH-dependency of basic ligand binding to alpha 1-acid glycoprotein (orosomucoid).

The binding interactions of a series of basic ligands with alpha 1-acid glycoprotein (AAG) were examined as a function of pH. The binding to AAG increased with increasing pH, and the binding data were satisfactorily fitted to a model that incorporates the effect of pH and discriminates the association constants of neutral (non-protonated) and protonated forms of ligands. It was shown that ligands in the neutral form have a markedly higher affinity for AAG than the protonated forms, resulting in a concomitant decrease in the pKa of bound ligands. The u.v.-visible difference spectra generated upon binding of a representative ligand to AAG also showed that there was a contribution to the binding arising from the deprotonation of the ligand. It is suggested that all tested ligands bind similarly to AAG and that hydrophobic interactions dominate high-affinity binding to AAG.

Hydrogen-Ion Concentration↗
PubMed1991

Partitioning of solutes in different solvent systems: the contribution of hydrogen-bonding capacity and polarity.

Published partition coefficient values of 121 solutes in five solvent systems (1-octanol-water, n-heptane-water, chloroform-water, diethyl ether-water, and n-butyl acetate-water) were correlated with solute properties, namely intrinsic molecular volume (indicator of cavity formation) and the solvatochromic parameters pi* (dipolarity/polarizability), beta (H-bond acceptor basicity), and alpha (H-bond donor acidity). While the cavity term and the H-bond accepting capacity played a comparable role in all solvent systems, the H-bond donor acidity was significant only in the alkane-water and chloroform-water systems. Comparison of the regression coefficients of pi*, beta, and alpha demonstrated the important role that water content at saturation in the organic solvents plays in the partitioning of solutes. Analysis of the differences between 1-octanol-water and n-heptane-water partition coefficients (delta log Poct-hep) and between 1-octanol-water and chloroform-water partition coefficients (delta log Poct-chf) showed that these values mainly quantitate the capacity of solute to donate hydrogen bonds. In contrast, the differences between 1-octanol-water and diethyl ether-water or n-butylacetate-water partition coefficients, (delta log Poct-dee and delta log Poct-ba, respectively) contain no structural information.

Chemical Phenomena↗
PubMed1991

Percutaneous penetration of drugs: a quantitative structure-permeability relationship study.

Human skin permeation data taken from the literature were analyzed for quantitative relationships with physicochemical properties and structural descriptors. No correlations exist with molecular weights and solvent-accessible surface areas. In most cases, skin permeation was inversely correlated with the parameter delta log Poct-hep (i.e., log Poctanol minus log Pheptane), which is mainly a measure of the H-bond donor acidity of the solutes. Lipophilicity itself, as expressed by log Poctanol, also contributes positively to skin permeation in some cases. The results of this quantitative structure-permeability relationship study are interpreted in terms of a unified mechanistic model whereby drugs can permeate via an intercellular route (correlation with both delta log Poct-hep and log Poct) and/or a transcellular route (correlation with log Poct only).

Administration, Topical↗
PubMed1991

The concept of molecular structure in structure-activity relationship studies and drug design.

We can justify the use of any model, method, or algorithm if we clearly state our goals, understand the basis of our procedures, and fully appreciate the true nature and limitations of the results. As we have illustrated here, the creation of new wisdom may appear to be a consequence of our labors. There are cases, however, where this creation may be only an illusion. In any analysis of structure-activity, property-activity, or structure-property relationships, the degree of understanding of the nature of the starting data therefore determines the level of confidence ascribable to any result and prediction. This is, in essence, the message of our inquisitive meditations on the deep nature of structure-activity relationships.

Chemistry, Pharmaceutical↗
PubMed1991

Bicarbonate-catalyzed hydrolysis of hexamethylene diisocyanate to 1,6-diaminohexane.

The hydrolysis of hexamethylene diisocyanate (HDI) in water was tested in a dynamic and stationary system. Without catalysts, the reaction was very slow (less than 1% in 10 min at 30 degrees C) while the addition of simple carboxylic-acid-containing neutral buffers markedly catalyses the formation of 1,6-diaminohexane as the known hydrolysis product. The catalytic efficiency of formic acid, oxalic acid, acetic acid, lactic acid, citric acid and carbonic acid increased in this order while phosphate, glycine and glutamate were inactive even at very high concentrations. A 20 mM bicarbonate buffer was the optimal catalyst, but below this concentration the rate of HDI hydrolysis was drastically reduced. It is suggested that the hydrolysis of inhaled HDI in the lungs may be catalysed by bicarbonate in the blood, giving rise to amines found as urinary metabolites following occupational exposure.

Bicarbonates↗
PubMed1991

Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity.

Morphine 6-glucuronide, but not morphine 3-glucuronide, is a highly potent opiate receptor agonist. In fact, there is converging evidence that much of the analgesic effect occurring after morphine treatment in humans is due to this metabolite rather than to the parent drug. Yet glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier and rapidly excreted by the urinary and/or biliary routes. Here, we report that morphine 6-glucuronide, and to a lesser extent morphine 3-glucuronide, are far more lipophilic than predicted, and in fact not much less lipophilic than morphine itself. Force-field and quantum mechanical calculations indicate that the two glucuronides can exist in conformational equilibrium between extended and folded forms. The extended conformers, because they efficiently expose their polar groups, must be highly hydrophilic forms predominating in polar media such as water; in contrast, the folded conformers mask part of their polar groups, thus being more lipophilic and likely to predominate in media of low polarity such as biological membranes.

Calorimetry↗
PubMed1991

Structure-metabolism relationships in the hydrolysis of nicotinate esters by rat liver and brain subcellular fractions.

Rat liver and brain subcellular esterase activities toward nicotinic acid esters were studied, under varying conditions, such as pH, organic solvents, protein concentration, duration of incubation, and substrate concentration. Esterases in each subcellular fraction displayed activities that obey Michaelis-Menten kinetics, although subcellular fractions are heterogeneous. The Km values were of the same magnitude, and the Vmax values were lower in microsomes than in cytosol of the liver. Brain activities normalized to protein concentration, were much lower than liver activities, aromatic nicotinates being the best substrates in both tissues. Myelin and brain mitochondria of nerve-ending and neuroglial origin display esterase activity toward phenyl nicotinate. In contrast to brain esterases, liver esterases appear homogeneous, and esterase activities in both tissues react differently to changes in pH. Qualitative and quantitative structure-metabolism relationships are not suggestive of tissue-specific ester hydrolysis.

Animals↗
PubMed1991

Determination of lipophilicity and hydrogen-bond donor acidity of bioactive sulphonyl-containing compounds by reversed-phase HPLC and centrifugal partition chromatography and their application to structure-activity relations.

The lipophilic character of two large series of substituted benzenesulphonamides (BzSA) and 4-aminodiphenylsulphones (4-ADS) has been assessed by two chromatographic methods, i.e. reversed-phase HPLC using a relatively novel octadecylpolyvinyl packing and centrifugal counter-current chromatography (CPC). The octadecylpolyvinyl stationary phase proved an interesting alternative to the more common octadecylsilane type stationary phase for obtaining retention parameters correlated to partition coefficients (i.e. log P). The CPC method, being far less time-consuming and markedly more precise than the classical shake-flask method, offers a promising alternative for measuring partition coefficients. The parameter delta log Poct-hep, i.e. log Poctanol minus log Pheptane, was also determined for both congeneric series and was indicative of a similar H-bonding capacity for the SO2NH2 and 4-NH2-C6H4-SO2 groups. QSAR analyses of carbonic anhydrase inhibition by BzSA and antimycobacterial activity of 4-ADS show the capacity of the new lipophilicity parameters to express the hydrophobic component of the drug-enzyme interactions and to reveal a possible role of H-bond donor capacity in governing the antimycobacterial activity of 4-ADS.

Carbonic Anhydrase Inhibitors↗
PubMed1990

Toxication of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and analogs by monoamine oxidase. A structure-reactivity relationship study.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) elicits motor deficits similar to those observed in Parkinson's disease. Before exerting its neurotoxic action, MPTP must be activated by brain monoamine oxidase (MAO) to the neurotoxic metabolite MPP+ (1-methyl-4-phenylpyridinium). MPTP derivatives differ in their reactivity as MAO substrates and in their neurotoxicity. A structure-reactivity relationship study based on literature data was undertaken in order to determine the key features in the structure of MPTP and analogs that are responsible for the reactivity towards MAO. Thirty-three MPTP derivatives (including MPTP itself) were included in the study. To explain the reactivity towards MAO of the 33 MPTP analogs, different statistical methods (principal component analysis, multiple linear regression analysis) as well as the CoMFA (Comparative Molecular Field Analysis) approach, a new tool in structure-activity correlations, were used. Linear regression analysis failed to yield any predictive model, but suggested some trends. In contrast, the CoMFA approach was successful in correlating structural features and MAO reactivity. Coefficient contour maps showed where differences in the steric field (van der Waals' interactions) are most highly associated with differences in MAO reactivity. Several positive (in the ortho- and meta-position of the phenyl group) and negative (in the para-position of the phenyl group; beyond the N-methyl group) interaction regions were identified. Some structural features of the MAO active site could be postulated. First, the N-methyl group has the ideal size and elicits ideal interactions within the MAO active pocket, while smaller or larger groups are less favorable; second, para-substituent on the phenyl ring produce steric hindrances and are unfavorable to reactivity; third, ortho- and meta-substituents may have stabilizing interactions within the active pocket and are favorable to the reactivity. Moreover the model derived by CoMFA allowed us to make successful predictions of reactivity towards MAO for several additional tetrahydropyridines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

[Chiral drugs: pharmacological tools and/or therapeutic problems?].

Various issues connected with chiral drugs are discussed. They include definitions, the concept of stereoselectivity in pharmacodynamic and pharmacokinetic processes, the need for a stereochemically informative generic name system, and the debate surrounding eutomers versus racemates in pharmacotherapy.

Humans↗
PubMed1990

Metabolic chiral inversion of ibuprofen in isolated rat hepatocytes.

Ibuprofen was used to demonstrate that isolated rat hepatocytes offer a suitable in vitro model to investigate the metabolic chiral inversion of anti-inflammatory 2-arylpropionic acids (profens). The inversion of the pharmacologically inactive (-)-(R)-ibuprofen to the active (+)-(S)-ibuprofen was shown to obey apparent first-order kinetics during 5 h and to increase linearly with increasing hepatocyte concentration up to 4 x 10(5) cells/ml. No elimination of (R)-ibuprofen by routes other than inversion was seen, whereas the elimination of (S)-ibuprofen appeared to be saturable.

Animals↗