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Biomedical subjects

B Testa

Publications and source records attributed to B Testa.

At least 109 records · Page 6Linked to original sources
PubMed1993

The so-called "interconversion" of stereoisomeric drugs: an attempt at clarification.

A variety of reactions can be categorized under the global concept of the "interconversion of stereoisomers." Thus, racemization or epimerization can result from inversion of labile chiral centers. From the examples available, some predictive rules are suggested for a chiral center of the type R"R'RC-H undergoing base-catalyzed inversion and a provisional table of affecting groups is presented. Unimolecular inversion of nonsymmetrical, nonplanar ring systems can also result in racemization or epimerization, but no generalization can yet be offered. Beside these cases of nonenzymatic reactions, a limited variety of enzymatic reactions can operate to interconvert stereoisomers, the outcome rarely being a racemic mixture. An important aspect of stereoisomer interconversion is the time scale in which the phenomenon is observed. Thus, several reactions to nonezymatic racemization or epimerization are fast compared to the duration of action of the drug and therefore have pharmacological significance, while other are slower and are of pharmaceutical relevance only.

Molecular Conformation↗
PubMed1993

Substituted xanthones as selective and reversible monoamine oxidase A (MAO-A) inhibitors.

1,3-Dihydroxy-2-methylxanthone (X1), its 4-chloro and 4-bromo derivatives (X1-Cl and X1-Br), and 1,3-dihydroxy-4-methylxanthone were investigated for their inhibition activities toward MAO. A hyperbolic function was derived to fit the data and to calculate IC50 values. The compounds proved to be reversible and selective inhibitors of MAO-A, with X1 displaying the highest activity (IC50 = 3.7 microM).

Animals↗
PubMed1993

Human serum albumin conformational changes as induced by tenoxicam and modified by simultaneous diazepam binding.

The binding of tenoxicam to human serum albumin has been shown by affinity chromatography proton titration and equilibrium dialysis to be dependent on the neutral to basic conformational change of the protein. The influence of diazepam on the interaction was also investigated using the same techniques, suggesting that diazepam increases the association of tenoxicam to albumin. Affinity chromatography revealed that the reciprocal effect also occurs. Displacement studies indicated that diazepam causes a significant increase in the affinity of tenoxicam to its main binding site, albumin site I, which is different from the diazepam site (site II). Tenoxicam seemed to cause an allosteric change in the conformation of the protein during its own binding, as did warfarin. The mechanism of this effect was a pH-dependent conformational change of albumin induced by electrostatic forces within the protein. Diazepam induced a distant accommodation of the protein, an effect accompanied by an enhanced inhibition of the release of protons from albumin.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

The role of H2 antagonists in perennial allergic rhinitis.

The biological effects of anti-H2 in allergic reactions are dose dependent: low doses enhance, and high doses significantly decrease the reaction of hypersensitivity. The administration of cimetidine H2 antagonist to 20 perennial allergic rhinitis patients brought about an abatement in the symptoms and a decrease in the total serum immunoglobulin E (IgE) levels in 72% of treated patients, but no variation was perceived in placebo-treated patients. These results strengthen the hypothesis of anti-H2-induced immunoregulatory effects and suggest a possible way of inhibiting IgE synthesis in vivo.

Adolescent↗
PubMed1993

Nasal formulations of ketorolac tromethamine: technological evaluation--bioavailability and tolerability in rabbits.

This paper describes the development of a novel formulation of the powerful non narcotic analgesic ketorolac tromethamine. This drug is given orally three to four times/day to deliver a total of 30 to 60 mg of drug. Higher doses cannot be given orally because of gastrointestinal side effects and intramuscular injections, three times/day must then be used. The need for injections limits the drug to a clinical setting. Nasal delivery offers a method of achieving the high blood levels of repeated intramuscular injections in a formulation that can be easily applied by the patients. Four formulations were evaluated in "in vitro" and "in vivo" rabbit tests. The best formulation consisted of a 5% solution of ketorolac tromethamine containing 0.3% sodium glycocolate as a known mucosal drug absorption enhancer. Ketorolac applied in this way had a bioavailability greater than 80%. The controlled release nature of nasal delivery also doubled the drug's apparent half life. The drug formulation was stable in three-months stability tests and produced minimal nasal irritation.

Administration, Intranasal↗
PubMed1993

Clinical pharmacology of oxicams: new insights into the mechanisms of their dose-dependent toxicity.

Six oxicams, sudoxicam, isoxicam, piroxicam, tenoxicam, meloxicam and lornoxicam, were compared in an attempt to understand why, despite close chemical structures, two of them were associated with an increased risk of toxicity in patients. Different factors have been revealed which may explain these differences. A weak association constant to human serum albumin (HSA), together with a high plasma concentration, favours a rapid increase in unbound concentration (Cu) when total plasma concentration rises (peak of absorption). Pathological states may enhance this increase when both HSA plasma concentration is decreased and free fatty acid concentrations are increased. However, the main cause of toxicity may be the existence in some subjects of HSA natural mutants whose ability to bind oxicams is markedly lower than normal.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

[Herpes of the larynx. Apropos of 3 cases].

Herpes laryngis is a rare inflammatory disease, caused by herpes simplex (HSV) or herpes zoster virus (HZV). Three cases of acute viral laryngitis are described. The first case of laryngitis is caused by HZV, with involvement of VII., VIII., IX. and X. cranial nerves. In the second and third cases, caused by HSV, only the laryngeal mucosa is involved. Laryngeal symptoms, diagnostic criteria and therapeutic results are described.

Adult↗
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.

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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↗