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B Testa

Publications and source records attributed to B Testa.

At least 37 records · Page 2Linked to original sources
PubMed1990

Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline.

Previous work has suggested that cytisine and lobeline are of low potency in producing nicotine-like behavioural effects, despite having some nicotine-like peripheral effects and potently inhibiting the binding of tritiated nicotine to the brain of the rat. Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. It was confirmed that cytisine had a nicotine-like discriminative effect, but it was much less potent than nicotine itself. Lobeline failed to produce a nicotine-like discriminative effect, even at doses that greatly reduced overall rates of responding. Neither drug attenuated discriminative responses to nicotine. The concentrations of drugs in plasma and brain were determined by HPLC in rats of the same sex, strain and age as those used in the behavioural experiments. The rank order of the ratios of concentrations in brain to plasma was lobeline greater than nicotine greater than cytisine, which was directly proportional to their lipophilicity determined by reversed-phase HPLC. Based on the concentrations in brain and known affinities for high-affinity nicotine binding sites, in vivo tests should show cytisine to be slightly more potent than nicotine and lobeline to have nicotine effects in the doses used. These predictions were not fulfilled and thus, the behavioural effects of cytisine and lobeline cannot be correlated with their effects at the binding site for tritiated nicotine. Since pharmacokinetic factors do not account for this discrepancy, a pharmacodynamic explanation will be necessary.

Alkaloids↗
PubMed1990

Mechanisms of inhibition of xenobiotic-metabolizing enzymes.

1. Various molecular mechanisms underlie the action of inhibitors of xenobiotic-metabolizing enzymes acting upon the enzyme itself and not elsewhere. 2. The activity of directly acting inhibitors is due to the compounds themselves rather than to metabolic intermediates thereof. When the enzyme's ground state is the target, competitive or non-competitive inhibition can be seen, depending on a number of factors. 3. Some inhibitors are transition-state analogues and bind slowly but with high affinity to the enzyme. Inhibition may be due to the compound itself and/or a metabolic intermediate. 4. Mechanism-based inhibitors are those which act via an in situ generated metabolic intermediate that can bind reversibly or irreversibly to the enzyme. 5. These various mechanisms are exemplified and discussed in terms of selectivity and reversibility.

Animals↗
PubMed1989

Histamine 2 antagonists in allergic rhinitis. Relationship of clinical response and serum concentrations of total and specific IgE antibody levels.

During a double-blind clinical trial of a histamine (H2) antagonist (ranitidine) in monitoring allergic rhinitis, the clinical response, total serum IgE levels, and Parietaria IgE antibody levels were measured. Ranitidine induces an improvement in scores of subjective and objective symptoms, a decrease in total serum IgE levels, and no significant variations in Parietaria IgE antibody levels. Since H2 antagonists seem to induce these improvements by acting on suppressor T cells bearing H2 receptor, as shown in our previous studies, it is hypothesized that the lymphocytic subset that regulates the total IgE synthesis is not the same as that governing specific IgE synthesis.

Adolescent↗
PubMed1989

Pattern recognition study of QSAR substituent descriptors.

Parameter values for 59 common substituents and 74 descriptors used in QSAR studies were compiled. This data matrix was analysed by a variety of multivariate techniques. Linear regression confirmed that lipophilicity can be factorized into two terms, one related to molecular bulk and the other to polarity. Principal component analysis (PCA) of parameters revealed 5 significant principal components and a grouping of lipophilic, steric and electronic parameters. The different loadings of parameters with 5 PCA were also explored. The classification of substituents by cluster analysis (CA) proved rather disappointing. In contrast, the SIMCA method classified substituents of increasing bulk into 5 groups of increasing polarity.

Analysis of Variance↗
PubMed1989

Signs of the times: the need for a stereochemically informative generic name system.

'Research and clinical pharmacologists frequently present data on impure drugs.' Because generic drug names often hide the fact that different stereoisomers (possibly with different pharmacological properties) may be present in the 'pure' preparation, this statement is all too frequently true. However, the problem may be overcome by pharmacologists and publishers adopting the user-friendly SIGNS nomenclature devised and explained here by Miklòs Simonyi, Joseph Gal and Bernard Testa. The acronym stands for 'stereochemically informative generic name system'. Seven prefixes are offered to describe the stereochemical nature of any drug. The appropriate prefix would be attached to the generic name. A generic name without prefix would indicate a single agent with no stereoisomers.

Methods↗
PubMed1989

Stereoelectronic study of zetidoline, a dopamine D2 receptor antagonist.

A combination of experimental and theoretical methods were used to investigate the stereoelectronic structure of zetidoline, a dopamine D2 receptor antagonist showing Na+-dependent binding. The solid-state conformation of zetidoline is characterized by synplanarity (coplanarity of the two rings with the chloro substituent and the carbonyl group on the same side). The side chain in the crystal adopts a folded conformation which places the azetidine nitrogen atom at about 8 A from the center of the aromatic ring. Quantum mechanical calculations indicate the synperiplanar and antiperiplanar conformations of the ring system to be of approximately equal energies. The molecular electrostatic potential of zetidoline in a nearly extended conformation shows a remarkable similarity with that of orthopramides (e.g. metoclopramide) and indolones (e.g. piquindone), i.e. two groups of drugs displaying the same D2 selectivity and Na+-dependent binding. We postulate that the close stereoelectronic similarity between zetidoline, orthopramides, and indolones accounts for their identical mechanism of action in the molecular level.

Chemical Phenomena↗
PubMed1989

[The diffuse lymphatic system of the nasal mucosa in allergic rhinitis].

Morphologic and immunologic study were performed on the mucosa associated lymphoid tissue (MALT) of patients with allergic rhinitis. Scraping from 14 healthy subjects and 36 allergic ones were used. Besides ordinary hystological methods immunohistochemical ones wilk polyclonal antibodies were employed to study IgG, IgA, IgM, IgE and monoclonal antibodies used for B and T lymphocyte and subset T-suppressor cell identification. In a comparison between normal and allergic mucosa, the morphopathology show an accentuated edema and a slight fibrosis. Among the IgG, IgA and IgM do not show any substantial differences in the samples in normal or in allergic subjects; white traces of IgE are found in allergic patients, but are totally absent in normal ones. In the lymphocyte populations does not show any substantial changes between the two groups. Was also analyzed the mechanism and the majority of the factors by which were obtained the results.

Antibodies, Monoclonal↗
PubMed1988

Ex vivo inhibition of rat brain cytochrome P-450 activity by stiripentol.

Stiripentol is an anti-epileptic drug of novel structure with previously demonstrated strong in vitro inhibitory activity on rat cerebral cytochrome P-450 mediated naphthalene hydroxylation [6]. When administered to rats as a single i.p. dose, the drug is presently shown to have the same in vitro effect. Maximal inhibition is seen 2 hr after administration, but at this time the brain concentrations of intact drug, although peaking, appear too low (ca. 11 micrograms/g tissue) to account for the intensity of the effect seen in vitro. This suggests in vivo activation to a metabolic intermediate forming a complex with cerebral cytochrome P-450, which 2 hr after dosing is fully insensitive to stiripentol added to incubates. Restoration of enzymic activity and of sensitivity to added stiripentol occurs progressively and is practically complete 24 hr after dosing.

Animals↗
PubMed1988

Flavonoids as inhibitors of rat liver monooxygenase activities.

Flavanone and six hydroxylated derivatives, and cianidanol and eight ethers and esters thereof, were investigated as inhibitors of cytochrome P-450 mediated reactions in rat liver microsomes. The IC50 values towards aminopyrine N-demethylation varied over a 20-fold range and were shown to depend on the pattern of hydroxylation (flavanone derivatives) and on lipophilicity (cianidanol derivatives). In the latter case, a bilinear relationship exists, the optimal log P being 2.92. Using selected compounds, IC50, Km and Vmax values were determined for aminopyrine N-demethylation, biphenyl 4-hydroxylation, and biphenyl 2-hydroxylation. Depending on the inhibitor and on the activity examined, non-competitive, competitive, or mixed inhibition was seen. Interaction with cytochrome P-450 was also studied spectrally and was always found to result in a modified type II difference spectrum (ligand binding). A dual binding mode is postulated, involving electrostatic and lipophilic interactions.

Aminopyrine N-Demethylase↗
PubMed1988

Substrate and product stereoselectivity in monooxygenase-mediated drug activation and inactivation.

In this overview, stereoselective aspects of drug metabolism have been examined in a biochemical and pharmacodynamic perspective. From the facts and concepts presented, the conclusion to emerge is that the pharmacokinetic behaviour of mixtures of stereoisomers (e.g. racemates) is not always the simple addition of the behaviour of individual stereoisomers; as a consequence, stereoisomeric mixtures might display pharmacodynamic effects differing somewhat from those caused by the separate eutomers and distomers. In some circles, the notion of "isomeric ballast" is being mentioned with increasing regularity, leading almost fatally to the conclusion that eutomers should be purified from their distomeric ballast for therapeutic use. A number of examples discussed here show that in vitro and also in vivo, a racemate often displays a pharmacokinetic and pharmacodynamic behaviour which is not the mere addition of the behaviour of its separate enantiomers. This may seem as an additional argument for the therapeutic use of pure eutomers since a number of interactions are thus avoided. But does this imply that distomers must always be considered as detrimental ballast? Enforcing compulsory resolution of stereoisomeric mixtures, in particular racemates, would increase severalfold the cost of many drugs. This is a small price to pay if the benefit is an improved therapeutic index. But, to reword the question, would such a legislation automatically result in therapeutic benefits?

Animals↗