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Biomedical subjects

B Testa

Publications and source records attributed to B Testa.

At least 145 records · Page 8Linked to original sources
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↗
PubMed1988

Modeling of beta-adrenoceptors based on molecular electrostatic potential studies of agonists and antagonists.

The molecular electrostatic potential (MEP) of 32 beta-adrenoceptor ligands, mainly antagonists, was calculated by the STO-3G ab initio quantum mechanical method. The MEP of phenylethanolamines (PEAs) features a negative minimum in the meta region (designated M1) which is topographically equivalent to a minimum (designated M2) found in the vicinity of the aromatic ring in all (aryloxy)propanolamines (AOPAs). In these compounds, a second negative zone located beyond the meta position and designated M3 is found in all beta 1-selective antagonists and in some nonselective and beta 2-selective antagonists. The beta 1-selective antagonists feature in the para position an additional zone which is positive (P4) in the full antagonists and negative (M4) in the antagonists displaying intrinsic sympathomimetic activity (ISA). The MEP-based pharmacophoric models of PEAs, AOPAs, and oxime ethers show common elements and lead to a proposed general model for beta-adrenoceptor ligands.

Adrenergic beta-Agonists↗
PubMed1988

The interaction of substituted benzamides with brain benzodiazepine binding sites in vitro.

1. The interaction of substituted benzamides with brain benzodiazepine (BDZ) binding sites was examined by their ability to displace [3H]-flunitrazepam ([3H]-FNM) from specific binding sites in bovine cortical membranes in vitro. 2. Clebopride, Delagrange 2674, Delagrange 2335 and BRL 20627 displayed concentration-dependent displacement of [3H]-FNM with IC50 values of 73 nM, 132 nM, 7.7 microM and 5.9 microM, respectively. Other substituted benzamides including metoclopramide, sulpiride, tiapride, sultopride and cisapride were inactive at 10(-5) M. 3. Inhibition by clebopride and Delagrange 2674 of [3H]-FNM binding was apparently competitive and readily reversible. 4. In the presence of gamma-aminobutyric acid (GABA), the ability of diazepam and Delagrange 2674 to displace [3H]-Ro 15-1788 binding was increased 3.6 and 1.6 fold respectively, compared to the absence of GABA, while ethyl beta-carboline-3-carboxylate (beta CCE) and clebopride were less potent in the presence of GABA. 5. Diazepam was 30 fold less potent at displacing [3H]-Ro 15-1788 in membranes that had been photoaffinity labelled with FNM than in control membranes, whereas the potency of beta CCE did not differ. Clebopride and Delagrange 2674 showed a less than two fold loss of potency in photoaffinity labelled membranes. 6. The pattern of binding of clebopride and Delagrange 2674 in these in vitro tests is similar to that found previously with partial agonists or antagonists at BDZ binding sites. 7. Clebopride and Delagrange 2674 inhibited [3H]-FNM binding with similar potency in rat cerebellar and hippocampal membranes, suggesting they have no selectivity for BDZ1 and BDZ2 binding sites. 8. Clebopride and Delagrange 2674 are structurally dissimilar to other BDZ ligands and represent another chemical structure to probe brain BDZ binding sites.

Affinity Labels↗
PubMed1988

Influence of lipophilicity and chirality on the selectivity of ligands for beta 1- and beta 2-adrenoceptors.

Eudismic and QSAR analyses are reported for the beta 1- and beta 2-adrenoceptor affinities and beta 1-selectivity of 10 enantiomeric pairs of ligands with only N-isopropyl or N-t-butyl groups. For both receptors, the eudismic index (ratio of affinity) increases with the affinity of the eutomers. However, the affinity of the distomers for the beta 2-adrenoceptor is relatively high, suggesting additional hydrophobic interactions. This is confirmed by various correlations between affinities and lipophilicities, showing that the affinity for beta 2-adrenoceptors is slightly more dependent on lipophilicity than that for beta 1-adrenoceptors. As a result, the beta 1-selectivity of the investigated beta 1-adrenoceptor ligands is strongly and negatively correlated with their lipophilicity (r = -0.942).

Adrenergic beta-Agonists↗
PubMed1988

Metabolic chiral inversion of anti-inflammatory 2-arylpropionates: lack of reaction in liver homogenates, and study of methine proton acidity.

1. Enrichment in the (S)-enantiomers for (R)-flurbiprofen, (R)-naproxen, (R)-suprofen and (R;S)-ibuprofen was investigated in various subcellular hepatic preparations containing coenzyme A. While such preparations were able to form hippuric acid from benzoic acid, the chiral inversion was never seen. 2. Using 2-dimethylaminoethanethiol 2-phenylpropionate (DEPP) as a model acyl thioester, the acidity of the methine proton was investigated by monitoring the proton/deuterium exchange occurring in deuterated solvents using high-resolution n.m.r. The compound was inert up to 22 h in D2O at 37 degrees C and pD 7.4. In pure methanol or a methanol-water mixture, only solvolysis was seen. In contrast, competitive hydrolysis (k = 0.005 h-1) and proton/deuterium exchange (k = 0.09 h-1) were seen in a CD3CN/D2O (50:50) mixture at 37 degrees C. 3. It is speculated that the failure to characterize chiral inversion of 2-arylpropionates in subcellular preparations may be due to the absence of a microenvironment of adequately moderate polarity.

Animals↗
PubMed1988

In vitro inhibition by stiripentol of rat brain cytochrome P-450-mediated naphthalene hydroxylation.

1. The formation of 1-naphthol from naphthalene was investigated in rat brain 105,000 g particulate fraction. The reaction showed NADPH dependency and was inhibited by carbon monoxide. Michaelis-Menten kinetics were apparent with Vmax = 0.264 pmol/mg protein per min and Km = 22.6 microM. 2. Stiripentol, an antiepileptic drug containing a methylenedioxybenzene moiety, proved to be a potent inhibitor of the reaction, with an IC50 value close to 1 microM under the conditions of study and without preincubation. 3. The inhibitory activity of stiripentol was seen mainly after metabolic activation of the drug. The inhibitory effect appeared progressively when substrate and inhibitor were added together to the incubates, whereas its appearance was more rapid following preincubation of stiripentol.

Animals↗
PubMed1988

[Comparison of the efficacy of two H2 antagonists of histamine in allergic rhinitis. Considerations on the mechanism of action].

A random study has been made on perennial atopic rhinitis patients divided into two homogeneous groups and treated with HH2 antagonists of different chemical structure: Cimetidine and Ranitidine. An identity of clinical and humoral results was noted in the two groups. This leads us to believe that the effects induced by the two drugs are linked to the properties of H2 antagonists and not to other potential action as hypothesised for Cimetidine by Drazen. The improvement in all subjective and objective parameters, decrease in total serum IgE, the delayed onset of clinical improvement and its duration in time, suggest that the vascular type action mechanism hypothesised by some Authors is quite secondary to the immunomodulatory one. H2 antagonists in fact induce, together with the clinical improvement and the total serum IgE decrease, a modulatory effect on the T-lymphocyte subsets with a variation in the OKT4/OKT8 ratio towards the latter subset that identifies the suppressor cells. Since lymphocyte histamine receptors are uniquely present on suppressor T-cell, it is on these the H2 antagonists would act, modulating the suppressive function positively.

Adolescent↗
PubMed1988

[Changes in serum immunoglobulins in allergic rhinitis induced by histamine H2 antagonists].

The authors discuss their double-blind experiments on 40 allergic rhinitis affected patients, aged 15 to 50 years. Twenty were treated with H2 antagonists (Cimetidine) and twenty with placebo. The clinical assessment of the effectiveness of the treatment was carried out on a range of subjective and objective parameters taken before and after treatment. The IgE, IgA, IgG and IgM serum rate was measured. An improvement in the symptomatology was noted in 15 of the 20 Cimetidine treated patients and none in the placebo group. The results have shown a significant percentage decrease in the total serum IgE values after treatment, compared to initial ones, while no significant change was observed in the values of IgA, IgG and IgM. This decrease in IgE is thus a specific class. As it has been demonstrated that a subpopulation of lymphocyte T suppressors acts selectively on IgE producing B cells, the authors believe that only on these elements, carriers of H2 membrane receptors, can Cimetidine act to induce a decrease in total serum IgE levels and therefore a reduction in degranulation processes.

Adolescent↗
PubMed1987

Analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as monoamine oxidase substrates: a second ring is not necessary.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is oxidised to a neurotoxic metabolite by monoamine oxidase B (MAO B). Using two colorimetric assays, we have examined a range of its structural analogues as possible further substrates of this enzyme in order to identify the types of environmental or endogenous compounds that might also be neurotoxic. Compounds with fully saturated or unsaturated pyridine rings were not substrates; nor were a range of tetrahydro-beta-carbolines or isoquinolines. Four substrates for MAO were found, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-Me-MPTP), 4-phenyl-1,2,3,6-tetrahydropyridine (PTP), 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine (Cl-PTP) and ethyl-1-methyl-1,2,3,6-tetrahydro-4-pyridine-carboxylate (ethyl-MTP-carboxylate). Ethyl-MTP-carboxylate is of particular interest as it shows that a tetrahydropyridine without a phenyl ring can also be a substrate. Cl-PTP, PTP and ethyl-MTP-carboxylate appeared to be partially metabolised by MAO A. The inhibitor sensitivity of 2'-Me-MPTP oxidation was more complex.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Quantitative structure-activity relationships and eudismic analyses of the presynaptic dopaminergic activity and dopamine D2 and sigma receptor affinities of 3-(3-hydroxyphenyl)piperidines and octahydrobenzo[f]quinolines.

Data from the preceding paper were examined by QSAR and eudismic analyses. A fair parabolic relationship was found between the lipophilicity (measured by a RP-HPLC method) and the sigma-receptor affinity of 3-(3-hydroxyphenyl)piperidines (3HPP derivatives) and octahydrobenzo[f]quinolines (OHBQ derivatives). As far as the dopamine D2 receptor is concerned, the trans-7-hydroxy-OHBQ derivatives show a 10-fold higher affinity than the eutomeric S enantiomers of 3HPP derivatives, once lipophilicity has been accounted for. This difference in affinity is suggested to correspond to the energy necessary for the 3HPP derivatives to adopt the receptor-bound conformation. The R enantiomers of 3HPP derivatives display no apparent increase in D2 affinity with increasing lipophilicity, and indeed the eudismic index in this series increases with affinity (eudismic affinity quotient = 0.70), in agreement with a recent model of the binding of N-propyl-3HPP (3PPP) enantiomers to the D2 receptor. The selectivity in sigma/D2 affinities was found to depend on both lipophilicity and configuration of the ligands; thus, the selectivity is maximal for log kw values of ca. 1.7-2.1 and is much larger for the R than for the S enantiomers of 3HPP derivatives.

Phenanthrenes↗
PubMed1987

L-dopa esters as potential prodrugs: behavioural activity in experimental models of Parkinson's disease.

Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in reserpine-pretreated mice with equal intensity and duration to that observed following administration of L-dopa itself. Administration of the 2-(1-methoxy)propyl ester produced a more prolonged effect while the p-methoxyphenylethyl, n-propyl, phenylethyl, m-trifluoromethylbenzyl, cyclohexyl, p-chlorophenylethyl and benzyl ester prodrugs were less active than L-dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L-dopa in reversing reserpine-induced akinesia in mice. The 2-tetrahydropyranylmethyl, 2-(1-methoxy)propyl, 2-hydroxypropyl, n-propyl, benzyl and phenoxyethyl ester prodrugs produced effects comparable with those of L-dopa. In contrast, the cyclohexyl, m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs were less effective than L-dopa on oral administration. Intraperitoneal administration of L-dopa and the ester prodrugs of L-dopa to rats with a prior 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB) produced contraversive circling responses. Rotation observed following administration of the n-propyl, 2-tetrahydropyranylmethyl, methyl and ethyl ester prodrugs was more intense than that observed following administration of L-dopa itself. Rotation produced by the administration of L-dopa and the cyclohexyl, 2-(1-methoxy)propyl, phenylethyl, p-chlorophenylethyl, p-methoxyphenylethyl, benzyl, 2-hydroxypropyl, phenoxyethyl and m-trifluoromethylbenzyl ester prodrugs was identical. Ester prodrugs of L-dopa may be as effective as L-dopa itself in producing motor activity but overall none of the compounds tested was markedly more potent or of longer duration than L-dopa itself.

Animals↗