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E Rosa

Publications and source records attributed to E Rosa.

35 records · Page 2Linked to original sources
PubMed1996

Synthesis and affinities for dopamine (D2) and 5-hydroxytryptamine (5-HT2A) receptors of 1-(benzoylpropyl)-4-(1-oxocycloalkyl-2-ethyl)-piperazines as cyclic butyrophenone derivatives.

Starting from benzo- or thienocycloalkaneacetic acids, we have prepared a series of 1-(3-p-fluorobenzoylpropyl)-4-(1-oxo-benzo- or thienocycloalkyl-2-ethyl)piperazines 8a-e containing both semirigid and linear butyrophenones pharmacophores. The affinities of these compounds for dopamine (D2) and 5-hydroxytryptamine (5-HT2A) receptors were evaluated in vitro in receptor-binding assays and in functional experiments. The ratios of pKi's for 5-HT2A/D2 receptors may be useful for rapid screening of new compounds and assessing potential induction of extrapyramidal symptoms; ratio values > or = 1.12 (Meltzer's ratio) are predictive of an atypical antipsychotic profile. The new molecules had a ratio in the range of 0.96-1.11 while haloperidol showed a ratio of 0.93. The 2-piperazinoethyl thiotetralone derivative 8d (QF 0506B) with a ratio of 1.11 was the most active compound.

Animals↗
PubMed1996

Evaluation of carbon-14-colchicine biodistribution with whole-body quantitative autoradiography in colchicine-sensitive and -resistant xenografts.

UNLABELLED: Quantitative autoradiography (QAR) with radiolabeled monoclonal antibodies in xenografted animals has been extensively described in the past, either on individual tissues or on the whole body. We applied whole-body QAR to identify multidrug resistant tumors using 14C-colchicine (14C-CHC). METHODS: Two groups of five animals each were xenografted with CHC-sensitive and CHC-resistant human neuroblastoma cells. Animals were injected intravenously with 4 microCi/0.11 mumole 14C-CHC per gram of body weight and sacrificed after 60 min. Whole-body QAR was carried out using 25-microns thick sections. RESULTS: Fusion images allowed direct comparison of 14C-CHC uptake in tumor and nontumor tissues. Mean 14C-CHC distribution in sensitive and resistant tumors was 882.0 +/- 43.6 and 399.6 +/- 157.7 nCi/g corresponding to 24.5 +/- 1.21 and 11.1 +/- 4.38 nmole/g, respectively (p < 0.001), with normal tissue distribution in both groups being similar. Three-dimensional QAR showed that the uptake of 14C-CHC was in the cellular zones of the tumor. This method has potential in biodistribution studies of novel radiopharmaceuticals such as 14C-CHC. CONCLUSION: These studies further suggest that PET imaging of 11C-CHC is feasible to distinguish between sensitive and resistant tumor deposits in vivo.

Animals↗
PubMed1995

In vivo imaging and specific targeting of P-glycoprotein expression in multidrug resistant nude mice xenografts with [125I]MRK-16 monoclonal antibody.

Multidrug resistance (MDR) in tumors is associated with P-glycoprotein (Pgp) expression. In vivo quantitation of Pgp may allow MDR to be evaluated noninvasively prior to treatment planning. The purpose of this study was to radiolabel MRK-16, a monoclonal antibody that targets an external epitope of P-glycoprotein, and perform in vivo quantitation of P-glycoprotein in a MDR xenograft nude mouse model. MRK-16 was labeled with 125I by the iodogen method, with subsequent purification by size exclusion chromatography. Groups of 10 Balb c mice were each xenografted with colchicine-resistant or sensitive neuroblastoma cell lines, respectively. Whole body clearance and tumor uptake over time was quantitated by gamma camera imaging, and biodistribution studies were performed with [125I]MRK-16 and an isotype matched control antibody, A33. Quantitative autoradiography and immunohistochemistry analysis of tumors was also evaluated to confirm specific targetting of [125I]MRK-16. Peak tumor uptake was at 2-3 days post-injection, and was significantly greater in resistance compared to sensitive tumors (mean % injected dose/g +/- SD) (18.76 +/- 2.94 vs 10.93 +/- 0.96; p < 0.05). Quantitative autoradiography verified these findings (19.13 +/- 0.622 vs 12.08 +/- 0.38, p < 0.05). Specific binding of [125I]MRK-16 was confirmed by comparison to [131I]A33 in biodistribution studies, and localized to cellular components of tissue stroma by comparison of histologic and autoradiographic sections of sensitive and resistant tumors. Immunoblot analysis demonstrated a 4.5-fold difference in P-glycoprotein expression between sensitive and resistant cell lines without colchicine selective pressure. We conclude that in vivo quantitation of P-glycoprotein in MDR tumors can be performed with [125I]MRK-16.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Calculated and TLD-based absorbed dose estimates for I-131-labeled 3F8 monoclonal antibody in a human neuroblastoma xenograft nude mouse model.

Preclinical evaluation of the therapeutic potential of radiolabeled antibodies is commonly performed in a xenografted nude mouse model. To assess therapeutic efficacy it is important to estimate the absorbed dose to the tumor and normal tissues of the nude mouse. The current study was designed to accurately measure radiation does to human neuroblastoma xenografts and normal organs in nude mice treated with I-131-labeled 3F8 monoclonal antibody (MoAb) against disialoganglioside GD2 antigen. Absorbed dose estimates were obtained using two different approaches: (1) measurement with teflon-imbedded CaSO4:Dy mini-thermoluminescent dosimeters (TLDs) and (2) calculations using mouse S-factors. The calculated total dose to tumor one week after i.v. injection of the 50 microCi I-131-3F8 MoAb was 604 cGy. The corresponding decay corrected and not corrected TLD measurements were 109 +/- 9 and 48.7 +/- 3.4 cGy respectively. The calculated to TLD-derived dose ratios for tumor ranged from 6.1 at 24 h to 5.5 at 1 week. The light output fading rate was found to depend upon the tissue type within which the TLDs were implanted. The decay rate in tumor, muscle, subcutaneous tissue and in vitro, were 9.5, 5.0, 3.7 and 0.67% per day, respectively. We have demonstrated that the type of tissue in which the TLD was implanted strongly influenced the in vivo decay of light output. Even with decay correction, a significant discrepancy was observed between MIRD-based calculated and CaSO4:Dy mini-TLD measured absorbed doses. Batch dependence, pH of the tumor or other variables associated with TLDs which are not as yet well known may account for this discrepancy.

Animals↗
PubMed1994

Synthesis and atypical antipsychotic profile of some 2-(2-piperidinoethyl)benzocycloalkanones as analogues of butyrophenone.

Four new 2-(2-piperidinoethyl)benzocycloalkanone derivatives, 20-23, were prepared and evaluated as potential antipsychotic agents in receptor binding assays for dopamine (DA) and 5-HT2A receptors and in functional and behavioral screens. Their affinities for D2 receptors (Ki's in the nanomolar range: 46.7-70.7) and D1 receptors (Ki's in the micromolar range: 1.09-2.81) were slightly lower than that showed by haloperidol (Ki's in the nanomolar range: 5.01 and 97.72 for D2 and for D1 receptors, respectively). The ratio of pKi's values D1/D2 showed that the new molecules are more D2-selective than haloperidol. In contrast, in the [3H]-ketanserin binding assays the new compounds had greater affinity for 5-HT2A receptors (pKi's 7.89-8.60) than haloperidol (pKi 7.70) and in functional studies, endothelium-stripped aorta rings, the pA2 values (6.75-8.12) were slightly lower than that of ketanserin (8.87) in suppressing serotonin-induced contractions. The pKi's for D2 binding (and to a lesser extent pKi's for D1 binding) tend to be greater among typical (classical) than among atypical antipsychotics, while these two classes of antipsychotics exhibit no difference with regard to pKi's for 5-HT2A receptors. The ratios of pKi's for 5-HT2A/D2 receptors may be useful for rapid screening of new compounds, and its potential induction of extrapyramidal symptoms (ratio values > 1.12 were predictive of an atypical antipsychotic profile). The new molecules had a ratio value in the range 1.08-1.20, while haloperidol showed a ratio of 0.93. In the behavioral screening tests, the new molecules showed antagonist activity of amphetamine-inducing hyperactivity and apomorphine-induced climbing (predictive tests for antipsychotic activity). In the catalepsy test (predictive test for induction of extrapyramidal symptoms), the values obtained were in accordance with an atypical antipsychotic drugs profile.

Amphetamine↗
PubMed1994

[Mercury content in bleaches sold in the southeastern region of Brazil].

In order to determine the mercury content present as a contaminant in samples of bleach used in water and food disinfection, a method for sample treatment using chloridric acid to eliminate the chlorine was proposed. The technique of cold vapour atomic absorption spectrophotometry, used to quantify the mercury, showed a recovery of 103%. Sixty nine samples of bleach were analysed and the values found for the median and 90th percentil were respectively, 15 and 67 micrograms/L. According to the values of residual mercury found and using the quantities of bleach recommended by the Brazilian Sanitary Authorities, the use of these disinfectants offers no risk to human health.

Brazil↗
PubMed1994

In vivo uptake of carbon-14-colchicine for identification of tumor multidrug resistance.

UNLABELLED: A major limitation in the treatment of cancer with natural product chemotherapeutic agents is the development of multidrug resistance (MDR). Multidrug resistance is attributed to enhanced expression of the multidrug resistance gene MDR1. Colchicine (CHC) is known to be one of the MDR drugs. We have previously demonstrated that it is possible to distinguish multidrug-resistant tumors from multidrug-sensitive tumors in vivo on the basis of tritium (3H) uptake following injection of 3H-CHC. METHODS: The present studies were carried out in xenografted animals using 14C-CHC which may be more indicative of 11C-labeled CHC distribution with regard to circulating metabolites, since metabolic processes following injection of (ring C, methoxy-11C)-CHC may produce significant amounts of circulating 1-carbon fragments (i.e., methanol and/or formaldehyde). Experiments were carried out at a dose of 2 mg/kg. RESULTS: Activity concentration per injected dose was approximately twice as great in sensitive as in resistant tumors (p < 0.05) at 60 min following intravenous injection of 14C-CHS. About 75% of total activity was CHC in the sensitive tumors. The findings are further confirmed by the quantitative autoradiographic evaluation of resistant and sensitive tumors. CONCLUSIONS: These studies confirm our previous observations that it is possible to noninvasively distinguish multidrug-resistant tumors from sensitive tumors in vivo based on uptake of an injected MDR drug using a 14C-labeled CHC at the same position and of comparable specific activity to a 11C-CHC tracer used for PET imaging.

Animals↗
PubMed1992

The microsomal demethylation of N,N-dimethylbenzamides. Substituent and kinetic deuterium isotope effects.

The metabolism of N,N-dimethylbenzamides by phenobarbital-induced rat liver microsomes results in the formation of N-methylbenzamides and formaldehyde. The reaction proceeds via the formation of an intermediate N-hydroxymethyl-N-methylbenzamide, which, for the microsomal oxidation of N,N-dimethylbenzamide, was isolated and characterized. Confirmation of the N-hydroxymethyl-N-methylbenzamide was obtained by its independent synthesis from N-methylbenzamide and formaldehyde. The intermolecular kinetic deuterium isotope effects for the reaction are 0.9 (+/- 0.1) for Vmax and 1.4 (+/- 0.1) for Vmax/Km. The intramolecular kinetic deuterium isotope effect, determined from the relative amounts of N-methylbenzamide and N-trideuteriomethylbenzamide formed in the microsomal demethylation of N-trideuteriomethyl-N-methylbenzamide, is 6.0 +/- 0.3. There is no correlation of Vmax or Vmax/Km with the substituent in the aromatic ring, nor with the calculated ionization potentials of the benzamides. The results are interpreted in terms of a mechanism in which the benzamide undergoes direct hydrogen atom abstraction to form a carbon centred radical. This carbon centred radical subsequently forms an N-hydroxymethyl-N-methylbenzamide that decomposes to formaldehyde and an N-methylbenzamide. Semi-empirical AM1 self consistent field molecular orbital calculations identify that loss of a hydrogen atom from the E-methyl group is thermodynamically more favourable than from the Z-methyl group by ca. 5 kJ/mol.

Amides↗
PubMed1992

In-vivo identification of tumor multidrug resistance with 3H-colchicine [corrected].

Multidrug resistance (MDR) is a major obstacle in the clinical treatment of cancer with natural-product anticancer agents. Identification of MDR in vivo could be important in the design of chemotherapeutic regimens. As a first step in developing radiolabeled drugs to detect MDR, we measured the in vivo distribution of radiolabel from [ring C, methoxy-3H]-colchicine ([3H]-CHC) in immunosuppressed mice bearing xenografts of colchicine-resistant and sensitive tumor cell lines. Experiments were done at trace (1 microgram/kg) and LD50 (4 mg/kg) dose levels. Activity concentration/injected dose was more than twice as great in sensitive as in resistant tumors (p less than 0.01) at 60 min following retroorbital injection of [3H]-CHC. There was no significant difference in activity distribution between trace- and high-dose injections for any of the tissues sampled. Chromatographic analysis of plasma and tumor extracts demonstrated extensive extravascular metabolic degradation of [3H]-CHC. The ratio of [3H]-CHC concentration of injected dose between sensitive and resistant tumors was 3:1 (p less than 0.05), due primarily to protein-bound [3H]-CHC. This preliminary study demonstrates that it is possible to distinguish multidrug resistant from sensitive tumors in vivo on the basis of radiolabel uptake from an injected MDR drug. Colchicine, labeled with 11C at the [ring C]-methoxy group, may be useful as a radiopharmaceutical for quantitative identification of MDR in human tumors using PET.

Animals↗