Biomedical subjects
Publications and source records attributed to A Carotti.
A series of pyrrolo[3,2-c]pyridines, isosteres of the antithrombotic drug ticlopidine, has been synthesized and evaluated in vitro for the ability to inhibit aggregation of human platelet-rich plasma induced by adenosin 5'-diphosphate (ADP). Structure-activity relationships showed their antiplatelet effects to be related to the lipophilicity.
The anticonvulsant properties of 1,4-benzodiazepines (BDZs), pyrazoloquinolones (CGS), 2-aryl-2,5-dihydropyridazino[4, 3-b]indol-3(3H)-ones (PIs) 1 1i 1d 1f 1e 1b 1c 1h, and 1a, the latter being inactive against audiogenic seizures. Some PIs 1 and abecarnil showed anticonvulsant properties against seizures induced by PTZ with a potency lower than that observed in audiogenic seizures. The pharmacological actions of 1d, 1f, and 1i were significantly reduced by a treatment with flumazenil (8.24 micromol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of 1d, 1f, and 1i was also evaluated against seizures induced by two beta-carbolines namely methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), in DBA/2 mice: they gave better protection against seizures induced by beta-CCM than the ones by DMCM. The potency of various BDZs and PIs as inhibitors of specific [3H]flumazenil binding to neuronal membranes, was also evaluated. The radioligand binding study, carried out on stable cell lines expressing definite combinations of benzodiazepine receptor subunits, demonstrated that 1b, 1e, 1d, and 1h have preferential interaction with alpha(1), beta(3), gamma(2), receptor subtypes.
2-(1-Piperazinyl)-4H-pyrido[1,2-a]pyrimidin-4-one (5a) is a recently described in vitro inhibitor of human platelet aggregation which specifically inhibits the activity of high affinity cAMP phosphodiesterase. A number of substitution derivatives, isosteres, and analogues of 5a were now synthesized and tested in vitro for their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen, or the Ca2+ ionophore A23187. Among the most effective compounds, the 6-methyl, 8-methyl and 6,8-dimethyl derivatives of 5a resulted nearly as active as the lead when platelet aggregation was induced by ADP or A23187, but less active when collagen was the inducer. On the basis of present results and those previously obtained by us in this and 2-aminochromone structural fields, we have developed a statistically significant 3-D QSAR model, using comparative molecular field analysis (CoMFA), describing the variation of the antiplatelet activity in terms of molecular steric and electrostatic potential changes.
The acid-base properties of pyridine-2(1H)-one derivatives, analogues of the cardiotonic agent milrinone, were studied by capillary zone electrophoresis (CZE). Electrophoretic mobility and pH data were fitted to equilibrium expressions and apparent dissociation constants (pKa) calculated by non-linear regression. Compared with the ultraviolet (UV) spectrophotometric method and potentiometric titrations, the CZE technique showed advantages, such as rapidity and applicability to compounds that are sparingly soluble in water. Based on the pKa values, intramolecular electronic interactions were assessed. The lipophilicity of a number of derivatives was also examined, by determining their n-octanol/water distribution coefficients over a wide pH range, and found to be significantly affected by 2-pyridone/2-hydroxypyridine tautomerism. As revealed by a comparison between experimental and calculated log P values, electron withdrawing substituents, especially at the C(6) position of 2-pyridone, favour the less polar hydroxypyridine tautomers both in water and octanol. Our results indicate that the positive inotropism of milrinone-related compounds could be explained taking ionization and tautomerism into account.
Different classes of Peripheral-type Benzodiazepine Receptor (PBR) ligands were examined and common structural elements were detected and used to develop a rational binding model based on energetically allowed ligand conformations. Two lipophilic regions and one electrostatic interaction site are essential features for high affinity ligand binding, while a further lipophilic region plays an important modulator role. A comparative molecular field analysis, performed over 130 PBR ligands by means of the GRID/GOLPE methodology, led to a PLS model with both high fitting and predictive values (r2 = 0.898, Q2 = 0.761). The outcome from the 3D QSAR model and the GRID interaction fields computed on the putative endogenous PBR ligands DBI (Diazepam Binding Inhibitor) and TTN (Tetracontatetraneuropeptide) was used to identify the amino acids most probably involved in PBR binding. Three amino acids, bearing lipophilic side chains, were detected in DBI (Phe49, Leu47 and Met46) and in TTN (Phe33, Leu31 and Met30) as likely residues underlying receptor binding. Moreover, a qualitative comparison of the molecular electrostatic potentials of DBI, TTN and selected synthetic ligands indicated also similar electronic properties. Convergent results from the modeling studies of synthetic and endogenous ligands suggest a common binding mode to PBRs. This may help the rational design of new high affinity PBR ligands.
UNLABELLED: Foetal cardiac surgery is the ultimate goal in the treatment of congenital cardiac malformations. The aim of our research is to elucidate some of the features of the necessarily invasive experimental protocol to be used in an animal model of foetal cardiac surgery. In particular, we assessed the foetal placental reactivity to prolonged cardiac bypass in steady-flow conditions. METHODS: Two cases were selected to show the outcome of prolonged (> 30 minutes) extracorporeal circulation (ECC) instituted without oxygenator under steady-flow assistance. Following the instrumentation of the animal (placement of pressure, flow and myocardial fiber length transducers) and the baseline recordings, a 60-minute bypass period was established with an axial turbopump (Hemopump 14 Fr), after systemic heparinisation and artero-venous cannulation. At the end of the circulatory assistance, the cannulae were removed and a 90 minute observation period followed. The cardiac function was assessed by means of indirectly obtained P-V loops. RESULTS: Case A showed a marked reduction in the end-systolic pressure-volume relationship (ESPVR) during ECC, corresponding to a rightward shift of the P-V loop, with a gradual recovery after the assisted circulation. On the contrary, case B was subjected to progressive placental dysfunction, as evidenced by haemogasanalytical data. Consequently, the haemodynamic data also outlined a negative outcome, with high ESPVR values after bypass. CONCLUSIONS: The present study, while confirming the possibility of cardiac intervention in the foetus, underlines the critical role of minimally invasive protocol to limit both foetal stress and placental dysfunction.
R-(-)-Carnitine (vitamin B(T)) plays an important role in human energy metabolism, by facilitating the transport of long-chained fatty acids across the mitochondrial membranes. Its (S)-enantiomer acts as a competitive inhibitor of carnitine acetyltransferase, causing depletion of the body R-(-)-carnitine stock. Consequently, the separation of carnitine enantiomers is very important both to study their biological activities and to control the enantiomeric purity of pharmaceutical formulations. In the present paper we describe an easy, fast and convenient procedure for the separation of the enantiomers of carnitine and O-acylcarnitines by enantioselective HPLC on a laboratory-made chiral column containing covalently bonded teicoplanin as selector. High enantioselectivity factors (alpha values ranging from 1.31 to 3.02) and short-time analyses characterize the analytical procedure; in addition, analytes are easily detected by evaporative light scattering with no need for preliminary derivatization. The effects of pH and ionic strength of the mobile phase and of the nature of the organic modifier on the enantioselective separations were also investigated.
The substituent effects at positions 6 and 8 (compounds 17-31) as well as at the amide nitrogen (compounds 32-40) of a series of 2-phenylimidazo[1,2-a]pyridineacetamides were evaluated at both central (CBR) and peripheral (PBR) benzodiazepine receptors. The structure-activity relationship studies detailed herein indicate the key structural features required for high affinity and selectivity for PBR. Substitution on the imidazopyridine nucleus at position 8 with lipophilic substituents and the presence of one chlorine atom at the para position of the phenyl ring at C(2) are crucial features for high binding affinity and selectivity toward PBR. A small subset of active ligands (i.e., 17, 20, 26, 34, and 35) were evaluated in vitro in Xenopus oocytes expressing cloned human GABA(A) receptors for their effects at CBR and in vivo for their ability to stimulate the synthesis of neurosteroids such as pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone (THDOC). Compounds 17, 20, 26, and 34 markedly increased the levels of neuroactive steroids in plasma and cerebral cortex, unlike compound 35.
A series of novel conformationally restricted butyrophenones (2-(aminoethyl)- and 3-(aminomethyl)thieno- or benzocycloalkanones bearing (6-fluorobenzisoxazolyl)piperidine, (p-fluorobenzoyl)piperidine, (o-methoxyphenyl)piperazine, or linear butyrophenone fragments) were prepared and evaluated as atypical antipsychotic agents by in vitro assays of affinity for dopamine receptors (D(1), D(2)) and serotonin receptors (5-HT(2A), 5-HT(2C)) and by in vivo assays of antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cycloalkanone structure. As a group, compounds with a benzisoxazolyl fragment had the highest 5-HT(2A) activities, followed by the benzoylpiperidine derivatives; in general, alpha-substituted cycloalkanone derivatives were more active than the corresponding beta-substituted congeners. CoMFA (comparative molecular field analysis) and docking studies showed electrostatic, steric, and lipophilic determinants of 5-HT(2A) and D(2) affinities and 5-HT(2A)/D(2) selectivity. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4H-5, 6-dihydrocyclopenta[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisox azol-3 -yl)piperidine (23b, QF 0510B), N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisoxazol- 3-y l)piperidine (24b, QF 0610B), and N-[(7-oxo-4,5,6, 7-tetrahydrobenzo[b]thiophene-6-yl)ethyl]-4-(6-fluorobenzisoxazol- 3-y l)piperidine (29b, QF 0902B) suggest that they may be effective antipsychotic drugs with low propensity to induce extrapyramidal side effects.
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The in vitro antibacterial and antifungal activities of a series of pyridazinoindolonic acids II against some selected representative of Gram-positive, Gram-negative bacteria and fungi have been investigated. Some interesting observations among the structural features necessary for high antibacterial activity are presented and discussed.
A series of 2-aryl-3-chloro-2H-pyridazino[4,3-b]indoles, 2-aryl-3-methoxy-2H-pyridazino[4,3-b]indoles, and 2-aryl-2,5-dihydroindeno[1,2-c]pyridazino-3(3H)-ones has been prepared and tested for their ability to inhibit the [3H]flunitrazepam binding to the central benzodiazepine receptor. SAR are presented and discussed in comparison with existing pharmacophore models.
A set of TIBO derivatives endowed with reverse transcriptase (RT) inhibitory activity were analyzed by comparative molecular field analysis (CoMFA). Besides conventional steric and electrostatic fields, molecular lipophilicity potential (MLP) was also used as a third field in CoMFA. An informative and statistically significant model (q2 = 0.70, r2 = 0.90, s = 0.46) was obtained by taking into account the three field types together. The key molecular determinants governing the RT inhibition by TIBO congeners were detected at the 3-D level by a careful analysis of the CoMFA isocontour maps. To challenge the predictive ability of the CoMFA model, an external set of thiazolobenzimidazole (TBZ) derivatives were examined. Good predictions, suggesting a similar binding mode for TIBO and TBZ derivatives, emerged. Flexible docking experiments on TBZ, TIBO and other NNIs confirmed common binding characteristics, as found out also by CoMFA, and moreover a good correlation between calculated binding energies and inhibitory potency was found.
Diverse series of piperazines linked at N1 to 4, 5, or 6 positions of 3-(2H)-pyridazinone ring and at N4, by a suitable alkyl spacer, to some classical alpha1-adrenoceptor pharmacophore moieties, were tested in vitro for their alpha1-adrenoceptor antagonist activity. The modeling of their biological activity (pKb) by comparative molecular field analysis led to the development of a statistically significant partial least squares (PLS) model able to detect at 3-D level the main physicochemical interactions responsible for alpha1-adrenoceptor antagonist activity.
From November 1985 through December 1996, 128 patients aged 1 day to 18 years (mean age, 4.7 yrs; median, 3 years) were listed for heart transplant. Forty-seven (36.1%) died after a mean wait of 3.1 months, and 62 underwent transplant after a mean wait of 4 months. Two patients underwent retransplantation. The 1-, 5-, and 11-year actuarial survival rate for the patients who underwent heart transplantation is 68%, 62%, and 42%, respectively. The follow-up ranges from O to 132 months, with a mean follow-up of 39 months. At present, 36 patients, including the 2 who received a retransplant, are alive. Most of them have normal growth, development, and neurologic outcome.
Heart transplantation on the first day of life, and graft harvesting from anencephalic donors, have been very rare events in the history of transplantation. At Bambino Gesù Hospital (Rome), heart transplantation was performed on a newborn 9 h after birth, using a graft harvested from an anencephalic donor. This graft achieved a good cardiocirculatory function, but the recipient died of necrotizing enterocolitis (NEC) on post-operative day (POD) 10. Despite failure, this case and other reports support the concept that hearts from anencephalic donors can work normally, and indicate that heart transplantation on the first day of life may have a favorable outcome if postoperative maintenance of multi-organ balance and function is successful.
PURPOSE: To eliminate the risk of rejection and lower the risk of relapse after T-cell-depleted bone marrow transplants in acute leukemia patients, we enhanced pretransplant immunosuppression and myeloablation. PATIENTS AND METHODS: Antithymocyte globulin and thiotepa were added to standard total-body irradiation/cyclophosphamide conditioning. Donor bone marrows were depleted ex vivo of T lymphocytes by soybean agglutination and E-rosetting. This approach was tested in 54 consecutive patients with acute leukemia who received transplants from HLA-identical sibling donors or, in two cases, from family donors mismatched at D-DR. No posttransplant immunosuppressive treatment was given as graft-versus-host disease (GVHD) prophylaxis. RESULTS: Neither graft rejection nor GVHD occurred. Transplant-related deaths occurred in six (16.6%) of 36 patients in remission and in seven (38.8%) of 18 patients in relapse at the time of transplantation. The probability of relapse was .12 (95% confidence interval [CI], 0 to .19) for patients with acute myeloid leukemia and .28 (95% CI, .05 to .51) for patients with acute lymphoblastic leukemia who received transplants at the first or second remission. At a median follow-up of 6.9 years (minimum follow-up, 4.9 years), event-free survival for patients who received transplants while in remission was .74 (95% CI, .54 to .93) for acute myeloid leukemia patients and .59 (95% CI, .35 to .82) for acute lymphoblastic leukemia patients. All surviving patients have 100% performance status. CONCLUSION: Adding antithymocyte globulin and thiotepa to the conditioning regimen prevents rejection of extensively T-cell-depleted bone marrow. Even in the complete absence of GVHD, the leukemia relapse rate is not higher than in unmanipulated transplants.