Biomedical subjects
Publications and source records attributed to R Cirillo.
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We investigated the effect of cyclosporin A (CsA) on in vitro release of chemical mediators from mast cells purified from human lung tissues. CsA (3 X 10(-2) to 1 microgram/ml) dose-dependently inhibited IgE-mediated release of histamine and peptide leukotriene C4 (LTC4) from human lung mast cells. The same concentrations of CsA also inhibited the release of histamine from lung mast cells challenged with the Ca2+ ionophore A23187. Therefore, CsA in pharmacological concentrations inhibits the IgE- and non-IgE-mediated release of inflammatory mediators from mast cells purified from human lung tissues.
5'-N-ethylcarboxamideadenosine (NECA) greater than 2-chloroadenosine greater than adenosine greater than (-)-N6-(R-phenyl-isopropyl)-adenosine [(-)-R-PIA] greater than (+)-N6-(S-phenyl-isopropyl)-adenosine [(+)-S-PIA] inhibited in vitro human platelet aggregation in a dose-dependent fashion. 6-nitrobenzylthioinosine and dipyridamole, which inhibit adenosine uptake, and erythro-9-(2-hydroxy-3-nonyl)-adenine, which blocks adenosine metabolism, did not impair the inhibition induced by NECA and adenosine. 8-phenyltheophylline and theophylline, two competitive antagonists of adenosine receptors, blocked the inhibition of platelet aggregation caused by NECA and adenosine. NECA greater than 2-chloroadenosine greater than adenosine greater than (-)-R-PIA greater than (+)-S-PIA increased platelet cyclic adenosine monophosphate (cAMP) levels in a dose-dependent fashion. A significant linear correlation (r = 0.70, p less than 0.001) was found between the increase of platelet cAMP and the inhibition of platelet aggregation induced by adenosine and its analogs. 8-phenyltheophylline, which is a competitive antagonist of adenosine in platelets, also blocked the cAMP accumulation caused by NECA. These data suggest that NECA and other adenosine analogs activate a specific cell surface adenylate cyclase-linked adenosine receptor whose properties are similar to those of an adenosine A2/Ra receptor.
The aim of this review is to consider the role of endothelium in the establishment of injury induced by ischaemia and reperfusion with particular emphasis on the vascular beds of the legs. We review the main abnormalities found in the macro- and microcirculation in these conditions and discuss the various theories put forward to explain the mechanism by which endothelial injury is induced. Endothelial cells play a key role in maintaining patent and functional capillaries. When blood vessels are damaged they become unresponsive to vasodilatory stimuli and intraluminal thrombosis may occur. The relative contribution of platelets and leukocytes in the formation of final ischaemic damage is widely discussed. Furthermore, the role of reperfusion in causing damage to post-ischaemic vascular beds is considered as well. The degree to which post-ischaemic injury is reversible might define the opportunity for therapeutic interventions.
We have investigated the pharmacological properties of MEN 11467, a novel partially retro-inverse peptidomimetic antagonist of tachykinin NK(1) receptors. MEN 11467 potently inhibits the binding of [(3)H] substance P (SP) to tachykinin NK(1) receptors in the IM9 limphoblastoid cell line (pK(i) = 9.4 +/- 0.1). MEN 11467 is highly specific for the human tachykinin NK(1) receptors, since it has negligible effects (pK(i) <6) on the binding of specific ligands to tachykinin NK(2) or NK(3) receptors and to a panel of 30 receptors ion channels unrelated to tachykinin receptors. The antagonism exerted by MEN 11467 at tachykinin NK(1) receptors is insurmountable in saturation binding experiments, both K(D) and B(max) of SP were significantly reduced by MEN 11467 (0.3-10 nM). In the guinea-pig isolated ileum, MEN 11467 (0.03-1 nM) produced a nonparallel rightward shift of the concentration-response curve to SP methylester with a concomitant reduction of the Emax to the agonist (pK(B) = 10.7 +/- 0.1). Moreover the antagonist activity of MEN 11467 was hardly reversible despite prolonged washout. In vivo, MEN 11467 produced a long lasting (> 2-3h) dose-dependent antagonism of bronchoconstriction induced by the selective tachykinin NK(1) receptor agonist, [Sar(9), Met(O(2))(11)]SP in anaesthetized guinea-pigs (ID(50)s' = 29+/-5, 31+/-12 and 670+/-270 microg/kg, after intravenous, intranasal and intraduodenal administration, respectively), without affecting bronchoconstriction induced by methacholine. After oral administration MEN 11467 produced a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar(9), Met(O(2))(11)] (ID(50) = 6.7 +/- 2 mg/kg) or by antigen challenge in sensitized animals (ID(50) = 1.3 mg/kg). After i.v. administration MEN 11467 weakly inhibited the GR 73632-induced foot tapping behaviour in gerbil (ED(50) = 2.96 +/- 2 mg/kg), indicating a poor ability to block central tachykinin NK(1) receptors. These results demonstrate that MEN 11467 is a potent, highly selective and orally effective insurmountable pseudopeptide antagonist of peripheral tachykinin NK(1) receptors with a long duration of action.
Recently, a method similar to ER.ICA has been proposed for the progesterone receptor (PgR) using two monoclonal antibodies, JZB39 and KD68, specific for human PgR and characterized by a molecular weight of 95 and 120 Kd, respectively. A series of 73 breast cancer patients was studied with regards to ER and PgR using both immunocytochemical (ICA) and biochemical (DCC) assays. Results showed no substantial differences between the two methods when considering common clinical-pathological parameters. Overall agreement between ICA and DCC methods was found: 79% for PgR and 78% for ER. A slight quantitative correlation was also observed between the "score values" of the ICA method and the Fmol content of ER and PgR using the Brave-Pearson test (r = 0.49 for PgR; r = 0.43 for ER). Specificity of PgR.ICA method was 77% for PgR and 72% for ER; sensitivity was 82% and 83%, respectively. The ICA method is a reliable technique to assess PgR presence as well as ER. Further studies are necessary to evaluate the prognostic role of nuclear PgR.
This study was carried out in Sardinia, an Italian region with a very high IDDM incidence. HLA class I and class II antigens were studied in 97 unrelated IDDM patients, 33 complete families with at least one affected member each, and 559 healthy controls. Molecular typing of the DQB1 alleles was carried out in 31 patients and 61 controls. The haplotypes were determined by family studies. The HLA-DR3, DQw2, and DR4 antigens were positively associated with IDDM. The DR3 antigen was nearly always associated to B18 and frequently carried by the extended haplotype A30 Cw5 B18 3F130 DR3 DQw2. The genotype analysis of the patients showed a strong increase of the DR3/DR4 heterozygotes with a relative risk higher than that of the DR3 and DR4 homozygotes. The DR2 antigen was negatively associated with IDDM in the central island districts but not in the southern districts. The DQB1 molecular analysis showed only three alleles in the patients: DQB1*0201 (75.8 per cent), DQB1*0302 (16.1 per cent), and DQB1*0502 (8.1 per cent). These alleles are non Asp 57, so it would seem that nearly if not all Sardinian IDDM patients are NA/NA homozygotes. The DQB1*0502 allele, extremely rare in other Caucasian populations, represents in Sardinia about 70 per cent of the HLA-DR2 haplotypes, contributing to the increase of the pool of IDDM susceptible genes. Moreover it is carried in 27 per cent of the DR2 positive individuals with the extended haplotype A2 Cw7 Bw58 3F31 DR2 DQw1.AZH.
The authors report their experience of 143 transluminal angioplasties performed over a three-year period on outpatients. Retrospective analysis of this case study did not demonstrate any late complications, and the only immediate complication (thrombosis at the arterial puncture) was treated surgically, a few days later, with thromboarterectomy. Of the 121 patients who underwent dilatation, 116 reached their home 6-8 hours after treatment; 4 were hospitalised for the following night, and 1 underwent TEA of the iliac artery. The authors conclude that most transluminal angioplasties can be performed on outpatients.
In the present study the interaction of doxofylline, a new antiasthmatic drug, with A1- and A2-adenosine receptors of the guinea-pig brain and rat striatum was investigated in comparison with known methylxanthine derivatives. Inhibition studies of N6-cyclohexyl-3H-adenosine (3H-CHA), 1,3-diethyl-8-3H-phenylxanthine (3H-DPX) binding and 3H-5'-N-ethylcarboxamidoadenosine (3H-NECA) binding showed how doxofylline did not bind to adenosine receptors in a pharmacological fashion, since doxofylline affinity for A1- and A2-adenosine receptors lies in a 10(-4) M range, a concentration which is too high to have any pharmacological meaning or predictability. However, saturation binding studies demonstrate that doxofylline behaves as a competitive inhibitor of the 3 radioligands used to label adenosine receptors. These data seem to corroborate the theory that antagonism to adenosine receptors is not necessarily associated with bronchodilator activity of methylxanthines, and explain the lack of the typically unwanted side effects induced by methylxanthine derivatives after doxofylline administration.
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