Effects of selective phosphodiesterase inhibitors on platelet-activating factor- and antigen-induced airway hyperreactivity, eosinophil accumulation, and microvascular leakage in guinea pigs

There is currently interest in the potential use of selective inhibitors of cyclic nucleotide phosphodiesterases (PDE) in the treatment of asthma. In this study we examined the effects of three selective PDE inhibitors, milrinone (PDE III), rolipram (PDE IV) and zaprinast (PDE V), on the broncoconstriction produced by antigen and histamine, the airway hyperreactivity and microvascular leakage after aerosol exposure to platelet-activating factor (PAF) and antigen, and the antigen-induced eosinophil infiltration in guinea-pig lung. Inhaled rolipram (0.01–10 mg ml^–1) inhibited dose dependently the bronchospasm produced by aerosol antigen (5 mg ml^–1) an anaesthetised, ventilated guinea-pigs. Rolipram (10 mg ml^–1) produced maximal inhibition of antigen-induced bronchoconstriction but only partial inhibition of the response to aerosol histamine (1 mg ml^–1). Milrinone and zaprinast (each 10 mg ml^–1) showed weak, or no, inhibitory effects against bronchoconstriction produced by aerosol antigen or histamine. Pretreatment with rolipram (10 mg kg^–1, i.p.) prevented airway hyperreactivity to histamine which develops 24 h after exposure of conscious guinea-pigs to aerosol PAF (500 g ml^–1) or antigen (5 mg ml^–1). The pulmonary eosinophil infiltration obtained with 24 h of antigen-exposure was inhibited by rolipram. In contrast, milrinone and zaprinast (each 10 mg kg^–1, i.p.) failed to reduce either the airway hyperreactivity of the eosinophil accumulation in these animals. Rolipram (1–10 mg ml^–1) reduced the extravasation of Evans blue after aerosol PAF (500 g ml^–1) at all airway levels while a lower dose (0.1 mg ml^–1) was only effective at intrapulmonary airways. Rolipram (0.01–1 mg ml^–1) markedly reduced airway extravasation produced by inhaled antigen (5 mg ml^–1). Zaprinast (1–10 mg ml^–1) was also effective against airway microvascular leakage produced by aerosol PAF or antigen while milrinone (10 mg ml^–1) had no antiexudative effect. These data support previous suggestions that pharmacological inhibition of PDE IV results in anti-spasmogenic and anti-inflammatory effects in the airways and may be useful in the treatment of asthma.     

Genetic markers in primary open-angle glaucoma

Purpose: To investigate possible associations between genetic markers and Primary Open-Angle Glaucoma (POAG). Methods: A number of genetic markers were typed in 84 unrelated patients with POAG and compared with a random sample of healthy individuals. The markers were Transferrin, Group Specific Component, G1m (1), G1m (2) and G3m (5) Allotypes, Adenylate Kinase, Adenosin Deaminase, Glyoxalase I and Acid Phosphatase and PCR-based markers HLA-DQA1 and D1S80. Results: No significant differences were found except the strong association between the group of POAG patients and Acid Phosphatase ACP^*C allele (² = 32.86; p < 0.0001). Conclusions: Since Acid Phosphatase gene is localized to chromosome 2p23, this result could be a first comprehensive step in the localization of POAG genes.     

Semiconductor diode laser transscleral cyclophotocoagulation versus filtering surgery with Mitomycin-C

Both filtering surgery with Mitomycin-C and diode laser cyclophotocoagulation have proved to be effective alternatives in cases of glaucoma with poor surgical prognosis. The right eyes of 40 pigmented rabbits were randomly divided into 2 groups: Mitomycin-C group underwent filtering surgery with application of 0.4 mg/ml of Mitomycin-C whereas the diode laser (DL) group received 15 applications of 1.8 J (1800 mW. 1000 ms) distributed in 270°. Mean IOP showed statistical differences in two periods between days 3–13 and 45–60 — Mann-Whitney U test — with a higher IOP lowering in the DL group. The comparison of IOP survival curves (Log-Rank test) was not significant p = 0.070809. Ocular hypertension, hyphema and inflammatory signs were higher in the DL group, both in short and long term, but in terms of statistical significance only ocular hypertension showed differences p = 0.00011717 - Fisher exact test. Microscopic examination revealed patent sclerostomies in 60% of the MMC group eyes with different grades of fibroblastic proliferation. In the DL group we observed necrosis of the sclieral stroma and of the pigmented and unpigmented ciliary epithelium, with signs of thermal coagulation of the ciliary stroma and of the stromal vasculature. We must point out that the treatment with laser has proved to be more effective although both treatments showed very acceptable IOP lowering until 2 months after the surgery.     

Pharmacological and molecular discrimination of brain I2-imidazoline receptor subtypes

I₂-imidazoline receptors labelled with [³H]-idazoxan in the rabbit and rat brains displayed high and low affinity, respectively, for the guanidide amiloride; reinforcing the previous definition of I_2A-imidazoline receptors expressed in the rabbit brain and Its-imidazoline receptors expressed in the rat brain. Other drugs tested displayed biphasic curves in competition experiments, indicating the existence of high and low affinity sites for both subtypes of I₂-imidazoline receptors. Among the drugs studied, bromoxidine, moxonidine, (+)- and (-)-medetomidine and clorgyline were more potent on the high and/or low affinity sites of 1_2B- than on their corresponding of I_2A-imida-zoline receptors (K _iH ratios 20 to 65). No correlation was found for the potencies of the drugs tested at the low affinity sites of both I₂-imidazoline receptor subtypes. Preincubation (30 min at 25°°C) with 10^-6 M clorgyline reduced by 60% the B _max of [³H]-idazoxan binding to I₂ B-imidazoline receptors in the rat brain, but it did not affect the binding parameters of the radioligand saturation curves to I_2A-imidazoline receptors in the rabbit brain. These results indicated that I_2A- and I_2B-imidazoline receptor subtypes differ in the pharmacological profiles of their high and low affinity sites and in the ability to irreversibly bind clorgyline. In rat cortical membranes western blot detection of immunoreactive imidazoline receptor proteins revealed a double band of 29/30 kDa and two less intense bands of 45 and 66 kDa. In rabbit cortical membranes the antibody used detected proteins of 30, 57 and 66 kDa. It is suggested that different imidazoline receptor proteins (45 vs 57 kDa) may account for the different pharmacological profiles of I2-imidazoline receptor subtypes.     

Polymorphism analysis of the VNTR locus D17S5 in Central Spain

The fragment length polymorphism YNZ22 (D17S5) was analysed for a sample of 207 unrelated individuals living in Madrid (Spanish Caucasians) using PCR-methodology and high resolution separation. Hardy-Weinberg expectations (HWE) were calculated after pooling alleles into four groups. No deviations from HWE were detectable using the conventional ²-test. The power of discrimination was estimated as 0.96 and the mean paternity exclusion chance as 0.7587. A comparison of the allele frequency distribution with those of other Caucasian groups revealed no major differences.     

Epidemic outbreak of interstitial lung disease in aerographics textile workers--the "Ardystil syndrome": a first year follow up.

BACKGROUND: The longer term respiratory effects of massive inhalational exposure of textile printing sprayers to Acramin (the "Ardystil syndrome") are not well established. METHODS: A 12 month follow up of 27 heavily exposed textile sprayers was performed. RESULTS: Twenty one patients experienced cough, 18 dyspnoea, and 17 nose bleeding at initial exposure, with histological evidence of organising pneumonia in 13 cases, radiological abnormalities detected by computed tomographic scanning in 20 cases, and diminution of diffusion capacity to below 80% of predicted in seven cases. At one year after exposure symptoms persisted in 15 cases, radiological alterations in six, and diffusion capacity was reduced in nine. CONCLUSIONS: Whilst most of our patients showed improvement at one year, evidence of persistent lung involvement was present in an appreciable minority of exposed cases.     

Diet and mortality from common cancers in Brazil: an ecological study

A prospective ecological evaluation of mortality from common malignancies with dietary risk factors and alcohol consumption was carried out among 10 state capitals of Brazil. Regression analysis was used to examine the association of dietary intake with mortality rates of the most common cancers among adults age 30 years and older. Age-adjusted cancer mortality rates varied 2.4 to 3.3 fold across the state capitals. A positive relationship was observed between energy intake and colon, lung, and esophageal cancer (p相似文献   

Involvement of GABA(B) receptors in the motor inhibition produced by agonists of brain cannabinoid receptors

The present study was designed to investigate the possibility of activation of GABA(B) receptors during the motor inhibition caused by cannabimimetics. Adult male rats were injected with an acute dose of arachidonylethanolamide (AEA), Delta(9)- tetrahydrocannabinol (THC), beclofen or vehicle, after pretreatment with CGP 35348, a specific antagonist for GABA(B) receptors, or vehicle, and the behavioral response produced by these compounds tested in an open field. As expected, the administration of either AEA or THC produced a very pronounced motor inhibition, reflected by decreased ambulation and increased time spent in inactivity. The administration of baclofen also produced a marked motor deficit, with similar changes to those observed with both cannabimimetics. Pretreatment with the GABA(B) antagonist, CGP 35348, prevented the motor inhibition induced by baclofen and also attenuated the motor deficit caused by both cannabimimetics, suggesting a role for this receptor. In summary, a GABAergic influence, acting through GABA(B) receptors, seems to be involved in mediating motor effects of cannabimimetics, since the blockade of these receptors attenuates cannabimimetic-induced signs of motor inhibition.     

Effect of antimicrobial and antineoplastic drugs on the uptake of fluconazole by human neutrophils and tissue culture cells

The effect of eight antimicrobial and three antineoplastic drugs on the uptake of fluconazole by human neutrophils and culture epithelial cells was evaluated. Fluconazole reached higher concentrations intracellularly than extracellularly (cellular to extracellular concentration ratio C/E 1.3) in the presence of therapeutical concentrations of the antimicrobial and antineoplastic agents evaluated.