Coaerosolization of phosphodiesterase inhibitors markedly enhances the pulmonary vasodilatory response to inhaled iloprost in experimental pulmonary hypertension. Maintenance of lung selectivity.

Inhalation of aerosolized iloprost, a stable prostacyclin analog, has been suggested for treatment of primary and secondary pulmonary hypertension, but demands multiple daily inhalation maneuvers because of the short-term effect of this approach. In intact rabbits, pulmonary hypertension was induced by continuous infusion of the stable thromboxane mimetic U46619. Thereafter, the influence of aerosolized iloprost on pulmonary and systemic hemodynamics and gas exchange was investigated in the presence and absence of phosphodiesterase (PDE) inhibitors for stabilization of the second-messenger cAMP. First, dose-effect curves for pulmonary artery pressure (Ppa) decline were established for the nonspecific PDE inhibitors pentoxifylline and dipyridamole and for the dual-selective PDE3/4 inhibitor tolafentrine when being applied as sole agent, either via the intravenous or the inhalative route. Subthreshold doses for each agent and each route of administration were then combined with a standardized iloprost aerosolization maneuver, which resulted in a substantial prolongation, but not augmentation, of the lung vasodilatory response for the prostanoid. Next, higher doses of each PDE inhibitor were employed for nebulization, causing per se some pulmonary vasodilative effect, in the absence of arterial pressure decrease or impairment of gas exchange. Coaerosolization of these PDE inhibitor doses with standardized iloprost caused approximate doubling of the immediate pulmonary vasodilator response, marked prolongation of the pressure relief overtime, and a 2- to 4-fold increase in the area under the curve of pulmonary vasodilation (efficacy tolafentrine > dipyridamole > pentoxifylline). Still, systemic arterial pressure was not suppressed and gas exchange was fully maintained. We conclude that coadministration of PDE inhibitors with inhaled iloprost markedly enhances the prostanoid-induced pulmonary artery pressure decrease while maintaining the lung selectivity of the vasodilatory response, and that coaerosolization is a particularly suitable route of administration. Even nonselective clinically approved PDE inhibitors may be employed for this purpose.

1H magnetic resonance spectroscopy evidence that aberrant crypt foci are preneoplastic lesions in the colon.

BACKGROUND: Histopathological and genetic studies support the hypothesis that aberrant crypt foci (ACF) represent one of the earliest events in colon carcinogenesis. The purpose of this study is to make use of 1H MRS in conjunction with multivariate methods of analysis to ascertain the validity of the above mentioned hypothesis. MATERIALS AND METHODS: ACF, colonic mucosa and tumor samples taken from thirty-two carcinogen (azoxymethane)-treated Sprague Dawley rats, and of colon mucosa taken from ten healthy animals, were investigated ex vivo by 1H MRS and analyzed using multivariate methods of analysis. RESULTS: The 1H magnetic resonance peak intensities and areas of ACF lie between those from normal and carcinogen- treated mucosa samples and tumors. Multivariate analysis classification of the spectra suggests that the ACF exhibit biochemical characteristics intermediate between the control and AOM-mucosa samples and the tumor groups. CONCLUSION: The use of sophisticated methods of data classification has enabled us to support the hypothesis that ACF represent preneoplastic lesions of the colon.

Diagnostic potential for cancer via 1H magnetic resonance spectroscopy of colon tissue.

Specimens of colon tissue were examined by 1H MRS (360 MHz) in order to determine the usefulness of rat colon (n = 44) as a model for human colon (n = 60), particularly for the characterization of preneoplastic lesions. Human tissue was characterized by 1H MRS as a precursor to in vivo studies. For both tissues, resonances from mobile lipids were not characteristic of pure mucosa, but correlated with the presence of submucosa. The mean intensities of the resonances at 3.2 and 3.4 ppm (assigned mainly to choline-containing compounds and taurine, respectively) of rat mucosa compared to those of human mucosa, and of rat tumours compared to human tumours, were not significantly different, while both resonances were significantly more intense in rat tumours compared to rat mucosa. The spectra of premalignant lesions in rat colon have features between those due to tumours and normal tissue. We conclude that rat colon is a useful model for human colon in 1H MR spectroscopic studies. MR spectra from human colon control tissue and tumours were classified with 100% accuracy using multivariate analysis.

Butyrylcholinesterase activity in the developing auditory brainstem, the choroid plexus and the pituitary of the perinatal rat.

The butyrylcholinesterase activity in the vasculature of the brain, choroid plexus, and pituitary, was studied histochemically in rats during postnatal days 1, 7, 14, 21 and 28. The brainstem auditory nuclei were used for comparison of vessels at different ages. We found intense butyrylcholinesterase activity in all intraparenchymal blood vessels, especially capillaries, in all ages. In the meningeal vessels, activity was especially prominent in 1 and 7 day old animals when the perineural meninges was relatively thick. In the pituitary, reaction for the enzyme was found in nonvascular elements, especially in the intermediate and posterior lobes. Vessels of the choroid plexus were associated with punctate regions of butyrylcholinesterase activity. These results do not support the suggestion of a major role for butyrylcholinesterase in the blood-brain barrier.