RESUMEN
Alkylation of the selective type IV phosphodiesterase inhibitor, 8-amino-1,3-bis(cyclopropylmethyl)-xanthine (1, BRL 61063), led exclusively to the N-7 substituted derivatives 2-9, which showed varying selectivities for the PDE type IV isoenzyme relative to PDE Va. The 4-methoxybenzyl derivative 6 in particular was a highly potent PDE Va inhibitor (IC50 0.14 microM) and showed a 24-fold selectivity for this isoenzyme relative to PDE IV. Sulfonation of 1 was more complex, with the product profile being highly dependent on the reaction conditions. As with alkylation, sulfonation at N-7 generally increased potency against PDE Va, especially in the aryl-containing moieties lacking strongly electron-withdrawing substituents (12, 15-17, 19). Bis-arylsulfonation at the exocyclic amino group generally reduced inhibitory potency against both PDE IV and Va. An 8-amidino compound 33, formed by the unusual reaction of 1 with N-methylpyrrolidinone in the presence of benzenesulfonyl chloride, had an IC50 value of 0.05 microM against PDE Va and is believed to be the most potent inhibitor of this isoenzyme reported. No correlation of PDE IV inhibition with displacement of [3H]rolipram from its high-affinity binding site was demonstrated. This suggests that either the catalytic site and the rolipram binding site are not the same or that PDE IV can exist in two conformations, only one of which binds to rolipram with high affinity, and that the compounds described vary in their selectivity for this isoform.
Asunto(s)
Inhibidores de Fosfodiesterasa/síntesis química , Xantinas/síntesis química , Xantinas/farmacología , Adenosina/antagonistas & inhibidores , Alquilación , Animales , Sitios de Unión/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Masculino , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirrolidinonas/metabolismo , Ratas , Ratas Sprague-Dawley , Rolipram , Relación Estructura-Actividad , Xantinas/químicaRESUMEN
Evidence is mounting that susceptibility to pressure ulcers in the spinal cord injured is due to the interactive effects of prolonged immobilization and injury-related autonomic dysfunction associated with reduced tissue perfusion. To determine whether tissue oxygenation at the sacrum is reduced in spinal cord injury, we compared transcutaneous oxygen tension (PtcO2) levels in 21 subjects with spinal cord injury and 11 able-bodied controls lying prone and supine on egg-crate mattresses. Spinal cord injured subjects above and below the median supine PtcO2 value were also compared in terms of the presence or absence of pressure ulcers. The PtcO2 level of the spinal cord injured (mean +/- SD) was lower than that of the controls in the prone position (65.3 +/- 16mmHg vs 76.4 +/- 13mmHg; F = 3.9, df = 1, p = .053), and markedly lower in the supine position (49.1 +/- 26mmHg versus 74.2 +/- 10mmHg; F = 9.7, df = 1, p = .004). Examination of mean PtcO2 levels over time showed that those of the controls fell slightly following supination but returned to the previous level within 15 minutes. In contrast, those of the spinal cord injured fell rapidly by 18mmHg and stabilized after 15 minutes at a level 27mmHg below that of the controls. Five of the 10 (50%) spinal cord injured subjects with PtcO2 levels below the median supine PtcO2 level had a pressure ulcer compared to one among the 11 (9%) spinal cord injured subjects with PtcO2 levels above the median (p = .055, by Fisher's exact test). These results suggest the need for further studies on the role of reduced tissue oxygenation in the etiology of pressure ulcers.
Asunto(s)
Monitoreo de Gas Sanguíneo Transcutáneo , Úlcera por Presión/etiología , Traumatismos de la Médula Espinal/sangre , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Posición Prona , Factores de Riesgo , Sacro , Posición SupinaRESUMEN
Evidence is mounting that spinal cord injured (SCI) persons may be at increased risk of pressure ulcers due to prolonged immobilization together with the injury-induced loss of sympathetic tone and decreased vascular resistance. With a view to developing a new method of preventing pressure ulcers, the objective of this study was to determine whether high voltage pulsed galvanic stimulation (HVPGS) could increase sacral transcutaneous oxygen tension (PtcO2) in SCI persons lying prone and supine. In experiment 1, HVPGS applied to the back at spinal level T6 led to a sustained, dose-related increase in sacral PtcO2 in 3 subjects lying prone. In experiment 2, carried out on 29 subjects lying supine on egg-crate mattresses, HVPGS (75 volts, 10 Hz) produced a 35% increase in sacral PtcO2, from a baseline level (Mean +/- SD) of 49 +/- 21 mmHg to 66 +/- 18 mmHg after 30 minutes of stimulation (F = 39.4, p < .00001). In experiment 3, simulated HVPGS was found to have no effect on sacral PtcO2 in 5 subjects lying supine. In experiment 4, HVPGS was repeated on 10 subjects and its effects found to be highly reproducible. It is hypothesized that HVPGS restores sympathetic tone and vascular resistance below the level of the spinal cord lesion, thereby increasing the perfusion pressure gradient in the capillary beds. Randomized controlled trials are now indicated to determine the efficacy of HVPGS for preventing pressure ulcers.
Asunto(s)
Monitoreo de Gas Sanguíneo Transcutáneo , Terapia por Estimulación Eléctrica , Úlcera por Presión/prevención & control , Traumatismos de la Médula Espinal/terapia , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Posición Prona , Reproducibilidad de los Resultados , Sacro , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/fisiopatología , Posición SupinaRESUMEN
8-(4-Chlorophenyl)thio-cyclic AMP (8-CPT-cAMP), extensively used as selective activator of cyclic AMP-dependent protein kinase, has been found to be a potent inhibitor of the cyclic GMP-specific phosphodiesterase (PDE VA). Indeed, 8-CPT-cAMP (IC50 = 0.9 microM) inhibited PDE VA with a potency identical to that of zaprinast. 8-CPT-cAMP was also metabolized by PDE VA at a rate half that of cyclic GMP. The cyclic GMP-inhibited phosphodiesterase (PDE III) (IC50 = 24 microM) and the cyclic AMP-specific phosphodiesterase (PDE IV) (IC50 = 25 microM) were also inhibited by 8-CPT-cAMP. In contrast, most of the other cAMP-derivative studies showed little inhibition of any phosphodiesterase isoenzyme. These observations provide further reasons why the mechanism of the physiological effects of 8-CPT-cAMP should be interpreted with caution.