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101.
102.
103.
Allan M. Lefer Nobuo Aoki Donna Mulloy 《Naunyn-Schmiedeberg's archives of pharmacology》1990,341(3):246-250
Summary Defibrotide is known to enhance prostacyclin (PGI2) release from the vascular endothelium. We investigated the vasoactive effects of defibrotide in isolated rat hearts perfused at constant flow subjected to ischaemia and reperfusion. Defibrotide at 10–7 or 100 g/ml did not exert any direct vasoactive effect on normal rats hearts. However, ischaemia and reperfusion resulted in an impaired vasodilation to acetylcholine, an endothelium-dependent vasodilator. In contrast, the vasodilator response to the endothelium-independent dilator, nitroglycerin, was unaffected. Defibrotide, at 10–7 or 100 g/ml, markedly restored the vasodilation to acetylcholine 10–7 nmol/l to 1 mol/l (P < 0.01) without influencing the vasodilator response to nitroglycerin (2 to 200 g/1). Haemoglobin (150 nmol/l) inhibited the dilation to acetylcholine in response to defibrotide. However, no evidence of (PGI2) release was observed with acetylcholine-induced vasodilation in the presence or absence of defibrotide. Additionally, 10–100 g/ml of defibrotide did not significantly decrease superoxide radicals generated by a xanthine-xanthine oxidase synthetic system under conditions in which superoxide dismutase was effective. Thus, defibrotide appears to exert an endothelium-protective effect preserving endothelium-derived relaxing factor (EDRF) without directly scavenging free signals.Supported in part by Research Grant No. HL-25575 from the National Heart, Lung and Blood Institute of the NIH
Send offprint requests to A. M. Lefer at the above address 相似文献
104.
Milne Robert W. Jensen Rikke Holm Larsen Claus Evans Allan M. Nation Roger L. 《Pharmaceutical research》1997,14(8):1014-1018
Purpose. Humans and guinea pigs metabolise morphine extensively, forming the isomers morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs.
Methods. Livers were perfused at 30 ml/min in a non-recirculating manner with Krebs bicarbonate buffer containing morphine (6 to 7 M). Perfusing medium, venous perfusate and bile were collected at regular intervals and concentrations of morphine, M3G and M6G determined by reversed-phase HPLC.
Results. Concentrations of morphine, M3G and M6G in perfusate and the rates of biliary excretion of M3G and M6G were consistent between 20 and 50 min of perfusion. The mean (±s.d.) ratio for the rate of formation of M3G relative to M6G was 3.7 ± 1.5. A mean 33 ± 3% of morphine extracted by the liver was recovered as summed M3G and M6G. Of the M3G and M6G formed during a single passage, 19 ± 11% and 9 ± 9%, respectively, was excreted into bile; the values were significantly different (P = 0.002).
Conclusions. A greater fraction of hepatically-generated M3G excreted into bile compared to that for M6G reflects differences in their relative transport across sinusoidal and canalicular membranes of hepatocytes, possibly via carrier-mediated systems. 相似文献
105.
Casley William L.; Menzies Allan; Girard Michel; Larocque Lyse; Mousseau Nicole; Whitehouse Larry W.; Moon Thomas W. 《Toxicological sciences》1997,40(2):228-237
The 3-demethylation of caffeine can be used as an index of cytochromeP450 CYP1A2 activity in vivo. We compared the plasma levelsof caffeine and the 3-demethylated metabolite, 1,7-dimethylxanthine,in six common inbred strains (A/J, P/J, BALB/cJ, C3H/HeJ, AKR/J,and SWR/J) and one inbred strain (APN) derived in our laboratoryfrom outbred Swiss-Webster mice on the basis of its relativesusceptibility to acetaminophen-induced hepatotoxicity. We foundsignificant variations between a number of the common strains,all of which produced significantly higher caffeine 3-demethylationindices than our APN strain. In three of the six common strains,there was a significant difference between males and females,with the females having consistently lower 1,7-xanthine/caffeineratios. Hepatic Cyp1a2 expression was compared between APN andC3H/HeJ males. Microsomal methoxyresorufin O-demethylation,acetanilide 4-hydroxylation, and CYP1A2 immunoreactive proteinlevels were significantly higher in C3H/HeJ relative to APNmice, as were hepatic CYP1A2 mRNA levels. These results indicatethe importance of strain and gender to the outcome of pharmacologicalor toxicological studies involving CYP1A2-mediated metabolism,as well as the suitability of the plasma 1,7-dimethylxanthine/caffeineratio as a marker of CYP1A2 activity in the mouse. The strikingdifferences observed between the APN and C3H/HeJ mice suggestthat these strains may be suitable for a genetic analysis ofthe regulation of the basal expression of CYP1A2, a key enzymeIn procarcinogen activation. 相似文献
106.
Stolnik Snjezana Dunn Susan E. Garnett Martin C. Davies Martyn C. Coombes Allan G. A. Taylor D. C. Irving M. P. Purkiss S. C. Tadros T. F. Davis Stanley S. Illum Lisbeth 《Pharmaceutical research》1994,11(12):1800-1808
The modification of surface properties of biodegradable poly(lactide-co-glycolide) (PLGA) and model polystyrene nanospheres by poly(lactide)-poly(ethlene glycol) (PLA:PEG) copolymers has been assessed using a range of in vitro characterization methods followed by in vivo studies of the nanospheres biodistribution after intravenous injection into rats. Coating polymers with PLA:PEG ratio of 2:5 and 3:4 (PEG chains of 5000 and 2000 Da, respectively) were studied. The results reveal the formation of a PLA: PEG coating layer on the particle surface resulting in an increase in the surface hydrophilicity and decrease in the surface charge of the nanospheres. The effects of addition of electrolyte and changes in pH on stability of the nanosphere dispersions confirm that uncoated particles are electrostatically stabilized, while in the presence of the copolymers, steric repulsions are responsible for the stability. The PLA:PEG coating also prevented albumin adsorption onto the colloid surface. The evidence that this effect was observed for the PLA:PEG 3:4 coated nanospheres may indicate that a poly(ethylene glycol) chain of 2000 Da can provide an effective repulsive barrier to albumin adsorption. The in vivo results reveal that coating of PLGA nanospheres with PLA:PEG copolymers can alter the biodistribution in comparison to uncoated PLGA nanospheres. Coating of the model polystyrene nanospheres with PLA:PEG copolymers resulted in an initial high circulation level, but after 3 hours the organ deposition data showed values similar to uncoated polystyrene spheres. The difference in the biological behaviour of coated PLGA and polystyrene nanospheres may suggest a different stability of the adsorbed layers on these two systems. A similar biodistribution pattern of PLA:PEG 3:4 to PEG 2:5 coated particles may indicate that poly(ethylene glycol) chains in the range of 2000 to 5000 can produce a comparable effect on in vivo behaviour. 相似文献
107.
Mackinnon JR Noh S Laliberte D Allan DE Lariviere J 《Physical & occupational therapy in pediatrics》1995,15(1):1-15
This paper reviews the literature on the benefits of therapeutic horseback riding and the outcomes of eleven data-based studies purpoting to validate the claims that horseback riding offers therapeutic benefits. These studies have focused on physical and psychosocial variables. The literature on the benefits of riding reported obvious beneficial effects, while the outcome studies were able to document only some of these claims. The studies generally reported some significant effects from the therapeutic intervention. An examination of the outcome studies revealed weak scientific rigor, small sample sizes, and a lack of homogeneous populations. Furthermore, use of standardized measures was limited as authors frequently relied on nonstandardized observational techniques to evaluate change. This review indicates a need for further research into both the physical and psychosocial areas with both children and adults. In addition, there is a need for research which would improve the methodological rigor, homogeneity of populations, sample size, and use of standardized measurement instruments. 相似文献
108.
Shigeru Masamura Herman Adlercreutz Harold Harvey Allan Lipton Laurence M. Demers Richard J. Santen Steven J. Santner 《Breast cancer research and treatment》1995,33(1):19-26
Summary Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue.To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hrurine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples. These data suggest that CGS 20267 can be expected to bring improved response rates in the treatment of metastatic hormone-dependent breast cancer without substantial side effects.Presented by R.J. Santen at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993; Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhône-Poulenc Rorer). 相似文献
109.
Robert Maggisano MD Avery Nathens MD Natalia A. Alexandrova MD Claudio Cina MD Bernard Boulanger MD Robert McKenzie MD Allan W. Harrison MD 《Annals of vascular surgery》1995,9(1):44-52
Although the traditional therapy for blunt traumatic rupture of the thoracic aorta (TRA) is immediate operative repair, there may be a selective role for delayed repair, particularly in patients with head trauma, respiratory failure, or cardiac dysfunction. The present study examines the hypothesis that TRA can be managed by selective delayed operative repair. Clinical data were collected from 59 consecutive patients with TRA at a regional trauma unit. All TRAs were at the aortic isthmus. Patients were retrospectively classified into three groups: group I (n=12) included patients who either arrived in extremis or rapidly became unstable during triage; group II (n=3) included patients who had no contraindications to early repair and underwent repair at the time of diagnosis; and group III (n=44) consisted of patients who because of concomitant injuries or sepsis required initial admission and management in the intensive care unit until their clinical status had improved sufficiently to allow for deliberate delayed operative repair of the TRA. The delay ranged from 1 day to 7 months. Eight patients have yet to undergo repair and remain well at follow-up from 1 to 4 years. Overall survival rates in groups I, II, and III were 17%, 100%, and 82%, respectively. The surgery-related mortality rate in group III was 10% (three patients). Only two (4.5%) patients in group III died as a result of a ruptured aorta within 72 hours of admission. In conclusion, contrary to surgical doctrine, TRA may not require immediate operative repair in all cases, but may instead be managed selectively depending on the patient's clinical status. 相似文献
110.
Cooper RA Cowan RA Owens SE Jeans SP Roberts JK Hillel PG Slevin NJ Allan E Gupta NK Collins CD 《European journal of nuclear medicine》1999,26(3):220-225
This study was undertaken to determine whether standard salivary gland scintigraphy may be used for the objective assessment of salivary gland sialogogues, in particular oral pilocarpine, in the treatment of post-radiotherapy xerostomia. Nine patients, with xerostomia following radiotherapy to the head and neck region underwent salivary gland scintigraphy with technetium-99m pertechnetate (40 MBq) both before and following 1 month of oral pilocarpine (5 mg tds). For each scan, the percentage uptake in the first 14 min, the peak uptake, time to peak uptake and the percentage of activity excreted following lemon juice stimulation were calculated. The results were correlated with the subjective response as assessed by questionnaire and visual analogue scale. We found no correlation between subjective response and any of the four scan parameters analysed. We could not identify any parameter that predicted those patients who would respond to pilocarpine. In addition, only one parameter, the percentage of activity excreted following stimulation, correlated with previous dose of radiotherapy to the gland. In conclusion, in this study salivary gland scintigraphy did not appear to correlate with or predict response to oral pilocarpine. However, future studies might consider performing salivary gland scintigraphy prior to radiotherapy as well as at differing time points following the commencement of pilocarpine. 相似文献