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41.
Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase. 下载免费PDF全文
R. M. McMillan K. E. Spruce G. C. Crawley E. R. Walker S. J. Foster 《British journal of pharmacology》1992,107(4):1042-1047
1. This paper describes the pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase which is undergoing clinical evaluation. 2. ICI D2138 potently inhibited leukotriene synthesis in murine peritoneal macrophages (IC50 = 3 nM) and human blood (IC50 = 20 nM). In human and dog blood, ICI D2138 did not inhibit thromboxane B2 synthesis at a concentration of 500 microM, thus the selectivity ratio (cyclo-oxygenase: 5-lipoxygenase) was greater than 20,000. In contrast, zileuton (a 5-lipoxygenase inhibitor also undergoing clinical evaluation) exhibited a selectivity ratio of 15-100. 3. ICI D2138 potently and dose-dependently inhibited ex vivo leukotriene B4 (LTB4) synthesis by rat blood with ED50 values of 0.9, 4.0 and 80.0 mg kg-1 p.o. at 3, 10 and 20 h respectively after dosing. Similar activity was observed for inhibition of LTB4 production in a zymosan-inflamed rat air pouch model. Zileuton produced ED50 values of 5 and 20 mg kg-1 at 3 and 10 h respectively. 4. Oral administration of 1, 3 or 10 mg kg-1 ICI D2138 to dogs produced maximal inhibition of ex vivo LTB4 synthesis by blood for 5, 9 and 31 h respectively. A dose of 5 mg kg-1 p.o. of zileuton caused maximal inhibition of LTB4 for 24 h. 5. Oral administration of 10 mg kg-1 ICI D2138 caused total inhibition of LTB4 production in zymosan-inflamed rabbit knee joint. 6. Topical administration of ICI D2138 to rabbit skin caused a dose-related inhibition of arachidonic acid-induced plasma extravasation with an ID30 of 1.08 nmol per site.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
42.
Role of substance P in several models of bladder inflammation 总被引:1,自引:0,他引:1
Judith Luber-Narod Tammy Austin-Ritchie Carl Hollins III Mani Menon Rajwant K. Malhotra Stephen Baker Robert E. Carraway 《Urological research》1997,25(6):395-399
Substance P (SP) is a peptide found in the sensory nervous system which has multiple biologic effects including stimulation of muscle contraction, pain nociception, immune cell functions, plasma extravasation and a constellation of inflammatory effects. Here we investigate the role of SP in several animals models of bladder inflammation. Using the female Lewis rat, inflammation was induced using either xylene, lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (polyIC). Inflammation occurred rapidly (4 h) and was maintained in each model for at least 7 days. Each of these protocols decreased the bladder content of immunoreactive SP by approximately 50%, suggesting enhanced release. There was no change in the urinary frequency of these animals over 3 weeks, suggesting that urinary frequency changes are not mediated by acute inflammation. We also found that the SP receptor (NK1) antagonist, (?)CP96345, was unable to block the inflammation produced by polyIC, suggesting that SP is not an obligatory mediator of immune cell stimulation in this model. 相似文献
43.
44.
Jesper Carl Thomas Bro Christensen Hans von der Maase 《Acta oncologica (Stockholm, Sweden)》1992,31(7):749-753
This study presents an analysis on longitudinal tumour marker series in twenty-two patients with non-seminomatous germ cell cancers treated with cisplatinum (DDP) based combination chemotherapy. Series of alphafoetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH) were analyzed applying a dynamic mathematical marker model. The model analysis provided quantitated values for growth rate and treatment response in the marker producing cells. The analysis showed that LDH had to be above 2 000 U/l to be a trustworthy tumour marker. HCG producing cells tended to grow faster than AFP producing cells, and were 3-5-fold more sensitive to the chemotherapy given than AFP producing cells. Treatment response versus DDP dose appeared to be bi-phasic, but with no significant change in treatment efficiency within the given range of DDP doses. 相似文献
45.
46.
The Melanesians of the North Solomons are exposed to intense equatorial sunlight and yet have a very low incidence of skin cancer. This study reveals no proven cases of basal cell carcinoma in these people, and demonstrates the rarity of squamous cell carcinoma and melanoma arising in normal pigmented skin. Most, if not all squamous cell carcinomas, arise in skin damaged by tropical ulceration, burns or osteomyelitis. Melanoma arises from the unpigmented skin of the sole of the foot. North Solomon Islanders are very deeply pigmented. Presumably, dense cutaneous melanin in normal undamaged skin provides the highly effective protection against solar carcinogenesis which these people enjoy. Chronic or recurrent skin ulceration with subsequent repair, scarring and loss of pigment is the precursor to almost all non-melanoma skin cancer in these people. Most of these cancers could be prevented by split thickness skin grafting of chronic ulcers, and protection of ulcerated, depigmented and scarred skin from solar radiation. 相似文献
47.
Mark F. Cotton Peter R. Donald Johan F. Schoeman Lana E. Van Zyl Cor Aalbers Carl J. Lombard 《Child's nervous system》1993,9(1):10-15
Intracranial pressure (ICP) monitored shortly after admission over a period of 1 h in 31 children with tuberculous meningitis (TBM) was significantly higher (median 22.5 mm Hg, range 8.4–50.9 mmHg) in 19 children with laboratory evidence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) than in 12 children without such evidence (median 16.2 mmHg, range 5.8–42.5 mmHg; P = 0.027). Neither plasma nor cerebrospinal fluid arginine vasopressin (AVP) was related to ICP (r = 0.33 and 0.13 respectively). Mean arterial pressure (MAP) was measured in 23 children and a moderate correlation was found with plasma AVP (r = 0.62; P = 0.0019). In TBM, plasma AVP may be secreted as a response to raised ICP in an effort to raise MAP and maintain cerebral perfusion pressure. In this setting excess fluid may be inappropriately retained, leading to hyponatremia and hypo-osmolemia. 相似文献
48.
H M Foster 《The Australian and New Zealand journal of surgery》1988,58(1):47-50
A series of 227 consecutive laparoscopies performed over 3 years at a provincial hospital in the North Solomons Province is presented. There were no deaths due to the procedure and morbidity was 2.4%. Positive findings were revealed in 89% of patients, allowing rapid decisions to be made regarding patient management: a vital consideration in a busy surgical unit with limited resources. Laparoscopy provides an efficient, safe, rapid and direct approach to many abdominal problems encountered in general surgery, particularly liver disease, blunt abdominal trauma, intraperitoneal infection and neoplasia. 相似文献
49.
Harry L June Rancia Cummings William J A Eiler Katrina L Foster Peter F McKay Regat Seyoum Marin Garcia Shannan McCane Collette Grey Stephanie E Hawkins Dynesha Mason 《Neuropsychopharmacology》2004,29(2):285-299
The exact opioid-sensitive receptors participating in EtOH-seeking behaviors remains unclear. Previous studies have reported higher densities of micro-opioid receptor binding in the nucleus accumbens (NACC) of P relative to NP rats; however, no differences were seen in delta-receptor binding. In contrast to the NACC, substantially lower levels of micro-receptor binding have been observed in the ventral tegmental area (VTA) of both P and NP rats, albeit no line differences have been observed. In the present study, opioid receptors in the NACC, VTA, and hippocampus were evaluated for their capacity to regulate both EtOH- and saccharin-motivated behaviors in the genetically selected alcohol-preferring (P) rat. To accomplish this, nalmefene, an opiate antagonist with preferential binding affinity for the micro-opioid receptor was unilaterally or bilaterally infused during concurrent availability of 1 h daily EtOH (10% v/v) and saccharin (0.025 or 0.050% w/v) solutions. Rats performed under a two-lever fixed ratio (FR) schedule in which four responses on one lever produced the EtOH solution, and four on a second lever produced the saccharin solution. The results demonstrated that when responding maintained by both EtOH and saccharin are matched at basal levels, unilateral (1-60 microg) or bilateral (0.5-10 microg) microinjections of nalmefene into the NACC produced selective dose-dependent reductions on responding maintained by EtOH. Unilateral (40, 60 microg) and bilateral (10 microg) VTA infusions were also observed to selectively reduced EtOH responding; however, greater nalmefene doses were required and the magnitude of suppression on EtOH responding was markedly less compared with the NACC. The greater sensitivity of nalmefene to suppress EtOH responding in the NACC is likely due to the greater number of opioid receptors in the NACC relative to the VTA. Only bilateral infusion of the 40 microg dose in the NACC and VTA suppressed responding maintained by both EtOH and saccharin. In contrast, intrahippocampal infusions dose dependently suppressed EtOH- and saccharin-maintained responding over a range of doses (1-20 microg). The present study provides evidence that nalmefene suppresses EtOH-motivated behaviors via blockade of opioid receptors within the NACC and VTA, and under various dose conditions both reinforcer and neuroanatomical specificity can be observed. 相似文献
50.
Carl Ganter 《Magnetic resonance in medicine》2004,52(2):368-375
A previously developed eigenvector formalism is adapted to off-resonance in the transient response of quasiperiodic steady-state free precession (SSFP) sequences, including TrueFISP as a special case. The effective relaxation rates for essentially parallel and perpendicular deviations from the steady state are determined analytically in leading order perturbation theory. The latter are a known cause of oscillatory artifacts and therefore constitute the main target of a variety of preparation techniques. In addition, the former also play a dominating role in applications such as inversion recovery (IR) TrueFISP, which intentionally measure far away from the equilibrium. For both components, the approach toward equilibrium turns out to depend sensitively on field inhomogeneities, especially for smaller ratios of T2/T1. For the perpendicular deviations, the calculations show that--except very close to banding artifacts, where the steady-state signal is almost zero--field inhomogeneities additionally increase their effective relaxation rate almost as much as in the free induction decay (FID). The analytical results are tested against numerical simulation and MR measurements. 相似文献