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At least 19 recordsLinked to original sources
PubMed1990

Structure of 6 alpha-methyl-3,20-oxo-1,4,9(11)-pregnatrien-17 alpha-yl acetate.

C24H30O4, Mr = 382.5, orthorhombic, P2(1)2(1)2(1), a = 13.091 (2), b = 19.711 (1), c = 8.242 (1) A, V = 2126.7 (5) A3, Z = 4, Dx = 1.195 Mg m-3, lambda(Cu K alpha) = 1.54184 A, mu(Cu K alpha) = 0.56 mm-1, F(000) = 824, T = 295 K. Final R = 0.045 for 2446 unique reflections. The planar A ring is bent relative to the rest of the steroid skeleton. The B ring has a typical chair conformation and the C and D rings assume 13 beta,14 alpha-half-chair and 13 beta-envelope conformations, respectively. The conformation of the progesterone side chain is similar to the conformation observed in other 17 alpha-ester pregnanes: C16-C17-C20-O20 torsion angle -27.4 (3) degrees.

Molecular Conformation↗
PubMed1983

3-Chloro-1,3,5-pregnatriene derivatives with glucocorticoid activity.

Novel synthetic glucocorticoid analogues were tested for receptor binding and glucocorticoid activity. They were of unusual structure, insofar as they had a 3-chloro rather than a 3-oxo function. 3-Chloro analogues of fluorinated glucocorticoids formed extremely stable complexes with the rat liver glucocorticoid receptor. 3-Chloro derivative of fluocinolone acetonide also had in vivo glucocorticoid activity. It induced tyrosine aminotransferase in the liver and repressed thymidine kinase in the thymus very effectively. It is concluded that 3-chloro analogues may retain glucocorticoid activity as well as the ability to bind to the glucocorticoid receptor protein.

Acetylation↗
PubMedDate not supplied

The metabolic fate of triamcinolone acetonide in laboratory animals.

The metabolic fate of 9-fluoro-11beta,16alpha,17,21-tetrahydroxy-1,4-pregnadiene-3,20-dione cyclic 16,17-acetal with 2(-14)C-acetone, triamcinolone acetonide (TA) was studied in rabbits, dogs, monkeys and rats and found to be qualitatively similar in all species. In the dog, rat and monkey the major excretory route was the feces irrespective of the mode of administration. In the rabbit the excreted radioactivity was equally distributed between urine and feces. The metabolites were isolated by preparative thin layer chromatography, located by autoradiography, eluted and analyzed by MS, IR, UV and NMR. The major metabolites of triamcinolone acetonide (TA) were identified as the C-21 carboxylic acids of TA and of the 6beta hydroxy-TA, (6BETA-OH-TA) and the previously identified (1,2) 6beta-OH-TA. In addition MS and UV data indicate the presence of 9-fluoro-11beta,16alpha, 17-trihydroxy-3,20-dioxo-1,4,6-pregnatrien-21-oic acid cyclic 16,17 acetal with 2(-14)C-acetone.

Animals↗
PubMed1987

Analysis of steroids. XXXVIII. The use of high-performance liquid chromatography with diode-array UV detection for estimating impurity profiles of steroid drugs.

High-performance liquid chromatography (HPLC) diode-array UV-spectrophotometric detection is used for estimating impurity profiles of steroid drugs. It is shown to be a very useful first screening method for the identification of UV-active impurities and degradation products, giving a rapid answer to many questions or at least providing important initial information to complement the results obtained by other spectroscopic techniques. In this paper the estimation of the impurity profiles of ethynyloestradiol, norgestrel, and norethisterone, and of the degradation product of RGH-1113 (3-chloro-, 6,9-difluoro-11 beta,16 alpha,17 alpha,21-tetrahydroxy-1,3,5-pregnatrien-20-one 16,17-acetonide 21-acetate) will be discussed.

Chromatography, High Pressure Liquid↗
PubMed1998

Synthesis and biological evaluation of (23R)- and (23S)-24,24-difluoro-1 alpha,23,25-trihydroxyvitamin D3.

The syntheses and biological evaluations of (23R)- and (23S)-24,24-difluoro-1 alpha,23,25-trithydroxyvitamin D3 (3a and 3b), new C-24 fluorinated analogs of 1 alpha,25-dihydroxyvitamin D3, are described. The syntheses of these compounds were achieved in 3 steps from (5Z,7E,20R)-1 alpha,3 beta-bis-[(tert-butyldimethylsilyl)oxy]-20-formylmethyl-9,10-seco- 5,7,10(19) pregnatriene (5) which is derived from vitamin D2. The absolute configuration at the C-23 position of 3a and 3b was determined by the modified Mosher method. The relative affinities of 3a and 3b to the vitamin D receptor were both 10 and 14 times lower than that of 1 alpha,25-dihydroxyvitamin D3 (1), and to vitamin D binding protein were also both 130 and 40 times lower. The HL-60 cell differentiating activity of 3a was 6 times more potent than that of 1, while there was no remarkable difference in activity between 3b and 1.

Animals↗
PubMed1998

New steroidal antiinflammatory agents: prednisolone derivatives with an isoxazoline fusion at the 16- and 17-carbons and an alkyl carboxylate at the 16 alpha-position.

In a continuing effort to synthesize potent antiinflammatory steroids without systemic side effects based on the antedrug concept, prednisolone derivatives with a carboxylate ester group at the C-16 and isoxazoline rings at the C-16 and C-17 were obtained by 1,3-dipolar cycloaddition of nitrile oxides to 1,4,16-pregnatriene-3,20-diones. Most of the new steroids retained the antiinflammatory activities of their parent compounds as evidenced by the croton oil-induced ear edema assay. They also demonstrated substantial or almost complete reductions in systemic side effects as shown by the 5-day ear edema and cotton pellet bioassays. In the case of the new steroids with alkyl carboxylate groups, the improved pharmacological profile is ascribed to their metabolically labile ester function which should be readily hydrolyzed to inactive carboxylic acid, thus eliminating the systemic side effects. The pharmacological profiles of the isoxazoline derivatives remain to be explained, partly due to insufficient information on the metabolic fate of these compounds.

Animals↗
PubMed1994

Effects of a novel 21-aminosteroid or methylprednisolone in experimental total intestinal ischemia.

OBJECTIVE: To investigate whether tirilazad mesylate, a 21-aminosteroid, protects the small intestinal mucosa from injury following total warm or cold ischemia and reperfusion. DESIGN: Randomized vehicle-controlled experimental study. SETTING: A university department of surgery. ANIMALS: Wistar rats. The warm ischemia series preceded the cold ischemia series. Animals were randomized within each series. Microscopic evaluation was performed on coded tissue slides. INTERVENTIONS: Warm ischemia was induced by a hydrostatic pressure cuff inflated to 10 mm Hg above the systolic arterial pressure for 60 minutes. Cold ischemia was studied after small intestinal transplantation. The transplant was stored for 5 hours in University of Wisconsin solution at 8 degrees C. Ischemia was followed by 60 minutes of reperfusion. In both series, tirilazad mesylate (3 mg/kg) or methylprednisolone sodium succinate (30 mg/kg) was given. Controls were given tirilazad vehicle or saline solution. MAIN OUTCOME MEASURE: Microscopic grade of small intestinal mucosal injury. RESULTS: Mucosal injury was evident in all groups of animals that were subjected to warm or cold ischemia. Reperfusion following cold ischemia induced a significant reperfusion injury. Neither tirilazad nor methylprednisolone protected the small intestinal mucosa during ischemia or reperfusion. CONCLUSION: Mucosal injury following warm or cold intestinal ischemia and reperfusion is caused by factors other than or in addition to lipid peroxidation, which is preventable by use of a 21-aminosteroid.

Animals↗
PubMed1995

Suppressors of oxygen metabolites fail to reduce vein graft intimal hyperplasia.

OBJECTIVE: To evaluate the role of reactive oxygen metabolites in the initiation of intimal hyperplasia of vein grafts inserted into the arterial circulation. SETTING: University pathologic research laboratory. ANIMALS: Sprague-Dawley rats. INTERVENTION: Animals were randomized to receive either the xanthine oxidase inhibitor allopurinol, the iron chelating agent starch-conjugated deferoxamine, or the free-radical scavenger 21-aminosteroid U74389G. Control animals were included for each group. The epigastric vein was inserted into the right common femoral artery. Vein grafts were harvested 30 days postoperatively. The degree of intimal hyperplasia at the two anastomoses as well as at the midgraft was calculated. MAIN OUTCOME MEASURES: The vein grafts were divided into three sections designated proximal anastomosis, midgraft, and distal anastomosis. Intimal and medial areas were determined in an observer-blind fashion and expressed as intimal area-medial area ratios. RESULTS: Pretreatment of the animals with any of these agents resulted in no significant reduction in the degree of intimal hyperplasia in any treated groups compared with the control animals 30 days postoperatively. CONCLUSIONS: Arterial reconstruction often involves interposition of vein segments into the arterial circulation. These veins are subject to ischemia and reperfusion, with the potential for generation of reactive oxygen metabolites and subsequent vein graft injury, resulting in intimal hyperplasia. We hypothesized that perioperative pharmacologic intervention either to scavenge or to reduce the production of reactive oxygen metabolites would attenuate the initial vein graft injury and thus limit the subsequent development of intimal hyperplasia. These data create doubt as to the influence of reactive oxygen metabolites in the initiation of intimal hyperplasia in the vein graft.

Allopurinol↗
PubMed1998

Hemangioma.

Explore the source record for details and available documents.

Angiography↗
PubMed1996

Inhibition of lipid peroxidation attenuates axotomy-induced apoptotic degeneration of facial motor neurons in neonatal rats.

The purpose of this study was to investigate the role of oxygen radical-induced lipid peroxidative mechanisms in trophic deprivation-induced apoptotic motor neuronal degeneration by testing the ability of the 21-aminosteroid lipid peroxidation inhibitor tirilazad mesylate (U-74006F) to attenuate the retrograde degeneration of facial motor neurons following axotomy in 14-day-old rat pups. On day 0, the right facial nerve of each rat was transected at its point of exit from the stylomastoid foramen. Pups were treated orally with either 10 or 30 mg/kg U-74006F or cyclodextrin vehicle 10 min before axotomy, and post-treated once a day from days 1 to 6, and then once every other day from days 8 to 21. The rats were sacrificed 3 weeks post-transection and the surviving motor neurons, identified through choline acetyltransferase immunocytochemistry, were counted in three regions (planes) in the facial nucleus. In vehicle-treated rats, 56.2% (region A), 50.6% (region B), and 57.4% (region C) of the motor neurons in the ipsilateral facial nucleus survived 21 days following facial nerve axotomy in comparison to the non-axotomized contralateral nucleus (P < 0.0001). Treatment with 10 mg/kg U-74006F significantly enhanced motor neuron survival in regions B and C to 72.8% (P < 0.01) and 66.7% (P < 0.02%), respectively. The 30 mg/kg dose level also increased survival rates to 64.2% (P < 0.02) and 67.9% (P < 0.01), respectively. A second experiment demonstrated that oral dosing with U-74006F (30 mg/kg), when limited to the first 5 days after axotomy, also significantly blunted retrograde degeneration measured at 21 days post-axotomy. The efficacy of the lipid peroxidation inhibitor U-74006F in protecting a portion of the facial motor neuron pool from post-axotomy degeneration suggests that lipid peroxidation may play a mechanistic role in trophic deprivation-induced apoptotic neuronal death.

Animals↗
PubMed2000

Effects of new antioxidant compounds PNU-104067F and PNU-74389G on antioxidant defense in normal and diabetic rats.

Diabetes mellitus and its complications are associated with elevated oxidative stress, leading to much interest in antioxidant compounds as possible therapeutic agents. Two new classes of antioxidant compounds, the pyrrolopyrimidines and the 21-aminosteroids, are known to inhibit lipid peroxidation and other biomolecular oxidation. We hypothesized that in the presence of excess oxidants or the impaired antioxidant defense seen in diabetes mellitus, administration of antioxidants such as these may reverse the effects of diabetes on antioxidant parameters. This study measured the effects of subchronic (14 day) treatment with a pyrrolopyrimidine (PNU-104067F) or a 21-aminosteroid (PNU-74389G) in normal and diabetic Sprague-Dawley rats. Activity levels of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, concentrations of oxidized and reduced glutathione, and lipid peroxidation were used as measures of antioxidant defense in liver, kidney, heart, and brain tissue. In normal rats, the only effect was a 43% increase in cardiac lipid peroxidation after treatment with PNU-104067F. In diabetic rats, the only reversals of the effects of diabetes were a 30% decrease in hepatic glutathione peroxidase activity after PNU-74389G treatment and a 33% increase in cardiac glutathione disulfide concentration after PNU-104067F treatment. In contrast to these effects, increased cardiac glutathione peroxidase and catalase activities, increased brain glutathione peroxidase activity, increased hepatic lipid peroxidation, decreased hepatic glutathione content, and decreased hepatic catalase activity were seen in diabetic rats, reflecting an exacerbation of the effects of diabetes.

Animals↗
PubMed1998

Induction of tirilazad clearance by phenytoin.

Tirilazad is a membrane lipid peroxidation inhibitor being studied for the management of subarachnoid hemorrhage; phenytoin is used for seizure prophylaxis in the same disorder. The induction of tirilazad clearance by phenytoin was assessed in 12 volunteers (6 male, 6 female). Subjects received phenytoin orally every 8 h for 7 days (200 mg for nine doses and 100 mg for 13 doses) in one phase of a crossover study. In both study phases, 1.5 mg kg-1 tirilazad mesylate was administered by i.v. infusion every 6 h for 29 doses. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. After the final dose, tirilazad clearance was increased by 91.8% in subjects receiving phenytoin + tirilazad versus tirilazad alone. AUC0-6 for U-89678 after the last tirilazad dose was reduced by 93.1% by concomitant phenytoin. These effects were statistically significant. The time course of induction was consistent with that of phenytoin's effect on the ratio of urinary 6 beta-hydroxycortisol to cortisol, a measure of hepatic CYP3A activity. The results show that phenytoin induces metabolism of tirilazad and U-89678 in healthy subjects and that, under these conditions, tirilazad clearance approaches liver blood flow.

Adult↗
PubMed1998

Estimating country-specific cost-effectiveness from multinational clinical trials.

Because costs and outcomes of medical treatments may vary from country to country in important ways, decision makers are increasingly interested in having data based on their own country's health care situations. This paper proposes methods for estimating country-specific cost-effectiveness ratios from data available from multinational clinical trials. It examines how clinical and economic outcomes interact when estimating treatment effects on cost and proposes empirical methods for capturing these interactions and incorporating them when making country-specific estimates. We use data from a multinational phase III trial of tirilazad mesylate for the treatment of subarachnoid haemorrhage to illustrate these methods. Our findings suggest that it is possible for meaningful country-by-country differences to be found in such trial data. These differences can be useful in informing reimbursement, utilization, and other decisions taken at the country level.

Clinical Trials as Topic↗
PubMed1999

Effects of joint lavage and steroid injection in patients with osteoarthritis of the knee: results of a multicenter, randomized, controlled trial.

OBJECTIVE: To evaluate the efficacy of joint lavage and intraarticular steroid injection, alone and in combination, in the treatment of patients with symptomatic knee osteoarthritis (OA). METHODS: Ninety-eight patients with painful tibiofemoral OA were enrolled in a prospective, randomized, controlled, 2 x 2 factorial-design trial of 6 months' duration. The 4 treatment groups consisted of 1) intraarticular placebo (1.5 ml of 0.9% normal saline), 2) intraarticular corticosteroids (3.75 mg of cortivazol in 1.5 ml), 3) joint lavage and intraarticular placebo, and 4) joint lavage and intraarticular corticosteroid. Outcome measures evaluated at baseline, week 1, week 4, week 12, and week 24 included severity of pain (100-mm visual analog scale [VAS]), global status (100-mm VAS), and Lequesne's functional index. RESULTS: No interaction between steroid injection and joint lavage was demonstrated. Patients who had undergone joint lavage had significantly improved pain VAS scores at week 24 (P = 0.020). In contrast, corticosteroid injection had no long-term effect (P = 0.313); corticosteroid injection was associated with a decrease in pain only at week 1 (P = 0.003) and week 4 (P = 0.020). After week 4, Lequesne's functional index was not significantly improved regardless of the assigned treatment. CONCLUSION: Compared with placebo, both treatments significantly relieved pain but did not improve functional impairment. The effects of the 2 treatments were additive. Cortivazol provided short-term relief of pain (up to week 4). The effects of joint lavage persisted up to week 24.

Aged↗
PubMed1992

Novel inhibitors of iron-dependent lipid peroxidation for neurodegenerative disorders.

A considerable body of information supports the occurrence and pathophysiological importance of oxygen radical-mediated lipid peroxidation in acute cerebral damage secondary to traumatic or ischemic injury. Moreover, peroxidative mechanisms have been implicated in chronic neurodegenerative (e.g., Alzheimer's and Parkinson's diseases) and demyelinating (e.g., multiple sclerosis) disorders. Consequently, there has been interest in identification of pharmacological agents with potent ability to interrupt oxygen radical formation or cell membrane lipid peroxidative mechanisms. Our laboratories have developed a novel series of potent lipid peroxidation inhibitors known as the 21-aminosteroids or "lazaroids." One of these compounds, U-74006F or tirilazad mesylate, has shown efficacy in animal models of brain injury and focal cerebral ischemia. In addition, the compound has been found to attenuate the increased lipid peroxidation observed in Alzheimer's brain tissue, to retard anterograde degeneration of motor nerve fibers, and to be effective in decreasing the clinical disease severity and blood-brain barrier disruption observed in the multiple sclerosis model of experimental allergic encephalomyelitis. Another series of antioxidants, the 2-methylaminochromans typified by the compound U-78517F, have been discovered that are even more potent and effective inhibitors of lipid peroxidation than the 21-aminosteroids.

Animals↗
PubMed1994

Role of lipid mediators in the pathogenesis of skeletal muscle infarction and oedema during reperfusion after ischaemia.

During revascularization of skeletal muscle lipid mediators are released that may have a role in the pathogenesis of reperfusion injury. This study investigated the efficacy of the lipid mediator antagonists U74500A (a lipid peroxidation inhibitor), GR32191 (a thromboxane A2 receptor antagonist) and SC41930 (a leukotriene B4 (LTB4) receptor antagonist) in altering muscle viability and oedema, in a rat hindlimb model of 6-h ischaemia and 4-h reperfusion. Study groups comprised normal, ischaemic (6-h ischaemia) and control rats, and animals receiving the lipid mediator antagonists. Ischaemia itself did not result in muscle oedema or necrosis but both occurred following reperfusion (P < 0.01). Muscle viability was preserved by all lipid mediator antagonists (P < 0.01 versus controls, P not significant versus normal and ischaemia), with the LTB4 receptor antagonist ameliorating limb oedema (P < 0.01 versus controls). These results demonstrate a role for lipid mediators in reperfusion injury and suggest that their antagonists might aid the management of acute limb ischaemia.

Animals↗
PubMed1993

Evaluation of the pharmacokinetics and tolerability of tirilazad mesylate, a 21-aminosteroid free radical scavenger: I. Single-dose administration.

The single-dose tolerability and pharmacokinetics of tirilazad mesylate, a 21-aminosteroid free radical scavenger, were assessed in 47 healthy male subjects. Subjects were randomized to receive citrate vehicle (n = 12) or 0.25 mg/kg (n = 9), 0.5 mg/kg (n = 9), 1.0 mg/kg (n = 8), or 2.0 mg/kg (n = 9) tirilazad mesylate by 0.5-hour intravenous infusion. Injection site pain was observed with approximately equal frequency in both vehicle and tirilazad mesylate treatment groups. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, liver enzymes, or renal function were apparent. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Maximal plasma concentrations of tirilazad mesylate increased linearly with dose. Limited assay sensitivity at the lower two doses prevented determination of the dose proportionality of tirilazad area under the curve. The apparent elimination half-life at the higher doses was 3.7 hours. Clearance of tirilazad mesylate approached liver blood flow. Results indicate that intravenous infusions at these doses are well tolerated and devoid of glucocorticoid effects. Tirilazad mesylate appears to be efficiently cleared by the liver, and its pharmacokinetics are apparently linear over the dosage range studied.

Adrenocorticotropic Hormone↗