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PubMed1996

Calculation of inversion half-lives of aryl propionic acid class nonsteroidal antiinflammatory drugs.

Although inversion of the R-enantiomers of the aryl propionic acid (APA) class of nonsteroidal antiinflammatory drugs (NSAIDs) in humans and other mammals has been known for more than 20 years, no satisfactory method has been developed for evaluating the half-life of the inversion process. This parameter is useful in assessing the pharmacodynamic contribution of the R-prodrug to the cyclooxygenase-inhibiting S-enantiomers. Further, it provides a similar means of evaluating the analgesic contributions of R-enantiomers to racemic mixtures. Using human and animal data, we have mathematically determined the inversion half-life (t1/2i) for ibuprofen, ketoprofen, and fenoprofen. The relation of the sensitivity of this value to the terminal half-life (t1/2) of the R-enantiomers of APA class drugs also is discussed.

Animals↗
PubMed1997

Pharmacokinetics and safety of the novel amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist YM90K in healthy men.

YM90K is a novel, selective and competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist with neuroprotective properties, and it is currently under development for the intravenous treatment of stroke and other conditions of acute neuronal degeneration. The safety and pharmacokinetics of YM90K in healthy men was investigated after single doses up to 36 mg and repeated doses of 24 mg given by intravenous infusion over 3 hours. YM90K was well tolerated in healthy men and induced only mild changes in kidney function markers. Unchanged plasma drug concentration reached a near steady state during 3-hour infusion and rapidly decreased in a biphasic manner after the completion of infusion. YM90K showed linear pharmacokinetics. In the repeated-dose study, no significant differences were observed in pharmacokinetics of YM90K between the first and fifth dose. Unchanged urinary drug excretion was as high as 63.2% to 78.3% of the dose, most of which was excreted within 1 hour after the completion of infusion. YM90K is thought to be excreted mainly by renal tubular secretion. YM90K showed neither significant adverse reactions nor severe abnormalities in physical and laboratory examinations of the study participants and demonstrated safety and pharmacokinetic profiles compatible with clinical use.

Adult↗
PubMed2005

Comparison of potential protective effects of melatonin, indole-3-propionic acid, and propylthiouracil against lipid peroxidation caused by potassium bromate in the thyroid gland.

Potassium bromate (KBrO3) is a prooxidant and carcinogen, inducing thyroid tumors. Melatonin and indole-3-propionic acid (IPA) are effective antioxidants. Some antioxidative effects of propylthiouracil (PTU)--a thyrostatic drug--have been found. The aim of the study was to compare protective effects of melatonin, IPA, and PTU against lipid peroxidation in the thyroids, collected from rats treated with KBrO3, and in homogenates of porcine thyroids, incubated in the presence of KBrO3. Wistar rats were administered KBrO3 (110 mg/kg b.w., i.p., on the 10th day of the experiment) and/or melatonin, or IPA (0.0645 mmol/kg b.w., i.p., twice daily, for 10 days), or PTU (0.025% solution in drinking water, for 10 days). Homogenates of porcine thyroids were incubated for 30 min in the presence of KBrO3 (5 mM) plus one of the antioxidants: melatonin (0.01, 0.1, 0.5, 1.0, 5.0, 7.5 mM), or IPA (0.01, 0.1, 0.5, 1.0, 5.0, 7.5, 10.0 mM), or PTU (0.01, 0.1, 0.5, 1.0, 5.0, 7.5, 10.0 mM). The level of lipid peroxidation products (MDA + 4-HDA) was measured spectrophotometrically in thyroid homogenates. In vivo pretreatment with either melatonin or with IPA or with PTU decreased lipid peroxidation caused by KBrO3--injections in rat thyroid gland. Under in vitro conditions, PTU (5.0, 7.5, and 10.0 mM), but neither melatonin nor IPA, reduced KBrO3-related lipid peroxidation in the homogenates of porcine thyroids. In conclusion, melatonin and IPA may be of great value as protective agents under conditions of exposure to KBrO3.

Animals↗
PubMed2002

The DNA damaging agent etoposide activates a cell survival pathway involving alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors and mitogen-activated protein kinases in hippocampal neurons.

Etoposide, an inhibitor of topoisomerase II that induces DNA damage and can trigger cell death, is used as a chemotherapeutic agent. Because chemotherapies can result in neurological complications and because DNA damage in neurons is implicated in the pathogenesis of several neurodegenerative disorders, we studied the effects of etoposide on cultured hippocampal neurons. We found that etoposide induces neuronal apoptosis and that, prior to the cell death commitment point, there is an increase in whole-cell alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-induced current but no change in N-methyl-D-aspartate (NMDA)-induced current. Associated with the increase in AMPA-induced current was an increase in the amounts of AMPA receptor subunits GluR1 and GluR4, whereas levels of the NMDA receptor subunit NR1 were unaffected by etoposide. AMPA receptor activation can result in excitotoxic cell death but can also activate signaling pathways that promote synaptic plasticity and cell survival. We found that etoposide increases the activation of p42 and p44 mitogen-activated protein (MAP) kinases, and that activation of the MAP kinases by etoposide requires AMPA receptor activation. Pharmacological blockade of AMPA receptors and p42/p44 MAP kinases, but not of NMDA receptors, exacerbated etoposide-induced cell death. These findings suggest that, although etoposide is neurotoxic, it also activates a cell survival pathway involving AMPA receptor-mediated activation of p42/p44 MAP kinases. Agents that selectively inhibit the cell life or death pathways triggered by DNA damage may prove useful in the settings of cancer and neurodegenerative disorders, respectively.

Animals↗
PubMed2006

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-mediated excitotoxic axonal damage is attenuated in the absence of myelin proteolipid protein.

In vivo and in vitro studies have shown that alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor-mediated excitotoxicity causes cytoskeletal damage to axons. AMPA/kainate receptors are present on oligodendrocytes and myelin, but currently there is no evidence to suggest that axon cylinders contain AMPA receptors. Proteolipid protein (PLP) and DM20 are integral membrane proteins expressed by CNS oligodendrocytes and located in compact myelin. Humans and mice lacking normal PLP/DM20 develop axonal swellings and degeneration, suggesting that local interactions between axons and the oligodendrocyte/myelin unit are important for the normal functioning of axons and that PLP/DM20 is involved in this process. To determine whether perturbed glial-axonal interaction affects AMPA-receptor-mediated axonal damage, AMPA (1.5 nmol) was injected into the caudate nucleus of anesthetized Plp knockout and wild-type male mice (n = 13). Twenty-four hours later, axonal damage was detected by using neurofilament 200 (NF 200) immunohistochemistry and neuronal damage detected via histology. AMPA-induced axonal damage, assessed with NF 200 immunohistochemistry, was significantly reduced in Plp knockout mice compared with wild-type mice (P = 0.015). There was no significant difference in the levels of neuronal perikaryal damage between the Plp knockout and wild-type mice. In addition, there was no significant difference in the levels of glutamate receptor subunits GluR1-4 or KA2 in Plp knockout compared with wild-type littermates. The present study suggests that PLP-mediated interactions among oligodendrocytes, myelin, and axons may be involved in AMPA-mediated axonal damage.

Animals↗
PubMed2002

Transport and local metabolism of budesonide and fluticasone propionate in a human bronchial epithelial cell line (Calu-3).

Calu-3 cells grown on microporous filters at an air interface for 16-18 days were incubated with the glucocorticosteroid (GCS) budesonide (BUD). Apparent permeability (P(app)) of BUD across Calu-3 cell monolayers was determined. Amount of BUD transported across Calu-3 cells was clearly concentration dependent, and no polarised transport was detected. When cells were loaded with BUD by incubation with drug solution (30 microM) for 2 h, 9.35 +/- 0.53% of the initial dose of BUD, corresponding to 5.5 microg BUD/mg cell protein was retained intracellularly, and released over a time period of 10 h. Apical release of BUD was significantly higher than release to the basolateral side of the monolayer. In comparison, when Calu-3 cells were loaded with fluticasone propionate (FP) solution (0.8 microM), about 20% of the initial dose of FP, corresponding to 0.3 microg FP/mg total cell protein content was detected intracellularly and released immediately (45 min). There was no difference in FP release between the apical and basolateral side of the cell layer. Mass spectrometry of cell extracts indicated the presence of fatty acid conjugates of BUD. We conclude that Calu-3 cells are able to store BUD by intracellular conjugation to fatty acids. We, therefore, suggest the use of the Calu-3 cell model as a tool for examination of local pharmacokinetics and metabolism of GCS at the bronchial epithelium.

Androstadienes↗
PubMed2004

Evaluation of in vivo bioequivalence methodology for topical clobetasol 17-propionate based on pharmacodynamic modeling using Chinese skin.

The United States Food and Drug Administration recommends pilot dose duration-response and pivotal bioequivalence studies to be conducted using reflectance colorimetry for assessment of the in vivo bioequivalence of topical dermatologic corticosteroids. The major objectives of the present studies were to examine the applicability of the standardized pharmacodynamic modeling-based methodology to super-potent clobetasol 17-propionate (CP) in the Chinese population and to evaluate the bioequivalence of two generic ointments and four generic creams containing 0.05% (w/w) CP with respect to Dermovate formulations using such methodology. In the pilot dose duration-response study, although the E(max) model (where E(max) is the maximum fitted value of AUEC, which is the area under the baseline-corrected, untreated control-site-corrected a* scale data from 0 to 24 h after drug removal) did not provide acceptable model fits, E(max) parameter estimates of -38.97 +/- 3.62 and -41.89 +/- 11.28 a*-scale. h, and ED(50) (dose duration required to achieve 50% of the fitted E(max) value) estimates of 0.40 +/- 0.37 and 0.42 +/- 0.16 h were obtained for Dermovate ointment and cream, respectively, by population analyses. The estimates for the two formulations were not statistically different, so in vivo bioequivalence studies were conducted at an ED(50)dose duration of approximately 0.5 h for both Dermovate formulations. The results demonstrated that one generic ointment was bioequivalent to Dermovate, whereas the other was not. None of the generic creams were shown to be bioequivalent to Dermovate cream. The in vivo bioequivalence data from the vasoconstriction assay were linearly correlated with stratum corneum uptake of the drug at the same dose duration until the maximal vasoconstriction response was achieved. The studies illustrated the applicability of the standardized pharmacodynamic modeling-based methodology in detecting the product differences between a variety of generic 0.05% CP formulations and reference Dermovate formulations in Chinese skin.

Administration, Topical↗
PubMed1978

Quaternary acetate and propionate esters of 3-hydroxyquinolizidine.

The preparation of the quaternary acetate and propionate esters of 3-hydroxyquinolizidine is described. Tentative structures are assigned on the basis of NMR data. Results of preliminary pharmacological screening of the methiodide and hydrochloride salts are given.

Acetylcholine↗
PubMed2005

GC separation of 2-substituted ethyl propionate enantiomers on permethylated and 2,6-dimethyl-3-pentyl beta- and gamma-cyclodextrin stationary phases.

In this work, the capillary gas chromatographic enantiomer separation of eight congeneric compounds with general formulae CH3-HCX-COOC2H5 (where X = Cl, Br, I, CN, OH, OC2H5, OC6H5 and NHCOCF3) on four different permethyl- and 2,6-di-O-methyl-3-O-pentyl- beta- and gamma-CD stationary phases has been studied. The separation of enantiomers was evaluated in terms of the interactions of the X substituent of studied derivatives, as well as the nature of the 3-O-alkyl group in the 2,6-di-O-methyl-3-O-alkyl-CDs and the CDs cavity size. The differences in thermodynamic data [deltaH and -deltaS] obtained for studied compounds and the selectivity of modified beta- and gamma-cyclodextrin phases in gas chromatographic separation were evaluated. deltaH values were compared with a deltaH value of an achiral standard (ethyl propionate, where X = H) in order to obtain the contribution of a particular substituent to the overall interaction energy. It was shown that the variation in the enantiomeric separation with temperature and the retention order of these compounds on a given cyclodextrin capillary column depends on the nature of the substituents bonded to stereogenic carbon atom. It was found that the temperature dependencies of selectivity factors, In a on 1/T, were both linear as well as non-linear, inter alia depending on the number of glucopyranose units of the CD derivatives. The enantiospecific thermodynamic data [delta21(deltaH)] and [-delta21(deltaS)] which characterize the chiral recognition in the separation system were used to gain more insight into the mechanistic aspects of the enantioseparations on permethylated and 2,6-di-O-methyl-3-O-pentyl-beta- and gamma-cyclodextrins.

Journal Article↗
PubMed1993

Testosterone propionate administration prevents the loss of neurons within the central part of the medial preoptic nucleus.

In the rat, the central part of the medial preoptic nucleus (MPNc) of the male is larger in volume and has a greater number of neurons than that of the female. The nucleus of the female, however, can be "sex reversed" by exposing the rat to gonadal steroids perinatally. The purpose of the present study was to examine the development of the MPNc to determine when the sex difference first appears and whether this difference occurs due to the relative accumulation of neurons into the compact part of the MPNc of the male and sex-reversed female rat or to the loss of MPNc neurons in the control female. Pregnant, female Sprague-Dawley rats were given an injection of [3H]methyl thymidine on embryonic day 18 (E18). Rats were exposed to testosterone propionate (TP) or vehicle from E20 to postnatal day 10 (PN10) or until the time of sacrifice. Pups from three groups [males (oil), females (oil), and sex-reversed females (TP)] were sacrificed on PN2, PN4, PN7, PN10, or PN30. The volume of the compact part of the MPNc increased in males and sex-reversed females after PN4 but the volume in the nucleus of females remained relatively constant. The number of neurons and [3H]thymidine-labeled cells remained elevated from PN2-PN30 in males or sex-reversed females but decreased dramatically in oil-treated females between PN4 and PN7, reaching a minimal number by PN10. Cell cross-sectional area increased with age while cell density decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Effect of high-dose fluticasone propionate on bone density and metabolism in children with asthma.

Significant concern remains over the long-term side effects of inhaled steroids. This cross-sectional study evaluates the effect of high-dose inhaled fluticasone propionate (FP) on biochemical markers of bone metabolism and bone density in children with asthma. Children with chronic asthma using FP >/= 1,000 mcg daily for at least 6 months, and healthy controls, were entered in the study. No children had taken oral prednisolone within the previous month. Fasting morning serum was analyzed for bone formation markers, and spot urine for bone resorption markers. Dual-energy X-ray absorptiometry (DEXA) results were reviewed in a subgroup of patients. Forty-nine children with asthma and 32 controls were recruited. The mean FP dose was 771.2 +/- 253.35 mcg/m2/day. Unpaired t-test analysis revealed no significant difference in biochemical markers studied. In subjects with asthma; 13 of 37 (35.1%) had lumbar spine density more than one standard deviation below the mean (P = 0.001). This fell to 6/37 (16.2%) with bone age correction (NS). In conclusion, no significant reduction in bone metabolism or bone age-corrected bone mineral density was observed in children with asthma on prolonged high doses of inhaled FP.

Absorptiometry, Photon↗
PubMed2004

Effects of inhaled fluticasone propionate in children less than 2 years old with recurrent wheezing.

Our objective was to evaluate the efficacy and safety of two doses of fluticasone propionate (FP) in young children with recurrent wheezing and risk factors for asthma. Our study design was a randomized, double-blind, placebo-controlled comparison of inhaled FP 50 mcg twice daily (FP 100) and 125 mcg twice daily (FP 250), for 6 months. Outcome measures included number of wheezing episodes, days on albuterol, height standard deviation score (height SDS), osteocalcin (OC), bone alkaline phosphatase fraction (AKP), insulin-like growth factor-binding protein 3 (IGFBP-3), and serum levels of cortisol (SC). Our subjects were 30 patients, aged 7-24 months. Mean wheezing episodes were 6.0 +/- 1.9, 1.9 +/- 1.9, and 2.8 +/- 1.2; mean days of albuterol use were 24.3 +/- 1.3, 6.5 +/- 0.8, and 9.1 +/- 0.8, per patient for placebo, FP100, and FP250 groups, respectively. There was a significant reduction in clinical outcome in the two FP groups compared to placebo (P < 0.01). No significant correlations were found between FP dosage and height SDS, OC, AKP, IGFBP-3, and SC. In conclusion, in young children with asthmatic symptoms, FP at 50 and 125 mcg b.i.d. for 6 months significantly improved respiratory symptoms without causing significant side effects on growth and bone metabolism.

Administration, Inhalation↗
PubMed2006

A comparative study of inhaled ciclesonide 160 microg/day and fluticasone propionate 176 microg/day in children with asthma.

Ciclesonide (CIC) is an inhaled corticosteroid (ICS) with high anti-inflammatory activity and low incidence of local and systemic adverse effects. The objective of this study was to compare the efficacy and safety of CIC with fluticasone propionate (FP) in children and adolescents with persistent asthma. This was a 12-week, randomized, double blind, parallel-group study. After a 2-to 4-week baseline period, a total of 556 children (ages 6-15 years) with asthma (forced expiratory volume in 1 sec [FEV(1)], 50% to 90% predicted) were treated twice daily with CIC 80 microg (ex-actuator, equivalent to 100 microg ex-valve) or FP 88 microg (ex-actuator, equivalent to 100 microg ex-valve) administered via a hydrofluoroalkane-propelled metered-dose inhaler. A statistically significant increase from baseline was observed in FEV(1) for both CIC (285 +/- 16 ml) and FP (285 +/- 15 ml) (P < 0.0001 for both) and in morning and evening peak expiratory flow (P < 0.0001 for both). Significant improvements were seen in asthma symptoms, use of rescue medication, and asthma symptom-free days in both treatment groups, without any differences between the treatment groups in changes from baseline. Two FP-treated patients experienced oral candidiasis and one patient experienced voice alteration. Creatinine-adjusted 24-hr urine cortisol levels increased from baseline levels by 10% in the CIC group (P < 0.05) and by 6% in the FP group (not significant). The efficacy and safety of CIC 160 microg/day were comparable to those of FP 176 microg/day in children with asthma.

Administration, Inhalation↗
PubMed1992

Induction of proliferative lesions of ventral prostate, seminal vesicle, and other accessory sex glands in rats by N-methyl-N-nitrosourea: effect of castration, pretreatment with cyproterone acetate and testosterone propionate and rat strain.

Wistar (Cpb:WU), F344 or Sprague-Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague-Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophic-hyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague-Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU-induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA + TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU-induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate.

Androgens↗
PubMed2001

Effects of substituent and temperature on enantioselectivity for lipase-catalyzed esterification of 2-(4-substituted phenoxy) propionic acids in organic solvents.

Substituent effects on the enantioselectivity for the lipase-catalyzed esterifications in organic solvents were studied by use of 2-(4-substituted phenoxy)propionic acids as the substrates with various substituents of H, F, Cl, CF(3), CH(3), CH(3)CH(2), and CH(3)O. The distinction in the behavior of their enantioselectivity was primarily responsible for the size effects of the substituents, although the substituents are far away from the stereocenter of the substrates. For the similar substituents in size, CH(3) and CF(3), however, their electronic effects played an important role in controlling the enantioselectivity. This variation of the enantioselectivity due to the electronic effects is also supported by the discussion based on the value of the Michaelis constant (K(m)) obtained. In addition, by raising the reaction temperature with enough water added to isopropyl ether as the reaction medium, the enantioselectivity is found to be dramatically enhanced for the substrate bearing CH(3)O group due to the strong electron-donating effect.

Candida↗
PubMed1993

Effects of testosterone propionate upon the sexual and aggressive behavior of adult male marmosets (Callithrix jacchus) castrated as neonates.

In New World monkeys of the family Callitrichidae (marmosets and tamarins), females frequently give birth to dizygotic twins. Twins share a placental circulation throughout fetal development and are hemopoietic chimeras. Despite this, there is no masculinization (freemartinism) in females which develop next to a male co-twin. It has been suggested that the organizing effects of testicular androgen upon sexual differentiation of the brain occur mainly during early postnatal development in male callitrichids, rather than in utero. However, this report demonstrates activation of masculine copulatory behavior by testosterone propionate (TP) administered to adult male marmosets (N = 8) which were castrated in infancy (between Days 1-7). Effects of neonatal castration upon aggressive behavior during pair tests with females (high frequencies of aggression) and intact adult males (low frequencies of aggression) were also reversed by TP treatment in adulthood. While early postnatal androgen secretion plays an important role in behavioral development in marmosets, it appears that a substantial degree of neural sexual differentiation occurs in utero in males of this callitrichid species.

Aggression↗
PubMed1999

Indole-3-pyruvic and -propionic acids, kynurenic acid, and related metabolites as luminophores and free-radical scavengers.

Chemiluminescence associated with oxidation by free radicals was investigated in an alkaline, hemin-catalysed hydrogen peroxide system, using the following tryptophan metabolites as radical scavengers: indole-3-pyruvic, indole-3-propionic, kynurenic, xanthurenic and quinaldic acids and 4-hydroxy-quinoline. Light emission from oxidation of the indolic compounds was only partially inhibited by the hydroxyl-radical scavenger DMSO, but strongly suppressed by the superoxide-anion scavenger Tiron, whereas chemi-luminescence generated from kynurenic acid was strongly inhibited by either of these compounds. Light emission from oxidation of kynurenic acid lasts for a surprisingly long period of time: At 0.4 mM and 20 degrees C, luminescence increased for 5 hours and continued at a high rate for more than a day. Comparison of structural analogues indicated that the 4-hydroxyl and carboxyl groups of kynurenic acid are essential for effective light emission, and that an additional 8-hydroxyl residue leading to an intramolecular hydrogen bond diminishes the reaction rate.

Dimethyl Sulfoxide↗