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PubMed1976

Antilipidemic drugs. Part 2: Experimental study of a new potent hypolipidemic drug, isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-propionate (LF178).

Pharmacological investigations have been carried out on a new p-chlorobenzoyl substituted phenoxy-isobutyric acid derivate with potent antilipidemic activity, isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]propionate (LF 178; procetofene; Lipanthyl¿). The compound depressed total lipids and total cholesterol significantly in the normal rat from 15-20 mg/kg upwards. At 100 mg/kg, the drug-induced depression of total lipids was twice the effect observed with 300 mg/kg of clofibrate. Significant depression of lipid parameters was induced in the senescent rat, in the dietary hyperlipidemic and in the triton hyperlipidemic rat. In the two last models clofibrate failed to affect lipid parameters at 300 mg/kg. The absence of pharmacological side effects indicates a high pharmacological specificity with respect to lipid metabolism. It might be concluded that LF 178 presents an antilipidemic profile different from the well known hypolipidemic drug clofibrate.

Animals↗
PubMed1999

Different expressions of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptor subunit mRNAs between visceromotor and somatomotor neurons of the rat lumbosacral spinal cord.

The glutamatergic transmission system plays a key role in afferent and efferent pathways involved in micturition. By in situ hybridization combined with retrograde Fast Blue labeling, expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor (GluR-A to -D) and N-methyl-D-aspartate (NMDA) receptor (NR1 and NR2A-D) subunit mRNAs were examined in visceromotor and somatomotor neurons of the rat lumbosacral spinal cord. Parasympathetic preganglionic neurons (PGNs) in the intermediolateral nucleus highly expressed GluR-A and GluR-B subunit mRNAs, with very low levels for GluR-C and GluR-D subunits. As for the NMDA receptor, PGNs were associated with abundant signals for NR1 subunit mRNA, but without any NR2 subunit mRNAs. On the other hand, somatomotor neurons in the ventral horn (dorsolateral nucleus) express all four AMPA receptor subunit mRNAs, showing relatively abundant expressions of GluR-C and GluR-D subunit mRNA compared with PGNs. In addition to high levels of NR1 subunit mRNA, dorsolateral nucleus neurons moderately expressed NR2A and NR2B subunit mRNAs. These results suggest that molecular organization of both AMPA and NMDA receptor channels are distinct between PGNs and dorsolateral nucleus neurons. Considering that native NMDA receptors are heteromeric channels composed of NR1 and NR2 subunits, it seems likely that dorsolateral nucleus neurons, not PGNs, are provided with functional NMDA receptors, which could induce activity-dependent changes in synaptic transmission in the efferent pathway for the lower urinary tract.

Amidines↗
PubMed1997

Growth during one year of treatment with fluticasone propionate or sodium cromoglycate in children with asthma.

The aim of this study was to compare accurately measured growth over 12 months in asthmatic children treated with either fluticasone propionate (FP) 50 micrograms twice daily (b.i.d.) or sodium cromoglycate (SCG) 20 mg four times daily (q.i.d.). After a 2-week run-in, asthmatic children aged 4-10 years from 15 UK centers were randomized in a 3:4 ratio to open-label FP (n = 52) or SCG (n = 70). After 8 weeks, those whose asthma was not adequately controlled were switched from SCG to FP or withdrawn. Standing height was measured (Holtain stadiometry) at baseline, after 8 weeks and at 6 weeks intervals thereafter for 1 year. Morning peak flows (PEFam) were recorded by patients for 2 weeks during baseline, and 1 week before each visit during treatment. Urinary free cortisol (24 h) was measured at baseline, 6 months, and 1 year. After 8 weeks, 22 patients were withdrawn from SCG group (and were switched to FP), and five patients were withdrawn from the FP group due to poor asthma control. A further 21 and 11 patients were withdrawn from the SCG and FP groups, respectively, during the course of the study. There were no significant differences between patients who received FP and SCG for 1 year (n = 34 and n = 26, respectively) in terms of height velocity adjusted for age and gender (HV), or height velocity standard deviation scores adjusted for gender (HVSDS). Mean HV (mean HVSDS) were 6.0 cm/yr (0.1) and 6.5 cm/yr (0.5) for FP and SCG, respectively. There were no treatment differences in mean 24 h urinary free cortisol levels at 6 and 12 months. Mean % predicted PEFam improved over 1 year in both groups but to a greater degree in the FP group. We concluded that growth was normal in mildly asthmatic children receiving FP (50 micrograms bid) for 1 year. There were fewer withdrawals and lung function improved to a greater extent in FP treated patients than in patients receiving SCG.

Administration, Inhalation↗
PubMed1998

Decomposition of beclomethasone propionate esters in human plasma.

The kinetics of decomposition of beclomethasone dipropionate (BDP), the 17-monopropionate ester (17-BMP), and beclomethasone (BOH) were characterized in whole human plasma (HP), pH 7.1, and in solutions of 1% human serum albumin (HSA), pH 7.4, and 0.067 M phosphate buffer, pH 7.4 (mu = 0.17). A reversed-phase, high-performance liquid chromatography (HPLC) assay enabled simultaneous separation and quantification of beclomethasone propionate esters and six degradation products including three unidentified products, D1-D3, not previously reported. Following incubation of BDP, products were formed in the following sequence, D1, 17-BMP, beclomethasone-21-monopropionate (21-BMP), D3, BOH, and D2. Following incubation of 17-BMP, the same sequence of degradation products was formed with the exception of D1. Following incubation of BOH, only D2 was formed. The decomposition reactions of BDP, 17-BMP, and BOH in HP exhibit pseudo-first-order kinetics. However the degradation reactions of BDP in solutions of 1% HSA and phosphate buffer were found to follow pseudo-zero-order kinetics. At an initial concentration of 40 micrograms mL-1, the half-lives for BDP, 17-BMP, and BOH in HP were 10.9 +/- 0.4, 3.0 +/- 0.2 and 24.8 +/- 0.2 h, respectively.

Albumins↗
PubMed1999

Resolution, absolute stereochemistry, and enantiopharmacology of the GluR1-4 and GluR5 antagonist 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid.

The phosphono amino acid, (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl+ ++]propio nic acid (ATPO), is a structural hybrid between the NMDA antagonist (RS)-2-amino-7-phosphonoheptanoic acid (AP7) and the AMPA and GluR5 agonist, (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA). ATPO has been resolved into (S)-ATPO and (R)-ATPO using chiral HPLC, and the absolute stereochemistry of the two enantiomers was established by an X-ray crystallographic analysis of (R)-ATPO. (S)-ATPO and (R)-ATPO were characterized pharmacologically using rat brain membrane binding and electrophysiologically using the cortical wedge preparation as well as homo- or heteromeric GluR1-4, GluR5-6, and KA2 receptors expressed in Xenopus oocytes. (R)-ATPO was essentially inactive as an agonist or antagonist in all test systems. (S)-ATPO was an inhibitor of the binding of [(3)H]AMPA (IC(50) = 16 +/- 1 microM) and of [(3)H]-6-cyano-7-nitroquinoxaline-2,3-dione ([(3)H]CNQX) (IC(50) = 1.8 +/- 0.2 microM), but was inactive in the [(3)H]kainic acid and the [(3)H]-(RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([(3)H]CPP) binding assays. (S)-ATPO did not show detectable agonist effects at any of the receptors under study, but antagonized AMPA-induced depolarization in the cortical wedge preparation (IC(50) = 15 +/- 1 microM). (S)-ATPO also blocked kainic acid agonist effects at GluR1 (K(i) = 2.0 microM), GluR1+2 (K(i) = 3.6 microM), GluR3 (K(i) = 3.6 microM), GluR4 (K(i) = 6.7 microM), and GluR5 (K(i) = 23 microM), but was inactive at GluR6 and GluR6+KA2. Thus, although ATPO is a structural analog of AP7 neither (S)-ATPO nor (R)-ATPO are recognized by NMDA receptor sites.

Animals↗
PubMed2000

Age-related resistance to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-induced hippocampal lesion.

This study compares the effects of acute alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) administration in the hippocampus in adult (3 months) and middle-aged (15 months) rats at 15 days postinjection. Injection of 1 and 2.7 mM AMPA produced dose-dependent neurodegeneration, assessed by Nissl staining; a glial reaction shown by glial fibrillary acidic protein immunocytochemistry; and calcification, revealed by alizarin red staining. Furthermore, at both doses, these alterations were significantly greater in 3-month-old rats. Finally, at AMPA 2.7 mM, no significant changes in the density of hippocampal parvalbumin- or calbindin-immunoreactive neurons or in choline acetyltransferase, glutamate uptake, or GABA uptake activities were found in 15-month-old animals, whereas significant reductions in parvalbumin (-76%) and calbindin (-32%) immunostaining and in GABA uptake (-27%) were observed in 3-month-old animals compared to the respective sham-operated or control animals. In conclusion, this study clearly demonstrates that in rats the vulnerability of hippocampal neurons and the glial and calcification reactions to AMPA-induced injury decreased with age between 3 and 15 months. Our results also indicate that hippocampal cholinergic, glutamatergic, and GABAergic systems show an adaptive response to excitotoxic damage in both adult and middle-aged animals.

Aging↗
PubMed2001

Inhaled fluticasone propionate for chronic asthma.

BACKGROUND: Inhaled fluticasone propionate (FP) is a relatively new inhaled corticosteroid for the treatment of asthma. OBJECTIVES: 1. To assess efficacy and safety outcomes in studies that compared FP to placebo for treatment of chronic asthma. 2. To explore the presence of a dose-response effect. SEARCH STRATEGY: We searched the Cochrane Airways Group Trial Register (1999), reference lists of articles, contacted trialists and searched abstracts of major respiratory society meetings (1997-1999). SELECTION CRITERIA: Randomised trials in children and adults comparing FP to placebo in the treatment of chronic asthma. Two reviewers independently assessed articles for inclusion and methodological quality. DATA COLLECTION AND ANALYSIS: One reviewer extracted data. Quantitative analyses where undertaken using Review Manager 4.0.3 with MetaView 3.1. MAIN RESULTS: 28 studies were selected for inclusion (5788 subjects). Methodological quality was high. In non-oral steroid treated asthmatics with mild-moderate disease FP produced improvements from baseline compared to placebo: FEV1 Weighted Mean Difference (WMD) 0.31 litres (95% confidence interval (CI) 0.27 to 0.36 litres); morning PEF WMD 29 /min (95% CI 24 to 33 L/min); symptom scores Standardised Mean Difference (SMD) 0.59 (95% CI 0.47 to 0.71); reduction in rescue beta2 agonist use WMD 1.1 puffs/d (95% CI 0.9 to 1.4). Similar effects were seen for all doses up to 1000 mcg/d. A shallow dose response effect was apparent: eg change in morning PEF with FP 1000 mcg/d WMD 49 L/min (95% CI 41 to 58 L/min). High dose FP reduced the number of patients dependent on prednisolone: FP 1000-1500 mcg/d Peto Odds Ratio 0.07 (95% CI 0.05 to 0.10). FP at all doses led to a greater likelihood of sore throat, hoarseness and oral Candidiasis. REVIEWER'S CONCLUSIONS: Doses of FP in the range 100-1000 mcg/d are effective. Although there appears to be a dose-response effect, in most patients with mild-moderate asthma improvements with low dose FP are only a little less than those with high doses. High dose FP appears to have worthwhile oral-corticosteroid reducing properties. FP use is accompanied by an increased likelihood of oropharyngeal side effects and this appears to be dose dependent.

Administration, Inhalation↗
PubMed1997

Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis.

The cause of the selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) remains unexplained. One potential pathogenetic mechanism is chronic toxicity due to disturbances of the glutamatergic neurotransmitter system, mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive glutamate receptors. Functional AMPA receptors consist of various combinations of four subunits (designated GluR1-4). The GluR2 subunit is functionally dominant and renders AMPA receptors impermeable to calcium. Most native AMPA receptors in the mammalian central nervous system (CNS) contain the GluR2 subunit and are calcium impermeable. We have investigated the composition of AMPA receptors expressed on normal human spinal motor neurons by in situ hybridization to determine their likely subunit stoichiometry. Highly significant levels of mRNA were detected for the GluR1, GluR3, and GluR4 subunits. However, GluR2 subunit mRNA was not detectable in this cell group. The absence of detectable GluR2 mRNA in normal human spinal motor neurons predicts that they express calcium-permeable AMPA receptors unlike most neuronal groups in the human CNS. Expression of atypical calcium-permeable AMPA receptors by human motor neurons provides a possible mechanism whereby disturbances of glutamate neurotransmission in ALS may selectively injure this cell group.

Aged↗
PubMed1997

A Bcl-2 antisense oligonucleotide increases alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) toxicity in cortical cultures.

Both alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated neurotoxicity and the induction of death-regulatory genes have been implicated in the pathophysiology of delayed ischemic neuronal injury. To assess the role of the antiapoptotic gene Bcl-2 in the modulation of AMPA toxicity, we exposed neuron-enriched cultures from rat cerebral cortex to AMPA, in the absence or presence of an antisense oligodeoxynucleotide (ODN) directed against Bcl-2. AMPA produced concentration-dependent toxicity detected by a decrease in fluorescence of the redox indicator Alamar blue and by an increase in lactic acid dehydrogenase release. This effect was accompanied by the induction of Bcl-2 protein expression, with maximal induction at 100 microM AMPA. A phosphorothioate antisense ODN against Bcl-2 reduced the AMPA-stimulated induction of Bcl-2 protein levels, detected by western blotting, by about 70%. In the presence of the antisense ODN, but not sense or scrambled ODNs, the toxicity of 100 microM AMPA was increased by about 60%. These findings suggest that induction of Bcl-2 expression by AMPA may have a protective role to limit AMPA receptor-mediated neuronal damage and that modifying Bcl-2 expression could have therapeutic potential in ischemia.

Animals↗
PubMedDate not supplied

Protective effects of melatonin and indole-3-propionic acid against lipid peroxidation, caused by potassium bromate in the rat kidney.

Potassium bromate (KBrO(3)) is classified as a carcinogenic agent. KBrO(3) induces tumors and pro-oxidative effects in kidneys. Melatonin is a well known antioxidant and free radical scavenger. Indole-3-propionic acid (IPA), an indole substance, also reveals antioxidative properties. Recently, some antioxidative effects of propylthiouracil (PTU)-an antithyroid drug-have been found. The aim of the study was to compare protective effects of melatonin, IPA, and PTU against lipid peroxidation in the kidneys and blood serum and, additionally, in the livers and the lungs, collected from rats, pretreated with KBrO(3). Male Wistar rats were administered KBrO(3) (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). The level of lipid peroxidation products-malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA)-was measured spectrophotometrically in thyroid homogenates. KBrO(3), when injected to rats, significantly increased lipid peroxidation in the kidney homogenates and blood serum, but not in the liver and the lung homogenates. Co-treatment with either melatonin or with IPA, but not with PTU, decreased KBrO(3)-induced oxidative damage to lipids in the rat kidneys and serum. In conclusion, melatonin and IPA, which prevent KBrO(3)-induced lipid peroxidation in rat kidneys, may be of great value as protective agents under conditions of exposure to KBrO(3).

Administration, Oral↗
PubMed1983

6-Halogen derivatives of 2-(3-benzoylphenyl)propionic acid.

The synthesis of the 6-fluoro (I a), 6-chloro (I b) and 6-bromo (I c) derivatives of the known antiinflammatory agent 2-(3-benzoylphenyl)propionic acid (ketoprofen) is reported. The procedure employed involves the direct phase-transfer methylation of the appropriate arylacetonitriles and the subsequent hydrolysis of the alpha-methyl arylacetonitriles (V) thus obtained. It is noteworthy that (V b) and (V c) were not accompanied by alpha, alpha-dimethylated contaminants, owing to the steric hindrance of the chloro and bromine substituent. The pharmacological evaluation of (I a-c) showed that the presence of the halogen unexpectedly abolished the antiinflammatory and antipyretic activities of the model drug. The 6-ethoxy derivative (I d), isolated as by-product of the synthesis of (I a) was also found inactive. A hypothesis has been formulated on the loss of activity of these compounds.

Animals↗
PubMed2002

Practical enantioresolution of alcohols with 2-methoxy-2-(1-naphthyl)propionic acid and determination of their absolute configurations by the (1)H NMR anisotropy method.

The enantioresolution of racemic alcohols as esters of 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid 1) and the determination of their absolute configurations on the basis of (1)H NMR anisotropy effect are described. The enantiopure MalphaNP acid (S)-(+)-1 was allowed to react with racemic 2-alkanols and 1-octyn-3-ol, yielding diastereomeric mixtures of esters, which were easily separated by HPLC on silica gel. To determine the absolute configurations of the first-eluted diastereomeric esters by the (1)H NMR anisotropy method, the general scheme was proposed. Separated esters were reduced with LiAlH(4) or hydrolyzed with KOH/EtOH to recover enantiopure alcohols.

Journal Article↗
PubMed2005

Investigations of molecular recognition aspects related to the enantiomer separation of 2-methoxy-2-(1-naphthyl)propionic acid using quinine carbamate as chiral selector: An NMR and FT-IR spectroscopic as well as X-ray crystallographic study.

The chiral recognition mechanism of a cinchona alkaloid-based chiral stationary phase (CSP) showing high enantiomer discrimination potential for 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid) was investigated. Conformational and structural analyses of the 1:1 complexes of 9-O-(tert-butylcarbamoyl) quinine selector (SO) and MalphaNP acid (selectand, SA) were carried out employing NMR spectroscopy in solution, Fourier-transform infrared (FT-IR) spectroscopy, and solid-state X-ray diffraction analysis. Intramolecular NOEs of a soluble analogue of the CSP afforded the conformational states of the free and complexed form of the selector. The (1)H-NMR spectra revealed that the free form of the SO constitutes anti-open as well as anti-closed and/or syn-closed conformers. Upon complexation with the (S)-MalphaNP acid enantiomer to form the more stable diastereomeric associate, a conformational transition of the selector takes place, resulting in the synthesis of the anti-open conformer nearly exclusively. FT-IR spectra reveal that, besides the primary ion-pairing interaction, stereoselective hydrogen bonding stabilizes the more stable complex via the amide hydrogen of the SO. X-ray diffraction analysis of 9-O-(tert-butylcarbamoyl)quinine and (S)-MalphaNP acid complex further revealed the occurrence of a bidentate H-bond-mediated ionic interaction between SO and SA as well as the lack of pi-pi interaction in the 1:1 complex, and corroborated the conclusions derived from spectroscopic and chromatographic studies.

Journal Article↗
PubMed1990

Optical resolution and absolute configuration of a nonsteroidal antiinflammatory drug, 2-(10,11-dihydro-10-oxodibenzo- [b,f]thiepin-2-yl)propionic acid.

The title compound (+/-)-1 (CN-100) was efficiently resolved into a pair of enantiomers by fractional crystallization of the diastereomeric salts of (-)- and (+)-phenylethylamine. The purity of the enantiomers was determined using the chiral cellulose column (CHIRALCEL OJ) which was allowed direct separation of the enantiomers. A separation factor (alpha) of 1.73 was obtained. X-Ray crystallographic analysis of the (+)-isomer [salt of (-)-1-(4-bromophenyl)ethylamine] showed that this enantiomer has S-configuration. Biological studies have shown that only the (+)-isomer has antiinflammatory activity. Racemizaiton of (-)-isomer was carried out by heating its propionic acid solution in the presence of mineral acid, such as HBr.

Animals↗
PubMed2006

Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. I. Rodent cerebral white matter and cortex.

This is the first part of a two-part study to investigate the cellular distribution and temporal regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunits in the developing white matter and cortex in rat (part I) and human (part II). Western blot and immunocytochemistry were used to evaluate the differential expression of AMPAR subunits on glial and neuronal subtypes during the first 3 postnatal weeks in the Long Evans and Sprague Dawley rat strains. In Long Evans rats during the first postnatal week, GluR2-lacking AMPARs were expressed predominantly on white matter cells, including radial glia, premyelinating oligodendrocytes, and subplate neurons, whereas, during the second postnatal week, these AMPARs were highly expressed on cortical neurons, coincident with decreased expression on white matter cells. Immunocytochemical analysis revealed that cell-specific developmental changes in AMPAR expression occurred 2-3 days earlier by chronological age in Sprague Dawley rats compared with Long Evans rats, despite overall similar temporal sequencing. In both white and gray matter, the periods of high GluR2 deficiency correspond to those of regional susceptibility to hypoxic/ischemic injury in each of the two rat strains, supporting prior studies suggesting a critical role for Ca2+-permeable AMPARs in excitotoxic cellular injury and epileptogenesis. The developmental regulation of these receptor subunits strongly suggests that Ca2+ influx through GluR2-lacking AMPARs may play an important role in neuronal and glial development and injury in the immature brain. Moreover, as demonstrated in part II, there are striking similarities between rat and human in the regional and temporal maturational regulation of neuronal and glial AMPAR expression.

Age Factors↗
PubMed2006

Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. II. Human cerebral white matter and cortex.

This report is the second of a two-part evaluation of developmental differences in alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit expression in cell populations within white matter and cortex. In part I, we reported that, in rat, developmental expression of Ca2+-permeable (GluR2-lacking) AMPARs correlated at the regional and cellular level with increased susceptibility to hypoxia/ischemia (H/I), suggesting an age-specific role of these receptors in the pathogenesis of brain injury. Part II examines the regional and cellular progression of AMPAR subunits in human white matter and cortex from midgestation through early childhood. Similarly to the case in the rodent, there is a direct correlation between selective vulnerability to H/I and expression of GluR2-lacking AMPARs in human brain. For midgestational cases aged 20-24 postconceptional weeks (PCW) and for premature infants (25-37 PCW), we found that radial glia, premyelinating oligodendrocytes, and subplate neurons transiently expressed GluR2-lacking AMPARs. Notably, prematurity represents a developmental window of selective vulnerability for white matter injury, such as periventricular leukomalacia (PVL). During term (38-42 PCW) and postterm neonatal (43-46 PCW) periods, age windows characterized by increased susceptibility to cortical injury and seizures, GluR2 expression was low in the neocortex, specifically on cortical pyramidal and nonpyramidal neurons. This study indicates that Ca2+-permeable AMPAR blockade may represent an age-specific therapeutic strategy for potential use in humans. Furthermore, these data help to validate specific rodent maturational stages as appropriate models for evaluation of H/I pathophysiology.

Adult↗
PubMed1996

Dynamic modeling of cortisol reduction after inhaled administration of fluticasone propionate.

Fluticasone propionate (FP) is a new corticosteroid that has been developed for the treatment of asthma. The compound has a very high receptor affinity, 18 times that of dexamethasone. After inhalation, FP is systemically available because of inhaled bioavailability. In healthy subjects this may lead to measurable systemic effects, such as cortisol reduction. A clinical study was conducted in 12 healthy volunteers to determine the systemic effects after inhaled administration of single 500-micrograms, 1,000-micrograms, and 2,000-micrograms doses of FP. Blood samples were collected over a 24-hour period after administration. Concentrations of FP and cortisol were measured in plasma by immunoassay. Cortisol reduction was chosen as the pharmacodynamic parameter. A novel linear release rate model was used to parameterize the cortisol data. The pharmacokinetics of FP were linear over the dose range studied. The cortisol release parameters were determined from baseline data (before drug administration). Based on these results, the E50 values for cortisol reduction were then determined for each dose of FP. The average E50 was 0.134 ng/mL for total FP concentrations and 0.013 ng/mL for unbound FP concentrations; these results were not dose dependent. These in vivo pharmacodynamic values measured in healthy subjects are in good agreement with the relatively high receptor affinity of FP.

Administration, Inhalation↗