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PubMed2004

Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist.

The aim of this study was to investigate the antiandrogenic activity of a new monoester of cortexolone, cortexolone 17alpha-propionate (CAS 19608-29-8, CB-03-01). Although the compound displayed a strong local antiandrogenic activity in hamster's flank organ test, it did not exhibit antiandrogenic activity in rats after subcutaneous injection, nor did it affect gonadotropins hypersecretion when injected to parabiotic rats. As topical antiandrogen, the steroid resulted about 4 times more active than progesterone (CAS 57-83-0) and, when compared to known antiandrogen standards, it was about 3 times more potent than flutamide (CAS 13311-84-7), about 2 times more effective than finasteride (CAS 98319-26-7) and approximately as active as cyproterone acetate (CAS 427-51-0). Its pharmacological activity seemed to be primarily related to its ability to antagonistically compete at androgen receptor level; nevertheless its primary pharmacological target needs to be further investigated. Its topical activity, along with the apparent absence of systemic effects, anticipates this compound to have the potential of representing a novel and safe therapeutic approach for androgen-dependent skin disorders.

Administration, Topical↗
PubMed1984

Cerebellar hemorrhage complicating methylmalonic and propionic acidemia.

Methylmalonic (MMA) and propionic (PPA) acidemias are inherited disorders characterized by a wide spectrum of clinical and biochemical findings. We report the neuropathologic findings in two young infants with MMA and PPA in which death probably resulted from cerebellar hemorrhage. When combined with a previous report of isovaleric acidemia complicated by diffuse subarachnoid and parenchymal cerebellar hemorrhage, it is apparent that cerebellar hemorrhage must be considered in any infant with a fulminating organic acidemia. Rapid neurologic deterioration despite an improvement in acidosis and hyperammonemia is an indication for computed tomography of brain. Surgical evacuation of the blood may improve the chance for survival in this catastrophic illness.

Acidosis↗
PubMed1999

Spectrum of CFTR mutations in the Middle North of Spain and identification of a novel mutation (1341G-->A). Mutation in brief no. 252. Online.

We have analyzed 39 unrelated cystic fibrosis (CF) families by denaturing gradient gel electrophoresis (DGGE) and direct sequencing in order to determine the spectrum of CF mutations in our population. This approach has allowed us to detect 72 out of the 78 CF chromosomes (92.3%). The DF508 mutation was found to be present in 51/78 (65.4%) CF chromosomes, in accordance with the predicted Northwest-Southeast gradient within the European population. Another 14 known mutations, and the novel 1341G-->A mutation were identified. Nine out of fifteen non DF508 mutations were present in a single chromosome. The 1341G-->A mutation, found in 2 unrelated patients, is a new mutation associated to severe phenotype, causing pancreatic insufficiency and chronic lung infections. Our data suggest a different distribution of non-DF508 mutations in our population when compared with previous studies carried out in Spanish CF families. Six out of the 14 non-F508 in our study were not present in a recent study carried out in 640 Spanish families with CE These six mutations account for 29.6% non DF508 chromosomes in our sample.

Cystic Fibrosis↗
PubMed1996

In vivo studies of acetylcholinesterase activity using a labeled substrate, N-[11C]methylpiperdin-4-yl propionate ([11C]PMP).

Two esters, N-[11C]methylpiperidyl acetate ([11C]AMP) and N-[11C]methylpiperidyl propionate ([11C]PMP), were synthesized in no-carrier-added forms and evaluated as in vivo substrates for brain acetylcholinesterase (AChE). After peripheral injection in mice, each ester showed rapid penetration into the brain and a regional retention of radioactivity (striatum > cortex, hippocampus > cerebellum) reflecting known levels of AChE activity in the brain. Regional brain distributions after [11C]PMP administration showed better discrimination between regions of high, intermediate, and low AChE activities. Chromatographic analysis of blood and brain tissue extracts showed rapid and nearly complete hydrolysis of [11C]PMP within 10 min after injection. For both [11C]AMP and [11C]PMP, retention of radioactivity in all regions was reduced by pretreatment with diisopropylfluorophosphate (DFP), a specific irreversible AChE inhibitor. DFP treatment also significantly increased the proportions of unhydrolyzed ester in both blood and brain. Radioactivity localization in brain after peripheral injection was thus dependent on AChE-catalyzed hydrolysis to the hydrophilic product N-[11C]methylpiperidinol. PET imaging of [11C]AMP or [11C]PMP distributions in monkey brain showed clear accumulation of radioactivity in areas of highest AChE activity (striatum, cortex). These esters are thus in vivo substrates for brain AChE, with potential applications as in vivo imaging agents of enzyme action in the human brain. [11C]PMP, the ester with a slower rate of hydrolysis, appears to be the better candidate radiotracer for further development.

Acetates↗
PubMed2002

Catalytic enantioselective addition of propionate units to imines: an efficient synthesis of anti-alpha-methyl-beta-amino acid derivatives.

Optically active anti-alpha-methyl-beta-amino acid derivatives have been prepared based on catalytic enantioselective addition of propionate units to simple and inert imines using a chiral zirconium complex. High reactivity and selectivity with wide substrate scope were attained by using a new chiral ligand, (R)-6,6'-bis(pentafluoroethyl)-1,1'-bi-2-naphthol ((R)-6,6'-C(2)F(5)BINOL). The reactions using geometrically isomeric ketene silyl acetals gave excellent anti-selectivity with high enantiomeric excess in both cases. Synthetic utility of this reaction has been demonstrated by the preparation of various anti-alpha-methyl-beta-amino acid and trans-3,4-disubstituted beta-lactam derivatives.

Amino Acids↗
PubMed2000

Comparison of the inhibition of the cytosolic phospholipase A2-mediated arachidonic acid release by several indole-2-carboxylic acids and 3-(pyrrol-2-yl)propionic acids in bovine and in human platelets.

The inhibition of the cytosolic phospholipase A2 (cPLA2)-mediated arachidonic acid release by several indole-2-carboxylic acids and 3-(pyrrol-2-yl)propionic acids was measured in intact human platelets using calcium ionophore A23187 as stimulant. The comparison of the obtained data with the inhibition data evaluated with bovine platelets showed that analogous results were obtained with both cell types.

Animals↗
PubMed1993

Nonsteroidal antiinflammatory agents, XVII: Inhibition of bovine cyclooxygenase and 5-lipoxygenase by N-alkyldiphenyl-pyrrolyl acetic and propionic acid derivatives.

A series of 19 N-alkyl-diarylpyrrolyl-acetic and-propionic acid derivatives was synthesized and tested. Using bovine blood as enzyme source the inhibition of cyclooxygenase and 5-lipoxygenase, respectively, was applied to determine the antiinflammatory activity. In general all compounds tested inhibit 5-lipoxygenase more effectively than cyclooxygenase. A structure-activity relationship is discussed.

Acetates↗
PubMed2005

2, 3-Bis(5-alkyl-2-thiono-1, 3, 5-thiadiazin-3-yl) propionic acid: one-pot domino synthesis and antimicrobial activity.

In a search for promising antibacterial and antifungal compounds, two new series of 2, 3-bis(5-alkyl-2-thiono-1, 3, 5-thiadiazin-3-yl)propionic acid 1 and their corresponding N, N-dimethylpropionamide 6 have been synthesized. The reaction of 2, 3-diaminopropionate 3, carbon disulfide, formaldehyde, and the appropriate alkyl amines furnished the title compound 1. N, N-dimethylpropionamides 6 were obtained by the reaction of 1 with dimethyl amine in the presence of POCl(3). The newly prepared compounds were screened in vitro against certain strains of Gram-positive and Gram-negative bacteria and compared with nalidixic acid and ciprofloxacin. Moreover, the title compounds were tested for their antifungal activity in vitro against Candida albicans, phytopathogenic, Penicillum expansum and Trichoderma hazianum, and aflatoxin-producing Aspergillus flavus. These compounds exhibit varied activity against the tested pathogenic bacteria and remarkable inhibitory effects on growth or sporulation of some of the tested fungal species.

Anti-Bacterial Agents↗
PubMed1982

The identification of (E)-2-methylglutaconic acid, a new isoleucine metabolite, in the urine of patients with beta-ketothiolase deficiency, propionic acidaemia and methylmalonic acidaemia.

The identification of (E)-2-methylglutaconic acid, a 'new' metabolite of isoleucine, is described. The substance was detected in urine samples from patients with propionic acidaemia, methylmalonic acidaemia and so-called beta-ketothiolase deficiency; in the majority of cases together with N-tiglylglycine. (E)-2-Methylglutaconic acid is thought to be the end product of the 3-methylcrotonyl-CoA carboxylase-catalysed carboxylation of tiglyl-CoA. Prerequisites for the quantitative gas chromatographic analysis of the unstable 2- (and 3-) methyl-glutaconic acid ditrimethylsilyl ester are given.

Acetyl-CoA C-Acyltransferase↗
PubMed1995

Determination of the enantiomers of citalopram, its demethylated and propionic acid metabolites in human plasma by chiral HPLC.

A stereoselective HPLC assay has been developed to analyze the enantiomers of citalopram and of its three main metabolites in plasma after their separation on a Chiracel OD column. Using a fluorescence detector, the limit of quantification in plasma samples was 15, 4, 5 and 2 ng/ml for the enantiomers of citalopram (CIT), desmethylcitalopram (DCIT), didesmethylcitalopram (DDCIT), and for the citalopram propionic acid derivative (CIT-PROP), respectively. Except for CIT, all metabolites were derivatized with achiral reagents. Identification of the enantiomers was realized with an optical rotation detector which showed that the enantiomers invert their rotation depending on the polarity and nature of the solvent. Under varying conditions, a racemization study has shown that the pure enantiomers of CIT and its demethylated metabolites are configurationally stable. Preliminary results obtained with five patients treated with CIT show a mean S/R ratio of 0.7 for both CIT and its active metabolite DCIT and of 3.6 for CIT-PROP in plasma. This suggests that the pharmacologically relevant (+)-(S)-isomers of CIT and DCIT could be preferentially and stereoselectively metabolized to CIT-PROP.

Antidepressive Agents↗
PubMed1992

The propionic acids: a personal perspective.

In searching during the early 1950s for new drugs for the treatment of rheumatoid arthritis, little information was available to allow a rational approach. The mode of action of the few drugs available was unknown and even the analgesic action of aspirin could not be demonstrated in animals. A speculative concept was developed that aspirin possessed a specific unidentified action in rheumatoid arthritis and that this and its analgesic properties were related to its ability to delay the development of ultraviolet (UV) erythema in the guinea pig. A series of substituted phenoxypropionic acids proved to be active as antierythemic agents, but the most potent was inactive clinically in rheumatoid arthritis. Refinements to the testing systems led to a series of substituted phenylacetic acids, three of which although active in rheumatoid arthritis produced unacceptable adverse reactions (ADRs). Attempts to relate laboratory data to clinical ADRs suggested that the substituted phenylpropionic acids (originally rejected because of concerns about toxicity) might be better tolerated than we had anticipated. Ibuprofen was selected from this large group. It was proven to be effective and well tolerated and became "the first of the propionics" when it was launched in 1969. In the 1970s, ibuprofen proved to be effective as a prescription drug in a range of painful nonrheumatic conditions and on the basis of its good safety record was approved as an OTC analgesic in 1983 in the United Kingdom and in 1984 in the USA. It has proven to be popular and effective and much safer than aspirin or acetaminophen in overdosage.

Analgesia↗
PubMed1994

Drug chirality: on the mechanism of R-aryl propionic acid class NSAIDs. Epimerization in humans and the clinical implications for the use of racemates.

This review summarizes and comments on the current understanding of both the biochemical and clinical implications of the epimerization of R-aryl propionic (APA) class (1) nonsteroidal anti-inflammatory agents (NSAIDs) to S-enantiomers in humans. This article focuses principally on rac-ibuprofen and its enantiomers. In the United States, five commercialized NSAIDs are APAs. Only two of them, rac-ibuprofen and rac-fenoprofen, are subject to significant epimerization in humans. The remaining three, rac-flurbiprofen, rac-ketoprofen, and S-naproxen, are not of interest in this context.

Animals↗
PubMedDate not supplied

Comparison of tamoxifen and testosterone propionate in male rats: differential prevention of orchidectomy effects on sex organs, bone mass, growth, and the growth hormone-IGF-I axis.

Testis dysfunction can weaken bone and reduce muscle mass as well as impair sexual function. Testosterone (T) therapy has useful effects on sex organs, bone, and muscle in T-deficient males, but prostate concerns can preclude T use in some men. Although estrogens or other drugs can protect bone in men, gynecomastia makes estrogens unappealing, and other drugs may also be undesirable in some cases. Selective estrogen receptor modulators (SERMs) inhibit estrogen-evoked sex organ growth but mimic estrogen effects on bone and cholesterol and are advantageous for some women. SERMs may also be useful in men who must avoid androgens. As a preclinical test of this idea, tamoxifen (a SERM) and testosterone propionate (TP, a classic androgen) were compared for their efficacy in preventing varied effects of orchidectomy (ORX) in adult male rats. ORX led to ventral prostate and seminal vesicle atrophy and decreases in somatic growth, proximal tibia bone mineral density (BMD), and serum growth hormone (GH) and insulin-like growth factor I (IGF-I). ORX also increased anterior pituitary glandular kallikrein, serum cholesterol, and body temperature. Pituitary prolactin (PRL) content was unaltered. ORX effects on sex organs, somatic growth, IGF-I, cholesterol, body temperature, and pituitary kallikrein were prevented by TP at 1 mg/kg (3 doses per week), but BMD and GH were unresponsive. ORX effects on BMD and GH were prevented by TP at 10 mg/kg, but this dose evoked supraphysiologic increases in sex organs and PRL, failed to restore somatic growth, and further reduced IGF-I. Tamoxifen (1 mg/kg daily) prevented ORX effects on BMD, GH, and cholesterol without altering basal or TP-induced sex organ growth and further reduced IGF-I and somatic growth. Tamoxifen did not alter basal PRL but blocked increases caused by TP at 10 mg/kg. In summary, tamoxifen prevented ORX effects on bone and cholesterol in male rats without affecting sex organs or PRL and might be useful for men who must avoid androgens. Unexpectedly, a TP dose that replicated testis effects on sex organs and other targets had no effect on BMD or GH, and a larger TP dose that restored BMD and GH was worse at replicating normal male physiology. In addition, correlation/regression results suggested that the GH-IGF-I axis contributes to changes in BMD.

Animals↗
PubMedDate not supplied

Changes in serum alpha2u-globulin levels in castrated male rats treated with testosterone propionate in a Hershberger assay.

The Hershberger assay has been proposed as a candidate screening test method for the detection of androgenic and anti-androgenic chemicals and is being validated presently under the test guideline programme of the Organization for Economic Cooperation and Development (OECD). Rat alpha2u-globulin is male rat-specific protein appearing in their serum and urine, and the protein is known to be induced by androgens. We investigated the usefulness of measuring serum alpha2u-globulin levels as a parameter for the androgenic activity of chemicals tested in the Hershberger assay. The serum alpha2u-globulin level was measured after the administration of testosterone propionate at dosages of 0, 20, 100 or 500 microg kg(-1) day(-1) for ten consecutive days in the castrated male rats. The ventral prostate, balbocavernosus/levator ani muscles, glans penis and Cowper's gland were collected and weighed. Although all the androgen-responsive organ weights were increased significantly at dosages of 100 and 500 microg kg(-1) day(-1), the serum alpha2u-globulin level was increased significantly only at a dosage of 500 microg kg(-1) day(-1). These results show that the serum alpha2u-globulin level may be a useful biomarker for detecting androgenic activity caused by test chemicals, but it is less sensitive than the organ weights of androgen-responsive tissues in the Hershberger assay.

Alpha-Globulins↗
PubMed2001

3-Ureidopropionate contributes to the neuropathology of 3-ureidopropionase deficiency and severe propionic aciduria: a hypothesis.

3-Ureidopropionate (3-UPA) is a physiologic metabolite in pyrimidine degradation. Pathological accumulation of 3-UPA in body fluids is found in 3-ureidopropionase deficiency and severe forms of propionic aciduria. Both diseases clinically present with a severe neuropathology involving gray and white matter as well as with a dystonic dyskinetic movement disorder. To date nothing is known about the toxic nature of this metabolite. The aim of the present study was to elucidate whether 3-UPA may act as endogenous neurotoxin. Exposure of cultured chick neurons to 3-UPA induced a concentration- and time-dependent neurodegeneration. Neuronal damage was reduced by the antioxidant alpha-tocopherol and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. In contrast, the non-NMDA receptor antagonist CNQX, the metabotropic glutamate receptor antagonist L-AP3, and succinate showed no protective effect. Furthermore, 3-UPA elicited an increased production of reactive oxygen species followed by a delayed increase in intracellular calcium concentrations. Activity measurement of single respiratory chain complexes I-V revealed an inhibition of complex V activity, but not of the electron-transferring complexes I-IV by 3-UPA. In contrast, 3-UPA did not affect the mitochondrial beta-oxidation of fatty acids. In conclusion, our results provide strong evidence that 3-UPA acts as endogenous neurotoxin via inhibition of mitochondrial energy metabolism, resulting in the initiation of secondary, energy-dependent excitotoxic mechanisms.

Animals↗
PubMed1981

Tissue distribution studies of [18F]haloperidol, [18F]-beta-(4-fluorobenzoyl)propionic acid, and [82Br]bromperidol by external scintigraphy.

Tissue distribution studies of [18F]haloperidol and [82Br]bromperidol, two potent neuroleptic drugs, were performed in rats by serial sacrifice. The usefulness of external scintigraphy in obtaining tissue distribution data in large animals is demonstrated by the tissue distribution of [18F]haloperidol in rhesus monkeys. Both serial sacrifice and external scintigraphic studies demonstrated that uptake of the two drugs after intravenous administration into their target organ, the brain, was very fast and that the ratio of brain to blood levels was high throughout the 2-hr observation. Bromperidol appeared to reach peak brain levels faster than its chloro analog, haloperidol. Both bromperidol and haloperidol concentrated overwhelmingly in the rat lung. Haloperidol also showed a high affinity for the monkey lung. The disposition pattern in rats of [18F]-beta-(4-fluorobenzoyl)propionic acid, an apparent intermediate in butyrophenone metabolism, was entirely different from that of the parent drugs. This metabolite did not concentrate in the rat brain.

Animals↗