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At least 685 records · Page 38Linked to original sources
PubMed1993

Mechanisms of action in the liver of crilvastatin, a new hydroxymethylglutaryl-coenzyme A reductase inhibitor.

Crilvastatin is a drug from the pyrrolidone family that had been shown to induce non-competitive inhibition of rat hydroxymethylglutaryl-coenzyme A reductase activity in vitro. The aim of this study was to evaluate the activity of crilvastatin on the hepatic metabolism of cholesterol in rats. Crilvastatin increased low density lipoprotein (LDL)-cholesterol uptake by the liver more than high density lipoprotein (HDL) uptake, thus increasing by up 30% the clearance of excess plasma cholesterol. In normolipidemic rats, crilvastatin significantly enhanced acyl coenzyme A:cholesterol acyl transferase and cholesterol 7 alpha-hydroxylase activity. In rats with a previous high cholesterolemia, crilvastatin also enhanced cholesterol 7 alpha-hydroxylase activity and did not increase liver acyl coenzyme A:cholesterol acyl transferase activity. These findings suggest that a drug such as crilvastatin could have a hypocholesterolemic effect by a mechanism other than the sole inhibition of cholesterol synthesis, possibly by stimulating cholesterol and bile salt secretion via the biliary tract in previously hypercholesterolemic rats.

Animals↗
PubMed1993

DM-9384, a new cognition-enhancing agent, increases the turnover of components of the GABAergic system in the rat cerebral cortex.

DM-9384 (nefiracetam) (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide), a pyrrolidone derivative (or a cyclic derivative of gamma-aminobutyric acid (GABA)), is a newly developed nootropic (or cognition-enhancing) agent. In the present study, we examined the biochemical effect of DM-9384 on GABAergic neurons in adult rat brains. DM-9384, when administered orally at a daily dose of 10 mg/kg for 7 days, significantly increased GABA turnover and glutamic acid decarboxylase activity in the cortex and hippocampus, and stimulated Na(+)-dependent high-affinity GABA uptake in cortical synaptosomes. In in vitro experiments, the K(+)-evoked release of [14C]GABA from cortical slices was markedly increased by low concentrations (10(-8), 10(-9) M) of DM-9384. The binding of GABAA and benzodiazepine to their receptors in the brain was not affected by DM-9384 (10(-10)-10(-3) M). The results suggest that DM-9384 increases the turnover of components of the GABAergic system by influencing presynaptic sites rather than postsynaptic sites.

Administration, Oral↗
PubMed1994

Effects of nefiracetam on drug-induced impairment of latent learning in mice in a water finding task.

We investigated the effects of nefiracetam (DM-9384), a pyrrolidone derivative, on chlordiazepoxide-, apomorphine-, and methamphetamine-induced impairment of latent learning in a water finding test in mice. Pretreatment with nefiracetam reversed the inhibitory effects of chlordiazepoxide and apomorphine, but not those of methamphetamine, on latent learning. The ameliorative effects of nefiracetam on apomorphine-induced, but not chlordiazepoxide-induced impairment of latent learning were antagonized by scopolamine. These results provide further evidence that nefiracetam has anti-amnesic effects. Further, it is suggested that the cholinergic neuronal system may be involved in the ameliorative effects exerted by nefiracetam on apomorphine-induced impairment of latent learning.

Animals↗
PubMed1994

Dynorphin potentiation of [3H]CGP-39653 binding to rat brain membranes.

Dynorphin A-(1-13) and related peptide fragments were tested for their ability to modulate the binding of the competitive NMDA receptor antagonist, [3H]2-amino-4-propyl-5-phosphono-3-pentanoic acid ([3H]CGP-39653), to rat brain membranes. Dynorphin A-(1-13) produced a dose-dependent (1 nM to 10 microM) potentiation of [3H]CGP-39653 binding. The potentiation was insensitive to the kappa-opioid receptor antagonist norbinaltorphimine and it was also observed with the non-opioid peptides dynorphin A-(2-13) and dynorphin A-(6-10). Among various compounds which interact with distinct sites on the NMDA receptor complex, glycine (Gly; 1 microM) and the Gly receptor antagonist, (+/-)-3-amino-1-hydroxy-2-pyrrolidone ((+/-)-HA-966; 10 microM), blocked the dynorphin A-(1-13) induced potentiation of [3H]CGP-39653 binding. In equilibrium binding experiments, dynorphin A-(1-13) (10 microM) caused a significant increase in the binding capacity (Bmax) of [3H]CGP-39653 (from 111 to 306 fmol/mg protein) but not change in the apparent dissociation constant (Kd of 8.5 nM as compared with 8.7 nM in the absence of the peptide). The results indicate that dynorphin A and related peptides modify the expression of [3H]CGP-39653 binding sites consecutive to a non-opioid interaction with the NMDA receptor complex.

2-Amino-5-phosphonovalerate↗
PubMed1995

Crilvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, inhibits cholesterol absorption in genetically hypercholesterolemic rats.

Crilvastatin is a new drug from the pyrrolidone family, which acts as a non-competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The long-term effects of oral crilvastatin treatment (200 mg per day per kg body weight for 4 and 10 weeks) were investigated on in vivo cholesterogenesis in male adult normocholesterolemic (SW) and genetically hypercholesterolemic (RICO) rats. In both strains of rats, the treatment had no effect on the plasma cholesterol level, but efficiently inhibited cholesterol synthesis in liver and intestine, as shown by the decreased incorporation of exogenous [14C]acetate into hepatic (3.5-fold in SW, 1.7-fold in RICO rats) and intestinal (2.5-fold in SW, 3.3-fold in RICO rats) sterols. In RICO rats in which the dietary cholesterol absorption coefficient was two-fold lower in treated (38%) than in untreated (78%) rats, this drug reduced intestinal cholesterol absorption. As a result, the total plasma cholesterol input (absorption + synthesis), measured by isotope analysis in RICO rats, was markedly lower in treated (11.3 mg per day) than in untreated animals (28.8 mg per day).

Absorption↗
PubMed1996

NMDA receptor antagonists block development of tolerance to m-CPP-induced increases in ACTH concentrations in rats.

We have recently demonstrated that a single administration of m-chlorophenylpiperazine (m-CPP, a preferential 5-HT2C receptor agonist) produces tolerance to its stimulatory effect on adrenocorticotropic hormone (ACTH) concentrations when challenged 24 h later with the same dose of m-CPP. In the present study, we studied the effects of pretreatment with various N-methyl-D-aspartate (NMDA) receptor antagonists on development of tolerance to m-CPP's stimulatory effect on ACTH concentrations. Pretreatment with various NMDA receptor antagonists such as 5.7-dichlorokynurenic acid (1.0 mg/kg), 3-amino-1-hydroxy 2-pyrrolidone (1.0 mg/kg), dizocilpine (0.1 mg/kg) and ifenprodil (1.0 mg/kg) injected 30 min before the first injection of m-CPP (2.5 mg/kg) blocked development of tolerance to m-CPP's stimulatory effect on ACTH concentrations in rats injected 24 h later with the same dose (2.5 mg/kg) of m-CPP. These findings suggest that tolerance to postsynaptic 5-HT2C receptor-mediated response is initiated though stimulation of NMDA receptor complex and, furthermore, demonstrate a functional interaction between the 5-HT and glutamate systems.

Adrenocorticotropic Hormone↗
PubMed1986

The single proline-glutamine substitution at position 5 enhances the potency of amyloid fibril formation of murine apo A-II.

The primary structure of murine apolipoprotein A-II (apo A-II) has been determined. Apo A-II consists of a single polypeptide chain of 78 amino acid residues, of which the amino-terminus is pyrrolidone carboxylic acid. Except for residues 5 and 38, the amino acid sequence is identical to that of murine senile amyloid protein (ASSAM), which has a common antigenicity with apo A-II. Substitution of glutamine (ASSAM) for proline (apo A-II) at position 5 is distinct and may possibly be related to murine senile amyloid-ogenesis.

Amino Acid Sequence↗
PubMed1986

High homology is present in the primary structures between murine senile amyloid protein (ASSAM) and human apolipoprotein A-II.

The primary structure of a murine senile amyloid protein (ASSAM) was determined. The protein consists of a single polypeptide chain of 78 amino acid residues. The amino-terminus is blocked with pyrrolidone-carboxylic acid. The sequence differs from that of the known murine amyloid A protein and is highly homologous to human apolipoprotein (apo) A-II. The result indicates that the putative precursor of the senile amyloid protein is apo A-II in mice.

Amino Acid Sequence↗
PubMed1989

Primary structure of a new cysteine proteinase inhibitor from pig leucocytes.

The primary structure of a pig leucocyte cysteine proteinase inhibitor, also called cathelin, was determined. The sequence was obtained from analyses of peptides isolated from the chymotryptic, endoproteinase Lys-C and protease V8 digests, and by analysis of the peptides derived from the hydrolysis of the aspartyl-prolyl bond of the carboxymethylated inhibitor. The inhibitor consists of 96 residues. The N-terminal residue of the inhibitor is pyrrolidone-carboxylic acid. The amino acid sequence of cathelin suggests the appearance of a new family of cysteine proteinase inhibitors.

Amino Acid Sequence↗
PubMed1989

Intestinal lymphangiectasia markedly improved with antiplasmin therapy.

A 35-yr-old woman with intestinal lymphangiectasia was treated with trans-4-aminomethyl cyclohexane carboxylic acid. After 6 wk of antiplasmin therapy, her serum total protein increased to normal levels and 131I-polyvinyl pyrrolidone excretion was also normalized. With a daily administration of trans-4-aminomethyl cyclohexane carboxylic acid, the patient has manifested no symptoms for 8 yr up to the present. Throughout the clinical course, the values for euglobulin lysis time showed a close relationship to changes in serum total protein. It was then suggested that increased plasma fibrinolysis may enhance lymphatic permeability to plasma proteins. During this treatment, a decreased percentage of T lymphocytes became normalized together with serum immunoglobulin values. In addition, the therapy has resulted in the disappearance of duodenal lesions observed endoscopically.

Adult↗
PubMed1988

Self-generating density gradients of Percoll provide a simple and rapid method that consistently enriches natural killer cells.

The separation or enrichment of natural killer (NK) cells from the heterogeneous cell populations in murine spleen or bone marrow is a vital step for the study of NK cells. We report in this study a simple and rapid method for the enrichment of NK cells from B cell-depleted spleen cells, using a self-generating density gradient of polyvinyl pyrrolidone-coated silica (Percoll). Nylon wool-passed spleen cells are suspended in Percoll that is isotonic and isosmotic with mouse blood at a density of 1.087 g/ml and ultracentrifuged at 30,000 x g for 10 min. This method consistently enriches for NK cell cytotoxic activity, in spleen cells of both unstimulated and interferon-stimulated mice, as measured in the chromium release assay. There is a concomitant enrichment for cells bearing the NK marker asialo GM-1 and depletion of L3T4 or Lyt-2-bearing T cells. In contrast to discontinuous, step-wise gradients, the self-generating Percoll gradient, which relies on the intrinsic property of Percoll to form a continuous density gradient, appears to provide the cells with a physiological environment both before and during the centrifugation step.

Animals↗
PubMed1990

A method for preparing biologically active aqueous cyclosporin A solutions avoiding the use of detergents or organic solvents.

The immunosuppressive agent cyclosporin A (CsA) is highly hydrophobic and is, therefore, being taken for in vitro use directly from ethanolic stock solutions. In the present study it is demonstrated that ethanol itself affects several immunological activities in vitro, thus interfering with the immunosuppressive effects of CsA. As an alternative, it is demonstrated that CsA can be solubilized and retain its activity in aqueous solutions of polyvinyl pyrrolidone (PVP). Unlike ethanol, PVP has no effect on the various immunological activities in vitro and therefore the immunosuppressive effects of CsA can be evaluated without interference.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

Quantitation of pinocytosis in human monocytes during in vitro maturation into macrophages.

Methods are reported for the quantitative measurement of pinocytosis in human monocytes isolated from peripheral blood. The cells, in adherent culture in plastic wells, were exposed for periods of up to 48 h to culture medium containing 125I-labelled polyvinylpyrrolidone (50 micrograms/ml) and the pinocytosis enhancer suramin (500 micrograms/ml). Uptake of radiolabel was linear with time and was inhibited by colchicine (100 micrograms/ml), results that are consistent with uptake of radiolabelled substrate by pinocytosis but not with superficial adsorption of radiolabel. Similar results were obtained using a 125I-labelled vinylamine-vinyl-pyrrolidone copolymer as radiolabelled substrate. The rates of pinocytotic uptake of 125I-labelled polyvinylpyrrolidone (in the presence of suramin) and of 125I-labelled copolymer were measured at various stages of in vitro monocyte-to-macrophage maturation. In contrast to an earlier report, we found no consistent differences in pinocytotic activity between cells at different stages of differentiation.

Cell Differentiation↗
PubMed1991

Radioimmunoassay for activin A/EDF. Method and measurement of immunoreactive activin A/EDF levels in various biological materials.

A radioimmunoassay (RIA) for the measurement of activin A, which is identical to erythroid differentiation factor (EDF), has been developed. A specific antiserum against activin A/EDF was raised in rabbits using a mixture of recombinant EDF and polyvinyl pyrrolidone. Of the compounds tested this polyclonal antibody cross-reacted only with bovine inhibin (3.2%) and human TGF-beta (4.2%). The least detectable value in this assay was 0.06 ng/tube. The within- and between-assay coefficients of variation at three different concentrations were 3.6-9.8% and 3.4-7.7%, respectively. Using this RIA, immunoreactive activin A/EDF levels in various biological fluids and tissues were examined. The dose-response curves of porcine follicular fluid and ovarian extract were parallel to the standard curve, and porcine follicular fluid contained high activin A/EDF immunoreactivity (1050 ng/ml). On gel chromatography of porcine follicular fluid, the major immunoreactivity was eluted in the same position as authentic activin A/EDF. Human placental extract and amniotic fluid had relatively high immunoreactive activin A/EDF levels (174 ng/g wet wt. and 63.9 ng/ml, respectively), but the dose-response curve of amniotic fluid was not parallel to the standard curve. Among rat tissues, the ovary showed the highest activin A/EDF immunoreactivity (163 ng/g wet wt.) much lower than that of porcine ovary (1020 ng/g wet wt.). Low immunoreactive activin A/EDF levels were detected in most parts of rat brain (8.7-14.2 ng/g wet wt.), except for the pituitary gland (70.0 ng/g wet wt.). The initial plasma half clearance time (t1/2) of exogenous activin A/EDF was 14 min in the rat and the plasma FSH concentration did not change significantly during this period. These results suggest that this RIA system has sufficient sensitivity and specificity to measure activin A/EDF concentrations in biological materials, and that the reproductive tissues are the main sources of activin A/EDF.

Activins↗
PubMed1994

Surgical treatment of pulmonary hydatidosis in children: experience in 92 patients.

Ninety-two patients with a total of 112 pulmonary hydatid cysts underwent surgical treatment in our clinic between January 1980 and January 1992. Nine patients were found to have concomitant liver and pulmonary hydatid cysts. There were 65 boys and 27 girls; the age range was 5 to 14 years. The authors performed cystotomy and capitonnage in 78 patients, lobectomy in 9, segmentectomy in 3, and wedge resection in 2. Of 9 cases with concomitant liver and pulmonary hydatid cysts, 8 were approached by right thoracophrenotomy and 1 by median sternotomy and right phrenotomy. A one-stage operation via median sternotomy was performed in 3 patients who had bilateral pulmonary hydatid cysts. To prevent the development of secondary hydatid cysts because of spillage of hydatid fluid, the authors used 10% povidone-iodine poly (1-vinyl-2-pyrrolidone)-iodine complex intraoperatively as a scolicidal agent. There was no mortality or recurrence in the series.

Adolescent↗
PubMed1984

An alkylating derivative of oxotremorine interacts irreversibly with the muscarinic receptor.

A 2-chloroethylamine derivative of oxotremorine was studied in pharmacological experiments and muscarinic receptor binding assays. The compound, N-[4-(2-chloroethylmethylamino)-2-butynyl]-2-pyrrolidone (BM 123), forms an aziridinium ion in aqueous solution at neutral pH that stimulates contractions of the guinea pig ileum with a potency similar to that of oxotremorine. Following the initial stimulation, there is a long lasting period of lack of sensitivity of the guinea pig ileum to muscarinic agonists. BM 123 also produces muscarinic effects in vivo. When homogenates of the rat cerebral cortex were incubated with BM 123 and assayed subsequently in muscarinic receptor binding assays, a loss of binding capacity for the muscarinic antagonist, [3H]N-methylscopolamine ( [3H]NMS), was noted without a change in affinity. Similar observations were made in [3H]1-3-quinuclidinyl benzilate ( [3H]1-QNB) binding assays on the forebrains of mice that had been injected with BM 123 24 hr earlier. The loss in receptor capacity for both [3H]NMS and [3H]1-QNB was prevented by atropine treatment. Kinetic studies of the interaction of BM 123 with homogenates of the rat cerebral cortex in vitro showed that the half-time for the loss of [3H]1-QNB binding sites increased from 10 to 45 min as the concentration of BM 123 decreased from 10 to 1 microM. In contrast to the aziridinium ion, the parent 2-chloroethylamine compound and the alcoholic hydrolysis product were largely devoid of pharmacological and binding activity.

Animals↗
PubMed1990

[3H]D-serine labels strychnine-insensitive glycine recognition sites of rat central nervous system.

In the central nervous system, glycine binds to two recognition sites; one of them (G2), associated with the glutamate receptor, is insensitive to strychnine. Strychnine-insensitive sites were predominant in the forebrain areas and bound D-serine and D-alanine better than the respective L stereoisomers. [3H]D-serine was a more selective radioligand than [3H]glycine for the strychnine-insensitive sites. In the forebrain, the binding of both ligands was inhibited by the putative G2 receptor antagonists, 7-chlorokynurenate and 3-amino-1-hydroxy-2-pyrrolidone, while in pons and in spinal cord only the latter drug was effective. This may indicate the heterogeneity of strychnine-insensitive glycine recognition sites.

Animals↗
PubMed1993

Dopamine and TRH-induced prolactin secretion in pseudopregnant rats.

The stimulatory effect of TRH on prolactin (Pr1) secretion by the anterior pituitary gland (APG) of the pseudopregnant (PSP) rat was studied in vivo and in vitro. TRH, 500 micrograms, did not increase Pr1 release during the Pr1 peaks which are generated daily between 01.00 and 12.00 for about 10 days (mean height of the peaks: 302 +/- 99 ng mL-1), nor did TRH induce Pr1 secretion during the phase of low (12 +/- 1 ng Pr1 mL-1) secretion (the "interphase", between 20.00 and 01.00 h). 25 mg/kg b.w. of the dopamine- (DA) release blocking drug, 1-hydroxy-3-amino-pyrrolidone-2 (HA 966) did not itself induce peaks of Pr1 during the interphase, but in 1 animal out of 6 which were treated with this dose of HA 966, TRH (500 micrograms) induced a peak of Pr1 with a height of 264 ng mL-1 x 100 mg HA 966/kg b.w. induced during the interphase peaks of Pr1 which were as high as spontaneous Pr1 peaks (343 +/- 95 ng mL-1). TRH increased these Pr1 peaks to 844 +/- 48 ng mL-1. Apparently, HA 966 not only lowers DA concentrations but also somehow increases the TRH-responsiveness of the lactotrophs. In vitro, the secretion of Pr1 by incubated pituitary glands was suppressed to the same extent by 5 x 10(-8) and 10(-6) M DA. TRH stimulated Pr1 secretion in the presence of 5 x 10(-8) M DA, but not in the presence of 10(-6) M DA or in the absence of DA. It is concluded that in vitro TRH acts as a physiological antagonist of DA. It is suggested that in vivo the effectivity of TRH as a Pr1-releasing factor may be modulated by DA and that this effect of DA is independent from its Pr1-release suppressing effect.

Animals↗