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P George

Publications and source records attributed to P George.

At least 19 recordsLinked to original sources
PubMed2004

SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one], a new, reversible, and mixed inhibitor of monoamine oxidase-A and monoamine oxidase-B: biochemical and behavioral profile.

SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one] is a new, nonselective, and reversible monoamine oxidase (MAO) inhibitor, belonging to a oxazoloquinolinone series. In vitro studies showed that SL25.1131 inhibits rat brain MAO-A and MAO-B with IC50 values of 6.7 and 16.8 nM and substrate-dependent Ki values of 3.3 and 4.2 nM, respectively. In ex vivo conditions, the oral administration of SL25.1131 induced a dose-dependent inhibition of MAO-A and MAO-B activities in the rat brain with ED50 values of 0.67 and 0.52 mg/kg, respectively. In the rat brain, duodenum, and liver, the inhibition of MAO-A and MAO-B by SL25.1131 (3.5 mg/kg p.o.) was reversible, and the recovery of MAO-A and MAO-B activities was complete 16 h after administration. SL25.1131 (3.5 mg/kg p.o.) increased tissue levels of dopamine (DA), norepinephrine, and 5-hydroxytryptamine and decreased levels of their deaminated metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid. In mice, SL25.1131 induced a dose-dependent potentiation of 5-hydroxytryptophan-induced tremors and phenylethylamine-induced stereotypies with ED50 values of 0.60 and 2.8 mg/kg p.o., respectively. SL25.1131 was able to reestablish normal striatal dopaminergic tone and locomotor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice. In addition, when coadministered with L-DOPA, SL25.1131 increased the available DA in the striatum and the duration of L-DOPA-induced hyperactivity. The duration of the effect of L-DOPA on circling behavior in 6-hydroxydopamine-lesioned rats was also increased. The neurochemical profile of SL25.1131 demonstrates that this compound is a mixed, potent, and reversible MAO-A/B inhibitor in vitro, in vivo, and ex vivo. SL25.1131 has therapeutic potential as a symptomatic treatment during the early phase of Parkinson's disease and as an adjunct to L-DOPA therapy during the early and late phases of the disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Hereditary pancreatitis in a family of Aboriginal descent.

Hereditary pancreatitis is an autosomal dominant condition characterized by recurrent episodes of acute pancreatitis, usually starting in childhood. We present a family who was ascertained when an 11-year-old girl presented with an episode of acute pancreatitis. Her father and other family members had also had recurrent bouts of acute pancreatitis. Genetic testing revealed a pathogenic mutation in the cationic trypsinogen gene in the proband, her father and her paternal grandmother. As far as we are aware, this is the first Aboriginal kindred with mutation-proven hereditary pancreatitis. Hereditary pancreatitis is an important differential diagnosis to consider in a patient with recurrent episodes of acute pancreatitis with no obvious precipitating cause. This family is of Aboriginal descent and the implications of the family's background are also discussed when considering the aetiology of the condition. We emphasize the need to ascertain a full family history from patients with a history of repeated episodes of acute pancreatitis and also emphasize the need to avoid ethnic stereotypes when assessing patients.

Child↗
PubMed2003

SSR591813, a novel selective and partial alpha4beta2 nicotinic receptor agonist with potential as an aid to smoking cessation.

(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2',3':5,6]pyrano[2,3-d]azepine (SSR591813) is a novel compound that binds with high affinity to the rat and human alpha4beta2 nicotinic acetylcholine receptor (nAChR) subtypes (Ki = 107 and 36 nM, respectively) and displays selectivity for the alpha4beta2 nAChR (Ki, human alpha3beta4 > 1000, alpha3beta2 = 116; alpha1beta1deltagamma > 6000 nM and rat alpha7 > 6000 nM). Electrophysiological experiments indicate that SSR591813 is a partial agonist at the human alpha4beta2 nAChR subtype (EC50 = 1.3 micro M, IA =19% compared with the full agonist 1,1-dimethyl-4-phenyl-piperazinium). In vivo findings from microdialysis and drug discrimination studies confirm the partial intrinsic activity of SSR591813. The drug increases dopamine release in the nucleus accumbens shell (30 mg/kg i.p.) and generalizes to nicotine or amphetamine (10-20 mg/kg i.p.) in rats, with an efficacy approximately 2-fold lower than that of nicotine. Pretreatment with SSR591813 (10 mg/kg i.p.) reduces the dopamine-releasing and discriminative effects of nicotine. SSR591813 shows activity in animal models of nicotine dependence at doses devoid of unwanted side effects typically observed with nicotine (hypothermia and cardiovascular effects). The compound (10 mg/kg i.p.) also prevents withdrawal signs precipitated by mecamylamine in nicotine-dependent rats and partially blocks the discriminative cue of an acute precipitated withdrawal. SSR591813 (20 mg/kg i.p.) reduces i.v. nicotine self-administration and antagonizes nicotine-induced behavioral sensitization in rats. The present results confirm important role for alpha4beta2 nAChRs in mediating nicotine dependence and suggest that SSR591813, a partial agonist at this particular nAChR subtype, may have therapeutic potential in the clinical management of smoking cessation.

Animals↗
PubMed2001

Successful renal transplantation after endovascular bifurcated stent graft repair of an abdominal aortic aneurysm.

Renal transplantation after repair of aortoiliac aneurysms with traditional prosthetic vascular grafts has been shown to be effective. Vascular surgery continues to rapidly evolve, most notably with the advancement of endovascular repair of abdominal aortic aneurysms. Controlled trials continue to support the trend toward the use of endovascular bifurcated aortic stent grafts. For this we describe the first renal transplant in a patient with an endovascular bifurcated aortoiliac stent graft. No intraoperative difficulties were encountered. At 1-year follow-up, the transplanted kidney is functioning well with a normal serum creatinine level of 1.3 mg/dl, and the patient has no worsening of peripheral vascular disease. We recommend that the presence of an endovascular aortic graft not be a contraindication to renal transplantation.

Aged↗
PubMed2001

Interactions of metal ions with water: ab initio molecular orbital studies of structure, vibrational frequencies, charge distributions, bonding enthalpies, and deprotonation enthalpies. 2. Monohydroxides.

The formation and properties of a wide range of metal ion monohydroxides, M(n)(+)[OH(-)], where n = 1 and 2, have been studied by ab initio molecular orbital calculations at the MP2(FULL)/6-311++G**//MP2(FULL)/6-311++G** and CCSD(T)(FULL)/6-311++G**//MP2(FULL)/6-311++G** computational levels. The ions M(n)()(+) are from groups 1A, 2A, 3A, and 4A in the second, third, and fourth periods of the Periodic Table and from the first transition series. Geometrical parameters, vibrational frequencies, atomic charge distributions, orbital occupancies, and bonding enthalpies are reported. The M(n)(+)-O distances are shorter in the hydroxides than in the corresponding hydrates (published previously as Part 1, Inorg. Chem. 1998, 37, 4421-4431) due to a greater electrostatic interaction in the hydroxides. The natural bond orbitals for most of the first-row transition metal ion hydroxides do not contain a formal metal-oxygen bonding orbital; nevertheless the atomic charge distributions show that for both n = 1 and 2 a significant amount of electron density is consistently transferred from the hydroxide ion to the bound metal ion. Deprotonation enthalpies for the hydrates have been evaluated according to the simple dissociation process, M(n)(+)[OH(2)] --> M(n)(+)[OH(-)] + H(+), and also via proton transfer to another water molecule, M(n)(+)[OH(2)] + H(2)O --> M(n)(+)[OH(-)] + H(3)O(+). The drastic reduction in these deprotonation enthalpies as H(2)O molecules are sequentially bonded in the first coordination shell of the metal ion (amounting to 71, 64, 85, and 91 kcal/mol for the bonding of six water molecules to Mg(2+), Ca(2+), Mn(2+), and Zn(2+), respectively) is found to be due to the greater decrease in the bonding enthalpies for the hydroxides relative to the hydrates. Proton transfer to bases other than water, for example side chain groups of certain amino acids, could more than offset the decrease in deprotonation energy due to the filling of the first coordination shell. Linear relationships have been found between the pK(a) values for ionization of the Mg(2+), Ca(2+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), and Zn(2+) aquo ions, and Delta for the bonding of the first water molecule, for the bonding of the hydroxide ion, and for proton dissociation from the monohydrate. Similar relationships have also been found between the pK(a) values and the reciprocal of the M-O bond lengths in both the monohydrates and hydroxides. Thus the ionization of metal hydrates in water echoes the properties of the monomeric species M(n)(+)[OH(2)].

Metals↗
PubMed2001

Phospholipids reacylation and palmitoylcoa control tumour necrosis factor-alpha sensitivity.

From the hypothesis that in TNF-alpha-resistant cells the activity of mitochondrial phospholipase A2 could be reversed by a lysophospholipid acyltransferase, we report that the mitochondrial reacylation of phosphatidylcholine as phosphatidylethanolamine was considerably higher in C6 (TNF-alpha-resistant) than in WEHI-164 (TNF-alpha-sensitive) cells. TNF-alpha did not modify the phospholipids' reacylation in C6, while in WEHI-164 it was increased several-fold. These results suggest that TNF-alpha is not sufficient to restore the barrier permeability in sensitive cells, but may be enough to explain the absence of permeability change in resistant cells. AcylCoA esters, depending on whether the acyl group is unsaturated or saturated (palmitic acid), could control membrane permeability either by participating in the reacylation of phospholipids or keeping the pore in a closed state. The analysis of the endogenous acylCoA ester pools of both cell lines show that the amount of palmitoylCoA is higher in resistant than sensitive cell lines. TNF-alpha treatment does not change these results.

Acetylation↗
PubMed2001

Dietary spermidine and spermine participate in the maturation of galactosyltransferase activity and glycoprotein galactosylation in rat small intestine.

This study considered the role of dietary polyamines in the maturation of intestinal glycoprotein galactosylation during postnatal development. In the rat small intestine, O-glycan: beta-1,3-galactosyltransferase and N-glycan: beta-1,4-galactosyltransferase are, respectively, involved in the glycan chain biosynthesis of mucins and of glycoproteins in the brush border membranes. Their activities increase significantly at weaning, in parallel with a rise in the intestinal content of spermidine and spermine (as determined by high performance liquid chromatography) and in proportion to the polyamine increase in food intake. The oral ingestion of spermidine or spermine (at 0.4 micromol/g body) by immature suckling rats for 4 d reproduced the levels of spermine and spermidine in their intestines at the time of weaning and induced precocious and significant rises in O-glycan: and N-glycan: galactosyltransferase activities to those normally found after weaning. In parallel, more galactose residues (detected in the complex oligosaccharide chains of glycoproteins by specific lectins after electrophoresis and transfer to nitrocellulose membranes) were observed in the brush border membranes of spermidine- and spermine-treated rats. In contrast, the ingestion of putrescine or ornithine had no effect. Diets with different levels of polyamines (milks and commercial diet), when given at weaning, induced variable evolutions of the galactosylation process, partly in relation to the amounts of polyamines ingested. These results indicate that spermidine and spermine are maturation factors that can reproduce, in immature rats, the same increase in intestinal glycoprotein galactosylation that is normally observed during weaning. They also suggest that the maturation of glycoprotein galactosylation may be a multifactorial event in which spermidine and spermine are both involved.

Animal Feed↗
PubMed2001

Heterocellular gap junctional communication between alveolar epithelial cells.

We analyzed the pattern of gap junction protein (connexin) expression in vivo by indirect immunofluorescence. In normal rat lung sections, connexin (Cx)32 was expressed by type II cells, whereas Cx43 was more ubiquitously expressed and Cx46 was expressed by occasional alveolar epithelial cells. In response to bleomycin-induced lung injury, Cx46 was upregulated by alveolar epithelial cells, whereas Cx32 and Cx43 expression were largely unchanged. Given that Cx46 may form gap junction channels with either Cx43 or Cx32, we examined the ability of primary alveolar epithelial cells cultured for 6 days, which express Cx43 and Cx46, to form heterocellular gap junctions with cells expressing other connexins. Day 6 alveolar epithelial cells formed functional gap junctions with other day 6 cells or with HeLa cells transfected with Cx43 (HeLa/Cx43), but they did not communicate with HeLa/Cx32 cells. Furthermore, day 6 alveolar epithelial cells formed functional gap junction channels with freshly isolated type II cells. Taken together, these data are consistent with the notion that type I and type II alveolar epithelial cells communicate through gap junctions compatible with Cx43.

Animals↗
PubMed2001

SL651498: an anxioselective compound with functional selectivity for alpha2- and alpha3-containing gamma-aminobutyric acid(A) (GABA(A)) receptors.

SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one] is a novel pyridoindole derivative that displays high affinity for rat native GABA(A) receptors containing alpha(1) (K(i) = 6.8 nM) and alpha2 (K(i) = 12.3 nM) subunits, and weaker affinity for alpha5-containing GABA(A) receptors (K(i) = 117 nM). Studies on recombinant rat GABA(A) receptors confirm these data (K(i), alpha1beta2gamma2 = 17, alpha2beta2gamma2 = 73, alpha5beta3gamma2 = 215 nM) and indicate intermediate affinity for the alpha3beta2gamma2 subtype (K(i) = 80 nM). SL651498 behaves as a full agonist at recombinant rat GABA(A) receptors containing alpha2 and alpha3 subunits and as a partial agonist at recombinant GABA(A) receptors expressing alpha1 and alpha5 subunits. SL651498 elicited anxiolytic-like activity similar to that of diazepam [minimal effective dose (MED): 1-10 mg/kg, i.p.] in three conflict models, in the elevated plus-maze, the light/dark test, and the defense test battery in rats and mice. Results from activity tests and electroencephalogram analysis indicated that SL651498 induced muscle weakness, ataxia, or sedation at doses much higher than those producing anxiolytic-like activity (MED > or = 30 mg/kg, i.p.). Repeated treatment for 10 days with SL651498 (30 mg/kg, i.p., b.i.d.) in mice was not associated with the development of tolerance to its anticonvulsant effects or physical dependence. Furthermore, SL651498 was much less active than diazepam in potentiating the depressant effects of ethanol in mice. The "anxioselective" profile of SL651498 points to a major role for GABA(A) alpha2 subtype in regulating anxiety and suggests that selectively targeting GABA(A) receptor subtypes can lead to drugs with increased clinical specificity.

Animals↗
PubMed2000

Phosphinic derivatives as new dual enkephalin-degrading enzyme inhibitors: synthesis, biological properties, and antinociceptive activities.

The development of dual inhibitors of the two zinc metallopeptidases, neprilysin (neutral endopeptidase) and aminopeptidase N involved in the inactivation of the opioid peptides, enkephalins, represents an attractive physiological approach in the search for new analgesics devoid of the major drawbacks of morphine. Phosphinic compounds, corresponding to the general formula H(3)N(+)-CH(R(1))-P(O)(OH)-CH(2)-CH(R(2))-CONH-CH(R(3))-COO(-), able to act as transition-state analogues and to fit the S(1), S(1)', and S(2)' subsites of both enzymes were designed. Selection of the R(1), R(2), and R(3) residues for optimal recognition of these enzymes led to the first dual competitive inhibitors with K(i) values in the nanomolar range for neprilysin and aminopeptidase N. These compounds induce potent analgesic responses after intracerebroventricular or intravenous administrations in mice (hot plate test), and several of them were shown to be, at least, 10 times more potent than the previously described dual inhibitors.

Analgesics↗
PubMed2000

Influence of spermine on intestinal maturation of the glycoprotein glycosylation process in neonatal rats.

Previous work has shown an inverse evolution of the rat intestinal glycoprotein sialylation that decreases from birth to weaning and of fucosylation that increases markedly after weaning during postnatal development. At weaning time, an increase in the intestinal level of polyamines (and especially that of spermine) was observed, owing partly to the higher level of spermine found in solid food given to rats at this period in comparison with the level found in milk. To study the role of this polyamine as a possible maturation factor of the glycoprotein glycosylation, suckling rats were treated for 4 days with spermine administered orally. This treatment allowed us to mimic the spermine increase that was observed naturally in rat small intestine after weaning because, in intestines of spermine-treated suckling rats, spermine was the only polyamine to be increased and was at a level similar to that of weaned rats. Spermine treatment did not induce appreciable changes in sialyltransferase activity or in sialylation of the brush-border-membrane glycoproteins. On the contrary, this treatment induced a rise in an alpha-1, 2-fucosyltransferase activity that was regulated at the transcriptional level, but not by its inhibitor (fuctinin), and no change in the availability of substrate (GDP-fucose). As a consequence of the increase in alpha-1,2-fucosyltransferase level and of the decrease in alpha-l-fucosidase level after treatment with spermine, several alpha-1,2-fucoproteins, naturally found in brush border membranes after weaning time, appeared precociously in these membranes after the treatment of the immature suckling rats. These results indicate that spermine is a maturation factor for the fucosylation of intestinal brush-border-membrane glycoproteins but not for their sialylation, and that this polyamine might be implicated in the increased fucosylation naturally occurring at weaning time during postnatal development.

Animals↗
PubMed2000

Automated immature reticulocyte counts are early markers of engraftment following autologous PBSC transplantation in patients with lymphoma.

The traditional indicators of engraftment following PBSC transplantation (PBSCT) are the rising total WBC count and ANC. Reticulocytes may be an earlier indicator, since as reticulocytes mature, there is a gradual loss of cellular RNA, which can be measured using methylene blue and light scatter with an Abbott CD 3500 automated counter (Abbott Laboratories, Maidenhead, U.K.). Reticulocytes can be divided into three fluorescence ratios depending on the amount of light scatter generated, high, medium, and low. The most immature are the high fluorescence reticulocytes (HFR). Standard engraftment parameters together with HFR were measured in a homogeneous group of 25 patients with lymphoma after PBSCT using a standard conditioning protocol. An ANC of 0.5 x 10(9)/L was achieved after a median of 10 days (mean 11.2 days, range 9-22). The recovery of the HFR to 2% of the total reticulocytes was significantly shorter, with a median of 8 days (mean 7.5 days, range 6-10) (p < 0.0001). The values of HFR to 2% preceded the ANC of 0.5 x 10(9)/L in 24 of the 25 patients by a median of 3 days (mean 3.8 days, range 2-12 days). On this basis, it can be determined that in 96% of cases, engraftment was indicated earlier by HFR measurement. The HFR to 2% even preceded the ANC of 0.1 x 10(9)/L in 23 of the 25 patients, showing that engraftment was indicated earlier in 92% of patients. Immature reticulocytes appearing in peripheral blood can be reliably measured by automated cytometers, and HFR can, therefore, be used as an earlier indicator of engraftment following PBSCT. This information provides the opportunity for earlier cessation of antibiotics and growth factors and could lead to earlier discharge from hospital, with cost savings.

Adult↗
PubMed2000

Molecular interaction between reversible MAO-A inhibitors and the enzyme. Application to aryloxazolidinone, a prototype series.

Among the various chemical classes of monoamine oxidase A inhibitors, phenyloxazolidinone represent one of the major series. The purpose of this paper is to review the experimental (X-ray diffraction, NMR, electronic absorption spectroscopy, lipophilicity studies) and theoretical (quantum chemistry, molecular mechanics, molecular dynamics) studies which have led to the description of the mode of interaction between phenyloxazolidinone inhibitors and the MAO-A enzyme.

Animals↗