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Biomedical subjects

P M O'Brien

Publications and source records attributed to P M O'Brien.

At least 37 records · Page 2Linked to original sources
PubMed1997

A comparison between the pregnancy outcome of women with gestation diabetes treated with glibenclamide and those treated with insulin.

The pregnancy outcome of 33 women with gestational diabetes who were treated with glibenclamide and changed to insulin if glibenclamide failed, were compared with the pregnancy outcome of 21 women with gestational diabetes treated conventionally with insulin. The pregnancy outcome, with regard to the overall glycaemic control, rates of preterm labour, neonatal hypoglycaemia, fetal macrosomia, perinatal morbidity and mortality, were not statistically different between the two treatment groups. The limited number of women studied, and the non-random allocation of these women to each treatment group however, could have influenced these results. There were a few observed differences in the pregnancy outcome between the two treatment groups, which although were not statistically significant, caused some concern. In particular we noted an increased rate of fetal macrosomia in the glibenclamide treated group, which in theory could have been drug mediated.

Birth Weight↗
PubMed1996

Inhibitors of acyl-CoA:cholesterol O-acyltransferase. synthesis and pharmacological activity of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide and structurally related tetrazole amide derivatives.

A series of tetrazole amide derivatives of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide (1) was prepared and evaluated for their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in vivo. For this series of compounds, our objective was to systematically replace substituents appended to the amide and tetrazole moieties of 1 with structurally diverse functionalities and assess the effect that these changes have on biological activity. The ensuing structure-activity relationship (SAR) studies identified aryl (7b) and heteroaryl (7f,g) replacements for 2,4,6-trimethoxyphenyl that potently inhibit liver microsomal and macrophage ACAT in vitro and exhibit good cholesterol lowering activity (56-66% decreases in plasma total cholesterol at 30 mg/kg), relative to 1, when compared in the acute rat model of hypercholesterolemia. Replacement of the alpha-phenyl moiety with electron-withdrawing substituents (13e-h), however, significantly reduced liver microsomal ACAT inhibitory activity (IC50 > 1 microM). This is in contrast to electron-donating substituents (13ij,m-q), which produce IC50 values ranging from 5 to 75 nM in the hepatic microsomal assay. For selected tetrazole amides (1, 7b, 13n,o), reversing the order of substituents appended to the 2- and 5-positions in the tetrazole ring (36a-d), in general, improved macrophage ACAT inhibitory activity and provided excellent cholesterol-lowering activity (ranging from 65% to 77% decreases in plasma total cholesterol at 30 mg/kg) in the acute rat screen. The most potent isomeric pair in this set of unsubstituted methylene derivatives (13n and 36a) caused adrenocortical cell degeneration in guinea pigs treated with these inhibitors. In contrast, adrenal glands taken from guinea pigs treated with the corresponding alpha-phenyl-substituted analogs (7b and 36c) were essentially unchanged compared to untreated controls. Subsequent evaluation of 7b and 36c in a rabbit bioassay showed that both compounds and/or their metabolities were present in plasma after oral dosing. Unlike 7b and 36c, compound 1 and related 2,4,6-trimethoxyanilides (13j, 30c,d) showed poor oral activity in the rabbit bioassay. Nevertheless, in cholesterol-fed rabbits, both systemically available (7b, 36c) and poorly absorbed inhibitors (1, 36d) were more effective in lowering plasma total cholesterol than the fatty acid amide CI-976.

Animals↗
PubMed1996

Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 17. Structure-activity relationships of several series of compounds derived from N-chlorosulfonyl isocyanate.

Several series of acyl-CoA:cholesterol O-acyltransferase inhibitors were prepared by the stepwise addition of nitrogen, oxygen, and sulfur nucleophiles to N-chlorosulfonyl isocyanate. The (aminosulfonyl)ureas 3-44 were the most potent inhibitors in vitro, with several compounds having IC50 values < 1 microM. Although the other series of compounds were not as potent in vitro, many compounds did display good in vivo activity in cholesterol-fed rats. Several of the oxysulfonyl carbamates (including CI-999, 115) showed excellent lipid-lowering activity in the chronic in vivo screen, demonstrating significant cholesterol lowering in a pre-established hypercholesterolemic state.

Animals↗
PubMed1996

Near infrared spectroscopy applied to intrapartum fetal monitoring.

NIRS as a technique for intrapartum fetal monitoring is at present only able to be used as an investigative research tool. We feel that it has enormous potential to give access to previously inaccessible information about fetal cerebral haemodynamic and oxygenation changes in labour. The major limitations at present are technological, and the problems addressed in this review need to be resolved before clinicians can advance the technique. In the future, standardized measurement parameters that truly reflect cerebral oxygenation, along with a range of normality need to be established. This would require the study of very large numbers of uncomplicated labours. Comparison with data from labours complicated by what we currently call 'fetal distress' and correlation with outcome measures in the neonate would then be needed to determine abnormal patterns of change related to intracerebral hypoxia-ischaemia. This is severely limited by the current inability to measure absolute levels of oxygenation necessary to validate the method. To use the technique for routine surveillance in labour would require considerable refinement of both the equipment and the data analysis systems to improve the acceptability of the technique. It is not possible to envisage a role for NIRS in routine surveillance of low-risk pregnancies, but it may in future prove to have a role in the management of high-risk pregnancies and may well improve our understanding of intracerebral pathology.

Bias↗
PubMed1996

Management of an acute hemorrhagic ovarian cyst in a female patient with hemophilia A.

PURPOSE: This case report represents a description of a hemorrhagic ovarian cyst in a patient with hemophilia A. PATIENT: An 18-year-old female patient with severe factor VIII deficiency presented with the acute onset of a hemorrhagic ovarian cyst, meeting the standard indications for surgical intervention. Instead, because of the underlying coagulopathy, factor VIII therapy was instituted. RESULT: Within 1 day of starting the factor VIII therapy, the hemorrhage had clinically resolved and surgical intervention was avoided. CONCLUSIONS: Hemorrhagic ovarian cysts in the setting of hemophilia may respond to factor VIII replacement therapy without the need for surgical intervention. Because the incidence of functional ovarian cysts is high in the general population, female patients with hemophilia should be counseled regarding its possibility of occurrence. Moreover, if a female patient with hemophilia displays a propensity toward the development of ovarian cysts, the administration of prophylactic oral contraceptive pills should strongly be considered.

Adolescent↗
PubMed1995

Production and characterisation of ovine GM-CSF expressed in mammalian and bacterial cells.

A cDNA encoding ovine granulocyte-macrophage colony-stimulating factor (GM-CSF) was isolated and two forms of recombinant ovine GM-CSF were produced. A glycosylated form was produced in mammalian cells infected with a recombinant vaccinia virus encoding ovine GM-CSF. Recombinant ovine GM-CSF was also produced in Escherichia coli and purified by affinity chromatography. Both forms of the protein were detected by ovine GM-CSF-specific monoclonal antibodies, and exhibited activity on ovine bone marrow haemopoetic progenitor cells.

Animals↗
PubMed1995

Fetal and maternal lipoprotein metabolism in human pregnancy.

1. Lipid, apolipoprotein concentration and composition were determined in maternal venous and umbilical arterial and venous blood at delivery by elective Caesarean section in 13 full-term pregnancies and in 25 healthy non-pregnant females. The indications of Caesarean section were a previous Caesarean section or breech presentation. None of the women was in labour and there were no other complications of pregnancy or fetal distress. 2. The objectives of the study were to establish whether the placenta has a role in feto-maternal cholesterol metabolism through either synthesis or transplacental cholesterol flux. The potential for free cholesterol diffusion between mother and fetus and rates of cholesterol esterification and transfer between lipoproteins were determined and related to the differences in composition between fetal and maternal lipoproteins. 3. Pregnant women had raised levels of all lipid and lipoprotein fractions compared with control subjects. The greatest increases were in free cholesterol and triacylglycerol (P < 0.0001). Lipoprotein (a) levels were significantly greater in the pregnant women [112 (12.2) mg/l] than in the control women [50 (10.0) mg/l]. 4. The only significant correlation between maternal and fetal lipoprotein concentrations was in lipoprotein (a) levels (r = 0.791, P = 0.002). In both umbilical venous and arterial blood, concentrations of very-low- and low-density lipoproteins, particularly apolipoprotein B, cholesteryl ester and triacylglycerol, were lower than in maternal blood (P < 0.0001), but high-density lipoprotein levels were similar. 5. There was no umbilical arteriovenous differences in lipoprotein concentration or composition. This suggests that cholesterol synthesis or free cholesterol diffusion does not occur in the placenta.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 8. Incorporation of amide or amine functionalities into a series of disubstituted ureas and carbamates. Effects on ACAT inhibition in vitro and efficacy in vivo.

A series of disubstituted ureas containing amide or amine groups was prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyl transferase in vitro and to lower plasma total cholesterol in a variety of cholesterol-fed rat models in vivo. The presence of polar or ionizable functionalities within this class of compounds may impart greater aqueous solubility to those compounds and thus allow improved transport to the enzyme location within the intestinal enterocyte. Compounds from this class exhibit good cholesterol lowering in a chronic cholesterol-fed rat model of hypercholesterolemia even when dosed in an aqueous vehicle. In general, the amine-containing compounds were more potent and efficacious than the amides in the acute rat model of hypercholesterolemia. Further structure-activity relationship studies showed that the preferred position of the amide/amine group was beta to the urea moiety and not alpha, and that in this series, the presence of a secondary amine (or amide) proton is required for good in vitro potency. One of these compounds, 9n(-), lowered plasma total cholesterol (-47%) and elevated high-density lipoprotein cholesterol (+256%) when dosed in an aqueous vehicle to rats with preestablished hypercholesterolemia.

Amides↗
PubMed1994

Effect of oral gamolenic acid from evening primrose oil on menopausal flushing.

OBJECTIVE: To evaluate the efficacy of gamolenic acid provided by evening primrose oil in treating hot flushes and sweating associated with the menopause. DESIGN: Randomised, double blind, placebo controlled study. SETTING: District general hospital and teaching hospital. SUBJECTS: 56 menopausal women suffering hot flushes at least three times a day. INTERVENTION: Four capsules twice a day of 500 mg evening primrose oil with 10 mg natural vitamin E or 500 mg liquid paraffin for six months. MAIN OUTCOME MEASURES: Change in the number of hot flushes or sweating episodes a month. RESULTS: 56 diaries were analysed, 28 from women taking gamolenic acid and 28 from those taking placebo. Only 18 women given gamolenic acid and 17 given placebo completed the trial. The mean (SE) improvement in the number of flushes in the last available treatment cycle compared with the control cycle was 1.9 (0.4) (P < 0.001) for daytime flushes and 0.7 (0.3) (P < 0.05) for night time flushes in women taking placebo; the corresponding values for women taking gamolenic acid were 0.5 (0.4) and 0.5 (0.3). In women taking gamolenic acid the only significant improvement was a reduction in the maximum number of night time flushes (1.4 (0.6); P < 0.05). CONCLUSION: Gamolenic acid offers no benefit over placebo in treating menopausal flushing.

Administration, Oral↗
PubMed1994

Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation.

Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded iliac-femoral artery of hypercholesterolemic New Zealand White rabbits using inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which have previously been shown to possess varying degrees of hepatoselectivity in rats. Atorvastatin, previously known as CI-981 (2.5 mg/kg), PD135022 (1.0 mg/kg), simvastatin (2.5 mg/kg), lovastatin (2.5 mg/kg), PD134965 (1.0 mg/kg), pravastatin (2.5 mg/kg) and BMY22089 (2.5 mg/kg) were added to a 0.5% cholesterol, 3% peanut, 3% coconut oil diet and fed for 8 weeks. Although reductions in plasma total cholesterol of 27% to 60%, VLDL-cholesterol of 31% to 71% and plasma total cholesterol exposure of 37% to 43% were obtained, no correlation between these parameters and vascular lipid content, lesion size or monocyte-macrophage content was noted. Iliac-femoral lipid content was unchanged; however, atorvastatin and simvastatin significantly reduced the cholesterol content of the thoracic aorta by 45%-62%. Atorvastatin and PD135022 reduced the size of the iliac-femoral lesion by 67% and monocyte-macrophage content by 72%. Simvastatin, lovastatin and PD134965 decreased the monocyte-macrophage content; however, lesion size was unchanged. Pravastatin and BMY22089 had no effect on lesion size or content. No compound significantly reduced the extent of thoracic aortic lesions. We concluded that changes in plasma lipids and lipoproteins noted with the various HMG-CoA reductase inhibitors did not account for the beneficial effect on atherosclerotic lesion development. The antiatherosclerotic potential of the HMG-CoA reductase inhibitors was compound-specific and clearly not a class effect.

Animals↗
PubMed1994

Cloning and sequencing of an ovine granulocyte colony-stimulating factor cDNA.

A cDNA encoding an ovine (ov) granulocyte colony-stimulating factor (G-CSF) was cloned by polymerase chain reaction, using primers based on the 5' and 3' nucleotide (nt) sequence of the bovine (bov) G-CSF cDNA. RNA was isolated from IFN-gamma and LPS-stimulated alveolar macrophages. The isolated ovG-CSF cDNA is 522 bp in length and does not include coding sequence for a secretory signal peptide. The nt sequence is 95% identical to the bovG-CSF nt sequence, and includes conservation of 5 cysteine residues. The deduced amino acid (aa) sequence of the mature ovG-CSF protein shares 96%, 82% and 68% homology with the bov, human and murine mature G-CSF proteins, respectively. The estimated molecular weight of the 174 aa G-CSF protein is 18.8 kilodaltons.

Amino Acid Sequence↗