Search

Over the last 20 years in the United Kingdom, midwives have implemented the routine use of intrapartum fetal monitoring regardless of the risk status of laboring women. This practice is at odds with the published research. The discrepancy between practice and best evidence merits further investigation. A qualitative study was conducted to evaluate midwives' attitudes and experiences about the use of fetal monitoring for women at low obstetric risk. Fifty-eight midwives working in two hospitals in the north of England were interviewed by using a semistructured approach. The taped interviews were transcribed and analyzed by using a general thematic approach. Issues included midwives' perceptions of low-risk status, the socialization of midwives, and the loss of woman-centered care. Midwives subscribed to the notion of woman-centered care, but because of a complexity of factors experienced in their daily working lives, they felt vulnerable when attempting to implement evidence-based fetal monitoring practices. Midwives regretted the loss of a woman-centered approach to care when technologic methods of intrapartum fetal heart rate monitoring were used indiscriminately. An appreciation of the complex factors affecting the ability of midwives to implement evidence-based practice is important when attempting to facilitate the development of appropriate fetal monitoring practices for women at low obstetric risk.

A radioiodinated ligand, [125I]SB-236636 [(S)-(-)3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]3-[125I]i odo phenyl]2-ethoxy propanoic acid], which is specific for the gamma isoform of the peroxisomal proliferator activated receptor (PPARgamma), was developed. [125I]SB-236636 binds with high affinity to full-length human recombinant PPARgamma1 and to a GST (glutathione S-transferase) fusion protein containing the ligand binding domain of human PPARgamma1 (KD = 70 nM). Using this ligand, we characterized binding sites in adipose-derived cells from rat, mouse and humans. In competition experiments, rosiglitazone (BRL-49653), a potent antihyperglycemic agent, binds with high affinity to sites in intact adipocytes (IC50 = 12, 4 and 9 nM for rat, 3T3-L1 and human adipocytes, respectively). Binding affinities (IC50) of other thiazolidinediones for the ligand binding domain of PPARgamma1 were comparable with those determined in adipocytes and reflected the rank order of potencies of these agents as stimulants of glucose transport in 3T3-L1 adipocytes and antihyperglycemic agents in vivo: rosiglitazone > pioglitazone > troglitazone. Competition of [125I]SB-236636 binding was stereoselective in that the IC50 value of SB-219994, the (S)-enantiomer of an alpha-trifluoroethoxy propanoic acid insulin sensitizer, was 770-fold lower than that of SB-219993 [(R)-enantiomer] at recombinant human PPARgamma1. The higher binding affinity of SB-219994 also was evident in intact adipocytes and reflected its 100-fold greater potency as an antidiabetic agent. The results strongly suggest that the high-affinity binding site for [125I]SB-236636 in intact adipocytes is PPARgamma and that the pharmacology of insulin-sensitizer binding in rodent and human adipocytes is very similar and, moreover, predictive of antihyperglycemic activity in vivo.

A series of [(ureidoethoxy)benzyl]-2,4-thiazolidinediones and [[(heterocyclylamino)alkoxy]-benzyl]-2,4-thiazolidinediones was synthesized from the corresponding aldehydes. Compounds from the urea series, exemplified by 16, showed antihyperglycemic potency comparable with known agents of the type such as pioglitazone and troglitazone (CS-045). The benzoxazole 49, a cyclic analogue of 16, was a very potent enhancer of insulin sensitivity, and by modification of the aromatic heterocycle, an aminopyridine, 37, was identified as a lead compound from SAR studies. Evaluation of antihyperglycemic activity together with effects on blood hemoglobin content, to determine the therapeutic index, was performed in 8-day repeat administration studies in genetically obese C57 Bl/6 ob/ob mice. From these studies, BRL 49653 (37) has been selected, on the basis of antihyperglycemic potency combined with enhanced selectivity against reductions in blood hemoglobin content, for further evaluation.

The RR-enantiomer of the beta 3-adrenergic receptor agonist BRL 37344 was tritiated to yield a high specific activity compound, [3H]SB 206606. This new, potentially specific, beta 3-adrenergic receptor ligand was characterized by binding studies using membranes from both Chinese hamster ovary K1 cells transfected with the rat beta 3-adrenergic receptor and rat interscapular brown adipose tissue, where beta 1-, beta 2-, and beta 3-adrenergic receptor subtypes are known to coexist. [3H]SB 206606 was found to bind to a single population of binding sites in both preparations. The Kd values for [3H]SB 206606 binding to membranes from Chinese hamster ovary K1 cells and brown adipose tissue were quite comparable (58 and 38 nM, respectively). At 37 degrees, the time courses of association and dissociation of [3H]SB 206606 with membranes of brown adipose tissue were quite short. At 4 degrees, the T1/2 were found to be 13 and 40 min, respectively. The Ki values for various beta-adrenergic agonists and antagonists in brown adipose tissue membranes were similar to those obtained in Chinese hamster ovary K1 cell membranes with both [3H]SB 206606 and [125I]iodocyanopindolol. The order of binding affinity was BRL 37344 >> (-)-isoproterenol = (-)-norepinephrine > (-)-epinephrine = (+)-isoproterenol. The similarity of the Kd values and of the Ki values for various beta-adrenergic agonists and antagonists in both systems tested indicates that, in a complex membrane system, [3H]SB 206606 binds selectively to the beta 3-adrenergic receptor. The affinity of [3H]SB 206606 is 76 times higher for the beta 3-adrenergic receptor than for the beta 1/beta 2-adrenergic receptors, thus allowing, under controlled conditions, measurement of interactions only with the beta 3-adrenergic receptor in complex membrane systems.

1. When the novel hypolipidaemic compound 1-(4-carboxyphenoxy)-10-(4-chlorophenoxy) decane (CCD) was administered orally (250 mg/kg body weight for seven days) to rats, a lipophilic cholesterol-containing metabolite accumulated in the liver. 2. Analysis by n.m.r. spectroscopy and mass spectrometry identified the metabolite as the cholesterol conjugate of CCD. This structure was confirmed by comparison with reference material synthesized in our laboratories. 3. The xenobiotic cholesteryl ester was not further metabolized and, unlike the natural counterparts, was not transported by lipoproteins. 4. When added in vitro, the xenobiotic cholesteryl ester appeared to enhance the activity of hepatic lysosomal cholesteryl ester hydrolase and thus may contribute to the hypocholesterolaemic activity of CCD.

A series of compounds related to ethyl 4-benzyloxybenzoate was synthesized and evaluated for potential hypolipidemic activity in rats. Structure--activity relationships are discussed in terms of cholesterol-lowering activity together with effects on weight gain and liver lipids. A number of the compounds inhibited cholesterol and free fatty acid biosynthesis from [1-14C]acetate in rat liver slices in vitro. Ethyl 4-benzyloxybenzoate, ethyl-4-benzyloxybenzoic acid, ethyl 4-p-bromobenzyloxybenzoates, and 4-o-methoxybenzyloxyphenyl acetate exhibited the most favorable spectrum of activity.

A series of analogs of N-benzylimidazole was prepared and tested for hypolipidemic activity. Both plasma cholesterol and triglyceride-lowering activity were found in several members of the series. The most active compounds were N-3-methoxy-, N-4-methoxy-, and N-4-methylbenzylimidazole. Structure-activity relationships are discussed.

Investigation into the mechanism of action of BRL 10894 (ethyl 4-benzyloxybenzoate), a compound possessing hypolipidemic activity in the rat, disclosed participation in glycerolipid metabolism. In the presence of BRL 10894, an abnormal metabolite was synthesized in vitro using liver slices or rings of small intestine with glycerol, palmitate, or monoolein as substrate, and using adipose tissue with pyruvate as substrate. Esters related chemically to BRL 10894 and other pharmacologically active acids (e.g., ibuprofen) also produced abnormal metabolites in vitro. With BRL 10894 in the diet, a similar metabolite was produced in vivo in rats and accumulated in adipose tissue. Chemical characterization of the material synthesized in vivo showed that the metabolite was a triglyceride in which one fatty acid moiety was substituted by the acid of BRL 10894. Additional proof of this structure was obtained by comparison with reference material synthesized in our laboratories. The study of the initimate involvement of exogenous acids in glycerolipid turnover is of value in the characterization of pharmacologically important acids and may be of use in achieving a greater understanding of certain aspects of lipid metabolism.