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C Smith

Publications and source records attributed to C Smith.

At least 379 records · Page 21Linked to original sources
PubMed1996

Hypolipidaemic properties of a potent and bioavailable alkylsulphinyl-diphenylimidazole ACAT inhibitor (RP 73163) in animals fed diets low in cholesterol.

RP 73163 ((S)-2-[5-(3,5-dimethyl-l-pyrazolyl)pent-l-yl)-sulphinyl]-5, 6-diphenylimidazole) has been shown to be a potent and specific inhibitor of acyl-CoA:cholesterol acyltransferase (EC 2.3.1.26; ACAT) in vitro using the tissues of experimental animals as sources of the enzyme. The concentrations of RP 73163 required to produce 50% inhibition of ACAT activity (IC50 values) in microsomal preparations ranged from 86 nM for rat liver to 370 nM for rabbit intestine. In whole cell assays using human hepatic (HepG2), intestinal (Caco2), and monocytic (THP-1) cell lines, RP 73163 inhibited ACAT activity with IC50 values of 266, 158, and 314 nM, respectively. The addition of RP 73163 (0.03-1.0 microM) to the medium of cultured HepG2 cells produced a concentration-dependent decrease in apolipoprotein B (apoB) secretion. The compound has high systemic bioavailability. Using a bioassay, a concentration of active inhibitor equivalent to 29 microM of parent compound was present in plasma 1 hr after oral administration of RP 73163 (50 mg.kg-1). In rats that had been fed a basal diet ad libitum or starved for 18 hr prior to blood sampling, the administration of RP 73163 (50 mg.kg-1 b.i.d. for 7 days) reduced plasma triglyceride levels by 50% without affecting the concentration of cholesterol. This hypotriglyceridaemic effect was associated with reductions in plasma very-low-density-lipoprotein (VLDL) and low-density-lipoprotein (LDL) levels. RP 73163 decreased the rate of VLDL secretion by 24% in Triton WR-1339-treated rats that had been fasted overnight but did not affect the secretion rate in animals fed ad libitum, indicating that ACAT was only important in regulating VLDL secretion under certain nutritional conditions. RP 73163 reduced the accumulation of intraperitoneally administered [3H]leucine into the plasma VLDL-apoB pool in both fed and fasted states. The results suggest that, in fed animals at least, an increase in the clearance of VLDL from the bloodstream may contribute to the hypolipidaemic activity of the compound. In rabbits with casein-induced endogenous hypercholesterolaemia, RP 73163 specifically reduced the levels of cholesterol carried by LDL. In conclusion, the hypolipidaemic actions of RP 73163, a potent and systemically bioavailable ACAT inhibitor, are consistent with a reduction in the secretion of apoB containing lipoproteins by hepatic tissue and possibly with an increase in the clearance of these particles.

Animals↗
PubMed1996

Synthesis and biological activity of 1 alpha, 25-dihydroxy-18-norvitamin D3 and 1 alpha, 25-dihydroxy-18,19-dinorvitamin D3.

1 alpha, 25-dihydroxy-18-norvitamin D3 and 1 alpha, 25-dihydroxy-18,19-dinorvitamin D3 were prepared via Wittig-Horner coupling of 25-hydroxy-18-nor Grundmann type ketone with the corresponding A-ring phosphine oxides. Configuration at C-13 in the 18-nor Grundmann type alcohol (C,D-ring synthon), obtained by oxidative degradation of vitamin D3, was determined by 1H NMR spectroscopy and molecular mechanics calculations. Additional proof of the assigned trans-C/D-junction of the key intermediate 18-nor Grundmann type ketone follows from its chiroptical properties (circular dichroism data) and further chemical transformations. 1 alpha, 25-Dihydroxy-18-norvitamin D3 was found more potent than 1 alpha, 25-dihydroxyvitamin D3 in binding to the porcine intestinal vitamin D receptor (5-10x), in differentiation of HL-60 cells (5-10x), and in inhibition of HL-60 proliferation. 1 alpha, 25-Dihydroxy-18, 19-dinorvitamin D3 appeared equally active as 1 alpha, 25-dihydroxyvitamin D3 in these activities. In vivo, 1 alpha, 25-dihydroxy-18-norvitamin D3 was only slightly less active than 1 alpha, 25-dihydroxyvitamin D3 in intestinal calcium transport and bone calcium mobilization, while 1 alpha, 25-dihydroxy-18,19-dinorvitamin D3 showed activities 10 times lower. These studies imply that deletion of C-18 does not impair activity of analogs of 1 alpha, 25-dihydroxyvitamin D3.

Animals↗
PubMed1996

Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients.

BACKGROUND: Transplantation of bone marrow from unrelated donors is limited by a lack of HLA-matched donors and the risk of graft-versus-host disease (GVHD). Placental blood from sibling donors can reconstitute hematopoiesis. We report preliminary results of transplantation using partially HLA-mismatched placental blood from unrelated donors. METHODS: Twenty-five consecutive patients, primarily children, with a variety of malignant and non-malignant conditions received placental blood from unrelated donors and were evaluated for hematologic and immunologic reconstitution and GVHD. HLA matching was performed before transplantation by serologic typing for class I HLA antigens and low-resolution molecular typing for class II HLA alleles. In donor-recipient pairs who differed by no more than one HLA antigen or allele, high-resolution class II HLA typing was done retrospectively. Fordonor-recipient pairs who were mismatched for two HLA antigens or alleles, high-resolution typing was used prospectively to select the best match for HLA-DRB1. RESULTS: Twenty-four of the 25 donor-recipient pairs were discordant for one to three HLA antigens. In 23 of the 25 transplant recipients, the infused hematopoletic stem cells engrafted. Acute grade III GVHD occurred in 2 of the 21 patients who could be evaluated, and 2 patients had chronic GVHD. In vitro proliferative responses of T cells and B cells to plant mitogens were detected 60 days after transplantation. With a median follow-up of 12 1/2 months and a minimal follow-up of 100 days, the overall 100-day survival rate among these patients was 64 percent, and the overall event-free survival was 48 percent. CONCLUSIONS: HLA-mismatched placental blood from unrelated donors is an alternative source of stem cells for hematopoietic reconstitution in children.

Adolescent↗
PubMed1996

Hippocampal and cortical G protein (Gs alpha, G(o) alpha and Gi2 alpha) mRNA expression after electroconvulsive shock or lithium carbonate treatment.

GTP-binding proteins (G proteins) are heteromers composed of alpha, beta and gamma subunits. The expression of some G protein subunits is altered both by affective disorders and by antidepressant treatments. Here we have studied three G protein alpha subunit mRNAs in the hippocampus and frontoparietal cortex of rats treated with lithium for 14 days or with repeated electroconvulsive shock (five shocks over 10 days). After electroconvulsive shock, the three mRNAs changed differentially in the hippocampus. Specifically, Gs alpha mRNA was decreased in CA3 and CA1, whilst G(o) alpha mRNA was increased in dentate gyrus and Gi2 alpha mRNA was reduced in dentate gyrus and CA3. Lithium carbonate treatment produced a modest, uniform increase in the three mRNAs in dentate gyrus and CA3, and a selective elevation of G(o) alpha mRNA in CA1. Neither treatment altered the G protein mRNAs in the cortex nor cyclophilin mRNA in any region. These data extend the evidence that altered G protein expression is a part of the biochemical response to antidepressant treatments. Differences in the molecular and anatomical pattern of the alterations induced by electroconvulsive shock compared to lithium may contribute to their different therapeutic profiles.

Animals↗
PubMed1996

Increased soluble interleukin-1 type II receptor concentrations in postoperative patients and in patients with sepsis syndrome.

Plasma interleukin-1 (IL-1) activity is modulated in part through the simultaneous appearance of several inhibitors of IL-1 action, including interleukin-1 receptor antagonist (IL-1ra) and the soluble IL-1 type II receptor (IL-1RII). However, little is known concerning the plasma appearance of these inhibitors in patients following operative trauma or those with sepsis syndrome. In the present report, plasma IL-1beta, IL-1ra, and soluble IL-1RI and IL-1RII concentrations were evaluated in 118 patients with sepsis syndrome or after elective operative trauma. Plasma concentrations of IL-1ra increased significantly following elective operative repair of thoraco-abdominal and abdominal aortic aneurysms, and after bowel resection for inflammatory bowel disease, but did not increase after laparoscopic cholecystectomy. Plasma IL-1ra levels were also elevated in patients with sepsis syndrome. In contrast, soluble IL-1RII levels were only increased in patients after operative repair of thoraco-abdominal aortic aneurysms and in sepsis syndrome, whereas concentrations were unaffected by the other more modest surgical procedures. Plasma IL-1RI concentrations decreased in all postoperative patients in the first 24 hours after surgery. We conclude that both plasma IL-1ra and soluble IL-1RII concentrations often increase in sepsis and following some operative trauma. Less severe operative trauma increases the plasma concentration of only IL-1ra, whereas both IL-1ra and soluble IL-1RII are increased in patients with sepsis syndrome or following thoraco-abdominal aneurysm repair.

Adult↗
PubMed1996

Acyl-CoA:Cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT.

The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systematically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.

Animals↗
PubMed1996

Binding of O-alkyl derivatives of serotonin at human 5-HT1D beta receptors.

In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1D beta receptors (Ki < 5 nM) but demonstrate less than 50-fold selectivity relative to 5-HT1A receptors. Alkyl groups longer than eight carbon atoms impart reduced affinity for 5-HT1A receptors whereas groups longer than nine carbon atoms lead to compounds with reduced affinity at 5-HT1D beta receptors. 5-(Nonyloxy)tryptamine (10) represents a compound with optimal 5-HT1D beta affinity (Ki = 1 nM) and selectivity (> 300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with somewhat lower affinity (5-HT1D beta Ki = 2.3 nM) but with greater (i.e, 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or beta-carboline (i.e., 37), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1D beta versus 5-HT1D alpha sites; nevertheless, compounds 10 (recently shown to have as a 5-HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported to date.

Animals↗
PubMed1996

Inducible UDP-glucose dehydrogenase from French bean (Phaseolus vulgaris L.) locates to vascular tissue and has alcohol dehydrogenase activity.

UDP-glucose dehydrogenase is responsible for channelling UDP-glucose into the pool of UDP-sugars utilized in the synthesis of wall matrix polysaccharides and glycoproteins. It has been purified to homogeneity from suspension-cultured cells of French bean by a combination of hydrophobic-interaction chromatography, gel filtration and dye-ligand chromatography. The enzyme had a subunit of Mr 40,000. Km values were measured for UDP-glucose as 5.5 +/- 1.4 mM and for NAD+ as 20 +/- 3 microM. It was subject to inhibition by UDP-xylose. UDP-glucose dehydrogenase activity co-purified with alcohol dehydrogenase activity from suspension-cultured cells, elicitor-treated cells and elongating hypocotyls, even when many additional chromatographic steps were employed subsequently. The protein from each source was resolved into virtually identical patterns of isoforms on two-dimensional isoelectric focusing/PAGE. However, a combination of peptide mapping and sequence analysis, gel analysis using activity staining and kinetic analysis suggests that both activities are a function of the same protein. An antibody was raised and used to immunolocalize UDP-glucose dehydrogenase to developing xylem and phloem of French bean hypocotyl. Together with data published previously, these results are consistent with an important role in the regulation of carbon flux into wall matrix polysaccharides.

Alcohol Dehydrogenase↗
PubMed1996

Cutaneous lymphocyte antigen-positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis.

OBJECTIVE: To investigate whether T cell migration into different sites of inflammation (skin and synovium) within the same individual is principally regulated by tissue-specific homing or by more general mechanisms related to inflammation. METHODS: Expression of cutaneous lymphocyte antigen (CLA) and its ligand, E-selectin, was analyzed by immunohistochemistry and immunofluorescence using paired skin and synovial membrane (SM) samples from patients with psoriatic arthritis (PsA). To investigate disease specificity, delayed-type hypersensitivity (DTH) skin lesions, induced by tuberculin purified protein derivative, and SM from patients with rheumatoid arthritis (RA), were studied as controls. To directly examine cell migration in in vivo, the proportion of CLA+ T lymphocytes migrating into suction-induced skin blisters was assessed by flow cytometry. Using the same technique, levels of paired peripheral blood and synovial fluid (SF) T cells were also analyzed. RESULTS: CLA+ T cells preferentially accumulated in the skin, but not in the joint, of patients with PsA. Similarly, CLA+ T lymphocytes predominated in the DTH skin lesions of RA patients, but were very rare in the SM of RA patients, and were scarcely represented in the SF of patients with several chronic inflammatory arthropathies. In addition, CLA+ T lymphocytes preferentially migrated into epidermal skin blisters. This preferential pattern of CLA+ T cell accumulation was not related to the selective expression of E-selectin, since this was similar in the skin and SM of both PsA and RA patients. CONCLUSION: The distinct pattern of T cell infiltration into sites of inflammation within the skin and synovium is regulated by both organ-specific homing and general inflammation-related mechanisms.

Adult↗
PubMed1996

Paradoxical sleep deprivation and sleep recording following training in a brightness discrimination avoidance task in Sprague-Dawley rats: paradoxical effects.

Previously, we reported that posttraining paradoxical sleep deprivation (PSD) resulted in an enhancement of the subsequent avoidance performance for rats trained for 15 trials in a Y-maze brightness avoidance discrimination task. A series of experiments were conducted to try to further understand the reasons for results which were contrary to those of the bulk of the sleep-learning literature. Experiment 1 investigated the effectiveness of the PSD technique. Rats (N = 4) were sleep recorded while residing on a "swimming pool" apparatus for 24 h. Compared to their baseline values, all animals showed a very large reduction in paradoxical sleep and spent significantly more time awake. Slow-wave sleep was unchanged. In Experiment 2, proactive motor effects were tested. Rats were deprived of PS for 24 h and then tested in a hole board motor activity task. There was a slight effect of PS deprivation on the day following the PSD and no effect when the rats were retested 1 week later. Experiment 3 investigated possible proactive effects of PSD on avoidance performance. Rats exposed to PSD in the 24 h before training in the Y-maze task did not demonstrate any facilitative effect on the subsequent avoidance performance. Experiment 4 investigated the possibility that the PSD facilitative effect could be due to partial training. Rats were given 75 acquisition trials in the brightness discrimination Y-maze avoidance before being subjected to 24 h of PSD. PS-deprived animals showed superior avoidance scores compared to non-PSD controls when retested 24 h later. In Experiment 5, the same strain of rats (N = 11) were sleep recorded after exposure to a partial acquisition in a Y-maze brightness avoidance discrimination task. They were then continuously monitored for 4 consecutive days. The percent PS for the Trained rats was significantly lower than that for the Control animals. This drop in percent PS was not confined to any particular time period in the 24-h day. None of the other sleep parameters reached significance. Analyses of the present results suggest that PSD exerts its facilitative effects on posttraining consolidation processes. We present arguments suggesting that PSD can have effects opposite to those generally reported, in animals demonstrating poor avoidance abilities, in an avoidance task.

Animals↗
PubMed1996

Tissue-specific expression of the PAL3 promoter requires the interaction of two conserved cis sequences.

The bean PAL2 and PAL3 promoters confer expression in overlapping sets of tissue types in transgenic tobacco. The PAL3 promoter contains motifs that resemble two AC cis elements which are required for tissue-specific expression of the PAL2 promoter. The functions of these motifs in the PAL3 promoter were determined by analysis of mutated PAL3 promoter-GUS constructs in transgenic tobacco. This revealed that the AC motifs are necessary for tissue-specific expression of the PAL3 promoter. Therefore, a key role is indicated for AC elements, which are Myb-protein binding sites, in regulating tissue-specific expression of the bean PAL gene family.

Base Sequence↗
PubMed1996

Pharmacokinetics and bioavailability of midazolam after intravenous, subcutaneous, intraperitoneal and oral administration under a chronic food-limited regimen: relating DRL performance to pharmacokinetics.

The effects of midazolam on animal behavior often are evaluated under a chronically food-limited regimen, which is used to implement food-reinforced performance, but the corresponding pharmacokinetics are lacking. The present study investigated the pharmacokinetics of midazolam after i.v., s.c., i.p., and p.o. administration in food-limited rates. A two-compartment model best described the concentration-time profiles for the four routes of administration. The rate of midazolam absorption was rapid, and peak concentrations were attained in less than 7 min for the three extravascular routes. The mean volume of distribution of the central compartment and clearance were 0.77 l/kg and 2.03 l/h per keg, respectively. Midazolam elimination half-lives for the four routes of administration ranged from 23.1 to 49.5 min, and metabolites could not be detected. The mean absolute bioavailability was route-dependent: 39.3% (s.c.) 19.2% (i.p.) and 4.6% (p.o.). The markedly low oral bioavailability found in food-limited rats contrasted to the value reported for free-feeding rates (45%). Although the i.p. route yielded the highest maximum concentration on occasion, serum midazolam concentration-time profiles were variable, but did correspond to respective sedative responses. DRL 45-s performance after s.c., i.p., and p.o. administration further supported the advisability of using the s.c. route of administration, as opposed to the i.p. route, for studying midazolam dose-response relations. The bioavailability values assessed from DRL performance also agree with the measured pharmacokinetic values.

Administration, Oral↗
PubMed1996

Coping strategies and psychiatric morbidity in women attending breast assessment clinics.

This study examined the role of coping strategies and personality characteristics in mediating psychiatric morbidity in subjects facing possibly serious breast disease. Participating were 121 women aged 20 to 65 undergoing breast fine needle biopsy for a suspicious lesion on mammography. All subjects received psychosocial assessments including the 12-item General Health Questionnaire (GHQ-12), the Eysenck Personality Inventory (EPI) and the Coping Strategies Inventory. The results show that neuroticism was the only EPI subscore significantly correlated with GHQ-12 score. A habitual method of coping with adversity known as 'engagement' has a negative correlation with GHQ-12 score; that is, patients who actively confront their illness and the uncertainty that surrounds it show better psychological health. Stepwise multiple regression reveals that neuroticism and an engagement coping strategy are the most significant predictors towards GHQ-12 score prior to the diagnosis of breast cancer.

Adaptation, Psychological↗
PubMed1996

Evidence for a paradoxical sleep window for place learning in the Morris water maze.

Sprague-Dawley rats were given 4 consecutive days of training in the hidden platform version of the Morris water maze. They were then given paradoxical sleep deprivation (PSD) for 12 h either immediately after each training session or after a 12-h delay. The former group showed impaired learning on the second day of training compared to the 12-h-delayed PSD group or a nondeprived control group. In a second experiment, three groups of rats were trained as before and then given PSD for a 4-h interval beginning either immediately after, 4 h after, or 8 h after the end of each training session. Only rats exposed to PSD during the period beginning 4 h after the end of training each day showed an acquisition deficit. In a third experiment, rats were trained in a visible platform version of the water maze and exposed to PSD for a 12-h period either beginning immediately after the last training trial each day or after a 12-h rest delay. Neither of these groups was impaired on the task compared to a non-PSD control group. These results suggest that there is a PS window for place, but not cue, learning in the Morris water maze.

Animals↗