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D S Cox

Publications and source records attributed to D S Cox.

At least 19 recordsLinked to original sources
PubMed2001

Influence of multidrug resistance (MDR) proteins at the blood-brain barrier on the transport and brain distribution of enaminone anticonvulsants.

Previous in vitro studies evaluating the permeability of enaminones suggested that their blood-brain barrier (BBB) transport might be influenced by the presence of an efflux mechanism. Therefore, transport mechanisms responsible for these anticonvulsants across the BBB were examined. The transport of enaminones (1 x 10(-4) M) were evaluated over 120 min with verapamil (50 microM) and probenecid (100 microM) using bovine brain microvessel endothelial cells (BBMECs) to assess the role of multidrug resistant (MDR) transport proteins [i.e., P-glycoprotein (Pgp) and MDR protein 1 (MRP1)] on efflux, respectively. Uptake studies in the presence and absence of rhodamine 123 (R123; 3.2 and 5.0 microM) were also performed in a Pgp overexpressing cell line, MCF-7/Adr. Select enaminone esters (12.5 mg/kg) were administered intravenously to mdr 1 a/b (+/+), mdr 1 a/b (-/-) knockout and probenecid pretreated mice (20 +/- 5g). Enaminones and R123 were assayed with validated ultraviolet and fluorescence high-performance liquid chromatography methods, respectively. Verapamil and probenecid significantly ( p>0.05) inhibited the transport of select enaminone esters across BBMECs. Two enaminones caused a statistically significant increase in the uptake of R123 in MCF-7/Adr cells. Concentrations of select enaminones in mdr 1 a/b (-/-) mice brains were significantly higher ( p<0.05) compared with those in mdr 1 a/b (+/+) mice brains; however, no differences were observed in probenecid pretreated animals. Taken together, these results strongly suggest that Pgp may influence enaminone transport at the BBB and hence affect epilepsy treatment with these agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Enhancing the permeation of marker compounds and enaminone anticonvulsants across Caco-2 monolayers by modulating tight junctions using zonula occludens toxin.

Zonula occludens toxin (Zot), a protein elaborated from Vibrio cholerae, has been shown to be capable of reversibly opening tight junctions between intestinal cells The objective of this study was to examine the effect of Zot on the flux of various molecules across Caco-2 cell monolayers. In addition, the transport of a series of anticonvulsants, the enaminones was also evaluated in the presence of Zot. The flux of [(14)C]mannitol, [(14)C]inulin and various enaminones across Caco-2 cell monolayers (n=6) was examined after pre-incubation for 1h with Zot (0 or 4000ng/ml) or phosphate-buffered saline (PBS). At the end of the incubation period, the flux of radiolabeled compounds or enaminones (1x10(-4)M) was assessed over a 2-h period. In addition, dose-response studies with Zot (0, 1000, 2000 or 4000ng/ml) were performed using mannitol. The flux of both mannitol and inulin significantly increased (P<0.05) in the presence of Zot. The transport of the enaminones with Zot ranged from 9.42 to 26.83x10(-5)cm/s vs. 4.68 to 13.83x10(-5)cm/s without Zot. Zot significantly increased the transport of all agents tested. This suggests that the co-administration of drugs with Zot may be a useful delivery strategy to increase the intestinal permeability and hence oral absorption of poorly bioavailable agents.

Anticonvulsants↗
PubMed2000

Determination of the enaminone DM5, an anti-epileptic agent, in mouse plasma and brain tissue by high-performance liquid chromatography with ultraviolet detection.

Enaminone derivatives of the 4-carbomethoxy-5-methylcyclohexane-1,3-dione series represent a new and potentially active series of compounds for the treatment of Epilepsy. Enaminone esters have been previously evaluated as compounds with potent oral anticonvulsant activity similar to class 1 anticonvulsants phenytoin, carbamazepine, and lamotrigine. DM5, a member of this class with -Cl in the para-substituted position, has been assessed to have the most potent pharmacological activity (ED50) in both the mouse and rat. A selective and specific high-performance liquid chromatography method was developed to quantitate DM5 in plasma and brain tissue in mice. Reverse phase chromatography with ultraviolet (lambda = 307 nm) detection was utilized to quantitate eluate. A C18 analytical column was used and the mobile phase consisted of acetonitrile and 0.05 M NaH2PO4 buffer (60:40; v/v). Liquid-liquid extraction with ether was used to extract the DM5 from plasma or brain homogenates. DM5 and carbamazepine (internal standard) eluted at approximately 6.0 and 9.0 min without any interfering peaks. The calibration curves were found to be linear (r > or = 0.9999) in the range of 0.1-5.0 microg/ml or microg/g. Intra-run precision's were in all in the range of 90%. The absolute recovery of the analyte in brain and plasma samples was < or = 90%. The valid method accurately quantified DM5 in plasma and brain tissue samples collected from a pharmacokinetic study consisting of an intravenous bolus in the tail vein of wild type and genetically altered mice.

Aniline Compounds↗
PubMed2000

Enaminones-versatile therapeutic pharmacophores. Further advances.

Enaminones, enamines of ss-dicarbonyl compounds, have been know for many years. In our initial account (Current Med. Chem. 1994, 1, 159-175), we reported on the anticonvulsant activity of a series of enaminones, notably methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxo-cyclohex-3-en- 1-oate, 9a (R=CH3, R1=4-Cl), which, in animal tests, compared favorably to phenytoin and carbamazepine. Since that time, further research in our laboratory and other laboratories have expanded the therapeutic potential of these compounds. In addition to new anticonvulsant derivatives, we have uncovered a novel brain transport mechanism for the enaminones and developed a preliminary regression model for further synthetic direction. These topics will each be presented and elaborated.

Amines↗
PubMed1999

Phenytoin pharmacokinetics following oral administration of phenytoin suspension and fosphenytoin solution to rats.

The administration of phenytoin suspension in conjunction with enteral nutrition supplements through nasogastric (NG) feeding tubes to humans has been associated with suboptimal phenytoin absorption, subtherapeutic concentrations, and breakthrough seizures. Postulated mechanisms include chelation to proteins and electrolytes in the enteral feeding, binding to NG tubing, and alterations in gastrointestinal pH resulting in precipitation of phenytoin. The purpose of this pilot study was to evaluate the oral absorption of commercially available fosphenytoin injectable solution compared to phenytoin suspension in the rat to determine whether equivalent oral fosphenytoin and phenytoin suspension doses should be used for future human studies of fosphenytoin oral absorption in the presence of concomitant enteral nutrition. A single oral 30 mg/kg phenytoin equivalents dose of either commercially available fosphenytoin or phenytoin suspension was administered to male Wistar rats following an overnight fast. Blood samples (0.3 ml) for phenytoin plasma concentration were obtained from a jugular vein catheter at baseline and 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12 and 24 h post-study drug administration and analyzed by high performance liquid chromatography (HPLC) (CV% < 6). Mean phenytoin Cmax was 85% [corrected] (P = 0.010) higher in fosphenytoin vs phenytoin treated rats. Tmax was 2.4 h (62%, P=0.021) shorter in fosphenytoin vs phenytoin treated rats. No significant differences in AUClast were found. The presence of a phosphate ester moiety does not appear to inhibit the appearance of phenytoin following oral administration of fosphenytoin. Phenytoin plasma concentration profiles following oral administration of fosphenytoin are characterized by higher Cmax and shorter Tmax values relative to oral administration of phenytoin suspension.

Administration, Oral↗
PubMed1996

Are stress-induced immunological changes mediated by mood? A closer look at how both desirable and undesirable daily events influence sIgA antibody.

This investigation tested a three-path model of mood as a mediator of the relation between stress and immunity. Seventy-two married men completed end-of-day diaries in which they rated their mood for that day and the desirability of the day's events for I2 weeks. Events were coded as either desirable (nonstressful) or undesirable (stressful) in nature. Immunological functioning was assessed by secretory immunoglobulin-A NgA) antibody response lo an oral antigen. Regression analyses indicated that negative mood partially mediated the immunological response to both undesirable and desirable events. Undesirable events lowered antibody levels primarily by increasing negative mood: desirable events increased antibody levels by decreasing negative mood. Evidence for mediation by positive mood beyond that found for negative mood was weak.

Journal Article↗
PubMed1994

Daily events are associated with a secretory immune response to an oral antigen in men.

To examine a hypothesized link between daily stressful events and secretory immunoglobulin A (sIgA) antibody, 96 adults from the community completed daily event questionnaires and gave daily saliva samples for up to 12 weeks. They also ingested a capsule of a novel protein to challenge their secretory immune systems. The questionnaire yielded measures of negative and positive experiences, of their content, and of negative and positive affect. On a within-subjects, day-to-day basis, reporting more desirable events was related to more sIgA antibody, and reporting more undesirable events was related to less. Desirable events also had lagged (1 and 2 days), positive effects on sIgA levels. Undesirable work events and desirable leisure and household events were more strongly related to sIgA than events in other categories. Positive affect related directly to sIgA, and negative mood related inversely to same-day sIgA.

Administration, Oral↗
PubMed1993

TQM: a primer.

Explore the source record for details and available documents.

Consumer Behavior↗
PubMed1991

An alternative statistical treatment for summarizing the central tendency of replicate assay data.

Standard assay procedures call for multiple replicates for the purpose of averaging random error from individual replicate scores to obtain a reliable estimate of the true score and for the purpose of specifying the degree of variability within the assay. In this paper we focus on the variability and magnitude of within-assay replicates in order to improve the estimate of the true score. A rule is presented for deciding (1) when individual replicates should be omitted from the computation of the assay's summary score or (2) when an entire sample of replicates should be discarded based on the pattern of replicate scores. It is suggested that this rule improves the reliability of the estimated assay score and this is supported by an illustrative analysis of lymphocyte proliferation assays.

Data Interpretation, Statistical↗
PubMed1991

Effect of adoptive transfer of cloned Actinobacillus actinomycetemcomitans-specific T helper cells on periodontal disease.

Previously we isolated several Actinobacillus actinomycetemcomitans-specific T-cell clones from the spleens and lymph nodes of immunized Rowett rats. These clones were characterized as W3/13+, W3/25+, OX8-, and OX22-, suggesting a T helper (Th) phenotype. In the current experiments, 10(6) cells from a single A. actinomycetemcomitans-specific clone (A3) were adoptively transferred to a group (AaTh; n = 13) of normal heterozygous rats (rnu/+) at 28 days of age. A second group received no T cells (AaNT; n = 15), and a third group also received no T cells (NAaNT, n = 11). Beginning 1 day after transfer, the first and second groups were infected orally with A. actinomycetemcomitans for 5 consecutive days. The presence of infection was confirmed immediately after challenge and after 5 months, when the experiments were ended. Significantly higher numbers of lymphocytes were recovered from the gingival tissues of the first group than from those of either of the other groups. Also, this group showed significantly elevated (P less than 0.01) serum immunoglobulin G and immunoglobulin M antibody to A. actinomycetemcomitans in an enzyme-linked immunosorbent assay when compared with both other groups. Bone loss was significantly lower (P less than 0.01) in recipients of A. actinomycetemcomitans-specific cloned cells when compared with the other infected group and was approximately equal to the bone loss of the uninfected group. These results are consistent with the hypothesis that T-cell regulation can affect periodontal disease. In this regulation, T helper cells appear to interfere with periodontal bone loss.

Actinobacillus↗
PubMed1987

Evidence that secretory IgA antibody is associated with daily mood.

In this study, we examined the secretory immune system, the body's first line of defense against invading organisms, and its relation to daily fluctuations of mood. Specifically, secretory immunoglobulin A (sIgA) was studied. Unlike other psychoimmunity studies that examined all sIgA protein regardless of specificity to invading organisms, ours examined an antigen-specific sIgA response to the oral administration of a harmless protein (rabbit albumin) and monitored the antibody produced in response to the protein. Dental students recorded their daily mood thrice weekly for 8 1/3 weeks, and parotid saliva was obtained from subjects during these contacts. Using a within-subjects analyses strategy, we found that antibody response was lower on days with high negative mood relative to days with lower negative mood, and conversely, sIgA antibody response was higher on days with high positive mood relative to days with lower positive mood. Results from total sIgA protein were in the opposite direction, although not significantly so. These results extend our knowledge of immunological changes and mood, and they suggest that minor life events' role in health may be mediated by the secretory immune system.

Adult↗
PubMed1987

Secretory IgA as a measure of immunocompetence.

The field of psychoimmunology has rapidly expanded in recent years and various parameters of the immune system have been examined in relation to psychological factors. The secretory immune system is one of the more interesting aspects of the entire immune system because it protects mucosal membranes from invading organisms. Stress-produced changes in secretory immunoglobulin A (s-IgA) as measured by radial immunodiffusion assays have been reported in several studies. We present three reasons why total s-IgA protein, the measure derived from radial immunodiffusion assays, may not be a reasonable measure of immune system functioning, and we suggest an alternative method for examining secretory IgA that focuses on s-IgA antibody response to a novel antigen.

Animals↗
PubMed1985

Affinity of antibody at a secretory site in the rat.

Sprague-Dawley rats were administered DNP-BGG on day one of pregnancy by either local mammary gland vicinity injection or by gastric intubation. All rats later received local mammary gland vicinity injection of DNP-BGG on day 11 of pregnancy. Milk and serum were collected post-parturition. IgA and IgG antibody was separated in the milk and IgG antibody in the serum. The relative average affinity constant (KO) was determined by a modification of the Farr assay. Milk IgG affinity was found to be considerably higher than the affinity of IgG in the serum. IgA affinity in the milk of rats which received the antigen by gastric intubation demonstrated antibody affinity much greater than the affinity of milk antibody in rats which simply received mammary gland vicinity injection (1.8 x 10(8) vs. 1.4 x 10(6) l/M). The results indicate that much of the IgG antibody in milk may be locally synthesized. Gut-associated lymphoid tissue may act as a source of antigen specific memory cells for peripheral secretory tissues.

Animals↗
PubMed1984

IgA antibody produced by local presentation of antigen in orally primed rats.

The effect of the introduction of antigen by gastric intubation on the locally stimulated mammary gland IgA antibody (Ab) response was examined. Rats receiving a particulate DNP antigen by gastric intubation prior to injection in the vicinity of the mammary glands ( MGV ) demonstrated increased levels of IgA Ab in milk. Soluble DNP antigen introduction by gastric intubation did not lead to increased IgA Ab levels in milk. Prior administration of either form of DNP antigen by gastric intubation did not affect the IgG response. Only those rats receiving particulate DNP antigen by intubation demonstrated salivary IgA Ab. Particulate forms of antigen administered by intubation can provide a means of increasing the locally induced IgA response at a secretory site.

Animals↗