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Biomedical subjects

S Cox

Publications and source records attributed to S Cox.

At least 127 records · Page 7Linked to original sources
PubMed1991

Pharmacokinetic comparison of flurbiprofen in end-stage renal disease subjects and subjects with normal renal function.

This study compared the pharmacokinetics of flurbiprofen (F) and three major metabolites in patients with end-stage renal disease (ESRD) undergoing continuous ambulatory peritoneal dialysis (CAPD) with the pharmacokinetics of F in normal subjects. A single 100-mg dose of F was administered to each of nine normal subjects and eight ESRD subjects. Blood and urine samples were collected in both groups; serial and end of dwell dialysate samples were obtained from the ESRD subjects. Plasma was analyzed for both the R and S optical isomers of F and its major metabolite, 4'-hydroxy-flurbiprofen (HF). Urine and dialysate were analyzed for F and three known metabolites. Plasma concentrations of F in the ESRD subjects were approximately 50% of the values obtained from the normal subjects (P less than .05). Flurbiprofen half-life and Tmax were not different. Elimination of HF was reduced in ESRD subjects. Urinary data suggest that HF was the major metabolite excreted (36% of the dose) in normal subjects whereas 3',4'-dihydroxy-flurbiprofen was the major metabolite (9% of the dose) excreted in the ESRD group. Mean urinary recovery of the dose was 73% in the normal subjects, but only 16% in ESRD subjects. Neither F nor its metabolites were detected in dialysate. Small enantiomer differences were seen. This study suggests that ESRD subjects have lower plasma levels of F than normal subjects when administered equal size doses. Accumulation of metabolites may occur in ESRD subjects upon multiple dosing. Enantiomer differences are not clinically significant.

Adult↗
PubMed1991

Synergistic combinations and peptides in the inhibition of human immunodeficiency virus.

Various combinations of inhibitors of HIV reverse transcriptase were tested for inhibition of HIV replication in order to reveal any potential synergism or antagonism. PFA, a pyrophosphate analogue, gave synergistic inhibition of HIV replication in combination with both of the thymidine analogues AZT and FLT. The combination of PFA and AZT-TP gave only additive or weakly synergistic inhibition in a reverse transcriptase enzyme assay. The combination of AZT and FLT also gave synergistic inhibition of HIV replication, whilst the combination of AZT-TP and FLT-TP gave only additive or weakly synergistic inhibition of reverse transcriptase. Thus, the synergy does not arise from effects on reverse transcriptase alone but must be owing to other, cellular factors, such as effects on nucleoside metabolism or metabolism of the analogues. The results are consistent with the hypothesis that AZT may have an alternative mechanism of inhibition other than inhibition of reverse transcriptase. The diminished cytotoxicity observed in addition to the synergistic inhibition makes these combinations attractive from the point of view of combination chemotherapy. The inhibition of HIV replication by peptides from various parts of the V3 region of gp120 whose sequences were homologous with the tryptase inhibitor trypstatin was tested. Inhibitory activity was displayed by two peptides containing cysteine in their sequence. Antibodies to two peptides containing the two conserved cysteine residues from opposite sides of the neutralizing loop of gp120 were previously associated with protection from vertical transmission of HIV. The V3 region thus seems to be important for the function of gp120 and the transmission of HIV.

Alpha-Globulins↗
PubMed1991

Cell-free expression of the coxsackievirus 3C protease using the translational initiation signal of an insect virus RNA and its characterization.

We have expressed the 3C protease of coxsackievirus B3 (CVB3) in a cell-free system. This expression system employs the translational initiation signal of an insect virus RNA, black beetle virus (BBV) RNA 1, to direct CVB3-specific protein synthesis. Using this expression system, we demonstrate that a biologically active 3C protease is synthesized which possesses both cis and trans processing capabilities. This in vitro-synthesized 3C protease is analogous to the native 3C, which was obtained from cytoplasmic extracts of CVB3-infected HeLa cells, in all biological parameters that were evaluated. In addition, antibody prepared against the 3C protease purified from extracts of CVB3-infected HeLa cells cross-reacts with the 3C protease produced in this cell-free system. Using the translational initiation signal from BBV RNA 1, we also have expressed the CVB3 capsid precursor and part of the P2 region in vitro, and have shown that the capsid precursor is cleaved between 1C (VP3) and 1D (VP1) by the proteolytic activity of in vitro-synthesized 3C in trans. Evidence also is presented to implicate the 2A protein of CVB3 as having proteolytic function.

3C Viral Proteases↗
PubMed1991

Carbamazepine age-dose ratio relationship in children.

Steady-state plasma carbamazepine (CBZ) concentrations were measured in 196 pediatric inpatients taking CBZ alone or CBZ combined with other drugs. The steady-state CBZ concentrations divided by the daily administered dose (dose ratio, reciprocal of apparent clearance) increased significantly (r = 0.183, p less than 0.01) with age. The correlation between dose and CBZ concentration, while significant (r = 0.265, p = 0.023), was weak because of wide interindividual differences in dose ratio. There was a negative correlation between CBZ daily dose and CBZ dose ratio. This negative correlation was significant in children 4-6 (r2 = 0.481, p less than 0.01), 7-11 (r2 = 0.399, p less than 0.01), and greater than 11 years of age (r2 = 0.401, p less than 0.01), but not in children less than 4 years of age (r2 = 0.172, p greater than 0.1). The CBZ dose ratio was significantly (p less than 0.001) lower in patients taking CBZ in combination with more than one other antiepileptic drug compared with those on CBZ monotherapy. No significant (p greater than 0.1) difference in CBZ dose ratio was found between male and female patients. These findings suggest that CBZ clearance was influenced by age, dose, and comedication with more than one other antiepileptic drug but not sex. The concentration necessary for efficacy is a clinical, not an analytical decision. However, the dose-concentration relationships show that recommended pediatric CBZ doses of 10-30 mg/kg/day are not enough to attain published therapeutic CBZ concentrations in many children.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Valproic acid dosages necessary to maintain therapeutic concentrations in children.

Steady-state plasma valproic acid (VPA) concentrations were measured in 118 pediatric inpatients taking VPA. There was a significant (p less than 0.0001) inverse correlation between the daily VPA dosage and the VPA dose ratio (concentration/dose or 1/clearance). The VPA dose ratio was significantly lower in patients taking VPA in combination with phenobarbital (p less than 0.01), carbamazepine (p less than 0.05), or multiple other antiepileptic drugs (p less than 0.0001), compared with those on VPA monotherapy. Neither age nor sex had any influence on VPA dose ratios. No significant (p greater than 0.1) correlation was found between VPA doses and concentrations in children on monotherapy. The distribution of VPA dose concentrations suggests that children, especially those on VPA polytherapy, require higher than recommended pediatric VPA maintenance doses (greater than 60 mg/kg/day) to maintain concentrations greater than 50 mg/L. Results also indicate that at higher concentrations (greater than 80 mg/L), increasing doses may produce less than proportional increases in total VPA concentration.

Adolescent↗
PubMed1991

Phenobarbital doses necessary to achieve 'therapeutic' concentrations in children.

Steady-state plasma phenobarbital (PB) concentrations (n = 671) were measured in 438 inpatients. There was a significant relationship between age and PB dose ratio (concentration/dose or 1/clearance) for monotherapy patients; the dose ratio declined in the first year of life, but the dose ratio increased after age 1. The dose ratios were significantly higher in patients receiving PB in combination with other antiepileptic drugs. However, neither sex nor formulations used (tablet, elixir and intravenous) had any influence on the PB dose ratio. The age-dose-concentration relationships indicate that children, especially those under 11 years of age, may require maintenance PB doses more than 5 mg/kg/day to achieve the commonly recommended 'therapeutic' concentration range (10-40 mg/l).

Adolescent↗
PubMed1990

Improved sample preparation method for high-performance liquid chromatography of deoxyribonucleoside triphosphates from cell culture extracts.

The accurate determination of deoxyribonucleoside triphosphates in cells is difficult owing to the high concentrations of interfering ribonucleoside triphosphates. The latter can be degraded to their respective bases by periodate oxidation of cell extracts. However, the large amount of bases so produced can interfere with subsequent high-performance liquid chromatographic (HPLC) analysis. The use of a weak ion-exchange cartridge to partially purify and concentrate deoxyribonucleoside triphosphates in periodate-treated cell extracts, prior to HPLC, thus allowing accurate determination is described. The recovery of the deoxyribonucleoside triphosphates is greater than 95%, and greater than 90% of the interfering bases are removed.

Anion Exchange Resins↗
PubMed1990

Serum levels and catabolism of 3'-azido-3'-deoxythymidine in vivo measured using a specific radioimmunoassay.

The thymidine analogue 3'-azido-3'-deoxythymidine is an effective inhibitor of HIV replication in vitro and is used in the treatment of acquired immunodeficiency syndrome. We report here upon a rapid sensitive radioimmunoassay for the detection of azidothymidine in serum or plasma. The assay is simple to perform and levels as low as 1 ng azidothymidine/ml can be detected. The assay is specific for azidothymidine and shows almost no cross-reaction with closely related nucleoside analogues or with naturally occurring nucleosides. Using this radioimmunoassay we were able to measure the azidothymidine levels in the serum of monkeys and acquired immunodeficiency syndrome patients treated with AZT. Individual variation in the peak serum level and clearance rate of azidothymidine were seen, which emphasizes the need to tailor the dose to the individual.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Synergistic inhibition of human immunodeficiency virus replication in vitro by combinations of 3'-azido-3'-deoxythymidine and 3'-fluoro-3'-deoxythymidine.

The antiviral activity against human immunodeficiency virus type 1 of the two structurally related thymidine analogs azidothymidine and fluorothymidine, both alone and in combination, was tested. Fluorothymidine was tenfold more active than azidothymidine. The selectivity indices of the two compounds were similar. The combination of azidothymidine and fluorothymidine showed clearly synergistic antiviral activity, and diminished cytotoxicity. The inhibition of reverse transcriptase from human immunodeficiency virus type 1 by the triphosphates of azidothymidine and fluorothymidine, both alone and in combination was also tested. Azidothymidine triphosphate was a fourfold stronger inhibitor than fluorothymidine triphosphate. The combination of the two showed only additive (and not synergistic) effects upon reverse transcriptase. The combination of azidothymidine and fluorothymidine showed both synergistic antiviral activity and diminished cytotoxicity, and may therefore represent a promising therapeutic strategy. The additive (and not synergistic) inhibition of reverse transcriptase by the combination of the triphosphates indicates that in cell culture additional factors other than inhibition of the reverse transcriptase by the triphosphates influence the antiviral activity of the combination. Such factors might include effects upon normal nucleoside metabolism or metabolism of the analogs. Alternatively, one of the nucleosides might have an additional mechanism of action besides inhibition of the reverse transcriptase.

Antiviral Agents↗
PubMed1990

Complications of cholecystectomy in district general hospitals.

The aim of this retrospective study was to determine the incidence of the complications in one thousand consecutive cholecystectomies performed in three district general hospitals. Major post-operative complications occurred in 63 patients (6.3 per cent) and were responsible for 12 deaths (1.2 per cent operative mortality) and 31 reoperations. The incidence of retained stones was 5.8 per cent (10 patients) for those who underwent exploratory choledochotomy, and 10.9 per cent in those who were managed by common bile duct exploration and stone extraction. There were four cases of iatrogenic biliary trauma (0.4 per cent), all in cases operated by junior registrars. All (except one) occurred during elective 'non-complicated' cholecystectomy.

Adult↗
PubMed1989

Divergent effects of interferons on the growth of human benign prostatic hyperplasia cells in primary culture.

Epithelial cells from human benign prostatic hyperplasia tissues were grown in primary cultures for up to 21 days and the effects of interferons on the growth of the cells were investigated. Interferon-alpha (Wellferon) showed growth inhibition both in the presence and in the absence of 3 x 10(-10)M testosterone propionate (TP) whereas interferon-gamma stimulated growth in a dose dependent manner under similar conditions. Interferon-beta had little effect on growth at the dose levels used in the study. The growth inhibition by interferon-alpha can be induced after stimulation of growth is achieved either with TP or with interferon-gamma. Implications of these findings for clinical use of these lymphokines is discussed.

Cell Division↗
PubMed1989

Providing effective therapeutic drug monitoring services.

Therapeutic drug monitoring (TDM) can be an effective way to improve care, but only if accurate medication and clinical information necessary to interpret results is available. A multidisciplinary team consisting of medical technologists, clinical pharmacists, and physician pharmacologists is described in detail. This service analyzes and interprets more than 20,000 concentrations per year, most of which are interpreted by specially trained medical technologists. A description of the interactions between members of the team is presented, including qualifications, selection, and training of medical technologists. The outcome of the TDM service from reporting of drug concentrations to daily quality assurance activities is described, as are the benefits of this model relative to other published, mostly pharmacy-based services. A case is made for the routine involvement of specially trained medical technologists in the collection of data and interpretation of drug concentrations.

Allied Health Personnel↗
PubMed1989

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1.

One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.

Antiviral Agents↗
PubMed1989

Neonatal therapeutic drug monitoring--its clinical relevance.

The potential clinical usefulness of therapeutic drug monitoring (TDM) in neonates is discussed. The personnel performing neonatal TDM must be knowledgeable in the many clinical, analytical, and pharmacokinetic variables used for measuring drug concentrations to formulate rational, individualized dosing regimens. Examples of variables and their effects on TDM interpretations are given and some gaps in our knowledge are presented. The theoretical promise of neonatal TDM is contrasted with the practical realities.

Humans↗
PubMed1988

Regulation of polypeptide-chain initiation in rat skeletal muscle. Starvation does not alter the activity or phosphorylation state of initiation factor eIF-2.

In rats, 48-h starvation causes a decrease in the rate of protein synthesis in skeletal (e.g. gastrocnemius) muscle, due largely to impairment of peptide-chain initiation. In other cell types inhibition of initiation is associated with decreased activity and recycling of initiation factor eIF-2, and increased phosphorylation of its alpha-subunit. However, 48-h starvation has no effect on the activity or recycling of eIF-2 measured in extracts of gastrocnemius muscle, or on the level of alpha-subunit phosphorylation. The effects of starvation on peptide-chain initiation in skeletal muscle must therefore involve alterations in other components of the translational machinery.

Animals↗
PubMed1988

The effect of ethanol on polypeptide chain initiation in reticulocyte lysates. Inhibition of recycling of initiation factor eIF-2.

Using the reticulocyte cell-free system, we have investigated the mechanism by which ethanol inhibits the initiation of protein synthesis. Ethanol inhibited the formation of 40S-initiation complexes, and this effect correlated well with the inhibition by ethanol of overall peptide-chain initiation. Ethanol was a more potent inhibitor of translation at 37 degrees than at 30 degrees. The inhibition of peptide-chain initiation and 40S-initiation complex formation in reticulocyte lysates under other conditions is associated with increased phosphorylation of the alpha-subunit of protein synthesis initiation factor-2 (eIF-2 alpha) and the inhibition of recycling of this factor. Recycling of eIF-2 is mediated by another protein factor GEF (= guanine nucleotide-exchange factor). The addition of ethanol to reticulocyte lysates led to increased phosphorylation of eIF-2 alpha and to a decrease in the rate of exchange of guanine nucleotides bound to eIF-2. This second finding indicated that recycling of eIF-2 was impaired probably due to decreased availability of GEF. Using purified components it was found that ethanol inhibited the ability of GEF to stimulate eIF-2 and that this inhibition showed a similar temperature dependence to the effect of ethanol on overall protein synthesis. Taken together, these results suggest that ethanol leads to inhibition of peptide-chain initiation both through increased phosphorylation of eIF-2 alpha and by directly inhibiting the productive interaction of eIF-2 and GEF.

Ethanol↗