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Biomedical subjects

D Cutler

Publications and source records attributed to D Cutler.

At least 55 records · Page 3Linked to original sources
PubMed1995

Pharmacokinetics of isepamicin in paediatric patients.

The pharmacokinetics of isepamicin were evaluated in 50 paediatric patients ranging from newborn to 13 years old. Children with subdivided according to age: Group I (6-13 years); Group II (4 months to 6 years); Group III (16 days to 4 months); and Group IV (newborn to 16 days). All patients received isepamicin 7.5 mg/kg every 12 hours except those in Group IV who received 7.5 mg/kg once daily. Isepamicin was administered initially as an intravenous 30-minute infusion and then either intravenously or intramuscularly for between 4 and 12 days. Plasma samples were obtained after the first or second dose on day 1 at 0, 0.5, 1, 4, 6, 8 and 12 hours after the initiation of dosing and at 0.5 and 12 hours on other dosing days. Additional samples were collected in the Group IV patients at 18, 20 and 24 hours. Isepamicin showed a similar plasma concentration-time profile in Groups I, II and III (children from 16 days to 13 years), and in these groups the profile was generally similar to that observed in adults. Neonates up to the age of 16 days (Group IV) showed a distinctly different pharmacokinetic profile: a significantly larger AUC, longer half-life, lower Cmax and lower total body clearance. Isepamicin 7.5 mg/kg administered once daily to children less than 16 days old and twice daily to children aged 16 days to 13 years appears to be pharmacokinetically appropriate. The drug was very well tolerated by children of all age groups.

Adolescent↗
PubMed1994

Induction of in vivo DNA adducts by 4 industrial by-products in the rat-lung-cell system.

Benz[a]anthracene (BA), dibenz[a,h]anthracene (DBA), dibenzo[a,i]pyrene (DBP), and dibenz[a,h]acridine (DBAC) are by-products found in many industrial wastes and emissions. Workers in the related occupational settings are potentially exposed to these substances through inhalation. In the present study, induction of DNA adducts in vivo by these chemicals was investigated using 32P-postlabeling analysis in the rat-lung-cell system. The potency of DNA-adduct inducing activity was also compared to that of two cytogenetic endpoints i.e., sister-chromatid exchange (SCE) and micronucleus formation. Via intratracheal instillation, male CD rats (6/group) were dosed 3 times with BA, DBA, DBP or DBAC in a 24-h interval. Lung cells were enzymatically separated and used to determine the frequency of DNA adducts, SCE and micronuclei. Results show that all 4 test compounds induced DNA adducts, SCEs, and micronuclei in the rat-lung cell in vivo and that the postlabeling DNA adduct assay detected genotoxic activity at lower dose levels than the two cytogenetic assays. These findings suggest that BA, DBA, DBP or DBAC are rat pulmonary genotoxicants and the DNA-adduct assay is more sensitive than SCE or micronucleus assays for detecting the pulmonary genotoxicity of these industrial PAHs in the in vivo rat-lung-cell system.

Acridines↗
PubMed1993

Insights from pharmacokinetic and pharmacodynamic studies of hydroxychloroquine.

There is wide variability between subjects in the pharmacokinetic parameters of hydroxychloroquine. A range of concentrations is achieved by individuals receiving the same dosage. In a cross-sectional study, mean hydroxychloroquine concentrations in patients with shorter duration and lower intensity of morning stiffness and no rheumatoid factor were significantly higher than in patients with worse disease activity. Variable kinetic parameters, causing variable concentrations, are likely to be contributing to the variability in response to hydroxychloroquine in rheumatic diseases.

Adult↗
PubMed1990

Antimalarials in rheumatic diseases.

The antimalarials hydroxychloroquine and chloroquine remain established and effective agents for the treatment of rheumatoid arthritis and systemic lupus erythematosus. Although the mechanisms of action remain uncertain, evidence is accumulating that the antirheumatic and immunological effects of the antimalarials are related to their massive distribution into the cellular acid-vesicle system. These drugs are attracting new interest because their relative safety recommends their use in early rheumatoid arthritis and as a component of second-line antirheumatic drug combinations. The absence of data examining the effect of antimalarials upon radiological progression of rheumatoid arthritis needs to be rectified. Recent understanding of the pharmacokinetics of these drugs reveals that steady-state concentrations are not achieved for at least 3-4 months. Preliminary information also suggests a relationship between blood concentrations and effect. Taken together, these data suggest that more effective dosage regimens will be possible when therapeutic concentration ranges are properly established.

Antimalarials↗
PubMed1990

Prevalence of mental disorders after catastrophic financial loss.

In a controlled study, the authors determined the risk of developing major mental illness after catastrophic financial loss. Seventy-two adults who lost their retirement savings in a bank fraud were interviewed using the Diagnostic Interview Schedule. Major depression by DSM-III criteria was present in 29% of the victims during the first 20 months after their loss as compared with 2% of 66 age, gender, and residential area-matched control subjects (p less than .0001). Generalized anxiety disorder as defined by DSM-III criteria was experienced by 27% of victims after the loss as compared with 10% of control subjects (p = .03). After the loss, victims had lower subjective health ratings, more functional somatic complaints, and higher tranquilizer usage than control subjects. There was no difference between depressed and nondepressed in types of coping responses or use of social supports and confidants. Only four of 21 victims who suffered major depression sought help from a mental health professional. We conclude that catastrophic financial loss may result in the onset of major depressive disorder and generalized anxiety disorder.

Adaptation, Psychological↗
PubMed1986

Determinants for protein translocation across mammalian endoplasmic reticulum. Membrane insertion of truncated and full-length prelysozyme molecules.

The translocation of fragments of prelysozyme lacking varying portions of the COOH terminus of the protein is studied in comparison to full-length prelysozyme using transcription-coupled capping of RNA and subsequent translation in a wheat germ cell-free system. The fragments are generated by restricting cloned lysozyme cDNA at selected sites. We found that fragments of 102 and 74 amino acid residues could still be translocated by mammalian endoplasmic reticulum. Addition of signal-recognition particles (SRP) to the cell-free system blocked the nascent chain synthesis. The SRP-depleted membrane by itself could neither process nor translocate the prepolypeptide chain. The presence of both components was essential for processing and translocation as well as the release of the nascent chain arrest induced by SRP. However, when the size of the fragment was limited to 51 amino acids, the SRP-induced arrest, the translocation and processing failed to take place. These results define minimum length and structural requirements for translocation of the nascent chain across mammalian endoplasmic reticulum.

Animals↗
PubMed1985

Exocytotic pathways exist to both the apical and the basolateral cell surface of the polarized epithelial cell MDCK.

Secretion of a foreign protein--chicken oviduct lysozyme--and of endogenous proteins was studied in the polarized epithelial Madin-Darby Canine Kidney (MDCK) cell line. Cell clones that secrete enzymatically active chicken lysozyme were generated by transforming the cells with lysozyme cDNA inserted in a SV40-pBR322 recombinant vector and a dominant selectable marker gene. The kinetics and polarity of lysozyme secretion from one transformed cell clone were studied using cell monolayers grown on nitrocellulose filters. Lysozyme was secreted into the apical and the basolateral medium, demonstrating the existence of direct transport pathways to each cell surface. Control experiments excluded the effects of monolayer leakiness, reabsorption, transepithelial transport, and depolarization. In contrast, the secretion of a set of endogenous proteins of MW 30-40 kd was found to be strictly apical showing that polarized secretion also occurs in this cell line. The latter group of proteins appear to be generated from larger precursor molecules by intracellular cleavage.

Animals↗
PubMed1984

A novel in vitro transcription-translation system: accurate and efficient synthesis of single proteins from cloned DNA sequences.

A system is described which permits the efficient synthesis of single proteins in vitro. The essential element in this expression system is a strong promoter derived from coliphage T5 which produces, with high efficiency, specific RNAs in capped or uncapped form, depending upon the experimental conditions used. The transcription-coupled capping of RNA allows the direct translation of the RNA in eukaryotic extracts from wheat germ as well as from HeLa cells. The synthesis of three different proteins is reported, including lysozyme, which is shown to be translocated across membranes when appropriate assay conditions are used. The simplicity of the experimental procedure, the high purity and specific activity of the [35S]methionine-labelled proteins produced offer a number of possibilities for the study of structure-function relationships of proteins.

Cell-Free System↗
PubMed1983

The oocyte as a secretory cell.

Xenopus laevis oocytes secrete a large variety of foreign secretory proteins after the microinjection of mRNA or DNA. Two classes of such proteins are discussed in detail. These are the chick oviduct proteins ovalbumin and lysozyme, and the mouse MOPC 21 immunoglobulin. The injection of mRNAs for mouse immunoglobulin heavy or light chain leads to the synthesis, segregation, but not secretion of the encoded proteins unless the two mRNAs are simultaneously or sequentially injected into the same oocytes. Chicken ovalbumin and lysozyme are synthesized and secreted from oocyte after the injection of either oviduct mRNA or cloned DNA (ovalbumin). The secreted lysozyme is exported considerably faster than ovalbumin; however, 40% of the lysozyme synthesized cannot be secreted and, after fractionation of oocytes on sucrose gradients, is found in a higher density position than ovalbumin. No competition at the level of secretion or translation was noted when different amounts of immunoglobulin and ovalbumin mRNAs were injected into oocytes. However, the co-injection of ovalbumin mRNA and mRNAs encoding anti-ovalbumin immunoglobins resulted in the formation of a complex of the two types of protein within the oocyte. In these circumstances, secretion of the immunoglobulin was severely reduced.

Animals↗