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Biomedical subjects

C Whalen

Publications and source records attributed to C Whalen.

51 records · Page 3Linked to original sources
PubMed1986

Pharmacokinetic determinants of 6-mercaptopurine myelotoxicity and therapeutic failure in children with acute lymphoblastic leukemia.

The pharmacokinetics of oral 6-mercaptopurine (6MP) was assessed in 20 children with acute lymphoblastic leukemia during maintenance therapy. The AUC was between 0 and 6 X 10 ng X min/ml, and AUC normalized to 1 mg/m2 of 6MP was between 0 and 815 ng X min/ml. Good correlation existed between peak concentrations and AUC (r = 0.866; P less than 0.001). In more than half of the cases there was evidence of prolonged elimination t1/2 or rebound of a serum concentration during the elimination phase corresponding to either an additional compartment or enterohepatic circulation of 6MP. One child did not achieve detectable concentrations on 2 different study days and was switched to a different protocol. The two children who had severe myelotoxicity achieved the largest AUC values per milligram per square meter of 6MP. Our results indicate that pharmacokinetic variability may contribute to either severe myelotoxicity or therapeutic failures. This suggests that monitoring of this drug in children with acute lymphoblastic leukemia may be helpful.

Administration, Oral↗
PubMed1985

Leaf k interaction with water stress inhibition of nonstomatal-controlled photosynthesis.

The relationship between leaf K(+) concentration, in vitro dehydration, and nonstomatal-controlled photosynthesis was investigated using leaf slices that were vacuum infiltrated with media containing varying sorbitol concentrations. The leaf slices were from plants either supplied with complete or K(+)-deficient medium throughout a 35-day growth period. During this time, leaf K(+) concentration, water potential, osmotic potential, and turgor pressure were monitored. Leaf K(+) concentration averaged 239 micomoles per gram (fresh weight) in control plants, and dropped to 74.3 micromoles per gram (fresh weight) in K(+)-deficient plants. Less negative osmotic potentials and resultant turgor loss in K(+)-deficient plants indicated that the osmotically active pool of cellular K(+) was lower in those plants.The decrease in leaf K(+) concentration enhanced the dehydration inhibition of photosynthesis. For example, increasing sorbitol from 0.33 to 0.5 molar during incubation inhibited photosynthesis in the controls by 14% or less. This same protocol resulted in an inhibition of photosynthesis by as much as 41% in K(+)-deficient tissue. In contrast to the data obtained with leaf slices, dehydration inhibition of isolated chloroplast photosynthesis was not affected by K(+) status of parent plant material. These data are consistent with the hypothesis that one effect of leaf K(+) deficiencies on photosynthetic response to dehydration may be mediated by extra-choloroplastic factors.Ammonium ions, which facilitate stromal alkalinization, reversed the increased sensitivity of K(+)-deficient leaf slice photosynthesis to cell dehydration. However, NH(4) (+) had no effect on photosynthesis of K(+)-deficient leaf slices under nonhypertonic conditions. These data suggest that endogenous extra-chloroplastic K(+) may modulate dehydration inhibition of photosynthesis, possibly by facilitating stromal alkalinization.

Journal Article↗
PubMed1984

Vomitoxin (4-deoxynivalenol): effects on reproduction of mice and rats.

Weanling male and female mice (F0) were fed daily diets containing 4-deoxynivalenol (DON) at concentrations that resulted in a dose of 0 or 2.0 mg/kg body wt in Experiment I and 0, 0.375, 0.75, or 1.5 mg/kg body wt in Experiment II. The test diets were continuously fed to the F0 parents and their progeny for the entire duration of these two experiments, which were similar in design. After 30 days of dietary feeding, the mice were allowed to mate within experimental groups for a maximum of three 5-day trials. Females found to have mated successfully were allowed to litter normally. The F1a progeny from 10 dams of each control and 1.5-mg DON/kg groups were cross-fostered at birth, whereas all of the remaining F1a progeny were reared by their natural dams. The progeny were examined until 21 days of age and discarded. The F0 mice were rebred. The females bred to produce the F1b litters were killed on Day 19 of gestation and their fetuses were examined for gross, visceral, and skeletal malformations. Reductions were observed in feed and water intakes and body weight of F0 male and female mice, the number of live pups and postnatal survivors, postnatal body weight of F1a progeny, number of live fetuses, and mean fetal weight of F1b fetuses. No adverse effects on fertility of F0 male and female mice and no major malformations in F1b were found. Cross-fostering offspring between control dams and 1.5-mg DON/kg-treated dams revealed that both postnatal survival and body weight were adversely affected by prenatal exposure as well as by a combined pre- and postnatal exposure. Male and female Sprague-Dawley rats were fed diets containing DON so as to deliver daily doses of 0.25, 0.5, or 1.0 mg/kg body wt. After 6 weeks of feeding, the rats were bred within groups and the males were then discarded. The mated females, maintained on their respective diets for the entire period of pregnancy, were killed on the last day of pregnancy and fetuses evaluated for effects on prenatal development. Except for dilation of renal pelvis and urinary bladder, the significance of which remains undetermined, no other adverse effect was observed.

Abnormalities, Drug-Induced↗
PubMed1982

Teratogenicity study on pyrethrum and rotenone (natural origin) and ronnel in pregnant rats.

Insecticidal formulations in the form of dusts or aerosols containing rotenone from the root of Derris elliptica and pyrethrum from the flower of Chrysanthemum cinerariaefolium are commonly used in homes and gardens. Ronnel (fenchlorphos), a systemic insecticide, is used to control house flies and, upon oral treatment, ectoparasites of cattle. These insecticides are extensively used and their teratologic potential has not been fully investigated. Technical grades of rotenone at 0, 2.5, 5, or 10 mg/kg, pyrethrum at 0, 50, 100, or 150 mg/kg (rotenone and pyrethrum were of natural origin) and ronnel at 0, 400, 600 or 800 mg/kg were tested. Each of these was suspended in corn oil and administered orally in single daily doses on d 6-15 of pregnancy to Wistar rats. The dams were killed on the last day of pregnancy, and all fetuses were evaluated following routine teratologic methods. Rotenone was associated with an increased number of nonpregnant rats and resorptions, at a dose of 10 mg/kg; reductions in maternal body weight gain, fetal weight, and skeletal ossification, together with an increased incidence of extra rib, were found at 5 and 10 mg/kg; but no significant effects were found at 2.5 mg/kg. Increases in the incidence of resorptions in pyrethrum-treated groups and of extra rib in ronnel-treated groups were also observed.

Animals↗
PubMed1979

Teratologic assessment of maleic hydrazide and daminozide, and formulations of ethoxyquin, thiabendazole and naled in rats.

Teratogenicity studies were conducted in rats treated orally from days 6-15 of gestation with single daily doses of 400-1600 mg/kg of maleic hydrazide, 300-1000 mg/kg daminozide, 125-500 mg/kg ethoxyquin or thiabendazole, or 25-100 mg/kg naled. Dams were killed on the 22nd day of gestation, and fetuses were evaluated by routine teratologic methods. No adverse effect was related to any treatment other than an increased incidence of anomalous fetuses at the highest dose (500 mg/kg) of thiabendazole.

Animals↗
PubMed1979

The significance of augmented radiocolloid uptake by the spleen in patients with malignant melanoma.

Increase in splenic uptake of Tc-99m sulfur colloid was noted in 47 of 147 (32%) patients with cutaneous malignant melanoma early in the coure of disease. Patients with disseminated disease and/or clinical or laboratory evidence of hapatic dysfunction were excluded from study. Recurrence rate of 2 yr was higher for those patients with splenic scans demonstrating augmented uptake compared with patients having normal scans, 36% against 16% (p less than 0.02). These differences resulted from a much more favorable prognosis in women with normal scans contrasted with women with increased uptake, 6% against 26% (p less than 0.05). Women with increased splenic uptake, and all men regardless of scan status, seemed to have a higher rate of recurrence than women with normal spleen scans. Scan status may be an adjunctive prognostic marker in women.

Colloids↗
PubMedDate not supplied

Soluble IL-2 receptor beta and gamma subunits: ligand binding and cooperativity.

Biologically relevant interleukin-2 receptors (IL-2Rs) are present in two affinity states on responsive cells. High affinity receptors (HAR) apparently exist as heterotrimers (alpha, beta and gamma) while the other functional complex, the intermediate affinity receptor (IAR), is comprised of beta and gamma chains. The mechanisms by which the beta and gamma subunits contribute the formation of HAR and IAR are still unclear. Soluble forms of the beta and gamma chains were cloned, epitope-tagged, expressed in insect cells and purified. IL-2 binding and neutralization of IL-2 bioactivity by beta and gamma extracellular domains (ectodomains) was analyzed by several biochemical and biological approaches. The results indicate that beta clearly binds IL-2 with low affinity (KI-KD = 3 microM) whereas gamma binding is detectable, but of very low affinity (apparent KI > 15 microM) in the absence of beta. Interestingly, combinations of beta and gamma ectodomains interact to bind IL-2 with higher affinity and greater stability than either chain alone. An apparent stable binding complex is formed when beta, gamma, and IL-2 are combined. Ligand binding by the beta and gamma chains in solution is specific for IL-2 and is of sufficient affinity and stability to effectively neutralize IL-2 in biological assays (binding IC50 = biological IC50). Direct analyses of binding kinetics by surface plasmon resonance reveals that the increased affinity and biological neutralizing ability of beta gamma, as compared to beta, is due to a very slow dissociation rate contributed by the gamma ectodomain. While IL-2R beta and gamma cytoplasmic and transmembrane domains are not essential for interactive binding of IL-2, they may contribute to IL2 binding affinity. The recognition and association of IL-2 by the beta gamma IAR appears to be contributed primarily by the beta chain while the stability and dissociation is likely dominated by the gamma chain. It is anticipated that the gamma subunit functions in a similar manner when participating in high affinity IL-4 and IL-7 binding.

Binding, Competitive↗