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Biomedical subjects

G Stoner

Publications and source records attributed to G Stoner.

At least 19 recordsLinked to original sources
PubMed2000

Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis.

Exisulind (sulindac sulfone; FGN-1), a metabolite of sulindac without known effects on prostaglandin synthesis, can promote apoptosis and inhibit tumorigenesis in preclinical systems. We performed a Phase I trial of this compound in patients with familial adenomatous polyposis (FAP) to examine the tolerability and safety of this drug in the cancer chemoprevention setting. Six patients each were treated with exisulind at doses of 200, 300, and 400 mg p.o. twice a day. Reversible hepatic dysfunction was noted in four of six patients treated at the 400-mg p.o., twice-a-day dose level, but in only one to two of six patients treated at each of the lower dose levels. The serum half-life of exisulind was 6-9 h; little drug accumulation was noted over time. A nonsignificant trend toward increased apoptosis in polyps was noted at the maximum tolerated dose, but no decrease in polyp numbers or significant effects on cellular proliferation was noted. After treatment, polyps tended to display a "halo" appearance grossly and mucinous differentiation histologically. The maximum safe dose of exisulind is 300 mg p.o. twice a day in patients with subtotal colectomies. Reversible hepatic dysfunction limits further dose escalation. A decrease in polyp numbers could not be demonstrated, but the trend toward increased apoptosis at the MTD and the observation of mucinous change histologically suggest that further investigation of drugs of this class might be warranted.

Adenomatous Polyposis Coli↗
PubMed1996

Carcinogenicity, DNA adduct formation and K-ras activation by 7H-dibenzo[c,g]carbazole in strain A/J mouse lung.

N-Heterocyclic polynuclear aromatic hydrocarbons (NHA) are environmental pollutants formed during the combustion of organic materials. 7-H-Dibenzo[c,g]carbazole (DBC) is a potent carcinogen in lung, liver and skin. We undertook these studies to determine whether tissue specificity for DBC lung carcinogenicity in the strain A/J mouse is mirrored by formation of DBC-DNA adducts in lung tissue and whether these adducts are consistent with mutation patterns in the K-ras gene. Strain A/J mice were given a single i.p. injection of DBC at doses of 0, 5, 10, 20 or 40 mg/kg and levels of DNA adducts in the lung were monitored by 32P-postlabeling on days 1, 3, 5, 7, 14 and 21. The remaining animals were sacrificed 8 months after DBC treatment and lung tumor multiplicity and K-ras mutation patterns in the tumors were determined. The lung tumor response to DBC was dose related, with an average of 4.7 +/- 1.2 tumors/mouse at 5 mg/kg and 48.1 +/- 5.5 tumors/mouse at 40 mg/kg. As many as seven DBC-DNA adducts were observed in the lung. DNA binding levels in the lung were highest at 40 mg/kg, with maximum binding at 5-7 days. At lower dose levels the maximum binding to DNA decreased and shifted to earlier time points. The DBC-DNA adduct in the lung with the highest level of binding at all dose levels was DBC-DNA adduct 3. The majority of DBC-induced mutations in the K-ras gene in the lung were A-->T (80%) transversions in the third base of codon 61, a mutation that has not been previously observed in chemically induced lung tumors in strain A/J mice.

Animals↗
PubMed1994

The utility of curriculum-based measurement for evaluating the effects of methylphenidate on academic performance.

Two case studies were conducted to investigate the utility of curriculum-based measurement of math and reading for evaluating the effects of methylphenidate on the academic performance of 2 students diagnosed with attention deficit hyperactivity disorder. Following baseline measurement, double-blind placebo-controlled procedures were employed to evaluate each student's response to three levels (5 mg, 10 mg, and 15 mg) of the medication. Results of the first study suggest that the curriculum-based measures were sensitive indicators of the student's response to medication. This finding was replicated in the second study. In the second study, when the student's follow-up dose of medication was based on trial-phase data, follow-up performance was improved compared to baseline performance. These case studies suggest that further research is warranted on the utility of curriculum-based measurements for monitoring and evaluating stimulant medication interventions with children with this disorder.

Adolescent↗
PubMed1993

ras mutations in 2-acetylaminofluorene-induced lung and liver tumors from C3H/HeJ and (C3H x A/J)F1 mice.

Previous studies have demonstrated mutagenic specificity of 2-acetylaminofluorene (AAF) in several strains of bacteria and mammalian cells. Examination of AAF-induced B6C3F1 mouse liver tumor DNAs indicates a G-->T (or C-->A) transversion in the H-ras gene. In the present study, 6 mouse lung tumors [2 were from C3H/HeJ mice and 4 were from (C3H x A/J)F1 mice] and 20 C3H/HeJ mouse liver tumors induced by AAF were analyzed for the presence of activating mutations in the ras gene by utilizing polymerase chain reaction, single-strand conformation polymorphism, and direct DNA sequencing analysis. All of the lung tumors contained an activated K-ras protooncogene with an A-->T transversion at the second base of codon 61. The activating mutations in the H-ras gene were detected in 14 of 20 AAF-induced mouse liver tumors with 13 of 14 having a C-->A transversion at the first base of codon 61 and 1 of 14 having an A-->T transversion at the second base of codon 61. The selectivity of mutations in the ras oncogene observed in AAF-induced mouse lung and liver tumors, as compared to those in spontaneously occurring mouse lung and liver tumors, suggests that AAF may directly induce point mutations in the ras gene. The difference in the ras mutation spectra between lung and liver tumors induced by AAF indicates that AAF mutagenesis could be tissue-specific.

2-Acetylaminofluorene↗
PubMed1992

Parental bias of Ki-ras oncogenes detected in lung tumors from mouse hybrids.

A mouse strain with low lung tumor susceptibility (C3H) and a strain with high lung tumor susceptibility (A/J) were reciprocally crossed to produce C3A and AC3 F1 hybrid mice. Ki-ras oncogenes were detected in spontaneous and chemically induced lung tumors obtained from the C3A and AC3 mice. To further explore the genetics of the Ki-ras gene in mouse lung tumor susceptibility, the parental origin of Ki-ras oncogenes detected in lung tumors from the F1 hybrids was determined by a strategy based on a 37-base-pair deletion in the second intron of the A/J Ki-ras allele. Ki-ras oncogenes were derived from the A/J parent in 38 of 40 tumors obtained from C3A mice and 30 of 30 tumors from AC3 mice. The observation that the activated oncogene in hybrids originates from the susceptible parent suggests that the Ki-ras gene is directly linked to mouse lung tumor susceptibility. This finding may have implications for pulmonary adenocarcinoma development in humans, since Ki-ras oncogenes are detected in 35% of this human tumor type.

3T3 Cells↗
PubMed1992

Metabolism of N-nitrosomethyl-n-amylamine by microsomes from human and rat esophagus.

Asymmetric dialkylnitrosamines induce esophageal cancer in rats and hence might be involved in the etiology of this cancer in humans. As a test of this hypothesis, we examined whether nitrosamines can be activated by segments of human esophagus and by microsomes of human and rat esophagus and liver. Specimens of 8 human esophagi were removed less than 6 h after death, and segments were incubated for 6 h with 23 and 300 microM N-nitrosomethyl-n-amylamine (NMAA). Hydroxy-NMAA yields were determined by gas chromatography-thermal energy analysis and were insignificant except for those of 5-hydroxy-NMAA, which were low. Microsomes were prepared from 4 batches of human esophagi and samples with 0.6 mg protein were incubated for 20 min with NMAA and cytochrome P-450 cofactors. We determined hydroxy-NMAAs as before and aldehydes by high-performance liquid chromatography of their 2,4-dinitrophenylhydrazones. Incubation of these microsomes with 12 mM NMAA yielded mean values of 0.64 nmol formaldehyde ("demethylation"), 0.21 nmol pentaldehyde ("depentylation"), and 0.56 nmol total hydroxy-NMAAs/min/mg protein. Metabolite yields under various conditions were determined, including a demonstration that carbon monoxide inhibited 81% of NMAA demethylation, indicating that cytochrome P-450 enzymes were involved. We also examined N-nitrosodimethylamine (NDMA) demethylation by the same microsomes. Rat esophageal microsomes dealkylated NMAA and NDMA similarly to human esophageal microsomes, but with 2-6 times and twice the activity, respectively. Human and rat esophageal microsomes demethylated 6 mM NMAA 18-20 times as rapidly as they demethylated 5 mM NDMA, in contrast to liver microsomes of these species, which demethylated 6 mM NMAA only 0.9-1.4 times as rapidly as they demethylated 5 mM NDMA. However, liver microsomes of both species were more active than esophageal microsomes for NMAA depentylation. The occurrence of NMAA demethylation and (to a lesser extent) depentylation with both human and rat esophageal microsomes is important because these are the activating reactions, and suggests that both human and rat esophagus contain P-450 isozymes that specifically dealkylate asymmetric dialkylnitrosamines.

Animals↗
PubMed1988

Adrenal renin: a possible local hormonal regulator of aldosterone production.

The complete renin-angiotensin system is present in the adrenal cortex: prorenin, renin, angiotensinogen, angiotensin I and II, and converting enzyme. Most of the renin found is probably synthesized there since the renin concentration increases after nephrectomy, and the mRNA for renin is present. The renin-angiotensin system has the highest activity in the zona glomerulosa cells, the site of aldosterone formation. A low-sodium diet or a high-potassium diet, or nephrectomy markedly increases the adrenal renin concentration in the zona glomerulosa cells without any effect on the fasciculata-medullary cells. There is a close correlation between adrenal renin and aldosterone production. The adrenal renin angiotensin system may be a local regulator of aldosterone production.

Adrenal Glands↗
PubMed1986

Hyperactivity and frustration: the influence of control over and size of rewards in delaying gratification.

This study examined the differential effects of frustration on normal children and those diagnosed as having Attention Deficit Disorder with Hyperactivity. Each group consisted of 16 boys between the ages of 6 and 8 years who were prematched for age, grade, and classroom placement. All children completed a series of arithmetic problems in order to earn toy rewards. Using a variant of Mischel's (1974) delay-of-gratification paradigm, children were presented with two choice-of-delay conditions in a randomly assigned, counterbalanced sequence: a free-choice conflict situation involving a long-passive or short-active reward delay, and a short-active delay. Results showed that a significantly greater proportion of hyperactive children chose to complete problems for an immediate reward compared to their normal control counterparts (p less than .01). Group differences were no longer apparent in the short-active delay trial. The results are discussed in terms of frustration tolerance and contributing factors such as cognitive-attentional style. Implications for treatment and future directions are delineated.

Attention Deficit Disorder with Hyperactivity↗
PubMed1986

Regulation of proliferation and differentiation of respiratory tract epithelial cells by TGF beta.

In this paper we examined the effects of transforming growth factor beta (TGF beta) on the proliferation and differentiation of rabbit tracheal epithelial cells in primary culture. Treatment of these cells with TGF beta inhibits cell proliferation in a time- and dose-dependent manner; concentrations as low as 1 pM are able to inhibit cell growth. Concomitantly, TGF beta causes cells to accumulate in the G0/G1 phase of the cell cycle and a sharp reduction in the ability of the cells to form colonies after subculture at clonal density. These results indicate that TGF beta induces terminal cell division in these cells. The inhibition of cell growth is accompanied by changes in cell morphology and a stimulation of the formation of cross-linked envelopes. TGF beta enhances the levels of transglutaminase activity and cholesterol sulfate, two markers of squamous differentiation. Our results indicate that TGF beta induces terminal squamous cell differentiation in rabbit tracheal epithelial cells. Retinoic acid (RA) does not affect the commitment to terminal cell division induced by TGF beta, but inhibits the expression of the squamous phenotype. Growth of normal human bronchial epithelial cells was affected by TGF beta in a way similar to that of rabbit tracheal epithelial cells. Several carcinoma cell lines tested were quite resistant to TGF beta, whereas growth of one carcinoma cell line was stimulated by TGF beta. These results indicate that a modified response to TGF beta could be one mechanism involved in the aberrant growth control of malignant cells.

Animals↗
PubMed1986

Cholecystokinin-dopamine coexistence: electrophysiological actions corresponding to cholecystokinin receptor subtype.

Cholecystokinin (CCK)-like peptides when administered intravenously produce 2 distinct actions on the single-unit activity of mesencephalic dopamine (DA) neurons in the rat: an excitatory action and a potentiation of the inhibitory effects of DA agonists. The ability of several CCK fragments that have been shown to bind selectively to the peripheral and/or the central CCK-binding sites were examined for their ability to induce either excitation or a potentiation of DA. Only sulfated CCK-8 was able to induce excitation of mesencephalic DA neurons, but both sulfated and unsulfated CCK-8, as well as CCK-4, potentiated the inhibitory effects of the DA agonist apomorphine (APO). CCK-3 failed to potentiate APO-induced inhibition. Both of these effects appeared to be confined to cell bodies in regions of the ventral tegmental area and substantia nigra, zona compacta that have been reported to contain both DA and CCK. Thus, CCK-like peptides that have been shown to bind to the high-affinity CCK binding site in brain potentiated the effects of DA. In contrast, the ability of CCK-like peptides to induce neuronal excitation corresponds with their affinity for the peripheral-type CCK binding site.

Animals↗
PubMed1985

Methylphenidate in hyperactive children: differential effects of dose on academic, learning, and social behavior.

Methylphenidate (Ritalin) has been shown to have differential effects on hyperactive children's behavior as a function of dose level. In the present investigation, a triple-blind, placebo-control, within-subject (crossover) experimental design was employed in which 12 hyperactive boys between 6 and 10 years received three different dosages of methylphenidate (5, 10, and 15 mg) in a randomly assigned sequence. Dosage effects were assessed on clinic-(PAL--Paired Associates Learning test) and school-(percent on task, teacher ratings, work completion rates, and accuracy) related behaviors. For 10 of the children, classified as responders to medication by the PAL using the criteria of Swanson, Kinsbourne, and colleagues, a series of ANCOVAs with repeated measures showed significant dosage effects on teacher ratings (p less than .01), percent on task (p less than .01), academic accuracy (p less than .05), and assignment completion rates (p less than .05). PAL performance was also significantly enhanced (p less than .01) after optimal dose levels were considered. Subsequent trend analysis showed a significant positive linear relationship between dose and each of the dependent variables. A comparison of fixed-dose and miligram-per-kilogram plots showed that children's performance across the different dosages were clearly individualistic and task-specific, even when similar body weights were compared. The implications of using clinic-based testing to determine optimal medication responsivity were discussed.

Achievement↗
PubMed1985

Attention deficit disorder with hyperactivity: differential effects of methylphenidate on impulsivity.

The impulsivity component of attention deficit disorder with hyperactivity requires regulation because its effects interfere with children's school performance and persist into adulthood. The present investigation examined the effects of low to intermediate doses of methylphenidate on impulsivity (measured by the Matching Familiar Figures test, a primary index of cognitive tempo) in 14 children with attention deficit disorder with hyperactivity. The mean percentile error score in the highest dose (15 mg) group was significantly lower than those in placebo (P less than .01), 5-mg (P less than .01), and 10-mg (P less than .01) groups. Trend analysis revealed a linear relationship between dose and error score with total errors decreasing as dose increased. Changes in children's error scores were examined using both fixed-dose and milligram per kilogram data-plotting methods. This work demonstrates the need to consider specific task and child characteristics while assessing the child's responsivity to psychostimulants across a range of safe doses and a variety of behavioral domains.

Attention Deficit Disorder with Hyperactivity↗