Search PubMed⌕ Search

Biomedical subjects

K Johnson

Publications and source records attributed to K Johnson.

At least 163 records · Page 9Linked to original sources
PubMed1998

Cellular but not plasma pharmacokinetics of lometrexol correlate with the occurrence of cumulative hematological toxicity.

Lometrexol inhibits the first folate-dependent enzyme in de novo purine biosynthesis and is avidly polyglutamated and retained in tissues expressing folylpolyglutamate synthetase. Although clinical studies have been limited by cumulative toxicity, preclinical studies show that pretreatment with folic acid can protect normal tissue while maintaining tumor cytotoxicity. Therefore, a Phase I study of lometrexol every 21 days preceded by i.v. folic acid was initiated. Lometrexol was studied in six patients at 15 mg/m2, in six patients at 20 mg/m2, in three patients at 25 mg/m2, and in nine patients at 30 mg/m2. Patients received either 5 mg of folic acid 1 h before or 25 mg/m2 3 h before lometrexol. Blood samples were obtained around the first course and weekly thereafter for determination of plasma and erythrocyte (RBC) lometrexol concentrations. Bioactive folates in plasma and RBCs were determined in a subset of patients. Lometrexol pharmacokinetics were best described by a three-compartment model. Mean clearance and volume of distribution were 1.6 +/- 0.6 liters/h/m2 and 8.9 +/- 4.1 liters/m2. Mean half-lives were 0.23 +/- 0.1, 2.9 +/- 1.4, and 25.0 +/- 48.7 h. Pharmacokinetics were independent of either lometrexol or folic acid dose. In the weekly blood samples, RBC lometrexol levels rose, long after plasma lometrexol was undetectable. RBC lometrexol levels were independent of folic acid or lometrexol dose. Bioactive folates measured in plasma and RBCs during this same time period did not accumulate. Rising RBC levels were correlated with a fall in hematocrit, hemoglobin, and platelet count. This study indicates that the cumulative toxicity of lometrexol is related to tissue concentration and not plasma pharmacokinetics. RBC lometrexol may be an indicator of cumulative drug exposure and effect.

Antimetabolites, Antineoplastic↗
PubMed1998

Activity of secreted Kunitz domain 1 variants of tissue factor pathway inhibitor.

Tissue factor pathway inhibitors (TFPI and TFPI-2) are Kunitz domain-type serine protease inhibitors which inhibit factor VIIa/tissue factor (VIIa/TF) complexes in a factor Xa-dependent manner. The VIIa/TF and Xa inhibitory activity has been localized to the first two Kunitz domains, respectively. Unlike TFPI, TFPI-2 has been reported to exhibit significant Xa-independent VIIa/TF inhibitory activity, perhaps due to an arginine at the P1 residue in the first Kunitz domain of TFPI-2 as opposed to a lysine at the comparable residue in TFPI. Two domain TFPI variants, differing in the first Kunitz domain but containing the second Kunitz domain of TFPI, were constructed and secreted by Saccharomyces cerevisiae in order to test the possibility that a TFPI first Kunitz domain with a P1 lysine to arginine change or a hybrid containing the TFPI-2 first Kunitz domain may represent more potent VIIa/TF inhibitors. When yeast supernatants were analyzed for specific activity in the Xa-dependent inhibition of VIIa/TF, neither variant was as active as the truncated TFPI.

Aprotinin↗
PubMed1998

Neuropsychological functioning in HIV-positive African-American women with a history of drug use.

This preliminary investigation examined neuropsychological performance in a sample of human immunodeficiency virus (HIV)-positive and HIV-negative African-American women with a history of drug use. The study population was comprised of 10 HIV-negative, 9 asymptomatic HIV-positive, 13 symptomatic HIV-positive, and 10 acquired immunodeficiency virus (AIDS) patients. A neuropsychological battery designed to assess attention, psychomotor processing, verbal memory, and visual memory was administered to participants. No evidence of HIV-related cognitive impairment was found in patients in the early stages of HIV infection. Multivariate analyses of variance revealed significant deficits in psychomotor processing and verbal recall in persons with AIDS. These individuals showed greater difficulty in tasks requiring maintained attention and performed poorly on measures of immediate and delayed verbal recall. In contrast, HIV status was not related to visual memory, verbal recognition, or the number of errors made during a verbal recall task. The pattern of cognitive deficits observed in persons with AIDS resembles that commonly associated with subcortical pathology. The cognitive deficits observed were not related to depression or recentness of drug use.

Adult↗
PubMed1997

Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression patterns.

BACKGROUND: Growth factor receptor-signaling pathways are potentially important targets for anticancer therapy. The interaction of anticancer agents with specific molecular targets can be identified by correlating target expression patterns with cytotoxicity patterns. We sought to identify new agents that target and inhibit the activity of the epidermal growth factor (EGF) receptor and of c-erbB2 (also called HER2 or neu), by correlating EGF receptor, transforming growth factor (TGF)-alpha (a ligand for EGF receptor), and c-erbB2 messenger RNA (mRNA) expression levels with the results of cytotoxicity assays of the 49000 compounds in the National Cancer Institute (NCI) drug screen database. METHODS: The levels of mRNAs were measured and used to generate a molecular target database for the 60 cell lines of the NCI anticancer drug screen. The computer analysis program, COMPARE, was used to search for cytotoxicity patterns in the NCI drug screen database that were highly correlated with EGF receptor, TGF-alpha, or c-erbB2 mRNA expression patterns. The putative EGF receptor-inhibiting compounds were tested for effects on basal tyrosine phosphorylation, in vitro EGF receptor tyrosine kinase activity, and EGF-dependent growth. Putative ErbB2-inhibiting compounds were tested for effects on antibody-induced ErbB2 tyrosine kinase activity. RESULTS: EGF receptor mRNA and TGF-alpha mRNA levels were highest in cell lines derived from renal cancers, and c-erbB2 mRNA levels were highest in cells derived from breast, ovarian, and colon cancers. Twenty-five compounds with high correlation coefficients (for cytotoxicity and levels of the measured mRNAs) were tested as inhibitors of the EGF receptor or c-erbB2 signaling pathways; 14 compounds were identified as inhibitors of these pathways. The most potent compound, B4, inhibited autophosphorylation (which occurs following activation) of ErbB2 by 50% in whole cells at 7.7 microM. CONCLUSIONS: Novel EGF receptor or c-erbB2 pathway inhibitors can be identified in the NCI drug screen by correlation of cytotoxicity patterns with EGF receptor or c-erbB2 mRNA expression levels.

Antineoplastic Agents↗
PubMed1997

Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic.

The TGF-beta (transforming growth factor-beta)-related signalling proteins, including Decapentaplegic (Dpp) in Drosophila-and bone morphogenic proteins and activin in vertebrates, affect the growth and patterning of a great variety of structures. However, the mechanisms by which these ligands regulate gene expression are not understood. Activation of complexes of type I with type II receptors results in the phosphorylation and nuclear localization of members of the SMAD protein family, which are thought to act as co-activators of transcription, perhaps in conjunction with sequence-specific cofactors. Here we show that the amino-terminal domain of the Drosophila Mothers against dpp protein (Mad), a mediator of Dpp signalling, possesses a sequence-specific DNA-binding activity that becomes apparent when carboxy-terminal residues are removed. Mad binds to and is required for the activation of an enhancer within the vestigial wing-patterning gene in cells across the entire developing wing blade. Mad also binds to Dpp-response elements in other genes. These results suggest that Dpp signalling regulates gene expression by activating Mad binding to target gene enhancers.

Animals↗
PubMed1997

Brief physician advice for problem alcohol drinkers. A randomized controlled trial in community-based primary care practices.

OBJECTIVE: Project TrEAT (Trial for Early Alcohol Treatment) was designed to test the efficacy of brief physician advice in reducing alcohol use and health care utilization in problem drinkers. DESIGN: Randomized controlled clinical trial with 12-month follow-up. SETTING: A total of 17 community-based primary care practices (64 physicians) located in 10 Wisconsin counties. PARTICIPANTS: Of the 17695 patients screened for problem drinking, 482 men and 292 women met inclusion criteria and were randomized into a control (n=382) or an experimental (n=392) group. A total of 723 subjects (93%) participated in the 12-month follow-up procedures. INTERVENTION: The intervention consisted of two 10- to 15-minute counseling visits delivered by physicians using a scripted workbook that included advice, education, and contracting information. MAIN OUTCOME MEASURES: Alcohol use measures, emergency department visits, and hospital days. RESULTS: There were no significant differences between groups at baseline on alcohol use, age, socioeconomic status, smoking status, rates of depression or anxiety, frequency of conduct disorders, lifetime drug use, or health care utilization. At the time of the 12-month follow-up, there were significant reductions in 7-day alcohol use (mean number of drinks in previous 7 days decreased from 19.1 at baseline to 11.5 at 12 months for the experimental group vs 18.9 at baseline to 15.5 at 12 months for controls; t=4.33; P<.001), episodes of binge drinking (mean number of binge drinking episodes during previous 30 days decreased from 5.7 at baseline to 3.1 at 12 months for the experimental group vs 5.3 at baseline to 4.2 at 12 months for controls; t=2.81; P<.001), and frequency of excessive drinking (percentage drinking excessively in previous 7 days decreased from 47.5% at baseline to 17.8% at 12 months for the experimental group vs 48.1% at baseline to 32.5% at 12 months for controls; t=4.53; P<.001). The chi2 test of independence revealed a significant relationship between group status and length of hospitalization over the study period for men (P<.01). CONCLUSIONS: This study provides the first direct evidence that physician intervention with problem drinkers decreases alcohol use and health resource utilization in the US health care system.

Adult↗
PubMed1997

Mechanisms of drug-induced lupus. III. Sex-specific differences in T cell homing may explain increased disease severity in female mice.

OBJECTIVE: To determine if sex-specific differences in lymphocyte trafficking could contribute to increased disease severity in female mice. METHODS: A lupus-like disease was induced by injecting male and female mice with procainamide-treated T cell clones. Trafficking was examined by labeling the injected cells with 51Cr or 5-chloromethylfluorescein diacetate. RESULTS: Females developed more autoimmune liver disease and greater titers of anti-DNA antibodies than did males, and 2-7 times more cells accumulated in the female spleens. Splenectomy prevented the development of autoantibodies and renal and liver disease. Oophorectomy decreased the splenic homing, autoantibody titer, and liver disease severity, to levels found in males. CONCLUSION: T cells traffic differently to the spleen in male and female mice, and the spleen appears to be essential in the disease process. This suggests that differences in T cell homing could contribute to sex-specific disease severity in this murine model, and also possibly in human disease.

Adoptive Transfer↗
PubMed1997

Mechanisms of drug-induced lupus. IV. Comparison of procainamide and hydralazine with analogs in vitro and in vivo.

OBJECTIVE: T cells treated with DNA methylation inhibitors overexpress lymphocyte function-associated antigen 1 (LFA-1), which results in autoreactivity, and the autoreactive cells cause a lupus-like disease in vivo, suggesting a mechanism by which some agents may cause drug-induced lupus. This study compared the effects of procainamide (Pca) and hydralazine (Hyd) with those of structural analogs, to determine if the degree of LFA-1 overexpression and T cell autoreactivity correlated with the ability of the agents to induce autoimmunity. METHODS: Cloned murine T helper 2 cells were treated with Pca, N-acetylprocainamide, Hyd, Phthalazine, or hydroxyurea (HU). The treated cells were then compared for LFA-1 overexpression, autoreactivity, and the ability to induce autoimmunity in vivo. RESULTS: Pca and Hyd were more potent than their analogs or HU in all 3 assays. CONCLUSION: The results support a relationship between LFA-1 overexpression, T cell autoreactivity, and autoimmunity, and suggest a mechanism by which Pca and Hyd, but not the analogs, may cause drug-induced lupus.

Animals↗
PubMed1997

Do individuals at risk for eating disorders exhibit negative priming deficits?

Fifty people (25 at risk for an eating disorder, 25 controls) performed a simple reaction-time (SRT) task and a negative-priming (NP) task. The two groups did not differ on the SRT task. For the NP task, the controls displayed the NP effect (responses on critical trials were slower than responses on control trials). At-risk participants, however, revealed no such NP effect. Although the pattern of NP performance in the at-risk participants may indicate that they as a group had deficiencies in their ability to inhibit irrelevant information, it is also possible that issues related to obsessionality, perfectionism, and restraint in the at-risk group affected the results.

Adult↗