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Biomedical subjects

E Rubin

Publications and source records attributed to E Rubin.

At least 37 records · Page 2Linked to original sources
PubMed2000

Pharmacokinetics of orally administered camptothecins.

Phase I trials of oral camptothecins, including camptothecin (CPT) and irinotecan (CPT-11), have reported substantial interpatient variability in systemic exposure, which could result in suboptimal antitumor activity in some patients or enhanced risk for toxicity in others. This investigation evaluates the contribution of intestinal absorption and first-pass metabolism in the disposition of oral CPT and CPT-11, respectively. The transport of CPT in Caco-2 cell lines (validated model of intestinal drug transport) was concentration dependent and saturable (Vmax: 34 x 10(-5) cm/sec and Km: 20 microM), and was temperature dependent with an activation energy (Ea) of 11.7 kcal/mole. Cumulatively, this data was indicative of carrier-mediated intestinal transport. In addition, a reduction of transport in the presence of sodium azide plus deoxyglucose suggested ATP dependence. Thus, variable expression and availability of intestinal transporters could contribute to the observed wide variability in the exposure to oral CPT. CPT-11 is hydrolyzed by the ubiquitous enzyme carboxyl esterase to active SN-38, and first-pass metabolism of oral CPT-11 would include both intestinal and hepatic hydrolysis. Incubation of CPT-11 with S9 fractions of human liver and intestinal tissues resulted in variable rates of formation of SN-38. The mean (+/- SD) specific activities (pmoles/min/mg) were: liver (8.57 +/- 10.4, n = 8), duodenum (5.06 +/- 3.7, n = 4), jejunum (6.44 +/- 2.8, n = 5), ileum (4.81 +/- 2.4, n = 5), colon (1.93 +/- 1.5, n = 6), and rectum (0.82, n = 1). Interestingly, there was a decrease in SN-38 formation by tumor tissue compared to matched normal liver and colon tissues. Therefore variable first-pass metabolism could contribute to the substantial differences in the systemic exposures to CPT-11 and SN-38 in patients receiving oral CPT-11.

Administration, Oral↗
PubMed2000

Changes in activity and regulation of the cardiac Ca2+ channel (L-type) by protein kinase C in chronic alcohol-exposed rats.

BACKGROUND: It has been reported recently that long-term alcohol exposure in rats increases the number of dihydropyridine binding sites in cardiac membrane preparations. We fed Sprague Dawley rats a liquid diet that contained ethanol as 36% of total calories for 4 to 6 months and studied how alcohol exposure affected the activity and regulation of the cardiac Ca2+ channel. METHODS: Dihydropyridine-sensitive cardiac Ca2+ channel activity was measured as the rate of Mn2+ quench of the cytosolic fura-2 signal in electrically stimulated myocytes. RESULTS: In control rat myocytes, pretreatment with phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), reduced the rate of Mn2+ quench to 68% of the untreated cell response. Pretreatment with GF109203X, a protein kinase C inhibitor, enhanced the rate of influx by 56%, whereas Gö6976, an inhibitor of PKC alpha, beta, and gamma, did not affect the rate of influx. By contrast, PMA did not affect the rate of Mn2+ quench in alcoholic myocytes; however, the PKC inhibitor GF109203X still enhanced the rate of Mn2+ quench by 33%. Similar to control myocytes, no effect was observed after pretreatment with Gö6976 in the alcoholic cells. In both Western blot and immunoprecipitation experiments, PKC epsilon expression in alcohol-exposed myocytes was reduced to 68% of the control. However, the ratio of membrane/ cytosolic distribution of PKC epsilon in alcoholic myocytes was increased from 1.6 to 2.6. No change was detected in the expression of PKC alpha and PKC delta. PKC activity, measured in the presence of Gö6976, which inhibits PKC alpha, beta, and gamma, was reduced in alcoholic myocytes to 57% of the control, but the proportion of PKC activity in the particulate fraction was increased from 26% in the control myocytes to 36% in the alcoholic myocytes. CONCLUSIONS: Altered expression and activity of PKC may be associated with changes in the regulation of the cardiac Ca2+ channel found in the hearts of rats chronically exposed to alcohol. Specifically, we found that the novel class of PKC isozymes is responsible for regulating the cardiac Ca2+ channel in control cardiomyocytes, and that the loss of PMA modulation found in the alcoholic cells may be due, in part, to reduced expression and altered distribution of PKC epsilon.

Alcoholism↗
PubMed2000

Modeling alcohol's effects on organs in animal models.

Researchers have developed numerous animal models to investigate the development of various alcohol-related diseases. Such models have provided insights into the mechanism through which alcohol can induce liver damage. Animal models also have helped researchers explore the mechanisms by which both short-term (e.g., binge) and long-term drinking can interfere with the function of the heart, a condition referred to as alcoholic cardiomyopathy. Furthermore, animal models have provided substantial information on the causes of fetal alcohol syndrome. Such models have demonstrated that exposure to alcohol during gestation can lead to prenatal and postnatal growth retardation, characteristic facial malformations, immune system deficiencies, and alterations in the central nervous system.

Alcoholism↗
PubMed1999

The camptothecin-resistant topoisomerase I mutant F361S is cross-resistant to antitumor rebeccamycin derivatives. A model for topoisomerase I inhibition by indolocarbazoles.

DNA topoisomerase I is a major cellular target for antitumor indolocarbazole derivatives (IND) such as the antibiotic rebeccamycin and the synthetic analogue NB-506 which is undergoing phase I clinical trials. We have investigated the mechanism of topoisomerase I inhibition by a rebeccamycin analogue, R-3, using the wild-type human topoisomerase I and a well-characterized recombinant enzyme, F361S. The catalytic activity of this mutant remains fully intact, but the enzyme is resistant to inhibition by camptothecin (CPT). Here we show that the mutated enzyme is cross-resistant to the rebeccamycin analogue. Despite their profound structural differences, CPT and R-3 interfere similarly with the activity of the wild-type and mutant topoisomerase I enzymes, and the drug-induced cleavable complexes are equally sensitive to the NaCl concentration. CPT and IND likely recognize identical structural elements of the topoisomerase I-DNA covalent complex; however, differences do exist in terms of sequence-specificity of topoisomerase I-mediated DNA cleavage. For the first time, a molecular model showing that CPT and IND share common steric and electronic features is proposed. The model helps to identify a specific pharmacophore for topoisomerase I inhibitors.

Amino Acid Substitution↗
PubMed1999

Stomatocytosis is absent in "stomatin"-deficient murine red blood cells.

To examine the relationship between erythrocyte membrane protein 7. 2b deficiency and the hemolytic anemia of human hereditary stomatocytosis, we created 7.2b knock-out mice by standard gene targeting approaches. Immunoblots showed that homozygous knock-out mice completely lacked erythrocyte protein 7.2b. Despite the absence of protein 7.2b, there was no hemolytic anemia and mouse red blood cells (RBCs) were normal in morphology, cell indices, hydration status, monovalent cation content, and ability to translocate lipids. The absence of the phenotype of hereditary stomatocytosis implies that protein 7.2b deficiency plays no direct role in the etiology of this disorder and casts doubt on the previously proposed role of this protein as a mediator of cation transport in RBC.

Anemia, Hemolytic, Congenital↗
PubMed1999

Characteristics of medical students completing an honors program in pathology.

The Honors Program in pathology at Jefferson Medical College provides a voluntary enrichment opportunity for students who have demonstrated a superior ability to cope with the pathology curriculum and who rank in the upper fifth of their class. This study was performed to determine whether honor students possess cognitive and psychosocial attributes that distinguish them from their classmates. Students from five academic years (entering classes 1991 to 1995) were divided into 3 groups: (1) those who completed the Honors Program (n = 85), (2) those in the top 20% of the class who were offered the option but chose not to participate in the Honors Program (n = 128), and (3) students who did not qualify for the program (n = 953). Comparisons between these three groups were made on the basis of selected measures of academic achievement retrieved from the Jefferson Longitudinal Study database and psychosocial data obtained from a questionnaire completed during the first-year orientation. Students who completed the Honors Program in pathology had scored higher on the physical science section of the Medical College Admission Test (MCAT) and had obtained higher first-year grade point averages than students in both of the other groups. Subsequently, they attained higher second-year grade point averages and scored higher on Step 1 and Step 2 of the United States Medical Licensing Examination (USMLE), compared with their peers in the other groups. There were no significant differences in psychosocial measures between honor students and the rest of the cohort (group 3). However, students in the top 20% of the class who declined the invitation to participate in the Honors Program (group 2) showed higher scores on the Taylor Manifest Anxiety Scale and the Eysenck Emotional Instability (Neuroticism) Scale than did their classmates. Despite these differences, students who completed the Honors Program (group 1) and eligible students who declined participation (group 2) selected similar pathways of postgraduate residency training: both groups preferred internal medicine to family practice, and both were more likely than the rest of the cohort to begin residency training at a top-ranked academic/research medical center. Voluntary participation in an Honors Program is a self-selection system that identifies students who are most likely to succeed academically at the highest levels. Residency selection committees may wish to pay dose attention to student involvement in similar programs, because this information may provide insights into student personality and general aptitude.

Anxiety↗
PubMed1999

Topoisomerase-I inhibitors in gynecologic tumors.

The first section of this article reviews recent studies that have clarified both the cellular role of topoisomerase I and the mechanisms of cytotoxicity of the topoisomerase inhibitors, the camptothecins. Different analogs of this new class of antitumor drug have been studied using various dose schedules in the treatment of refractory or recurrent gynecologic cancer. Response rates are between 13% and 25%. The main toxic effects are hematologic and gastrointestinal, the latter remains problematic. Radiotherapy, alkylate, platinum analogues, and topoisomerase II inhibitors are currently being studied in combination with camptothecins.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Leucovorin, 5-fluorouracil, and gemcitabine: a phase I study.

Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU). The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0-2, and signed informed consent. Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m2, 5FU 255 mg/m2 and gemcitabine 600 mg/m2. 5FU and gemcitabine were escalated in tandem to 340 mg/m2 and 800 mg/m2 and thereafter to 425 mg/m2 and 1000 mg/m2, respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1-32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses. The maximum tolerated dose is leucovorin 20 mg/m2, 5FU 340 mg/m2, and gemcitabine 800 mg/m2. The impact of drug sequence remains undetermined.

Adult↗
PubMed1999

Protein 4.1R-deficient mice are viable but have erythroid membrane skeleton abnormalities.

A diverse family of protein 4.1R isoforms is encoded by a complex gene on human chromosome 1. Although the prototypical 80-kDa 4.1R in mature erythrocytes is a key component of the erythroid membrane skeleton that regulates erythrocyte morphology and mechanical stability, little is known about 4.1R function in nucleated cells. Using gene knockout technology, we have generated mice with complete deficiency of all 4.1R protein isoforms. These 4.1R-null mice were viable, with moderate hemolytic anemia but no gross abnormalities. Erythrocytes from these mice exhibited abnormal morphology, lowered membrane stability, and reduced expression of other skeletal proteins including spectrin and ankyrin, suggesting that loss of 4. 1R compromises membrane skeleton assembly in erythroid progenitors. Platelet morphology and function were essentially normal, indicating that 4.1R deficiency may have less impact on other hematopoietic lineages. Nonerythroid 4.1R expression patterns, viewed using histochemical staining for lacZ reporter activity incorporated into the targeted gene, revealed focal expression in specific neurons in the brain and in select cells of other major organs, challenging the view that 4.1R expression is widespread among nonerythroid cells. The 4.1R knockout mice represent a valuable animal model for exploring 4.1R function in nonerythroid cells and for determining pathophysiological sequelae to 4.1R deficiency.

Animals↗
PubMed1999

Service use by elderly patients after psychiatric hospitalization.

The extent and source of services used by older adults discharged to a community setting after a psychiatric hospitalization were examined in a prospective follow-up study. Patients were asked about service use in structured telephone interviews one month after hospital discharge. Subjects had comorbid medical conditions and high levels of functional impairment. Service use was low, highly skewed, and spread across three sectors of care-mental health specialty care (38 percent of the services), general medical care (35 percent), and social services and formal aging services (27 percent). Most service episodes were related to mental disorder.

Aftercare↗
PubMed1999

Phase I clinical and pharmacologic study of 13-cis-retinoic acid, interferon alfa, and paclitaxel in patients with prostate cancer and other advanced malignancies.

PURPOSE: Recent studies demonstrate that retinoids decrease expression of the anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and act synergistically with interferon alfa (IFNalpha) to inhibit tumor cell growth in vitro. A phase I trial of 13-cis-retinoic acid (CRA), IFNalpha, and paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination. Pharmacodynamic studies were performed to determine whether CRA and IFNalpha could modulate bcl-2 expression in vitro and in patients. PATIENTS AND METHODS: Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFNalpha and escalating doses of TAX. The effect of CRA/IFNalpha on TAX pharmacokinetics was analyzed in both patients and human liver microsomes. The effect of CRA/IFNalpha on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting. RESULTS: CRA 1 mg/kg on days 1 to 4, IFNalpha 6 MU/m(2) subcutaneously on days 1 to 4, and TAX 175 mg/m(2) on day 3 was well tolerated. Pharmacokinetic studies demonstrated that CRA/IFNalpha caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-time curve values of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced conversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFNalpha decreased bcl-2 expression in vitro and in PBMCs. CONCLUSION: CRA/IFNalpha and TAX is a well-tolerated regimen. CRA/IFNalpha increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFNalpha can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFNalpha/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response.

Adult↗
PubMed1999

Sonographic evaluation of infiltrating lobular carcinoma.

OBJECTIVE: Infiltrating lobular carcinoma (ILC), which accounts for 7-10% of all breast malignancies, often poses diagnostic difficulties. The purpose of our study was to correlate the clinical, mammographic, and sonographic findings in each histologic subtype of ILC and to evaluate the sensitivity of sonography in its diagnosis. MATERIALS AND METHODS: We reviewed 208 cases of invasive lobular carcinoma. In 81 of these tumors, sonography was performed to further examine a mammographically invisible palpable abnormality or a mammographically subtle lesion. A dedicated breast pathologist classified each of these tumors as pure invasive lobular carcinoma or mixed invasive lobular and ductal carcinoma. Pure ILC tumors were further subclassified as one of five histologic subtypes. We retrospectively studied the clinical, mammographic, and sonographic findings in each histologic tumor subtype. RESULTS: The most common sonographic appearance of ILC was a heterogeneous, hypoechoic mass with angular or ill-defined margins and posterior acoustic shadowing, which was seen in 60.5% (49/81) of tumors. Of the remaining 32 tumors, 15% (12/81) showed focal shadowing without a discrete mass, 12% (10/81) appeared as a lobulated, well-circumscribed mass, and 12% (10/81) were sonographically invisible. Although considerable overlap occurred among histologic subtypes, classic ILC tended to present as focal shadowing without a discrete mass; pleomorphic ILC typically was seen as a shadowing mass; and, of all the tumor subtypes, signet, alveolar, and solid ILC were most likely to be revealed on sonography as a lobulated, well-circumscribed mass. In the 81 mammographically subtle or invisible lesions, sonography detected the tumor in 87.7% (71/81). The sensitivity of sonography in tumors smaller than 1 cm was 85.7% (12/14). CONCLUSION: High-resolution sonography of the breast is a useful adjunct in the evaluation of ILC, a neoplasm that frequently presents a clinical and mammographic diagnostic challenge.

Breast↗