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Biomedical subjects

B Osborne

Publications and source records attributed to B Osborne.

At least 19 recordsLinked to original sources
PubMed2001

Primary hepatic lymphoma: favorable outcome after combination chemotherapy.

BACKGROUND: Primary hepatic non-Hodgkin lymphoma (PHL) is a rare and difficult to diagnose lymphoproliferative disorder of unknown etiology. It is believed that the prognosis in affected patients is dismal, consisting of early recurrence and short survival. METHODS: A retrospective cohort review of patients with PHL diagnosed between 1974 and 1995 at a university cancer center was performed. RESULTS: Twenty-four patients with PHL were identified. Typically, the disease occurred in middle-aged men (median age, 50 years). The primary presenting complaint was right upper quadrant abdominal pain, with hepatomegaly found at physical examination. Serum liver enzymes, lactate dehydrogenase, and beta-2-microglobulin levels all were elevated, but alpha-fetoprotein and carcinoembryonic antigen levels were within normal range. Hypercalcemia was found in 6 of 15 patients who were tested. Six of 10 patients who were tested were positive for the hepatitis C virus (HCV). Liver scans demonstrated either a solitary lesion or multiple lesions. Pathologic examination revealed diffuse large cell lymphoma in 23 patients (96%). Combination chemotherapy was the mainstay of treatment; surgery consisted of diagnostic biopsy. The complete remission rate was 83.3%, and the 5-year cause specific and failure free survival rates were 87.1% and 70.1%, respectively. HCV infection did not appear to influence the outcome of therapy. CONCLUSIONS: The outcome of patients with PHL who are treated with combination chemotherapy may be more favorable than that reported elsewhere. The frequent association of PHL with HCV infection observed in this series warrants further investigation.

Adult↗
PubMed2001

Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells.

We investigated the interaction between two elements critical for differentiation of hemopoietic cells, the Notch-1 receptor and the transcription factor NF-kappaB. These factors were studied in hemopoietic progenitor cells (HPC) using Notch-1 antisense transgenic (Notch-AS-Tg) mice. DNA binding of NF-kappaB as well as its ability to activate transcription was strongly decreased in HPC from Notch-AS-Tg mice. NF-kappaB-driven transcriptional activity was completely restored after transduction of the cells with retroviral constructs containing activated Notch-1 gene. HPC from Notch-AS-Tg mice have decreased levels of several members of the NF-kappaB family, p65, p50, RelB, and c-Rel and this is due to down-regulation of the gene expression. To investigate functional consequences of decreased NF-kappaB activity in transgenic mice, we studied LPS-induced proliferation of B cells and GM-CSF-dependent differentiation of dendritic cells from HPC. These two processes are known to be closely dependent on NF-kappaB. B cells from Notch-AS-Tg mice had almost 3-fold lower response to LPS than B cells isolated from control mice. Differentiation of dendritic cells was significantly affected in Notch-AS-Tg mice. However, it was restored by transduction of activated Notch-1 into HPC. Taken together, these data indicate that in HPC NF-kappaB activity is regulated by Notch-1 via transcriptional control of NF-kappaB.

Animals↗
PubMed2001

Selective COX-2 inhibitors: a review of their therapeutic potential and safety in dentistry.

Anti-inflammatory analgesics are commonly used medications in dental and medical practice. Their uses in dentistry include use as analgesics and as anti-inflammatory agents. In addition, antipyretic action accompanies the medication. The action of these groups of drugs depends on the dose provided. Analgesic and antipyretic effects occur at low dose, whereas analgesic effects occur at high dose. Among the common side effects of this class of medications are gastrointestinal irritation with potential for ulceration, increased tendency for bleeding due to antiplatelet effects, and long-term chronic dosing effects on renal function may occur. Recent developments in the anti-inflammatory group of medications include the introduction of cyclooxygenase-II inhibitors. These agents offer potentially significant advantages because of their relative lack of gastrointestinal irritation. Because of this, it is likely that these medications will be frequently used in the management of dental and medical conditions. Patients will present while on these medications, and these agents may serve as medications for management of dental pain, postsurgical pain, and for anti-inflammatory effects. The current literature indicates that COX-2 inhibitors offer substantial benefits because of their favorable gastrointestinal profiles and because of their lack of effect on platelet function.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Arbiter of differentiation and death: Notch signaling meets apoptosis.

Notch-ligand interactions are a highly conserved mechanism that regulates cell fate decisions. Over the past few years, numerous observations have shown that this mechanism operates to regulate cell differentiation in an enormous variety of developmental and cell maturation processes. Recent studies indicate that in addition to cell differentiation, Notch signaling has direct effects on proliferation and programmed cell death. The picture emerging from these findings suggests that, depending on cellular and developmental context, Notch signaling may function as a general "arbiter" of cell fate, regulating differentiation potential, rate of proliferation, and apoptotic cell death. In this review, we briefly summarize the current knowledge of the structure and function of Notch receptors and discuss the recent evidence that Notch signaling regulates apoptotic cell death. The possible mechanisms of this effect and its potential implications for developmental biology, immunobiology, neuropathology, and tumor biology are discussed.

Alzheimer Disease↗
PubMed1999

Characterization of a mutant T-cell hybridoma line with defects in the TCR-mediated apoptotic pathway.

A mutant T-cell hybridoma line named mutant 51 was developed that, unlike the parental line, did not die after T-cell receptor (TCR) engagement and demonstrated reduced death in response to dexamethasone. Intracellular calcium measurements showed that available calcium stores were markedly reduced in the mutant cell line. Unlike control cells, secretion of IL-2 from mutant cells was also greatly reduced, although addition of exogenous IL-2 did not facilitate increased apoptosis. Although levels of the cell death gene product Nur77 were equivalent, additional studies showed that mutant cells expressed Nur77 predominantly in the cytoplasm following TCR engagement, while parental cells displayed a nuclear translocalization of Nur77. In addition, Fas levels and Fas ligand dependant killing were both markedly reduced in the mutant clone. From these data we hypothesize a role for available calcium stores and Nur77 nuclear localization in TCR-mediated apoptosis in T-cell hybridomas.

Apoptosis↗
PubMed1999

Concurrent administration of the erythromycin breath test (EBT) and oral midazolam as in vivo probes for CYP3A activity.

Given the prominent role of CYP3A in the metabolism of drugs, it is important to identify whether new chemical entities will affect this enzyme system and produce clinically relevant drug interactions. This study evaluated concomitant administration of intravenous [14C N-methyl] erythromycin (3 microCi) (erythromycin breath test; EBT) and 2 mg oral midazolam as probes of systemic and of systemic plus presystemic CYP3A activity, respectively. Twelve males received the probes in a two-period crossover fashion: one period included the probes on two occasions, 5 days apart; in the second period, 200 mg ketoconazole was given orally 2 hours prior to the probes. The within-subject CV for EBT (%14CO2/h) and midazolam AUC0-last was 4.9% and 16.9%, respectively. Ketoconazole reduced %14CO2/h by 43% and increased midazolam AUC0-last by approximately fivefold. In a nonrandomized third period (N = 5), ketoconazole was given simultaneously with midazolam (no EBT); midazolam AUC0-last was similar whether ketoconazole was given 2 hours prior to or simultaneously with the midazolam. The low midazolam dose was generally well tolerated; mild sedation was occasionally seen. Concurrent administration of the EBT and oral midazolam is a sensitive and reproducible tool to screen new chemical entities for potentially important CYP3A interactions.

Administration, Oral↗
PubMed1998

Malignant lymphoma involving the prostate: report of 62 cases.

BACKGROUND: Malignant lymphoma involving the prostate is rare, and to the authors' knowledge the factors determining patient outcome have not been studied in a large series. METHODS: The authors evaluated the clinical and pathologic findings in 60 cases of non-Hodgkin's lymphoma and 2 cases of Hodgkin's lymphoma involving the prostate. A variety of clinical and histologic findings were considered as factors predictive of patient outcome. RESULTS: Lymphoma tended to occur in elderly men, with a mean age at diagnosis of 62 years (range, 5-89 years), although 6 patients were age < 40 years (ages 5, 19, 30, 32, 38, and 38 years, respectively). Clinical signs and symptoms were due to lower urinary tract obstruction. Twenty-two patients (35%) presented with primary extranodal lymphoma of the prostate with a variety of histologic subtypes, including small lymphocytic (4 patients); follicular center cell, diffuse, small cell (2 patients); follicular center cell, Grade 1 (according to the revised European-American classification (small cleaved) (1 patient); Grade 2 (mixed) (1 patient); diffuse large B-cell (12 patients); and high grade B-cell lymphoma, Burkitt-like (2 patients). At the time of presentation, none of these patients had hepatosplenomegaly, inguinal lymphadenopathy, or an abnormal complete blood count. Thirty other patients (48%) with previously documented lymphoma at other sites developed prostatic involvement; these secondary prostatic lymphomas displayed a variety of subtypes, including small lymphocytic (8 patients, all with concomitant leukemia); follicular center cell lymphoma, diffuse, small cell (2 patients); follicular center, Grade 1 (small cell) (1 patient); follicular center, Grade 2 (1 patient); diffuse large B-cell (11 patients); peripheral T-cell lymphoma (2 patients); high grade B-cell lymphoma, Burkitt-like (1 patient); Burkitt's lymphoma (1 patient); Hodgkin's lymphoma (nodular sclerosing [1 patient] and mixed cellularity [1 patient]); and unknown (1 patient). Ten cases were not classifiable as primary or secondary lymphomas. Twenty-five patients died of malignant lymphoma, 14 died of unknown or other causes, 18 patients were alive 12-20 months after diagnosis (8 primary and 10 secondary tumors; 3 had persistent lymphoma; all treated since 1981), and 5 were lost to follow-up. Lymphoma specific survival was 64% at 1 year (95% confidence interval [CI], 51-80%), 50% at 2 years (95% CI, 36-68%), 33% at 5 years, 33% at 10 years, and 16% at 15 years. There was no difference in median survival after diagnosis of prostatic involvement between primary and secondary lymphoma (23 months vs. 28 months, respectively) or among histologic types. CONCLUSIONS: Although malignant lymphoma involving the prostate is rare, it should be considered in the differential diagnosis of lower urinary tract obstruction, particularly in patients with a previous history of lymphoma.

Adult↗
PubMed1998

Effect of multiple doses of rifampin on the [14C N-methyl] erythromycin breath test in healthy male volunteers.

The erythromycin breath test (EBT), which measures 14CO2 produced from [14C N-methyl] erythromycin, is one of the most frequently employed measures to examine drug interactions involving cytochrome P450 3A4 (CYP3A). However, the reproducibility and reliability of this test, and the effects of drugs that alter CYP3A activity, continue to be defined. In this study, the reproducibility of the EBT was evaluated in eight healthy volunteers before and after oral administration of 600 mg of rifampin daily for 8 days. Two sequential EBT determinations performed 5 days apart before rifampin administration were highly reproducible. Rifampin induced CYP3A, reflected in a mean percent (+/- standard deviation) increase in EBT values of 86 +/- 30%. Recovery of enzyme function after discontinuation of rifampin for 17 days was manifested as a return of EBT values to preinduction levels. These results support the utility of EBT as a valid, reproducible, and reliable measure of CYP3A activity in vivo.

Administration, Oral↗
PubMed1998

Single-dose pharmacokinetics of indinavir and the effect of food.

Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at approximately 0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 microM.h in the fasted state versus 1.54 microM.h in the fed state; n = 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 microM.h in the fasted state versus 22.71 and 21.36 microM.h, respectively, in the fed state; n = 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water.

Adult↗
PubMed1997

Ds excision from extrachromosomal geminivirus vector DNA is coupled to vector DNA replication in maize.

Analysis of transposition products generated after Activator (Ac) excision from the P locus in maize suggest that Ac excises either during or after replication of the P locus. The frequency of excision of the non-autonomous Ac derivative, Dissociation (Ds), from extrachromosomal replicating and nonreplicating vector DNAs in transfected black mexican sweet maize protoplasts was compared to assess directly a role of extrachromosomal vector DNA replication in Ds excision. Replicating (rep+) and nonreplicating (rep-) vector DNAs comprised a Ds element that harbored a geminivirus, wheat dwarf virus (WDV), origin of replication and WDV genes required for viral DNA replication (rep+) or mutant, inactive derivatives of these genes (rep-). Excision of Ds was detected only in those cell nuclei co-transfected with the replicating Ds-vector DNA and a transposase expression vector. Quantitative reconstruction experiments showed that Ds excised at least 3 x 10(5)-fold more frequently from replicating vector DNA as compared with nonreplicating vector DNA. Therefore, these results provide direct evidence for a coupling of Ds excision from extrachromosomal vector DNA to vector DNA replication in maize.

Cell Nucleus↗
PubMed1997

The effect of azodicarbonamide concentrations on ethyl carbamate concentrations in bread and toast.

A series of baking experiments have been undertaken in order to test the proposition that the use of the flour improver azodicarbonamide influences ethyl carbamate concentrations in baked bread. Samples were prepared in a laboratory and contained 0, 20 and 45 mg azodicarbonamide/kg; 20 mg/kg reflecting normal commercial usage and 45 mg/kg the UK statutory limit. Samples incorporating 0 and 20 mg/kg of the additive were also prepared in a commercial bakery. Toast made from these breads was examined since it is known that toasting can lead to increased ethyl carbamate concentrations. Statistical analysis of the data indicated that, at 45 mg/kg, azodicarbonamide led to significant increases in ethyl carbamate concentrations in both bread and the toasts made from it. At 20 mg/kg some small increases in ethyl carbamate were seen for bread and this approached statistical significance for those samples made in the commercial plant. When these breads were toasted an increase in ethyl carbamate was observed but this was not attributable to the use of azodicarbonamide.

Azo Compounds↗
PubMed1996

Pharmacokinetics and pharmacodynamics of tepoxalin after single oral dose administration to healthy volunteers.

This study was conducted to examine the pharmacokinetics and pharmacodynamics of tepoxalin in healthy volunteers, an antiinflammatory compound that inhibits cyclooxygenase and lipoxygenase. Tepoxalin was absorbed after oral administration of single doses from 35 to 300 mg, after which it was rapidly converted to an acidic metabolite, RWJ 20142, which inhibits cyclooxygenase but not lipoxygenase. The areas under the concentration-time curve (AUC) of tepoxalin and RWJ 20142 in plasma increased in a dose-dependent fashion. Administration of the lowest dose of tepoxalin completely inhibited whole blood cyclooxygenase for the entire period of observation. This inhibition correlated closely with that of secretion and aggregation induced by collagen of platelets obtained from these subjects. Similarly, administration of tepoxalin was associated with significant inhibition of lipoxygenase in whole blood. Lipoxygenase was inhibited a maximum of 60% in a time-dependent fashion, and the duration of inhibition was dose-dependent. These studies demonstrate that tepoxalin inhibits whole blood cyclooxygenase, lipoxygenase, and platelet function after oral administration in humans.

Administration, Oral↗
PubMed1995

Losartan does not affect the pharmacokinetics and pharmacodynamics of warfarin.

Losartan, on orally active, nonpeptide angiotensin II receptor antagonist is being developed as a therapeutic agent for the treatment of hypertension and heart failure. Many patients requiring anticoagulant therapy with warfarin also may have hypertension or heart failure, and thus, are potential candidates for losartan therapy. This study was designed to investigate whether losartan at likely dosage levels would alter the anticoagulant response to warfarin. In a two-period, placebo-controlled, randomized, crossover study, ten healthy male subjects received a single oral dose of 30 mg warfarin sodium on the seventh day of a 13-day treatment with losartan, 100 mg daily by mouth, or placebo. Multiple plasma samples were collected over a 6-day period after both warfarin doses for the measurements of R- and S-warfarin concentrations and prothrombin times. The pharmacokinetics of R- and S-warfarin were comparable in the absence and presence of losartan (no significant effects of losartan on area under the curve, Cmax, or tmax). Losartan also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction between warfarin and losartan observed in this investigation suggests that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.

Administration, Oral↗
PubMed1995

Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation--a prospective, randomized, double-blind study.

A randomized, double-blind, placebo-controlled trial assessed the efficacy and toxicity of 400 mg/day fluconazole in preventing fungal infections during the first 75 days after marrow transplantation. During prophylaxis, systemic fungal infections occurred in 10 (7%) of 152 fluconazole-treated patients compared with 26 (18%) of 148 placebo-treated patients (P = .004). There were no Candida albicans infections in fluconazole recipients compared with 18 in placebo recipients (P < .001) and no significant increase in Candida infections other than C. albicans. Fluconazole also significantly reduced the incidence of superficial fungal infections (P < .001), fungal colonization (P = .037), and empiric amphotericin B use (P = .005). The probability of survival was improved in fluconazole recipients, in whom 31 deaths occurred up to day 110 after transplantation compared with 52 deaths in placebo recipients (P = .004). No clinically significant toxicity was detected with fluconazole use. Prophylactic fluconazole was safe and significantly reduced systemic fungal infections with other benefits, including improved survival at day 110 after marrow transplantation.

Adolescent↗