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S O'Keefe

Publications and source records attributed to S O'Keefe.

At least 19 recordsLinked to original sources
PubMed2006

Phase I trial of three-weekly docetaxel, carboplatin and oral lenalidomide (Revlimid) in patients with advanced solid tumors.

INTRODUCTION: Lenalidomide is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and a different toxicity profile. In preclinical trials it has shown synergy with chemotherapy. PATIENTS AND METHODS: Primary objective of this study was to determine the maximum tolerated doses of docetaxel and carboplatin when combined with oral lenalidomide in a standard phase I study design. Between September 2004 and May 2005, 14 patients with pathologically proven solid tumors, < or =2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function were enrolled. Dose limiting toxicities (DLT) were defined as > or = grade 3 non-hematological, or grade 4 hematological toxicity. No growth factors were used during cycle 1. RESULTS: Three of four patients treated at dose level 1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 10 mg orally daily on Days 1-14 of a 21 day cycle experienced DLT (grade 3 electrolyte changes in two patients, and grade 4 neutropenia in one patient). Ten patients were treated at dose level -1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 5 mg orally daily on Days 1-14 of a 21 day cycle with one DLT (Grade 4 neutropenia). There were no treatment-related deaths or irreversible toxicities. Of the 14 response-evaluable patients, five achieved a partial response (5 out of 9 patients with non-small cell lung cancer. CONCLUSIONS: Docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, with lenalidomide 5 mg orally daily on Days 1-14 days of a 21 day cycle is the maximum tolerated dose without the use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted.

Administration, Oral↗
PubMed2004

Preferential inhibition of T helper 1, but not T helper 2, cytokines in vitro by L-826,141 [4-[2-(3,4-Bisdifluromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]3-methylpyridine-1-oxide], a potent and selective phosphodiesterase 4 inhibitor.

L-826,141 [4-(2-(3,4-bis-difluromethoxyphenyl)-2-(4-(1,1,1, 3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl)-3-methylpyridine-1-oxide] is a selective and potent inhibitor of phosphodiesterase 4 (PDE4) with an IC(50) value of 0.26 to 2.4 nM for inhibition of the catalytic activity of PDE4A, B, C, and D. The cAMP elevation that can be maintained by PDE4 inhibitors attenuates the signaling cascades that lead to the production of certain cytokines. In cellular-based assays, L-826,141 transcriptionally down-regulates production of tumor necrosis factor (TNF)-alpha in peripheral blood mononuclear cell and whole blood assays with IC(50) values of 31 and 310 nM, respectively. Profiling the effect of this compound on various cytokines in the signaling cascade attenuated by cAMP elevation demonstrates that L-826,141 is also a potent inhibitor of interleukin (IL)-12, granulocyte macrophage-colony stimulating factor, and interferon (IFN)gamma (IC(50) values of 0.3-0.9 microM) as well as TNF-alpha formation. We have also shown that the PDE4 inhibitors rolipram and L-826,141 are potent inhibitors of CD3-plus CD28-stimulated IL-2 production in naive human T cells. To address the effect of PDE4 inhibitors on cytokine release from T helper (Th)1 and Th2 effector cells, we used a well characterized model in which T cells are derived from ovalbumin (323-339)-specific T cell receptor transgenic mice. L-826,141 inhibits Th0-mediated IL-2 production with an IC(35) value of 25 nM and Th1-mediated IFNgamma production with an IC(30) value of 46 nM. In contrast, L-826,141 had no significant inhibitory effect (IC(30) value > 2.5 microM) on Th2 cell-mediated IL-4 nor IL-13 production. Together, these data demonstrate that specific inhibition of PDE4 preferentially blocks the production of Th1 versus Th2 effector cytokines in vitro.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Substituted imidazoles as glucagon receptor antagonists.

A modestly active, nonselective triarylimidazole lead was optimized for binding affinity with the human glucagon receptor. This led to the identification of a 2- and/or 4-alkyl or alkyloxy substituent on the imidazole C4-aryl group as a structural determinant for significant enhancement in binding with the glucagon receptor (e.g., 41, IC(50)=0.053 microM) and selectivity (>1000x) over p38MAP kinase in this class of compounds.

Animals↗
PubMed2000

Celiac disease in older people.

In recent years, there has been increasing recognition that the classical textbook presentation of celiac disease with a malabsorption syndrome and a flat jejunal mucosa is only part of a broad spectrum of clinical and histological features associated with gluten sensitivity. Diagnosis of this treatable condition is often delayed or missed because of a failure to appreciate that celiac disease can present at any age and that symptoms are often subtle and not clearly related to gastrointestinal disease. Nonspecific symptoms and nutritional deficiencies are especially common in older patients and may not always be investigated thoroughly. Use of serological screening tests has improved ease of detection of celiac disease in patients without classical symptoms.

Age Distribution↗
PubMed1999

Effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis.

Tramadol and morphine were compared for treatment of severe chronic pancreatitis pain and their interaction with gut motor function. Oral tramadol or morphine doses were titrated double-blinded and randomized for five days in 25 patients and pain, side effects, bowel function, orocecal and colonic transit, anal resting pressure, and rectal distension thresholds were measured. Pain intensities (mean+/-SD, 0 = none, 100 = unbearable) before treatment and on day 4 were 75+/-19 and 8+/-13 with tramadol (P < 0.001), and 65+/-21 and 5+/-6 with morphine (P < 0.001). On day 4, 67% of patients with tramadol and 20% with morphine rated their analgesia as excellent (P < 0.001) with mean respective doses of 840 mg (range: 80-1920) and 238 mg (20-1125). Orocecal transit was unchanged after five days of tramadol, but increased with morphine (P < 0.05). More patients had prolonged colonic transit times with morphine by day 5 (P < 0.05). Rectal distension threshold pressures increased only with tramadol (P < 0.01). It is concluded tramadol and morphine are potent analgesics in severe chronic pancreatitis pain when individually titrated. Tramadol interfered significantly less with gastrointestinal function and was more often rated as an excellent analgesic than morphine.

Adult↗
PubMed1999

Re-engineering an Australian emergency department: can we measure success?

In 1996, in response to perceived deficiencies of the Emergency Department, Sir Charles Gairdner Hospital made emergency medicine a key strategic initiative. Major staffing and functional changes occurred as a result, including creation of the first Chair in Emergency Medicine in Australasia. We present a before and after study, using a range of measured variables, including the accepted Australian Council on Healthcare Standards emergency medicine clinical indicators. Clinically, there were great improvements in waiting times, time to thrombolysis in acute myocardial infarction, complaint rate, and misdiagnosed fracture rate. Increased throughput of short stay patients in a re-opened observation ward greatly shortened average length of stay for patients with a range of acute conditions. Data also indicated significant improvements in teaching and research. We conclude that with firm commitment from hospital management, re-engineering an emergency department can be shown to improve the quality-of-care.

Australia↗
PubMed1995

Epidermal cell-specific quantitation of dopa decarboxylase mRNA in Drosophila by competitive RT-PCR: an effect of Broad-Complex mutants.

The quantitation of RNA in tissue homogenates by amplifying the product of reverse transcription (RT-PCR) is sufficiently sensitive to detect molecules in the range of 10(-1)-10(-2) amole. We describe here the steps we believe necessary to validate a protocol that used a DNA competitor and visualization of the amplification products by ethidium bromide staining. The procedure was designed to quantitate one of the tissue specific transcripts of the Dopa decarboxylase gene (Ddc) in Drosophila. We demonstrate that the amount of epidermal Ddc transcript is much lower at pupariation in several mutants of the Broad-Complex, one of the primary response loci of the moulting hormone, ecdysone. The mutant effects were allele specific and the molecular basis of one of these alleles is known. This implicates a particular family of the zinc finger proteins encoded by the locus in the hormone dependent induction of Ddc expression.

Animals↗
PubMed1995

Use of the abbreviated mental test to detect postoperative delirium in elderly people.

We investigated the validity of the abbreviated mental test (AMT) as a guide to the diagnosis of delirium in 100 patients aged more than 65 yr. Patients were assessed using the AMT on the day before and on the third day after operation. Fifteen patients were delirious on the third postoperative day; 10 of 43 patients undergoing orthopaedic surgery and five of 57 patients undergoing non-orthopaedic surgery. Delirium developed in four of 16 patients with a preoperative AMT score less than 8 and in 11 of 84 patients with a preoperative AMT score of 8 or more. Patients who developed delirium had a greater decline in AMT score (mean 2.7 (SD 0.9)) than patients who did not develop delirium (0.7 (1.0)) (P < 0.001). The sensitivity and specificity of a decline in AMT score of 2 or more points after surgery for diagnosis of postoperative delirium were 93% and 84%, respectively.

Aged↗
PubMed1995

A new advanced practice role focused on outcomes management in women's and children's health.

Outcomes management involves goal-directed coordination of transdisciplinary teams. It focuses on achieving measurable outcomes for select populations of patients. The article presents a new advanced practice role focused on outcomes management for the perinatal population. Practice pattern reforms accomplished during 3 years of work and the associated favorable clinical, functional, service, quality, and financial outcomes are described. Supports required for the success of an outcomes management program as well as lessons learned from 2 years work are presented.

Case Management↗
PubMed1992

Purine-induced block to mouse embryo cleavage is reversed by compounds that elevate cyclic adenosine monophosphate.

The second or third cleavage of mouse embryos from several strains of females is blocked in the presence of hypoxanthine. To begin to determine the mechanism of the block, we studied several aspects of cell metabolism in blocked embryos, including the stage of the cell cycle and the levels of transcription, translation, and protein phosphorylation. In addition, we attempted to reverse the block by transfer of cytoplasm, transfer of RNAs from dividing cells, and co-culture with compounds that elevate cAMP. Our results indicate the following: 1) that the embryos were blocked in interphase; 2) the expression of lac Z linked to SV40 promoter was depressed, but not blocked; 3) overall protein synthesis was depressed but the appearance of early embryonic proteins was not blocked; 4) overall phosphorylation of proteins was not affected; 5) microinjection of additional cytoplasm from non-blocking embryos did not reverse the block; and 6) compounds that elevate cAMP did reverse the block. Thus, the purines apparently do not prevent early embryonic gene expression or most phosphorylation events, but do inhibit a critical cell process occurring during interphase of the cell cycle that can be compensated by elevations in cAMP.

Adenosine Monophosphate↗
PubMed1990

Adjunctive therapy (whole body hyperthermia versus lonidamine) to total body irradiation for the treatment of favorable B-cell neoplasms: a report of two pilot clinical trials and laboratory investigations.

Based on earlier clinical and preclinical investigations, we designed two different pilot trials for patients with nodular lymphoma or chronic lymphocytic leukemia. These studies evaluated the use of either 41.8 degrees C whole body hyperthermia (WBH), or the nonmyelosuppressive chemotherapeutic drug, lonidamine (LON), as an adjunct to total body irradiation (TBI) (12.5 cGy twice a week, every other week for a planned total dose of 150 cGy). Whole body hyperthermia was initiated approximately 10 min after total body irradiation; lonidamine was administered orally (420 mg/m2) on a daily basis. Although entry to the studies was nonrandomized, the two patient populations were accrued during the same time frame and were comparable in terms of histology, stage of disease, performance status, and prior therapy. Of 8 patients entered on the TBI/WBH study, we observed 3 complete responses (CR), 4 partial responses (PR), and 1 improvement (i.e., a 48% decrease in tumor burden). Of 10 patients entered in the TBI/LON study, there was 1 CR and 4 PR. For the TBI/WBH study, myelosuppression was not treatment-limiting; there were no instances of infection or bleeding and platelet support was never required. The median survival time for the TBI/WBH study is 52.5 months based on Kaplan Meir estimates. Two patients remain in a CR. The median time to treatment failure (MTTF) is 9.4 months (90% confidence interval = 7-15.4 months). In the TBI/LON study, 50% of patients receiving TBI required treatment modification due to platelet-count depression during therapy, but there were no instances of infection or bleeding. Frequently observed LON-related toxicities included myalgias, testicular pain, photophobia and ototoxicity. For the TBI/LON study, median survival is 7.6 months; MTTF was 2.4 months. In analyzing the results of these pilot studies, our subjective clinical impressions lead to the hypothesis that WBH protected against TBI-induced thrombocytopenia during therapy, whereas LON had no effect on TBI-induced myelosuppression. This speculation was tested and confirmed in a series of in vitro and in vivo experiments.

Adult↗
PubMed1988

A pilot study of whole body hyperthermia and local irradiation for advanced non-small cell lung cancer confined to the thorax.

Six patients with Stage III non-small cell lung cancer completed therapy which consisted of 4 whole body hyperthermia (WBH) treatments during the first 2 weeks of a 6 week course of radiotherapy (60 Gy). A radiant heat system was used to deliver the 41.8 degree C WBH. To reduce the danger of transverse myelitis, the spinal cord (and therefore part of the mediastinum and contralateral hilar region) was not irradiated during the first 2 weeks of radiotherapy and concurrent WBH. Subsequent treatments (weeks 3-6) included conventional irradiation to the primary tumor, mediastinal lymph nodes and spinal cord. Areas of gross disease responded to therapy in 5/6 patients. No radiation pneumonitis was observed. In 2/6 patients, relapse (after 10 months and 6 months, respectively) occurred with malignant pericardial effusions. The mediastinum in these patients was not an area of bulky disease involvement initially. To eliminate such WBH-radiation sanctuary zones, the protocol was modified to include greater combined WBH-radiation treatment. This is accomplished by having one WBH treatment "sandwiched" between 2 radiation fractions. The preclinical basis for the revised protocol is presented.

Adult↗
PubMed1987

Medical school performance of initially rejected students.

At the University of Texas Medical School at Houston we had a unique opportunity to examine performance through the medical curriculum and one year of postgraduate training of 50 students initially rejected for medical school. Each had been interviewed by the same Admissions Committee, which earlier had selected 150 students through the traditional process. In contrasting the initially accepted and initially rejected groups, academic and demographic variables accounted for only 28% of group difference. The 72% of group difference not accounted for by the variables examined was presumed to relate to Admissions Committee preference. In attrition and in both preclinical and clinical performance through medical school and one year of postgraduate training, there were no meaningful differences between the groups. The observations suggest that the traditional interview process probably does not enhance the ability to predict performance of medical school applicants.

Achievement↗