bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of the University of California Los Angeles Integrated Staging System to Predict Survival in Renal Cell Carcinoma: An International Multicenter Study
Authors: Patard Jean-Jacques , Kim Hyung L. , Lam John S. , Dorey Frederick J. , Pantuck Allan J. , Zisman Amnon , Ficarra Vincenzo , Han Ken-Ryu , Cindolo Luca , De La Taille Alexandre , Tostain Jacques , Artibani Walter , Dinney Colin P. , Wood Christopher G. , Swanson David A. , Abbou Claude C. , Lobel Bernard , Mulders Peter F.A. , Chopin Dominique K. , Figlin Robert A. , Belldegrun Arie S.
Published: August 2004

Purpose

To evaluate ability of the University of California Los Angeles Integrated Staging System (UISS) to stratify patients with localized and metastatic renal cell carcinoma (RCC) into risk groups in an international multicenter study.

Patients and Methods

4,202 patients from eight international academic centers were classified according to the UISS, which combines TNM stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status. Distribution of the UISS categories was assessed in the overall population and in each center.

Results

The UISS stratified both localized and metastatic RCC into three different risk groups (P < .001). For localized RCC, the 5-year survival rates were 92%, 67%, and 44% for low-, intermediate-, and high-risk groups, respectively. A trend toward a higher risk of death was observed in all centers for increasing UISS risk category. For metastatic RCC, the 3-year survival rates were 37%, 23%, and 12% for low-, intermediate-, and high-risk groups, respectively; in 6 of 8 centers, a trend toward a higher risk of death was observed for increasing UISS risk category. A greater variability in survival rates among centers was observed for high-risk patients.

Conclusion

This study defines the general applicability of the UISS for predicting survival in patients with RCC. The UISS is an accurate predictor of survival for patients with localized RCC applicable to external databases. Although the UISS may be useful for patients with metastatic RCC, it may be less accurate in this subset of patients due to the heterogeneity of patients and treatments.
Prophylactic Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Decrease Febrile Neutropenia After Chemotherapy in Children With Cancer: A Meta-Analysis of Randomized Controlled Trials
Authors: Sung Lillian , Nathan Paul C. , Lange Beverly , Beyene Joseph , Buchanan George R.
Published: August 2004

Purpose

To determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) used in children with cancer reduce the rate of febrile neutropenia, hospitalization duration, documented infection rate, parenteral antibiotic duration, amphotericin B use, or infection-related mortality.

Methods

We included studies in this meta-analysis if their populations consisted of children, if there was randomization between CSFs and placebo or no therapy, if CSFs were administered prophylactically (before neutropenia or febrile neutropenia), and if chemotherapy treatments preceding CSFs and placebo or no therapy were identical. From 971 reviewed study articles, 16 were included.

Results

The mean rate of febrile neutropenia in the control arms was 57% (range, 39% to 100%). Using a random effects model, CSFs were associated with a reduction in febrile neutropenia, with a rate ratio of 0.80 (95% CI, 0.67 to 0.95; P = .01), and a decrease in hospitalization length, with a weighted mean difference of −1.9 days (95% CI, −2.7 to −1.1 days; P < .00001). CSF use was also associated with reduction in documented infections (rate ratio, 0.78; 95% CI, 0.62 to 0.97; P = .02) and reduction in amphotericin B use (rate ratio, 0.50; 95% CI, 0.28 to 0.87; P = .02). There was no difference in duration of parenteral antibiotic therapy (weighted mean difference, −4.3; 95% CI, −10.6 to 2.0 days; P = .2) or infection-related mortality (rate ratio, 1.02; 95% CI, 0.34 to 3.06; P = .97).

Conclusion

CSFs were associated with a 20% reduction in febrile neutropenia and shorter duration of hospitalization; however, CSFs did not reduce infection-related mortality.
Acetaminophen (Paracetamol) Improves Pain and Well-Being in People With Advanced Cancer Already Receiving a Strong Opioid Regimen: A Randomized, Double-Blind, Placebo-Controlled Cross-Over Trial
Authors: Stockler Martin , Vardy Janette , Pillai Avinesh , Warr David
Published: August 2004

Purpose

To determine whether adding regular acetaminophen (paracetamol) could improve pain and well-being in people with advanced cancer and pain despite strong opioids.

Patients and Methods

Participants took acetaminophen for 48 hours and placebo for 48 hours. The order (acetaminophen or placebo first) was randomly allocated. Pain was the primary outcome. Preferences, number of opioid breakthrough doses, overall well-being, nausea and vomiting, drowsiness, constipation, and cold sweats were secondary outcomes. Patients rated themselves daily with visual analog scales (VAS) and a verbal numeric scale (VNS) for pain, all scaled from 0 to 10.

Results

Thirty patients completed the trial. The oral opioid was morphine in 23 patients and hydromorphone in seven patients. The median daily opioid dose in oral morphine equivalents was 200 mg (range, 20 to 2,100 mg). Nonsteroidal anti-inflammatory drugs, corticosteroids, or both were used by 16 patients. Pain and overall well-being were better for patients receiving acetaminophen than for those receiving placebo. The mean difference was 0.4 (95% CI, 0.1 to 0.8; P = .03) in VNS for pain, 0.6 (95% CI, −0.1 to 1.3; P = .09) in VAS for pain, and 0.7 (95% CI, 0.0 to 1.4; P = .05) in VAS for overall well-being. More patients preferred the period they took acetaminophen (n = 14) than the period they took placebo (n = 8), but many had no preference (n = 8). There were no differences in the other outcomes.

Conclusion

Acetaminophen improved pain and well-being without major side effects in patients with cancer and persistent pain despite a strong opioid regimen. Its addition is worth considering in all such patients.
Platelet-Derived Growth Factor Receptor Inhibitor Imatinib Mesylate and Docetaxel: A Modular Phase I Trial in Androgen-Independent Prostate Cancer
Authors: Mathew Paul , Thall Peter F. , Jones Donnah , Perez Cherie , Bucana Corazon , Troncoso Patricia , Kim Sun-Jin , Fidler Isaiah J. , Logothetis Christopher
Published: August 2004

Purpose

To study the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate in androgen-independent prostate cancer (AIPC), alone and in combination with docetaxel, we designed a modular phase I trial. Our goals were to (1) evaluate the toxicity and maximum-tolerated dose of docetaxel with imatinib, and (2) evaluate the decline of prostate-specific antigen (PSA) induced by imatinib alone, and imatinib and docetaxel.

Patients and Methods

Twenty-eight men with AIPC and bone metastases were enrolled to receive imatinib 600 mg daily lead-in for 30 days, then imatinib 600 mg daily and one of six possible doses of docetaxel weekly for 4 weeks every 6 weeks.

Results

During the imatinib lead-in module, one dose-limiting toxicity (DLT) event was observed, while two (7%) of 28 had PSA decline (both < 50%). With imatinib and docetaxel, cycle 1 DLT was found in three of 12 patients at docetaxel 30 mg/m2, in three of four patients at docetaxel 45 mg/m2, and in five of six patients at docetaxel 35 mg/m2. DLTs (n = 40 total events) were principally fatigue (35%) and nausea (20%). Eight (38%) of 21 had PSA decline greater than 50%, and six (29%) of 21 had PSA decline less than 50%. Serial PSA declines beyond 18 months were observed. PDGFR-expressing tumor declined on serial bone marrow biopsies with combination therapy alone.

Conclusion

With imatinib 600 mg daily, the maximum-tolerated dose of docetaxel was determined to be 30 mg/m2 weekly for 4 weeks every 6 weeks. Long-term responses were observed. The role of imatinib in modulating outcomes to docetaxel in AIPC is being tested in a randomized phase II trial.
Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung Cancer
Authors: Pérez-Soler Román , Chachoua Abraham , Hammond Lisa A. , Rowinsky Eric K. , Huberman Mark , Karp Daniel , Rigas James , Clark Gary M. , Santabárbara Pedro , Bonomi Philip
Published: August 2004

Purpose

Erlotinib is a highly specific epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. This phase II study of erlotinib in patients with HER1/EGFR-expressing non–small-cell lung cancer previously treated with platinum-based chemotherapy evaluated tumor response, survival, and symptom improvement.

Patients and Methods

Fifty-seven patients received an oral, continuous daily dose of 150 mg of erlotinib. Assessments of objective response used WHO and Response Evaluation Criteria in Solid Tumors criteria. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, supplemented with a lung cancer module, Quality of Life Questionnaire LC13, was used to measure health-related quality of life. Additional analyses were performed to identify predictors of response and survival.

Results

The objective response rate was 12.3% (95% CI, 5.1% to 23.7%). Responses were observed regardless of type or number of prior chemotherapy regimens. Median survival time was 8.4 months (95% CI, 4.8 to 13.9 months), and the 1-year survival rate was 40% (95% CI, 28% to 54%). Erlotinib therapy was associated with tumor-related symptom improvement. The drug was well tolerated; drug-related cutaneous rash and diarrhea were observed in 75% and 56% of patients, respectively. One patient experienced toxicity consisting of severe grade 3 rash and diarrhea. Time since diagnosis and good performance status were significant predictors of survival in a multivariate Cox proportional hazards model, whereas HER1/EGFR staining intensity was not. Additionally, survival correlated with the occurrence and severity of rash.

Conclusion

Erlotinib was active and well tolerated in this patient population, and further clinical development is clearly warranted. Cutaneous rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies.
Patient Beliefs and Tamoxifen Discontinuance in Older Women With Estrogen Receptor—Positive Breast Cancer
Authors: Fink Aliza K. , Gurwitz Jerry , Rakowski William , Guadagnoli Edward , Silliman Rebecca A.
Published: August 2004

Purpose

To investigate the patterns and predictors of tamoxifen discontinuance throughout a 2-year period in a cohort of women 65 years or older with newly diagnosed, estrogen receptor (ER)–positive breast cancer, focusing on the role of patients’ beliefs about the risks and benefits of tamoxifen therapy.

Subjects and Methods

We enrolled a convenience sample of women cared for in four geographic regions of the United States with stage 1 (≥ 1 cm), stage II, or stage IIIA disease; no prior history of breast cancer; and no simultaneously diagnosed second primary breast cancer. Data sources included medical records and telephone interviews with patients at 3, 6, 15, and 27 months following definitive surgery.

Results

Of the 597 women with ER-positive tumors, 516 women (86%) were prescribed tamoxifen, and of these, 88 (17%) stopped taking tamoxifen during the 2-year follow-up period. Of the women who stopped taking tamoxifen, the majority (68%) took it for less than 1 year. Women with neutral or negative beliefs about the value of tamoxifen (3.0; 95% CI, 1.6 to 5.6) and those with positive nodes (odds ratio = 2.5; 95% CI, 1.0 to 6.3) were more likely to discontinue tamoxifen therapy.

Conclusion

How women with early-stage breast cancer perceive the risks and benefits of tamoxifen therapy seems critical for sustaining adherence to adjuvant tamoxifen therapy. Interventions designed to educate women about the benefits and risks of tamoxifen therapy may help to reduce discontinuance.
Phase I and Pharmacokinetic Study of the Novel Oral Cell-Cycle Inhibitor Ro 31-7453 in Patients With Advanced Solid Tumors
Authors: Dupont Jakob , Bienvenu Bryan , Aghajanian Carol , Pezzulli Sandra , Sabbatini Paul , Vongphrachanh Phothisath , Chang Christine , Perkell Christina , Ng Kenneth , Passe Sharon , Breimer Lars , Zhi Jianguo , DeMario Mark , Spriggs David , Soignet Steven L.
Published: August 2004

Purpose

To determine maximum tolerated dose, pharmacokinetics (PK), and safety of Ro 31-7453, a novel, oral cell-cycle inhibitor.

Patients and Methods

Using an accelerated dose-escalation schedule, 48 patients with advanced solid tumors were treated with doses of Ro 31-7453 ranging from 25 to 800 mg/m2/d given for 4 consecutive days, every 3 weeks. The total daily dose was taken as a single dose (schedule A) or divided into two equal doses taken 12 hours apart (schedule B). PK samples of blood and urine were collected on the first and last days of dosing in cycles 1 and 2.

Results

Forty-five patients completed at least one cycle of therapy. Myelosuppression and stomatitis were dose-limiting toxicities, occurring at the 800 mg/m2/d dose level for both schedules. Toxicity was independent of body-surface area, leading to the recommended phase II flat dose of 1,000 mg daily for 4 days for both schedules. Common adverse events included diarrhea, nausea, vomiting, fatigue, alopecia, and elevated liver-function tests. One death, related to neutropenic sepsis, occurred on study. The PK of the parent compound and major metabolites were apparently linear, with a half-life of approximately 9 hours and a maximum concentration of approximately 4 hours. Minor antitumor activity was observed against carcinoma of the lung, breast, pancreas, and ovary.

Conclusion

Ro 31-7453 was well tolerated, with manageable adverse effects. Significant PK variability (absorption, metabolism, and excretion) was observed, and a substantial number of additional patients are needed to confirm the recommended phase II dose. Additional pharmacology and phase II studies are under way to explore the dose-toxicity relationship.
The Microanatomic Location of Metastatic Melanoma in Sentinel Lymph Nodes Predicts Nonsentinel Lymph Node Involvement
Authors: Dewar D.J. , Newell B. , Green M.A. , Topping A.P. , Powell B.W.E.M. , Cook M.G.
Published: August 2004

Purpose

Sentinel node biopsy is now widely accepted as the most accurate prognostic indicator in melanoma, and is important in guiding management of patients with clinical stage I or II disease. Patients with a positive sentinel node have conventionally undergone completion lymphadenectomy (CLND) of the involved basin, but only 20% have involvement beyond the sentinel node, suggesting that CLND may be unnecessary for the other 80% of patients. This study seeks to identify criteria that might be used to be more restrictive in selecting those who should undergo CLND.

Methods

A total of 146 patients were identified who had had a positive sentinel node biopsy for malignant melanoma. Their sentinel nodes and lymphadenectomy specimens were re-evaluated pathologically. The metastatic melanoma in each sentinel node was assessed according to its microanatomic location within the node (subcapsular, combined subcapsular and parenchymal, parenchymal, multifocal, or extensive), and this was correlated with the presence of involved nonsentinel nodes in the CLND. The depth of the metastases from the sentinel node capsule was also recorded.

Results

The metastatic deposits in the sentinel node were subcapsular in 26.0% of patients. None of these patients had any nonsentinel nodes involved on CLND. In the patients whose sentinel node metastases had a different microanatomic location, the rate of nonsentinel node involvement was 22.2% overall.

Conclusion

The microanatomic location of metastases within sentinel nodes predicts nonsentinel lymph node involvement. In patients with only subcapsular deposits in the sentinel node, it is possible that CLND could safely be avoided.
Evaluation of analgesic and anti-inflammatory activities of Nectandra megapotamica (Lauraceae) in mice and rats
Authors: Filho Ademar A da Silva , Silva Márcio L Andrade e , Carvalho José Carlos T , Bastos Jairo K
Published: August 2004

The bioactivity-guided phytochemical investigation of the crude hydralcoholic extract of Nectandra megapotamica was carried out using the abdominal constriction test in mice, which led to the isolation of three active compounds: α-asarone (1), galgravin (2) and veraguensin (3). The crude extract (EBCA, 300 mg kg−1) and isolated compounds 1, 2, and 3, at different doses, were evaluated using the acetic acid-induced abdominal constriction test in mice, carrageenan-induced paw oedema in rats, and hot plate tests in rats. The EBCA showed a significant effect in the abdominal constriction and hot plate tests, but did not show activity in the rat paw oedema assay. All isolated compounds displayed activity in the abdominal constriction test, but only compound 1 was active in the hot plate test. Compounds 2 and 3 displayed activity in the anti-inflammatory assay. It was suggested that the analgesic effects obtained for EBCA could be due mainly to the presence of its major compound, α-asarone (1).
In-vitro trypanocidal activity evaluation of crude extract and isolated compounds from Baccharis dracunculifolia D. C. (Asteraceae)
Authors: Filho Ademar A da Silva , Bueno Paula C Pires , Gregório Luís E , Silva Márcio L Andrade e , Albuquerque Sérgio , Bastos Jairo K
Published: August 2004

We have performed a trypanocidal bioactivity-guided study of Baccharis dracunculifolia (Asteraceae), the main botanical origin of Brazilian green propolis. The leaf rinse extract of B. dracunculifolia, at a concentration of 3.0 mg mL−1, displayed 100% lysis of trypomastigote forms of the Y strain of Trypanosoma cruzi (2 times 106 parasites mL−1). The chromatographic fractionation of the leaf rinse, using several techniques, afforded the isolation of the compounds isosakuranetin (1), aromadendrin-4′-methylether (2), baccharis oxide (3), ferulic acid (4), dihydrocinnamic acid (5), 3-prenyl-4-(dihydrocinnamoyloxy)-cinnamic acid (6), and friedelanol (7). The chemical structures of all compounds were established by UV-vis, 1H and 13C NMR data analysis in comparison with the literature. Compounds 1 and 3 were the most active in the trypanocidal assay, showing IC50 values (inhibitory concentration required for 50% inhibition) of 247.6 and 249.8 μM, respectively. Compounds 2, 4, and 6 displayed moderate activity, whilst compounds 5 and 7 were inactive.
Improved drug dissolution and product characterization using a crescent-shaped spindle
Authors: Qureshi Saeed A
Published: August 2004

Drug release characteristics of two amoxicillin capsule products, 250 and 500 mg strength each, have been described using USP Paddle and crescent-shaped spindles. Using the same spindles, dissolution experiments were conducted with USP disintegrating (prednisone) and non-disintegrating (salicylic acid) calibrator tablets. Dissolution tests were conducted at 50 and 25 rev min−1 using USP Paddle and crescent-shaped spindles, respectively. In all cases, even with the higher 50 rev min−1, lower percent drug release results were observed with the Paddle spindle than with the crescent-shaped spindle, which was operated at 25 rev min−1. The observed lower dissolution for amoxicillin capsule products (< 36 vs > 87% at 30 min) and USP prednisone calibrator tablets (45.5 vs 99.8% at 30 min) with Paddle spindles appeared to occur because of the accumulation of the disintegrated material (cone formation) at the bottom, thus restricting product-medium interaction. Crescent-shaped spindles did not allow any accumulation of the product and provided improved interaction by mixing and stirring, and thus appeared to provide true drug dissolution characteristics of the products. On the other hand, in the case of non-disintegrating USP salicylic acid tablets (18.5 vs 24.4% at 30 min), lower results with Paddle spindles appeared to be because of stagnation of the tablets, which provided poor product-medium interaction for the surface touching the vessel surface. In this case, the crescent-shaped spindles moved the tablets at the base of the vessel, providing improved and efficient product-medium interaction, thus appearing to reflect truer dissolution characteristics of the tablets. The results highlight the possible artifacts of the USP Paddle spindle, which could lead to inaccurate characterization of drug release properties of test products. As reported previously, the artifacts of high variability in results and lack of relevance to product properties appeared to be related to poor mixing and variable hydrodynamics within a dissolution vessel. Results from this study provide further evidence that these artifacts might be addressed adequately using the crescent-shaped spindle, thus resulting in improved drug release as well as better product characterization.
Mucoadhesive and penetration enhancement properties of three grades of hyaluronic acid using porcine buccal and vaginal tissue, Caco-2 cell lines, and rat jejunum
Authors: Sandri Giuseppina , Rossi Silvia , Ferrari Franca , Bonferoni Maria Cristina , Zerrouk Naima , Caramella Carla
Published: August 2004

The influence of the molecular weight on mucoadhesive and penetration enhancement properties of three grades of hyaluronic acid (1878, 693 and 202 kDa) has been evaluated. The mucoadhesive properties were investigated using buccal and vaginal porcine mucosa by means of a tensile stress method and using rat jejunum by means of an inclined plane method. The mucoadhesive performances observed using animal tissues were compared with the mucoadhesive properties observed using submaxillary or gastric mucin dispersions. The penetration enhancement properties were investigated using porcine buccal epithelium membrane or vaginal tissue and a cell monolayer (Caco-2 cell line). Chitosan hydrochloride, already described as a penetration enhancer towards buccal and vaginal mucosae and Caco-2 cell monolayers, was used as reference. Aciclovir (acyclovir), a poorly soluble and absorbable drug, commonly used in the treatment of Herpes simplex virus (type I and II), was used as the model drug. Unlike chitosan hydrochloride, which does not show any mucoadhesive potential at pH close to neutrality (buccal and intestinal), all hyaluronic acid grades show mucoadhesive properties in all the environments considered (buccal, vaginal and intestinal). In all cases, a decrease in molecular weight of hyaluronic acid produced an increase in the mucoadhesive performance. The hyaluronic acid with the lowest molecular weight (202 kD) exhibited the best penetration enhancement properties, that, depending on the substrate under consideration, was either comparable with or even better than chitosan hydrochloride. Therefore, this grade would be the most promising for buccal, vaginal and intestinal delivery of aciclovir.
The in-vivo effect of bakumondo-to (TJ-29), a traditional Japanese medicine used for treatment of chronic airway disease, on cytochrome P450 1A2, xanthine oxidase and N-acetyltransferase 2 activity in man
Authors: Saruwatari Junji , Hisaeda Shinichirou , Higa Yoko , Tomiyasu Yuko , Nakagawa Kazuko , Ishizaki Takashi
Published: August 2004

In Japan, patients with chronic airway disease are administered bakumondo-to (TJ-29), a mixture of six herbal components. We have assessed the effects of TJ-29 on the activities of cytochrome P450 (CYP) 1A2, xanthine oxidase and N-acetyltransferase 2 in 26 healthy subjects under a double-blind, randomized, placebo-controlled cross-over study design. The baseline activities of the three enzymes were assessed by the respective urinary metabolic ratios of an 8-h urine sample after an oral 150-mg dose of caffeine. Thereafter, the subjects received a thrice-daily 3.0-g dose of TJ-29 or placebo for seven days, and underwent the same caffeine test on the post-dose days 1 and 7. No statistically significant difference was observed in the activity of the three enzymes between those at baseline, and on day 1 after dosing with TJ-29 or placebo. The mean activity of CYP1A2, xanthine oxidase and N-acetyltransferase 2 tended to be lower on day 7 after dosing with TJ-29 compared with those at baseline and on day 7 after dosing with placebo. However, these changes were not statistically significant in CYP1A2 (P=0.120), xanthine oxidase (P=0.123) or N-acetyltransferase 2 (P=0.056). In conclusion, TJ-29 did not appear to substantially affect the activity of CYP1A2, xanthine oxidase or N-acetyltransferase 2 in man.
Phytochemical analysis and anti-allergic study of Agave intermixta Trel. and Cissus sicyoides L.
Authors: Quílez A M , Saenz M T , García M D , de la Puerta R
Published: August 2004

Agave intermixta Trel. (Maguey) and Cissus sicyoides L. (Bejuco caro) are Caribbean plant species from the Dominican Republic used locally in traditional popular medicine that have shown an anti-inflammatory effect in experimental animal models. A phytochemical analysis on these species allowed us the isolation and identification of the steroidal sapogenins hecogenin and diosgenin from Maguey and the hydroxystilbene resveratrol from Bejuco caro. The effects of these plant extracts and their isolated constituents on compound-48/80-induced histamine release from peritoneal mast cells were investigated. Significant inhibition was produced by 0.5 mg mL−1 of a methanolic extract of Bejuco (41.1%) and by its constituent resveratrol (82.4%) at a dose of 250 μM. However, none of the steroidal sapogenins from A. intermixta showed a significant inhibitory effect on histamine release from mast cells. From these results, it can be deduced that the in-vitro anti-allergic activity towards the release of histamine from mast cells shown by the methanolic extract of C. sicyoides may be mediated by its constituent resveratrol and might contribute to the anti-inflammatory activity shown by this species.
Effect of dexamethasone, 2-bromopalmitate and clofibrate on L-FABP mediated hepatoma proliferation
Authors: Rajaraman G , Burczynski F J
Published: August 2004

Cytosolic liver fatty acid binding protein (L-FABP) is involved in many intracellular functions including cellular mitogenesis. We investigated the role of L-FABP and the plasma membrane liver fatty acid binding proteins (L-FABPpm) in the modulation of hepatoma growth and proliferation, hypothesizing that agents that affect either the content of, or ligand binding to, L-FABP would affect hepatocellular mitogenesis. L-FABP expressing 1548-rat hepatoma cells were treated with 0.5 μM dexamethasone or 500 μM clofibrate for 4 days to downregulate and upregulate L-FABP expression, respectively. The competitive inhibitor 2-bromopalmitate (BrPA, 600 μM) was used to inhibit ligand binding to L-FABP. The peripherally present plasma membrane fatty acid transporter was inactivated by treating cells with 1:50 rabbit antisera (FABP-Ab) raised against L-FABP. Western blot analysis was used to monitor L-FABP levels while [3H]-thymidine incorporation and growth curves were used to monitor hepatocellular proliferation. [3H]-Palmitate clearance studies were performed using monolayer cultures. Palmitate clearance in dexamethasone-, BrPA- and FABP-Ab-treated cells was significantly reduced when compared with control (P < 0.05), while clofibrate treatment moderately increased the rate. [3H]-Thymidine incorporation by dexamethasone- and BrPA-treated cells was significantly lower than control (P < 0.05), suggesting that hepatocellular proliferation was inhibited. Clofibrate treatment did not statistically affect growth rate. Lowering L-FABP using dexamethasone or interfering with its activity using BrPA significantly affected hepatocellular proliferation. This may be due to the non-availability of long-chain fatty acids or other intracellular mediators that are transported by L-FABP to the nucleus.
An investigation into the biological activity of the selected histidine-containing diketopiperazines cyclo(His-Phe) and cyclo(His-Tyr)
Authors: McCleland K , Milne P J , Lucieto F R , Frost C , Brauns S C , Van De Venter M , Du Plessis J , Dyason K
Published: August 2004

Although cyclic diketopiperazines have been known since the beginning of the century, only now have they attracted considerable interest with respect to their biological activity. The aim of this study was to determine if the diketopiperazines cyclo(L-histidyl-L-phenylalanyl) (cyclo(His-Phe)) and cyclo(L-histidyl-L-tyrosyl) (cyclo(His-Tyr)) have significant biological activity relevant to the treatment of cardiovascular-related disease states, cancer and infectious diseases. Haematological studies were performed, including thrombin substrate binding, blood clotting time, platelet adhesion, platelet aggregation and fibrinolysis assays. A cytotoxicity screening utilizing a tetrazolium-based assay on the cell lines HeLa, WHCO3, and MCF-7 was performed. The whole-cell patch-clamp technique was used to investigate ion-channel activity in ventricular myocytes of rats, and isolated rat heart studies were performed to investigate the cardiac effects involving heart rate and coronary flow rate. Cyclo(His-Tyr) produced a significant prolongation of blood clotting time, slowing of clot lysis and inhibition of ADP-induced platelet adhesion and aggregation (P < 0.05). Cyclo(His-Phe) showed significant (P < 0.05) anti-tumour activity, causing greatest reduction of cell viability in cervical carcinoma cells. Preliminary results from patch-clamp studies indicate that both diketopiperazines caused blocking of sodium and calcium ion channels, but opening of inward rectifying potassium ion channels. In the rat isolated heart studies, cyclo(His-Phe) caused a gradual reduction in heart rate (P = 0.0027) and a decrease in coronary flow rate (P = 0.0017). Cyclo(His-Tyr) significantly increased the heart rate (P = 0.0016) but did not cause any significant change of coronary flow rate (P > 0.05). Cyclo(His-Tyr) showed notable (P < 0.05) antibacterial activity and both diketopiperazines showed excellent antifungal activity (P < 0.05). These observations reveal diketopiperazines to be ideal lead compounds for the rational design of an agent capable of preventing metastasis, inhibiting tumour growth, and as potential chemotherapeutic, antiarrhythmic and antihypertensive agents, as well as potential antibacterial and antifungal agents.
Absorption and fluorescence study of the interaction between (2-hydroxy-benzimido)ethyl-n-hexylselenide and bovine serum albumin
Authors: Chang-Ying Yang , Yi Liu , Jun Wu , Ran Li , Yan-Jun Hu , Song-Sheng Qu
Published: August 2004

The binding of Schiff base selenide, (2-hydroxy-benzimido)ethyl-n-hexylselenide, to bovine serum albumin (BSA) was studied using fluorescence spectroscopy. The measurement was performed in Tris-HCl buffer aqueous medium at pH 7.4. Stern-Volmer graphs were plotted and quenching constants were estimated. The quenching constant at 303 K was (1.639 ± 0.046) × 1013 L mol−1 s−1. Decreased quenching was observed as temperature increased, but at the temperature range of 303–313 K, the association of Schiff base selenide to BSA was not significantly different. The static quenching presented in the system of Schiff base selenide and BSA. A complex was possibly formed between Schiff base selenide and BSA, which was responsible for the quenching of the fluorescence of BSA. This fact was also confirmed by differences in the absorption spectra of BSA before and after Schiff base selenide addition. The hydrophobic interaction was found to play a main role in the binding according to the thermodynamic parameters, enthalpy change (ΔH) and entropy change (ΔS) of reaction. Schiff base selenide most likely binds to the hydrophobic pockets within sub domain IIA of BSA, which can be proved by competition experiments for sodium dodecyl sulfate. By constant-wavelength synchronous fluorescence spectra, the influence of (2-hydroxy-benzimido)-ethyl-n-hexylselenide on the surrounding environment of tyrosine and tryptophan residues in BSA was also investigated. The red shift of the fluorescence peak of tryptophan residues indicated that the hydrophobic amino acid structure surrounding tryptophan residues in BSA collapsed slightly after the addition of (2-hydroxy-benzimido)ethyl-n-hexylselenide.
Analysis of the interaction of substituted coumarins with the DPPH free radical by means of multivariate statistics
Authors: Vrakas Demetris , Hadjipavlou-Litina Dimitra , Tsantili-Kakoulidou Anna
Published: August 2004

The interaction of some substituted coumarin derivatives with the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical was analysed by means of multivariate statistics using a variety of molecular descriptors. The compounds contain a conjugated double bond system, which was considered to be an essential structural characteristic for the free-radical scavenging activity. Partial least-square analysis led to an adequate two-component model based on bulk descriptors and the electronic properties concerning atoms involved or next to the double-bond system.
Efficacy of chitosan microspheres for controlled intra-articular delivery of celecoxib in inflamed joints
Authors: Thakkar Hetal , Sharma R K , Mishra A K , Chuttani Krishna , Murthy R S R
Published: August 2004

The use of polymeric carriers in formulations of therapeutic drug delivery systems has gained widespread application, due to their advantage of being biodegradable and biocompatible. In this study, we aimed to prepare celecoxib-loaded chitosan microspheres for intra-articular administration and to compare the retention of the celecoxib solution and chitosan microspheres in the joint cavity. The microspheres were characterized for entrapment efficiency, particle size and surface morphology by scanning electron microscopy. In-vitro drug release studies of microspheres revealed that the microspheres are able to control the release of celecoxib over a period of 96 h. Biodistribution studies of celecoxib and chitosan microspheres were performed by radiolabelling with 99mTc and injecting intra-articularly in rats. The study indicated that following intra-articular administration the distribution of the drug to the organs, like liver and spleen, is very rapid compared with that of the microspheres. Compared with the drug solution, a 10-fold increase in the concentration of the drug in the joint was observed 24 h post intra-articular injection (P < 0.005) when drug was encapsulated in microspheres.
Fluorescein permeability and electrical resistance of human skin during low frequency ultrasound application
Authors: Cancel Limary M , Tarbell John M , Ben-Jebria Abdellaziz
Published: August 2004

Transdermal drug delivery offers an alternative to injections and oral medication but is limited by the low skin permeability of most drugs. The use of low-frequency ultrasound over long periods of time, typically over an hour, has been shown to enhance skin permeability, a phenomenon referred to as sonophoresis. In this study, we investigated the effects of short time sonication of human skin at 20 kHz and at variable intensities and duty cycles on the dynamics of fluorescein transport across the skin (permeability) as well as the changes in the skin's structural integrity (electrical resistance). We found that a short application of ultrasound enhanced the transport of fluorescein across human skin by a factor in the range of 2–9 for full thickness skin samples and by a factor in the range of 2–28 000 for heat-stripped stratum corneum samples (however, samples with very high (103) enhancement were likely to have been damaged by ultrasound). The electrical resistance of the skin decreased by an average of 20% for full thickness samples and 58% for stratum corneum samples. Increasing the duty cycle from 10 to 60% caused a significant increase in permeability enhancement from 2.3 to 9.1, and an increase in intensity from 8 to 23 mW cm2 induced a significant increase in permeability enhancement from 2 to 7.4, indicating a clear dependence of the permeability on both duty cycle and intensity. The increase in solute flux upon ultrasound exposure was immediate, demonstrating for the first time the fast response dynamics of sonophoretic enhancement. In addition, a quantitative analysis of the thermal and convective dispersion effects associated with ultrasound application showed that each contributes significantly to the overall permeability enhancement observed.
Cytotoxicity of 3,4-dihalogenated 2(5H)-furanones
Authors: Lattmann Eric , Kinchington Derek , Dunn Simon , Singh Harjit , Ayuko Washington O , Tisdale Michael J
Published: August 2004

Mucohalogen acids have been used for the preparation of a variety of 3,4-dihalogenated 2(5H)-furanones. In one synthetic step the carbamates 2a-c and the pseudoanhydrides 4a-e were prepared using isocyanates and acid anhydrides. A series of 5-alkoxylated 3,4-dichloro-2(5H)-furanones 5a-o have been synthesized with a wide range of lipophilicity, using the hydroxy-form of mucohalogen acids 1a and 1b. The 5-allyl-3,4-dichloro-2(5H)-furanone 5f was derived into the dihydro-isoxazol 6 and the oxirane 7. The methyl ester 5a was converted with ammonia into the tetramic acid chloride 11. The pseudo acid chloride 3 was reacted further into the bis aziridine 8. Reduction of the mucochloric acid 1a furnished the trichlorofuranone 3. The cytotoxicity of these simple and bis-cyclic butenolides have been evaluated in tissue culture on MAC13 and MAC16 cancer cell lines using the MTT cytotoxicity assay. The ester 5g, the acetate 4b and the carbamate 2b displayed a cytotoxicity in the low micromolar range. Further, an IC50 (50% inhibitory concentration) of 50 nM and 30 nM was determined for the epoxide 7 and the aziridine 8.
Oral delivery of spray dried PLGA/amifostine nanoparticles
Authors: Pamujula Sarala , Graves Richard A , Freeman Thomas , Srinivasan Venkataraman , Bostanian Levon A , Kishore Vimal , Mandal Tarun K
Published: August 2004

Amifostine (Ethyol, WR-2721) is a cytoprotective drug approved by the US Food & Drug Administration for intravenous administration in cancer patients receiving radiation therapy and certain forms of chemotherapy. The primary objective of this project was to develop orally active amifostine nanoparticles using spray drying technique. Two different nanoparticle formulations (Amifostine-PLGA (0.4:1.0 and 1.0:1.0)) were prepared using a Buchi B191 Mini Spray Dryer. A water-in-oil emulsion of amifostine and PLGA (RG 502) was spray dried using an airflow of 600 Lh−1 and input temperature of 55°C. A tissue distribution study in mice was conducted following oral administration of the formulation containing drug-polymer (0.4:1.0). The efficiency of encapsulation was 90% and 100%, respectively, for the two formulations while the median particle sizes were 257 and 240 nm, with 90% confidence between 182 and 417 nm. Since amifostine is metabolized to its active form, WR-1065, by intracellular alkaline phosphatase, the tissue levels of WR-1065 were measured, instead of WR-2721. WR-1065 was detected in significant amounts in all tissues, including bone marrow, jejunum and the kidneys, and there was some degree of selectivity in its distribution in various tissues. This work demonstrates the feasibility of developing an orally effective formulation of amifostine that can be used clinically.
A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence
Authors: Sawicka M , Kalinowska M , Skierski J , Lewandowski W
Published: August 2004

It is assumed that proteins from the ABC family (i.e., glycoprotein P (Pgp)) and a multidrug resistance associated protein (MRP) play a main role in the occurrence of multidrug resistance (MDR) in tumour cells. Other factors that influence the rise of MDR are mechanisms connected with change in the effectiveness of the glutathione cycle and with decrease in expression of topoisomerases I and II. The aim of this review is to characterize drugs applied in anti-tumour therapy and to describe the present state of knowledge concerning the mechanisms of MDR occurrence, as well as the pharmacological agents applied in reducing this phenomenon.
A role for the PDZ-binding domain of the coxsackie B virus and adenovirus receptor (CAR) in cell adhesion and growth
Authors: Excoffon Katherine J. D. Ashbourne , Hruska-Hageman Alesia , Klotz Michael , Traver Geri L. , Zabner Joseph
Published: August 2004

The coxsackie and adenovirus receptor (CAR) plays a role in viral infection, maintenance of the junction adhesion complex in polarized epithelia, and modulation of cellular growth properties. As a viral receptor, the C-terminus appears to play no role indicating that the major function of CAR is to tether the virus to the cell. By contrast, the C-terminus is known to play a role in cellular localization and probably has a significant function in CAR-mediated adhesion and cell growth properties. We hypothesized that the CAR PDZ (PSD-95/Disc-large/ZO-1) binding motif interacts with PDZ-domain-containing proteins to modulate the cellular phenotype. CAR was modified by deleting the last four amino acids (CARΔGSIV) and evaluated for cell-cell adhesion in polarized primary human airway epithelia and growth characteristics in stably transfected L-cells. Although ablation of the CAR PDZ-binding motif did not affect adenoviral infection, it did have a significant effect both on cell-cell adhesion and on cell growth. Expression of CARΔGSIV failed to increase the transepithelial resistance in polarized epithelia to the same degree as wild-type CAR and failed to act as a growth modulator in L-cells. Furthermore, we provide evidence for three new CAR interacting partners, including MAGI-1b, PICK1 and PSD-95. CAR appears to interact with several distinct PDZ-domain-containing proteins and may exert its biological function through these interactions.
Anticonvulsant Hypersensitivity Syndrome: Lymphocyte Toxicity Assay for the Confirmation of Diagnosis and Risk Assessment
Authors: Bavdekar Sandeep B , Muranjan Mamta N , Gogtay Nithya J , Kantharia Vishakha , Kshirsagar Nilima A
Published: August 2004

OBJECTIVE

To report a case of anticonvulsant hypersensitivity syndrome (AHS) precipitated by exposure to phenobarbital.

Case Summary

An 11-year-old girl receiving phenobarbital developed fever, exfoliative skin rash, mucous membrane lesions, alopecia, and hepatic inflammation. Investigations ruled out an infectious etiology; an adverse event following phenobarbital administration was considered. Applying the Naranjo probability scale for objective causality assessment showed the adverse reaction was probably due to phenobarbital. The diagnosis was confirmed by in vitro lymphocyte toxicity assay, which demonstrated increased cell death following exposure to phenobarbital, as well as other aromatic anticonvulsants and lamotrigine.

DISCUSSION

AHS is a rare, potentially fatal event with multisystem manifestations. It is reported following exposure to aromatic antiepileptics. The mechanism proposed for AHS is accumulation of toxic arene oxide metabolites due to a defect in epoxide hydrolase—mediated detoxification. Despite the difference in chemical structure of lamotrigine, in vitro susceptibility to AHS was demonstrated in our patient.

CONCLUSIONS

Although AHS is a rare event, it should be suspected in patients who develop unexplained systemic manifestations following exposure to aromatic antiepileptics. The potential of lamotrigine to cause AHS should be remembered when this drug is used in subjects who have developed AHS on exposure to phenobarbital and other first-line antiepileptic agents.
Service Quality Perceptions and Customer Satisfaction: Evaluating the Role of Culture
Authors: Laroche Michel , Ueltschy Linda C. , Abe Shuzo , Cleveland Mark , Yannopoulos Peter P.
Published: August 2004

The authors examine the influence of culture on the measurement of service quality and satisfaction in dentists’ office settings. Respondents from the United States, Canada, and Japan participated in a 2 × 2 factorial experiment in which the authors manipulated both expectations (high/low) and service performance (high/low) in a series of scenarios. With partial metric invariance, latent mean comparisons revealed that regardless of expectations, Japanese respondents reported lower quality perceptions and satisfaction ratings when performance was high and higher satisfaction ratings when performance was low than did their U.S. and Canadian counterparts. Thus, there is some evidence that Japanese consumers are more conservative in their evaluations of superior service but are less critical (or more forgiving) of inferior service. The authors also discuss managerial implications and future research directions.
The Neurotransmitter Glutamate Reduces Axonal Responsiveness to Multiple Repellents through the Activation of Metabotropic Glutamate Receptor 1
Authors: Kreibich Thomas A. , Chalasani Sreekanth H. , Raper Jonathan A.
Published: August 2004

Glutamate is the major excitatory neurotransmitter in the mammalian CNS. Here, we propose a new role for this neurotransmitter in the developing nervous system. We show that glutamate or the metabotropic class I agonistS-3,5-dihydroxyphenyl glycine, acting through the metabotropic glutamate receptor 1 (mGluR1), can reduce the activity of multiple axonal repellentsin vitro. This effect is mediated by a pertussis toxin-sensitive activation of protein kinase A and the subsequent inactivation of Rho. This signaling pathway appears to be identical to the one we described previously for stromal derived factor-1-induced reduction of axonal repellent activities. Activation of mGluR1 can also promote increased survival of embryonic retinal ganglion cells in culture. We propose that neurotransmitter-induced modulation of repellent strength provides a novel mechanism by which activity can influence neuronal morphology.
A Physiologically Based Model of Interaural Time Difference Discrimination
Authors: Hancock Kenneth E. , Delgutte Bertrand
Published: August 2004

Interaural time difference (ITD) is a cue to the location of sounds containing low frequencies and is represented in the inferior colliculus (IC) by cells that respond maximally at a particular best delay (BD). Previous studies have demonstrated that single ITD-sensitive cells contain sufficient information in their discharge patterns to account for ITD acuity on the midline (ITD = 0). If ITD discrimination were based on the activity of the most sensitive cell available (“lower envelope hypothesis”), then ITD acuity should be relatively constant as a function of ITD. In response to broadband noise, however, the ITD acuity of human listeners degrades as ITD increases. To account for these results, we hypothesize that pooling of information across neurons is an essential component of ITD discrimination. This report describes a neural pooling model of ITD discrimination based on the response properties of ITD-sensitive cells in the IC of anesthetized cats.

Rate versus ITD curves were fit with a cross-correlation model of ITD sensitivity, and the parameters were used to constrain a population model of ITD discrimination. The model accurately predicts ITD acuity as a function of ITD for broadband noise stimuli when responses are pooled across best frequency (BF). Furthermore, ITD tuning based solely on a system of internal delays is not sufficient to predict ITD acuity in response to 500 Hz tones, suggesting that acuity is likely refined by additional mechanisms. The physiological data confirms evidence from the guinea pig that BD varies systematically with BF, generalizing the observation across species.