Biomedical subjects

Celeste Lindley

Publications and source records attributed to Celeste Lindley.

16 recordsLinked to original sources

PubMed2006

Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies.

BACKGROUND: Bevacizumab is a recombinant humanized monoclonal antibody that was approved by the US Food and Drug Administration (FDA) in February 2004 for use as part of combination therapy with fluorouracil-based regimens for metastatic colorectal cancer (mCRC). OBJECTIVES: This article reviews the mechanism of action, clinical pharmacology, and pharmacodynamic and pharmacokinetic properties of bevacizumab. It summarizes data on the clinical efficacy and tolerability of bevacizumab from Phase II/III trials in mCRC, breast cancer, non-small-cell lung cancer, and renal cell carcinoma and preliminary data from investigational studies in pancreatic cancer and soft-tissue sarcomas. The dosing and administration of bevacizumab also are discussed. METHODS: A comprehensive search of the English-language literature indexed on MEDLINE (1966-April 2006) was performed using the terms Avastin, bevacizumab, vascular endothelial growth factor, angiogenesis, and bevacizumab plus colorectal cancer, breast cancer, non-small-cell lung cancer, pancreatic cancer, and renal cell carcinoma. Published abstracts from American Society of Clinical Oncology annual meetings from 2002 to 2006, FDA submission documents, and the product information for bevacizumab also were reviewed. Pertinent review articles, preclinical studies, and editorials and all published Phase II/III clinical trials were selected for review. The reference lists of identified articles were examined for additional publications. RESULTS: Bevacizumab exhibits linear pharmacokinetics in the dose range between 0.3 and 10 mg/kg q2-3wk and steady state, which is reached in approximately 100 days. The estimated t(1/2) of bevacizumab is approximately 20 days. After correction for body weight, clearance and V(d) are reported to be a respective 26% and 22% higher in men than in women. Statistical analyses have not been performed, however, and the clinical impact of these gender differences has not been assessed. No dose adjustment is currently recommended based on age, sex, or renal function. Bevacizumab has been reported to result in changes in exposure to concomitant chemotherapy, although formal drug-interaction studies have not been performed. Surrogate markers of disease progression or treatment response to bevacizumab have been studied, but no significant correlations with any outcome measure have been found. When combined with standard chemotherapy regimens, bevacizumab has been associated with significant improvements compared with chemotherapy alone in the efficacy end points of overall survival, progression-free survival, and response rates in patients with mCRC (all, P < 0.05). Based on these findings, bevacizumab is considered a first-line option for this disease. Combination bevacizumab regimens have been associated with clinical activity in breast cancer, non-small-cell lung cancer, renal cell carcinoma, pancreatic cancer, and soft-tissue sarcoma. The observed toxicities of bevacizumab include hypertension, proteinuria, mild to moderate hemorrhage, wound healing complications, and thromboembolic events. A bevacizumab dose of 5 mg/kg q2wk has been established as effective and well tolerated in the setting of mCRC. A variety of dosing schemes have been investigated in other solid neoplasms, but no consensus has been reached on the optimal bevacizumab regimen. CONCLUSIONS: Bevacizumab is effective and generally well tolerated as first-line therapy for mCRC. The results from clinical studies of bevacizumab as a single agent or as part of combination regimens for breast cancer, non-small-cell lung cancer, renal cell carcinoma, and other solid malignancies have been promising. The most effective regimens for various malignancies and predictive markers of treatment response have not been fully determined. Combining bevacizumab with chemotherapy or other novel targeted agents appears to be a rational approach that may enhance efficacy while limiting the traditional nonselective toxicities.

Angiogenesis Inhibitors↗

PubMed2005

Capecitabine: a review.

BACKGROUND: Fluorouracil (FU) is an antimetabolite with activity against numerous types of neoplasms, including those of the breast, esophagus, larynx, and gastrointestinal and genitourinary tracts. Systemic toxicity, including neutropenia, stomatitis, and diarrhea, often occur due to cytotoxic nonselectivity. Capecitabine was developed as a prodrug of FU, with the goal of improving tolerability and intratumor drug concentrations through tumor-specific conversion to the active drug. OBJECTIVES: The purpose of this article is to review the available information on capecitabine with respect to clinical pharmacology, mechanism of action, pharmacokinetic and pharmacodynamic properties, clinical efficacy for breast and colorectal cancer adverse-effect profile, documented drug interactions, dosage and administration, and future directions of ongoing research. METHODS: Relevant English-language literature was identified through searches of PubMed (1966 to August 2004), International Pharmaceutical Abstracts (1977 to August 2004), and the Proceedings of the American Society of Clinical Oncology (January 1995 to August 2004). Search terms included capecitabine, Xeloda, breast cancer, and colorectal cancer. The references of the identified articles were reviewed for additional sources. In addition, product information was obtained from Roche Pharmaceuticals. Studies from the identified literature that addressed this article's objectives were selected for review, with preference given to Phase II/III trials. RESULTS: Capecitabine is an oral prodrug that is converted to its only active metabolite, FU, by thymidine phosphorylase. Higher levels of this enzyme are found in several tumors and the liver, compared with normal healthy tissue. In adults, capecitabine has a bioavailability of approximately 100% with a Cmax of 3.9 mg/L, Tmax of 1.5 to 2 hr, and AUC of 5.96 mg.h/L. The predominant route of elimination is renal, and dosage reduction of 75% is recommended in patients with creatinine clearance (CrCl) of 30 to 50 mL/min. The drug is contraindicated if CrCl is < 30 mL/min. Capecitabine has shown varying degrees of efficacy with acceptable tolerability in numerous cancers including prostate, renal cell, ovarian, and pancreatic, with the largest amount of evidence in metastatic breast and colorectal cancer. Single-agent capecitabine was compared with IV FU/leucovorin (LV) using the bolus Mayo Clinic regimen in 2 Phase III trials as first-line treatment for patients with metastatic colorectal cancer. Overall response rate (RR) favored the capecitabine arm (26% vs 17%, P < 0.001); however, this did not translate into a difference in time to progression (TTP) (4.6 months vs 4.7 months) or overall survival (OS) (12.9 months vs 12.8 months). In Phase II noncomparative trials, combinations of capecitabine with oxaliplatin or irinotecan have produced results similar to regimens combining FU/LV with the same agents in patients with colorectal cancer. In metastatic breast cancer patients who had received prior treatment with an anthracycline-based regimen, a Phase III trial comparing the combination of capecitabine with docetaxel versus docetaxel alone demonstrated superior objective tumor RR (42% vs 30%, P = 0.006), median TTP (6.1 months vs 4.2 months, P < 0.001), and median OS (14.5 months vs 11.5 months, P = 0.013) with the combination treatment. Noncomparative Phase II studies have also supported efficacy in patients with metastatic breast cancer pretreated with both anthracyclines and taxanes, yielding an overall RR of 15% to 29% and median OS of 9.4 to 15.2 months. The most common dose-limiting adverse effects associated with capecitabine monotherapy are hyperbilirubinemia, diarrhea, and hand-foot syndrome. Myelosuppression, fatigue and weakness, abdominal pain, and nausea have also been reported. Compared with bolus FU/LV, capecitabine was associated with more hand-foot syndrome but less stomatitis, alopecia, neutropenia requiring medical management, diarrhea, and nausea. Capecitabine has been reported to increase serum phenytoin levels and the international normalized ratio in patients receiving concomitant phenytoin and warfarin, respectively. The dose of capecitabine approved by the US Food and Drug Administration (FDA) for both metastatic colorectal and breast cancer is 1250 Mg/M2 given orally twice per day, usually separated by 12 hours for the first 2 weeks of every 3-week cycle. CONCLUSIONS: Capecitabine is currently approved by the FDA for use as first-line therapy in patients with metastatic colorectal cancer when single-agent fluoropyrimidine therapy is preferred. The drug is also approved for use as (1) a single agent in metastatic breast cancer patients who are resistant to both anthracycline- and paclitaxel-based regimens or in whom further anthracycline treatment is contra indicated and (2) in combination with docetaxel after failure of prior anthracycline-based chemotherapy. Single-agent and combination regimens have also shown benefits in patients with prostate, pancreatic, renal cell, and ovarian cancers. Improved tolerability and comparable efficacy compared with IV FU/LV in addition to oral administration make capecitabine an attractive option for the treatment of several types of cancers as well as the focus of future trials.

Animals↗

PubMed2005

Pemetrexed: a multitargeted antifolate.

BACKGROUND: The US Food and Drug Administration approved pemetrexed in February 2004 for the treatment of malignant pleural mesothelioma (MPM) in combination with cisplatin in patients with unresectable disease or for whom curative surgery is not an option. Pemetrexed is the first agent approved for the treatment of MPM. In August 2004, pemetrexed was approved as a second-line, single-agent treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). OBJECTIVES: The goals of this article were to summarize the pharmacology, pharmacokinetics, efficacy, and safety of pemetrexed, and to review its current and potential roles in therapy for MPM, NSCLC, and other oncologic conditions. METHODS: Relevant English-language literature was identified through searches of PubMed (1966-December 2004), International Pharmaceutical Abstracts, and the Proceedings of the American Society of Clinical Oncology (January 1995-December 2004). Search terms included pemetrexed, Alimta, MTA, multitargeted antifolate, LY231514, mesothelioma, MPM, non-small cell lung cancer, NSCLC, breast cancer, and pancreatic cancer. In addition to published literature, abstracts and posters presented at national and international scientific meetings were reviewed. RESULTS: Myelosuppression was the predominant dose-limiting toxicity of pemetrexed reported in Phase I studies. Identification of the correlation between poor folate status and increased pemetrexed toxicity in a multivariate analysis led to the requirement of folic acid and vitamin B12 supplementation for patients in all pemetrexed studies, with a resulting noted decrease in pemetrexed toxicity. A single, multicenter, randomized Phase III trial compared the efficacy of pemetrexed in combination with cisplatin versus cisplatin alone in the treatment of MPM. Response rates were 41.3% in the pemetrexed/cisplatin combination and 16.7% with single-agent cisplatin (P < 0.001). The median survival time for the pemetrexed/cisplatin combination was significantly longer at 12.1 months versus 9.3 months for cisplatin alone (P = 0.02). One international, multicenter, randomized Phase III trial in patients with NSCLC compared single-agent pemetrexed versus docetaxel in patients previously treated with chemotherapy. Overall response rates (9.1% and 8.8%) and median survival (8.3 months and 7.9 months) did not differ between pemetrexed and docetaxel (P = 0.105 and P = 0.226, respectively). Hematologic adverse effects-grade 3/4 neutropenia (40.2% vs 5.3%; P < 0.001), febrile neutropenia (12.7% vs 1.9%; P < 0.001), and neutropenic infections (3.3% vs 0%; P = 0.004)-were significantly greater in the docetaxel-treated patients than in the pemetrexed-treated patients, as was alopecia (37.7% vs 6.4%; P < 0.001). Results of an international, multicenter Phase III trial of pemetrexed in combination with gemcitabine conducted in patients with pancreatic cancer indicate that the combination is no more efficacious than single-agent gemcitabine. Results in other disease states are still preliminary. CONCLUSIONS: Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in various tumor types as a single agent and in combination with other chemotherapeutic agents. Efficacy for the treatment of MPM in combination with cisplatin has been demonstrated, and approval as a second-line agent in NSCLC was based on response rate as a surrogate end point for survival. The addition of folic acid and vitamin B12 supplementation markedly reduced.

Breast Neoplasms↗

PubMed2005

A phase I trial defining the maximum tolerated systemic exposure of topotecan in combination with Carboplatin and Etoposide in extensive stage small cell lung cancer.

PURPOSE: Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m2). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide. METHODS: Thirty-four chemotherapy-naïve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/mL*min and oral etoposide 100 mg/m2/day. Topotecan was administered as a 30-minute infusion either on Days 1-5 or Days 1-3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66. RESULTS: The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24-36 ng/mL*hr (median dose 0.82 mg/m2) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months. CONCLUSION: It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC.

Adult↗

PubMed2005

Prevention of delayed chemotherapy-induced nausea and vomiting after moderately high to highly emetogenic chemotherapy: comparison of ondansetron, prochlorperazine, and dexamethasone.

The purpose of this article is to assess the comparative antiemetic efficacy of prochlorperazine, ondansetron, and dexamethasone in the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) after moderately high to highly emetogenic chemotherapy. Cancer patients (n = 232) receiving moderately high to highly emetogenic chemotherapy were randomized to 1 of 3 treatments: 15 mg prochlorperazine spansules twice daily; 8 mg ondansetron tablets twice daily; or 8 mg dexamethasone tablets twice daily on days 2 through 5. All patients received 24 mg ondansetron and 20 mg dexamethasone orally before chemotherapy. Daily assessment (days 1 through 5) included the number of episodes of retching and vomiting, severity of nausea, restlessness, difficulty concentrating and fatigue, treatment satisfaction, and overall quality of life (measured using a 10-cm VAS). The Functional Living Index-Emesis (FLIE) was completed on day 5. Other side effects attributed to antiemetic therapy were recorded daily. For acute CINV, total control, defined as no vomiting, retching, nausea <1 cm on a 10-cm visual analog scale, and no administration of rescue medications, was achieved in 78% in the overall group and was not significantly different in the patients randomized to the 3 treatment arms for delayed CINV. Delayed CINV was reported by 43% to 57% of patients, with the highest incidence reported on day 3. For delayed CINV, patients receiving prochlorperazine reported the lowest average nausea score on days 2 to 5, whereas patients receiving ondansetron reported the highest nausea score (P = 0.05). No statistically significant differences in CINV or side effects of antiemetic therapy were noted between treatment groups on days 2 to 5. For patients similar to those included in this study, there does not appear to be a clinically important difference in efficacy, adverse effects, or treatment satisfaction among dexamethasone, prochlorperazine, and ondansetron in the doses used in these delayed CINV regimens on days 2 to 5 in this study.

Adult↗

PubMed2005

Bioavailability and metabolism of prochlorperazine administered via the buccal and oral delivery route.

Prochlorperazine has been accepted as an effective antiemetic for more than 50 years; however, its therapeutic success has been limited by its low and variable absorption and high first-pass metabolism. A buccal dosage form of prochlorperazine has been developed. This article discusses 2 clinical studies conducted to characterize the single-dose and multiple-dose pharmacokinetics of prochlorperazine and its metabolites after buccal administration. The results of these studies demonstrate that buccal administration of prochlorperazine produces plasma concentrations more than twice as high as an oral tablet, with less than half the variability. In addition to the metabolites, N-desmethyl prochlorperazine and prochlorperazine sulfoxide, 2 new metabolites, prochlorperazine 7-hydroxide and prochlorperazine sulfoxide 4'-N-oxide, were identified and quantitated. Exposure to metabolites after the buccal prochlorperazine formulation was approximately half that observed after the oral tablet. Buccal administration of prochlorperazine, twice daily, should enhance the therapeutic role of prochlorperazine in preventing and treating nausea and vomiting.

Administration, Buccal↗

PubMed2004

Intraindividual variability in busulfan pharmacokinetics in patients undergoing a bone marrow transplant: assessment of a test dose and first dose strategy.

Busulfan systemic exposure correlates with regimen-related toxicity, engraftment and relapse in select patients receiving high-dose oral busulfan (HD-BU) (1 mg/kg dose or 40 mg/m dose every 6 h for 16 doses) as part of a preparative regimen for bone marrow transplantation. Therapeutic drug monitoring is frequently conducted after the first HD-BU dose in order to determine necessary dose adjustments. Limitations with this method include the need for rapid determination of busulfan plasma concentration and difficulties with estimating apparent oral clearance in patients who exhibit delayed absorption of HD-BU. This pharmacokinetic study was conducted to evaluate the ability of the apparent oral clearance obtained after administering a lower (0.25 mg/kg) test dose and the traditional (1 mg/kg) first dose to predict the dose required to achieve a desired area under the concentration-time curve (AUC) at steady-state (13th dose). In addition, the pharmacokinetic parameters of test, first and 13th dose were compared to assess intrasubject variability. Twenty-nine patients received a test dose of oral busulfan (0.25 mg/kg) the day immediately prior to initiation of HD-BU. Busulfan serum concentrations were measured following the test, first and 13th doses using gas chromatography with electron capture detection. The AUC and apparent oral clearance were calculated using non-compartmental analysis. Therapeutic drug monitoring following the first dose of HD-BU was conducted for clinical purposes in six patients, and dose adjustment between the first and 13th dose occurred in only two patients. The dose-corrected test dose and first dose AUC and apparent oral clearance were not bioequivalent (two one-sided t-tests, +/-20%). The first dose and 13th dose AUC and apparent oral clearance were also not bioequivalent. Six of the 29 patients receiving HD-BU dose based on weight (1 mg/kg) would have achieved a steady-state AUC of 3600-5400 ng x h/ml, a frequently used target AUC, as compared to eight and 13 patients if their dose was based on the apparent oral clearance following the test dose and first dose HD-BU, respectively. Monitoring busulfan concentrations after a test dose or a first dose provides a better estimate of the dose needed to achieve the target steady-state AUC as compared to traditional weight-based dosing. However, significant intraindividual variability exists in the apparent oral clearance of busulfan and follow-up therapeutic drug monitoring is recommended particularly if the desired target AUC range is narrow.

Administration, Oral↗

PubMed2004

Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers.

The objectives of this study were to evaluate the ability of 14 compounds, which differentially activate human pregnane X receptor (hPXR), to induce CYP2B6 expression and to compare CYP2B6 and CYP3A4 concentration- and time-dependent induction by select inducers. Three primary human hepatocyte preparations were treated daily for 3 days with three concentrations of all compounds. Additional concentration- and/or time-response studies were conducted with clotrimazole, phenytoin, phenobarbital, and rifampin in six preparations. CYP2B6 and CYP3A4 protein and activities were assessed by Western blotting, bupropion hydroxylation, and testosterone 6beta-hydroxylation, respectively. To evaluate hPXR activation by the 14 compounds, reporter gene assays were conducted using Huh7 cells cotransfected with hPXR and a CYP2B6 (NR1)5-LUC reporter plasmid. Clotrimazole, phenobarbital, rifampin, and ritonavir strongly induced CYP2B6 and activated hPXR; dexamethasone t-butylacetate and sulfinpyrazone induced CYP2B6 weakly and activated hPXR moderately; paclitaxel strongly activated hPXR but did not increase CYP2B6 expression; carbamazepine and phenytoin moderately or strongly increased CYP2B6 expression but weakly activated hPXR; and dexamethasone, methotrexate, probenecid, sulfadimidine, and troleandomycin demonstrated weak or negligible effects on CYP2B6 and hPXR. EC50 values for CYP2B6 and CYP3A4 induction by clotrimazole, phenobarbital, phenytoin, and rifampin were strongly correlated (r2 = 0.99) and were statistically indistinguishable for clotrimazole, phenytoin, and rifampin. Kinetic constants governing time-dependent induction by phenobarbital and rifampin were also similar between CYP2B6 and CYP3A4. These results indicate that CYP2B6 is highly inducible by known CYP3A4 inducers and suggest that hPXR is a major determinant of CYP2B6-inducible expression for many, but not all, compounds evaluated in this study.

Algorithms↗

PubMed2003

Randomized double-blind study of the Reliefband as an adjunct to standard antiemetics in patients receiving moderately-high to highly emetogenic chemotherapy.

GOALS: Our goal was to evaluate the efficacy and tolerability of the Reliefband as an adjunct to standard antiemetics in patients receiving moderately-high to highly emetogenic chemotherapy. PATIENTS AND METHODS: Forty-nine adult cancer patients receiving moderately-high or highly emetogenic chemotherapy were randomized to receive either the active Reliefband ( n=26) or an inactive device ( n=23). Patients continued to receive all scheduled and as needed antiemetic agents as prescribed. The device was worn the day of chemotherapy administration for 5 days (days 1-5). Patients maintained a daily dairy of nausea severity, vomiting and retching episodes, and antiemetic medications taken. Each patient completed a Functional Living Index Emesis (FLIE) and a tolerability survey at the conclusion of the study. A Wilcoxon rank sum test was used to compare the number of vomiting episodes, severity of nausea and FLIE scores between the two groups. MAIN RESULTS: Patients wearing the active Relifband experienced less vomiting (Reliefband 1.9 versus inactive device 4.6 mean episodes; p=0.05), retching (1.4 versus 3.6 mean episodes; p=0.05), and nausea severity (0.91 versus 1.65 mean cm/day; p=0.01) over the 5-day period compared to patients wearing the inactive device. Vomiting was statistically significantly reduced during the delayed period (0.42 versus 1; p=0.032), whereas nausea was significantly reduced during the acute (0.71 versus 2.3; p=0.028) and delayed (1.8 versus 3.3; p=0.020) periods. FLIE scores did not differ between the two treatment groups (91 versus 80; p=0.088). CONCLUSIONS: This study suggests that patients receiving moderately-high to highly emetogenic chemotherapy who experience nausea and vomiting despite scheduled antiemetics may benefit from the use of the Reliefband as an adjunct to antiemetics. Limitations of this study include differences in risk factors for emesis, chemotherapy, and antiemetic regimens. A larger, better, controlled randomized study is needed to better define optimal use of this device.

Adult↗

PubMed2003

Gemcitabine pharmacokinetics and interaction with paclitaxel in patients with advanced non-small-cell lung cancer.

PURPOSE: Gemcitabine administered at a fixed dose rate of 10 mg/m(2) per min has been reported to achieve plasma steady-state concentrations ranging from 10 to 20 microM in patients with acute leukemia. These concentrations have been shown to saturate the intracellular accumulation of the active triphosphate metabolite. We designed this pharmacokinetic study to assess the ability of a fixed dose rate of gemcitabine to achieve the desired steady-state concentration in the absence and presence of paclitaxel in patients with solid tumors. PATIENTS AND METHODS: A group of 14 patients with advanced non-small-cell lung cancer received paclitaxel 110 mg/m(2) over 3 h on days 1 and 8 and gemcitabine 800 mg/m(2) over 80 min on days 1 and 8 every 21 days. Patients received gemcitabine alone on cycle (C) 1, day (D) 1. Pharmacokinetic samples were collected at 0, 15, 30, 45, 60 and 80 min during infusion and 0.25, 0.5, 1, 2, 4, 6, and 8 h after infusion on C1D1, C1D8, C2D1, C4D1 and C6D1. RESULTS: Of 13 patients included in the pharmacokinetic analysis, 61% achieved the desired steady-state concentration (C(ss)) with gemcitabine alone (C1D1), whereas only 0 to 45% of patients achieved the desired C(ss) with paclitaxel and gemcitabine, depending on the treatment cycle. Paclitaxel significantly decreased systemic clearance (Cl(T); P=0.012) and volume of distribution (V(d); P=0.050) and significantly increased C(ss) ( P=0.009). Gemcitabine plasma pharmacokinetic parameters demonstrated great interpatient variability in the absence of paclitaxel (C(ss) 30%, Cl(T) 30%, V(d) 55%). Interpatient and intrapatient variability in gemcitabine pharmacokinetics were not observed when gemcitabine was administered in combination with paclitaxel (P>0.05). CONCLUSIONS: Gemcitabine plasma pharmacokinetic parameters are significantly altered in the presence of paclitaxel.

Adult↗

PubMed2003

Is patient satisfaction a legitimate outcome of pain management?

Though many studies have measured patient satisfaction with pain management using the American Pain Society (APS) Satisfaction Survey or its variants, little is known about the relationship among the survey items, or whether items relate to satisfaction at all. In an effort to refine the measurement of patient satisfaction, a modified version of the APS survey, which was given to 787 patients as part of a study of postoperative pain management in six community hospitals, was subjected to principal components analysis to determine the survey's empirical structure. Correlations among the five components found were low; a weak relationship (r = -0.24) was discovered between pain intensity and satisfaction. A heuristic model estimated by structural equations analysis yielded additional insights. Though many items thought to influence patient satisfaction were not closely related to patient-reported satisfaction, they indicate important clinical factors relevant to quality of care, and thus, to continuing quality improvement (CQI) efforts. Results suggest that satisfaction was influenced by effectiveness of medication, independent of pain intensity, and by communication. Pain severity ratings near the time satisfaction was measured were more influential than earlier ratings.

Female↗

PubMed2003

Use of NSAIDs for the chemoprevention of colorectal cancer.

OBJECTIVE: To discuss the role of nonsteroidal antiinflammatory drugs (NSAIDs) in the chemoprevention of colorectal cancer. DATA SOURCES: A MEDLINE search (1966-May 2003) was performed to identify key literature. Search items included, but were not limited to, NSAIDs, colorectal cancer, chemoprevention, cyclooxygenase-2 (COX-2)-specific inhibitors, and familial adenomatous polyposis (FAP). STUDY SELECTION AND DATA EXTRACTION: The search included experimental (in vitro and animal models) and clinical studies evaluating the use of NSAIDs for the chemoprevention of colorectal cancer. The MEDLINE search was supplemented by references from selected articles. DATA SYNTHESIS: Numerous experimental, epidemiologic, and clinical studies suggest that NSAIDs have promise as anticancer agents. The mechanism by which NSAIDs lead to decreased colon carcinogenesis is not fully understood, but may involve restoration of apoptosis and inhibition of prostaglandin-mediated angiogenesis. Compelling evidence from many observational studies has consistently documented a 40-50% reduction in the risk of adenomatous polyps, colorectal cancer incidence, and mortality in patients using NSAIDs. Recent randomized, controlled trials have demonstrated a benefit with aspirin in reducing the rate of development of new or recurrent adenomas in high-risk patients. In addition, randomized studies using sulindac and celecoxib in patients with FAP have documented significant regression of existing adenomatous polyps. CONCLUSIONS: Inhibition of COX-2 is an example of a targeted approach to the chemoprevention of colorectal cancer. However, controversy exists about the safety, efficacy, and optimal treatment regimen of NSAIDs as long-term chemopreventive agents in the general population. Ongoing studies in high-risk patients with both selective and nonselective COX inhibitors will provide important information in the area of colorectal chemoprevention, but clinical trials' use of adenomas as surrogate markers for chemoprevention trials makes their application to the general population limited.

Animals↗

PubMed2003

Aprepitant--a novel NK1-receptor antagonist.

Recently, a new class of agents, the substance P antagonists, has heralded a novel approach for the control of emesis. Aprepitant (Emend, Merck & Co., Inc.), the first of this class, was recently approved by the FDA for the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). Of interest is the vast array of processes in which substance P is involved such as pain, anxiety, depression and inflammation and the potential wide applicability of substance P antagonists to a number of medical conditions outside of the nausea and vomiting realm. The following review provides an overview of aprepitant including pharmacokinetics, pharmacology and clinical evidence for its use in CINV. A brief discussion of other possible indications for aprepitant will also be presented.

Antiemetics↗

PubMed2002

The effect of cyclophosphamide with and without dexamethasone on cytochrome P450 3A4 and 2B6 in human hepatocytes.

The purpose of this study was to characterize the concentration-response effects of cyclophosphamide (CPA) with and without dexamethasone (DEX; 10 microM) on the expression of CYP3A4 and CYP2B6 in cultured human hepatocytes at concentrations representative of standard- and high-dose CPA therapy (25 to 750 microM). CPA produced concentration-dependent increases in CYP3A4 and CYP2B6 activity and immunoreactive protein that peaked at 250 and 125 microM, respectively, and declined thereafter. The inductive effect of CPA alone and in combination with DEX was greater in magnitude for CYP2B6 compared with CYP3A4. To further examine the inductive effect of CPA on CYP3A4, CPA (250 microM) and DEX (10 microM) alone and in combination were examined in 10 hepatocyte preparations. The combination of CPA and DEX yielded higher rates of 6beta-hydroxytestosterone formation than either agent alone. However, the effect was less than additive in human hepatocyte cultures with relatively high baseline CYP3A4 activity and additive or synergistic in human hepatocyte cultures with relatively low baseline CYP3A4 activity. Induction index was highly correlated with CYP3A4 baseline activity for both CPA (r(2) = 0.75) and CPA plus DEX (r(2) = 0.85). To investigate the potential mechanism for CPA-induced increases in CYP3A4 activity, the ability of CPA alone and in combination with DEX to activate pregnane X receptor (PXR) was explored using transient transfection assays. CPA produced a dose-dependent increase in PXR activation that was maximal at the highest CPA concentration studied (500 microM). The addition of DEX to CPA resulted in a minor increase in PXR activation compared with CPA alone. These results indicate that CPA alone and in combination with DEX differentially induces the expression of CYP3A4 and 2B in a concentration-dependent manner, which may be mediated partially through activation of PXR. The impact of these effects on the efficacy and toxicity of CPA therapy warrants further investigation.

Aryl Hydrocarbon Hydroxylases↗

PubMedDate not supplied

Developments in breast cancer therapy.

The lifetime risk of breast cancer in women is 1 in 8, with an increasing incidence in each decade of life after age 40. Breast cancer is considered curable with detection and treatment during Stages I and II, but disease-free survival drops in Stage III and is essentially zero in Stage IV. Breast-conserving surgical removal of tumors has been the standard of care for primary local therapy for more than a decade. For prevention of recurrence, tamoxifen is recommended in dosages of 20 mg/day for 5 years. The aromatase inhibitors are now considered first-line therapy in metastatic disease, and use of the monoclonal antibody trastuzumab has increased 5-year survival rates.

Adult↗

PubMedDate not supplied

Oxaliplatin biotransformation and pharmacokinetics: a pilot study to determine the possible relationship to neurotoxicity.

BACKGROUND: Both oxaliplatin and ormaplatin undergo biotransformation to Pt(dach)Cl2 with studies suggesting a predictive relationship between systemic exposure to Pt(dach)Cl2 and the severity of the delayed sensory neuropathy associated with ormaplatin. Studies characterizing the pharmacokinetic parameters of oxaliplatin and Pt(dach)Cl2 in humans have not been reported. This study was conducted to characterize the pharmacokinetic parameters of oxaliplatin and Pt(dach)Cl2 and to determine the extent to which oxaliplatin undergoes biotransformation to Pt(dach)Cl2 in humans. MATERIALS AND METHODS: Ten adult patients with metastatic colon cancer received oxaliplatin with or without fluorouracil-based chemotherapy. Blood samples were obtained during cycles 1 and 2. Total platinum, oxaliplatin and Pt(dach)Cl2 in the plasma ultrafiltrate were measured using high performance liquid chromatography and atomic absorption spectrometry. All patients underwent a thorough neurological evaluation after each cycle. RESULTS: The median steady-state concentration (C(SS)) (interquartile range, 25% to 75%) for oxaliplatin 85 mg/m2 was 0.33 microg Pt/ml (0.28 to 0.38 microg Pt/ml). The area under the curve (AUC) was 0.79 microg Pt/ml/h (0.62 to 0.88 microg Pt/ml/h) and the elimination half-life was 0.32 h (0.27 to 0.46 h). The median C(SS) for Pt(dach)Cl2 was 0.008 microg Pt/ml (0.004 to 0.014 microg Pt/ml). The C(SS) ratio of oxaliplatin to Pt(dach)Cl2 was 31 (24 to 51). All patients reported acute cold-induced neuropathy following cycles 1 and 2. Only two patients reported delayed sensory neuropathy (grade 1). CONCLUSION: The parent drug oxaliplatin is the major active platinum complex detected in plasma ultrafiltrate for at least the first few hours following oxaliplatin infusion in humans. Therefore, the plasma biotransformation products of oxaliplatin are unlikely to contribute to its efficacy or toxicity. In particular, plasma Pt(dach)Cl2 is unlikely to significantly contribute to the delayed sensory neuropathy associated with oxaliplatin, since only a limited amount (<3%) of oxaliplatin undergoes biotransformation to Pt(dach)Cl2.

Adenocarcinoma↗