Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), toxicity profile, and antitumor activity of gemcitabine and paclitaxel combination therapy when administered to patients with advanced solid tumors, using two infusion schedules of each agent. Paclitaxel was administered on day 1, followed by gemcitabine, and gemcitabine alone was administered on day 8, of each 21-day treatment course. In the initial phase of the trial, paclitaxel was administered during 3 hours and gemcitabine during 30 minutes (schedule A). After the MTD was determined on this schedule, patients were then treated with paclitaxel during 1 hour and gemcitabine at a fixed dose-rate of 10 mg/m(2)/min (schedule B). Forty-six patients were treated with 176 courses at 7 dose levels. The MTD for schedule A was 1,300 mg/m(2) and 200 mg/m(2) and for schedule B was 1,000 mg/m(2) and 200 mg/m(2) for gemcitabine and paclitaxel, respectively. The DLT for schedule A was neutropenia and for schedule B was neutropenia and thrombocytopenia. Nonhematologic toxicity was relatively mild. Gemcitabine and paclitaxel, using both schedules of administration in the current trial, is a promising chemotherapeutic regimen.
 ...
PMID:Phase I trial of gemcitabine, administered as a standard and constant dose-rate infusion, in combination with paclitaxel in patients with advanced solid tumors (LOA-2). 1239 98

We performed a phase I study combining gemcitabine and interferon (IFN)- 2b in patients with advanced solid tumors to determine the maximum tolerated dose (MTD) and recommended doses for phase II trials. Five dose levels of gemcitabine (mg/m )/IFN- (x10 IU) were planned: 500/5, 1000/5, 1000/7, 1000/10 and 1200/10. Gemcitabine was given once weekly and IFN 3 x weekly for 3 consecutive weeks followed by 1 week of rest (28-day cycles). Between February 1997 and June 1999, 21 patients with advanced pancreatic ( =3), ovarian ( =1), renal ( =10) and non-small cell lung cancer (NSCLC; =7) were enrolled. The MTD was reached at gemcitabine 1000 mg/m and IFN- 7 x 10 IU, with two of three patients having dose-limiting toxicity (thrombocytopenia). The predominant hematologic toxicities (grade 3/4) were neutropenia and thrombocytopenia (13 and five patients, respectively). Three patients had moderate neutropenic fever and one had grade 4 AST/ALT; none required hospitalization. Of the 18 evaluable patients, responses included one partial response (NSCLC) and 10 stable diseases (eight renal cancer). We conclude that the recommended phase II study regimen is gemcitabine 1000 mg/m and IFN- 5 x 10 IU, every 28 days. The results, particularly those in metastatic renal carcinoma, are encouraging and worthy of further evaluation in phase II trials.
 ...
PMID:Gemcitabine and interferon-alpha 2b in solid tumors: a phase I study in patients with advanced or metastatic non-small cell lung, ovarian, pancreatic or renal cancer. 1239 52

The drugs concerned by this review are cytarabine (ara-C), gemcitabine and fludarabine. Seventy-eighty per cent of a dose of ara-C are excreted under the form of ara-U (main metabolite). Plasma concentrations of ara-C are not related to drug pharmacodynamics (response to treatment) in contrast to intracellular levels of ara-CTP (active metabolite) which are associated with cytotoxic activity. Gemcitabine is able to autoactivate its own mechanism of action. Gemcitabine is characterized by a short half-life of elimination (15-20 min) and plasma pharmacokinetics of the drug are not linked to pharmacodynamics. Prolonged administration of gemcitabine is pharmacokinetically and pharmacologically justified and should deserve more intense clinical investigations. Total body clearance of F-ara-A (main circulating metabolite of fludarabine) is linked to creatinine clearance and drug-related neutropenia are more frequent in patients with creatinine clearance below 50 mL/min. So far there are no relationships between intracellular levels of F-ara-CTP and response to treatment.
 ...
PMID:[Clinical pharmacology of nucleoside analogues]. 1244 33

Combination chemotherapy with newer, more active drugs in patients with advanced and/or metastatic bladder cancer might show improved response rate and survival. Gemcitabine (GEM) and Epidoxorubicin (EPI) have demonstrated activity in this disease. In addition, experimental studies in vitro have shown that the two agents have additive-synergistic effects when used in combination. Our prior phase I dose-finding study in previously untreated patients with advanced or metastatic bladder cancer defined recommended doses for further trials of GEM 1000 mg/m2 and EPI 25 mg/m2 on days 1, 8 and 15 every 28 days. A phase II trial at this dose level was initiated in previously untreated patients to assess efficacy and toxicity. Eligible patients had measurable disease; Karnofsky performance status (PS) of > 40; no prior chemotherapy; and adequate bone marrow reserve, cardiac, hepatic and renal function. Thirty- one patients (22 males, 9 females) with median age of 64 (range 44-75) and median PS of 80 were accrued, and all were eligible. Twelve patients had T4N1-2 M0, 8 had lymph node only metastases, while 11 had visceral metastases (liver, bone, lung). A total of 181 cycles was administered (range 3-7 per patient). Major toxicities (WHO grade > or = 3) were: neutropenia in 5 patients, thrombocytopenia in 2 patients, and anemia in 2 patients. Three patients had febrile neutropenic episodes and only 3 patients required dose reduction. Grade 1-2 non-hematological toxicities included nausea/vomiting, stomatitis and alopecia. No cardiac toxicity was observed. Of the 30 response evaluable patients, 17 (57%) demonstrated a major response (3 complete and 14 partial) (95% CI: 39%-75%), 7 had stable disease (23%) and 6 progressed (20%). These preliminary results confirm the phase I observation that the combination of GEM--EPI is highly active in the treatment of advanced and metastatic bladder cancer with a favourable toxicity profile.
 ...
PMID:Gemcitabine plus Epi-doxorubicin as first-line chemotherapy for bladder cancer in advanced or metastatic stage: a phase II. 1253 29

A phase I study was conducted to determine the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of gemcitabine and irinotecan combination therapy as second line treatment in patients with advanced non-small cell lung cancer (NSCLC). Twelve patients with measurable NSCLC (age range 46-74 years; 7 males, 5 females; performance status 0 = 4, 1 = 8) who progressed or failed first-line chemotherapy were enrolled. Prior chemotherapy was platinum-based without gemcitabine or irinotecan. Gemcitabine was administered at a fixed dose of 1,000 mg/m2 after irinotecan administration, and irinotecan was administered at doses from 50 to 125 mg/m2 with an increment of 25 mg/m2, both on day 1 and 8. Chemotherapy was repeated every 3 weeks. Grade 3/4 leukopenia occurred in three patients (25%), neutropenia in four (33%), anemia in one (8%), and thrombocytopenia in one (8%). Grade 3 nausea and vomiting was observed in three (25%), grade 2 diarrhea in one (8%), and liver dysfunction in one (8%). Other toxicities were mild. Two of the three patients at level 4 (irinotecan 125 mg/m2) experienced dose limiting toxicity: one patient experienced grade 4 leukopenia and neutropenia, and the other experienced treatment delay of more than 2 weeks. The objective response rate was 16.6% (2/12). The maximum tolerated dose in this combination therapy was gemcitabine 1,000 mg/m2 and irinotecan 125 mg/m2. The dose level of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 on day 1 and 8 of a 3-week cycle is recommended for a phase II study.
 ...
PMID:[A phase I study of gemcitabine and irinotecan as second line treatment for advanced non-small cell lung cancer]. 1261 Aug 72

Pancreatic cancer has one of the worst prognosis of any malignant disease. Systemic therapy is often administered because the disease is usually detected at advanced stages. Gemcitabine (Gemzar trade mark, Eli Lilly & Co.) has proven activity in the treatment of pancreatic cancer. Gemcitabine 1000 mg/m(2) was given on days 1, 8 and 15, every 4 weeks. A total of 100 chemonaive patients with locally advanced or metastatic pancreatic cancer were enrolled; 32 and 68% had stage III and IV disease, respectively. The average number of administered cycles was 3.5 (range: 1 - 12). The overall response rate was 13%, with 13 partial responders. The median time to progression was 13.5 weeks (range: 3 - 56; 95% CI = 12 - 14). The median survival was 32 weeks (range: 4 - 104; 95% CI = 27 - 36). Clinical benefit response was acheived for 26 patients (26%). Grade 3/4 haematological toxicities occurred infrequently (anaemia: 5%; neutropenia: 8% and thrombocytopenia: 3% of patients). Grade 3/4 non-haematological toxicities were not observed. There were no treatment-related deaths. Gemcitabine treatment of patients with locally advanced or metastatic pancreatic cancer is effective and well-tolerated.
 ...
PMID:Gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer: a prospective observational study. 1266 20

Single agent gemcitabine was used in recurrent epithelial ovarian cancer patients after standard treatment with debulking surgery and platin-paclitaxel based chemotherapy. Response rates and toxicity results were evaluated retrospectively. Gemcitabine was given in 1000 mg/m2 intravenous infusion over 30 minutes at 1, 8, 15 days of every 28 days. Clinical response was evaluated with clinical findings, serum CA 125 levels, and computerized tomography. Twenty-two patients--ten as second-line, 11 as third-line, and one as fourth line--received gemcitabine. Seven patients received six courses, nine cases three, five cases two and one case one course of treatment. There were four (18.2%) partial and two (9.1%) complete responses with an overall response rate of 27.3%. Stable disease was also observed in three more cases. The progression-free interval was found to be a median of three months. Grade 3-4 neutropenia was seen in two (9.1%) and grade 3-4 thrombocytopenia was seen in four (18.2%) cases. Pancytopenia was observed in one (4.5%) patient. There was no grade 3-4 non-hematological toxicity. Antitumoral activity is encouraging in heavily pretreated ovarian cancer patients. A short progression-free interval is noticeable in responding cases. Toxicity is mainly hematologic and moderate.
 ...
PMID:Efficacy of gemcitabine in heavily pretreated advanced ovarian cancer patients. 1270 71

Anthracyclines are among the most active drugs in breast cancer. Gemcitabine is a novel agent that has also shown good antitumor activity in advanced breast cancer. This compound has a favorable toxicity profile, no apparent multidrug resistance, and retains its activity in anthracycline-pretreated patients. Therefore, it was logical to combine gemcitabine with anthracyclines. The combinations of gemcitabine and anthracyclines (doxorubicin, liposomal doxorubicin, epirubicin) have been tested in a few phase I and II studies. Generally, these combinations have been shown to be feasible and well tolerated. The pharmacokinetics of gemcitabine and anthracyclines was not affected by their combined use. Myelosuppression was the most common adverse event; neutropenia was easily reversible. Data from phase II clinical studies suggest that gemcitabine/anthracycline combinations are relatively effective in first- or second-line therapy for women with locally advanced and metastatic breast cancer. Future randomized clinical trials are warranted to further elucidate the role of these regimens in breast cancer care.
 ...
PMID:Gemcitabine and anthracyclines in breast cancer. 1272 19

In a previous study of prevalidation, a standard operating procedure (SOP) for two independent in vitro tests (human and mouse) had been developed, to evaluate the potential hematotoxicity of xenobiotics from their direct and the adverse effects on granulocyte-macrophages (CFU-GM). A predictive model to calculate the human maximum tolerated dose (MTD) was set up, by adjusting a mouse-derived MTD for the differential interspecies sensitivity. In this paper, we describe an international blind trial designed to apply this model to the clinical neutropenia, by testing 20 drugs, including 14 antineoplastics (Cytosar-U, 5-Fluorouracil, Myleran, Thioguanine, Fludarabine, Bleomycin, Methotrexate, Gemcitabine, Carmustine, Etoposide, Teniposide, Cytoxan, Taxol, Adriamycin); two antivirals (Retrovir, Zovirax,); three drugs for other therapeutic indications (Cyclosporin, Thorazine, Indocin); and one pesticide (Lindane). The results confirmed that the SOP developed generates reproducible IC90 values with both human and murine GM-CFU. For 10 drugs (Adriamycin, Bleomycin, Etoposide, Fludarabine, 5-Fluorouracil, Myleran, Taxol, Teniposide, Thioguanine, and Thorazine), IC90 values were found within the range of the actual drug doses tested (defined as the actual IC90). For the other 10 drugs (Carmustine, Cyclosporin, Cytosar-U, Cytoxan, Gemcitabine, Indocin, Lindane, Methotrexate, Retrovir, and Zovirax) extrapolation on the regression curve out of the range of the actual doses tested was required to derive IC90 values (extrapolated IC90). The model correctly predicted the human MTD for 10 drugs out of 10 that had "actual IC90 values" and 7 drugs out of 10 for those having only an extrapolated IC90. Two of the incorrect predictions (Gemcitabine and Zovirax) were within 6-fold of the correct MTD, instead of the 4-fold range required by the model, whereas the prediction with Cytosar-U was approximately 10-fold in error. A possible explanation for the failure in the prediction of these three drugs, which are pyrimidine analogs, is discussed. We concluded that our model correctly predicted the human MTD for 20 drugs out of 23, since the other three drugs (Topotecan, PZA, and Flavopiridol) were tested in the prevalidation study. The high percentage of predicitivity (87%), as well as the reproducibility of the SOP testing, confirm that the model can be considered scientifically validated in this study, suggesting promising applications to other areas of research in developing validated hematotoxicological in vitro methods.
 ...
PMID:Application of the CFU-GM assay to predict acute drug-induced neutropenia: an international blind trial to validate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive xenobiotics. 1288 91

Forty-nine patients with unresectable pancreatic cancer (stage IV disease) received gemcitabine in a multi-center trial in the Fukuoka pancreatic cancer chemotherapy group, Japan. No complete remissions, 5 partial remissions (10%) and 25 no changes (51%) were obtained. Gemcitabine could maintain QOL. Main toxicities were hematologic, especially neutropenia. Neutropenia tended to appear in early administration. Non-hematologic toxicities were anorexia, nausea/vomiting, and skin rash. The mean overall survival period was 7.5 months. Carcinomatous ascites and/or pleural effusion resulted in a poor prognosis (average survival 3.1 months). Gemcitabine could be given without severe toxicities in outpatient clinics. These results suggested that gemcitabine is currently a first-line therapeutic agent for advanced pancreatic cancer.
 ...
PMID:[Multi-center trial of gemcitabine for 49 patients with advanced pancreatic cancer]. 1289 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>