Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article reviews the preliminary but encouraging clinical data obtained from patients with platinum-refractory clear cell or mucinous carcinoma of the ovary who were treated with a chemotherapy regimen including irinotecan hydrochloride (CPT-11). Twenty-five patients with platinum-refractory macroscopic disease of which histologic type was either clear cell or mucinous carcinoma were treated. CPT-11 was administered at a dose of 120 mg/m2 intravenously (i.v.) over 4 hours on days 1 and 15, and mitomycin-C (MMC) was given IV as a bolus at a dose of 7 mg/m2 on days 1 and 15. At least 2 cycles of this regimen, 4 weeks apart, were given to the 25 patients. After a median of 4 cycles (range 2 to 8), we observed objective responses in 13 patients (52%), with 5 complete responses (CRs; 20%) and 8 (32%) partial responses (PRs) (95% confidence interval, 32.4% to 71.6%, 4.3% to 35.7%, 13.7% to 50.3%, respectively). The median overall survival time for all 25 patients was 15.3 months (range 3.5 to 38.0). Median overall survival time of the responders was 33.7 months versus 6.1 months of the non-responders (Log-rank, P = 0.0003). The median progression-free survival times for patients obtaining CR, PR, and CR+PR were 31.8 months (range 12.9 to 34.4), 10.5 months (range 5.6 to 18.2), and 12.9 months (range 5.6 to 34.4), respectively. Toxic effects were acceptable and included manageable haematologic reactions, diarrhoea, nausea/vomiting, and alopecia.
 ...
PMID:A phase II study of combined CPT-11 and mitomycin-C in platinum refractory clear cell and mucinous ovarian carcinoma. 991 34

CPT-11 + ADM therapy (CPT-11 40 mg/body x 2 days; Day 1 & 2, combined with ADM 20 to 60 mg/body x 1 day; Day 3) was given to four patients with relapsed and advanced non-Hodgkin's lymphoma, which was refractory to conventional chemotherapies. The symptoms of the patients at the beginning of CPT-11 + ADM therapy were fever (in two cases), dyspnea due to pleural effusion (in two), severe backache (in one), and jaundice with splenomegaly (in one). Their Karnofsky performance scales were 20 or 30%. Soon after the initiation of CPT-11 + ADM therapy, their clinical conditions improved dramatically, and they obtained a partial remission lasting 3.5 to 9 months. During the period of controlling lymphomas by this therapy, all patients had some time at home for 2 to 8 months. The adverse effects were vomiting, diarrhea, neutropenia and thrombocytopenia, but no lethal infection or hemorrhage was seen. We conclude that CPT-11 + ADM therapy is very useful for improvement of QOL and life prolongation of patients with non-Hodgkin's lymphoma, which is refractory to conventional chemotherapies and is even disseminated.
 ...
PMID:[Improvement of quality of life (QOL) and life prolongation by CPT-11 + adriamycin (ADM) therapy: report of 4 cases of non-Hodgkin's lymphoma refractory to conventional chemotherapies]. 1023 5

Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine chemotherapy-naive patients with advanced or recurrent cervical cancer were treated with CPT-11 (60 mg/m(2)) on days 1, 8, and 15 by intravenous infusion over 90 min, followed by cisplatin (60 mg/m(2) i.v.) on day 1 over 90 min. The patients' median age was 57 years (range 35-75). Nineteen patients (66%) had advanced primary disease. Six patients with recurrent disease (21%) had been treated with prior radiotherapy. The remaining 4 patients (14%) had residual or recurrent disease after radical surgery. The histologic diagnoses were squamous cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell carcinoma in 1. All eligible patients were included in the toxicity and response analysis based on the intent to treat. Two patients (7%) achieved a complete response and 15 (52%) a partial response (overall response rate: 59%, 95% confidence interval; 41-74%). Stable disease was recorded in 6 patients (21%) and progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation of response was judged to be unfeasible at the time of independent extramural review (10%). The median time to response was 32 days (range 16-62 days). The median survival was 27. 7+ months (range, 6.4-52.8+ months). Two dose-limiting side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%) or 4 (7%) diarrhea. Other severe toxicities included anemia (45%), thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination of CPT-11 with cisplatin is an active regimen for treatment of advanced or recurrent cervical cancer albeit with a significant degree of myelosuppression.
 ...
PMID:Phase II study of irinotecan and cisplatin as first-line chemotherapy in advanced or recurrent cervical cancer. 1064 38

Based upon the results of phase I study of irinotecan (CPT-11) combined with cisplatin (CDDP) on non-small cell lung cancer (NSCLC), a combination phase II study on NSCLC was carried out from Feb., 1992 to Sep., 1992. CPT-11 (60 mg/m2) and CDDP (80 mg/m2) were administered by i.v. drip infusion, with administration schedules of Days 1, 8, 15 and only Day 1, respectively. This therapy course was repeated every 4 weeks. Subjects were NSCLC patients of stage III B or IV disease. Those without prior chemotherapy (Group A) and those with prior therapy (Group B) were enrolled separately. Seventy patients were entered into Group A and 32 patients into Group B. One of the patients of Group A was ineligible. The characteristics of the eligible cases of Group A were: male/female, 51/18; median age, 61 years old; PS 0/1/2, 18/39/12; stage IIIB/IV, 26/43; and adeno/squamous/large, 51/15/3. Those of group B were: male/female, 20/12; median age, 62 years old; PS 0/1/2, 5/18/9; stage I/IIIB/IV, 1/7/24, adeno/squamous/large/ad-sq, 28/2/1/1. Thirty-three patients (47.8%) responded in Group A and B patients (25.0%) responded in Group B. Major adverse reactions (grade 3 or higher) of Group A/Group B were neutropenia (80.3%/73.3%), anemia (35.3%/34.4%), diarrhea (18.8%/28.1%) and nausea/vomiting (34.8%/34.4%). Median survival times for Group A and Group B were 308 and 295 days, respectively. CPT-11 in combination with CDDP is effective against NSCLC, suggesting that further studies are needed to determine the usefulness of this therapy.
 ...
PMID:[A phase II study of irinotecan combined with cisplatin in non-small cell lung cancer. CPT-11 Lung Cancer Study Group]. 1074 Jun 35

A Phase I study was performed to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic profile of irinotecan (CPT-11) and its active metabolites when given on a once-every-3-week schedule. Thirty-four patients with advanced refractory solid malignancies were treated with CPT-11 (240-340 mg/m2) administered as a 90-min i.v. infusion every 3 weeks. Patients were divided into two groups: those with and those without prior abdominal/pelvic (AP) radiotherapy. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and hematological toxicity (leukopenia and neutropenia) were dose-limiting side effects. Other common toxicities included anorexia, asthenia, and acute cholinergic symptoms (abdominal cramps, diaphoresis, and lacrimation). For patients with no prior AP radiation therapy, the MTD was determined to be 320 mg/m2, whereas those with prior AP radiation therapy had a MTD of 290 mg/m2. Dose-proportional increases in the mean area under the concentration-time curves for CPT-11, SN-38, and SN-38G were not observed over the narrow dose range studied. Mean values of terminal phase half-life, clearance, terminal phase volume of distribution, and steady-state volume of distribution for CPT-11 were 12.4 +/- 1.8 h, 13.0 +/- 3.8 liters/h/m2, 234 +/- 83 liters/m2, and 123 +/- 38 liters/m2, respectively. The pharmacodynamic analyses indicated the strongest correlation to be between SN-38 area under the concentration-time curves and neutropenia (p = 0.60; P = 0.001). A total of five responses (one complete response and four partial responses) were observed in the cohort of 32 patients with previously treated metastatic colorectal carcinoma. In conclusion, gastrointestinal toxicity and hematological toxicity were the dose-limiting toxicities of CPT-11 when administered as a 90-min infusion every 3 weeks. In this trial, the recommended Phase II starting dose for patients with no prior AP radiation therapy was found to be 320 mg/m2; for patients with prior AP radiation, the recommended Phase II starting dose was 290 mg/m2. This once-every-3-week schedule has been incorporated into a Phase I trial of CPT-11 combined with 5-fluorouracil and leucovorin.
 ...
PMID:Phase I dose-finding and pharmacokinetic trial of irinotecan hydrochloride (CPT-11) using a once-every-three-week dosing schedule for patients with advanced solid tumor malignancy. 1087 73

Three active antitumor agents, i.e. 5-fluorouracil (5-FU), oxaliplatin and CPT-11, are available for the treatment of advanced colorectal cancer (CRC) patients and have been successfully combined in two-drug regimens. Hence, CRC has become a chemosensitive disease, but the optimal combination of these agents in first-line treatment remains to be determined. We report the first case of the combination of CPT-11 with oxaliplatin, 5-FU and folinic acid (FA) as first-line chemotherapy for a patient with a pre-occlusive sigmoid adenocarcinoma and synchronous bulky liver metastases. CPT-11 was given at 125 mg/m2, prior to the start of a chronomodulated 4-day infusion of oxaliplatin 25 mg/m2/day, 5-FU 800 mg/m2/day and FA 300 mg/m2/day repeated every 2 weeks. The doses could be escalated to 150 mg/m2 for CPT-11 and 900 mg/m2/day for 5-FU. After six cycles of chemotherapy 70% reduction in tumor size was documented in the liver. The primary tumor was no longer detectable by barium enema. The toxicity included three episodes of grade 4 neutropenic fever, and two episodes of severe diarrhea and vomiting with dehydration. A cumulative grade 2 neurosensory toxicity was observed after six cycles. Following surgery of the primary tumor, because of the major hepatic tumor response and of the absence of extra-hepatic metastases, the patient might be registered for a liver transplantation program. This first report of combining the three active agents in CRC every 2 weeks led to a high dose intensity of each agent and was associated with a dramatic tumor response of a very advanced disease in a patient with already altered performance status. The antitumor activity in this patient suggests that a three-drug intensified regimen might be feasible and active. A prospective study appears warranted to further examine the efficacy and toxicity of this therapeutic approach, and to determine whether it may increase the fraction of advanced CRC patients becoming resectable. This aggressive chemotherapy program may contribute to a re-examination of the usefulness of liver transplantation in patients with metastatic CRC confined to the liver.
 ...
PMID:Dramatic tumor response of bulky liver metastases following treatment with CPT-11 and a chronomodulated 4-day infusion of 5-fluorouracil, folinic acid and oxaliplatin every 2 weeks in a colorectal cancer patient. 1089 41

We report a patient with metastatic colon carcinoma who was treated effectively with a continuous intrahepatic artery-infusion of 5-FU, Leucovorin and cisplatin, and systemic chemotherapy with CPT-11. A 50-year-old man was diagnosed as having well differentiated adenocarcinoma of the sigmoid colon with multiple liver metastases in March, 1997. Left hemicolectomy and subsequent catheterization into the common hepatic artery via the gastroduodenal artery were performed in April, 1997. He was treated with 3 courses of continuous intrahepatic artery-infusion of 5-FU, Leucovorin and cisplatin, and two courses of systemic chemotherapy with CPT-11 during hospitalization, followed by 6 courses of a similar intraarterial therapy in an outpatient setting. Reinstallation of the catheter into the hepatic artery via the femoral artery was performed because of occlusion of the reservoir. During the 6th course of intraarterial therapy, diarrhea, nausea, and vomiting appeared and angiography revealed a narrowing of the hepatic artery. Therefore, the intrahepatic artery-infusion therapy was reinitiated with doses of 5-FU, Leucovorin and cisplatin reduced to approximately 80%. After 5 courses of this therapy, the computed tomography scan showed a marked decrease in the size of the metastatic hepatic lesions by 90%, and the serum level of CEA decreased from 657.7 ng/ml to 4.5 ng/ml. No severe side effects were seen during the treatment. Though multiple lung metastases were indicated during the intrahepatic artery-infusion therapy, both the liver and lung metastases have been well controlled with continuous intrahepatic artery-infusion chemotherapy and systemic chemotherapy. The continuous intrahepatic arterial infusion of 5-FU, leucovorin and cisplatin appears to be very effective for the treatment of colon carcinoma with liver metastasis without reducing the quality of life.
 ...
PMID:[A case of metastatic colon carcinoma in which a continuous intrahepatic artery-infusion of 5-FU leucovorin and cisplatin, and systemic chemotherapy with CPT-11 was very effective]. 1096 4

In preclinical studies, the topoisomerase I inhibitor irinotecan (Camptosar, CPT-11) has demonstrated activity as a radiosensitizer, probably due to its ability to inhibit potentially lethal radiation damage repair. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly irinotecan with concurrent thoracic radiation therapy for patients with unresectable stage III non-small-cell lung cancer. For this study, 13 patients received three dose escalations (from 30 to 40 to 50 mg/m2/wk). At the first dose level, one patient developed grade 5 esophagitis. Accrual was expanded to seven patients. None of the remaining six patients developed esophagitis. At the second dose level (40 mg/m2/wk), the worst toxicity, which developed in one patient, was grade 2 esophagitis. At the third dose level (50 mg/m2/wk), two of three patients developed grade 4 nausea and vomiting; grade 3 or 4 esophagitis also occurred in two patients. Of the 12 evaluable patients, seven achieved a partial response, for an overall response rate of 58%. In conclusion, nausea, vomiting, and esophagitis appear to be the principal DLTs of concurrent weekly irinotecan and thoracic radiation in the outpatient setting. The MTD of concurrent weekly irinotecan with thoracic radiation therapy appears to be 40 mg/m2 weekly for 6 weeks. To confirm the MTD of this combination, this study is still open to accrual at the second dose level (40 mg/m2) in combination with carboplatin.
 ...
PMID:Weekly irinotecan and concurrent radiation therapy for stage III unresectable NSCLC. 1098 Dec 90

The binding of camptothecin (CPT) to the DNA-topoisomerase complex is reversible, but it needs to be maintained for maximal inhibitory activity. It is also dependent on the chemical structure of CPT. The lactone form is thought to be necessary for the activity. In human serum, the equilibrium between lactone and carboxylate is in favor of the latter. For these reasons, alternative administration of CPT analogues is being evaluated. The ideal compound would remain in lactone form and would expose the host for long periods of time to its effects. Oral administration of irinotecan (CPT-11) and topotecan (TPT) is discussed by other investigators. We studied oral rubitecan and reported a low lactone to total drug area under the plasma concentration-time curve (AUCP) ratio (14.7%), with low plasma concentration over time despite repeated administrations and the presence of an enterohepatic cycle. Aerosolization of a liposomal formulation of rubitecan is currently under study. Six patients have been treated once a day for 5 days every 3 weeks. The dose was 6.7 micrograms/kg/day. Plasma levels are dose for dose higher than those after oral administration, but the ratio of lactone versus total drug is low. No toxicity was observed. The study will continue with increasing doses and lengths of administration. Intrathecal administration of topotecan has been studied in a phase I trial in children. Doses of 0.4 mg are tolerated without toxicity, and clinical responses have been seen in patients with refractory meningial carcinomatosis. Phase II studies are planned. Intraperitoneal (i.p.) administration of topotecan has been studied in a phase I trial as a 24-hour infusion in 5% dextrose at pH 3.5 every 21 days. Dose-limiting toxicity is 4 mg/m2. Toxic effects are neutropenia, anemia, emesis, fever, and pain. Five of 10 patients with ascites had symptomatic relief. Pharmacokinetic analysis demonstrates a second-order kinetics with elimination half-lives of 0.49 and 2.7 hours. The peritoneal to plasma AUC ratio was 31.2. Intramuscular, transdermal, and subcutaneous administrations have been extensively studied in the mouse.
 ...
PMID:Alternative administration of camptothecin analogues. 1119 99

Exatecan mesylate (DX-8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT-11, including watersolubility, greater potency against topoisomerase I, lack of esterase-dependent activation, broad antitumor activity, and low cross-resistance against MDR-1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose-limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX-8951 and lactone DX-8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose-dependent and reversible. Neutropenia was dose-limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose-limiting in heavily pretreated patients. Non-hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting > diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non-small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT-11 and topotecan-resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX-8951f-induced neutropenia in individual patients was developed. The daily x5, every 3-week schedule with the drug administered as a 30-minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.
 ...
PMID:DX-8951f: summary of phase I clinical trials. 1119 1


<< Previous 1 2 3 4 5 6 Next >>