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

Topotecan (SK&F 104864) is a novel antitumor agent whose mechanism of action is inhibition of the DNA unwinding protein topoisomerase I. An analog of camptothecin, topotecan was designed to be more water soluble in an effort to decrease the severe and sporadic toxicities experienced during phase I/II trials of the parent compound. In this phase I clinical and pharmacological trial, topotecan was given as a bolus intravenous (i.v.) infusion over 30 min every 21 days. A total of 42 patients entered the study, receiving doses ranging from 2.5 to 22.5 mg/m2. The maximum tolerated dose (MTD) of topotecan given in this schedule was 22.5 mg/m2. Myelosuppression, primarily neutropenia, was dose-limiting. The extent of prior therapy did not predict for more severe neutropenia. Non-hematologic toxicities were mild and included low-grade to moderate fever, nausea, vomiting, alopecia, diarrhea and skin rashes. There were no objective partial or complete responses, although there was a suggestion of antitumor activity in three patients. Topotecan undergoes pH-dependent hydrolysis of the lactone ring; only the closed, lactone form is active. The lactone form predominated during infusion, with hydrolysis occurring rapidly following the end of infusion. There were linear relationships between dose administered and peak plasma lactone concentrations as well as AUC lactone to AUC total. The lactone was rapidly cleared from plasma with a total body clearance of 25.7 (+/- 6.7) l/h/m2. The plasma lactone concentration declined rapidly with a harmonic mean terminal half-life of 3.4 (+/- 1.1)h. Lactone hydrolysis and renal excretion were the major routes of elimination.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 days. 133 81

Topotecan (SK&F 104864-A, NSC 609699) is a water-soluble, semi-synthetic analog of camptothecin which is an inhibitor of topoisomerase I. Since topoisomerase I is cell specific for S phase, we undertook a phase I study to determine the maximum tolerated dose and toxicities of continuous infusion (CI) topotecan. This phase I trial first explored a 5 day CI every 21 day schedule. Doses of topotecan included 0.17, 0.34 and 0.68 mg/m2/day. Fourteen patients [median age 60; median performance status (PS) of 1] with refractory malignancies received 59 courses of drug. Hematologic toxicities occurred only at the highest dose level; NCI grade 3-4 granulocytopenia and thrombocytopenia occurred in 4/8 and 3/8 patients, respectively. The protocol was amended to a 3 day infusion in an effort to ameliorate toxicity and obtain greater dose intensity (DI). Doses of 0.68, 0.85, 1.05, 1.3 and 1.6 mg/m2/day were evaluated. Thirty-two patients (median age 60; median PS of 1) received a total of 115 courses. The major toxicity seen was hematologic with 9/32 and 5/32 patients demonstrating grade 3-4 granulocytopenia and thrombocytopenia, respectively. Non-hematologic toxicities were mild (grade 1-2) in the two schedules and included nausea, vomiting, fatigue and alopecia. At the maximum tolerated dose (MTD) on the 5 day schedule, patients received 0.87 mg/m2/week, whereas they received 1.08 mg/m2/week at the MTD on the 3 day schedule (24% increase in relative dose intensity). A steady-state plasma lactone concentration of 5.5 mg/ml of topotecan was achieved at the phase II recommended dose of 1.6 ng/m2/day as a 3 day continuous infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phase I and pharmacokinetic studies of topotecan administered as a 72 or 120 h continuous infusion. 794 42

The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to-moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.
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PMID:Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia. 838 70

Topoisomerase I inhibitors are interesting anti-cancer agents with a novel mechanism of action. We performed a phase I study with intravenous GI147211, a new semisynthetic camptothecin analogue, using a daily x 5 schedule administered every 3 weeks, to evaluate the side-effects and pharmacokinetics of the agent. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard froms of therapy were eligible for the study. GI147211 was given as a 30 min intravenous infusion daily for 5 consecutive days, repeated every 3 weeks. In subsequent patient cohorts the dose was escalated from 0.3 to 1.5 mg m-2 day-1. Pharmacokinetics analysis was performed on days 1 and 4 of the first course using a validated high-performance liquid chromatographic assay and non-compartmental methods. A total of 19 patients were entered into the study, one patient was not evaluable for toxicity because only one drug administration was given. Eighteen patients received a total of 67 courses through four dose levels. The dose-limiting toxicities were neutropenia and thrombocytopenia at the dose of 1.5 mg m-2 day-1. Nadirs occurred on day 15 and day 15 respectively. Other toxicities were mild and infrequent and included nausea/vomiting, headache and alopecia. The maximal tolerated dose was 1.2 mg m-2 day-1. One partial response was observed in a patient with colorectal cancer. The total plasma clearance was 999+/-184 ml min-1 (range 640-1329). The volume of distribution was 190+/-461 m-2 and the terminal half-life was 3.7+/-1.2 h. The AUC increased linearly with the administered dose. A steep and significant sigmoid relationship was established between the AUC and the percent decrease of ANC. GI147211 is a new topoisomerase I inhibitor that induced dose-limiting neutropenia and thrombocytopenia in this phase I study. The recommended dose for phase II studies with this schedule is 1.2 mg m-2 x 5 every 3 weeks.
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PMID:Phase I and pharmacological study of the new topoisomerase I inhibitor GI147211, using a daily x 5 intravenous administration. 861 74

GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m2/day. Severe neutropenia precluded dose escalation above 1.5 mg/m2/day in minimally pretreated patients, and both severe neutropenia and thrombocytopenia were dose limiting in heavily pretreated patients at doses above 1.0 mg/m2/day. These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparable prior therapy. Nonhematological toxicities, including nausea, vomiting, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, with renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI147211 and effects on neutrophils; however, patients who developed dose-limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug. The hydrolysis kinetics of GI147211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in erythrocytes, perhaps accounting for the observed lactone:total area under the concentration-time curve ratio of 0.27. These results indicate that GI147211 exhibits predictable toxicities and that further studies are warranted to determine the distinct role of this compound among currently available camptothecin analogues.
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PMID:Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks. 953 26

Preclinical schedule dependency suggests that prolonged maintenance of low plasma levels of topotecan, a specific inhibitor of the nuclear enzyme topoisomerase I, results in optimal antitumor activity. The pharmacokinetics and pharmacodynamics of topotecan, administered as single agent in second-line therapy as a continuous low-dose infusion for 21 days, were evaluated in nine patients with small cell lung cancer (SCLC). Topotecan was administered i.v. as a 21 day continuous infusion every 28 days via an ambulatory pump. Dosages ranged from 0.4 to 0.6 mg/m2/day. Plasma levels of topotecan, the sum of topotecan, and its hydroxy acid congener and the N-desmethyl metabolite were determined at 1, 7, 14 and 21 days during infusion, using a validated high-performance liquid chromatography method with fluorescence detection. Myelosuppression was the most important toxicity. All patients experienced anemia, being severe (grade 3/4) in 55% of all courses. Other adverse effects were relatively mild and reversible, and included nausea, vomiting, diarrhea and fatigue. Three patients achieved a partial response. Mean steady-state concentrations of topotecan (C(ss)) in the first course were 0.46+/-0.17 and 0.47+/-0.19 ng/ml after doses of 0.4 and 0.5 mg/m2/day, respectively. Steady-state levels of the total of topotecan and hydroxy acid (C(ss,tot)) were 1.28+/-0.25 (range 0.93-1.58) and 1.57+/-0.19 (range 1.43-1.70) ng/ml at doses of 0.4 and 0.5 mg/m2/day, respectively. The percentage of the administered topotecan dose excreted in the urine within 24 h was 40+/-14 and 1.2+/-1.0% for total topotecan and N-desmethyltopotecan, respectively. During the second course, C(ss,tot) was significantly higher (p=0.032, paired t-test), which suggests altered topotecan disposition. A sigmoidal relationship was found between C(ss,tot) and the percent decrease in platelets (r=0.76, p=0.018). We conclude that topotecan administered as a 21 day continuous low-dose infusion has activity as single-agent, second-line therapy in patients with SCLC. There was considerable interpatient and intrapatient variability in systemic exposure to topotecan. Differences in organ function might contribute to this variation. Serum aspartate aminotransferase and albumin levels were predictive of topotecan pharmacokinetics.
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PMID:Continuous infusion of low-dose topotecan: pharmacokinetics and pharmacodynamics during a phase II study in patients with small cell lung cancer. 966 May 38

The topoisomerase I inhibitor topotecan has shown antitumour activity against a variety of tumour types in vitro and in vivo. Topotecan in combination with drugs that induce DNA damage generally results in synergistic killing of tumour cells in vitro. As the activity of topotecan is related to exposure time, the drug is administered by intravenous infusion either continuously or once daily over a 30-minute period for several consecutive days. A 30-minute infusion of topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks produced response rates of up to approximately 20% in patients with advanced ovarian cancer who had failed to respond to platinum-based regimens or relapsed after initial response to such regimens. No significant differences in efficacy were apparent between topotecan and paclitaxel in a phase III study in patients with recurrent ovarian cancer, although a trend in favour of topotecan was evident for all major efficacy parameters. Non-cumulative myelosuppression, including neutropenia, thrombocytopenia and anaemia, is the dose-limiting toxicity associated with topotecan. Myelo-suppression was significantly more common with topotecan than with paclitaxel in a single comparative study. Non-haematological adverse events in topotecan recipients are generally mild and include alopecia, nausea, vomiting, and other gastrointestinal problems. Thus, topotecan has modest efficacy in the treatment of recurrent advanced ovarian cancer, with clinical activity similar to that of paclitaxel in a large randomised phase III study in this setting. Combinations of paclitaxel and a platinum compound are being used increasingly for first-line therapy, although relapse rates remain significant. Topotecan is therefore a suitable second-line option, providing antitumour response for some patients whose disease has relapsed after, or is refractory to, platinum-based therapy. Its wider potential when used either alone or in combination regimens should become clearer from ongoing studies.
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PMID:Topotecan. A review of its potential in advanced ovarian cancer. 980 12

Topotecan is a specific inhibitor to topoisomerase I. An oral formulation of topotecan is available with a bioavailability of 32-44% in humans. A phase I and pharmacological study of the oral formulation of topotecan administered daily for 5 days every 21 days was performed in adult patients with solid tumours to determine the maximum tolerated dose (MTD). Adult patients with a WHO performance status < or = 2 adequate haematological, hepatic and renal functions, with malignant solid tumours refractory to standard forms were entered into the study. Pharmacokinetics were performed on days 1 and 4 of the first course using a validated high performance liquid chromatographic assay. 29 patients entered the study, all patients were evaluable for toxicity and response. The doses studied in the 29 patients were 1.2, 1.8, 2.3, 2.7 mg/m2/day and a fixed dose of 4 mg/day without surface area adjustment. A total of 109 courses were given. Dose limiting toxicity (DLT) was reached at a dose of 2.7 mg/m2/day and consisted of CTC (NCI-Common Toxicity Criteria) grade IV granulocytopenia. The regimen was well tolerated. Non-haematological toxicities were mild, including fatigue, anorexia, nausea, vomiting and diarrhoea. A significant correlation was observed between the percentage decrease in white blood cells versus the area under the curve (AUC(t)) of topotecan lactone (R = 0.76 P < 0.01) which was modelled by a sigmoidal Emax function. The correlation coefficient between the absolute topotecan dose administered and the AUC(t) was R = 0.52 (P = 0.04). Pharmacokinetics of the fixed dose of 4 mg/day were comparable to the 2.3 mg/m2/day dose. DLT in this phase I study of five daily doses of oral topotecan every 21 days was granulocytopenia. The recommended dose for phase II studies is 2.3 mg/m2/day or alternatively, a fixed dose of 4 mg/day.
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PMID:Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours. 984 51

Topotecan is a topoisomerase I inhibitor with significant activity in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical data suggest a synergistic activity with DNA damaging agents such as cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide-induced DNA damage. We thus designed a combination including cyclophosphamide 500 mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL) (refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79 years). Eleven patients (17%) achieved a complete remission (CR), and two patients (3%) had a hematologic improvement (HI; met all criteria for CR except for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23 episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin complicating 74 courses of CAT. Non-hematologic toxicity was mostly gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was severe in only 8%. In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation.
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PMID:Cyclophosphamide, ara-C and topotecan (CAT) for patients with refractory or relapsed acute leukemia. 1078 92

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.
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PMID:Weekly irinotecan and concurrent radiation therapy for stage III unresectable NSCLC. 1098 Dec 90


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