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

The synergistic interaction of etoposide with cisplatin in certain tumors prompted an evaluation of its potential role in the i.p. treatment of ovarian cancer and other intraabdominal malignancies. We conducted a Phase I evaluation of etoposide as a single agent to determine the maximum tolerated dose i.p., to describe dose-limiting and other toxic effects, and to examine the pharmacokinetics of etoposide in this setting. Etoposide was diluted in 2 liters of normal saline, and instilled i.p. over 10 to 25 min following maximal drainage of ascites. The dwelling time was 4 h, followed by peritoneal drainage. Twenty-two patients received 56 courses at doses which ranged from 100 to 800 mg/m2. The median age was 49, the median performance status was 1, and 18 patients had received prior chemotherapy, with or without radiation. The principal acute toxicity was abdominal pain in 10 patients; this was usually accompanied by signs of peritoneal irritation and was always responsive to nonsteroidal antiinflammatory medications. The major toxicity was dose-related neutropenia; Grade 3 or 4 toxicity affected five of six patients at 800 mg/m2. Thrombocytopenia, nausea and vomiting, and alopecia were also observed. The recommended dose for further study is 700 mg/m2. The pharmacokinetics of etoposide in plasma and peritoneal fluid was measured in 19 patients. Peritoneal levels over the 4-h dwelling time declined monoexponentially with a harmonic mean half-life of 3.5 h (range, 1.9 to 7.8). Plasma levels rose to a peak at 2.9 +/- 1.7 (SD) h and then declined exponentially with a harmonic mean terminal half-life of 7.7 h (range, 4.2 to 15.6). The plasma area under the concentration-time curve increased linearly with respect to dose. The relative pharmacological advantage (ratio of peritoneal to plasma area under concentration-time curve) for i.p. administration was measured as 2.8 and was independent of dose. Based on the high plasma protein binding of etoposide (94%) and the minimal protein binding in the fluid instilled i.p., the ratio of the areas under the concentration-time curves of free drug is estimated to be 4%. These results illustrate that tumor confined to the peritoneal cavity would be exposed to substantially higher free (diffusible) drug concentrations following i.p. than following i.v. administration and support the further evaluation of etoposide by this route.
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PMID:Phase I pharmacokinetic study of intraperitoneal etoposide. 200 23

Amonafide, a benzisoquinoline-1,3-dione with anti-tumor activity in preclinical screens, was administered to patients with recurrent or metastatic bidimensionally measurable colorectal cancer. Fourteen patients with no prior chemotherapy for advanced disease, performance status 0-1, and normal bone marrow, renal, and hepatic function were entered. Amonafide 300 mg/m2 was administered intravenously over 1 hour daily for five consecutive days; courses were repeated every three weeks. The major side effect was neutropenia: Grade 3 or 4 toxicity occurred in 5/14 patients. Other toxicities included nausea and vomiting, flulike symptoms, fever, rash and alopecia. Three patients had stable disease, but there were no responses observed. Amonafide at this dose and schedule has no activity in the treatment of colorectal cancer.
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PMID:Phase II study of amonafide (nafidamide, NSC 308847) in advanced colorectal cancer. 202 85

In a Phase I trial SR 2508 was administered by rapid intravenous infusion to 102 patients receiving radiation therapy. The dose-limiting toxicity was peripheral sensory neuropathy (PN) which was related to the cumulative dose administered. The highest single daily dose, 3.7 g/m2, was tolerated without toxicity. The lowest cumulative toxic dose was 21.6 g/m2, and the highest non-toxic dose was 40.8 g/m2. Grade 1 neuropathies were mild and self-limited; grade 2 neuropathies were long-lasting and debilitating. In a retrospective analysis, the risk of developing neurotoxicity was related to the cumulative drug exposure calculated by the area-under-the-curve (AUC) of plasma concentration versus time. There was an increased incidence of neuropathy in patients with a cumulative AUC of greater than or equal to 36 mM-hr. At a total dose of 34 g/m2 over 6 weeks, the incidence of Grade 1 neuropathy was approximately 30%; no grade 2 neuropathy occurred at this dose and schedule. Additional toxicities observed included nausea and vomiting (6%), skin rash (4%), and transient arthralgias (3%). One patient had transient abnormalities in liver function tests of unknown etiology. (In a more recent Phase II trial neutropenia has been observed which may be related to SR2508). Approximately three times more SR 2508 is tolerable compared to misonidazole, and it appears that severe neuropathy can be avoided by monitoring individual patient pharmacokinetic parameters. Evaluation of the efficacy of this hypoxic cell sensitizer is in progress.
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PMID:Final report of the phase I trial of the hypoxic cell radiosensitizer SR 2508 (etanidazole) Radiation Therapy Oncology Group 83-03. 215 20

Fifteen patients with previously untreated extensive non-small cell lung cancer (E-NSCLC) were treated with oral 4-demethoxydaunorubicin (4-DMDR) at the dose of 10 mg/m2/day x 5 days every 3 weeks with routine administration of antiemetic drugs. They received a median of two courses of treatment with the cumulative dose range from 50-712.5 mg/m2. One patient achieved partial remission with a duration of 14 weeks. Two patients had minor responses with durations of 14 and 24 weeks. Stable disease occurred in three patients (21, 22, and 27 weeks). Median survival was 33 weeks (range 3-73+ weeks). Toxicities were tolerable. Neutropenia (less than 1,000 mm3) occurred in only 16% of all treatment courses. Three patients developed correctable arrhythmias (two with atrial fibrillation and one with accelerated junctional rhythm). The cause of arrhythmia was unclear. No clinical evidence of congestive heart failure or decreased cardiac ejection fraction was observed. Nausea and vomiting were common but tolerable. Alopecia and mucositis were uncommon. Clinical pharmacokinetic studies were done in nine patients. However, plasma 4-DMDR levels were below the limit of detection (3 ng/ml). Because 4-DMDR has shown some activity in previously untreated E-NSCLC and the toxicities at this dose schedule are mild, we suggest that further studies of this drug at a higher dose in this schedule are indicated.
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PMID:Phase II study of 4-demethoxydaunorubicin in previously untreated extensive disease non-small cell lung cancer. 216 7

We performed a phase I-II trial of escalating doses of cisplatin (CDDP: 50-100 mg/m2 per course) plus carboplatin (CBDCA: 300-400 mg/m2 per course) as a potential way in which to maximize platinum doses without causing excessive toxic effects in patients with advanced ovarian cancer. Thirty-three patients with nonoptimally debulked disease of FIGO (International Federation of Gynecology and Obstetrics) stages IIc-IV [median age: 60 yr; median WHO (World Health Organization) performance status: 2; no prior chemotherapy] received a median of six courses of therapy. CBDCA was infused on day 1 and CDDP on day 2 with an aggressive 48-hour hydration regimen. Myelosuppression was dose-limiting: at the highest dose levels, WHO grade 4 neutropenia and thrombocytopenia led to dose reduction and/or treatment delay in 45% of the patients. Nonhematologic toxic effects included acute nausea and vomiting (97% of the patients), mild alopecia (45%), ototoxic effects (39%), neurotoxic effects (21%), and renal toxic effects (serum creatinine greater than 1.5 mg/dL: 12.5%). The pathologic complete response rate was 22%. We conclude that CBDCA and CDDP can be given safely in combination at reasonably high doses (CBDCA at 300 mg/m2 per course and CDDP at 100 mg/m2 per course) over a 6-month period, provided a close hematologic follow-up is conducted. Randomized clinical trials are needed to define whether this regimen is any better than standard combination chemotherapy.
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PMID:Cisplatin combined with carboplatin: a new way of intensification of platinum dose in the treatment of advanced ovarian cancer. Belgian Study Group for Ovarian Carcinoma. 218 Nov 52

Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23-36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity (greater than or equal to grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 microM) and prolonged exposure to plasma levels exceeding 50 microM may result in a higher incidence of serious non-hematologic toxicity.
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PMID:Clinical toxicity associated with tiazofurin. 220 Jul 59

Thirty patients with advanced breast cancer, previously treated with anthracycline and 5 fluorouracil in bolus administration, were evaluated with a chemotherapy regimen generally used in head and neck cancer. Treatment schedule consisted of: cisplatin 100 mg/m2 on d 1 and 5 fluorouracil 1000 mg/m2 continuous infusion on d 2-3-4-5 every 21 d. With all measurable lesions and 27 evaluable patients, the response rate was 29% (95% confidence interval: 12-47%), with 5 complete responses (3 soft tissue - 2 lung) and 3 partial responses (1 lung - 2 liver). The median duration of response is 4.5 months (range 2-11 months). The 30 patients (93 courses) are evaluable for toxicity. Hematologic toxicity was mild: anemia 68% grade 0, neutropenia 68% grade 0 and thrombocytopenia 83% grade 0. Nausea and vomiting were severe 83% grade 3 + 4 at d 1. Others side effects were mild including 5/91 mucositis grade 2 + 3, peripheral neuropathy 1/31 grade 2 and 2/91 reversible rise in serum creatinine greater than 1.5 mg/dl.
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PMID:[Phase II trial as 2nd line chemotherapy with 5 fluorouracil and cisplatin (5FU-CDDP) for advanced breast cancer]. 220 69

Thirty-one elderly patients with measurable advanced breast cancer entered this phase II study. A dose of 15 mg/m2/day of Idarubicin (IDA) for 3 consecutive days every 3 weeks was given orally. Mean total cumulative dose of IDA received was 175 mg/m2 (range: 45-475 mg/m2). Mean number of cycles given was four (range: 1-15). Out of 27 evaluable patients, three achieved a complete response (CR), four had a partial response (PR) (CR + PR = 26 +/- 17%), nine showed no change, and 11 had a progressive disease. Median time to progression was 83 days (range: 19-728 days). Out of 26 patients evaluable for toxicity, hematologic toxicity at day 21 was moderate: neutropenia grades 3 and 4 = 16% of cycles: two patients had grade 1 thrombopenia; and three patients, grade 3. No cumulative hematologic toxicity was detected. Nonhematologic toxicities consisted of nausea and vomiting in 72% of patients [World Health Organization (WHO) grades 3 and 4 = 8%)] and alopecia in 76% (WHO grades 2-3 = 38%). Grade 1 stomatitis occurred in 4% of cycles. Chemotherapy was discontinued in one patient because of drop of left ventricular ejection fraction (LVEF) from 0.62 to 0.44 at a cumulative IDA dosage of 322 mg/m2. The results of this study show that IDA is an active drug in elderly patients with advanced breast cancer. Due to its simplicity of administration IDA deserves further investigations in combination with other drugs.
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PMID:Phase II study of oral idarubicin in elderly patients with advanced breast cancer. 222 Jun 64

Six children (ages 2 to 14 years) with recurrent or poor risk primary brain tumors were treated with the '8 drugs in 1 day' chemotherapy regimen. As renal function deteriorated (median after five cycles), carboplatin was substituted in place of cisplatin at a median dose of 300 mg/m2 as a one hour infusion at hour three. Four patients also had their lomustine deleted and replaced by etoposide 100 mg/m2 at hour four. Compared to earlier cycles of chemotherapy, there was a moderate increase in transfusion requirement (especially platelets) but the incidences of fever and neutropenia were unchanged. Glomerular function as measured by nuclear glomerular filtration rate (GFR) remained unchanged or improved at the end of therapy. The severity of nausea and vomiting after substitution was markedly improved. Four of the six patients are still in complete remission 19 to 41 months after diagnosis or recurrence. It is feasible to substitute carboplatin and etoposide into the '8 drugs in 1 day' regimen when extramedullary toxicity is found.
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PMID:Modification of the 8 drugs in 1 day regimen: feasibility of substitution of other agents. 226

Sixteen patients with metastatic ovarian cancer who had not previously been treated with anthracyclines were treated with 4'deoxydoxorubicin at a dose of 30 mg/m2 intravenously every 3 weeks. There were no clinical responses in this group of patients. Toxicities were infrequent with neutropenia and thrombocytopenia being dose limiting. Nausea and vomiting occurred in only 4 patients. We conclude that 4'deoxydoxorubicin is an inactive drug in this patient population and does not warrant further investigation in this disease.
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PMID:Phase II study of esorubicin (4'deoxydoxorubicin) in anthracycline naive patients with ovarian cancer. 227 74


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