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)

Thirty two patients with refractory or recurrent acute leukemia or blast crisis of chronic myelocytic leukemia were treated with 1-beta-D-arabinofuranosylcytosine (Ara-C), 100 mg/m2 [group I (n = 15)] or 200 mg/m2 [group II (n = 18)], and tetrahydrouridine (THU) 350 mg/m2, given concurrently as a 3 h continuous intravenous infusion at 12 h interval for eight doses. Two of 13 (15.3%) evaluable patients in group I achieved a complete response, both of whom had acute myelocytic leukemia. In group II, seven of 14 evaluable patients (50%) obtained objective responses--six with complete responses (42.8%) and one with partial response (7%). Myelosuppression was seen in all patients with a median duration of 32.5 days (group I) and 36.3 days (group II), respectively. Non-hematologic toxicity consisted of nausea, vomiting, diarrhea, conjunctivitis, skin rash, hepatocellular toxicity, hemorrhage, and renal toxicity. Pharmacokinetic studies revealed, for group I, mean peak plasma Ara-C levels at 3 h (Cp3h) of 1254 ng/ml, area under the curve (AUC) 4651 ng x h/ml, total body clearance (TBC) 32.65 l/h/m2, renal clearance (RC) 7.04 l/h/m2 with a mean of 12.36% of the injected amount of Ara-C excreted unchanged in urine over the first 24 h. The corresponding mean values for group II are Cp3h 3305 ng/ml, AUC 15080 ng x h/ml, TBC 20.48 l/h/m2, RC 7.02 l/h/m2 and 26.23%. Ara-C 200 mg/m2 combined with THU gave serum Ara-C levels and response rates comparable to those achieved with high dose Ara-C (HiDAC) (greater than or equal to 1 g/m2). Central nervous system toxicity associated with HiDAC was not seen. Pharmacokinetics for uracil arabinoside (Ara-U) in patients treated with Ara-C 200 mg/m2 plus THU, were comparable to values seen with Ara-C for Cp3h, AUC and 24 h urine, amounting to 3160 ng/ml, 21717 ng x h/ml and 23.62% whereas TBC was significantly lower (p less than 0.001) for Ara-U than for Ara-C (3.02 versus 20.48 l/h/m2).
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PMID:Therapy of refractory/relapsed acute leukemia with cytosine arabinoside plus tetrahydrouridine (an inhibitor of cytidine deaminase)--a pilot study. 196 Oct 42

Phase II study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate), a derivative of cytosine arabinoside, on hematological malignancies was conducted by multi-institutional cooperative group. YNK01 was administered orally at dose of 100-300 mg/body/day for more than 2 weeks. The number of registered and evaluated patients were 211 and 156, respectively. Of 23 patients with acute myelogeneous leukemia (AML), 2 complete response (CR), one partial response (PR) were observed (CR + PR: 13.0%). Hypoplastic leukemia (1/4: 25%), acute unclassified leukemia (1/1: 100%). Of 45 patients with MDS, 2CRs, 6 good response (GR) and 5PRs were observed (CR + PR: 28.9%). AML developing after a prior history of MDS (5/17: 29.4%), CML-BC (2/9: 22.2%). Of 19 patients with CML, 9 achieved CR, 3 achieved PR (63.2%). Of 11 patients with polycythemia vera, 4 achieved CR, 5 achieved PR (81.8%). Of 6 patients with essential thrombocytosis, 2 achieved CR, one achieved PR (50%). The major adverse effects included gastrointestinal toxicities such as nausea, vomiting, anorexia, diarrhea, and elevation of GOT and GPT which were tolerable and reversible. This study indicates that YNK01 is a useful agent against acute leukemia and MDS, especially RAEB, RAEB in T, CMMoL.
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PMID:[Phase II study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate) on hematological malignancies]. 226 Aug 76

Neutropenic enterocolitis is a symptom complex of fever, abdominal pain, distention, nausea, vomiting, diarrhea, and bloody stools occurring in a patient with a low neutrophil count and is most often seen in patients with acute leukemia after a course of chemotherapy. In most cases, neutropenic enterocolitis is a self-limited condition, but complications of transmural intestinal necrosis and bowel perforation may occur in a small number of patients. Surgical management should be reserved for those patients with bowel wall necrosis or perforation; however, early identification of these patients is difficult. We report our experience with the use of diagnostic peritoneal lavage in three patients with the symptoms and signs of neutropenic enterocolitis. In each case, Gram's stain of lavage fluid revealed no evidence of polymicrobial contamination of the peritoneal cavity. All three patients were managed medically, with resolution of their abdominal symptoms. Peritoneal lavage is helpful in excluding bowel perforation and avoiding unnecessary surgical intervention in patients with neutropenic enterocolitis.
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PMID:Selective management of patients with neutropenic enterocolitis using peritoneal lavage. 238 Dec 15

Fludarabine phosphate (NSC 312878), an adenosine deaminase resistant analogue of 9-beta-D-arabinofuranosyladenine, has entered clinical trials. Eleven patients with acute leukemia in relapse received 14 courses of fludarabine phosphate as a 5-day continuous infusion administered at doses of 40 to 100 mg/m2/day. Toxicity was characterized by uniform myelosuppression, as well as occasional nausea, vomiting, and hepatotoxicity. Three episodes of metabolic acidosis and lactic acidemia were noted. In addition, three patients suffered neurotoxicity. Two of these three patients had a severe neurotoxicity syndrome characterized by blindness, encephalopathy, and coma. Neither patient recovered neurological function. Neuropathological findings at autopsy were characterized by a diffuse, necrotizing leukoencephalopathy which was most severe in the occipital lobes. The medullary pyramids and posterior columns were also severely affected. This sporadic fatal neurotoxicity was observed only at doses greater than 40 mg/m2/day. The maximum tolerated dose for a 5-day infusion of fludarabine phosphate is thus 40 mg/m2/day.
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PMID:Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study. 242 88

From December, 1985 to October, 1987, 16 patients aged from 14 to 62 (median 34) with acute leukemia in relapse (10 affected by ANLL and 6 by ALL) were treated with the following regimen: Idarubicin 12 mg/m2/day on days 1-2-3, Ara-C 600 mg/m2 twice a day from day 1 to 6. Twelve patients (75%) achieved complete remission (C.R.). Two (12%) died during the induction phase from alveolar pneumonitis. One patient was resistant. The median duration of C.R. and survival was respectively 12 (range 6 to 100 +) and 23 weeks (4 to 108 +). The median duration of granulocytopenia was 16 days (range 10 to 24 days). The most frequent non-hematological complications consisted of nausea, vomiting, diarrhea and mucositis. Four patients had hepatic and splenic microabscesses of suspected mycotic etiology, and one showed a transient cardiac arrhythmia. The C.R. rate obtained in this series may be considered satisfaying since all but 3 patients were on treatment at the time of relapse. Yet the short duration of C.R. suggests the opportunity of performing consolidation cycles or suprelethal therapy followed by bone marrow transplantation.
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PMID:Idarubicin combined with intermediate-dose cytosine arabinoside in the treatment of refractory acute leukemia. 249 85

Twenty-eight adult patients with primary refractory or relapsed acute leukemia were treated. The regimens consisted of mitoxantrone plus cytosine arabinoside for 17 patients with acute non-lymphocytic leukemia (ANLL) and mitoxantrone accompanied with vincristine and prednisolone for 11 patients with acute lymphoblastic leukemia (ALL). In primary refractory patients, 1 of the 4 (25%) ANLL and 1 of the 3 (33%) ALL attained complete remission (CR). Excluding 2 patients who underwent bone marrow transplantation, 8 of the 13 (62%) relapsed ANLL and 4 of the 8 (50%) relapsed ALL achieved CR with a median duration of remission of 6.2 months and 3.8 months, respectively. Myelosuppression occurred in all treatment courses and was associated with pyrexia due to infections in 84% of the cases. Nausea, vomiting and stomatitis were mild. Abnormal liver function tests were observed in 8 (28%) patients. One patient, pretreated with 550 mg/m2 of doxorubicin, developed congestive heart failure. The results suggest that mitoxantrone is of value in the treatment of Chinese patients with refractory or relapsed acute leukemia.
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PMID:Treatment of refractory or relapsed adult acute leukemia by using mitoxantrone-containing regimens. 263 48

Epirubicin (4'-epidoxorubicin) is an antineoplastic agent derived from doxorubicin. The compounds differ in the configuration of the hydroxyl group at the 4' position. Epirubicin, like doxorubicin, exerts its antitumor effects by interference with the synthesis and function of DNA and is most active during the S phase of the cell cycle. Epirubicin is administered by intravenous (IV) injection. It is metabolized by the liver and primarily eliminated in the bile. About 10% of the drug is eliminated in the urine. Dosage adjustments are recommended for patients with liver metastases or elevated liver function tests. The elimination half-life of epirubicin is 30 to 40 hours. Clinical studies indicate activity in breast cancer, non-Hodgkin's lymphomas, ovarian cancer, soft-tissue sarcomas, and pancreatic cancer. There is also evidence of activity against gastric cancer, small-cell lung cancer, and acute leukemia. Epirubicin has limited activity as a single agent against head and neck tumors or non-small-cell lung cancer, but may be beneficial in combination with other agents. The overall activity of epirubicin appears to be comparable with that of doxorubicin. However, more studies are needed to define its role in combination chemotherapeutic regimens. The acute dose-limiting toxicity of epirubicin is myelosuppression. Nausea, vomiting, and alopecia are also common. Epirubicin may cause transient cardiac arrhythmias and alterations of the electrocardiogram. Chronic therapy is limited, but available data indicate that epirubicin can be administered in higher cumulative doses than doxorubicin before cardiotoxicity limits further therapy.
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PMID:Epirubicin: a review of the pharmacology, clinical activity, and adverse effects of an adriamycin analogue. 300 21

Fifteen children with acute leukemia in relapse, refractory to conventional therapy, were treated with idarubicin administered orally for 3 consecutive days in dosages ranging from 30 to 50 mg/m2 per day at 19- to 21-day intervals. Gastrointestinal complications, including nausea, vomiting, abdominal pain, diarrhea and stomatitis, were the major forms of dose-limiting toxicity, affecting the majority of patients at all levels of idarubicin dosage. Two patients who had received total-body irradiation for bone marrow transplantation developed life-threatening gastrointestinal toxicity suggestive of a radiation "recall" phenomenon. Echocardiographic evidence of depressed cardiac function, without clinical symptoms or signs, was noted in six of 11 patients, although the changes were judged to be significant in only one child. The maximal tolerated oral dose of idarubicin was 40 mg/m2 per day. The medium terminal plasma half-life of idarubicin was 9.2 h (range, 6.4-25.5 h). Both idarubicin and its metabolite, idarubicinol, accumulated during the 3 days of therapy. Among the five patients with acute nonlymphoblastic leukemia whose cells were tested for drug sensitivity in vitro, the idarubicin concentration resulting in 50% inhibition (IC50) of cluster and colony formation ranged from 1.6 x 10(-10) M to 5 x 10(-7) M. There was no obvious relationship between the IC50 for idarubicin and that for epirubicin or daunorubicin. Oral idarubicin produced definite antileukemic effects, clearing blast cells from the circulation in 13 of the 14 evaluable patients. Future studies should define an optimal dose schedule to circumvent the limiting gastrointestinal complications associated with this agent.
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PMID:Phase I clinical trial of orally administered 4-demethoxydaunorubicin (idarubicin) with pharmacokinetic and in vitro drug sensitivity testing in children with refractory leukemia. 316 8

DON (6-diazo-5-oxo-L-norleucine), a glutamine antagonist, has been subjected to limited clinical trials since 1957. Use of the drug in adults has been curtailed due to sparse reports of effectiveness as well as its dose-limiting toxicities, i.e., severe nausea, vomiting and mucositis. In earlier studies, children given DON orally in combination with 6-mercaptopurine had significant prolongation of remission of acute leukemias during maintenance therapy. As DON is acid-labile and relatively unstable in solution, oral administration does not appear to be ideal for DON. In the trial described in this report, i.v. DON therapy was studied, using i.v. chlorpromazine to control vomiting, in 20 children, 17 of whom were evaluable following treatment at DON dose levels ranging from 150 mg/m2 to 520 mg/m2. Nausea and vomiting, the dose-limiting toxicity for adults, was controlled with chlorpromazine. Mucositis, which has also been observed in adults, did not occur in the children given DON i.v. A maximum tolerated dose was not defined; however, the projected maximum tolerated dose appears to be in excess of 450 mg/m2. DON was measured in plasma using a rapid-sampling HPLC procedure. The total body clearance, plasma t1/2, and area under the plasma concentration curve (AUC) were calculated using a noncompartmental method. The drug is rapidly cleared from plasma (t 1/2 = 3 h), and its volume of distribution is approximately twice that of total body water in children. These pharmacokinetic data, differ from that of adults reported by others. Specifically, the plasma t 1/2 for children is longer: total body clearance (Cl), and volume of distribution at steady state (Vss) are greater. In addition, no dose dependency of t 1/2, Cl or Vss was observed in this study, and the DON pharmacokinetics were linear and predictable. Five of nine children with acute leukemia showed improvement, though insufficient for classification as partial response, and five of eight children with solid tumors also showed improvement. Further trials using DON in combination with thiopurines or other agents appear indicated.
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PMID:Pharmacokinetic and phase I study of intravenous DON (6-diazo-5-oxo-L-norleucine) in children. 334 70

Most studies using high-dose cytarabine (ara-c) for the therapy of acute leukemia have employed intermittent short infusions. In this study, we have evaluated the pharmacology and toxicity of high-dose ara-c by 72-hour continuous infusion. Plasma ara-c concentrations varied from 3.6 microM at the starting dose of 4 g/m2/72 hours to 22.6 microM at 18 g. Plasma clearance appeared to decrease progressively at doses greater than 10 g, suggesting that the route of elimination was saturable. CSF ara-c concentrations ranged from 1.2 microM at 4 g to 4.1 microM at 18 g; the ratio of CSF to plasma ara-c decreased progressively from 0.33 at 4 g to 0.18 at 18 g. The toxic effects were significant and included myelosuppression, nausea, and vomiting in all patients. No single dose-limiting toxicity was identified. Further dose escalation was precluded by combined organ system effects, which included hepatic, pulmonary, renal, and gastrointestinal toxic effects. Attempts to incorporate a 72-hour infusion of ara-c into a combination chemotherapy regimen should proceed cautiously with a starting dose of 6 g/m2/72 hours.
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PMID:Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion. 346 82


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