Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to determine the clinically optimal dose of KRN8602, a new anthracycline derivative, in combination therapy for acute leukemia, we performed a pilot late phase II study in combination with cytarabine (Ara-C) for acute myelogenous leukemia (AML), and with vincristine (VCR) and prednisolone (PSL) for acute lymphocytic leukemia (ALL). KRN8602 was given at a dose of 12 or 15 mg/m2 for 5 consecutive days, Ara-C at a dose of 100 mg/m2 for 7 consecutive days, VCR 1.4 mg/m2 (max. 2.0 mg/body) weekly for 4 weeks, and PSL 40 mg/m2 for principally 28 consecutive days. Of 14 patients with relapsed or refractory leukemia entered in the study, thirteen patients were evaluable for safety and 12 were evaluable for response. In AML, there was 1 partial response (PR) in 4 patients at a dose of 12 mg/m2. Against 1 complete response (CR) and 3 PRs in 4 patients at a dose of 15 mg/m2. In ALL, there was 1 PR in 1 case at a dose of 12 mg/m2, and 1 CR and 2 PR in 3 at a dose of 15 mg/m2. Major toxicities were nausea/vomiting and anorexia, but incidences and grades of toxicities were not dose-dependent, and all toxicities were tolerable and manageable. From these results it is concluded that the optimal dose of KRN8602 is 15 mg/m2 for 5 consecutive days in combination with Ara-C for AML, and with VCR and PSL for ALL.
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PMID:[Pilot late phase II study of KRN8602 (MX2), a novel anthracycline derivative, for acute leukemia--a dose finding study in combination]. 998 4

The majority of hematopoietic malignancies have aberrancies in the retinoblastoma (Rb) pathway. Loss in Rb function is, in most cases, a result of the phosphorylation and inactivation of Rb by the cyclin-dependent kinases (cdks), main regulators of cell cycle progression. Flavopiridol, the first cdk modulator tested in clinical trials, is a flavonoid that inhibits several cdks with evidence of cell cycle block. Other interesting preclinical features are the induction of apoptosis, promotion of differentiation, inhibition of angiogenic processes and modulation of transcriptional events. Initial clinical trials with infusional flavopiridol demonstrated activity in some patients with non-Hodgkin's lymphoma, renal, prostate, colon and gastric carcinomas. Main side-effects were secretory diarrhea and a pro-inflammatory syndrome associated with hypotension. Phase 2 trials with infusional flavopiridol in CLL and mantle cell lymphoma, other schedules and combination with standard chemotherapies are ongoing. The second cdk modulator tested in clinical trials, UCN-01, is a potent protein kinase C inhibitor that inhibits cdk activity in vitro as well. UCN-01 blocks cell cycle progression and promotes apoptosis in hematopoietic models. Moreover, UCN-01 is able to abrogate checkpoints induced by genotoxic stress due to modulation in chk1 kinase. The first clinical trial of UCN-01 demonstrated very prolonged half-life (approximately 600 h), 100 times longer than the half-life observed in preclinical models. This effect is due to high binding affinity of UCN-01 to the human plasma protein alpha-1-acid glycoprotein. Main side-effects in this trial were headaches, nausea/vomiting, hypoxemia and hyperglycemia. Clinical activity was observed in patients with melanoma, non-Hodgkin's lymphoma and leiomyosarcoma. Of interest, a patient with anaplastic large cell lymphoma refractory to high-dose chemotherapy showed no evidence of disease after 3 years of UCN-01 therapy. Trials of infusional UCN-01 in combination with Ara-C or gemcitabine in patients with acute leukemia and CLL, respectively, have commenced. In conclusion, flavopiridol and UCN-01 are cdk modulators that reach biologically active concentrations effective in modulating CDK in vitro, and show encouraging results in early clinical trials in patients with refractory hematopoietic malignancies. Although important questions remain to be answered, these positive experiences will hopefully increase the therapeutic modalities in hematological malignancies.
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PMID:Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies. 1124 75

Twenty-five adult patients with previously untreated acute non-lymphocytic leukemia (ANLL) were treated with mitoxantrone (Mto) 12 mg/m2 daily by 30 minutes intravenous (IV) infusion for 3 days and cytosine arabinoside (Ara-C) 200 mg/m2 daily by continuous infusion for 7 days, as an induction therapy. After complete remission (CR) was observed, they were given two more courses of consolidation therapy which was as Mto 12 mg/m2 daily by 30 minutes IV infusion for one day, and Ara-C 200 mg/m2 daily by 30 minutes IV infusion for 5 days. CR was obtained in 18 of 25 patients (72%). Median remission duration was 294 days and length of survival was 366 days. 11 patients (44%) are still in remission. Myelosupression developed in all patients following induction therapy, but it was not observed after consolidation therapies. Non-hematological side-effects consisted of nausea, vomiting, alopecia, stomatitis, and transient elevation in liver enzymes. Our therapeutic responses are similar to those obtained by others.
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PMID:Mitoxantrone and cytosine arabinoside in previously untreated adult patients with acute non-lymphocytic leukemia. 1465 Dec 26

From 1998 to 2001, 5 consecutive cases of AML/TMDS entered our hospital and achieved complete remission (CR) with continuous drip infusion of low-dose etoposide and low-dose Ara-C combined with mitoxantrone (MEtA regimen). The ages of the 5 patients (4 males and 1 female) ranged 32 to 50 years-old, respectively. WBCs were 1,560-45,150/microl, blasts were 12-62%. Bone marrow aspirates revealed trilineage myelodysplasia with various number of blasts. These patients had an acute onset and no preceding hematologic disorders. They were diagnosed M2/TMDS or M4/TMDS. Continuous drip infusion of etoposide (50 mg/body/day) and Ara-C (30 mg/body/day) were given for 11-14 days and a bolus injection of mitoxantrone (8 mg/m2) was added for 2-3 days. Patient 5 was given additional MIT (6.7 mg/m2 on day 6). All cases achieved CR in 21-24 days after the end of the therapy. Toxicities were nausea, vomiting, stomatitis, alopecia and fever due to infection. All were well tolerable, however. Two patients are alive more than 4 years without relapse. MEtA regimen is available for AML/TMDS.
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PMID:[Five cases of de novo acute myeloid leukemia with trilineage myelodysplasia (AML/TMDS) achieved CR with the continuous drip infusion of low-dose etoposide and low-dose cytosine arabinoside combined with mitoxantrone (MEtA)]. 1527 98

Fludarabine plus cytarabine (Ara-C) and idarubicin (FLAI) is an effective and well-tolerated induction regimen for the treatment of acute myeloid leukaemia (AML). This phase III trial compared the efficacy and toxicity of FLAI versus idarubicin plus Ara-C and etoposide (ICE) in 112 newly diagnosed AML patients <60 years. Fifty-seven patients received FLAI, as the first induction-remission course, and 55 patients received ICE. Post-induction treatment consisted of high-dose Ara-C (HDAC). After HDAC, patients in complete remission (CR) received a second consolidation course (mitoxantrone, etoposide, Ara-C) and autologous stem cell transplantation (auto-SCT) or allogeneic (allo)-SCT, according to the age, disease risk and donor availability. After a single induction course, CR rate was 74% in the FLAI arm and 51% in the ICE arm (P = 0.01), while death during induction was 2% and 9% respectively. Both haematological (P = 0.002) and non-haematological (P = 0.0001) toxicities, especially gastrointestinal (i.e. nausea, vomiting, mucositis and diarrhoea), were significantly lower in FLAI arm. In both arms, relapses were more frequent in patients who were not submitted to allo-SCT. After a median follow-up of 17 months, 30% and 38% of the patients are in continuous CR in FLAI and ICE arm respectively. Our prospective randomised study confirmed the anti-leukaemic effect and the low toxic profile of FLAI as induction treatment for newly diagnosed AML patients.
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PMID:Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. 1648 83

The purpose of the study was to identify the association between chemotherapy-induced nausea/vomiting and changes to the electrogastrogram (EGG) of two children suffering from leukemia. After receiving written consent/assent, the children, both with acute lymphoblastic leukemia (ALL), were recruited. One of the subjects, a ten year-old boy, was given 1.1 gm Cytarabine (intravenous infusion for six hours per day) for three days and Tropisetron 5 mg intravenous infusion for 24 hours. The other subject, an eight year-old girl, received the induction phase of TPOG 93HR chemotherapy, which included Epirubicin, Vincristin, L-asparaginase, and Prednisolone and Tropisetron 5 mg on Day 1. The EGG recordings of both patients were recorded for a total of 42 hours by cutaneous electrogastrography over a seven day period. This included two-hour and four-hour readings taken before and immediately following the administration of chemotherapy each day. The position, movements, and activities of the children while on the EGG were recorded on digital video. Four episodes of nausea and vomiting were detected during this period. Pre- and post-nausea and vomiting during the EGG were analyzed using spectrum analysis after the deletion of motion artifacts. The findings of this study indicated that two episodes of nausea were 5.3-10.3% bradygastria and 2.1-10.3% tachygastria, with 85.8% and 100% normal gastric slow waves detected by EGG during the pre-vomiting period. Tachygastria was present in 3.4% and 12.2% of the post-vomiting period of each episode. The association of artifacts with position, movement, and activities must be considered during data collection.
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PMID:[A pilot study: gastric motility and nausea/vomiting in two leukemia children receiving chemotherapy]. 1647 72

We evaluated efficacy and toxicity profiles of fludarabine, Ara-C, idarubicin, and G-CSF (Ida-FLAG) combination chemotherapy in 56 refractory and/or relapsed acute leukemia patients. Patients were treated with fludarabine phosphate 25 mg/m2/d (d1-5), Ara-C 2 g/m2/d (d1-5), idarubicin 12 mg/m2/d (d1-3), G-CSF was given subcutaneously from sixth day until absolute neutrophil count (ANC) >500/microL. One third of the acute myeloblastic leukemia (AML) and 45% of acute lymphoblastic leukemia (ALL) cases were primary refractory disease. In AML patients, complete remission (CR) was achieved in 15 cases (53.6%). One case showed partial remission (PR) (3.6%) and 12 cases (42.8%) had resistant to this regimen (RD). Grade IV hematologic toxicity occurred in all AML cases. Leukocyte recovery time was 16 days. Nonhematologic complications were mild to moderate nausea, vomiting, and mucositis and could be controlled by routine measures. Stem cell transplantation was performed in 5 patients and all achieved CR, 2 autologous and 3 allogeneic. In ALL patients, CR and PR were obtained in 8 (42.2%) and 2 (10.5%) of 22 cases; disease was resistant to Ida-FLAG in 9 (47.3%) cases. Grade IV hematologic toxicity occurred in all ALL cases. Leukocyte recovery time was 17 days. Nonhematologic toxicity consisted of nausea, vomiting, and mucositis and could be controlled by supportive therapy. Autologous transplantation was performed in 1 patient, but relapse disease occurred after 5 weeks. There was no correlation between response rate and leukemia subtype (AML versus ALL), leukocyte count, age, sex, disease status (de novo versus secondary), and RFS (early versus late relapse) (P > 0.05). Median survival was 16 weeks in all cases (22 weeks in AML versus 13 weeks). At present, only 3 patients are alive and 2 of these are in continuous remission. The rest of the patients died. In conclusion, Ida-FLAG is a good choice in cases with refractory/relapsing acute leukemia for salvage chemotherapy. High efficacy and a low-toxicity profile are preferable properties of this regimen, and this regimen has been found to be useful for cytoreduction, especially in candidates for allo-SCT.
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PMID:IDA-FLAG regimen for the therapy of primary refractory and relapse acute leukemia: a single-center experience. 1698 32

Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG+imatinib mesylate in AML patients. Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5mg/m(2) days 3-7, Cytarabine 2gm/m(2) days 3-7, G-CSF 300mcg days 2-7, and escalating doses of imatinib mesylate given on days 1-15. The level 1 Gleevec dose was 400mg, while level 2 was 600mg and the level 3 dose 800mg. A total of 16 patients were enrolled, 15 AML and 1 CML myeloid blast crisis. The dose escalation occurred as planned and there was no clear evidence of added toxicity due to imatinib mesylate. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy however no other deaths occurred within 30 days of starting therapy. One patient had a Grade 3 skin rash at dose level 2. The most common toxicities encountered during induction therapy were nausea, vomiting, rash and diarrhea that were transient and/or reversible. At the 800mg dose 1 patient developed a decline in cardiac ejection fraction on day 20 who later died of sepsis, so this was considered a dose limiting toxicity. Of 16 evaluable patients 11 achieved a hypocellular marrow after initial induction with 1 additional patient achieving a hypocellular marrow following a second course of the same regimen. Four patients (25%) achieved a complete morphologic response with normal cytogenetics, 2 patients (12.5%) achieved a complete morphologic response only and 1 patient had a complete response in the bone marrow but incomplete blood count recovery. The overall response rate was 43.8%. The median overall survival was 175 days (95% CI 16.24-333.76) and the median relapse free survival was 76 days. The addition of imatinib mesylate to CLAG was well tolerated with acceptable toxicities and response rates comparable to other salvage regimens. To assess the efficacy of imatinib mesylate in combination with CLAG, a larger phase II trial is now planned.
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PMID:Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML. 1857 21

A 24-year-old man was admitted to the hospital for pancytopenia. Peripheral blood test and bone marrow aspiration demonstrated an increase in hypogranular promyelocytes. Karyotype analysis and RT-PCR showed 47, XY, t(15;17)(q22;q12), +12, and PML-RARA, respectively. The patient was diagnosed as having acute promyelocytic leukemia microgranular type (M3v) and was therefore administered all-trans retinoic acid (ATRA). Idarubicin and Ara-C were later added to the treatment regimen because of an increased number of leukemic cells. Nausea, vomiting and general fatigue associated with hypercalcemia developed on day 30. There were no findings indicating infection. The administration of ATRA was thus suspected to have induced hypercalcemia. ATRA was therefore discontinued and prednisolone and elcatonin were administered instead. Five days after this change, the serum calcium level normalized. Complete remission was thereafter confirmed on day 45. Hypercalcemia associated with ATRA therapy for APL is rare, and to date, there have been no case reports describing hypercalcemia associated with M3v in the literature. Interaction of fosfluconazole was suspected of causing hypercalcemia when used concomitantly with ATRA.
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PMID:[Hypercalcemia associated with all-trans retinoic acid therapy for microgranular type acute promyelocytic leukemia]. 1864 8

Up to now, no consensus has been reached on the standard salvage regimen for patients with refractory or relapsed acute myeloid leukemia (AML). This study was purposed to evaluate the efficacy and safety of combination chemotherapy composing of cyclophosphamide (Cy), cytosine arabinoside (Ara-C) and topotecan (CAT regimen) for 37 refractory or relapsed AML patients. The dosing regimen was as follows: Cy 300 mg/m2 by intravenous infusion, every 12 hours on days 1-3, topotecan 1.25 mg/m2 by intravenous continuous infusion over 6 hours daily on days 2 to 6, Ara-C 500 mg/m2 by intravenous infusion over 2 hours daily for 5 days on days 2-6. The results showed that all patients completed one cycle of chemotherapy. 12 patients (32.4%) achieved complete remission (CR), 2 (5.4%) achieved partial remission (PR), and the 23 remaining patients achieved no remission (NR). The overall response rate (RR) was 37.8%. Among 18 relapsed cases, 6 cases had CR (33.3%), 2 cases achieved PR (11.1%), and 10 cases were with NR (55.6%). Among 19 refractory cases, 6 had CR (31.6%), and 13 (68.4%) were with NR. There was no statistically significant difference in RR between refractory and relapsed groups (31.6% and 44.4%, respectively) (p=0.42). Myelosuppression was universal. Mild non-hematologic toxicities were mainly gastrointestinal, as nausea, vomiting, diarrhea. The incidence of severe (grade III-IV) non-hematologic toxicity, such as oral mucositis and infection was 37.8% and 86.5% respectively. Only one patient died of severe infection during the observation (within 28 days from start of chemotherapy). The time of median follow-up was 4 (0-33) months, the median overall survival (OS) was 4 (1.8-6.2) months. The median OS for responders was longer than that for non-responders (9 vs 2 months respectively, p=0.00). In conclusion, the CAT regimen of lower dose is well tolerated and has certain anti-leukemia effect, and worthy to be further investigated.
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PMID:[Clinical study on regimen cyclophosphamide, Ara-C and topotecan (CAT) in treatment of patients with refractory or relapsed acute myelogenous leukemia]. 1984 Apr 80


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