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)

We performed an open, nonrandomized, multicenter phase-II trial to evaluate the efficacy and toxicity of 1 year of treatment with the oral iron chelator deferiprone in 38 mainly nonthalassemic patients with transfusional iron overload. Initial serum ferritin varied between 996 and 11.644 micrograms/l. Patients were treated with 3-6 g of deferiprone daily. Mean urinary iron excretion (UIE) in 36 evaluable patients was 21.0 mg/24 h and was significantly higher in the patients with thalassemia than in those with myelodysplasia. Negative iron balance was achieved in 20 patients (56%). The median duration of treatment was 10 months; due to side effects and other causes only 20 patients completed 1 year of treatment. Mean serum ferritin levels decreased from 3563 micrograms/l at the start of the trial to 2767 micrograms/l at 6 months (26 patients, p < 0.004) and to 2186 micrograms/l at 12 months (20 patients, p < 0.005). Serum ferritin levels normalized in two patients who were no longer transfusion dependent. Deferiprone was clearly not effective in three patients (two with myelofibrosis, one with myelodysplasia). One patient with myelodysplasia developed agranulocytosis after 12 months of treatment; this was rapidly reversible after stopping deferiprone. Three patients had a mild and transient decrease in white blood cell count. Other side effects leading to withdrawal from the trial consisted mainly of nausea (3 patients), arthralgia (2), and skin rash (1). No clinical signs of zinc deficiency were seen, although zinc excretion was increased in three patients. No changes were seen in liver enzymes, creatinine, antinuclear factor, T-cell subsets, cardiac function, visual acuity, and audiogram. Although our results confirm deferiprone as an effective iron chelator in patients with thalassemia and in some patients with other forms of iron overload, there is still some concern about the safety of this drug, which therefore, at this time, should be used exclusively in well-controlled clinical trials.
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PMID:Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial. 895 43

We have retrospectively reviewed the ability to safely deliver total body irradiation (TBI) in the outpatient setting in 10 pediatric patients undergoing stem cell transplantation. Patients had a median age of 14 years (range 9-17 years) with diagnoses that included ALL in second remission, AML in second remission, myelodysplastic syndrome, Ewing's sarcoma, and rhabdomyosarcoma. Patients received a total of 1375 cGy or 1440 cGy given in a hyperfractionated schedule (11 or 12 fractions) over a 4-day period. All children were seen in the outpatient clinic daily during TBI and all were housed within a 20 mile radius of our institution during this period. Eight patients achieved good control of nausea and emesis with ondansetron alone while two patients required ondansetron and diphenhydramine. Nine patients received some form of intravenous hydration during this period (hyperalimentation, fluid boluses in clinic, or night-time intravenous fluids). One patient maintained good hydration with oral intake alone. Only one child required admission during this period for persistent nausea and vomiting despite antiemetics and intravenous fluids. A cost approximation suggests that TBI delivered in the outpatient setting resulted in a saving of approximately $2400 per patient. We conclude that TBI administered to children and adolescents in the outpatient setting can be a safe and cost-effective practice.
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PMID:Outpatient total body irradiation for pediatric patients undergoing stem cell transplantation. 919 47

The aminothiol, amifostine (Ethyol; U.S. Bioscience, West Conshohocken, PA), is a cytoprotective agent that ameliorates the toxicities of anticancer therapy. In vitro, amifostine promotes the formation and survival of primitive hematopoietic progenitors derived from myelodysplastic bone marrow (BM) specimens. To evaluate the hematological effects of amifostine, 18 patients with myelodysplastic syndrome (MDS) and one or more refractory cytopenias received treatment with amifostine in a Phase I/II study. Four cohorts received intravenous treatment with 100, 200, or 400 mg/m2 amifostine three times a week, or 740 mg/m2 weekly for three consecutive weeks followed by 2 weeks observation. Nonresponding patients received a second course of therapy at the next higher dose level depending upon drug tolerance. Bone marrow (BM) progenitor growth was assessed before treatment and after day 21. Diagnoses included refractory anemia (7), refractory anemia with ringed sideroblasts (5), refractory anemia with excess blasts (RAEB) (4), and RAEB-in transformation (RAEB-t) (2). Single- or multi-lineage hematologic responses occurred in 15 patients (83%) treated with the three-times-a-week dose schedule. Fourteen patients had a 50% or greater increase in absolute neutrophil count with amifostine treatment (range, 426 to 11,348/microL). Platelet count increased in 6 (43%) of 14 patients with thrombocytopenia (absolute increase, 16, 000 to 110,000/microL), and 5 of 15 red blood cell transfusion-dependent patients had a 50% of greater reduction in transfusion needs. Assayable hematopoietic progenitors increased in 13 of 15 evaluable patients; including CFU-GEMM (12), BFU-E (8), and CFU-GM (6). Amifostine doses less than or equal to 200 mg/m2 were well tolerated, whereas grade II nausea, vomiting, and fatigue was limiting at higher doses. Three patients with excess blasts before enrollment experienced an increase in BM blast percentage and two patients had evolution to acute leukemia that persisted after treatment withdrawal. We conclude that amifostine administered at doses </=200 mg/m2 three times a week is well tolerated and has hematologic activity in patients with MDS.
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PMID:Stimulation of hematopoiesis by amifostine in patients with myelodysplastic syndrome. 1153 40

Forty-three patients with myelodysplastic syndromes (MDS) received treatment with oral etoposide 50 mg/day for 21 consecutive days every 4 weeks. Eighteen patients (42%) experienced hematological responses, including 12 of 17 (70%) patients with chronic myelomonocytic leukemia (CMML). Three of five CMML patients who failed treatment with hydroxyurea experienced major hematological responses with oral etoposide. Median response duration exceeded 9 months (range: 4-49 + months), and one patient remains in an unmaintained complete remission for 4 years. Toxicity included nausea/vomiting in five patients, fever (four patients), infection (three patients), mucositis (two patients), and anorexia (two patients). Two patients had grade 4 neutropenia with sepsis necessitating treatment withdrawal. We conclude that low-dose oral etoposide has remitting activity in MDS and is an effective treatment alternative for patients with CMML.
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PMID:Treatment with low-dose oral etoposide in patients with myelodysplastic syndromes. 958 73

HuM195 is a recombinant humanized IgG1 monoclonal antibody reactive with CD33, a Mr 67,000 glycoprotein expressed on early myeloid progenitor cells and myeloid leukemia cells. HuM195 has been shown to rapidly target and saturate acute myeloid leukemia (AML) cells after i.v. infusion into patients and is capable of mediating antibody-dependent cellular cytotoxicity. This activity is enhanced in vitro when natural killer (NK) effector cells are preincubated with low concentrations of interleukin 2 (IL-2). Previous Phase I trials of HuM195 in patients with relapsed AML demonstrated safety and attainment of complete responses, but significant antileukemic activity appears limited to patients with low leukemia tumor burdens. Therefore, in the present trial, we sought to determine whether low-dose IL-2 could safely enhance the numbers of NK cells and therefore the cytotoxic capability of HuM195 via presumptive NK cell antibody-dependent cellular cytotoxicity in vivo against myeloid leukemia cells. Thirteen patients with relapsed or refractory AML and one patient with advanced myelodysplastic syndrome were treated with 0.6x10(6) IU/m2 of s.c. IL-2 daily for 35 days. Starting on day 15, patients received twice weekly i.v. infusions of HuM195 (3.0 mg/m2) for 3 weeks. Immediately after the HuM195 infusion, the patients received IL-2 i.v. infusions over 2 h at one of three escalating dose levels of 0.5x10(6), 1.0x10(6), and 2.0x10(6) IU/m2. Peripheral blood mononuclear cells were quantitated and immunophenotyped by flow cytometry. Safety, tolerability, bone marrow mononuclear cell morphology, and immunophenotype, as well as responses were assessed. Of the 14 patients who entered the study, 10 were able to complete at least one cycle of therapy. Adverse effects to the s.c. IL-2 were relatively mild and included erythema and induration of the skin at the injection site and low-grade fever. Toxicity from the sequential HuM195 and i.v. IL-2 infusions included nausea, rigors, and fever. Toxicity was IL-2 dose related with dose-limiting toxicity seen at the 2.0x10(6) IU/m2 dose level. Three patients had stable disease at the completion of the first cycle and went on to receive a second cycle of treatment. CD3-positive, CD56-positive, and CD33-positive cells were generally found to significantly decrease immediately after each administration of i.v. IL-2 and HuM195. CD56-expressing cells increased in 6 of 10 patients from the beginning to the end of therapy. Among the 10 evaluable patients, 2 patients had significant decreases in the percentage of blasts in the bone marrow (one of which achieved a complete bone marrow remission), 5 patients had stable levels of bone marrow blasts, and 3 had progression of disease on therapy. The combination of IL-2 and HuM195 shows modest biological activity and clinical antileukemic activity but also produced significant toxicity.
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PMID:A phase I trial of humanized monoclonal antibody HuM195 (anti-CD33) with low-dose interleukin 2 in acute myelogenous leukemia. 1053 38

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

Pretransplant conditioning therapy with i.v. BuCy followed by allogeneic hematopoietic stem cell transplantation (BMT) was investigated in a phase II trial in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We gave i.v. Bu at a dose of 0.8 mg/kg every 6h x 16 doses, followed by Cy 60 mg/kg daily for 2 days. Twenty-six AML patients (18 males/eight females) were treated, only eight of whom were in CR1. The rest were either refractory to induction chemotherapy (four patients) or in a more advanced stage of their disease (14 patients). In addition, nine patients with MDS (1M/8F) were treated. Their median age was 41 years (range 21-64). Engraftment to > or =500 neutrophils/microl was reached at 14 days (range 10-29 days) post BMT, and the median time of neutropenia was only 11 days (range 4-28 days). The most common regimen-related toxicity was grade 2-3 nausea. In the post-BMT period (including BMT day +30), two patients died, one each from pulmonary hemorrhage secondary to CMV pneumonia and hepatic veno-occlusive disease (VOD), for an early treatment-related mortality (TRM) of 5.7%. Three patients developed VOD and two of them died. There was no direct regimen-related pulmonary or neurologic toxicity. Overall, the clinical side-effect spectrum was analogous to what would be expected from a high-dose oral Bu-based regimen; there was no unique toxicity experienced with the used solvent system. The disease-free survival in the high-risk subgroup (all patients not in CR1) at 1 and 2 years post transplant was 44% and 31%, respectively. The 13 patients still alive in CR have been followed for a median of 24 months (range 18-32). Pharmacokinetic analysis showed very good interdose reproducibility, and limited interpatient variability in area under the plasma concentration vs time curve, peak concentration, and clearance of Bu after this i.v. formulation. We conclude, that this new i.v. Bu formulation is well tolerated; it has an impressive safety profile, and we suggest that it should be considered as appropriate replacement for oral busulfan in pretransplant conditioning therapy prior to allogeneic BMT for patients with AML or MDS.
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PMID:Allogeneic stem cell transplantation (BMT) for AML and MDS following i.v. busulfan and cyclophosphamide (i.v. BuCy). 1093 85

Irofulven (MGI 114, 6-hydroxymethylacylfulvene, HMAF) is a semisynthetic illudin analog with broad in vitro anti-neoplastic activity. In this leukemia phase I study, we investigated the toxicity profile and activity of Irofulven in patients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndromes (MDS). Irofulven was given as an intravenous infusion over five minutes daily for five days. The starting dose was 10 mg/m2/day (50 mg/m2/course). Courses were scheduled to be given every 3-4 weeks according to toxicity and antileukemic efficacy. Twenty patients [AML: 17 patients; MDS: one patient; ALL: one patient; mixed lineage acute leukemia: one patient] were treated. Nausea, vomiting, hepatic dysfunction, weakness, renal dysfunction, and pulmonary edema were dose limiting toxicities, occurring in two of five patients treated at 20 mg/m2/day and two of three patients treated at 12.5 mg/m2/day. The MTD was defined as 10 mg/m2/day for five days. One patient with primary resistant AML achieved complete remission. Proposed phase II studies will further define the activity of Irofulven in patients with better prognosis AML and in other hematological malignancies, both as a single agent and in combination regimens, particularly with topoisomerase 1 inhibitors.
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PMID:Phase I study of irofulven (MGI 114), an acylfulvene illudin analog, in patients with acute leukemia. 1129 29

The antigen CD33 is expressed on blast cells in 80% to 90% of acute myeloid leukemia (AML) cases but, importantly, is not expressed on pluripotent hematopoietic stem cells or on nonhematologic cells. Gemtuzumab ozogamicin (CMA-676) uses a recombinant humanized anti-CD33 monoclonal IgG4 antibody to deliver the potent cytotoxin, calicheamicin, into cells. Three multicenter trials have evaluated the efficacy and safety of gemtuzumab ozogamicin as a single agent in 142 patients with CD33+ AML in untreated first relapse. The median age was 61 years (range, 22 to 84 years), none had prior myelodysplasia, and all had had a first complete remission lasting > or = 3 months. Two doses of 9 mg/m2 were given 14 days apart by 2-hour intravenous infusion. The overall response rate was 30% (ie, < or = 5% blasts remaining in the bone marrow, neutrophils > or = 1,500/microL, and red blood cell and platelet transfusion independence). There was no significant difference in response rate between patients less than 60 years of age and those > or = 60 years old (34% v 26%, respectively) or between patients whose first remission had lasted less than 12 months or > or = 12 months (28% v 32%, respectively). Overall survival was 31% at 1 year; median survival was 5.9 months. Median relapse-free survival was 6.8 months. An infusion-related syndrome (chills, fever, rigors, nausea, hypotension, and pain) was common. Severe myelosuppression occurred in all patients, but severe mucositis (4%) and infections (23%) were relatively infrequent. Severe hyperbilirubinemia (23%) and elevated hepatic transaminases (18%) were usually transient. Among all 142 patients, the median total hospitalization was 24 days; 16% of patients required < or = 7 days in hospital. Additional studies are currently evaluating gemtuzumab ozogamicin in combination with, or as an alternative to, other standard AML chemotherapy.
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PMID:Current use and future development of gemtuzumab ozogamicin. 1147 94

Treatment of healthy donors with recombinant human granulocyte colony-stimulating factor (rhG-CSF) allows the mobilization and peripheralization into circulating blood of an adequate number of CD34+ cells that can then be collected by leukapheresis (PBSC). This procedure avoids the invasiveness of bone marrow harvest and the risks related to general anesthesia. The main adverse effects of rhG-CSF are: bone pain, 84%, headache, 54%, fatigue, 31%, and nausea, 13%, which are usually scored by the donors as moderate to severe, resolving within 2-3 days after discontinuation of the cytokine. Analgesics, mainly acetaminophen, are sufficient to control the pain. Less than 5% of the donors experience non-cardiac chest pain, a local reaction at the injection site, insomnia, dizziness or a low-grade fever. Discontinuation of the PBSC procedure because of adverse effects of rhG-CSF or leukapheresis is rarely necessary (0.5%) but this good tolerability can be hampered by the need, in 5-20% of cases, for an adequate venous access that requires insertion of a central or venous catheter. There are no absolute contraindications to the stimulation of healthy donors with rhG-CSF but the description of cases of non-traumatic splenic rupture, iritis, cardiac ischemia, and gouty arthritis suggests that further precautionary restrictions are advisable when deciding eligibility for PBSC collection. The main advantages for patients receiving an allogeneic PBSC transplant are the faster hematologic and immunologic recovery and the potential for a greater efficacy in advanced disease by lowering the transplant-related mortality. One of the major concerns regarding the use of rhG-CSF in unrelated healthy donors is the uncertainty about its possible role in triggering malignancy, in particular myelodysplastic syndrome and acute myeloid leukemia. There are no studies with an adequate sample size and follow-up that can answer this question but two recent retrospective studies reported that in the medium term rhG-CSF is not associated with an excess of lymphoproliferative disorders. Currently, caution on the long-term safety of the use of rhG-CSF in healthy donor is still warranted but the data so far accumulated on allogeneic PBSC transplants are encouraging both as far as concerns the good short-medium tolerability profile of G-CSF-stimulation of the donor and the potential major efficacy in leukemia patients.
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PMID:The use of cytokine-stimulated healthy donors in allogeneic stem cell transplantation. 1241 88


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