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)

Farnesyltransferase inhibitors (FTIs) target multiple pathways including the Ras pathway implicated in the pathogenesis of some hematologic malignancies. R115777 and BMS-214662, selective FTIs in clinical development, exhibit preclinical activity against cell lines and tumor xenografts with or without ras mutations. Phase I dose-escalating trials at M.D. Anderson Cancer Center have explored the potential of these agents as monotherapy for leukemias and myelodysplastic syndrome (MDS). In 20 patients with MDS, two cycles of oral R115777 for 3 consecutive weeks followed by a 1-week rest produced an overall response rate of 30%, consistent with 29% reported in poor-prognosis acute leukemia or blast-phase chronic myelogenous leukemia (CML). Administration of BMS-214662 as a weekly intravenous infusion produced a decrease in bone marrow blasts of greater than 50% in 23% of patients with acute leukemia or MDS; 18% achieved normalization of blast counts to less than 5%. In both studies, most responding patients did not have ras mutations. The most common side effects at maximum tolerated doses of R115777 (400 mg twice daily) and BMS-214662 (118 mg/m(2) weekly) were myelosuppression and nausea, respectively. Further evaluation of FTIs for hematologic malignancies clearly is warranted. Future research should address whether molecular techniques can identify patients most likely to respond to an FTI, optimal administration schedules for these agents, and the value of incorporating an FTI into combination regimens for difficult-to-treat hematologic malignancies.
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PMID:Clinical development of farnesyltransferase inhibitors in leukemias and myelodysplastic syndrome. 1244 48

Two cases of scurvy diagnosed following presentation with a purpuric rash are presented. A 44-year-old man developed scurvy as a result of poor dietary intake of vitamin C. This occurred because of a number of factors. including poor dentition, diarrhoea, depression and benzodiazepine/narcotic dependence. A 69-year-old man with acute myeloid leukaemic transformation of myelodysplastic syndrome developed mucositis, nausea, vomiting and diarrhoea as complications of chemotherapy. This led to poor dietary intake and consequently scurvy. Both cases demonstrated specific and diagnostic cutaneous manifestations of scurvy, particularly perifollicular purpura, ecchymoses and coiled corkscrew hairs. The diagnosis was supported by specific diet history. Ascorbic acid tolerance test was used as a simple laboratory method to confirm the clinical diagnosis.
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PMID:Scurvy: a cutaneous clinical diagnosis. 1258 Oct 82

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

Clofarabine (2-chloro-2'-fluoro-deoxy-9-beta-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).(1) Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m(2) per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m(2) per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.
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PMID:Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. 1548 72

Acute myeloid leukemia (AML) is a disease of mostly elderly patients who are often unable to undergo intensive intravenous chemotherapy. In an attempt to provide an all-oral regimen suitable for palliative treatment, we assessed the antileukemic efficacy of combination therapy of idarubicin 20 mg/m(2) (days 1, 3, and 5) and etoposide (EI) in increasing doses (75-125 mg/m(2)) on days 1-5. Eleven patients were included (median age 69 years, range: 56-77) with prognostically unfavorable characteristics (myelodysplastic syndrome, relapse, or unfavorable karyotypes). No complete remission and five partial remissions were observed whereas four patients had persistent leukemia. There were two patients who succumbed to early death. Median overall survival was 100 days (range: 8-493 days). Nonhematological toxicities were acceptable with nausea/vomiting being the predominant side effect. Hematological toxicity with grade III/IV aplasia was seen in all patients. In this study EI did not show convincing antileukemic efficacy and was unable to induce clinically useful complete remissions, with a substantial risk profile. In contrast to the situation of elderly patients with standard-risk AML in which similar oral treatment has shown promising activity, EI cannot be recommended for elderly patients with high-risk AML.
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PMID:A phase I/II study of oral etoposide and idarubicin in elderly patients with high-risk acute myeloid leukemia unable to undergo intensive chemotherapy. 1551 68

JM-216 is an orally bioavailable platinum compound with activity against many tumor models. The objective of this study was to determine the safety profile and anti-tumor activity of JM-216 in patients with hormone refractory prostate cancer (HRPC) when given orally daily x 5 days. In this open label phase II study JM-216 was administered orally at the dose of 120 mg/m2/d for 5 days every 4 weeks. Patients continued on the therapy until evidence of disease progression or intolerable toxicity developed. Dose escalation and de-escalation were allowed according to patient's tolerance. Thirty-nine patients were enrolled onto the study and received a total of 155 courses (median 2, range 1-16) of JM-216. Dose delays (77% of courses) and dose reductions (31% of courses) were common and were mainly due to myelosupression. Treatment was discontinued in 5 patients due to treatment related toxicities. One patient developed myelodysplastic syndrome 11 months after the start of treatment. The most frequent grade III or higher adverse events included thrombocytopenia (54%), neutropenia (52%), anemia (24%) nausea (13%), vomiting (16%) and diarrhea (28%). PSA response was assessed in 32 patients, 10 (26%) had partial response, 14 (36%) had stable disease while PSA progression was seen in 8 (21%) patients. Of 20 (54%) patients with measurable disease two patients had a documented partial response. Although JM-216 had moderate activity in HRPC when given on daily basis for 5 days, it is associated with significant treatment related toxicities in this patient population.
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PMID:Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC). 1552 84

On May 19, 2004, azacitidine (5-azacytidine; Vidaza(trade mark); Pharmion Corporation, Boulder, CO, http://www.pharmion.com) for injectable suspension received regular approval by the U.S. Food and Drug Administration (FDA) for the treatment of all subtypes of myelodysplastic syndrome (MDS). This report summarizes the basis for this approval. Effectiveness was demonstrated in one randomized, controlled trial comparing azacitidine administered s.c. with best supportive care (observation group) and in two single-arm studies, one in which azacitidine was administered s.c. and in the other in which it was administered i.v. The dose of azacitidine, 75 mg/m2/day for 7 days every 28 days, was the same in all three studies. In the randomized trial, study participants were well matched with respect to age, sex, race, performance status, MDS subtype, and use of transfusion during the 3 months before study entry. Patients in the observation arm were permitted by protocol to cross over to azacitidine treatment if their disease progressed according to prespecified criteria. During the course of the study, more than half of the patients in the observation arm did cross over to the azacitidine treatment arm. The primary efficacy end point was the overall response rate. Response consisted of complete or partial normalization of blood cell counts and of bone marrow morphology. The response rate in the azacitidine arm was about 16%; there were no responses in the observation arm. The response rates in the two single-arm studies were similar (13% and 19%). The responses were sustained, with median durations of 11 months and 17 months respectively. Responding patients who were transfusion dependent at study entry lost the need for transfusions. In addition, about 19% of patients had less than partial responses (termed improvement), and two-thirds of them became transfusion independent. Common adverse events associated with azacitidine treatment were gastrointestinal (nausea, vomiting, diarrhea, constipation, and anorexia), hematologic (neutropenia, thrombocytopenia), fevers, rigors, ecchymoses, petechiae, injection site events, arthralgia, headache, and dizziness. Liver function abnormalities occurred in 16% of patients with intercurrent hepatobiliary disorders and in two patients with previously diagnosed liver cirrhosis. Renal failure occurred in patients during sepsis and hypotension. There were no deaths attributed to azacitidine. Azacitidine, the first drug approved by the U.S. FDA for MDS, has a favorable safety profile and provides a clinical benefit of eliminating transfusion dependence and complete or partial normalization of blood counts and bone marrow blast percentages in responding patients.
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PMID:FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. 1579 20

The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematological malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two non-peptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy with overall response rates of 30%, with complete remissions in about 15%. Dose-limiting side effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated with primarily diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this, significant clinical efficacy of the FTIs in MDS, on par with that of currently available chemotherapeutic agents, has been observed, leading to further development of this new class of drugs in MDS and AML.
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PMID:Farnesyltransferase inhibitors in myelodysplastic syndrome. 1586 70

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, leading to bone marrow failure and peripheral blood cytopenias. MDS is difficult to diagnose because of the absence of symptoms in the early stage of the disease; it often is discovered accidentally during routine physical examinations or blood tests. The U.S. Food and Drug Administration approved azacitidine (Vidaza, Pharmion Corporation, Boulder, CO) for the treatment of MDS. Prior to the approval of azacitidine, no approved therapies were available for the treatment of MDS. Azacitidine is believed to exert its anticancer effects by induction of hypomethylation and cytotoxicity. In clinical studies, the most common adverse events during treatment with azacitidine included nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection-site erythema, constipation, neutropenia, and ecchymosis. To ensure proper treatment with azacitidine, nurses should have an understanding of dosage and administration guidelines, commonly observed adverse events, monitoring and care of adverse events, and monitoring of laboratory tests. Having a comprehensive understanding of MDS, its underlying disease characteristics, and current treatments will enable oncology nurses to provide optimal patient care.
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PMID:Advances in myelodysplastic syndrome: nursing implications of azacitidine. 1611 8

Imatinib (STI571, Gleevec/Glivec) and other small-molecule tyrosine kinase inhibitors are highly effective in the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors and, for example, eosinophilia-associated chronic myeloproliferative disorders. This molecularly targeted approach disrupts abnormal tyrosine kinase dependent signalling pathways, thus providing a preferred treatment option for selected neoplastic disorders with activating mutations of Abelson-, Abl-related-, Kit-, and platelet-derived growth factor receptor A and B genes. Loss of response to imatinib may be due to an acquired resistance of emerging mutant tumor cell clones. Therapy is generally well tolerated. However, toxicities including edema, skin rashes, fatigue, nausea and myelosuppression have been reported. Philadelphia/Bcr-Abl-negative clonal chromosomal abnormalities may develop. Bone marrow trephines obtained from CML patients in complete remission with prolonged pancytopenia secondary to imatinib generally show marrow hypoplasia. Morphological features may be in keeping with either aplastic anemia or myelodysplasia developing in Philadelphia-negative hematopoiesis. Single or multilineage myelodysplasia may be accompanied by an excess of blasts and rarely evolves into acute leukemia in CML patients. Severe adverse hematological effects of imatinib are extremely rare. Current questions involve the molecular mechanisms of hematological side effects of tyrosine kinase inhibitors with special regard to the emergence of distinct aberrant clones.
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PMID:[Hematological side effects of tyrosine kinase inhibition using imatinib]. 1642 5


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