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)

One hundred and seven adult outpatients with Leriche stage II peripheral occlusive arterial disease took part in this open, controlled trial. Patients were randomly treated over a six-month period either with sulodexide capsules containing 250 lipoproteinlipase releasing units (LRU, two capsules twice daily for 176 days on average: 56 patients), or with pentoxifylline 400 mg tablets (one tablet three times a day for 180 days on average: 51 patients). The incidences of diabetes, hyperlipoproteinaemias, smoking habit and other risk factors were the same in the two groups. The drugs' efficacies were evaluated by monitoring, at the start of treatment and every month during it, the Winsor Index and the walking distance, both prior to (initial claudication distance-IDC) and after (absolute claudication distance-ACD) the symptom's onset. Compliance with treatment and occurrence of adverse events were constantly monitored; systemic tolerability was evaluated through the use of routine haematological and haematochemical tests. Both treatments brought about a progressive increase in the claudication-free walking distance, statistically significant versus baseline from the second month (ACD, sulodexide group) and third month (ACD and ICD, pentoxifilline and sulodexide groups). At the end of treatment, the absolute increase of ACD was significantly greater in sulodexide-treated patients (p < 0.01) with respect to the pentoxifylline-treated group. In both groups the Doppler test evidenced a good improvement in local arterial haemodynamics. In the sulodexide group, 3.6% of patients developed nausea, dyspepsia and other minor gastrointestinal phenomena. In the pentoxifylline group 17.6% of patients complained of gastroenteric disorders (nausea, vomiting, dyspepsia), or of headache and dizziness. In one patient of this latter group insomnia was also present. Systemic tolerance of both drugs was consistently good.
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PMID:Controlled clinical trial on the efficacy and safety of oral sulodexide in patients with peripheral occlusive arterial disease. 932 92

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity. (Blood. 2001;97:3361-3369)
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PMID:Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. 1136 25

Farnesyl protein transferase inhibitors (FTIs) represent a new class of anticancer agents specifically targeting aberrant biologic processes involved with cellular transformation and malignancy. Originally developed to inhibit tumors by preventing activation of oncogenic ras genes via suppression of their posttranslational farnesylation, their anticancer activity appears to stem from their ability to inhibit farnesylation of various proteins that mediate signal transduction, growth, apoptosis, and angiogenesis. The safety, biologic activity, clinical response, and pharmacokinetics of R115777, a potent, orally active FTI, were recently investigated in a phase I dose-ranging study in patients with acute leukemias. Patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), or chronic myelogenous leukemia (CML) in blast crisis received R115777 100 mg, 300 mg, 600 mg, 900 mg, or 1,200 mg twice daily for 21 days. Cycles were repeated every 28 to 31 days for up to four cycles. An overall response rate of 29% (10/34 evaluable patients) was observed across all R115777 doses. R115777 was well tolerated; common adverse events included fatigue, increased creatinine, nausea, and neutropenia. Dose-limiting toxicity occurred at 1,200 mg twice daily. Farnesylation of lamin A and HDJ-2, examined as biologic end points, was inhibited by R115777 doses > or = 600 mg twice daily. Pharmacokinetic evaluation suggests that R115777 is concentrated in bone marrow at steady state. The biologic and antitumor activity and favorable tolerability of R115777 support further clinical evaluation alone and in combination therapy in hematologic malignancies.
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PMID:Farnesyl protein transferase inhibitors as targeted therapies for hematologic malignancies. 1152 24