Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

CEP-2563 dihydrochloride (CEP-2563) is a soluble lysinyl-beta-alanyl ester of CEP-751, a potent inhibitor of the trk family of receptor tyrosine kinases and the platelet-derived growth factor (PDGF) receptor tyrosine kinase. CEP-2563 was developed because of the limited aqueous solubility of CEP-751. Preclinical models have demonstrated that both CEP-751 and CEP-2563 have antitumor activity in a variety of tumors. A Phase I clinical trial involving 18 patients was conducted to determine the toxicity profile, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of CEP-2563 in patients with advanced solid tumors refractory to standard therapy. CEP-2563 was administered over 1 hour via a central venous catheter once daily for five consecutive days every three weeks. A rapid dose titration strategy with initial single patient cohorts and 100% dose escalations was used. With the appearance of drug-related toxicity, escalations were decreased to 50% or 25% and cohorts were expanded to 3 or 6 patients until establishment of the MTD. Dose escalation rapidly proceeded to 320 mg/m(2)/d. The dose limiting toxicities (DLTs) observed were grade 3 hypotension and grade 2 allergic reaction. Other toxicities included anemia, thrombocytopenia, anorexia, asthenia, diarrhea, fatigue, headache, nausea, vomiting, and rash. Pharmacokinetic analysis showed that CEP-2563 is reliably converted to CEP-751. This study demonstrated that single agent CEP-2563 therapy is feasible with acceptable toxicities. The recommended phase II dose is 256 mg/m(2)/d. Rapid dose escalation with single patient cohorts was a safe and efficient method of conducting this phase I trial.
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PMID:Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors. 1529 15

The family of VEGF receptors are important mediators of angiogenesis, which is essential for tumour growth and metastasis. PTK/ZK is a multiple VEGF receptor inhibitor that blocks the activity of all known VEGF receptor tyrosine kinases. This phase I/II trial evaluated the safety, pharmacokinetics and efficacy of PTK/ZK in patients with liver metastases from solid tumours. Patients were administered oral PTK/ZK monotherapy once daily at doses of 300-1200 mg/day in 28-day cycles until unacceptable toxicity or tumour progression occurred. Twenty-seven patients were enrolled and treatment with PTK/ZK was generally well tolerated. The most frequently reported adverse events were fatigue, nausea, dizziness, and vomiting (mostly National Cancer Institute Common Toxicity Criteria grade 1 or 2). The area under the concentration-time curve (AUC) of PTK/ZK increased between 300 and 1000 mg/day with no further increase from 1000 to 1200 mg/day; the AUC decreased by 50% between day 1 and day 15. The DCE-MRI showed a statistically significant early reduction of tumour blood supply (measured as Ki) at day 2 at doses > or = 750 mg/day. Disease progression was significantly correlated with percent change from baseline Ki. Thirteen patients had stable disease for at least two cycles (56 days). Median overall survival was 11.8 months (95% CI = 6.6, 17.1 months). Long-term therapy with PTK/ZK demonstrated predictable pharmacokinetics, was safe and feasible in patients with metastatic disease, and showed promising clinical activity. The minimum biologically active dose was established at 750 mg/day whereas the recommended dose for phase III studies is 1200 mg/day.
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PMID:Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. 1593 65

We investigated the effect of 5-hydroxytryptamine 3A and 3B receptor (HTR3A and HTR3B) gene polymorphisms on nausea induced by paroxetine in Japanese psychiatric patients. Blood samples were collected from 78 individuals after at least 2 weeks treatment with the same daily dose of paroxetine. The patients visited every 2 weeks and the paroxetine dose was changed in response to their clinical symptoms. Nausea was assessed at each visit. The Tyr129Ser polymorphism of the HTR3B gene had a significant effect on the incidence of nausea (P=0.038). Logistic regression analysis also showed that patients with the Tyr/Tyr genotype had a 3.95-fold (P=0.048) higher risk of developing nausea than patients with the Ser allele. HTR3A gene polymorphisms and the CYP2D6 gene polymorphisms had no significant effect on the incidence of nausea. The mean score of nausea severity was corrected by the Bonferroni test. HTR3B gene polymorphisms are significant predictors of paroxetine-induced nausea.
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PMID:The effect of 5-hydroxytryptamine 3A and 3B receptor genes on nausea induced by paroxetine. 1653 7

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.
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PMID:Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. 1661 23

Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.
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PMID:The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. 1696 55

ErbB/HER receptor or its signal transduction pathway is an attractive therapeutic target for breast cancer. Lapatinib, an orally administered dual inhibitor of ErbB1 (EGFR) and ErbB2 (HER2) receptor tyrosine kinases has shown promising results for metastatic breast cancer (MBC). Lapatinib exhibited activity against trastuzumab-refractory MBC and showed an acceptable adverse event profile such as transient mild rash, diarrhea and nausea. The addition of lapatinib to capecitabine resulted in significantly prolonged time to progression. Large randomized trials using lapatinib following chemotherapy and surgery are ongoing for early stage HER2-overexpressing breast cancer. Various combinations with agents such as paclitaxel, aromatase inhibitors, or other molecular targeted agents are currently being investigated in clinical trials. If these approaches overcome the limitations of trastuzumab, lapatinib will become an effective treatment option for breast cancer in the near future.
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PMID:Does lapatinib, a small-molecule tyrosine kinase inhibitor, constitute a breakthrough in the treatment of breast cancer? 1748

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

Sorafenib (BAY 43-9006) is a novel oral bis-aryl urea compound originally developed as an inhibitor to RAF kinase for its anti-proliferative property. It also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-2/3, Flt-3/ and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Phase I studies demonstrated that sorafenib was well tolerated, and the recommended phase II dose was 400 mg twice daily continuously. Common toxicities included skin toxicity (rash and hand-foot syndrome), gastrointestinal toxicities (nausea and diarrhea) and fatigue. Anti-tumor activities were observed in multiple tumors types including renal cell carcinoma and hepatocellular carcinoma. Randomized phase III studies in these tumor types are ongoing, and results are eagerly waited.
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PMID:Sorafenib (BAY 43-9006): review of clinical development. 1866 47

Peptide tyrosine-tyrosine (PYY) is a prandially controlled hormone in endocrine ileal and colonic mucosa cells. In plasma, PYY appears as full-length PYY1-36 and truncated PYY3-36. Both have different pharmacological profile, and PYY3-36 seems to inhibit food intake. We aimed at investigating the effect of intravenously administered PYY1-36 and PYY3-36 on gastric emptying and short-term metabolic control. Eight healthy adults were studied in single-blinded, randomized design. At separate occasions, intravenous infusion of saline, PYY1-36 or PYY3-36 (0.8 pmol kg(-1) min(-1)) and a radio-labelled omelette were given. Gastric emptying (scintigraphy), appetite ratings (VAS), and plasma concentrations of insulin, glucose, GLP-1 and PYY were measured. PYY3-36 and PYY1-36 both inhibited gastric emptying, PYY3-36 most effectively. Half-emptying time was prolonged from 63.1+/-5.2 (saline) to 87.0+/-11.5 min (PYY3-36), whereas retention at 120 min was 2.5+/-1.4% for saline, 10.7+/-4.4 for PYY1-36 and 15.8+/-4.4 for PYY3-36. Neither form influenced glucose or GLP-1 concentrations, but both decreased the postprandial rise in insulin. PYY3-36 induced nausea (VAS increase 47.5+/-22.6 mm) and decreased prospective consumption (VAS change 39.5+/-7.7 mm). In conclusion, PYY3-36's reducing effect upon food intake might be mediated by a decreased gastric emptying rate.
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PMID:Differential effect of PYY1-36 and PYY3-36 on gastric emptying in man. 1965 Nov 63

IMATINIB MESYLATE (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, the so-called small molecules. They have a high selectivity against a specific molecular target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem-cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably Bcr-Abl. Imatinib has been shown to have remarkable clinical activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases.Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events (AE) include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression.Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of Bcr-Abl as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, respectively. Improved understanding of the underlying mechanisms of resistance has led to the development of new second-generation tyrosine kinase inhibitors (see Chaps. 7-9).
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PMID:Imatinib mesylate. 2007 27


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