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)

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

Angiogenesis is part of the pathophysiology of myelofibrosis with myeloid metaplasia (MMM). PTK787/ZK 222584 (PTK/ZK) is a novel inhibitor of vascular endothelial growth factor receptors. Twenty-nine patients with MMM received a continuous dosing schedule of PTK/ZK doses of 500 or 750 mg twice daily (BID). Transient potentially PTK/ZK related mild nausea, vomiting, dizziness, fatigue, thrombocytopenia, or anorexia occurred in 15% of patients. Dose limiting toxicities of dyspepsia, proteinurea, and/or mucositis were observed in patients treated with 750 mg BID. One (3%) and five (17%) patients achieved complete remission and clinical improvement, respectively. PTK/ZK has modest activity in patients with MMM.
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PMID:PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor of vascular endothelial growth factor (VEGF), has modest activity in myelofibrosis with myeloid metaplasia. 1756 Feb 85

Trastuzumab is a recombinant humanised monoclonal antibody specific for the growth factor receptor p185(HER2) (HER2) which is overexpressed in 25 to 30% of breast cancer tumours. The drug inhibits the growth of human breast cancer cells overexpressing HER2 in vitro and in vivo. It shows additive antitumour activity in vitro and in vivo when administered with paclitaxel, doxorubicin, various cytokines or tamoxifen. In patients with metastatic breast cancer whose tumours overexpressed HER2, trastuzumab (4 mg/kg loading dose then 2 mg/kg/week by intravenous infusion) produced objective responses in 21% of 213 patients. A further 7% of patients had minor responses and 30% had stable disease. Combination therapy with trastuzumab and either paclitaxel or doxorubicin (or epirubicin) plus cyclophosphamide produced a higher response rate (49%), longer median time to disease progression (7.6 months), a higher one-year survival rate (78%) and significantly increased median overall survival (25.4 months) than antineoplastic agents alone (response rate 32%, time to disease progression 4.6 months, one-year survival rate 67% and overall survival 20.3 months) in a phase III study in 469 patients. Trastuzumab is generally well tolerated. Chills, fever, nausea, vomiting, weakness and headache were among the most common adverse events in clinical trials and occurred in 40 to 50% of patients during the first infusion of the drug. Cardiac dysfunction was the most serious adverse event reported and was more common in patients receiving trastuzumab plus antineoplastic therapy than in those receiving trastuzumab alone.
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PMID:Trastuzumab. 1803 Nov 72

Concomitant chemo-radiotherapy is the standard treatment for advanced nasopharyngeal carcinoma (NPC). Induction chemotherapy may improve the results further by enhancing both loco-regional and distant control. Fifty patients with untreated, stage IV (UICC 1992) undifferentiated NPC were initially treated with three courses of epidoxorubicin, 90 mg/m(2), day 1 and cisplatin, 40 mg/m(2), days 1 and 2, every three weeks and then underwent three courses of cisplatin, 20 mg/m(2)/day, days 1-4 and fluorouracil, 200mg/m(2)/day, days 1-4 (weeks 1, 4, 7), alternated to three splits of radiation (week 2-3, 5-6, 8-9-10) up to 70 Gy. All patients but one received 3 cycles of induction chemotherapy. Toxicities from induction chemotherapy were grade III or IV mucositis (2%), grade III or IV nausea/vomiting (22%), grade III or IV hematological toxicity (6%). At the end of induction phase 12% of CRs, 84% of PRs were recorded. Toxicities from alternating chemo-radiotherapy were grade III or IV mucositis (30%), grade III or IV nausea/vomiting (8%), grade III or IV hematological toxicity (24%). Overall, 86% of CRs and 14% of PRs were observed. Four-year progression free survival and overall survival rates are 71% and 81%, respectively. In a small number of patients studied, no correlation between the level of EGFR overexpression and outcomes was detected. In locally advanced UNPC our combined program including induction chemotherapy followed by alternating chemo-radiotherapy is active and gives promising long-term outcomes with acceptable toxicity and optimal patients' compliance. This program merits to be tested in a phase III trial.
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PMID:Induction chemotherapy followed by alternating chemo-radiotherapy in non-endemic undifferentiated carcinoma of the nasopharynx: optimal compliance and promising 4-year results. 1806 19

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

The serotonin transporter protein (SERT) has been the target for the development of several modern antidepressants with an objective of achieving selectivity over other monoamine transporters, thereby minimising side effects observed in the older generation of tricyclic antidepressants. The clinical selective serotonin reuptake inhibitors (SSRIs) have been shown to be among the most effective therapies in the treatment of depression. However they have clinical disadvantages over other classes of antidepressant drugs such as slow onset of action nausea and sleep disruption. The negative feedback loop attributed to the presynaptic 5-HT(1A) receptors has been implicated in the "time lag" observed in many patients between the administration of the SSRI and its observed therapeutic action. In recent years the focus has been on developing compounds with dual affinity for serotonergic auto-receptors along with an inhibitory activity at SERT. These structurally diverse products promise to be the next generation of anti-depressant medicines. This review presents an analysis of the recently reported structural classes with SSRI activity and rationalises the unique relationship between their molecular properties and biological activities. Specific emphasis is placed on the development of molecular structures with dual serotonergic activity. Recent advances in the design and synthesis of single molecular entities possessing 5-HT reuptake inhibition together with 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), DAT, NET, alpha (2)-adrenoceptor and acetylcholinesterase antagonism are reviewed. The structural studies to identify proposed SERT binding sites together with the role of structure and ligand based design in the development of more effective SSRIs are summarised.
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PMID:Recent developments in the design of anti-depressive therapies: targeting the serotonin transporter. 1867 23

Experimental and occupational exposure to methyl tert-butyl ether (MTBE) has been reported to induce neurotoxicological and neurobehavioral effects, such as headache, nausea, dizziness, and disorientation, etc. However, the molecular mechanisms involved in MTBE-induced neurotoxicity are still not well understood. In the present study, we investigated the effects of MTBE on spatial memory and the expression and function of GABA(A) receptor in the hippocampus. Our results demonstrated that intraventricular injection of MTBE impaired the performance of the rats in a Morris water maze task, and significantly increased the expression of GABA(A) receptor alpha1 subunit in the hippocampus. The phosphorylation of ERK1/2 decreased after the MTBE injection. Furthermore, the decreased ability of learning and the reduction of phosphorylated ERK1/2 level of the MTBE-treated rats was partly reversed by bicuculline injected 30 min before the training. These results suggested that MTBE exposure could result in impaired spatial memory. GABA(A) receptor may play an important role in the MTBE-induced impairment of learning and memory by regulating the phosphorylation of ERK in the hippocampus.
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PMID:gamma-Aminobutyric acid(A) (GABA(A)) receptor regulates ERK1/2 phosphorylation in rat hippocampus in high doses of methyl tert-butyl ether (MTBE)-induced impairment of spatial memory. 1934 68


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