Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BAY 43-9006 is an oral inhibitor of CRAF, wild-type BRAF, mutant V599E BRAF, vascular endothelial growth factor receptor (VEGFR) 2, VEGFR3, mVEGFR2, FLT-3, platelet-derived growth factor receptor, p38, and c-kit among other kinases. A Phase I study of BAY 43-9006 identified 400 mg orally twice daily as the recommended Phase II dose. The Phase II results of a study of BAY 43-9006 at 400 mg orally twice daily were particularly interesting in patients with renal cell carcinoma. Data from the first 41 patients with renal cell carcinoma showed that 30% of patients had stable disease (defined as between 25% reduction and 25% growth), 40% had responded (defined as >25% reduction), and 30% had progressed. Disease could be stabilized for periods in excess of a year. Some lesions became cystic and could actually enlarge while developing a low attenuation core. This phenomenon is recognized in the treatment of gastrointestinal stromal tumors with imatinib mesylate. The toxic effects of BAY 43-9006 were manageable and included hypertension, edema, diarrhea, hand and foot syndrome, rash, and hair loss where the rash involved the scalp. There was an impression of tachyphylaxis such that patients who required a dose reduction could be restored to full dose after a few months. A Phase III randomized, placebo-controlled trial of BAY 43-9006 has started for patients whose renal cell carcinoma has progressed within 6 months of immunotherapy. Combination studies with interferon, interleukin 2, bevacizumab, and chemotherapy are under consideration. The therapeutic targets of BAY 43-9006 in renal cell carcinoma remain unclear. Unlike melanoma, BRAF mutations have not been found in renal cell carcinoma. Other candidate targets include VEGFR2 and VEGFR3.
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PMID:Kinase inhibition with BAY 43-9006 in renal cell carcinoma. 1544 36

A gastrointestinal stromal tumor of the stomach mimicking an adrenal tumor in a 67-year-old woman is reported. The patient sought medical attention for left flank pain in December 2001. A spherical calcification was evident in the left hypochondrium in an abdominal radiography, and computed tomography revealed a mass 8 cm in diameter at the upper pole of the left kidney. She then was admitted to our hospital. Physical examination and laboratory screening showed hypertension, diabetes mellitus and slight hemoconcentration. Endocrine examination showed normal serum adrenal hormone concentrations. Magnetic resonance imaging again demonstrated the mass, which showed enhancement along its margins after intravenous contrast administration. With a preoperative diagnosis of adrenal tumor, we performed total resection. The pediculated tumor, arising from the stomach, showed c-kit immunohistochemical staining permitting a histopathological diagnosis of gastrointestinal stromal tumor.
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PMID:[Gastrointestinal stromal tumor of the stomach mimicking adrenal tumor: a case report]. 1568 56

AG-013736 is an oral anti-angiogenesis agent with activity against a variety of receptor tyrosine kinases, including VEGFR-1, VEGFR-2, VEGFR-3, c-kit, and PDGFR-beta. A phase 2 study was conducted in patients with poor prognosis AML or MDS. Twelve patients (six AML; six MDS) were treated with AG-013736 at a dose of 10mg orally daily for a median of 56 days (range, 1-248 days). Median age was 80 years (range, 58-88 years). Grade 3 or 4 drug-related toxicities included hypertension (42%), mucositis (8%) and deep venous thrombosis (8%). No objective responses occurred; two patients with MDS had stable disease for 8.3 and 6.2 months, respectively. Bone marrow expression of VEGFR-1 and VEGFR-2 was observed in 11% and 0% of patients, respectively. Sustained decreases in soluble VEGFR-2 plasma levels with concomitant elevation in plasma VEGF and placental growth factor levels were obtained during the course of therapy with AG-013736. AG-01736 had minimal biologic or clinical activity in this elderly patient population.
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PMID:The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). 1633 90

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

Three patients with advanced renal-cell cancer were treated with sunitinib 50 mg daily for 4 weeks followed by a rest period of 2 weeks because of progressive disease. The first patient developed stomatitis and a painful blister on his foot. Complaints disappeared after temporary discontinuation of treatment. Re-treatment at a lower dosage was successful until disease progression. The second patient developed skin discolouration, fatigue, fever and diarrhoea. After treatment was interrupted shortly, these symptoms disappeared and sunitinib was recommenced at a lower dosage. The patient went on to develop stomatitis, thrombocytopenia and hypertension (treated with amlodipine). She subsequently had hand-foot syndrome. She died due to brain metastases. In the third patient symptoms of disease returned during the rest period, because of which he received a reduced dosage of sunitinib on a continuous base. He developed diarrhoea which disappeared after a short interruption of the drug. Sunitinib has been approved for the treatment of advanced renal-cell cancer and imatinib-resistant gastro-intestinal stromal tumours. This novel targeting molecule is a tyrosine-kinase inhibitor of vascular endothelial growth-factor receptors, platelet-derived growth-factor receptors and c-Kit. It can induce adverse events that differ from those observed in treatment with conventional cytotoxic agents. The adverse effects are reduced by lowering the dosage and in the rest period within the treatment cycle.
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PMID:[Adverse effects of the tyrosine-kinase inhibitor sunitinib, a new drug for the treatment of advanced renal-cell cancer]. 1755 72

A 73-year-old Japanese woman was referred for examination of right flank pain and progressive hypertension. Abdominal CT incidentally detected a right adrenal mass 8 cm in size. The tumor exhibited isodensity by CT and contained high-intense lesion by T2-weighted MRI. Scintigraphy with (131) I-metaiodobenzylguanidine and (131) I-adosterol showed no abnormal uptake by whole body scan. Positron emission tomography scan with (18) F-2-fluoro-D-deoxyglucose demonstrated an exclusive uptake in the right adrenal mass. Adrenocortical hormone levels and catecholamine secretion were within normal range; however, the level of serum neuron-specific enolase (NSE) was found to be markedly high. After controlling systemic blood pressure with an alpha1-blocker, the right adrenal tumor was surgically removed, along with the right kidney and inferior vena cava which adhered to it. The tumor was pathologically proven to be leiomyosarcoma, which was immunohistochemically positive with alpha-smooth muscle actin and negative with CD57, S-100 and c-kit proteins. Notably, NSE protein was massively expressed in the resected tumor. After surgery blood pressure was controlled with regular medication and serum NSE levels have since normalized. The possibility of leiomyosarcoma should be kept in mind in adrenal incidentalomas with rapid growth and atypical radiological images. Our findings suggest that circulating NSE levels may be clinically useful for early detection of recurrence.
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PMID:A rare tumor in the adrenal region: neuron-specific enolase (NSE)-producing leiomyosarcoma in an elderly hypertensive patient. 1825 May 40

Pazopanib, which is being developed by GlaxoSmithKline plc, is an oral, second-generation multi-targeted tyrosine kinase inhibitor that targets VEGFR, platelet-derived growth factor receptor and c-kit, key proteins responsible for tumor growth and survival. Pazopanib exhibited good potency against all of the human VEGFRs and closely related tyrosine receptor kinases in vitro, and demonstrated antitumor activity in several human tumor xenografts, including renal cell carcinoma (RCC), and breast and lung cancer. In phase I and II clinical trials, pazopanib was generally well tolerated with the main side effects being hypertension, fatigue or gastrointestinal disorders. Pazopanib alone caused a decrease in tumor size and stable disease in a significant number of patients, including those with RCC, NSCLC and gynecological tumors. The combination of pazopanib with lapatinib was effective in patients with breast cancer. At the time of publication, pazopanib monotherapy was being evaluated in phase III trials in patients with RCC and as combination therapy with lapatinib in patients with breast cancer. In addition, phase I and II trials were being conducted to assess pazopanib alone or in combination with a range of chemotherapeutics in patients with solid tumors or multiple myeloma.
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PMID:Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. 1903 39

We investigated how exercise training superimposed on chronic hypertension impacted left ventricular remodeling. Cardiomyocyte hypertrophy, apoptosis, and proliferation in hearts from female spontaneously hypertensive rats (SHRs) were examined. Four-month-old SHR animals were placed into a sedentary group (SHR-SED; n = 18) or a treadmill running group (SHR-TRD, 20 m/min, 1 h/day, 5 days/wk, 12 wk; n = 18). Age-matched, sedentary Wistar Kyoto (WKY) rats were controls (n = 18). Heart weight was greater in SHR-TRD vs. both WKY (P < 0.01) and SHR-SED (P < 0.05). Morphometric-derived left ventricular anterior, posterior, and septal wall thickness were increased in SHR-SED relative to WKY and augmented in SHR-TRD. Cardiomyocyte surface area, length, and width were increased in SHR-SED relative to WKY and further increased in SHR-TRD. Calcineurin abundance was increased in SHR-SED vs. WKY (P < 0.001) and attenuated in SHR-TRD relative to SHR-SED (P < 0.05). Protein abundance and mRNA of Akt was not different among groups. The rate of apoptosis was increased in SHR-SED relative to WKY and mitigated in SHR-TRD. The abundance of Ki-67(+) cells across groups was not statistically different across groups. The abundance of cardiac progenitor cells (c-Kit(+) cells) was increased in SHR-TRD relative to WKY. These data suggest that exercise training superimposed on hypertension augmented cardiomyocyte hypertrophy, despite attenuating calcineurin abundance. Exercise training also mitigated apoptosis in hypertension and showed a tendency to enhance the abundance of cardiac progenitor cells, resulting in a more favorable cardiomyocyte number in the exercise-trained hypertensive heart.
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PMID:Left ventricular remodeling with exercise in hypertension. 1966 35

VEGFR and c-Kit signaling pathways may contribute to the pathophysiology of acute myeloid leukemia (AML). Thirty-five patients with AML received cediranib (RECENTIN), an oral, highly potent VEGF signaling inhibitor with c-Kit activity, at doses of < or =30 mg/day. The most common adverse events were diarrhea, hypertension and fatigue. Six patients experienced an objective response (3 each at 20 and 30 mg). Dose- and time-dependent reductions in sVEGFR-2 were observed, and there was a positive correlation between cediranib exposure and the change in plasma VEGF levels from baseline. Cediranib was generally well tolerated and showed preliminary evidence of activity as a monotherapy.
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PMID:An open-label, Phase I study of cediranib (RECENTIN) in patients with acute myeloid leukemia. 1967 89

There is a high prevalence of hypertension and hypertension-related vascular disease in humans. Studies show that the expression of stem cell factor (SCF)/c-kit signalling proteins is relatively high during blood vessel repair. The aim of this study was to investigate the relationship between blood pressure (BP) and the expression of SCF/c-kit in peripheral blood. We carried out a cross-sectional analysis of 141 subjects in the health examination centre of our hospital. Information including waist circumference, BP, plasma glucose and serum lipids for each subject was collected. Endothelin-1 (ET-1) and tumour necrosis factor-alpha (TNF-alpha) levels in peripheral blood were determined by radio-immunity assay. Expression levels of SCF and its receptor, c-kit, in peripheral blood were measured by enzyme-linked immunosorbent assay (ELISA). We found a positive correlation between plasma SCF/c-kit levels and BP in these patients (SCF: hypertension 907.1+/-52.3 vs pre-hypertension 834.6+/-47.6 vs normal control 768.8+/-44.1 ng l(-1); c-kit: hypertension 13.2+/-1.6 vs pre-hypertension 11.1+/-2.1 vs normal control 9.6+/-1.5 mg l(-1), P<0.01). SCF/c-kit levels were also positively correlated with ET-1 and TNF-alpha levels (ET-1: hypertension 155.5+/-12.1 vs pre-hypertension 142.0+/-11.2 vs normal control 117.9+/-10.3 ng l(-1); TNF-alpha: hypertension 14.7+/-3.9 vs pre-hypertension 11.6+/-4.2 vs normal control 8.1+/-2.8 ng l(-1), P<0.01). Multiple linear regression analyses showed that SCF, c-kit and ET-1 are independent predictors for systolic blood pressure, and that SCF, c-kit, ET-1 and TNF-alpha are independent predictors for diastolic blood pressure. SCF/c-kit levels increase with BP levels are positively correlated with ET-1 and TNF-alpha levels.
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PMID:Relationship between stem cell factor/c-kit expression in peripheral blood and blood pressure. 1967 87


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