Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023380 (lethargy)
 5,697 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

Background: Patients with metastatic renal cell carcinoma (mRCC) are commonly treated with tyrosine kinase inhibitors (TKIs). An adverse effect frequently suffered by patients is lethargy, which often leads to dose reduction or drug cessation. We aimed to assess whether hypogonadism is related to treatment with TKIs. Methods: We prospectively assessed gonadal function in 41 consecutive males with mRCC treated with TKIs. Demographic, clinical, and biochemical variables were collected, and statistical analyses performed to assess correlation and survival. Data Capture for each patient was perfomred at the time of entry in the study. Results: There was a 77% incidence of hypogonadism in this cohort. Assessment of testosterone level and time on TKI treatment revealed a correlation with linear regression R2 of 0.24 and regression coefficient of -0.003 (p = 0.019). Odds ratio for hypogonadism at >30 months on TKIs was 12.1 (p = 0.011). Odds ratios above and below this value showed a confirmatory trend, suggesting that this may be a chronic adverse effect. Conclusions: Our findings provide an important and robust hypothesis for a prospective clinical trial to be performed. Expert Opinion: Given the present data, patients who have symptoms suggestive of hypogonadism must have an assessment of gonadal function and be treated.
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PMID:Chronic tyrosine kinase inhibitor (TKI) use in metastatic renal cell carcinoma (mRCC): can this lead to the adverse effect of hypogonadism? 3099 30