A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer

PURPOSE: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.     

Changes in blood pressure 24 hour monitoring data and quality of life in patients with systolic hypertension treated with arifon

AIM: The study of quality of life and 24-h monitoring blood pressure data in elderly patients with isolated systolic hypertension (SH) on arifon monotherapy. MATERIALS AND METHODS: 22 patients over 65 (mean age 69.8 +/- 1.3 years) suffering from SH entered the open trial. 24-h monitoring of blood pressure was performed at least 2 weeks after discontinuation of the previous antihypertensive treatment and after 4 weeks of arifon monotherapy (2.5 mg once a day). Quality of life was evaluated according to the standard SIP questionnaire. RESULTS: Arifon 4-week treatment resulted in a significant fall of systolic pressure for 24 hours, day and night (by 16.2, 13.7 and 17.4%, respectively; p < 0.001). Variability of blood pressure did not change much. 24-h index for systolic and diastolic blood pressure increased 2-fold and by 46%, respectively. Moreover, the rate of the systolic pressure growth in the morning hours decreased by 36.7% (p < 0.05). Psychosomatic status by SIP questionnaire changed for the best. CONCLUSION: Arifon is an effective treatment of SH and improves quality of life.     

CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation

The activity of cyclin-dependent kinase 2 (CDK2) is essential for progression of cells from G1 to the S phase of the mammalian cell cycle. CVT-313 is a potent CDK2 inhibitor, which was identified from a purine analog library with an IC50 of 0.5 microM in vitro. Inhibition was competitive with respect to ATP (Ki = 95 nM), and selective CVT-313 had no effect on other, nonrelated ATP-dependent serine/threonine kinases. When added to CDK1 or CDK4, a 8.5- and 430-fold higher concentration of CVT-313 was required for half-maximal inhibition of the enzyme activity. In cells exposed to CVT-313, hyperphosphorylation of the retinoblastoma gene product was inhibited, and progression through the cell cycle was arrested at the G1/S boundary. The growth of mouse, rat, and human cells in culture was also inhibited by CVT-313 with the IC50 for growth arrest ranging from 1.25 to 20 microM. To evaluate the effects of CVT-313 in vivo, we tested this agent in a rat carotid artery model of restenosis. A brief intraluminal exposure of CVT-313 to a denuded rat carotid artery resulted in more than 80% inhibition of neointima formation. These observations suggest that CVT-313 is a promising candidate for evaluation in other disease models related to aberrant cell proliferation.     

Hepatitis C: Part I. Routine serologic testing and diagnosis

Hepatitis C, which is caused by the hepatitis C virus (HCV), is a major public health problem in the United States. HCV is most efficiently transmitted through large or repeated percutaneous exposures to blood. Most patients with acute HCV infection develop persistent infection, and 70 percent of patients develop chronic hepatitis. HCV-associated chronic liver disease results in 8,000 to 10,000 deaths per year, and the annual costs of acute and chronic hepatitis C exceed $600 million. An estimated 3.9 million Americans are currently infected with HCV, but most of these persons are asymptomatic and do not know they are infected. To identify them, primary health care professionals should obtain a history of high-risk practices associated with the transmission of HCV and other bloodborne pathogens from all patients. Routine testing is currently recommended only in patients who are most likely to be infected with HCV.