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Summary CP-4126 is a gemcitabine (2′,2′-difluorodeoxycytidine; dFdC) 5′ elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100–3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1–2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.

Background CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid–drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile. Methods Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126. Results Forty-three patients, median age 59 years (range 18–76; male = 27, female = 16), received one of ten dose levels (30–1600 mg/m 2 ). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m 2 on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure. Conclusions CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.

Purpose Treatment of patients with recurrent ovarian cancer remains a challenge, and there is a need for new and more effective agents. A phase I-II study was designed to determine the recommended dose (RD) and the anti-tumour effect of a prolonged administration of elacytarabine, the elaidic ester of cytarabine, in patients with refractory/resistant recurrent ovarian cancer. Experimental design The primary objective of the dose escalation phase I part was to determine the RD for elacytarabine when given twice for five consecutive days in a 4-week schedule, D1-5 and D8(+2)-12(+2) q4w. Three to six patients were to be enrolled at each dose level. The start dose was elacytarabine 75 mg/m 2 /day. The phase II part was designed as a two-step study based on response. Results A total of 28 patients entered the study, 17 patients in the phase I part and 11 # patients in phase II. Three dose levels were tested: 75 mg/m 2 /day in 3 patients, 100 mg/m 2 /day in 7 + 11 # patients, and 125 mg/m 2 /day in 7 patients. Three (17.6%) patients in phase I experienced a dose limiting toxicity (DLT), all at the 125 mg/m 2 /day dose level, establishing the lower dose of 100 mg/m 2 /day as the RD. The DLTs were neutropenia grade 4 according to the Common Terminology Criteria for Adverse Events (CTCAE) and thrombocytopenia grade 4 (2 patients), and vomiting grade 2 with hospitalisation and hypokalaemia grade 3 (1 patient). The best response was a clinically meaningful stabilization observed in 3 patients. In two of them, the disease stabilization exceeded the previous platinum-free interval (PFI). Conclusions The RD for elacytarabine was 100 mg/m 2 /day, D1-5 and D8-12 q4w. The safety profile was comparable to the safety profiles reported in previous clinical studies with elacytarabine in solid tumours. Despite some longer-lasting disease stabilisations, two of them exceeding the previous progression-free interval, further investigations of elacytarabine in the ovarian cancer indication are not warranted.

To evaluate injection-associated pain, safety, and efficacy with the isotonic contrast medium iodixanol (Visipaque 270 mg I/ml) compared with iopromide (Ultravist 300 mg I/ml) in femoral arteriography. A multicenter, double-blind, randomized, parallel-group clinical investigation was carried out in 54 hospitals in Europe. Of the patients evaluated, 1225 received iodixanol and 1227 iopromide in conventional and/or digital subtraction angiography. The iodixanol group reported statistically significantly less injection-associated pain (0.9%) than the iopromide group (9.5%) (p << 0.001). Further, 4.1% in the iodixanol group experienced pain and/or severe heat sensation vs 19. 8% in the iopromide group (p << 0.001). In the iodixanol group, 1.8% of the patients experienced contrast-related adverse events vs 2.4% in the iopromide group (p = NS). Overall diagnostic information was optimal for 94.1% in the iodixanol group and 95.3% in the iopromide group (p = NS). Iodixanol 270 mg I/ml causes significantly less injection-associated pain during femoral arteriography and is as safe and efficacious as iopromide 300 mg I/ml.

During the 1930s, a worldwide depression created a fear of communism and a \"law-and-order\" mentality. The 1990s, by contrast, are marked by a social void in which guilt is ascribed to no one. As recent TV commercials show, dispensing reasonable consequences in response to negative actions is viewed as socially backward. Too often, behavior-disordered kids lead undisciplined lives. (MLH)

Part-time social studies instructor at two community colleges set out to disprove weekly news magazine's claim that large percentage of American students could not properly identify our enemy in World War II. Majority of his class thought Russia was our enemy, when asked to choose among Mexico, Vietnam, Russia, Germany. Furthermore, students recognized Joey Buttafuoco but not NAFTA, Al Gore, or Mother Teresa. (MLH)

The rush to label schoolchildren as suffering from attention deficit disorder (ADD) or attention deficit-hyperactivity disorder (ADHD) has reached nearly epidemic proportions. The diagnosis often meets parents' needs to assign behavior control to Ritalin; it should be an explanation leading to genuine help, not a license for unacceptable student behavior. (MLH)

Mandating inclusion for all special-needs students would return education to the 1950s, when student options were extremely limited. Full inclusion, requiring the regular education teacher to learn a monumental number of additional skills, may be state-of-the-art education for the 90s--the 1890s. Restricting all students to the same learning environment is legally and morally indefensible. (MLH)