naphthoquinones and Fatigue

YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors.. Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles.. Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m(2)/d. The MTD was determined to be 8.0 mg/m(2)/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m(2)/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients.. YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m(2)/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Fever; Humans; Imidazoles; Infusions, Intravenous; Inhibitor of Apoptosis Proteins; Male; Metabolic Clearance Rate; Microtubule-Associated Proteins; Middle Aged; Naphthoquinones; Neoplasms; Patient Dropouts; Survivin; Treatment Outcome

Recent evidence has established the effectiveness of Malarone and primaquine for chemoprophylaxis against Plasmodium falciparum malaria. Both have the advantage of providing causal prophylaxis and therefore require continued dosing for only 1 wk after departure from a malaria endemic area. Canadian Forces aircrews are often placed in situations that put them at risk for malaria infection but the safety of these drugs for use in aircrew has not been ascertained. This study was undertaken to determine whether or not Malarone or primaquine impact psychomotor performance.. Twenty-eight subjects (20 men and 8 women) ranging from 21 to 52 yr of age were assessed for psychomotor performance on 2 psychomotor test batteries at the end of a 7-d dosing protocol for each of placebo, Malarone, and primaquine treatment, in a double-blind crossover design with counterbalanced treatment order. All subjects were also assessed for psychomotor performance once per week during the 3-wk washout intervals. The daily Malarone dose was atovaquone 250 mg/proguanil 100 mg and the daily primaquine dose was 30 mg of base. In order to verify subject compliance with the medication dosing protocol, blood samples were drawn from all subjects at the end of each of the three 7-d loading protocols. All three medications were packaged in identical gelatin capsules for blinding purposes. At each psychomotor test session, all subjects completed a drug side-effect questionnaire, a mood questionnaire, and a sleepiness/fatigue questionnaire.. There was no significant impact of Malarone or primaquine on serial reaction time, logical reasoning, serial subtraction, or multitask performance. With respect to drug adverse effects there were no significant main effects or interactions for the documented adverse effects of these medications (abdominal cramps, epigastric distress, nausea, vomiting, anorexia, headache, coughing and dizziness).. There was no impact of either Malarone or primaquine on psychomotor performance, mood, sleepiness, or fatigue. The usual adverse effects of these medications were not significantly manifested in our subjects. These findings support the possible use of either Malarone or primaquine in aircrew for malaria chemoprophylaxis.

Topics: Adult; Affect; Antimalarials; Atovaquone; Colic; Cross-Over Studies; Diarrhea; Double-Blind Method; Drug Combinations; Fatigue; Female; Headache; Humans; Male; Middle Aged; Naphthoquinones; Nausea; Patient Compliance; Primaquine; Proguanil; Psychomotor Performance