naphthoquinones and Anemia

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

Whether administration of folic acid to children with malaria anemia is helpful is controversial. Therefore, we conducted a randomised, placebo-controlled trial of 14 days of treatment with folic acid (1 mg/d) in Zambian children with malaria anemia treated with either sulfadoxine/pyrimethamine (SP) or atovaquone/proguanil (AP). Among children who received SP, the prevalence of parasitemia was higher in children treated with folic acid than among those given placebo at days 3, 7, and 14 after the start of treatment, and the difference at day 3 was statistically significant (P = 0.013). Folic acid treatment had no effect on parasitemia in children treated with AP. Administration of folic acid led to a small increase in packed cell volume over that seen in the placebo group at days 14 and 28 after the start of treatment.

Topics: Anemia; Animals; Antimalarials; Atovaquone; Child; Child, Preschool; Drug Combinations; Folic Acid; Hematinics; Humans; Infant; Malaria, Falciparum; Naphthoquinones; Parasitemia; Population Density; Proguanil; Pyrimethamine; Sulfadoxine; Treatment Failure; Zambia

There is no safe, practical, and effective treatment for pregnant women infected with multidrug-resistant Plasmodium falciparum.. We recruited pregnant Karen women in the second or third trimesters of pregnancy who had uncomplicated falciparum malaria for a randomized, open-label trial with a restricted sequential trial design of 7 days of supervised quinine (SQ7) versus 3 days of artesunate-atovaquone-proguanil (AAP).. Eight-one pregnant women entered the study between December 2001 and July 2003; 42 were treated with SQ7 and 39 were treated with AAP. Fever, parasite clearance, and duration of anemia were significantly better with AAP; the treatment failure rate was 7 times lower (5% [2/39] vs. 37% [15/41]; relative risk, 7.1 [95% confidence interval, 1.7-29.2]; P = .001). There were no significant differences in birth weight, duration of gestation, or congenital abnormality rates in newborns or in growth and developmental parameters of infants monitored for 1 year.. AAP is a well-tolerated, effective, practical, but expensive treatment for multidrug-resistant falciparum malaria during the second or third trimesters of pregnancy. Despite the small number of subjects, our results add to the growing body of evidence that AAP is safe for the mother and the fetus.

Topics: Adolescent; Adult; Anemia; Animals; Antimalarials; Artemisinins; Artesunate; Atovaquone; Female; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Naphthoquinones; Parasitemia; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Proguanil; Quinine; Sesquiterpenes; Thailand

A naphthoquinone derivative, beta-lapachone (betaL; 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione), is receiving huge attention for its potent therapeutic effects against various diseases. However, during the preclinical safety evaluation, repeated oral treatment of betaL in rats induced anemia, i.e., a significantly decreased erythrocyte count. In this study, in an effort to elucidate the mechanism underlying the betaL-induced anemia, we investigated the effects of betaL on erythrocytes with freshly isolated human erythrocytes in vitro and rat in vivo. betaL did not induce erythrocyte hemolysis, indicating that direct hemotoxicity was not involved in betaL-associated anemia. Meanwhile, phosphatidylserine (PS) exposure along with spherocytic shape change and microvesicle generation, important factors in the facilitation of erythrophagocytosis, were increased significantly by betaL. The PS exposure on erythrocytes was from betaL-induced reactive oxygen species generation and subsequent depletion of reduced glutathione and protein thiol, which culminated in the modified activities of phospholipid translocases, i.e., inhibition of flippase and activation of scramblase. It is important to note that coincubation of macrophage with betaL-treated erythrocyte in vitro showed increased erythrophagocytosis, demonstrating that the removal of erythrocyte by macrophage can be facilitated by betaL-induced PS exposure. In good accordance with these in vitro results, after oral administration of betaL in rats, increased PS exposure and depletion of glutathione were observed along with enhanced splenic sequestration of erythrocytes. In conclusion, these results suggest that betaL-induced anemia might be mediated through the PS exposure and subsequent erythrophagocytosis, providing novel insight into the drug-induced anemia.

Topics: Adenosine Triphosphate; Adolescent; Adult; Anemia; Animals; Calcium; Erythrocyte Membrane; Erythrocytes; Flow Cytometry; Glutathione; Hemolysis; Humans; In Vitro Techniques; Male; Microscopy, Electron, Scanning; Naphthoquinones; Oxidative Stress; Phagocytosis; Phosphatidylserines; Phospholipids; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Young Adult

Topics: Administration, Oral; Anemia; Animals; Dogs; Erythrocytes; Female; Haplorhini; Heinz Bodies; Hemoglobinometry; Hemorrhage; Liver; Male; Mice; Naphthoquinones; Prothrombin Time; Rats; Reticulocytes; Sex Factors; Species Specificity; Vitamin K