Primaquine is an important antimalarial agent because of its activity against exoerythrocytic forms of Plasmodium spp. Methemoglobinemia and hemolytic anemia, however, are dose-limiting side effects of primaquine therapy. These hemotoxic effects are believed to be mediated by metabolites, although the identity of the toxic specie(s) and the mechanism underlying hemotoxicity have remained unclear. Previous studies showed that an N-hydroxylated metabolite of primaquine, 6-methoxy-8-hydroxylaminoquinoline, was capable of mediating primaquine-induced hemotoxicity. The present studies were undertaken to investigate the hemolytic potential of 5-hydroxyprimaquine (5-HPQ), a phenolic metabolite that has been detected in experimental animals. 5-HPQ was synthesized, isolated by flash chromatography, and characterized by NMR spectroscopy and mass spectrometry. In vitro exposure of 51 Cr-labeled erythrocytes to 5-HPQ induced a concentration-dependent decrease in erythrocyte survival (TC 50 of ca. 40 M) when the exposed cells were returned to the circulation of isologous rats. 5-HPQ also induced methemoglobin formation and depletion of glutathione (GSH) when incubated with suspensions of rat erythrocytes. Furthermore, when red cell GSH was depleted (Ͼ95%) by titration with diethyl maleate to mimic GSH instability in human glucose-6-phosphate dehydrogenase deficiency, a 5-fold enhancement of hemolytic activity was observed. These data indicate that 5-HPQ also has the requisite properties to contribute to the hemotoxicity of primaquine. The relative contribution of N-hydroxy versus phenolic metabolites to the overall hemotoxicity of primaquine remains to be assessed.

No abstract

No abstract

Lipid peroxidation and the accompanying translocation of phosphatidylserine (PS) from the inner to the outer leaflet of the lipid bilayer have recently been identified as key components of a signaling pathway for phagocytosis of apoptotic cells by macrophages. Drug-induced hemolytic anemia has long been known to be caused by an accelerated uptake of damaged (but intact) erythrocytes by macrophages in the spleen, and this process has been associated with enhanced formation of reactive oxygen species (ROS). However, the role of lipid peroxidation in hemolytic injury has remained unclear, and the effect of hemolytic agents on the distribution of PS in the erythrocyte membrane is unknown. The present studies were undertaken to determine whether lipid peroxidation and PS translocation could be detected in rat and human erythrocytes by three types of direct-acting hemolytic agents--dapsone hydroxylamine, divicine hydroquinone, and phenylhydrazine. 2',7'-Dichlorodihydrofluorescein diacetate was employed as a probe for intracellular ROS formation; lipid peroxidation was assessed by GC/MS analysis of F2-isoprostanes; and PS externalization was measured by annexin V labeling and the prothrombinase assay. The data confirmed that all three hemolytic agents generate ROS within erythrocytes under hemolytic conditions; however, no evidence for lipid peroxidation or PS translocation was detected. Instead, ROS production by these hemolytic agents was associated with extensive binding of oxidized and denatured hemoglobin to the membrane cytoskeleton. The data suggest that the transmembrane signal for macrophage recognition of hemolytic injury may be derived from oxidative alterations to erythrocyte proteins rather than to membrane lipids.

Blinded from clinical data, sonography has significant interobserver variability for the diagnosis of placenta accreta.

No abstract

Placenta accreta is characterized by an abnormal adherence of the placenta to the uterine wall. It can be diagnosed clinically when there is a failure of the placenta to normally separate during the third stage of labor, or it can be diagnosed histologically. 1 The risk for placenta accreta is highest for those women with a placenta previa and prior cesarean delivery, particularly multiple prior cesarean deliveries. 2-4 Moreover, the incidence of placenta accreta has increased over the last four decades concurrent with an increased incidence of cesarean delivery. 2-5 One recent estimate for the incidence of placenta accreta is 1 in 533 pregnancies, 6 which is increased from approximately 1 in 19,000 in the 1950s and 1 in 7,000 in the 1970s. 7 Lack of antenatal suspicion and/or attempted removal of the placenta at the time of delivery can lead to major obstetrical hemorrhage in women with placenta accreta. In turn, this often requires emergency hysterectomy and may result in massive blood transfusion, cystotomy, ureteral Keywords ► placenta accreta ► cesarean delivery ► placenta previa ► risk factors AbstractObjective Placenta previa and prior cesarean delivery are known risk factors for placenta accreta. However, other risk factors have not been identified. Our objective was to examine risk factors for accreta using data collected prospectively in a large multicenter cohort. Study Design Secondary analysis of women with accreta compared to those without accreta in a large multicenter cesarean delivery cohort. Potential accreta risk factors were examined by univariate and multivariate analyses. Results In this study, 196 of 73,257 (0.27%) cesarean deliveries were complicated by accreta. As expected, women with increasing numbers of prior cesareans were more likely to have an accreta (p < 0.001), as were women with previa (adjusted odds ratio [OR], 34.9; 95% confidence interval [CI], 22.4-54.3). We also considered only patients with previa and examined the following variables: maternal demographics, prior cesareans, interval between deliveries, parity, body mass index, tobacco use, and coexisting hypertension or diabetes. In this model, patients with previa and two or three prior cesarean deliveries had an adjusted OR for accreta of 4.9 (95% CI, 1.7-14.3) or 7.7 (95% CI, 2.4-24.9), respectively. However, no other variables were significantly associated with accreta. Conclusion Patients with previa have increased risk for accreta that increases with the number of prior cesarean deliveries. However, no other maternal characteristics were associated with accreta.

No abstract