Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics

Beneficial Effects of a Q-ter® Based Nutritional Mixture on Functional Performance, Mitochondrial Function, and Oxidative Stress in Rats

Mitochondrial dysfunction and oxidative stress are central mechanisms underlying the aging process and the pathogenesis of many age-related diseases. Selected antioxidants and specific combinations of nutritional compounds could target many biochemical pathways that affect both oxidative stress and mitochondrial function and, thereby, preserve or enhance physical performance. supplementation in rats at 29 months of age. supplementation may be particularly beneficial when initiated prior to major biological and functional declines that appear to occur with advancing age

Synthesis and antimalarial activities of novel 3,3,6,6-tetraalkyl-1,2,4,5-tetraoxanes

International audienc

Where schizophrenic patients commit suicide: A review of suicide among inpatients and former inpatients

OBJECTIVE: To review the literature on suicide of inpatients with schizophrenia, to identify suicide risk factors as well as typical patterns of behavior and to suggest a rationale and strategies for future interventions. METHOD: A computerized MedLine, Excerpta Medica and PsycLit search supplemented by an examination of cross-references and reviews. RESULTS: Up to half the suicides among patients with schizophrenia occur during inpatient admission. Inpatient suicides were found among those of a young age group who were predominantly single, childless and socially isolated. The vast majority experienced an illness characterized by long duration and prolonged psychiatric hospitalizations or multiple admissions and discharges. Up to 50% of the suicides occurred in the first few weeks and months following discharge from the hospital. The paranoid subtype of schizophrenia, where positive symptoms prevail and negative symptoms are few, is associated with a suicide risk that is three times greater than that associated with nonparanoid subtypes and eight times greater than the risk associated with the deficit subtype. CONCLUSIONS: Treatment of suicide is a major problem among inpatients with schizophrenia. Evidence suggests that suicide is generally carried-out by patients who have been recently discharged or by those who manage to get away from the hospital. Strategies aimed at preventing this phenomenon have been introduced to the medical personnel, but suicide in these patients does not seem to have been reduced. We emphasize the need to establish guidelines for the prevention of suicide in hospitalized patients with schizophrenia. PMID: 16240974 [PubMed - indexed for MEDLINE