RESUMO
Sickle cell disease, despite its recognition as a severely debilitating genetic condition affecting hundreds of thousands of neonates throughout the world each year, was not a target of pharmaceutical research focus for most of its 100-year existence in the medical consciousness. This has changed in recent years as many novel therapeutics are currently under investigation, with three new disease-modifying drugs achieving FDA approval in the last 4 years. One of these drugs, voxelotor, is especially encouraging as an inhibitor of sickling for its ability to safely improve the chronic hemolytic anemia of sickle cell disease. This was demonstrated during all clinical phases of investigation by an average improvement in hemoglobin of greater than 1 g/dL, as well as statistically significant improvements in established markers of hemolysis. While anemia itself represents a potential cause of morbidity, it is more importantly a marker of the hemolysis known to cause the long-term vascular and organ damage that makes sickle cell disease so debilitating and frequently fatal early in life. Given the recency of the approval, there has not been sufficient long-term follow-up to demonstrate improvement in the chronic sequelae of sickle cell disease as a result of voxelotor-induced improvements in hemolytic anemia. There is hope, however, based on the experience with hydroxyurea improving morbidity and mortality via reductions in sickling and improved rheology, that voxelotor may have similar long-term benefits by positively manipulating the kinetics of hemoglobin polymerization. This review aims to summarize the targeted pathobiology of sickle cell disease, the mechanism of action of voxelotor, and the safety and efficacy data from preclinical to late clinical stage investigations of this long-awaited medication, in the hopes of better informing the decision-making process behind prescribing or not prescribing it for patients in need of intervention.
RESUMO
BACKGROUND: Quaternary ammonium compounds are a large class of chemicals used for their antimicrobial and antistatic properties. Two common quaternary ammonium compounds, alkyldimethylbenzyl ammonium chloride (ADBAC) and didecyldimethyl ammonium chloride (DDAC), are combined in common cleaners and disinfectants. Introduction of a cleaner containing ADBAC+DDAC in the vivarium caused neural tube defects (NTDs) in mice and rats. METHODS: To further evaluate this finding, male and female mice were dosed in the feed at 60 or 120 mg/kg/day, or by oral gavage at 7.5, 15, or 30 mg/kg ADBAC+DDAC. Mice also received ambient exposure to ADBAC+DDAC from the disinfectant used in the mouse room. Embryos were evaluated on gestational day 10 for NTDs, and fetuses were evaluated on gestational day 18 for gross and skeletal malformations. RESULTS: We found increased NTDs with exposure to ADBAC+DDAC in both rats and mice. The NTDs persisted for two generations after cessation of exposure. Notably, male exposure alone was sufficient to cause NTDs. Equally significant, ambient exposure from disinfectant use in the vivarium, influenced the levels of NTDs to a greater extent than oral dosing. No gross or significant axial skeletal malformations were observed in late gestation fetuses. Placental abnormalities and late gestation fetal deaths were increased at 120 mg/kg/day, which might explain the lack of malformations observed in late gestation fetuses. CONCLUSION: These results demonstrate that ADBAC+DDAC in combination are teratogenic to rodents. Given the increased use of these disinfectants, further evaluation of their safety in humans and their contribution to health and disease is essential. Birth Defects Research 109:1166-1178, 2017. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.