Delayed administration of a potent cyclin dependent kinase and glycogen synthase kinase 3 beta inhibitor produces long-term neuroprotection in a hypoxia-ischemia model of brain injury.

We compared the neuroprotective efficacy of a potent and CNS-penetrant cyclin dependent kinase (CDK) and glycogen synthase kinase 3 beta (GSK3beta) inhibitor (Compound 1) in juvenile (postnatal day 21; P21) and adult C57Bl/6 mice (postnatal day 60; P60) using a model of hypoxic-ischemic brain injury (HI). Neuronal cell counts and density measures from brain sections stained with Cresyl Violet revealed that exposure of P21 mice to 60 min of HI resulted in extensive damage to the ipsilateral cornu ammonis 1 (CA1) region of the hippocampus (40% cell loss) and striatum (30% cell loss) 7 days later. Exposure of P60 mice to 40 min of HI produced a similar pattern of cell loss. Intraperitoneal administration of Compound 1 (3 mg/kg) 1, 5 and 9 h after 60 min of HI did not reduce brain injury in P21 mice relative to vehicle controls. By contrast, in P60 mice, this treatment significantly decreased cell loss in the ipsilateral hippocampus (10% cell loss) and striatum (15% loss) relative to vehicle controls. Terminal uridine deoxynucleotidyl transferase (TUNNEL) positive cell counts and infarct volume were also substantially reduced in P60 mice treated with Compound 1. A motor coordination test performed twice weekly until 5 weeks post-HI confirmed that Compound 1 produced long lasting functional recovery. Our results indicate that Compound 1 produced long lasting neuroprotective effects in adult but not juvenile mice suggesting that inhibition of the CDKs and GSK3beta plays a distinct neuroprotective role in the juvenile and adult brain.

Pharmacokinetic studies in pregnant women.

Prescription and over-the-counter drug use during pregnancy is necessary for many women today. A study of US and Canadian women found that, on average, 2.3 drugs were used during pregnancy; however, 28% reported using more than 4. For some women, this is because they become pregnant with preexisting conditions that require ongoing or intermittent pharmacotherapy. For others, this is because pregnancy itself can give rise to new medical conditions such as gestational diabetes and preeclampsia. The principal concern of prescribing physicians is whether or not agents will harm the fetus (i.e., have teratogenic effects). This concern rose to prominence primarily as a result of the thalidomide disaster. Marketed for use in morning sickness, thalidomide was found to be a potent teratogen capable of producing a variety of birth defects relating to development. Consequently, determining the teratogenicity of new drugs currently dominates the objectives of pregnancy-relevant experiments conducted throughout drug development. This often comes at the expense of valuable pharmacokinetic (PK) studies, which are seldom performed pre-market. Sex differences in PK parameters have been demonstrated in animals and humans since the 1930s. It is, therefore, not surprising that differences also arise in pregnancy. A wide array of physiological and hormonal changes occur during pregnancy; most begin early in the first trimester and increase linearly until parturition. Physicians lacking adequate PK information typically prescribe the standard adult dose in pregnancy, and this can be either inadequate or excessive depending on a variety of factors. The purpose of this report is to highlight this issue and illustrate how current methods used to obtain PK data in pregnancy are insufficient. The steps that are being taken to address this issue will also be discussed.