Effect of occipitoatlantal decompression on cerebral blood flow dynamics as evaluated by Doppler ultrasonography.

Context: Osteopathic manipulative treatment reduces symptoms in patients with headache disorders, but the underlying mechanisms are unclear. Objective: To evaluate blood flow in the intracranial and extracranial vasculature before and after occipitoatlantal decompression (OAD) using Doppler ultrasonography. Methods: Healthy, first-year osteopathic medical students from A.T. Still University's Kirksville College of Osteopathic Medicine participated in a randomized, single-blinded, two-period, two-treatment crossover study. The participants were randomly assigned to 1 of 2 treatment interventions: OAD or sham touch. After one week, participants returned to have the other intervention performed. Blood flow parameters-peak systolic velocity (PSV) and end-diastolic velocity (EDV)-in the middle cerebral artery (MCA), internal carotid artery (ICA), and vertebral artery (VA) were evaluated before, immediately after, 5 minutes after, and 10 minutes after treatment. Differences in PSV, EDV, heart rate (HR), and blood pressure (BP) for both interventions were analyzed for the four time points using mixed-effects models. Results: Thirty healthy medical students (11 men, 19 women; mean age, 24 years) participated in this study. EDV increased after OAD in the MCA, ICA, and VA (all p<0.001); no change occurred after sham touch (all p>0.05). EDV was greater for all post-treatment timepoints after OAD in the MCA, ICA, and VA than after sham touch (all p<0.001). Although baseline PSV in the MCA measured before treatment was different between treatment interventions (p=0.01), no difference was found between interventions at any post-treatment time point (all p>0.59). Changes in PSV in the ICA and VA and for HR and BP did not depend on treatment intervention (p>0.06). Conclusion: Increases in EDV occurred in major cranial arteries after OAD but not after sham touch, indicating that OAD improves blood flow to the brain. The exact mechanism of this increase is unknown; however, it can be explained by either parasympathetic stimulation through the secretion of vasodilating neurotransmitters or by a decrease in external tissue pressure on ICA and VA, with the resulting flow causing further dilation in the MCA.

Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies.

A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.