Is repeat head CT necessary in patients with mild traumatic intracranial hemorrhage

BackgroundPatients with traumatic intracranial hemorrhage (TIH) frequently receive repeat head CT scans (RHCT) to assess for progression of TIH. The utility of this practice has been brought into question, with some studies suggesting that in the absence of progressive neurologic symptoms, the RHCT does not lead to clinical interventions.MethodsThis was a retrospective review of consecutive patients with CT-documented TIH and GCS ≥ 13 presenting to an academic emergency department from 2009 to 2013. Demographic, historical, and physical exam variables, number of CT scans during admission were collected with primary outcomes of: neurological decline, worsening findings on repeat CT scan, and the need for neurosurgical intervention.ResultsOf these 1126 patients with mild traumatic intracranial hemorrhage, 975 had RHCT. Of these, 54 (5.5% (4.2–7.2 95 CI) had neurological decline, 73 (7.5% 5.9–9.3 95 CI) had hemorrhage progression on repeat CT scan, and 58 (5.9% 4.5–7.6 95 CI) required neurosurgical intervention. Only 3 patients (0.3% 0.1–0.9% 95 CI) underwent neurosurgical intervention due to hemorrhage progression on repeat CT scan without neurological decline. In this scenario, the number of RHCT scans needed to be performed to identify this one patient is 305.ConclusionsRHCT after initial findings of TIH and GCS ≥ 13 leading to a change to operative management in the absence of neurologic progression is a rare event. A protocol that includes selective RHCT including larger subdural hematomas or patients with coagulopathy (vitamin K inhibitors and anti-platelet agents) may be a topic for further study.     

Response of reperfusion-salvaged, stunned myocardium to inotropic stimulation

The purpose of this study was to determine whether myocardium salvaged by reperfusion following coronary occlusion could respond to inotropic stimulation by dopamine. Mongrel dogs underwent a 2-hour occlusion of the proximal left anterior descending coronary artery, followed by reperfusion for 5 or 28 hours. Dopamine (5 to 10 micrograms/kg/min) or dextrose was administered 1 hour or 24 hours after the onset of reperfusion. Serial, computer-assisted, two-dimensional echocardiographic determination of percentage of systolic wall thickening (%SWT) and cross-sectional ejection fraction (% delta area) were used to evaluate the response to treatment. Myocardium in the region of central ischemia contracted poorly after 1 hour of reperfusion (mean %SWT = 1.3 +/- 13.3% [mean +/- SD] compared to preocclusion value of 43.6 +/- 18.5%, p less than 0.001) and tended to thin at 24 hours of reperfusion (mean %SWT = -6.0 +/- 12.3%, p less than 0.001). After 1 hour of reperfusion, dopamine produced a greater than fourfold improvement in %SWT within the reperfused zone (to 15.3 +/- 7.3%, p less than 0.05). After 24 hours of reperfusion, dopamine again produced an improvement in %SWT (to 5.8 +/- 12.5%, p less than 0.05). There were no significant changes in %SWT with dextrose infusion. Thus, dopamine stimulates the reperfusion-salvaged but noncontracting (stunned) myocardium to contract as early as 1 hour after reperfusion.     

Preclinical pharmacokinetics of TPN729MA,a novel PDE5 inhibitor,and prediction of its human pharmacokinetics using a PBPK model

Aim:

TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model.

Methods:

The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance (CL) values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg.

Results:

After a single intravenous administration of TPN729MA at a dose of 1 mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL·min⁻¹·kg⁻¹ in rats and 26.3 mL·min⁻¹·kg⁻¹ in dogs, and the steady-state volumes of distribution (V_ss) were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 mg, and the predicted T_max, C_max and AUC values were within 2-fold of the observed values.

Conclusion:

TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans.