Detection of inflamed atherosclerotic lesions with diadenosine-5′,5‴-P1,P4-tetraphosphate (Ap4A) and positron-emission tomography

Diadenosine-5′,5-P¹,P⁴-tetraphosphate (Ap₄A) and its analog P²,P³-monochloromethylene diadenosine-5′,5-P¹,P⁴-tetraphosphate (AppCHClppA) are competitive inhibitors of adenosine diphosphate-induced platelet aggregation, which plays a central role in arterial thrombosis and plaque formation. In this study, we evaluate the imaging capabilities of positron-emission tomography (PET) with P²,P³-[¹⁸F]monofluoromethylene diadenosine-5′,5-P¹,P⁴-tetraphosphate ([¹⁸F]AppCHFppA) to detect atherosclerotic lesions in male New Zealand White rabbits. Three to six months after balloon injury to the aorta, the rabbits were injected with [¹⁸F]AppCHFppA, and microPET imaging showed rapid accumulation of this radiopharmaceutical in the atherosclerotic abdominal aorta, with lesions clearly visible 30 min after injection. Computed tomographic images were coregistered with PET images to improve delineation of aortoiliac tracer activity. Plaque macrophage density, quantified by immunostaining with RAM11 against rabbit macrophages, correlated with PET measurements of [¹⁸F]AppCHFppA uptake (r = 0.87, P < 0.0001), whereas smooth-muscle cell density, quantified by immunostaining with 1A4 against smooth muscle actin, did not. Biodistribution studies of [¹⁸F]AppCHFppA in normal rats indicated typical adenosine dinucleotide behavior with insignificant myocardial uptake and fast kidney clearance. The accumulation of [¹⁸F]AppCHFppA in macrophage-rich atherosclerotic plaques can be quantified noninvasively with PET. Hence, [¹⁸F]AppCHFppA holds promise for the noninvasive characterization of vascular inflammation.     

Molecular PET and CT Imaging of Inflammation and Metabolism in Atherosclerosis

The molecular and biological processes that take place in atherosclerotic plaque play an important role in determining the pathologic progression of the plaque. Current imaging techniques primarily inform about plaque structure and thus fail to assess the functional aspects of atherosclerosis. Accordingly, imaging of plaque biology might provide important incremental information about the underlying disease process. An emerging body of work shows that molecular imaging with fluorodeoxyglucose—positron emission tomography (PET) can provide information about plaque biology. This review provides an overview of the development of vascular PET imaging, with an evaluation of current and potential future uses of this imaging modality.     

Myocardial flow regulation in people with mitochondrial myopathy,encephalopathy, lactic acidosis,stroke-like episodes/myoclonic epilepsy and ragged red fibers and other mitochondrial syndromes

OBJECTIVE: This study tests the hypothesis that elevated levels of rest myocardial blood flow (MBF), indicative of inefficient aerobic metabolism, will be present in some patients with mitochondrial disorders but structurally normal hearts. BACKGROUND: Regulation of MBF is a complex process closely linked to myocardial energy production. Aerobic metabolism in turn depends on normal mitochondrial function and so investigation of patients with mitochondrial disorders may provide important information regarding heritable mechanisms involved in regulation of myocardial flow. METHODS: Rest and adenosine-stimulated MBF was measured by the positron emission tomography (PET) 13NH(3) technique in nine patients with mitochondrial disorders and compared with 15 age-matched control participants. RESULTS: Basal heart rate (beats/min) and rate pressure product (mm Hg/min) were elevated in patients (76+/-13 and 9302+/-1910, mean+/-SD, respectively) compared with control participants (63+/-9 and 7411+/-1531, P<0.01 and P<0.05, respectively). However, rest and adenosine-stimulated MBF (ml/min per g) did not differ significantly between groups (patients, 1.13+/-0.52 and 4.17+/-0.84, respectively; control participants, 0.85+/-0.30 and 3.56+/-0.63, respectively). Normalization of rest MBF to rate pressure product, however, demonstrated three patients whose values exceeded that of all control participants (chi2=5.71, P<0.05, Fisher's exact test). CONCLUSIONS: Elevated basal MBF, in some patients with mitochondrial disorders but structurally normal hearts, suggests the level of basal flow is responsive to efficiency of aerobic metabolism, which closely reflects mitochondrial function. Mitochondrial heteroplasmy with relative sparing of myocardial mitochondria may account for normal basal flow in others with these disorders.     

Population Analysis of the Pharmacokinetics of Tiagabine in Patients with Epilepsy

Summary: Purpose: In two open-label long-term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy.
Methods: In all, 2,147 plasma samples from 511 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one-compartment model with first-order absorption and elimination was used to fit the TGB plasma concentration-time data, with a population pharmacokinetic approach.
Results: The patients'average (±SD) weight and age were 73.8 ± 20.7 kg and 32.1 ± 12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 L/h, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (12.8 L/h). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates.
Conclusions: TGB pharmacokinetics are linear, influenced by enzyme-inducing AEDs, and largely unaffected by other demographic variables.     

Experimental evaluation of perfluorophenanthrene as a high specific gravity vitreous substitute: a preliminary report

Perfluorophenanthrene, a liquid fluorocarbon with a specific gravity approximately twice that of water, potentially offers certain advantages as a vitreous substitute in vitreoretinal surgery. To determine its efficacy and safety we first purified it by chemical methods used in the preparation of experimental blood substitutes to a level at which it was not at all or only minimally toxic to culture-grown retinoblastoma cells. Nineteen of 22 vitrectomized eyes of white New Zealand rabbits injected with this purified perfluorophenanthrene showed satisfactory clinical tolerance. Light and electron microscopy showed minimal or no toxic effects in the 19 eyes, although uptake of perfluorophenanthrene by some preretinal cells was observed 28 days after implantation. Postoperative light-adapted electroretinography recordings of eight of the injected eyes showed no significant change. Perfluorophenanthrene injected into the anterior chamber of the rabbit eyes had toxic effects on the cornea. If further experimentations confirm our findings, perfluorophenanthrene may be a suitable transparent high-density liquid for temporary use in surgery to repair retinal detachments.