Boundary layer drug delivery using a helical catheter

BACKGROUND: A catheter-based approach for local endovascular drug delivery has been developed. The catheter is deployed percutaneously, while the end of the catheter is in the form of a helix that is placed just proximal to the vascular site to be treated. The helices are in contact with the vessel wall. A number of small holes is drilled in the coils of the catheter through which drug is infused, so that the infused drug remains within the blood fluid 'boundary layer' adjacent to the vessel wall. This approach is expected to be highly efficient for administration of antithrombotic and antiproliferative agents that target processes leading to vascular occlusion, heart attacks, and strokes. METHODS: The helical catheter was qualitatively evaluated using optical dye density measurements of Evans blue dye infused using an in vitro steady flow system under a physiologic range of conditions. To further demonstrate the efficiency of the technique, its capacity to inhibit thrombosis was evaluated in a baboon thrombosis model. The catheter was inserted into a femoral arteriovenous shunt (blood flow rate = 100 ml/min) and placed proximal to a segment of highly thrombogenic Dacron vascular graft (4.0 mm i.d.). Integrelin (an inhibitor of platelet glycoprotein IIb/IIIa; doses: 0.25-1.0 microg/min) and hirudin (an antithrombin; doses: 10-100 microg/min) were used to inhibit thrombus formation. RESULTS: Experimental flow visualization studies demonstrated that high concentrations of the infused Evans blue dye were retained near the vessel wall. In the animal experiments, platelet deposition on the Dacron graft surface was reduced by 82-97% (Integrelin) and 68-92% (hirudin) over 1-2 h of blood exposure. The local antithrombotic effects produced were found to be 200-fold and 30-fold more efficient than systemic administration of the same agents. CONCLUSIONS: Local drug infusion using the helical catheter approach can achieve high drug concentration levels at target sites, may avoid systemic effects, and can reduce cost of therapy by reducing total drug requirements.     

Circulating soluble adhesion molecules E-cadherin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in patients with gastric cancer

The concentrations of the soluble adhesion molecules E-cadherin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were investigated in 45 patients with gastric cancer before treatment and their correlation with clinical, histological and routine laboratory parameters was examined. Data were collected on tumour stage at presentation, presence and sites of metastatic disease, tumour pathology, survival and results of routine laboratory tests. Serum concentrations of ICAM-1 and VCAM-1 were significantly elevated in the patients with gastric cancer in comparison with the group of healthy subjects (P < 0.00001 and P < 0.0001 respectively). Increased serum concentrations of VCAM-1 were associated with locally advanced and metastatic disease whereas ICAM-1 was significantly elevated both in local and in advanced/metastatic disease. Soluble E-cadherin and E-selectin concentrations did not show any significant elevation in gastric cancer patients. Concentrations of soluble adhesion molecules showed significant correlation with each other (except E-selectin and VCAM-1) and with alkaline phosphatase. Soluble ICAM-1 and VCAM-1 were significantly associated with an elevated total white cell count. Patients with elevated VCAM-1 had significantly poorer survival in comparison with patients with normal serum levels (P = 0.0361).     

Intestine-Specific, Oral Delivery of Captopril/Montmorillonite: Formulation and Release Kinetics

The intercalation of captopril (CP) into the interlayers of montmorillonite (MMT) affords an intestine-selective drug delivery system that has a captopril-loading capacity of up to ca. 14 %w/w and which exhibits near-zero-order release kinetics.     

CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation

The activity of cyclin-dependent kinase 2 (CDK2) is essential for progression of cells from G1 to the S phase of the mammalian cell cycle. CVT-313 is a potent CDK2 inhibitor, which was identified from a purine analog library with an IC50 of 0.5 microM in vitro. Inhibition was competitive with respect to ATP (Ki = 95 nM), and selective CVT-313 had no effect on other, nonrelated ATP-dependent serine/threonine kinases. When added to CDK1 or CDK4, a 8.5- and 430-fold higher concentration of CVT-313 was required for half-maximal inhibition of the enzyme activity. In cells exposed to CVT-313, hyperphosphorylation of the retinoblastoma gene product was inhibited, and progression through the cell cycle was arrested at the G1/S boundary. The growth of mouse, rat, and human cells in culture was also inhibited by CVT-313 with the IC50 for growth arrest ranging from 1.25 to 20 microM. To evaluate the effects of CVT-313 in vivo, we tested this agent in a rat carotid artery model of restenosis. A brief intraluminal exposure of CVT-313 to a denuded rat carotid artery resulted in more than 80% inhibition of neointima formation. These observations suggest that CVT-313 is a promising candidate for evaluation in other disease models related to aberrant cell proliferation.     

Antithrombotic potency of hirudin is increased in nonhuman primates by fibrin targeting

BACKGROUND: Inhibition of thrombin by either the indirect thrombin inhibitor heparin or by more potent direct thrombin inhibitors such as hirudin reduces thrombus formation after arterial injury. The present study was designed to determine if a fibrin-specific thrombin inhibitor could, by local thrombin inhibition, prevent thrombosis more effectively. METHODS AND RESULTS: We first studied antithrombotic potency in vitro, comparing fibrin-targeted hirudin (recombinant hirudin covalently linked to the Fab' fragment of the anti-fibrin monoclonal antibody 59D8) to recombinant hirudin in baboon plasma. Fibrin-targeted hirudin was nine times more effective than recombinant hirudin in inhibiting fibrin deposition on experimental clot surfaces in baboon plasma (P < .01). The potency of fibrin-targeted hirudin was then compared with that of recombinant hirudin in a baboon model of thrombus formation. 111In-labeled platelet deposition was measured in a synthetic graft segment of an extracorporeal arteriovenous shunt in control animals and in animals receiving either fibrin-targeted hirudin or hirudin. In these experiments, fibrin-targeted hirudin was 10-fold more potent than hirudin in inhibiting platelet deposition and thrombus formation (P < .05). CONCLUSIONS: These data indicate that targeting a thrombin inhibitors such as hirudin to an epitope present in thrombi results in increased antithrombotic potency.     

Measurement of T1 and T2 relaxation times of the pancreas at 7 T using a multi-transmit system

Objective

To determine T₁ and T₂ relaxation times of healthy pancreas parenchyma at 7 T using a multi-transmit system.

Materials and methods

Twenty-six healthy subjects were scanned with a 7 T MR system using eight parallel transceiver antennas, each with two additional receive loops. A Look-Locker sequence was used to obtain images for T₁ determination, while T₂ was obtained from spin-echo images and magnetic resonance spectroscopy measurements with different echo times. T₁ and T₂ times were calculated using a mono-exponential fit of the average magnitude signal from a region of interest in the pancreas and were tested for correlation with age.

Results

The age range of the included subjects was 21–72 years. Average T₁ and T₂ relaxation times in healthy pancreas were 896 ± 149 ms, and 26.7 ± 5.3 ms, respectively. No correlation with age was found.

Conclusion

T₁ and T₂ relaxation times of the healthy pancreas were reported for 7 T, which can be used for image acquisition optimization. No significant correlations were found between age and T₁ or T₂ relaxation times of the pancreas. Considering their low standard deviation and no observable age dependence, these values may be used as a baseline to study potentially pancreatic tissue affected by disease.

     

Tackling SNR at low-field: a review of hardware approaches for point-of-care systems

Objective

To review the major hardware components of low-field point-of-care MRI systems which affect the overall sensitivity.

Methods

Designs for the following components are reviewed and analyzed: magnet, RF coils, transmit/receive switches, preamplifiers, data acquisition system, and methods for grounding and mitigating electromagnetic interference.

Results

High homogeneity magnets can be produced in a variety of different designs including C- and H-shaped as well as Halbach arrays. Using Litz wire for RF coil designs enables unloaded Q values of ~ 400 to be reached, with body loss representing about 35% of the total system resistance. There are a number of different schemes to tackle issues arising from the low coil bandwidth with respect to the imaging bandwidth. Finally, the effects of good RF shielding, proper electrical grounding, and effective electromagnetic interference reduction can lead to substantial increases in image signal-to-noise ratio.

Discussion

There are many different magnet and RF coil designs in the literature, and to enable meaningful comparisons and optimizations to be performed it would be very helpful to determine a standardized set of sensitivity measures, irrespective of design.

     

23Na microscopy of the mouse heart in vivo using density-weighted chemical shift imaging

The mouse has become an important animal model for human cardiac disease, and the development of techniques for non-invasive imaging of the mouse heart in vivo is, therefore, of great potential interest. Previous magnetic resonance imaging studies have concentrated on pathologically induced changes in cardiac structure and dynamics by acquiring proton images. Further information can be gained by studying cardiac function and physiology using other nuclei, for example, sodium. Sodium imaging of such a small structure presents considerable technical challenges. In this work we show the first sodium images of the mouse heart, with an isotropic spatial resolution of 1 × 1 × 1 mm, acquired in a time of 1.5 h. The ventricles, septum and myocardium are readily distinguishable in these images, which were acquired through the combination of 3D density-weighted chemical shift imaging, optimized instrumentation, and a high magnetic field strength (17.6 T). Measurements of the myocardial:blood sodium concentration in the left and right ventricles agree well with theoretical values.     

Feasibility of pseudocontinuous arterial spin labeling at 7?T with whole-brain coverage

Object  

We studied the feasibility of pseudocontinuous arterial spin labeling (pCASL) at 7 T.