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Biomedical subjects

J C McRea

Publications and source records attributed to J C McRea.

14 recordsLinked to original sources
PubMed2001

Biodegradable block copolymers for delivery of proteins and water-insoluble drugs.

Release of several drugs from new ABA-type biodegradable thermal gels, ReGel, including proteins and conventional molecules, are presented. These are biodegradable, biocompatible polymers that demonstrate reverse thermal gelation properties. Organic solvents are not used in the synthesis, purification, or formulation of these polymers. The unique characteristics of ReGel hinge on the following two key properties: (1) ReGel is a water soluble, biodegradable polymer at temperatures below the gel transition temperature; (2) ReGel forms a water-insoluble gel once injected. This is consistent with a hydrophobically bonded gel state where all interactions are physical, with no covalent crosslinking. An increase in viscosity of approximately 4 orders of magnitude accompanies the sol--gel transition. The gel forms a controlled release drug depot with delivery times ranging from 1 to 6 weeks. ReGel's inherent ability to solubilize (400 to >2000-fold) and stabilize poorly soluble and sensitive drugs, including proteins is a substantial benefit. The gel provided excellent control of the release of paclitaxel for approximately 50 days. Direct intratumoral injection of ReGel/paclitaxel (OncoGel) results in a slow clearance of paclitaxel from the injection site with minimal distribution into any organ. Efficacies equivalent to maximum tolerated systemic dosing were observed at OncoGel doses that were 10-fold lower. Data on protein release (pGH, G-CSF, insulin, rHbsAg) and polymer biocompatibility are discussed.

Drug Delivery Systems↗
PubMed1985

Heparinized polyurethanes: in vitro and in vivo studies.

Heparin immobilization chemistry using alkyl spacer arms was adapted to optimize yield on polyurethane (PU) surfaces. The resultant biological activity of immobilized heparin (HI) was examined in vitro and in vivo, and compared with a heparin releasing (HR) system. Immobilized heparin retained its ability to bind and inactivate thrombin and Factor Xa; nonspecific coagulation factor binding was insignificant. Such activity cannot be attributed to the leakage of improperly bound heparin. Immobilized heparin-polyurethane catheters implanted in canine femoral and jugular veins for 1 h periods exhibited significant reduction in thrombus formation compared with untreated PU contralateral controls. Polyurethane catheters coated with a 9% heparin dispersion in PU (HR) system provided even greater improvement in antithrombogenicity.

Animals↗
PubMed1981

Prostaglandin releasing polymers - stability and efficacy.

In summary, PGI2 is approximately 3 orders of magnitude more potent than PGE1 in the prevention of platelet aggregation. Similarly PGE1 is an order of magnitude more potent than PGD2 (ID50's = 5.3 x 10(-10) M, 1.3 x 10(-7) M and 1.4 x 10(-6) M for PGI2, PGE1 and PGD2 respectively). Results from biological and infrared stability studies demonstrate that both PGI2 and PGE1 are stable for extended periods of time when dispersed within hydrophobic polymer matrices, an important consideration in the design of nonthrombogenic, prostaglandin controlled release polymers. Finally, both PGE1 and PGI2 controlled release polymers inhibit platelet aggregation in contacting blood, of which PGE1 produced greater platelet aggregation inhibition (90% inhibition) than did PGI2 (75% inhibition). However, PGE1 controlled release polymers significantly reduced platelet adhesion (11.25 +/- 3.68 platelets/mm2) compared to control polymers (50.65 +/- 8.8 platelets/mm2) while PGI2 controlled release polymers demonstrated no improvement in platelet adhesion (25.00 +/- 18.61 platelets/mm2) relative to control polymers (30.43 +/- 7.62 platelets/mm2). One cannot conclude that the lack of reduced platelet adhesion on the PGI2 controlled release surfaces is due to the instability of PGI2. The fact that significant inhibition of platelet aggregation in both blood fractions which contacted the PGI2 controlled release surfaces occurred substantiates that the released PGI2 was active. It must be concluded that PGI2 does not affect platelet adhesion. It is interesting to note that less platelets adhered to the PGI2 control PVC surfaces than on the PGE1 control PVC surfaces. The PGI2 control PVC surfaces were equilibrated with a TRIZMA buffer in 5% dextrose (to provide isotonicity) while the PGE1 control PVC surfaces were equilibrated in isotonic phosphate buffer saline.

Alprostadil↗
PubMed1980

Recovery of cardiac function with total transapical left ventricular bypass.

Transapical left ventricular bypass which withdraws blood directly from the left ventricular apex through a roller pump and outflow filter with return to the femoral artery has been applied in 6 patients with cardiac failure. All patients required total TALVB (with the aortic valve closed) for periods of one to 144 hrs, and 2 patients had recovery of life-sustaining myocardial function, allowing removal of the TALVB system. One patient had complete recovery without other organ dysfunction. Total TALVB continuously decompresses and unloads the left ventricle throughout systole and diastole, and maintains the circulation in otherwise terminal circumstances.

Adult↗
PubMed1978

Transapical left ventricular bypass: a method for partial or total circulatory support.

A simple cannula method of partial or total left ventricular bypass, utilizing a roller pump and outflow filter, has been developed and applied clinically. One of three patients with severe cardiac and multisystem failure was pumped with total left ventricular bypass for six days and decannulated with recovery of myocardial function after nine days. These results are encouraging and suggest that a number of patients could be salvaged from temporary cardiac failure with a simple cannula-roller-pump bypass system.

Adult↗
PubMed1978

Prolonged, transapical left ventricular bypass (TALVB) in sheep and man.

Transapical left ventricular bypass has been demonstrated in normal sheep and one lamb. Recently, TALVB was applied in 3 clinical cases of cardiac failure, with recovery of myocardial function in one patient after 9 days of bypass (6 days total TALVB). These studies suggest that LV apical cannula-roller pump bypass with low dose heparin anticoagulation and secondary surgery to remove the cannula may salvage some patients now dying of temporary cardiac failure.

Adult↗
PubMed1976

Transapical left ventricular bypass (TALVB) without an auxiliary ventricle.

A simple transapical left ventricular bypass system employing a roller pump, transapical LV withdrawal catheter, and outflow filter for continuous blood filtration, has been developed and evaluated in unanesthetized sheep for periods beyond 2 wks. The system provides continuous partial LV bypass and is capable of totally maintaining the circulation in the presence of a vasodilator or when total bypass is desired. Blood damage is minimal and blood transfusions have not been required. The transapical withdrawal catheter has been left in the LV apex beyond 4 mos and demonstrates thrombus formation and myocardial histological changes which suggest this catheter should be removed after pumping or long-term anticoagulation provided.

Animals↗
PubMedDate not supplied

Reversal of anticoagulation without protamine using a heparin removal device after cardiopulmonary bypass.

Protamine sulfate is routinely administered after cardiopulmonary bypass to reverse systemic heparinization, but may cause a severe hypotensive reaction in as many as 2% of patients. Research Medical, Inc., has developed an extracorporeal venovenous heparin removal device (HRD) for use in patients at high risk for a protamine reaction. Circulation through the HRD removes heparin by hollow fiber plasma separation and selective sorption of anionically charged heparin to a polycationically charged poly-L-lysine ligand coupled to a agarose substrate. The heparin depleted plasma then reenters the whole blood pathway and is returned to the patient through the double lumen catheter in the right atrium. To evaluate the HRD in a clinically relevant model, cardiopulmonary bypass was performed in pigs using RA-Ao cardiopulmonary bypass (120 min) with systemic heparinization (300 IU/kg), a nonpulsatile pump with a membrane oxygenator, and systemic hypothermia (28 degrees C). Group 1 (HEP n = 7) had no intervention to neutralize the heparin; Group 2 (HRD n = 7) used the HRD. After 19.7 +/- 4.2 min of circulation through the HRD, the activated clotting time had returned to baseline, whereas the pigs in the HEP group were still anticoagulated (activated clotting time = 396 +/- 152 sec; time to baseline was 124 +/- 9 min). There were no significant differences between groups with respect to hemodynamics, hematocrit levels, leukocyte profiles, or platelet counts, HRD is an effective heparin removal device in a pig model of cardiopulmonary bypass and awaits a phase I clinical trial in humans.

Animals↗
PubMedDate not supplied

Heparin clearance profiles after systemic anticoagulation using a heparin removal device system.

An extracorporeal heparin removal device system (HRDS) based on plasma separation and affinity adsorption has been developed to reduce the risks of protamine-related adverse reactions. The heparin clearance profile of the HRDS was characterized by the first-order exponential depletion. A mathematical model was established to predict the time to achieve 85% heparin removal for different body weights at 700 ml/min and 1400 ml/min extracorporeal HRDS blood flow. With an HRDS flow of 700 ml, 85% of total body heparin removal cannot be achieved within 30 min for subjects greater than 50 kg. With an HRDS flow of 1400 ml/min, 85% heparin removal can be achieved within 32 min for subjects larger than 90 kg. Such model predictions were validated in an adult swine (n = 10) model of 60-min, hypothermic (28 degrees C) cardiopulmonary bypass (CPB). Animals were given 300 U/kg intravenous heparin and 5000 U heparin in the circuit prime for initial heparinization, with subsequent heparin given to maintain activated clotting time above 450 sec. Immediately following CPB, plasma heparin concentration as determined by anti-factor Xa assays was 4.40 +/- 1.08 U/ml in the 700 ml/min group and 4.78 +/- 0.70 U/ml in the 1400 ml/min groups, respectively (p > 0.05). Target HRDS flow was 700 ml/min for animals below 75 kg and 1400 ml/min for animals above 75 kg. The mean body weight in the 1400 ml/min group (81.4 +/- 3.7 kg) was significantly higher than that in the 700 ml/min group (67.2 +/- 2.2 kg) (p < 0.05), with the actually achieved HRDS flow 658.5 +/- 20.8 and 1437.4 +/- 30.1 ml/min, respectively. During the HRDS run, plasma heparin concentration followed the predicted first-order exponential depletion (r2 = 0.97 for the 700 ml/min group and r2 = 0.99 for the 1400 ml/min group). In the 700 ml/min group, the time needed to achieve 85% heparin clearance was over 40 min, whereas in the 1400 ml/min group, this time was reduced to less than 30 min despite greater body weight. At 30 min on HRDS, the 700 ml/min group had 27.4 +/- 3.7% heparin left in the plasma, whereas the 1400 ml/min group had only 12.6 +/- 2.5% (p < 0.05). The authors conclude heparin clearance by the HRDS can be precisely predicted with the mathematical model of first-order exponential depletion. Increasing the HRDS flow can effectively reduce the time needed to achieve a targeted heparin removal.

Animals↗
PubMedDate not supplied

Lack of CNS depression from large doses of trimethaphan in sheep.

It is not uncommon to observe prolonged CNS depression for several hours following controlled hypotension and halothane anesthesia for neurosurgery. The present study evaluates possible contribution of large doses of trimethaphan to CNS depression. Four adult sheep were placed on transapical left ventricular bypass (TALVB) withdrawing blood from the apex of the left ventricle through a roller pump, Pall Ultipor filter, and returning the blood to a carotid artery. In the awake and unanesthetized animals, 1 to 2 gm of trimethaphan were administered IV during each experiment while maintaining mean arterial pressure at 60 to 75 torr. Two sheep stood up and knelt down without obvious correlation with dose of trimethaphan administered at the time; two remained standing and continued eating during the trimethaphan infusion. Cardiovascular recovery from these large doses of trimethaphan was within 15 to 30 minutes after the conclusion of drug infusion. The data strongly suggest that large doses of trimethaphan have no significant CNS depression in the awake and unanesthetized sheep.

Animals↗