Cardiac allotransplantation across the ABO-blood group barrier by the neutralization of preformed antibodies: the baboon as a model for the human.

The baboon, like the human, expresses A and/or B blood group antigens on its tissues. Anti-A and anti-B antibodies are directed against these antigens, the epitopes of which are carbohydrate structures. Portions of these carbohydrates have been synthesized (trisaccharides A and B, respectively). When infused intravenously, the synthetic trisaccharides form a complex with the specific antibodies and neutralize their activity preventing them from binding to the antigen targets on a transplanted organ. In nonimmunosuppressed, hyperimmunized baboons, the continuous intravenous infusion of the specific trisaccharide alone (for 6 days) inhibited rejection of ABO-incompatible cardiac allografts, extending survival from a mean of 19 min (n = 3) to 8 days (n = 2), at which time the grafts failed from cellular (not vascular) rejection. The combination of long-term pharmacologic immunosuppression plus trisaccharide infusion (for periods of 8 to 19 days) extended survival to a mean of > 28 days (n = 4) with one heart functioning > 52 days. Accommodation clearly occurred in three of the four cases. This form of therapy may permit cadaveric organ allotransplantation across the ABO blood-group barrier in the human.

Synthesis of potential metabolites of ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-1-propenyl] benzoate.

Potential metabolites of ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-1-propenyl] benzoate were synthesized. The new compounds include ethyl 3-[3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl]crotonate, 3-[3,4-dihydro-4,4-dimethyl-1H-1-benzopyran-6-yl]crotonic acid, 3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-carboxylic acid, 4-[3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl]delta 2-butenolide, ethyl (E)-4-[3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-3-hydroxy-1- propenyl]benzoate, ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-2-propenal] benzoate, and ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-2-propenoic+ ++ acid]benzoate. Stereospecific oxidizing reagents and/or conditions were developed for these sensitive systems and include the use of SeO2, Clorox bleach, activated MnO2, and NaClO2 in the presence of resorcinol as a chlorine scavenger.

Chronic bile duct cannulation in laboratory rats.

To our knowledge this is the first report of rat bile duct cannulations in which the distal cannula is hemisected but extends to the sphincter of Oddi. It is minimally invasive and requires only about 45 minutes preparation time. In contrast to studies described in the literature, enterohepatic recirculation remains intact but bile can always be separated from pancreatic secretions at investigator discretion in the model. In addition, biliary flow and pressure can be measured without compromise. Acute biliary secretory pressure, under anesthesia, was 17 cm water. Bile flow, averaging 9.6 microliters/min/100 g was measured in unanesthetized rats surviving for 2 weeks (60% of animals monitored). Gross necropsy findings indicated that animals dying in less than 7 days usually suffered bile peritonitis subsequent to catheter rupture of the bile duct or loss from the ligature restraint. Deaths after 2 weeks were usually related to cholestasis due to blockage of the catheter with mineral debris and/or duct tissue. A detailed literature review of bile duct cannulation in rats has been made.

Pharmacokinetics and tissue residues in channel catfish, Ictalurus punctatus, given intracardiac and intramuscular injections of gentamicin sulfate.

We studied the rate of absorption, distribution and elimination of gentamicin sulfate in the channel catfish, Ictalurus punctatus. It was determined that the plasma half-life of immunoreactive gentamicin was 12 to 15 hours in the catfish and the rate of elimination from fish after intracardiac and intramuscular (im) routes are not significantly different. Compared to mammals, the very extended half-life is probably the result of a greater unionized fraction of drug in the central compartment and increased reabsorption of drug from the alkaline urine of the fish. Tissue levels at the end of one dose experiments approximate what was predicted based on the intracardiac microconstants. A dosage regimen was established on a 24 hr interval that would keep peak plasma concentration between 10-13 micrograms/ml and allow trough concentrations of 3-4 micrograms/ml. Intramuscular gentamicin appears to have a bioavailability of approximately 37%. Finally, a renal lesion was produced by giving gentamicin im at 10 mg/kg every 33 hr for 6 treatments. The lesion was identical to that described for other mammals and was reversible even while medication was continued.

Experimental cantharidiasis in the horse.

Crystalline cantharidin in an alfalfa cake or in aqueous suspension was given to 8 horses at a dosage level of 450 to 489 micrograms/kg of body weight (group 1) and 2 horses at a dosage level of 720 micrograms/kg (group 2) via nasogastric tube. Both group 2 horses and 1 group 1 horse died. Horses were evaluated at 6-hour intervals for 36 hours and then again at postcantharidin hours 48. Data evaluation consisted of a comparison of the nonsurvival and survival data to one another and their respective base-line values at each sampling period, irrespective of the route of administration and dosage level. Consistent findings in both groups included significant (P less than or equal to 0.05) increases in cardiac rate, respiratory rate, and rectal temperature and decreases in total serum Ca, serum Mg, and K concentrations during at least one 6-hour period. Calcium and Mg concentrations were still significantly (P less than or equal to 0.05) depressed at postcantharidin hours 48, although other electrolytes and physiologic values had returned to base line. Arterial oxygen tension, total protein, serum creatine kinase, arterial CO2, and plasma bicarbonate were depressed in surviving horses during 1 or more periods. The most consistent clinical signs were anorexia and depression; severe gingival and oral mucosal erosions; washing of the muzzle in water; stiff, short-strided gait; and synchronous diaphragmatic flutter. One group 2 horse that died had microscopic histopathologic features compatible with blister beetle intoxication.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of acetazolamide and carbonic anhydrase inhibition on erythrocyte 2,3-diphosphoglycerate content and metabolism.

Experiments were designed to test the hypothesis that the change in erythrocyte 2,3-diphosphoglycerate (2,3-DPG) content which occurs when metabolic acidosis is induced by prolonged inhibition of carbonic anhydrase in vivo is the same as that which occurs with the induction of other types of metabolic acidosis states. 1) Thirteen-hour infusions of nondiuretic doses of a potent carbonic anhydrase inhibitor, acetazolamide (Diamox) did not alter erythrocyte 2,3-DPG levels in rats. 2) In vitro incubation of whole blood from rats for 10 days with high concentrations of two carbonic anhydrase inhibitors failed to alter the red cell content of 2,3-DPG. 3) Purified human carbonic anhydrase B had no phosphatase activity on 2,3-DPG and it appears unlikely that the enzyme hydrolyzes other phosphate esters of the erythrocyte which could indirectly alter 2,3-DPG content. 4) Acetazolamide administered in diuretic doses for 8 days to rats induced a metabolic acidosis which was accompanied by a decrease in erythrocyte 2,3-DPG. The change in 2,3-DPG content was similar to that produced by other methods of producing metabolic acidosis, namely NH4Cl treatment and nephrectomy. It appears that changes in 2,3-DPG content associated with effects of carbonic anhydrase inhibition can be ascribed to the metabolic acidosis resulting from the action of these drugs on the kidney.