Pravastatin sodium (pravastatin) is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and was found to be highly effective in animals and humans, in lowering the plasma cholesterol level by inhibiting cholesterol synthesis selectively in the liver. In the present study the disposition and metabolism of pravastatin was studied in rats, dogs and monkeys using [14C]-labelled compound. The extent of absorption was approximately 70% in rats and 50% in dogs. Tissue distribution examined by both whole-body autoradiography and radioactivity measurement demonstrated that the drug was selectively taken up by the liver, a target organ of the drug, and excreted via bile mainly in unchanged form. Since pravastatin excreted by the bile was reabsorbed, the enterohepatic circulation maintained the presence of unchanged pravastatin in the target organ. The profiles of metabolites were studied in various tissues and excreta and a metabolic pathway of pravastatin was proposed.

Animals↗

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Pavlov and genetics.

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Conditioning, Classical↗

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Does a porcine hepatocyte hybrid artificial liver prolong the survival time of anhepatic rabbits?

To examine cultured porcine hepatocytes as a bioreactor of a hybrid artificial liver (HAL) in rabbits, a small version of a multiplated HAL was manufactured. In vitro and ex vivo studies were performed to evaluate the small HAL. The HAL consisted of 50 glass plates (10 x 5 x 0.04 cm each) on which porcine hepatocytes were cultured in a monolayer at confluent cell density. After 2 days of standard cultivation, the glass plates with hepatocytes were placed in the module and were used for studies. The module contains about 5 grams of hepatocytes (1/10 of 2 kg.bw rabbit liver). After undergoing perfusion culture for 5 days, the HAL showed satisfactory hepatic function. Glucose and urea were synthesized at the rate of 4.06 +/- 0.7 mg/module/hr and 0.62 +/- 0.09 mg/module/hr, respectively, and loaded ammonia was metabolized at the rate of 1.29 +/- 0.26 mg/module/hr. Ex vivo extracorporeal plasma perfusion studies revealed that the module with cultured porcine hepatocytes, which were heterogeneous to rabbits, showed a tendency to prolong the survival time of anhepatic rabbits. These results indicate that the HAL system, using multiplated porcine hepatocyte monolayers, is a promising artificial liver support system for clinical cases.

Animals↗

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A new fluoroquinolone derivative exhibits inhibitory activity against human immunodeficiency virus type 1 replication.

The inhibitory activity of several fluoroquinolone antibiotics against human immunodeficiency virus type 1 (HIV-1) replication was investigated. R-71762, (+/-) 9-fluoro-3-fluoromethyl-2, 3-dihydro-10-[4-(2-pyridyl)-1-piperazinyl]-7-oxo-7H-pyrido[1,2, 3-de][1,4]benzoxazine-6-carboxylic acid, protected MT-4 cells from HIV-1-induced cytopathic effects. Furthermore, the compound inhibited virus replication both in acutely and in chronically HIV-1-infected cells. On the other hand, ofloxacin, levofloxacin, ciprofloxacin, norfloxacin and enoxacin, that were previously reported to be protective against HIV-1-induced cytopathic effects, did not show any protective activity in our assay system. These results indicate that R-71762 is a novel inhibitor of HIV-1 replication and is effective even in HIV-1 chronically infected cells.

Anti-HIV Agents↗

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Reduction of VX2 transplanted tumor by granulocyte depletion using extracorporeal circulation on rabbit models.

To investigate the role of granulocytes and the effect of granulocytosis on malignancies, we studied the relationship between white blood cell and granulocyte (Gr) counts, and tumor size. As we have reported that cancer patients with high granulocyte (G/L) ratio have a poor clinical prognosis, normalization of the G/L ratio could contribute to improvement in their condition. Tumor bearing rabbits treated with the extracorporeal granulocytte depletion device showed a decrease in tumor size and no tumor necrosis. Tumor-bearing rabbits with no extracorporeal granulocyte depletion showed a remarkable tumor progression and an increase in Gr count. Depletion of granulocytes considerably improved the survival ratio of tumor-bearing animals. The device used in this study could be a potential treatment for malignant tumors.

Animals↗

PubMedDate not supplied

A hybrid bioartificial liver composed of multiplated hepatocyte monolayers.

Monolayer cultures of hepatocytes were shown to have good function when compared with suspended cells. The authors manufactured a new hybrid artificial liver containing hepatocyte monolayers and evaluated its function. Hepatocytes isolated from an adult dog liver were cultured on collagen coated borosilicated glass (10 X 20 X 0.04 cm). A long-stroke artificial liver module was constructed by stacking 200 glass plates bearing hepatocytes, which were viable and functioned well during 4 weeks in perfusion culture; glyconeogenesis = 110 ng/micrograms DNA/min, urea synthesis = 3.6 ng/micrograms DNA/min and albumin synthesis = 29 micrograms/10(6) cells/day at the 5th day of perfusion. The levels were maintained for 2 weeks. The new device was applied to anhepatic dogs (Group 3) and compared with untreated (Group 1) and plasma exchange dogs (Group 2). The survival times were 21.3 +/- 5.6 hours in Group 1 (N = 6), 27.8 +/- 4.0 hours in Group 2 (N = 3), and 55.0 +/- 10.3 hours in Group 3 (N = 4). The longest survival was 65 hours. Serum ammonia increased to over 2,000 micrograms/dl after 12 hours in Groups 1 and 2, but remained under 400 micrograms/dl in Group 3. This new type of hybrid system may be a pilot design for the complete artificial liver.

Animals↗