Preceding haemorrhagic shock as a detrimental risk factor for respiratory distress after excessive allogeneic blood transfusion.

BACKGROUND AND OBJECTIVES: Whether transfusion-associated circulatory overload arises as a simple result of over-transfusion or requires another trigger remains unclear. Here, we examined whether respiratory distress could be reproduced by massive transfusion alone in an animal model. MATERIALS AND METHODS: A total of 20 anaesthetized swine were equipped with monitors. Allogeneic blood was obtained from 10 donor swine. A 4-stage loading protocol with each stage equivalent to 25% of the blood volume (BV) in the recipient swine was then used to infuse crystalloid (CR), hydroxyethyl starch (HES) or allogeneic blood (TR) (n = 5 each). The five remaining animals were subjected to a haemorrhagic shock (HS) prior to an allogeneic blood transfusion (TRS). RESULTS: The PaO2 /FiO2 (P/F) ratio did not decrease to the level of respiratory distress in either the CR group or the HES group after loading with a volume corresponding to 100% of the recipient BV. However, the TRS and TR groups exhibited significant reductions in the P/F ratio after fluid overloading (227 ± 29 and 267 ± 133, respectively). Blood transfusion after HS expanded the blood volume, but over-transfusion alone did not. HS was accompanied by an increase in the white blood cell count. CONCLUSION: The lung and the heart can tolerate volume overloads with HES, CR and even transfused blood. However, a preceding HS may induce an inflammatory response, making the lung vulnerable to subsequent blood overloads. In this study, a preceding haemorrhagic shock mediated respiratory distress following massive transfusion in a swine model. (247 words).

Pharmacokinetics of recombinant human soluble thrombomodulin, thrombomodulin alfa in the rat.

1. The study aimed to investigate the pharmacokinetics of thrombomodulin alpha (TM-alpha), human-soluble thrombomodulin in rats. 2. Intravenously administered TM-alpha was eliminated in two phases (T(1/2 alpha) = 0.2-0.3 h and T(1/2 beta) = 6-8 h), and the elimination curve was linear in a dose range of 10-250 microg kg(-1). Based on the results of tissue concentration studies after reaching the steady-state, the highest concentration of TM-alpha was seen in the plasma, suggesting the low levels of transfer to tissues (< or = 22% of plasma levels). 3. In vivo metabolism of TM-alpha was also analysed using high-performance liquid chromatography. The main peak observed in the plasma was TM-alpha, and even 72 h after the last dose of repeated administrations, 80% or more was unchanged form. Approximately half of the radioactivity excreted in the urine was recovered as a peak corresponding to TM-alpha. 4. The results reveal that although plasma clearance was lower in the renally impaired rats, the decrease was not large, with a difference of only about 20%. As a result, although the cause remains unclear, it is considered unlikely that the plasma concentrations of TM-alpha will vary considerably in patients with renal impairment.

Identification of a biologically functional novel IL-1 beta-specific receptor on adult rat hepatocytes.

Cellular receptors for interleukin-1 (IL-1) bind both IL-1 alpha and IL-1 beta with the same affinity, and both IL-1 alpha and IL-1 beta have the same potential in most IL-1-related biological responses, despite their low amino acid sequence homology (26%). Here, we identified and partially characterized a biologically functional novel IL-1 receptor, which specifically binds IL-1 beta but not IL-1 alpha, present on adult rat hepatocytes. Scatchard analysis of the binding of 125I-IL-1 beta to isolated adult rat hepatocytes showed that rat hepatocytes express a high affinity receptor for IL-1 beta with a Kd value of 9.6 x 10(-10) M at 1,200 sites/cell, whereas there was no specific binding of 125I-IL-1 alpha at least up to 10 ng/ml. Specific binding of 125I-IL-1 beta to hepatocytes was competitively inhibited by unlabeled IL-1 beta, but not by IL-1 alpha. Cross-linking of 125I-IL-1 beta to plasma membranes of hepatocytes indicated that the receptor for IL-1 beta has an apparent molecular mass of 80-100 kDa. Moreover, the formation of a cross-linked complex between 125I-IL-1 beta and the receptor was specifically inhibited by unlabeled IL-1 beta, but not by IL-1 alpha. Finally, DNA synthesis of adult rat hepatocytes was specifically inhibited by IL-1 beta, but not by IL-1 alpha, in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

[Use of primary cultured hepatocytes for toxicology].

Toxicological studies using primary cultured hepatocytes were reviewed. Primary cultures of mature hepatocytes retain many liver functions and various hormonal responses for long term. Therefore, this system overcomes various limitations of another in vitro system using liver. Toxicological studies using primary cultured hepatocytes showed high correlation to in vivo studies, for example, in vitro screening of inducible chemicals of hepatitis, and unscheduled DNA synthesis activity, etc. But there still remain some shortcomings, for example, rapid loss of cytochrome P450 and other drug metabolizing enzymes. A number of attempts to modify culture conditions resulted in long term maintenance of these enzymes. Recently Guzelian and colleagues established that using matrigel coated dishes, primary cultured hepatocytes expressed highly and maintained cytochrome P450 and other specific genes for long periods like in vivo. In the future study using cultured hepatocytes, if it can culture more long term or subculture as maintenance liver functions, not only rodent hepatocytes but also human hepatocytes are more useful for toxicological assessments and screening of drugs for liver diseases.

[Local irritation study of miporamicin in male rabbits].

Local irritation effect of miporamicin (MPM), a new macrolide antibiotics for animal use, on skin and ocular tissues was determined in rabbits by the primary skin irritation test and ocular irritation test, respectively. In the former test, P.I.I. and inflammatory findings increased with increasing exposure time to MPM. A short-time contact with MPM caused relatively little effect on ocular tissues. Contrarily, a long-time contact with MPM caused medium or high degree of inflammatory reactions on cornea, iris and conjunctiva tissues. The increased inflammation was naturally accompanied with increases of the DRAIZE score. All these results suggest that MPM per se has local irritation effect on both skin and ocular tissues.

[Local irritation study with isepamicin].

Local irritative effects of isepamicin (HAPA-B) were studied using muscle and blood vessel of Japanese White rabbits. Muscle irritation experiment was carried out with a single dosage of 100 mg HAPA-B, 100 mg amikacin (AMK), saline, 0.75% acetic acid or 6.0% acetic acid administered into musculus sacrospinalis. Vascular irritation experiment was carried out by allowing HAPA-B to remain in a sealed section of vena retroauricularis for 3 minutes after injection. In result, the muscular irritative activity of HAPA-B was less severe than 0.75% acetic acid but more than saline, and almost equal activity to AMK was observed. The HAPA-B caused very slight inflammation while thrombus was not formed. The vascular irritative activity was very little.