Effects of flecainide, a class I antiarrhythmic drug, on ventricular arrhythmias, ventricular abnormal automaticity and ventricular activation were examined in a canine model of myocardial infarction, and compared with those of lidocaine. The effects of the drugs were examined on (1) the arrhythmias developed 24 h after the left anterior descending coronary artery (LAD) ligation, (2) ventricular premature stimulation-induced arrhythmias 5 to 7 d after LAD ligation, (3) ventricular abnormal automaticity about 24 h after LAD ligation and (4) ventricular activation induced by a ventricular stimulation at various coupling intervals in animals 5 to 7 d after LAD ligation. Flecainide (1 and 3 mg/kg) showed a marked reduction in the frequency of ventricular ectopic beats 24 h after LAD ligation, and was more potent than lidocaine. The ventricular abnormal automaticity was inhibited by flecainide (1 and 3 mg/kg) and lidocaine (10 mg/kg). Flecainide (1 and 3 mg/kg) prolonged the activation time in the infarcted zones over a wide range of the coupling intervals, and produced block of seriously delayed activation. In contrast, lidocaine produced similar effects only at short coupling intervals. Ventricular premature stimulation produced ventricular arrhythmias, which were prevented by pretreatment with flecainide (3 mg/kg). In conclusion, flecainide showed antiarrhythmic effects in a canine model of myocardial infarction. A marked inhibition of ventricular abnormal automaticity and selective depression of delayed activation in the infarcted zone probably contribute to its antiarrhythmic effect.

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A program adapted for use on microcomputers (DCN) has been developed which permits one to perform operations of numerical convolution and deconvolution using polyexponential functions, that are often implemented in pharmacokinetic analysis. The program is written in Microsoft GWBASIC and can be used in personal computers with no modification. The user supplies information relating to the coefficients and exponentials defining the polyexponential equation of the response and weighting functions and the program performs the deconvolution operation by numerical integration using trapezoidal rule and provides numerical and graphic information concerning the input function. The program can be applied to the deconvolution of many linear pharmacokinetic systems and allows one to solve problems related to drug release, absorption, distribution, as well as others. Additionally, the program is able to perform the convolution operation if information about the input and weighting functions and is also able to simulate pharmacokinetic processes. The efficacy of the program was evaluated by comparison with several deconvolution algorithms, in particular that proposed by Veng-Pedersen and Iga.

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Our previous study suggested that squalane would be a good candidate for an antidote to reduce the toxicity of drug ingested accidentally at a high dose by enhancing the drug elimination from the body. In the present study, we investigated whether squalane given orally could enhance the elimination of theophylline, phenobarbital and strychnine which were administered parenterally to rats or mice. Squalane increased the fecal excretion of theophylline and reduced the serum level of the drug in rats. Squalane accelerated the fecal excretion of strychnine in mice. These results suggest that squalane may stimulate more the elimination of neutral (theophylline) or basic (strychnine) drugs which should be present in unionized form in intestinal lumen, than that of acidic drugs.

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The influence of angiotensin-converting enzyme (ACE) inhibitory octapeptide derived from tuna muscle (tuna AI) on the bovine aorta endothelial cell (BAEC) migration was investigated, as compared with captopril. BAEC migration was quantitated 6 d after release from contact inhibition by a teflon fence assay. The culture grown in the presence of tuna AI (1 and 10 μM) clearly exhibited an increase in migration, compared with the control. The media collected from tuna AI (1 and 10 μM)-stimulated BAECs significantly exhibited the interleukin (IL) -1 activity that was detected by the thymocyte costimulation assay with phytohemagglutinin. Although tuna AI was a weaker ACE inhibitor than captopril, the increasing effect of tuna AI on the migration and the IL-1 generation in BAECs was slightly greater than that of captopril. In quiescent BAECs, tuna AI (1 μM) apparently induced c-myc and platelet derived growth factor (PDGF) A-chain messenger ribonucleic acid (mRNA) expressions within 30 min, which persisted for 6 h. In contrast, captopril induced a very low expression of c-myc mRNA, and had no relation to PDGF A-chain mRNA expression. These results suggest that the increase of BAEC migration by tuna AI, unlike captopril, is likely related to the induction or activation of IL-1, and c-myc and PDGF mRNAs, in addition to the inhibition of the conversion of endogenous angiotensin I to angiotensin II.

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State analysis of low-sulfated chondroitin 4-sulfate (LSC) in human urine and serum was performed by the use of high performance liquid chromatography and Western blot analysis. It was revealed that the most amount of LSC in urine is present as urinary trypsin inhibitor and a small amount (about 10% of total LSC) is as an LSC chain. The LSC in serum is mainly present as a proteoglycan such as inter-α-trypsin inhibitor (ITI), with a molecular weight of 212 kDa, but a small amount of LSC-proteoglycans having molecular weights of 128 and 38 kDa were also observed on SDS-PAGE. Those two compounds may be fragments of ITI, or one of the compounds (128 kDa) may be pre-α-trypsin inhibitor which was found by Enghild et al. (J. Biol. Chem., 264, 15975 (1989))

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The effects of protocatechualdehyde (PAL), one of the metabolites of 3, 4-diacetoxy benzylidene diacetate (ACP), on proteogylcan metabolism and secretion of interleukin 1 (IL-1) like activity (lymphocyte activating factor ; LAF activity) were studied using rabbit articular chondrocytes culture under phorbol myristate acetate (PMA) and Ca²⁺ ionophore A23187 (A23187) or IL-1α stimulation. In IL-1α (20 u/ml) or PMA (0.1 μg/ml) and A23187 (0.2 μg/ml) treated culture of rabbit articular chondrocytes, PAL significantly reduced the degradation of ³⁵S-proteoglycan (³⁵S-PG) from the cells and matrix layers into the culture media in a dose dependent fashion without affecting proteoglycan synthesis. Similarly, the secretion or production of matrix metalloproteinases which degrade proteoglycans was also inhibited to the same extent under IL-1α stimulated condition. However, PAL caused no effect on the secretion of IL-1 like activity by chondrocytes. These results suggest that an attractive candidate for an anti-inflammatory drug, ACP, which is a prodrug of PAL, has also a favorable action on chondrocyte metabolism in terms of proteoglycan degradation via inhibition of matrix metalloproteinases secretion or production.

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A 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) containing diet was given to 6 weeks old female Donryu rats, and the number of adrenoceptors and the response of adenylate cyclase in the hepatocytes were measured. The treatment with 3'-MeDAB Ied to rapid increases in [¹²⁵I]-iodocyanopindolol ([¹²⁵I] ICYP)- and [³H] clonidine-binding sites to hepatic membranes without significant changes in the K_d values. The number or β-adrenoceptors defined by [¹²⁵I] ICYP binding sites was increased with a biphagic mode. The [³H] clonidine binding reached a peak 2 weeks after the start of the carcinogen diet and then began a slow descent. The α₂-adrenoceptor was defined by [³H] clonidine binding being selectively inhibited by an α₂-antagonist, yohimbine, but not by an α₁-antagonist, prazosin, or a β-antagonist propranolol. Catecholamine responsiveness to adenylate cyclase in hepatocytes also increased during treatment with 3'-MeDAB. However, the efficacy of norepinephrine (NE) in activating cyclase was lower than that of isoproterenol (IPN) during 4 to 8 weeks of the carcinogen diet. The difference between the efficacies of IPN and NE resulted from inhibiting adenylate cyclase through α₂-adrenoceptors by NE. Therefore, we noticed that the increasing pattern of the number of β-adrenoceptors did not always parallel IPN-stimulated adenylate cyclase activity and that the increase in the number of α₂-adrenoceptors preceded the difference between the efficacies of IPN and NE in activating adenylate cyclase. These findings suggest that the emergence of β- and α₂-adrenoceptors occurs before the receptors are able to be coupled with the guanine-nucleotide binding proteins in the adenylate cyclase system in the early stage of hepatocar cinogenesis induced by 3'-MeDAB.

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We have reported that OK-432 (a streptococcal preparation) prevents the development of autoimmune kidney disease in MRL/Mp-lpr/lpr (MRL/lpr) mice and prolongs their survival time. In the present study, to clarify the mechanism of this action of OK-432, we examined whether the cyclooxygenase inhibitor indomethacin (IND) affects this inhibition by OK-432. It was reconfirmed that OK-432 prevented the development of autoimmune kidney disease and prolonged the survival time. This OK-432 effect was counteracted when IND was coadministered. Furthermore, OK-432 produced tumor necrosis factor (TNF)-α and prostaglandin (PG) E2 in the peritoneal fluids in this strain of mice. The coadministration of IND suppressed the PGE2 but not the TNF-α production. These results suggest the possibility that the inhibition of autoimmune kidney disease by OK-432 might be due to the induction of cyclooxygenase metabolites of arachidonic acid.

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5, 6-trans-Prostaglandin E₂ (trans-PG E₂) was found to accelerate the fibrinolysis in a cell-free system. trans-PG E₂ decreased the lysis time by 15% in the fibrin clot lysis time method and increased the lysis area by 22% in the fibrin plate method. On the contrary, 5, 6-cis-prostaglandin E₂ did not have such effects. trans-PG E₂ did not exert the effect in the absence of either tissue-plasminogen activator or plasminogen. These results suggest that trans-PG E₂ enhances the generation of plasmin from plasminogen by tissue-plasminogen activator.

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