The antiarrhythmic effects of a new calcium channel blocking agent (SD-3211) and its stereoisomer with additional sodium channel blocking activity (SA3212), were compared with those of a known antiarrhythmic drug (bepridil), using the left coronary artery ligation- and reperfusion-associated arrhythmia models both in isolated rat hearts and in anaesthetized rats. Isolated and perfused rat hearts were subjected to regional ischaemia for 15 min and subsequent reperfusion for 5 min. SD-3211 and SA3212 showed dose-dependently prolongations of the time interval between coronary ligation and first appearance of ventricular premature beats, reductions in the number of total ventricular premature beats during the ligation period and reductions in the incidence of reperfusion-induced ventricular fibrillation. The values of the negative logarithm of IC50 (mol/l) of SD-3211, SA3212 and bepridil were 7.97, 7.41 and 6.64 for the reduction of ventricular premature beats during ligation and 6.43, 7.49 and 6.17 for the reduction of ventricular fibrillation during reperfusion, respectively. In a separate study on force of concentration and coronary flow in perfused heart paced at 340-360 beats/min SD-3211 caused a significant negative inotropic effect between 10(-7) and 10(-6) mol/l. SA3212 at the concentration of less than 10(-6) mol/l did not result in any significant change in force of contraction. The coronary flow was increased dose-dependently by SA3212, while it was first increased and then reduced in the presence of higher concentration of SD-3211 (greater than 10(-7) mol/l). Hearts of anesthetized rats were also subjected to regional ischaemia for 7 min and subsequent reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
S-1108, the prodrug of S-1006, was given to healthy volunteers three times a day (TID) for 8 days in a dose of 200 mg in a crossover placebo-controlled study. The safety of S-1108 and the pharmacokinetics of S-1006 and pivalic acid liberated from pivaloyloxymethyl ester of S-1108 were investigated. There were no abnormal symptoms or signs, as observed by physical and laboratory tests. The half-life and area under the concentration-time curve of S-1006 was reduced from 1.11 ± 0.17 h at the first dose to 0.87 + 0.18 h at the last dose and from 7.30 ± 1.10 to 5.20 ± 0.85 ,ug. h/ml, respectively. However, there was no significant difference in the peak concentration between the two doses. Pivalic acid was found to be completely detoxified by conijugation with carnitine. The total urinary recovery of pivalic acid as pivaloylcarnitine was 98.7 ± 3.6%, resulting in an increase of daily carnitine urinary excretion two-to threefold the predose value. During the multiple administration of S-1108, the plasma carnitine concentration was reduced to and maintained at 50 to 70%o of the control value, suggesting that there might be enough carnitine store in the body to detoxify the pivalic acid in a dose of 200 mg TID. Moreover, the reduced plasma carnitine was rapidly returned to the control value within a few days after the cessation of the administration of 200 mg TID. S-1108 is a new oral cephem antibiotic that possesses a pivaloyloxymethyl ester group. It is easily deesterified in the intestine and converted to its active form, S-1006, which is highly active against a wide range of gram-positive and gram-negative bacteria except several bacteria such as Pseu-domonas aeruginosa and enterococci. There are some other antibiotics that are esterified with a pivaloyloxymethyl group to increase the extent of absorption. These prodrugs, such as cefteram pivoxil, pivampicillin, and pivmecillinam, have already been used for the treatment of infectious diseases. The clinical efficacy, safety, and pharmacokinetics of these active forms were sufficiently investigated. Recently, it has been reported that prodrugs having a pivaloxyloxymethyl ester group might promote myopathic carnitine deficiency in humans (4). However, the pharmacological , toxicological, and pharmacokinetic properties of metabolites liberated from these prodrugs have not been sufficiently investigated. It is well known (2, 9) that a prodrug having a pivaloyloxymethyl ester group is further metabolized to produce pivalic acid and formaldehyde. Pivalic acid is excreted in urine mainly as a conjugate with carnitine, resulting in a decrease of carnitine stores in the body, especially in the case of long-term therapy with these prodrugs (4-6, 11). The metabolism of S-1108 was studied, as shown in Fig. 1 (10a). As, mentioned above, the liberated pivalic acid from S-1108 might reduce carnitine stores by the form'ation of pivaloylcarnitine. The purpose of this study is to investigate the safety of S-1108 and the pharmacokinetics of S-1006 and pivalic acid liberated in healthy...
The segment of the male canine abdominal vena cava (AVC) between the liver and the renal veins receives vasa vasorum from the right phrenicoabdominal artery, while the infrarenal segment of AVC does from the right testicular artery. These facts were confirmed by both macroscopic observation with dye injection into the arteries and measurement of contractile responses of the segments in vivo by the method with intravascular cuffs. The segmental distribution of vasa vasorum from arteries of the right side may closely correlate with the embryogenesis of the vein.An anomalous dog with totally inverted viscera, which we found during our study, exhibited another anomaly of AVC: It had the segment of AVC between the liver and the renal veins at the left side of the aorta and the infrarenal segment at the right. This anomaly shows that AVC is composed with at least two segments which is formed separately during its embryogenesis and may support our hypothesis.
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