Identification of the transcriptional regulatory sequences of human calponin promoter and their use in targeting a conditionally replicating herpes vector to malignant human soft tissue and bone tumors.

The calponin (basic or h1) gene, normally expressed in maturated smooth muscle cells, is aberrantly expressed in a variety of human soft tissue and bone tumors. In this study, we show that expression of the calponin gene in human soft tissue and bone tumor cells is regulated at the transcriptional level by the sequence between positions -260 and -219 upstream of the translation initiation site. A novel conditionally replicating herpes simplex virus-1 vector (d12.CALP) in which the calponin promoter drives expression of ICP4, a major trans-activating factor for viral genes was constructed and tested as an experimental treatment for malignant human soft tissue and bone tumors. In cell culture, d12.CALP at low multiplicity of infection (0.001 plaque-forming unit/cell) selectively killed calponin-positive human synovial sarcoma, leiomyosarcoma, and osteosarcoma cells. For in vivo studies, 10 animals harboring SK-LMS-1 human leiomyosarcoma cells were randomly divided and treated twice on days 0 and 9 intraneoplastically with either 1 x 10(7) plaque-forming units of d12.CALP/100 mm(3) of tumor volume or with medium alone. The viral treatment group showed stable and significant inhibition of tumorigenicity with apparent cure in four of five mice by day 35. Replication of viral DNA demonstrated by PCR amplification and expression of the inserted LacZ gene visualized by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside histochemistry was associated with oncolysis of d12.CALP-treated tumors, while sparing normal vascular smooth muscle cells. In mice harboring two SK-LMS-1 tumors, replication of d12.CALP was detected in a nontreated tumor distant from the site of virus inoculation. These results indicate that replication-competent virus vectors controlled by the calponin transcriptional regulatory sequence may be a new therapeutic strategy for treatment of malignant human soft tissue and bone tumors.

Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty.

BACKGROUND: Restenosis after percutaneous transluminal coronary (balloon) angioplasty (PTCA) remains a major drawback of the procedure. We previously reported that cilostazol, a platelet aggregation inhibitor, inhibited intimal proliferation after directional coronary atherectomy and reduced the restenosis rate in humans. The present study aimed to determine the effect of cilostazol on restenosis after PTCA. METHODS AND RESULTS: Two hundred eleven patients with 273 lesions who underwent successful PTCA were randomly assigned to the cilostazol (200 mg/d) group or the aspirin (250 mg/d) control group. Administration of cilostazol was initiated immediately after PTCA and continued for 3 months of follow-up. Quantitative coronary angiography was performed before PTCA and after PTCA and at follow-up. Reference diameter, minimal lumen diameter, and percent diameter stenosis (DS) were measured by quantitative coronary angiography. Angiographic restenosis was defined as DS at follow-up >50%. Eligible follow-up angiography was performed in 94 patients with 123 lesions in the cilostazol group and in 99 patients with 129 lesions in the control group. The baseline characteristics and results of PTCA showed no significant difference between the 2 groups. However, minimal lumen diameter at follow-up was significantly larger (1.65+/-0.55 vs 1.37+/-0.58 mm; P<0.0001) and DS was significantly lower (34.1+/-17.8% vs 45.6+/-19. 3%; P<0.0001) in the cilostazol group. Restenosis and target lesion revascularization rates were also significantly lower in the cilostazol group (17.9% vs 39.5%; P<0.001 and 11.4% vs 28.7%; P<0. 001). CONCLUSIONS: Cilostazol significantly reduces restenosis and target lesion revascularization rates after successful PTCA.

Final results of the STent versus directional coronary Atherectomy Randomized Trial (START)

OBJECTIVES: This study was designed to compare primary stenting with optimal directional coronary atherectomy (DCA). BACKGROUND: No previous prospective randomized trial comparing stenting and DCA has been performed. METHODS: One hundred and twenty-two lesions suitable for both Palmaz-Schatz stenting and DCA were randomly assigned to stent (62 lesions) or DCA (60 lesions) arm. Single or multiple stents were implanted with high-pressure dilation in the stent arm. Aggressive debulking using intravascular ultrasound (IVUS) was performed in the DCA arm. Serial quantitative angiography and IVUS were performed preprocedure, postprocedure and at six months. The primary end point was restenosis, defined as > or =50% diameter stenosis at six months. Clinical event rates at one year were also assessed. RESULTS: Baseline characteristics were similar. Procedural success was achieved in all lesions. Although the postprocedural lumen diameter was similar (2.79 vs. 2.90 mm, stent vs. DCA), the follow-up lumen diameter was significantly smaller (1.89 vs. 2.18 mm; p = 0.023) in the stent arm. The IVUS revealed that intimal proliferation was significantly larger in the stent arm than in the DCA arm (3.1 vs. 1.1 mm ; p < 0.0001), which accounted for the significantly smaller follow-up lumen area of the stent arm (5.3 vs. 7.0 mm2; p = 0.030). Restenosis was significantly lower (32.8% vs. 15.8%; p = 0.032), and target vessel failure at one year tended to be lower in the DCA arm (33.9% vs. 18.3%; p = 0.056). CONCLUSIONS: These results suggest that aggressive DCA may provide superior angiographic and clinical outcomes to primary stenting.

Mechanism of the protective action of taurine against isoprenaline induced myocardial damage.

The effect of the sulphur amino acid, taurine, on the biochemical changes induced by a toxic dose of isoprenaline was examined in chick hearts. Isoprenaline treatment (80 and 240 mg.kg-1 subcutaneously twice a day for four days) caused a dose dependent increase in heart to body weight ratio. Isoprenaline administration induced a substantial accumulation of calcium and caused a profound decrease of adenosine triphosphate content and creatine phosphokinase activity in the myocardium. A pronounced increase in lipoperoxide and decrease in phospholipid and reduced glutathione concentrations were also seen. Oral administration of taurine (200 mg.kg-1 for seven days) partially protected against these changes induced by isoprenaline. It is suggested that the beneficial effect of taurine may be due in part to inhibition of lipoperoxide formation and calcium accumulation and to protection against the deterioration of membrane phospholipids.

Disruption of cell-cell adhesion in an inbred strain of hereditary cardiomyopathic hamster (Bio 14.6).

OBJECTIVE: Disarrangement of cardiomyocytes is a pathological characteristic of dilated cardiomyopathy. Hereditary cardiomyopathic hamster Bio 14.6, a model of dilated cardiomyopathy, displays disorder of cardiomyocyte arrangement. The aim of this study was to analyse the disturbance of cell alignment from the point of view of the cell-cell adhesion system in Bio 14.6. METHOD: Cardiomyopathic hamster Bio 14.6 was used as a model of dilated cardiomyopathy. Histological study was performed by light and electron microscopy. Disorder of the adherens junction-specific cell-adhesion molecule (A-CAM) was analysed by immunofluorescent microscopy and immunoblotting with anti-A-CAM antibody. RESULTS: Hematoxylin-eosin staining revealed that intercalated disks were identifiable less clearly in cardiomyopathy than in a normal cardiac muscle. It was disclosed by electron microscopy that cardiomyocytes adhered to each other with reduction in subsarcolemmal electron density at intercalated disks in Bio 14.6 compared with normal hamsters. We examined the localization of the A-CAM molecule in heart by immunofluorescent microscopy. In contrast to normal cardiac samples, fluorescence was weak in intensity and unclearly demarcated in the Bio 14.6 hamsters. We measured the content of A-CAM in the heart. In Bio 14.6 hamsters, the content of A-CAM was 60 +/- 11% of that measured in normal adult hamsters. A-CAM was reduced to a lesser extent (81 +/- 12%) in the newborn hamsters. CONCLUSIONS: In Bio 14.6 hamster, structural disturbance of the intercalated disks was found on histological examination of the heart. Biochemically, A-CAM, which plays a role in intercellular adhesion in intercalated disk areas, decreased significantly. These results suggest that cardiomyopathy may be accompanied by structural disruption of cell-cell adhesion in intercalated disk regions, which may lead to the pathological feature of disarranged cardiomyocytes.

Acute haemodynamic effect of taurine on hearts in vivo with normal and depressed myocardial function.

The acute haemodynamic effects of taurine were studied in normal and in beta blocker (propranolol) or calcium antagonist (diltiazem) treated rabbits and in rabbits with experimentally produced chronic aortic regurgitation. The administration of taurine (25 mg.kg-1) did not affect heart rate and left ventricular end diastolic pressure but produced significant increases in left ventricular dP/dtmax, cardiac output, and left ventricular systolic pressure in control hearts, indicating that intravascularly administered taurine substantially increased cardiac performance. In propranolol (1 mg.kg-1) treated rabbits taurine significantly improved left ventricular dP/dtmax and cardiac output, which were previously depressed by propranolol. Taurine had the same effect on diltiazem (1 mg.kg-1) treated rabbits. In rabbits with aortic regurgitation a bolus injection of taurine improved cardiac performance. Continuous infusion of taurine (100 mg.h-1) also produced a significant increase in left ventricular dP/dtmax. These results suggest that taurine has a unique action as an inotropic agent and that it may be useful in the treatment of patients with congestive heart failure.

The effect of taurine on age-related immune decline in mice: the effect of taurine on T cell and B cell proliferative response under costimulation with ionomycin and phorbol myristate acetate.

Proliferative responses to the costimulation with phorbol-12-myristate-13-acetate (PMA) and suboptimal doses of ionomycin in the purified T and B cells from old mice were lower than those from young mice. The degree of the age-related decline was more significant in T cells than in B cells. Taurine, a sulfur containing amino acid, augmented the proliferative responses of T cells from both young and old mice. The augmentation of the proliferative response by taurine was more marked in old T cells than in young ones. The concentration of intracellular free calcium ion ([Ca2+]i) was significantly lower in the old T cells under the stimulation with PMA and ionomycin than that in the young ones. In the presence of taurine, the concentration of [Ca2+]i in the old T cell significantly increased under the stimulation. The results indicate that taurine improved the proliferative response of old T cells by the restoration of the increment of the concentration of [Ca2+]i under the stimulation.

Final results of the CAPAS trial.

BACKGROUND: The Cutting Balloon (Interventional Technologies Inc) is a new-concept balloon that incorporates 3 to 4 blades to create sharp incisions on the luminal surface of the lesion during dilation without causing severe tearing injury to the vessel wall. It may reduce restenosis and improve clinical outcome. METHODS: Two hundred forty-eight lesions were randomly assigned to Cutting Balloon angioplasty (CBA, 120 lesions) or conventional balloon angioplasty (PTCA, 128 lesions). Inclusion criteria were type B/C lesions (American College of Cardiology/American Heart Association classification) and reference diameter <3.0 mm by visual image on angiogram. Quantitative coronary angiography was performed before and after percutaneous coronary angioplasty and at 3-month follow-up. The primary end point was restenosis, defined as >/=50% diameter stenosis at follow-up. Clinical event rates at 1 year were assessed. RESULTS: Baseline characteristics were similar. Reference diameter was small in both groups (2.16 vs 2.18 mm, CBA vs PTCA). Preprocedural percent diameter stenosis (%DS) was similar (69.8% vs 69.6%). However, postprocedural and follow-up %DS were lower (26.2% vs 28.9%, P =.072; 40.8% vs 47.5%, P =.011) in the CBA group. Restenosis was significantly lower (25.2% vs 41.5%, P =.009) in the CBA group. At 1 year, event-free survival was achieved in 72.8% of the CBA group and in 61.0% of the PTCA group (P =.047). CONCLUSION: These findings suggest that CBA provides superior angiographic and clinical outcomes in comparison with PTCA in small coronary arteries.

Therapy of congestive heart failure with orally administered taurine.

The clinical efficacy of 2 gm BID of oral taurine (2-aminoethane sulfonic acid) was studied in 24 patients with congestive heart failure (CHF). We expressed the severity of CHF by a score based on clinical signs and symptoms and on roentgenographic data. The maximum possible score, corresponding to the worst CHF, was 23 points. How much the 24 patients improved after receiving taurine for four or eight weeks was estimated by the difference between their pretreatment and posttreatment scores. In 19 of the 24 patients, taurine was effective. In the group as a whole, mean (+/- SEM) scores fell significantly, from 7.3 +/- 0.6 before treatment to 4.4 +/- 0.5 after treatment. Thirteen of the 15 patients who were designated as New York Heart Association (NYHA) functional class III or IV before receiving taurine could be designated as class II after they completed the study. This pilot study should prompt further investigation into the possible use of taurine in the treatment of patients with CHF.

Mechanism of direct cardiostimulating actions of hydralazine.

The vasodilator, hydralazine, was reported to also exert a direct positive inotropic effect on the myocardium at high concentrations. In the present study we investigated the mechanism of this positive inotropic action by using the ventricular myocardium of isolated perfused chick hearts. Hydralazine (10(-3) M) enhanced contractile force and heart rate, and elevated the myocardial cyclic AMP level. To study the Ca2+-dependent slow action potentials, the fast N+ channels were voltage-inactivated with elevated K+ (25 mM), resulting in a loss of electrical excitability. Hydralazine (10(-4) M) rapidly (less than 3 min) allowed the generation of slow action potentials and accompanying contractions by electrical stimulation. These effects of hydralazine were only partially prevented by propranolol. The results suggest that the increase of myocardial contractility produced by hydralazine is the result, at least in part, of a direct effect on the myocardium to increase Ca2+ inflow. The increased Ca2+ influx and inward slow current is due partly to activation of beta-adrenoceptors, with resultant elevation of cyclic AMP, and partly to another mechanism.

Taurine's possible protective role in age-dependent response to calcium paradox.

When hearts were reperfused with Ca++ after a short period of Ca++-free perfusion, irreversible loss of electrical and mechanical activity was observed. This phenomenon, first described by Zimmerman and Hulsmann, was termed the "calcium paradox". Chizzonite and Zak recently reported that rat hearts exhibited an age-dependent response in a calcium paradox model. The taurine (2-aminoethanesulfonic acid) content of hearts in the newborn animal is high, and decreases rapidly during the first few days of life. The present experiments were performed to test whether the myocardial taurine content was closely linked to an age-dependent response in the calcium paradox model, using post-hatched chicks. The mechanical dysfunction of the heart was much more severe in 9-day-old post-hatched chicks than in 2-day-old chicks when the hearts were subjected to the calcium paradox. Myocardial taurine content was lower in the 9-day-old chicks than in the 2-day-old chicks. The age-related response to the calcium paradox was partially protected by oral pretreatment with taurine, and there was a small increase in myocardial taurine level. It is proposed that myocardial taurine is one factor in the protection against the calcium paradox phenomenon.

Impact of pre-stent plaque debulking for chronic coronary total occlusions on restenosis reduction.

BACKGROUND: While stenting improves the long-term angiographic outcomes of successfully recanalized chronic coronary total occlusions (CTO), the restenosis rate still remains high. The massive plaque burden in CTO is considered to be one of the causes of in-stent restenosis. METHODS: We examined the pre-stent plaque debulking strategy with high-speed rotational atherectomy (RA) for 50 CTO (Thrombolysis in Myocardial Infarction flow grade 0; estimated occlusive duration, 3 months). Angiographic follow-up results were compared to those of 120 consecutive CTO recanalized with primary stenting in which RA could be indicated retrospectively. Angiographic restenosis was defined as diameter stenosis > 50% at 6-month follow-up. RESULTS: RA could be performed safely in all lesions without any major complications. Adjunctive ballooning and stenting could be performed without high-pressure dilatation (8.4 +/- 1.7 atmospheres). Follow-up angiography was performed in 48 lesions 184 +/- 61 days after the procedure. There were no significant differences in baseline characteristics between the two groups; however, the implanted stent type was different. Quantitative coronary angiography revealed that diameter stenosis was smaller at follow-up (36.2 +/- 20.0% versus 52.2 +/- 26.7%; p = 0.0003) as well as post-procedure (7.8 +/- 11.5% versus 17.8 +/- 13.6%; p < 0.0001) compared with the control group. Angiographic restenosis was also significantly reduced (29.2% versus 52.5%; p = 0.0061). CONCLUSIONS: RA is a safe procedure for plaque debulking of CTO in selected cases. Plaque debulking of CTO facilitates subsequent stent expansion and may reduce the restenosis rate.

Novel immunoaffinity extraction for liquid chromatographic determination of major metabolites of 4-acetoxy-2-(4-methylphenyl)benzothiazole in plasma.

Group extraction of the metabolites of 4-acetoxy-2-(4-methylphenyl)benzothiazole has been achieved through the use of an immunoaffinity adsorbent. The antisera elicited from an immunogen, 4-hydroxy-2-(4-formylphenyl)benzothiazole O-carboxymethyloxime-bovine serum albumin conjugate, were characterized to have a broad affinity spectrum for major metabolites oxidized at the 4-methyl group of the benzene moiety. One millilitre of the immunoaffinity adsorbent prepared by immobilization of antibodies (12.5 mg ml-1) was capable of retaining up to 4 micrograms of benzothiazoles. The adsorbates were recovered quantitatively by elution with 90% (v/v) methanol without any interfering peaks on the high-performance liquid chromatogram. The peak-height ratio of each metabolite to an internal standard was plotted against the concentration of the former substance; good linearity was observed in the range of 10-500 ng ml-1.

Enzyme immunoassay for 4-hydroxy-2-(4-methylphenyl)benzothiazole.

A specific enzyme immunoassay (EIA) has been developed for 4-hydroxy-2-(4-methylphenyl)benzothiazole (KB-2714) (1), an active metabolite of 4-acetoxy-2-(4-methylphenyl)benzothiazole (KB-2683) (2) which is a promising anti-rheumatic agent. The EIA was based upon antiserum elicited against 5-(2-carboxyphenylazo)-4-hydroxy-2-(4-methylphenyl)benzothiazole (3)-bovine serum albumin conjugate and beta-galactosidase-labelled 5-amino-4-hydroxy-2-(4-methylphenyl)benzothiazole (5). The sensitivity of the EIA was significantly improved by the utilization of a bridge heterologous combination system. An appropriate dose-response curve of EIA for 4-hydroxy-2-(4-methylphenyl)benzothiazole was obtained in the range of 10 pg tube-1-20 ng tube-1. The specificity of EIA proved to be satisfactory in terms of cross-reactivities to 14 benzothiazole-related compounds including glucuronic acid and sulphuric acid conjugates. The proposed method was evaluated to be useful for the determination of 1 in urine and plasma with acceptable recovery and inter- and intra-assay precision.

Therapeutic effect of taurine in congestive heart failure: a double-blind crossover trial.

In a double-blind, randomized, crossover, placebo-controlled study, we investigated the effects of adding taurine to the conventional treatment in 14 patients with congestive heart failure for a 4-week period. Compared with placebo, taurine significantly improved the New York Heart Association functional class (p less than 0.02), pulmonary crackles (p less than 0.02), and chest film abnormalities (p less than 0.01). A benefit of taurine over placebo was demonstrated when an overall treatment response for each patient was evaluated on the basis of clinical examination (p less than 0.05). No patient worsened during taurine administration, but four patients did during placebo. Pre-ejection period (corrected for heart rate) decreased from 148 +/- 14 ms before taurine treatment to 137 +/- 12 ms after taurine (p less than 0.001), and the quotient pre-ejection period/left ventricular ejection time decreased from 47 +/- 9 to 42 +/- 8% (p less than 0.001). Side effects did not occur in the patients during taurine. The results indicate that addition of taurine to conventional therapy is safe and effective for the treatment of patients with congestive heart failure.

[Selective and sensitive determination of an antiallergic agent, emedastine difumarate (KG-2413), in human plasma by the radioreceptor assay combined with a high-performance liquid chromatography].

The selective and sensitive method for the determination of a new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-b enzimidazole difumarate (emedastine difumarate, KG-2413), in the human plasma has been developed. Emedastine was determined by the receptor assay after the separation from its metabolites by the use of high-performance liquid chromatography (HPLC). This combined method (HPLC-radioreceptor assay (RRA) method) allowed us the quantification only of 0.3 ng/ml of emedastine in the human plasma. The intra-assay coefficients of variation for the determination were below 12%. Furthermore, the total pharmacologically active metabolites, including unchanged emedastine, was determined by the extraction of the unconjugated metabolites in the human plasma with chloroform followed by the receptor assay (RRA method). The human plasma concentrations measured by the HPLC-RRA method were in good agreement with those by the RRA method. These results suggested that in human pharmacological activities occurred by unchanged emedastine itself.

[Cross-reactivities of active metabolites in the radioreceptor assay of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)- 1H-benzimidazole difumarate (KG-2413)].

A new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H- benzimidazole difumarate (KG-2413), was orally administered to guinea pigs at a dose of 2 mg/kg. The drug levels in the plasma measured by the radioreceptor assay (RRA) method were significantly higher by 7% than those by the gas chromatographic (GC) method which was selective for the intact drug. Among the metabolites of KG-2413, 1-(2-ethoxyethyl)-2-(hexahydro-1H-1,4-diazepin-1-yl)- 1H-benzimidazole (desmethyl metabolite) and 1-(2-ethoxyethyl)-5-hydroxy-2-(hexahydro-4-methyl-1H-1,4-diazepin- 1-yl)-1H- benzimidazole (5-hydroxy metabolite) had relatively high cross-reactivities of 29% and 21%, respectively, on the RRA method. However, the 5-hydroxy metabolite was not extracted with benzene under strongly basic conditions on the extraction procedure carried out prior to the receptor assay. Therefore, it was suggested that the desmethyl metabolite might affect the RRA method. In order to determine the amount of the desmethyl metabolite in the plasma, a high-performance liquid chromatographic method was established to determine the dansyl derivative of the desmethyl metabolite. By using this method, it was found that the desmethyl metabolite corresponding to 21-32% of the intact drug was present in the plasma after oral administration of KG-2413 at a dose of 2 mg/kg. Taking account of the cross-reactivity (29%) and extraction ratio (83%) of the desmethyl metabolite, this active metabolite affects the RRA method to give 5.1-7.7% overestimation of the intact drug concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

[Determination of the main metabolite (desethyl KBT-3022) of a new antiplatelet agent, KBT-3022 in plasma by gas chromatography].

A highly sensitive, accurate and reproducible gas chromatographic method for the determination of a main metabolite, 2-[4,5-bis(4-methoxy-phenyl)thiazol-2-yl] pyrrol-ylacetic acid (desethyl KBT-3022) of a new antiplatelet agent, ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate (KBT-3022), in the human or dog plasma has been developed. Desethyl KBT-3022 in the plasma was extracted with a mixture of n-hexane and dichloromethane (1:1), and was derivatized using pentafluorobenzyl bromide. The obtained pentafluorobenzyl derivative of desethyl KBT-3022 in the plasma was separated by high-performance liquid chromatography. After the separation, the pentafluorobenzyl derivative of desethyl KBT-3022 was detected by gas chromatography. Gas chromatography was performed with a Ultra 1 column (12 m x 0.22 mm i.d., film thickness 0.33 microns), using an electron capture detector. 2-[2-(4,5-Bis(4-methoxyphenyl)thiazol-2-yl)pyrrol-l-yl]propionic acid was used as an internal standard. The detection limit of desethyl KBT-3022 in the plasma was 0.2 ng/ml. The coefficients of variation were below 5.3%. This method was applied to the determination of the plasma concentration of desethyl KBT-3022 after oral administration of KBT-3022 to dogs.

[In vitro metabolism of an antiallergic agent, emedastine difumarate, in rats and guinea pigs].

In order to clarify the interspecies differences in the metabolism of emedastine difumarate (KG-2413), in vitro metabolism was studied with liver preparations of rats and guinea pigs. The activities of hydroxylase, N-oxidase and N-demethylase, of emedastine were evaluated with liver 9000 x g supernatant and microsomes. As the results, the orders of activities were as follows; 5-hydroxylase greater than or equal to N-oxidase greater than 6-hydroxylase greater than N-demethylase in rats, and N-oxidase much greater than N-demethylase greater than 6-hydroxylase greater than 5-hydroxylase in guinea pigs. Emedastine N-oxide, little excreted into the urine of rats, was largely formed in vitro, so it was assumed that N-oxide reduction was important in vivo. The reductase activity of emedastine N-oxide was evaluated, and compared with N-oxidase activity of emedastine. In rats, the reductase activity was nearly equal to the N-oxidase activity, and relatively high even under aerobic conditions. On the other hand, in guinea pigs, the reductase activity was lower than the N-oxidase activity. It was considered that relative activities of the N-oxidation of tertiary amine in a 1,4-diazepine ring of emedastine and the reduction of N-oxide once formed were one of the factors of interspecies differences of metabolism of emedastine in rats and guinea pigs.

[Metabolism of lomerizine hydrochloride (KB-2796) in rats].

The metabolism of lomerizine was investigated after the oral administration of [methine-14C] or [benzyl-14C]lomerizine hydrochloride in rats. 1. Urinary, fecal and biliary excretions of the unchanged drug were less than 1% of dose, showing that lomerizine was eliminated by the extensive biotransformation after the oral administration. 2. The main metabolites were 1-(2,3,4-trimethoxybenzyl)piperazine (M7) and 2,3-dimethoxy-4-hydroxybenzylpiperazine in the urine, and 1-[bis(4-fuluorophenyl)methyl]-4-(2,3-dimethoxy-4-hydroxybenzyl)pi perazine in the feces and bile. 3. The radioactive substances in the plasma, liver and brain mainly existed as unconjugated forms, of which the intact drug showed the highest concentration. 4. The main metabolites in the plasma, and in the liver and brain were 1-[bis(4-fuluorophenyl)methyl]-4-(3,4-dimethoxy-2-hydroxybenzyl)pi perazine and bis(4-fluorophenyl)methylpiperazine (M6), respectively. 5. The plasma level of M7 and the biliary excretion of bis(4-fluorophenyl)-methanol in male rats were higher than those in female rats, suggesting the sex difference in the N-dealkylation at the 4-position of piperazine ring of the drug.