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Optically active trans-isomers of diltiazem were synthesized and their cardiovascular effects were evaluated in anesthetized dogs and in isolated guinea pig hearts. Both (+)-2 (2R,3S) and (-)-2 (2S,3R) were much less active than diltiazem (1, 2S,3S) with short duration of action. No substantial enantiomeric difference in activity was seen between them. Their Ca-antagonistic activities on Ca(2+)-induced contractions in K(+)-depolarized canine basilar arteries were also examined. Absolute stereochemistry of (+)-2 was determined to be 2R,3S by X-ray crystallographic analysis.

The influence of chronic treatment with clentiazem ((+)(2S,3S)-3-acetoxy-8-chloro-5-[2-(dimethylamino)ethyl]-2,3-dihydro- 2-(4-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one maleate, TA-3090), on blood pressure, incidence of stroke, stroke-related mortality and histological changes of the brain and other organs were examined in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP that were fed an 8% NaCl-containing diet began to die of a stroke 3 weeks after salt-loading, accompanied by decreases in body weight and food intake. Most of the rats (16 out of 18) died by the 8th week of salt-loading. Chronic treatment with clentiazem (300 or 1000 ppm) delayed the occurrence of stroke and death in a dose-related manner without any hypotensive action when measured by the tail-cuff method. However, examination of circadian changes in arterial blood pressure with implanted cannula under a freely-moving condition 3 weeks after salt-loading revealed that 1000 ppm clentiazem produced significant hypotension in the dark phase but not in the light phase. Histological studies (3 weeks after salt-loading) showed that 1000 ppm Clentiazem significantly suppressed the cerebral and renal damages, and vascular hypertrophy in all organs studied. Thus, clentiazem prevents stroke and also protects renal damage and vascular hypertrophy in salt-loaded SHRSP. The hypotensive effect and organ-protective action by clentiazem may be involved in its prophylactic action against stroke.

The effect of a new 1,5-benzothiazepine calcium antagonist, clentiazem (TA-3090), on the cerebral circulation was studied in anesthetized animals. Intravenous infusion of clentiazem at doses of 2.5, 5, and 10 micrograms/kg/min increased vertebral blood flow without causing hypotension in anesthetized dogs. After i.v. injection to anesthetized dogs, clentiazem, diltiazem, and papaverine all dose-dependently increased the regional cerebral blood flow and raised the intracranial pressure (ICP). However, the effect of clentiazem on the ICP was weaker than that of diltiazem and papaverine. In anesthetized monkeys, clentiazem (3-100 micrograms/kg, i.v.) increased the internal carotid blood flow to the intracranial tissues. In anesthetized cats, topical or i.v. clentiazem inhibited basilar artery vasospasm induced by the topical application of serotonin, prostaglandin F2 alpha, and incubated blood. These findings suggest that clentiazem has favorable properties as a cerebral vasodilator.

A de novo and apparently balanced complex chromosome rearrangement (CCR) was found in monozygotic (MZ) twin infants with multiple congenital anomalies. The rearrangement involved 4 chromosomes with 6 breakpoints including 2p23, 2q13, 2q21.1, 3p23, 11q13.1, and 12q24.1. This seems to be the first report of a CCR in MZ twins. The relationship between this chromosome abnormality and MZ twinning is discussed.

A rare case of variant Philadelphia (Ph1) chromosome positive [46, XX, t (9; 22) (q34; q11), inv (9) (9q22; 22q13)] chronic myelocytic leukemia (CML) was described. The patient, 73 years old female, was hospitalized to our hospital because of leukocytosis. Hematological findings corresponded to those of CMLs. However, this case lacked hepatosplenomegaly. Southern blot analysis using a 3 breakpoint cluster region (bcr) probe revealed a bcr rearrangement. The patient has been in the chronic phase for sixteen months without treatment. Clinical and chromosomal changes are under observation in order to get accumulate data for a pathophysiological analysis of variant Ph1 positive CMLs.

Two patients with monosomy for the distal portion of the short arm of chromosome 3 are described. Chromosome analysis on prometaphase cells demonstrated a karyotype of 46,XX,del(3) (p25.3) in one patient and 46,XX,r(3)(p26.1q29) in the other. The former patient showed characteristic clinical manifestations of the 3p- syndrome, including growth failure, mental retardation, microcephaly with a flat occiput, triangular face, synophrys, blepharoptosis, hypertelorism, broad and flat nose, long philtrum, down-turned mouth, micrognathia, apparently lowset and malformed ears, fingers abnormalities, and deafness. The latter patient had a nonspecific phenotype with mental retardation, growth failure and microcephaly. Karyotype-phenotype comparisons in the present cases and 16 previously reported cases with deficiency of the distal portion of 3p suggests that deficiency of the 3p25.3 band is critical to produce the main clinical manifestations of the del(3p) syndrome.

A 9-year-old boy with non-resectable hepatocellular carcinoma was treated with irradiation and intra-hepatic arterial infusion of antitumor agents. His blood was positive for hepatitis B surface antigen (HBs Ag), but negative for hepatitis B e antigen (HBe Ag). Maternal transmission was suspected, because his mother's blood was positive for HBs Ag and his grand mother died from hepatic cirrhosis. The patient received a total dose of 4000 rad in 30 fractions. A chemotherapy cycle consisted of 5-FU (6 mg/M2/day, given continuously), EX (300 mg/M2, given on 1st, 3rd, 5th, 7th, and 9th week), VCR (1.5 mg/M2, on 2nd, 4th, 6th, 8th, and 10th week), and ADM (30 mg/M2, on 13th and 16th week). Since 6 months after the initiation of the chemotherapy, alpha-fetoprotein has become negative (less than or equal to 100n g/ml), and now, 2 years and 11 months after the diagnosis was settled, the patient remains a disease free state. His blood continues to be positive for HBs Ag.

Effects of TA-3090 ((+) (2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one maleate)and diltiazem on contractions induced by different spasmogens were investigated in isolated canine and monkey arteries. Ca2+-antagonistic action in canine arteries, assessed by suppression of Ca2+-induced contraction in Ca2+-free, K+-depolarizing solution, was as follows; basilar (pA2 = 8.34) greater than coronary (pA2 = 7.95) greater than renal (pA2 = 7.46) = mesenteric artery (pA2 = 7.36). The potency of TA-3090 was 10 times greater in basilar artery and 2 to 3 times greater in the other arteries than that of diltiazem. The effect of TA-3090 on the arterial segment was more persistent than that of diltiazem. Relative vasorelaxing potency of TA-3090 to diltiazem in K+-induced contractions was greatest in the basilar artery among the tested arteries of both monkeys and dogs. Spasmolytic activities of TA-3090 on 5-HT-, PGF2 alpha-, U-46619 (thromboxane A2/prostaglandin H2 agonist) and oxyhemoglobin-induced contractions in canine basilar arteries were more potent than those of diltiazem, especially on 5-HT-induced contraction. In addition, TA-3090 suppressed 3,4-diaminopyridine-induced rhythmic contraction in the canine coronary artery. These results indicate that TA-3090 has potent Ca2+-antagonistic and spasmolytic activities, and these actions are most selective for basilar artery.

Fumitremorgin A (FTA), a neurotropic mycotoxin induced dose-dependent abnormal behaviors, including tremor, clonic convulsion, kangaroo posture and tonic extensor convulsion in the mouse. FTA-induced tonic extensor convulsion was markedly suppressed by anticonvulsant, e.g. phenobarbital, phenytoin. Phenobarbital, trimethadione, valproic acid and mephenesin decreased the occurrence of abnormal behaviors induced by FTA. Although pentylenetetrazol-induced tonic extensor convulsion was not affected by antipsychotic drugs (dopaminergic drugs) except chlorpromazine, FTA-induced abnormal behaviors were inhibited by antipsychotic drugs, e.g. chlorpromazine, haloperidol. Chlordiazepoxide, diazepam and muscimol inhibited FTA-induced abnormal behaviors. These findings suggest that both dopaminergic and gamma-aminobutyric acid (GABA)-ergic systems are involved in FTA-induced abnormal behaviors. FTA-induced abnormal behaviors may be useful as a common experimental model for the primary evaluation of anticonvulsants, antipsychotic drugs and anxiolytic drugs.

We performed a cytogenetic study on 140 nonpolymalformed patients with mental retardation of clinically undefined origin, using a high resolution banding technique, to determine how much chromosome abnormalities contribute to the etiology of this condition. A total of 15 patients (10.7%) were found to have autosomal or sex chromosomal abnormalities. Autosomal abnormalities included partial monosomy (5 cases), reciprocal translocation (one case), 13/14 robertsonian translocation (3 cases), unbalanced translocation (one case), inverted duplication of 15q (one case) and mosaic trisomy 21 (one case). Sex chromosomal abnormalities comprised structural rearrangement of the short arm of the X chromosome (one case) and 47, XXY in a pure or mosaic form (two cases). It should be noted that four out of the 5 cases of partial monosomy had subtle interstitial deletions, which might have been unidentified by the conventional G-banding method alone. In one case of the robertsonian translocation 46,XY,t(13;14)/45,XY,t(13;14), a small deletion was thought to have occurred in the cells with a chromosome number of 45. Comparison of clinical features of the 15 chromosomally abnormal patients with those of patients with normal karyotypes did not show any clinical parameter indicative of chromosome imbalance. These results suggest that a subtle chromosomal deletion is specific to mental retardation associated with few malformations. We believe that diagnostic evaluation of mentally retarded patients, even if nonmalformed, should include chromosome analysis using a high resolution banding technique.

1. We examined the mechanisms underlying Ca2+-induced relaxation in the presence of clentiazem, a new Ca2+-antagonist, in depolarized coronary arteries of the dog. 2. Ca2+ (3 x 10(-5)-3 x 10(-3) M) caused an unexpected relaxation in the presence of a high concentration of clentiazem (10(-6) M) in coronary, but not in mesenteric or renal arteries. 3. The Ca2+-induced relaxation was also observed in the presence of established Ca2+-antagonists such as diltiazem (3 x 10(-6) M), nifedipine (3 x 10(-8) M) and verapamil (3 x 10(-6) M). 4. The Ca2+-induced relaxation was inhibited by removal of the endothelium, treatment with oxyhaemoglobin (1.5 x 10(-6) M) or methylene blue (10(-5) M), but not by treatment with indomethacin (5 x 10(-6) M). 5. The Ca2+-induced relaxation was observed in an endothelium-denuded coronary artery segment when closely apposed to an endothelium-containing segment of coronary or mesenteric artery. 6. These results suggest that Ca2+-induced relaxation in the presence of high concentrations of Ca2+-antagonists is mediated through endothelium-derived relaxing factor (EDRF). In addition, Ca2+-antagonists do not affect the Ca2+-influx necessary for the release and/or synthesis of EDRF.

Cardiovascular effects of TA-3090 ((+)(2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one maleate), a new 1,5-benzothiazepine derivative, were studied in pentobarbital anesthetized dogs. TA-3090 administered intraarterially (i.a.) was 3 times more potent than diltiazem in increasing vertebral and coronary blood flows. In the autoperfused preparation, TA-3090 i.a. exhibited weak negative inotropic effect as compared with its coronary vasodilating effect; negative inotropy was less than 10% at a dose which increased coronary blood flow by 50%. The selectivity of TA-3090 for coronary artery was greater than that of verapamil. Intravenous administration of TA-3090 (0.025-0.2 mg/kg) produced increases in cardiac output and arterial, especially vertebral and coronary blood flow as well as in left ventricular dp/dtmax. The increasing effect in blood flow was most prominent in the vertebral artery. Upon intraduodenal administration of 2 and 5 mg/kg TA-3090, the increases in vertebral and coronary blood flow lasted for more than 2-5 h; the effect of TA-3090 on vertebral blood flow was approximately twice as potent as that of diltiazem. Thus, TA-3090 could be demonstrated to possess potent and long-lasting vasodilating activity with selectivity for vertebral and coronary arteries, exerting however, weak negative inotropic effect.

The hypotensive effect of a new 1,5-benzothiazepine derivative, TA-3090 ((+) (2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one maleate), was studied in various models of experimental hypertension. In conscious spontaneously hypertensive rats (SHR), TA-3090 at a dose of 3 mg/kg p.o. or more caused significant hypotension. The effect was long-lasting, being observed for more than 8 h and 24 h at doses of 30 and 100 mg/kg p.o., respectively. Heart rate was not increased with doses up to 30 mg/kg p.o. TA-3090 like diltiazem, showed more potent hypotensive effect in SHR than in Wistar Kyoto rats (WKY). The enhancement of the hypotensive effect in SHR was more evident with TA-3090 and diltiazem than with 1,4-dihydropyridine calcium antagonists (1,4-DHPs). The enhanced hypotensive effect of TA-3090 was also observed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats in which the minimum hypotensive dose of TA-3090 was 1 mg/kg p.o. In SHR, reflex tachycardia induced by TA-3090 was smaller than those induced by 1,4-DHPs, while diltiazem decreased the heart rate. In WKY, all calcium antagonists except diltiazem at a low dose (30 mg/kg p.o.) increased the heart rate. Development of hypertension in young SHR was significantly suppressed by chronic treatment with TA-3090 at a daily dose of 10 mg/kg p.o. or more. The antihypertensive effect of TA-3090 was also observed by administration in the diet in matured SHR. In addition, TA-3090 exhibited a dose-related natriuretic but not kaliuretic effect in SHR at doses slightly higher than the hypotensive ones.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the arrhythmogenic activity of denopamine, in relation to its positive inotropic action, in dogs and compared it with those of catecholamines. The positive inotropic activities of the compounds as expressed in terms of the ED100 (microgram/kg, i.v.), that increased LV dp/dt max of anesthetized dogs by 100% of the control were 8.0 for denopamine, 0.27 for norepinephrine, 0.03 for isoproterenol, 3.8 for dobutamine and 16 for dopamine. On the other hand, the doses of these drugs at which the "non-sinus/total rate" increased significantly (about 30% of total beats, microgram/kg, i.v.) were more than 1000 for denopamine, 1.0 for norepinephrine and isoproterenol, and 300 for dobutamine and dopamine in coronary ligated dogs. The ratios of these doses to the ED100 are more than 126 for denopamine, 80 for dobutamine, 33 for isoproterenol, 19 for dopamine and 3.8 for norepinephrine. Arrhythmogenic activity of denopamine was also weaker than those of dobutamine and dopamine in halothane anesthetized dogs. The arrhythmogenic activity of dobutamine was weak as reported, but that of denopamine was the weakest among the drugs tested.