PubMed Health⌕ Search

Biomedical subjects

R Yamazaki

Publications and source records attributed to R Yamazaki.

At least 37 records · Page 2Linked to original sources
PubMed1998

Vasopressin-induction of the immediate early gene, NGFI-A, in cultured hippocampal glial cells.

Our earlier autoradiographic work had documented a wide distribution of vasopressin receptors in the hippocampus [R.E. Brinton, K.W. Gee, J.K. Wamsley, T.P. Davis, H.I. Yamamura, Regional distribution of putative vasopressin receptors in rat brain and pituitary by quantitative autoradiography, in: Proc. Natl. Acad. Sci. USA, 81 (1984) pp. 7248-7252; C. Chen, R.D. Brinton, T.J. Shors, R.F. Thompson, [Arg 8]-Vasopressin-induction of long lasting potentiation of synaptic transmission in the dentate gyrus, Hippocampus 3 (1993) 193-203.] which suggested the possibility that receptors for vasopressin were present in both neurons and glia. In the periphery, vasopressin is a potent mitogen in select proliferative cell types [E. Rozengurt, A. Legg, P. Pettican, Vasopressin stimulation of mouse 3T3 cell growth, Proc. Natl. Acad. Sci. USA, 76 (1979) pp. 1284-1287.] which also suggested a possible association between vasopressin receptor activation and the proliferative capacity of astrocytes. We therefore investigated whether vasopressin would induce the expression of the immediate early response gene, NGFI-A (also known as zif/268, ZENK, egr-1, krox 24), which is associated with initiation of mitogenesis [M. Sheng, M.E. Greenberg, The regulation and function of c-fos and other immediate early genes in the nervous system, Neuron, 4 (1990) pp. 477-485.]. Cultured hippocampal glial cells were exposed to vasopressin or a selective V1 vasopressin receptor agonist and in situ hybridization for NGFI-A mRNA was conducted. Results of these experiments demonstrated that vasopressin induced a highly significant dose-dependent increase in the number of cells expressing NGFI-A. Studies to determine the receptor subtype mediating vasopressin induction of NGFI-A were conducted utilizing the specific V1 agonist, [Phe2, Ile3, Orn8]-vasopressin. The V1 receptor agonist induced a highly significant dose dependent increase in the number of grains per NGFI-A positive cell. Time course analysis demonstrated that V1 agonist induction of NGFI-A occurred within 5 min, was maximally induced at 15 min of exposure and exhibited a gradual decline within 30 min of exposure which continued to decline over the 60 min time course. Glial cell responsivity was selective in that vasopressin and V1 agonist induction of NGFI-A occurred in a subpopulation of glial cells. Within a sea of glial cells, vasopressin and V1 agonist would induce islands of NGFI-A positive cells. Results of combined immunocytochemical labeling for the astrocyte specific marker, GFAP, and in situ hybridization for NGFI-A demonstrated that V1 agonist-induced NGFI-A expression occurred in GFAP positive cells. We observed no evidence for V1 agonist induction of NGFI-A in neurons. Collectively, these data document that vasopressin, acting via V1 vasopressin receptors, induces a highly significant increase in NGFI-A expression in select GFAP positive hippocampal astrocytes. To our knowledge, these data are the first report of a vasopressin mediated response in hippocampal glial cells. The potential functional significance of these findings is discussed.

Animals↗
PubMed1998

Anti-inflammatory effect of YPE-01, a novel diarylheptanoid derivative, on dermal inflammation in mice.

OBJECTIVE AND DESIGN: We investigated the anti-inflammatory effect of YPE-01, a novel diarylheptanoid derivative in vitro and in vivo. MATERIAL: In the in vitro study, rat basophilic leukemia (RBL-1) cells were used. For the in vivo study, ICR and ddY mice (male, 7 weeks old) were used. TREATMENT: In the in vitro study, the supernatant of RBL-1 cells lysate was incubated with 50 microM arachidonic acid (AA) and 0.01-100 microM test drugs for 15 min. RBL-1 cells were preincubated with 0.01-100 microM test drugs for 10 min before incubation with 0.5 microM calcium ionophore A23187 for 10 min. In the in vivo study, YPE-01 (0.1-3 mg/ear) was applied to the ear of mice at the same time as a 12-O-tetradecanoylphorbol 13-acetate (TPA) application or 1 h before an AA application. METHODS: In the in vitro study, the amounts of 5-hydroxyeicosatetraenoic acid and leukotrienes were measured by high-performance liquid chromatography and an enzyme immunoassay, respectively. In the in vivo study, a circular tissue sample from the ear of the mice was weighed. Statistical analysis was done using Dunnett's test. RESULTS: YPE-01 inhibited the 5-lipoxygenase activity (IC50, 0.28 microM) and the leukotriene B4 (IC50, 0.035 microM) and C4 (IC50, 0.046 microM) production by RBL-1 cells without any inhibition of cyclooxygenase activity in vitro. The topical application of YPE-01 significantly suppressed both the AA- and TPA-induced ear edemas in vivo. CONCLUSIONS: YPE-01 is a selective 5-lipoxygenase inhibitor with a suppressive effect against dermal inflammation.

Animals↗
PubMed1998

Omeprazole induces altered bile acid metabolism.

BACKGROUND: It has been reported that the acidity of gastric contents could be an important factor in regulating jejunal flora. AIMS: To investigate the effects of omeprazole induced changes in gastric pH on jejunal flora and bile acid metabolism. METHODS: Twenty one patients with gastric ulcer and 19 healthy volunteers were studied. Deconjugation of bile acids was detected using a bile acid breath test. Jejunal fluid was aspirated using a double lumen tube with a rubber cover on the tip and deconjugation was examined using thin layer chromatography. Fat malabsorption was detected by a triolein breath test. RESULTS: In the bile acid breath test, expired breath samples from all patients and healthy volunteers showed significantly greater 14CO2 specific activity after omeprazole treatment (20 mg/day) than before treatment. Bacterial overgrowth was found in the jejunal fluid and gastric juice of both ulcer patients and healthy volunteers after omeprazole treatment. The following species were identified: Escherichia coli, Candida albicans, enterococcus, Lactobacillus bifidus, Bacteroides vulgatus, B uniformis, Eubacterium lentum, Eu parvum, and Corynebacterium granulosum. All of these species, except E coli and C albicans, deconjugate bile acids. There was a significant correlation between 14CO2 activity and gastric pH, both before and after omeprazole treatment in both groups. The triolein breath test revealed impaired fat absorption in both groups after omeprazole treatment. CONCLUSIONS: Both patients with gastric ulcer and healthy volunteers exhibited increased deconjugation of bile acids caused by bacterial overgrowth in the jejunum and fat malabsorption after omeprazole treatment. The bacterial over-growth consisted of both anaerobes and aerobes with deconjugation ability and was probably associated with an omeprazole induced shift to neutral pH in the gastric juice.

Adult↗
PubMed1998

Continuous binding of the PAF molecule to its receptor is necessary for the long-term aggregation of platelets.

Human and rabbit platelets fully aggregated by platelet-activating factor (PAF) underwent slow disaggregation but were rapidly disaggregated by the PAF receptor antagonists WEB-2086, Y-24180, SM-12502, and CV-3988. Whereas the 1-alkyl-2-[3H]acetyl-sn-glycero-3-phosphocholine ([3H]acetyl-PAF) specifically bound to platelet receptors underwent slow and spontaneous dissociation, it dissociated promptly from its receptor when WEB-2086 was added, in parallel with platelet disaggregation and disappearance of P-selectin on the cell surface. Extracellular [3H]acetyl-PAF was rapidly deacetylated by normal rabbit platelets; some of the [3H]acetyl-PAF was bound to the cells and a very small amount of [3H]acetate was detected in the cells. In contrast, when 1-[3H]alkyl-2-acetyl-sn-glycero-3-phosphocholine was added to the platelets, the radioactivity was rapidly incorporated into the 1-alkyl-2-acyl-sn-glycero-3-phosphocholine fraction. These results indicate that 1) continuous binding of PAF to its receptor is necessary for prolonged platelet aggregation, which may be mediated through an unknown signaling system for a long-term cell response rather than a transient signaling system, and 2) most of the [3H]acetyl-PAF bound to platelets is metabolized extracellularly by ecto-type PAF acetylhydrolase, with the lyso-PAF generated being incorporated rapidly into the cells and converted to 1-alkyl-2-acyl-sn-glycero-3-phosphocholine.

Animals↗
PubMed1998

The effect of oral feeding of Lactobacillus casei strain Shirota on immunoglobulin E production in mice.

We investigated the effect of oral feeding of heat-killed Lactobacillus casei strain Shirota on immunoglobulin E (IgE) production in mice. The strain was orally administered to BALB/c mice that had been preinjected intraperitoneally with ovalbumin, and the level of IgE in serum was determined. Results indicated that the oral feeding of L. casei strain Shirota was effective in inhibiting IgE production in serum, and the IgE production in response to ovalbumin was significantly inhibited in the mice. The in vitro production of IgE by the spleen cells from mice fed L. casei strain Shirota in response to restimulation with ovalbumin was inhibited in contrast to that of spleen cells from the control group. We also examined the pattern of cytokine production by spleen cells from mice fed L. casei strain Shirota followed by restimulation with ovalbumin in vitro. In the mice fed L. casei strain Shirota, the production by the spleen cells of Th1 cell-associated cytokines, such as interferon-gamma and interleukin-2, was higher than that by the spleen cells from the control group. In contrast, the production of Th2 cell-associated cytokines, such as interleukin-4, interleukin-5, interleukin-6, and interleukin-10, by spleen cells in the group fed L. casei strain Shirota was lower than that by the cells from the control group. Furthermore, the interleukin-12 production of the spleen cells from mice fed L. casei strain Shirota was also higher than that of the control group.

Animals↗
PubMed1997

Aceclofenac blocks prostaglandin E2 production following its intracellular conversion into cyclooxygenase inhibitors.

Aceclofenac, 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid, is a novel non-steroidal anti-inflammatory drug. We investigated the effects of aceclofenac on prostaglandin E2 production by several kinds of human cells. Aceclofenac inhibited interleukin-1beta-induced prostaglandin E2 production by human rheumatoid synovial cells, but had no inhibitory effect on cyclooxygenase-1 or cyclooxygenase-2 activities by itself. We also observed that part of the aceclofenac was converted into diclofenac, the cyclooxygenase-1 and cyclooxygenase-2 inhibitor, when aceclofenac was incubated with human rheumatoid synovial cells. Aceclofenac was also converted into diclofenac and 4'-hydroxy diclofenac by human polymorphonuclear leukocytes and monocytes. 4'-Hydroxy diclofenac suppressed prostaglandin E2 production specifically by blocking cyclooxygenase-2 activity. These findings suggested that aceclofenac can be metabolized to cyclooxygenase inhibitors (diclofenac and/or 4'-hydroxy diclofenac) by these inflammatory cells. Although detailed examinations in non-inflammatory cells remain to be studied, we concluded that aceclofenac is shown to be a new type of non-steroidal anti-inflammatory drug which is intracellulary converted into active metabolites that inhibit the prostaglandin E2 production.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Antidiabetic effects of an oral administration of Lactobacillus casei in a non-insulin-dependent diabetes mellitus (NIDDM) model using KK-Ay mice.

The antidiabetic effects of Lactobacillus casei (LC) on a non-insulin-dependent diabetes mellitus (NIDDM) model, KK-Ay mice, were investigated. The oral administration of LC to male 4-week-old KK-Ay mice, or raising the mice on a 0.05% LC-containing diet significantly decreased the plasma glucose at 8 to 10 weeks of age compared with the control group. The body weights of the LC-treated groups were lower than those of the control group, although the food intake was nearly the same in all groups. Phenotypic analysis of spleen cell surface markers revealed that the increase in CD4+ T cells at 12 weeks was significantly inhibited by the oral treatment with LC. Cytokine production, especially that of interferon-gamma and interleukin 2, was also inhibited in the oral LC-treated group. The plasma insulin levels of the LC-treated groups were also lower than those of the control group, and the insulin binding potential of red blood cells in the LC-treated mice was augmented more than that in the control group. Taken together, these findings led us to conclude that the oral administration of LC in the NIDDM model mice, KK-Ay, was involved in the decrease in the plasma glucose level and modified the host immune responses.

Animals↗
PubMed1996

Decreased contractile effect of endothelin-1 on hyperplastic prostate.

1. The contractile activity, binding activity and localization of endothelin (ET)-1 were evaluated in human nonhyperplastic (control) and hyperplastic prostates. 2. ET-1 caused contraction of both prostates in a dose-dependent manner. However, this contraction was markedly decreased in hyperplastic prostates. 3. Bmax and Kd values of hyperplastic prostates were greater than those of the control. 4. The muscle and proliferative epithelium of hyperplastic prostates showed strong staining for the anti-ET-1 antibody. However, the glandular epithelium of control prostates was weakly stained. 5. These findings indicate that responsiveness to ET-1 is decreased, though the ET-1 and ET-1 receptors increase in the hyperplastic prostate. Namely, the increase in ET-1 receptors is not effective in regulating the contractile response of the prostate, because its expression is rather dominant in proliferated gland. 6. These suggest that ET-1 may not have an important role in the release of the obstructive symptoms of benign prostatic hypertrophy.

Aged↗
PubMed1996

Biliary excretion of estradiol-17 beta-glucuronide in the rat.

Estradiol-17beta-glucuronide (E217G) is a cholestatic agent and is considered to be related to the pathogenesis of intrahepatic cholestasis of pregnancy. In the current study, we examined the mechanism of the biliary excretion of E217G and estradiol metabolites in rats. Biliary excretion of tracer doses of [3H]estradiol-17beta-glucuronide and [14C]estradiol or [3H]taurocholate and ]14C]vinblastine, a P-glycoprotein (P-GP) substrate, intravenously administered as a bolus to bile-drained control rats or EHBR was studied. Biliary excretion of E217G and estradiol metabolites EHBR was markedly delayed. Analyses of biliary metabolites after estradiol injection showed less polar conjugates in EHBR. In contrast, the excretion of taurocholate and vinblastine (VLB) was only slightly delayed in EHBR. Although phenothiazine treatment to induce the expression of P-GP increased biliary vinblastine excretion, it did not affect biliary excretion of a tracer dose of [3H]estradiol-17beta-glucuronide. However, phenothiazine treatment inhibited the cholestasis induced by E217G infused at the rate of 0.075 micromol/min/100g for 20 minutes and increased biliary E217G excretion. Sulfobromophthalein infusion (0.2 micromol/min/100 g body 0 weight) markedly inhibited the biliary excretion of E217G and estradiol metabolites, whereas dibromosulfophthalein (DBSP) at the same infusion rate had no effect. These findings indicate that EG17G is excreted into bile by a canalicular organic anion carrier for sulfobromopthalein (BSP), not for DBSP, under physiological conditions, and that P-GP influences E217G excretion only at a high dose. under physiological conditions, and that P-GP influence s E217G excretion only at a high dose.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Urodynamic analysis of age-related changes of alpha 1-adrenoceptor responsiveness in female beagle dogs.

PURPOSE: We have evaluated age-related changes of alpha 1-adrenoceptor responsiveness in the lower urinary tract of female beagle dogs by urodynamic analyses. MATERIALS AND METHODS: Six aged parous and 6 young nonparous female beagle dogs were studied. Mean ages (+/- standard error of the mean) of the 2 groups were 68.3 +/- 2.3 and 12.4 +/- 0.08 months. Before and after 4 administrations of alpha 1-adrenoceptor agonist (midodrine hydrochloride 0.03, 0.1, 0.3 and 1.0 mg./kg. intravenously), cystometry, urethral pressure profilometry and external urethral sphincter electromyography were performed. RESULTS: After 0.3 mg./kg. midodrine administration, mean bladder capacity in the aged dogs significantly decreased, compared with that in the young dogs (p < 0.05). After the minimum dose administration (0.03 mg./kg.), the urethral closing pressure in both groups increased significantly (p < 0.05) with no changes in bladder capacity or arterial blood pressure. The proximal urethral closing pressure in the aged dogs increased dose dependently. After administration of 1.0 mg./kg. drug it reached 257% of the initial values (p < 0.01), which was significantly greater than that in the young dogs (p < 0.05). CONCLUSIONS: These findings suggest that 1) age-related increase of alpha 1-adrenoceptor responsiveness occurs in the bladder and in the proximal urethra. The former may be one of the etiologies of detrusor instability in the elderly. 2) A lower dose of midodrine hydrochloride may be useful for the treatment of stress incontinence, independent of age.

Adrenergic alpha-Agonists↗
PubMed1996

Alteration of bile acid metabolism by cimetidine in healthy humans.

BACKGROUND: To clarify an effect of cimetidine on bile acid metabolism, we evaluated whether an increased deconjugation of bile acids would occur in healthy humans who have received cimetidine. We examined: 1) whether healthy volunteers taking cimetidine would have positive bile acid breath tests because of bacterial overgrowth in the jejunum; 2) whether the isolated bacteria would exhibit deconjugation ability; and 3) whether a change in gastric pH was related to the bacterial overgrowth. METHODS: We evaluated 73 healthy Japanese volunteers; 53 of them received cimetidine and 20 did not. Deconjugation of bile acids was detected as 14CO2 specific activity of expired air measured by a bile acid breath test giving 5 muCi of oral glycine-1-(14)C labeled glycocholate. Aspiration of jejunal fluids was performed by a double lumen tube with a rubber cover on the tip, and deconjugation ability of bacteria was evaluated using thin layer chromotography. RESULTS: Samples of expired breath from the 53 healthy volunteers showed a significant increase in 14CO2 specific activity after the administration of cimetidine rather than before the administration of cimetidine. Bacterial over-growth was found in the jejunal fluid after the administration of cimetidine. The administration of tetracycline to 27 subjects significantly reduced the 14CO2 specific activity. The following species were identified in the jejunal fluid samples obtained from the subjects: enterococcus, Lactobacillus bifidus, Bacteroides vulgatus, B uniformis, Eubacterium lentum, E parvum, and Escherichia coli. Except for E coli, all of the bacterial species identified deconjugated bile acids. We observed a significant relationship between 14CO2's specific activity and gastric pH before and after administration of cimetidine, respectively. CONCLUSIONS: Healthy volunteers who received cimetidine showed an increased deconjugation of bile acid caused by overgrowth of bacteria in the jejunum, which can deconjugate bile acids. The bacterial overgrowth is probably associated with a shift to neutral pH in the gastric juice caused by cimetidine.

Adult↗
PubMed1995

Colchicine inhibits lithocholate-3-O-glucuronide-induced cholestasis in rats.

BACKGROUND/AIMS: It has been suggested that vesicular transport of bile acids in hepatocytes occurs, especially at high-dose loads. METHODS: The effect was studied of colchicine, a vesicular transport inhibitor, on lithocholate-3-O-glucuronide-induced cholestasis in rats. Cholestasis was induced by an intravenous infusion of lithocholate-3-O-glucoronide at the rate of 0.1 mumol.min-1.100 g-1 for 40 min. RESULTS: Colchicine treatment almost completely inhibited cholestasis and increased biliary excretion of lithocholate-3-O-glucoronide, whereas lumicolchicine had no effect. Treatment with vinblastine, another vesicular transport inhibitor, also reduced the cholestasis. Colchicine did not affect biliary excretion of taurocholate infused at the rate of 0.3 mumol.min-1.100 g-1 for 40 min, but markedly inhibited its biliary excretion when infused at the rate of 1.5 mumol.min-1.100 g-1 for 40 min. Colchicine had no effect on biliary excretion of tauroursodeoxycholate (1.5 mumol.min-1.100 g-1 for 40 min), lithocholate-3-sulfate (0.3 mumol.min-1.100 g-1 for 40 min), or a trace amount of lithocholate-3-O-glucuronide. CONCLUSIONS: These findings indicate that lithocholate-3-O-glucoronide-induced cholestasis is caused by its increased access to the vesicular transport pathway, possibly beyond the capacity of the transport by the cytosolic binders, and that the transport of lithocholate-3-O-glucoronide via the vesicular pathway induces cholestasis. Furthermore, the contribution of the vesicular pathway to hepatic transport may be different among bile acids, and lithocholate-3-O-glucuronide seems to have higher accessibility to this transport system.

Animals↗
PubMed1995

[Hemorrhagic cerebral infarction at the old age in a case with familial antithrombin III (ATIII) deficiency].

An old woman had stroke at age 67. Cerebral CT scan disclosed the low-density lesion with high-density area in the left temporal lobe, but no empty delta sign in the superior sagittal sinus. Thereafter, she had sometimes panic attacks. At the age of 70, she was admitted because of loss of consciousness probably caused by the same attack. On admission, Brain CT scan showed no fresh lesions. During the stay in the hospital, she had an episode of deep vein thrombosis of her left leg. The patient was found to have not only reduced biochemical activity but also low immunological level of AT III. Her nephew had also the low plasma AT III antigen concentration. Transesophageal echocardiography showed no abnormality, but atherosclerotic change at the aortic arch. We speculated that hemorrhagic cerebral infarction in the territory of the branch of middle cerebral artery could be induced by the arterial thrombus which was related to the hypercoagulable state associated with familial AT III deficiency, although the possibility of cardiogenic embolic infarction or of cerebral vein thrombosis could not be ruled out. Familial AT III deficiency is one of the causes of cerebral infarction even in the elderly.

Aged↗
PubMed1994

Development of a novel method for determination of acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase activity and its application to screening for acetyltransferase inhibitors. Inhibition by magnolol and honokiol from Magnoliae cortex.

A method was developed for determining the activity of acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase (EC 2.3.1.67), a key enzyme in the biosynthesis of platelet-activating factor (PAF, 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine). The assay involves measurement of the radioactivity in the trichloroacetic acid (TCA)-precipitated complex of radioactive product and albumin after incubation of 1-alkyl-sn-glycero-3-phosphocholine and [3H]acetyl-CoA with rat spleen microsomes or membrane fractions of human polymorphonuclear leukocytes (PMNs). The radioactive product associated with the precipitate was identified as PAF using an ultrahigh-sensitivity TV camera system after extraction and separation by TLC. This TCA method was then used to screen the components of crude preparations that inhibited acetyltransferase activity. Major components from the cortex of Magnoliae (magnolol and honokiol), which have anti-inflammatory and anti-bacterial actions, inhibited the acetyltransferase activity in rat spleen microsomes (IC50, 150 and 150 microM, respectively) and membrane fractions of human PMNs (IC50, 70 and 60 microM, respectively). The inhibitory action of magnolol and honokiol was reversible, and similar to or higher than that of nordihydroguaiaretic acid. PAF production in human PMNs stimulated by the ionophore A23187 was also suppressed dose dependently by magnolol and honokiol. These activities may be relevant to the claimed therapeutic effects of the extract from Magnoliae cortex.

Acetyltransferases↗
PubMed1994

Multidirectional contraction of human hypertrophied prostate.

1. The purpose of the present investigation is to evaluate muscle contraction in two directions (longitudinal and circumferential to urethra) physiologically and morphologically for alpha-adrenoceptor agonists. 2. Norepinephrine (10(-7)-10(-4) M), phenylephrine (10(-7)-10(-4) M) and clonidine (10(-7)-10(-4) M) induced contractions in a dose-dependent manner on human prostate from patients with benign prostatic hypertrophy (BPH). 3. No significant differences were observed between longitudinal and circumferential directions of human prostate in 50% of the maximal muscle contraction (EC50 values) and the maximal muscle contractions caused by any agents used. 4. Morphometric analysis for muscle in prostates was performed using formalin-fixed, paraffin-embedded sections stained by the Mallory-Azan method. 5. There was no significant difference in the density of the muscle area between longitudinal and circumferential directions of prostatic strips. 6. These results suggest that there are no significant differences in responsiveness of alpha-adrenoceptor agonists and the smooth muscle contents in longitudinal and circumferential directions to urethra, for human hypertrophied prostate.

Adrenergic alpha-Agonists↗
PubMed1993

Antitumor agents. 3. Synthesis and biological activity of 4 beta-alkyl derivatives containing hydroxy, amino, and amido groups of 4'-O-demethyl-4-desoxypodophyllotoxin as antitumor agents.

A series of 4 beta-alkyl (7-10), 4 beta-aminoalkyl (12a-y), and 4 beta-amidoalkyl derivatives (14a-g) of 4'-O-demethyl-4-desoxypodophyllotoxin have been synthesized, and their cytotoxicity, inhibition of DNA topoisomerase II (Topo II), and tubulin polymerization were evaluated. All derivatives of 12a-y and 14a-g did not inhibit tubulin polymerization. Many compounds exhibited cytotoxicity and inhibition of Topo II. In particular, 12o, 12s, 12t, and 12u strongly inhibited Topo II (IC50 (microM) 32.5, 60.9, 58.8, and 33.6, respectively) and were strong cytotoxicity against P388 cells (IC50 (M) 1.0, 4.1, 3.3, and 3.0 x 10(-9), respectively), compared with VP-16 (IC50 (microM) 59.2, IC50 (M) 1 x 10(-8), respectively). These compounds were nearly equal to or superior to VP-16 in antitumor activity in vivo (L1210, P388, and Lewis lung) and were more cytotoxic against various human cell lines in vitro than VP-16.

Animals↗
PubMed1993

Synthesis and pharmacological evaluation of (nitrooxy)alkyl apovincaminates.

A series of (nitrooxy)alkyl apovincaminates has been synthesized and evaluated for their effects on vertebral and femoral blood flow. These derivatives were prepared from apovincaminic acid (4). In cerebral circulation, compound 5 (0.03-1.0 mg/kg iv) caused a dose-dependent increase in cerebral blood flow (CerBF) without affecting the blood pressure. It was more potent than vinpocetine (2). The structures of 2 and 5, determined by X-ray crystallography, showed differences in the electrostatic potential image and in the conformation of the ethyl group at the 16-position.

Animals↗