Postcomparison of [(18) F]-fluorodeoxyglucose uptake in the brain after short-term bright light exposure and no intervention.

OBJECTIVE: Bright light therapy is widely used as the treatment of choice for seasonal affective disorder. Nonetheless, our understanding of the mechanisms of bright light is limited and it is important to investigate the mechanisms. The purpose of this study is to examine the hypothesis that bright light exposure may increase [(18) F]-fluorodeoxyglucose (FDG) uptake in olfactory bulb and/or hippocampus which may be associated neurogenesis in the human brain. METHOD: A randomized controlled trial comparing 5-day bright light exposure + environmental light (bright light exposure group) with environmental light alone (no intervention group) was performed for 55 participants in a university hospital. The uptake of [(18) F]FDG in olfactory bulb and hippocampus using FDG positron emission tomography was compared between two groups. RESULTS: There was a significant increase of uptake in both right and left olfactory bulb for bright light exposure group vs. no intervention group. After adjustment of log-transformed illuminance, there remained a significant increase of uptake in the right olfactory bulb. CONCLUSION: The present findings suggest a possibility that 5-day bright light exposure may increase [(18) F]FDG in the right olfactory bulb of the human brain, suggesting a possibility of neurogenesis. Further studies are warranted to directly confirm this possibility.

Molecular cloning and characterization of Th1 and Th2 cytokines of African buffalo (Syncerus caffer).

The African buffalo (Syncerus caffer) has been implicated as the reservoir of several bovine infectious agents. However, there is insufficient information on the protective immune responses in the African buffalo, particularly in infected animals. In this study, we analysed Th1 cytokines IL-2 and IFN-γ, and Th2 cytokines IL-4 and IL-10. The cloned cDNA of IL-2, IL-4, IL-10 and IFN-γ contained an open reading frame of 468, 501, 408 and 540 nucleotides, encoding polypeptides of 155, 166, 135 and 179 amino acids, respectively. Nucleotide sequence homology of IL-2, IFN-γ and IL-4 was more than 98% between the African buffalo and cattle, which resulted in identical polypeptides. Meanwhile, IL-10 gene of African buffalo and cattle had 95% homology in nucleotide sequence, corresponding to thirteen amino acid residues substitution. Cysteine residues and potential glycosylation sites were conserved within the family Bovinae. Phylogenetic analyses including cytokines of the African buffalo placed them within a cluster comprised mainly of species belonging to the order Artiodactyla, including cattle, water buffalo, sheep, goat, pig and artiodactyl wildlife. A deeper understanding of the structure of these cytokines will shed light on their protective role in the disease-resistant African buffalo in comparison with other closely related species.

Effects of tea catechin inhalation on methicillin-resistant Staphylococcus aureus in elderly patients in a hospital ward.

We investigated the effects of inhalation of tea catechin on MRSA in the 24 elderly in patients, who were known to carry MRSA in sputum. The patients in the catechin group (N=12) were administered an inhalation of tea catechin extracts (in saline/bromhexine) (3.7 g/L catechins, 43% of them are composed of epigallocatechin gallate), three times daily with hand nebulizer for four weeks. The clinical effects were compared with the control group (N=12) who were given an inhalation of saline/bromhexine alone. After a week of the course, the numbers of the patients with decreased or disappearance of MRSA in their sputum was significantly higher in the catechin group, compared with that in the control group (seven vs. no patients; P<0.05). The number of patients discharged during the study was significantly increased, and the days of hospital stay were significantly decreased in the catechin group compared with those in the control group (six vs. one patient; P<0.05, 51+/-22 vs. 85+/-50 days, mean+/-S.D.;P <0.05, respectively). No adverse effects were observed in any patients during the study. Catechin inhalation seemed to be safe, and at least temporarily effective in the reduction of MRSA and shortening of hospitalization.

Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19.

BACKGROUNDS AND AIM: Lansoprazole is mainly metabolized by cytochrome P4502C19 (CYP2C19) in the liver. The effect of lansoprazole is assumed to be insufficient in subjects who are homozygous extensive metabolizers of CYP2C19. This study aimed to examine whether the CYP2C19 genotype status affected the acid-inhibitory effects of lansoprazole and to develop a strategy to overcome this pharmacogenetic problem. METHODS: Eighteen Helicobacter pylori-negative healthy volunteers, whose CYP2C19 genotypic status had been assessed, participated in the study. They consisted of 7 subjects who were homozygous extensive metabolizers, 7 subjects who were heterozygous extensive metabolizers, and 4 subjects who were poor metabolizers of CYP2C19, who took a placebo or lansoprazole 30 mg once daily in the morning for 8 days. On day 8 of dosing, 24-hour intragastric pH values were recorded. Five of the homozygous extensive metabolizer subjects underwent the 24-hour intragastric pH monitoring on day 8 of dosing of lansoprazole 30 mg 4 times daily. RESULTS: When lansoprazole 30 mg was given once daily, the mean 24-hour intragastric pH values in the subjects who were homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 4.5, 4.9, and 5.5, respectively (P <.005). On day 8 of dosing of lansoprazole 30 mg 4 times daily in subjects who were homozygous extensive metabolizers, the mean 24-hour intragastric pH value was 7.4. CONCLUSION: The effect of lansoprazole on intragastric pH depended significantly on CYP2C19 genotype status. Complete acid inhibition could be achieved by the frequent administration of lansoprazole (eg, 30 mg 4 times daily) in subjects who were homozygous extensive metabolizers. A genotyping test of CYP2C19 status appears useful for prescribing an optimal dosing scheme of lansoprazole.

Insulin inhibits coronary endothelial cell calcium entry and coronary artery relaxation.

Hyperinsulinemia is closely related to coronary artery disease. Endothelial cells are important for the control of vascular tone, and dysfunction of endothelial cells has been implicated in coronary artery disease. The direct effects of insulin on coronary endothelial cells are nonetheless unknown. In this study, the acute effects of high-dose insulin were investigated on agonist-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) in porcine coronary endothelial cells and coronary relaxation. Bradykinin (10 n M ) and cyclopiazonic acid (100 microM), an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, provoked large increases in [Ca(2+)](i) in coronary endothelial cells. This increase was dose-dependently inhibited by a 10-min preincubation with high doses of insulin (10, 30, 100 mU/ml). Under Ca(2+)-free conditions, bradykinin and cyclopiazonic acid provoked transient, small increases in [Ca(2+)](i). These increases were not affected by pretreatment with insulin (100 mU/ml). Bradykinin (1, 10, 100, 1,000 n M ) and cyclopiazonic acid (10 microM) significantly relaxed porcine coronary artery rings precontracted with histamine (1 microM). The vasodilator effects of bradykinin and cyclopiazonic acid were dose-dependently inhibited by insulin. These acute effects were not observed at physiologic concentrations. Our data indicate that high-dose insulin inhibits agonist-induced Ca(2+) response in coronary endothelial cells and attenuates agonist-induced coronary vasodilatation. The study suggests that hyperinsulinemia might be associated with coronary artery disease via derangement of endothelial Ca(2+)-dependent functions.

Expression of two subtypes of human IFN-alpha in transgenic potato plants.

Plant expression systems have advantages over other in vitro expression systems in terms of low production costs and low risk of contamination by animal viruses or bacterial endotoxins. In this study, cDNA encoding two subtypes of human interferon-alpha2b and 8 (HuIFN-alpha2b and HuIFN-alpha8) were introduced into potato plants (Solanum tuberosum) using Agrobacterium-mediated transformation. Transcription and translation of the inserted HuIFN-alpha cDNA were confirmed by Northern blot analysis and ELISA, respectively. Bioactivity of the products was assayed by inhibition of vesicular stomatitis virus (VSV) replication on a human amniotic cell line. However, because of the presence of substances in potato tissue extracts that were toxic to animal cells, successful demonstration of IFN bioactivity in the transformants was achieved only after removal of such substances by dialysis. The maximum level of IFN activity in plant extracts was 560 IU/g of tissue. These results indicated that the HuIFN-alpha gene introduced into the potato plant was correctly translated and transcribed in plant cells. This report for the first time shows that biologically active animal cytokines with potential pharmaceutical applications could be expressed in transgenic potato plants.

Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin.

Rabeprazole is a potent proton pump inhibitor and is mainly reduced to thioether rabeprazole by a non-enzymatic pathway and partially metabolized to demethylated rabeprazole by CYP2C19 in the liver. We intended to determine a cure rate for Helicobacter pylori infection by dual rabeprazole/amoxicillin therapy in relation to CYP2C19 genotype status prospectively. Ninety-seven patients with gastritis and H. pylori infection completed the dual therapy with 10 mg of rabeprazole bid and 500 mg of amoxicillin tid for 2 weeks. At 1 month after treatment, cure of H. pylori infection was assessed on the basis of histology, a rapid urease test, culture, polymerase chain reaction (PCR), and 13C-urea breath test. CYP2C19 genotype status was determined by a PCR-restriction fragment length polymorphism method. Of the 97 patients, 33 were homozygous extensive metabolizers (homEM), 48 were heterozygous extensive metabolizers (hetEM), and 16 were poor metabolizers (PM). Cure of H. pylori infection was achieved in 79 of the 97 patients (81.4%, 95%CI = 71.9-88.7). Significant differences in cure rates among the homEM, hetEM, and PM groups were observed; 60.6% (95%CI = 42.1-77.3), 91.7% (95%CI = 80.0-97.7), and 93.8% (95%CI = 69.8-99.8), respectively (P = 0.0007). Twelve patients without cure after initial treatment (10 homEMs and 2 hetEMs) were successfully retreated with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. for 2 weeks. The cure rates for H. pylori infection by dual rabeprazole/amoxicillin therapy depended on the CYP2C19 genotype status. This dual therapy appears to be effective for hetEM and PM patients. However, high dose dual rabeprazole/amoxicillin therapy was effective even for homEM patients. Therefore, the genotyping test of CYP2C19 appears to be a clinically useful tool for the optimal dual treatment with rabeprazole plus amoxicillin.

Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin.

BACKGROUND: Proton pump inhibitors such as omeprazole and lansoprazole are mainly metabolized by CYP2C19 in the liver. The therapeutic effects of proton pump inhibitors are assumed to depend on CYP2C19 genotype status. OBJECTIVE: We investigated whether CYP2C19 genotype status was related to eradication rates of H pylori by triple proton pump inhibitor-clarithromycin-amoxicillin (INN, amoxicilline) therapy and attempted to establish a strategy for treatment after failure to eradicate H pylori. METHODS: A total of 261 patients infected with H pylori completed initial treatment with 20 mg of omeprazole or 30 mg of lansoprazole twice a day, 200 mg of clarithromycin three times a day, and 500 mg of amoxicillin three times a day for 1 week. CYP2C19 genotypes of patients were determined with polymerase chain reaction-restriction fragment length polymorphism analysis. Patients without eradication after initial treatment were retreated with 30 mg of lansoprazole four times daily and 500 mg of amoxicillin four times daily for 2 weeks. RESULTS: Eradication rates for H pylori were 72.7% (95% confidence interval, 64.4%-81.8%), 92.1% (confidence interval, 86.4%-97.3%), and 97.8% (confidence interval, 88.5%-99.9%) in the homozygous extensive, heterozygous extensive, and poor metabolizer groups, respectively. Thirty-four of 35 patients without eradication had an extensive metabolizer genotype of CYP2C19. Nineteen of those patients were infected with clarithromycin-resistant strains of H pylori. However, there were no amoxicillin-resistant strains of H pylori. Re-treatment of H pylori infection with dual high-dose lansoprazole-amoxicillin therapy succeeded in 30 of 31 patients with extensive metabolizer genotype of CYP2C19. CONCLUSION: The majority of patients without initial eradication of H pylori had an extensive metabolizer CYP2C19 genotype but were successfully re-treated with high doses of lansoprazole and an antibiotic to which H pylori was sensitive, such as amoxicillin, even when the patients were infected with clarithromycin-resistant strains of H pylori.

Antibacterial action of tryptanthrin and kaempferol, isolated from the indigo plant (Polygonum tinctorium Lour.), against Helicobacter pylori-infected Mongolian gerbils.

We evaluated the effect of tryptanthrin and kaempferol, both isolated from Polygonum tinctorium Lour., against Helicobacter pylori colony formation in vitro and in H. pylori-infected Mongolian gerbils. H. pylori suspension was mixed with solution of tryptanthrin and/or kaempferol and placed onto agar plates. These plates were incubated at 37 degrees C, under 10% CO2 for 5 days, and the H. pylori colonies were counted. For the in vivo experiment, Mongolian gerbils were inoculated with H. pylori ATCC 43504 orally. After 4 weeks, the infected gerbils were given tryptanthrin and/or kaempferol, administered orally, twice a day for 10 days. The animals were killed and the number of live H. pylori in their stomachs was determined. In vitro both tryptanthrin and kaempferol significantly decreased the numbers of H. pylori colonies a dose-dependent manner. An additive effect on colony formation was observed with the combined use. In the in vivo experiment, oral administration of tryptanthrin and/or kaempferol significantly decreased the numbers of colonies in the gerbils' stomachs. We concluded that tryptanthrin and kaempferol were effective against H. pylori in vivo.

Analysis of anti-rotavirus activity of extract from Stevia rebaudiana.

Anti-human rotavirus (HRV) activity of hot water extracts from Stevia rebaudiana (SE) was examined. SE inhibited the replication of all four serotypes of HRV in vitro. This inhibitory effect of SE was not reduced on the prior exposure of SE to HCl for 30 min at pH 2. Binding assay with radiolabeled purified viruses indicated that the inhibitory mechanism of SE is the blockade of virus binding. The SE inhibited the binding of anti-VP7 monoclonal antibody to HRV-infected MA104 cells. The inhibitory components of SE were found to be heterogeneous anionic polysaccharides with different ion charges. The component analyses suggested that the purified fraction named as Stevian with the highest inhibitory activity consists of the anionic polysaccharide with molecular weight of 9800, and contains Ser and Ala as amino acids. Analyses of sugar residues suggest uronic acid(s) as sugar components. It did not contain amino and neutral sugars and sulfate residues. These findings suggest that SE may bind to 37 kD VP7 and interfere with the binding of VP7 to the cellular receptors by steric hindrance, which results in the blockade of the virus attachment to cells.

[Chirality of natural products: hyoscyamine and scopolamine].

Monthly changes of the content-ratio between S-(-)- and R-(+)-hyoscyamine as well as those between S-(-)- and R-(+)-scopolamine in the leaves of Datura metel L. cultivated in the field, were quantitatively analyzed by the use of HPLC with a chiral adsorbent. It was found that S-(-)-isomer was predominant for hyoscyamine and the ratio of R-(+)-isomer gradually increased during the growth, whereas in the case of scopolamine, S-(-)-isomer was the sole one found throughout the cultivation period. The 1H-NMR study in the CD3OD solution has suggested that S-(-)-hyoscyamine (1) and S-(-)-scopolamine (2) take a "face-to-face" conformation between their tropane skeletons and the benzene rings of the tropic acid moieties. In the presence of an equimolar NaOD in the CD3OD solution, the racemization at C-2' of 1 and 2 proceeded more rapidly than the hydrolysis at the tropic acid ester bond, presumably due to the steric hindrance caused by their "face-to-face" conformations. In the D2O and H2O solutions, on the other hand, the racemization and the hydrolysis of 1 proceeded smoothly, while those of 2 did not occur. It has been supposed that these individual reaction manners are ascribable in considerable extent to the different basicity of N atom in each tropane skeleton of 1 and 2 and to stronger intramolecular hydrogen bond occurring between the carbonyl oxygen at C-1' and the hydroxyl group at C-3' in the tropic acid moiety of 1.

Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.

Abetalipoproteinemia (ABL) is an inherited disease characterized by the virtual absence of apolipoprotein B (apoB)-containing lipoproteins from plasma. Only limited numbers of families have been screened for mutations in the microsomal triglyceride transfer protein (MTP) gene. To clarify the genetic basis of clinical diversity of ABL, mutations of the MTP gene have been screened in 4 unrelated patients with ABL. Three novel mutations have been identified: a frameshift mutation caused by a single adenine deletion at position 1389 of the cDNA, and a missense mutation, Asn780Tyr, each in homozygous forms; and a splice site mutation, 2218-2A-->G, in a compound heterozygous form. The frameshift and splice site mutations are predicted to encode truncated forms of MTP. When transiently expressed in Cos-1 cells, the Asn780Tyr mutant MTP bound protein disulfide isomerase (PDI) but displayed negligible MTP activity. It is of interest that the patient having the Asn780Tyr mutation, a 27-year-old male, has none of the manifestations characteristic of classic ABL even though his plasma apoB and vitamin E were virtually undetectable. These results indicated that defects of the MTP gene are the proximal cause of ABL.

Cure of refractory duodenal ulcer and infection caused by Helicobacter pylori by high doses of omeprazole and amoxicillin in a homozygous CYP2C19 extensive metabolizer patient.

A 53-year old female patient with duodenal ulcer and Helicobacter pylori infection was treated three times with a proton pump inhibitor-based triple therapy, such as lansoprazole-clarithromycin-amoxicillin (INN, amoxicilline) and lansoprazole-minocycline-cefaclor. However, the H pylori infection was not cured. A culture test revealed that her infection was a clarithromycin-resistant but amoxicillin-sensitive strain of H pylori. Moreover, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis revealed that she was a homozygous extensive metabolizer of cytochrome P450 (CYP) 2C19 (wt/wt). The usual dose of the proton pump inhibitor was therefore assumed to be insufficient for her and then she was treated with a high dose of omeprazole (120 mg/day) and amoxicillin (2,250 mg/day) for 2 weeks. The H pylori infection and the ulcer lesion were then cured. One of the factors associated with success or failure of cure of H pylori infection by the proton pump inhibitor-based triple therapy appeared to be CYP2C19 genotype status. Dual treatment with a sufficient dose of a proton pump inhibitor plus amoxicillin could cure H pylori infection even after the failure to cure H pylori infection by a usual proton pump inhibitor-based triple therapy in patients with the wt/wt homozygous extensive metabolizer genotype of CYP2C19.

Expression of protein tyrosine phosphatases and its significance in esophageal cancer.

Expression of mRNA protein tyrosine phosphatases (PTPs) was surveyed in an esophageal cancer cell line by RT-PCR using degenerate primers. The mRNAs for eight kinds of PTPs were expressed in the cell line. We examined mRNA expression of these PTPs in 12 cases of esophageal cancer by Northern analysis. Significant signals were obtained for three kinds of PTPs, PTP1B, PTPH1, and PTPD1. The magnitude of expression of each PTP was measured as the ratio of the signal intensity of each PTP to that of a control gene (NADPH), and the ratio was then compared to normal mucosa around the cancer lesion. Among the three kinds of PTPs, the expression of PTP1B mRNA was significantly depressed in cancer lesions compared with that in the surrounding normal mucosa. In contrast, the expression of PTPH1 mRNA was significantly increased in cancer lesions compared with that in normal mucosa. PTPD1 did not show any significant trend in comparisons of cancer and surrounding normal mucosa. The results suggest that PTP1B and PTPH1 are engaged in opposing signaling pathways, the tumor-suppressive and tumor-promoting pathways, respectively, in esophageal carcinogenesis.

[Antihypertensive substance in the leaves of kumis kucing (Orthosiphon aristatus) in Java Island].

The water decoction of leaves of kumis kucing, Orthosiphon aristatus (BL.) MIQ (Lamiaceae) which has been prescribed in Javanese traditional medicine (jamu) for the treatment of hypertension etc., was partitioned into a mixture of chloroform and water. The chloroform-soluble portion showed an inhibitory effect on the contractile responses on rat thoracic aorta smooth muscle stimulated with KCl beforehand, while the water-soluble portion showed no effect. The chloroform-soluble portion was separated to afford a new benzochromene [orthochromene A (7)], two new isopimarane-type diterpenes [orthosiphonone A (10), orthosiphonone B (11)], and two novel migrated pimarane-type diterpenes [neoorthosiphol A (12), neoorthosiphol B (13)], together with eight known compounds (1-6, 8, 9). Among those thirteen substances, it was found that a major constituent in the water decoction of leaves, methylripariochromene A (5), exhibited a continuous decrease in systolic blood pressure after subcutaneous administration in conscious stroke-prone spontaneously hypertensive rats (SHRSP).

Indonesian medicinal plants. XXIII. Chemical structures of two new migrated pimarane-type diterpenes, neoorthosiphols A and B, and suppressive effects on rat thoracic aorta of chemical constituents isolated from the leaves of Orthosiphon aristatus (Lamiaceae).

Two novel migrated pimarane-type diterpenes named neoorthosiphols A (1) and B (2) were isolated from the water decoction of the leaves of Orthosiphon aristatus (Lamiaceae), which has been prescribed in Javanese traditional medicine (jamu) for the treatment of hypertension, etc. The absolute chemical structures have been elucidated on the basis of physicochemical properties. It has been found that two migrated pimarane-type diterpenes (1, 2), four isopimarane-type diterpenes (3, 4, 5, 6), three benzochromenes (7, 8, 9) and two flavones (12, 13) exhibit a suppressive effect on contractile responses in rat thoracic aorta, among thirteen chemical constituents (1-13) isolated from the leaves.

Antihypertensive actions of methylripariochromene A from Orthosiphon aristatus, an Indonesian traditional medicinal plant.

Methylripariochromene A (MRC) was isolated from the leaves of Orthosiphon aristatus (Lamiaceae) and subjected to the examination of several pharmacological actions related to antihypertensive activity. The following four findings were revealed from the present study: 1) MRC caused a continuous decrease in systolic blood pressure and a decrease in heart rate after subcutaneous administration in conscious male SHRSP, 2) MRC exhibited the concentration-dependent suppression of contractions induced by high K+, l-phenylephrine or prostaglandin F2alpha in endothelium-denuded rat thoracic aorta, 3) MRC showed a marked suppression of contractile force without a significant reduction in the beating rate in isolated bilateral guinea pig atria, and 4) MRC increased urinary volume and the excretion of Na+, K+ and Cl- for 3 h after oral administration with a load of saline in fasted rats. These findings indicate that MRC possesses some actions related to a decrease in blood pressure, i.e. vasodilating action, a decrease in cardiac output and diuretic action. Furthermore, it is presumed that the traditional use of this plant in the therapy of hypertension may be partially supported by these actions with MRC.

Effects of oral administration of interferon-alpha on antibody production in mice with induced tolerance.

In vivo systemic effects and the immunomodulating potential of the oral administration of murine interferon-alpha (IFN-alpha) were investigated through mRNA expression of both IFN-alpha-inducible factors, interferon regulatory factor-1 (IRF-1) and 2,5-adenylate synthetase [2-5(A) synthetase] and 2-5(A) synthetase enzymatic activity in spleen and antibody production. The daily administration of IFN-alpha (0.1, 1, 10, and 100 IU/body) for 1 week augmented IRF-1 and 2-5(A) synthetase mRNA expression levels, as well as 2-5(A) synthetase enzymatic activity in spleen cells but not in cervical lymph nodes. The in vivo immunomodulating potential of the oral administration of IFN-alpha was also evaluated through antibody production in mice with induced tolerance. Ovalbumin (OVA) was administered intraperitoneally (i.p.) to induce systemic antibody production on day 0 when OVA feeding was initiated. The OVA was fed every 2-3 days for a total of 14 doses to suppress serum antibody levels. Oral administration of murine IFN-alpha was initiated on day 0 and was continued for 5 consecutive days weekly for 5 weeks (24 doses). On every sampling date (days 10, 17, 24, and 32), specific antibody levels in the IFN-alpha-administered groups were significantly higher than those in the control (nonadministered) group. This was especially noted in early phases (days 10 and 17) of antibody production when the levels of antibody in serum from the IFN-alpha-administration groups were equivalent to those of the nontolerance group. Altogether, it is suggested that oral use of IFN-alpha can elicit immunomodulating actions (e.g., antibody levels) by affecting the systemic immune system(s).

Hyperthermo-chemo-hypoxic isolated liver perfusion for hepatic metastases: a possible adjuvant approach.

As a possible intraoperative adjuvant approach to treating hepatic metastases we developed a method of hyperthermo-chemo-hypoxic isolated liver perfusion in combination with hepatic resection. This method was applied to 11 patients with colorectal hepatic metastases between 1992 and 1995. One patient died on postoperative day 14 of hepatic failure (9% mortality), the cause of which was live temperature that reached 42.9 degree C, which seems to be the maximum limit for thermal toxic effect on the human liver. The other 10 patients tolerated the perfusion well, with mild hepatic and non systemic toxicity after minor or even major hepatic resection; the serum aminotransferase and total bilirubin levels returned to normal levels by postoperative day 14. Only one of eight patients (13%) for whom cytotoxic drugs were added to the perfusate (mitomycin C 10 micrograms/ml or cisplatin 2 micrograms/ml) had hepatic recurrence by 19 months after the perfusion (mean follow-up 25.8 months; median 23 months; range 8-57 months). Two patients were alive with no evidence of disease at 13 and 57 months, respectively after the perfusion; the other five patients had postperfusion extrahepatic recurrences (median: 19 months; range 7-20 months). In contrast, hepatic metastases recurred 7 and 20 months after the perfusion, respectively, in the two patients not given a cytotoxic drug.

Effects of astemizole on ventricular activation delay and RT intervals in a canine myocardial infarction model.

In order to clarify the arrhythmogenic effects of nonsedating antihistamines, we examined the effects of astemizole, a nonsedating antihistamine, on ventricular activation and RT intervals in a canine myocardial infarction model. Myocardial infarction was produced by two-stage ligation of the left anterior descending coronary artery in dogs. Seven days after ligation, bipolar electrodes were sutured on the ventricular surface of the infarcted and normal zones to apply an electrical stimulation or record the ventricular activation. An electrical stimulation with coupling intervals between 300 and 140 ms was applied on the ventricular surface of the normal zone during atrial pacing, and the ventricular activation delay was measured. The effect of astemizole on the RT interval was also determined during atrial pacing, sinus rhythm or after premature stimulation. The ventricular activation delay increased after astemizole at doses of 0.3 to 3 mg/kg in the infarcted and at 3 mg/kg in the normal zones, and the effect of astemizole was greater in the infarcted zone. Astemizole increased the RT interval in the normal zone to a greater extent at a long coupling interval. The increase in the RT interval was greater in the infarcted zone compared with that in the normal zone. In conclusion, astemizole increased the activation delay in the infarcted zone, probably through prolongation of the repolarization time, and its effect on the activation delay may be arrhythmogenic.