Risk factors increasing blood pressure in Japanese colorectal cancer patients treated with bevacizumab.

Bevacizumab has been reported to increase blood pressure. However, the factors, including patient characteristics and laboratory data contributing to this side effect remain unclear. Therefore, we investigated the relationships between increased blood pressure and bevacizumab administration, patient characteristics, and laboratory data. Between April 2007 and January 2018, factor analysis was retrospectively conducted by monitoring increases in blood pressure, the status of bevacizumab administration, patient characteristics, and laboratory data before the first administration in Japanese patients with colorectal cancer who satisfied the criteria for this study. Sixty-seven patients were included, 34 of whom (50.7%) had an increase in blood pressure after bevacizumab administration. On univariate analysis, liver metastasis, antihypertensive drug use, systolic blood pressure at rest before the first bevacizumab administration, body mass index, creatinine, and blood platelet count were significantly different between the two groups. Multivariate analysis was conducted using increased blood pressure as an objective variable and the factors extracted by the univariate analysis as explanatory variables. The results suggested that liver metastasis, antihypertensive drugs, systolic blood pressure at rest before the first bevacizumab administration, and creatinine were associated with the increase in blood pressure. Furthermore, a log-rank test performed based on Kaplan-Meier curves demonstrated that liver metastasis in patients not taking antihypertensive drugs and antihypertensive drug use in patients without liver metastasis were significantly associated with increased blood pressure. Additionally, liver metastasis in patients with antihypertensive drug use was significantly associated with increased blood pressure. Our findings suggest that liver metastasis and antihypertensive drug use, which was previously reported, are risk factors for increased blood pressure.

Dopamine and serotonin uptake inhibitors on the release of dopamine and serotonin in the nucleus accumbens of young and aged rats.

Nucleus accumbens (ACC) of young (4 months old) and aged (24 months old) Wistar rats were perfused with dopamine (DA) uptake blocker, cocaine, or the serotonin (5-HT) selective reuptake inhibitor, fluoxetine, through the microdialysis probe membrane, used to assess the dopamine transporter (DAT) or serotonin transporter (SERT) modulation. The basal extracellular DA release in the ACC was significantly lower in aged rats than young rats. Analysis of DA and 5-HT concentrations in the ACC with increased positive GFAP revealed that DA and DOPAC levels of aged rats were decreased to 55 and 60% of those in young rats, respectively. After co-perfusion with cocaine, both DA and 5-HT releases in the ACC were increased in the young and aged groups. However, the magnitude of the increased DA release was lower in aged rats than young rats. Co-perfusion with fluoxetine showed lower magnitude of the increased DA release in aged rats. It appears that the DAT and SERT system responds initially to ACC cell loss with age, and that especially ACC DAT in the aged rat is more degenerative compared with the young rats. These findings suggest that the serotonergic system with SERT in the remaining ACC neurons show an early adaptive response and resistance to the normal aging and maintain the multiple regulatory system in the ACC despite neural loss since the dopaminergic neurons in the aged animals are vulnerable to aging.

Effect of experimental renal failure on the pharmacodynamics of cefoselis-induced seizures in rats.

We investigated the effect of infusion rate and experimental renal failure on the pharmacodynamics of cefoselis (CFSL)-induced seizures. As an animal model of CFSL-induced seizures, male Wistar rats received an intravenous infusion of CFSL at one of three different rates (1.4-5.8 g/h/rat) until the onset of maximal seizures (which occurred after 8.0 to 36.0 min of infusion). Samples of cerebrospinal fluid (CSF), blood (for serum), and brain were obtained immediately after stopping infusion of CSFL. The serum concentration of CFSL at the onset of seizures increased with increasing infusion rate, but brain and CSF concentrations of CFSL at the onset of seizures were not affected by the infusion rate. Ureter-ligated (UL) and control rats received an intravenous infusion of CFSL at 1.4 g/h/rat until the onset of seizures. Then the same procedure as used to determine the effect of infusion rate on the concentrations of CFSL was carried out. Renal failure was associated with a significant decrease in the amount of CFSL required to induce seizures. Serum, brain, and CSF concentrations of CFSL in UL rats were significantly lower than those in control rats. These results indicate that the experimental strategy and animal model in this investigation would be useful to assess the effects of diseases and other variables on the pharmacodynamics of CFSL-induced seizures and that renal failure is one of the risk factors for neurotoxicity of CFSL.

Effects of fluvastatin and its major metabolites on low-density lipoprotein oxidation and cholesterol esterification in macrophages.

We investigated effects of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and its major metabolites, M2 and M4, on CuSO4-induced low-density lipoprotein (LDL) oxidation and cholesteryl ester accumulation in mouse peritoneal macrophages. All the test compounds inhibited LDL oxidation, and M2 had the most potent effect comparable to vitamin E. When LDL was previously incubated with the test compounds in the presence of CuSO4, the pre-treatment resulted in a marked reduction of facilitated cholesteryl ester accumulation in macrophages. Supplementation of mevalonate did not overcome the inhibitory effects of fluvastatin and its metabolites on both LDL oxidation and facilitated cholesterol esterification. Pravastatin, another HMG-CoA reductase inhibitor, did not show any inhibitory effect. Consequently, these effects of fluvastatin and its metabolites are considered to be derived from their own unique chemical structures. Moreover, fluvastatin and M2 directly inhibited cholesterol esterification induced by oxidized LDL in macrophages, but pravastatin was also found to have a weak effect. As their inhibitory effects were overcome by addition of mevalonate, the direct inhibitory effect on cholesterol esterification would be a common property of HMG-CoA reductase inhibitors. The inhibitory effects of fluvastatin and its metabolites on both LDL oxidation and cholesterol esterification in macrophages may contribute to the antiatherogenic action in vivo.

Quantitative estimation of renal clearance of N-acetylprocainamide in rats with various experimental acute renal failure.

The dosage regimen of a drug eliminated predominantly through the kidney need to be adjusted for the patients with renal disease. The objective of the present study was to establish a quantitative approach to precisely predicting the renal clearances of basic drugs using N-1-methylnicotinamide (NMN). A variety of experimental acute renal failure (ARF) in rats were prepared and N-acetylprocainamide (NAPA) was used as a model drug. The renal clearances of NAPA were significantly decreased in rats with ARF, resulting in significantly increased plasma concentrations. Remarkable reduction in clearance ratios (CL(ratio)) was observed, indicating that the impairment in tubular and glomerular function did not proceed in a parallel manner. The renal clearance of NAPA (CL(rNAPA)) was better predicted from the renal clearance of NMN (CL(rNMN)) than from GFR. A mathematical equation was also constructed to estimate the CL(rNMN) from the NMN plasma concentration. Therefore, the renal clearance of basic drugs excreted predominantly from the kidney can be easily and more accurately estimated based on the concentrations of endogenous NMN to provide a precise dosage regimen for patients with renal failure.

A possible role for BDNF, NT-4 and TrkB in the spinal cord and muscle of rat subjected to mechanical overload, bupivacaine injection and axotomy.

Neurotrophins play a crucial role in the regulation of survival and the maintenance of specific functions for various populations of neurons. Neurotrophin-4 (NT-4) is most abundant in skeletal muscle, and is thought to promote sciatic nerve sprouting, inhibit agrin-induced acetylcholine receptor (AChR) clustering, evoke postsynaptic potentiation and induce mitochondrial proliferation. Using Western blot analysis, immunoprecipitation and immunohistochemistry, we investigated the distribution of NT-4 in slow- and fast-type muscles. We also tested the adaptive response of this protein in the mechanically overloaded muscle, in the regenerating muscle following bupivacaine injection and in the denervated muscle. Additionally, we investigated whether TrkB phosphorylation in the spinal cord and in the sciatic nerve occurs through the interaction with BDNF or NT-4 when the innervating muscle is damaged. Markedly more NT-4 was expressed in fast-type muscles compared with the slow types. TrkB protein was more frequently observed around the edge of myofibers (neuromuscular junction) of the soleus muscle compared with the gastrocnemius muscle. TrkB tyrosine phosphorylation occurred in the spinal cord but not in the sciatic nerve 24 h after bupivacaine injection of the innervating muscle. At the same time, the amount of TrkB co-precipitating with BDNF was markedly increased in the spinal cord. A rapid activation of TrkB (1-8 h) was also observed in the spinal cord after axotomy,while the amount of TrkB co-precipitating with NT-4 was markedly lower after axotomy. These results indicate that NT-4 is preferentially distributed in fast-type muscles. Furthermore, by interacting with BDNF and NT-4, the TrkB in the spinal cord may be important for the survival of motoneurons and outgrowth of injured peripheral axons following muscle damage.

Effect of experimental renal dysfunction on bioavailability of ajmaline in rats.

The effect of renal dysfunction on the bioavailability of ajmaline has been investigated in rats, where experimental renal dysfunction was induced by subcutaneous injection of uranyl nitrate (10 mg kg(-1)). Renal dysfunction did not cause any change in the blood ajmaline concentration after intravenous administration (2 mg kg(-1)), but it increased the blood ajmaline concentration by approximately 2.8-fold after intraduodenal administration (10 mg kg(-1)). The availability of ajmaline in control rats was 16.7%, whereas the availability was increased to 41.1% in rats with renal dysfunction. The unbound fraction in the blood and the metabolic activity in the liver, was assessed with the 10000-g supernatant fraction and with isolated hepatocytes, respectively. The values were found to be similar in both groups. The blood concentration following intraportal infusion was only slightly increased in rats with renal dysfunction, but the hepatic first-pass extraction was infusion rate-dependent and saturable. The initial absorption rate of ajmaline from the small intestine in rats with renal dysfunction was significantly greater compared with control rats. These results indicated that the increased availability of ajmaline in renal dysfunction was mainly a result of partially saturated extraction in the liver, which was caused by an increased absorption rate in the intestine and non-linear extraction in the liver.

Electroacupuncture stimulation suppresses the increase in alcohol-drinking behavior in restricted rats.

BACKGROUND: Although a number of studies on traditional eastern or Chinese medicine, such as acupuncture, moxibustion, and herbal drugs, have been reported, few reports describe electroacupuncture (EAC) effects on drug- and alcohol-seeking behaviors in animal models. The purpose of the present study was to investigate the effect of EAC on changes in alcohol-drinking behavior in rats challenged with restriction and immobilization stress. MATERIAL AND METHODS: Male Sprague Dawley rats (260-280 g) were tightly hung and immobilized in restriction models for 10 min. These immobilization stresses were performed twice a week for 1 week and for 3 consecutive weeks for the short- and long-restricted stress groups, respectively. EAC was applied for 10 min to the hindlimb point, Tsu-San-Li (ST 36), and the lumbar point, Shen-Shu (BL 23). These points are used to treat mental and psychosomatic disorders and are known clinically to produce a sedation effect. Time-access alcohol-drinking behavior was determined at 24 hr after the termination of EAC. Finally, brain dopamine (DA) levels were assayed in the two groups. A sham-control group underwent only restricted stress without EAC. RESULTS: Time-access alcohol-drinking behavior increased significantly in the long-restricted group compared with the short-restricted group and controls. EAC applied to the ST 36 (Tsu-San-Li) point suppressed the increased alcohol-drinking behavior in restricted rats. However, EAC applied to the Shen-Shu (BL 23) point was not effective, because alcohol-drinking behavior was significantly increased in long-restricted rats compared with short-restricted rats. Striatal DA levels of restricted rats with EAC stimulated at Tsu-San-Li were increased significantly compared with the rats with EAC applied to the Shen-Shu point. CONCLUSION: These findings suggest that EAC applied at ST 36 (Tsu-San-Li) was more effective for reducing the increased alcohol-drinking behavior in restricted rats, and they showed that a point specific in EAC procedure was associated with an increase of striatal DA levels. These findings provide new information for understanding alcohol-drinking behavior and for treating human alcoholics.

Novel hydroxyphenylurea dual inhibitor against acyl-CoA: cholesterol acyltransferase (ACAT) and low density lipoprotein (LDL) oxidation as antiatherosclerotic agent.

Novel hydroxyphenylurea derivatives were synthesized and their inhibitory potency evaluated against acyl-CoA: cholesterol acyltransferase (ACAT). Quantitative structure activity relationship analysis revealed that their ACAT inhibitory activities were controlled by the hydrophobicity of the whole molecule. the substitution pattern of urea moiety, and the existence of carboxylic acid. The derivatives with strong activities inhibited foam cell formations. Moreover, these compounds showed antioxidative effects against low density lipoprotein (LDL), owing to their characteristic 3-lert-butyl-2-hydroxy-5-methoxyphenyl substructure. Based on the mechanism of atherosclerosis generation, this hydroxyphenylurea-type dual inhibitor against both ACAT and LDL oxidation is expected to be a promising drug for atherosclerosis.

[L-glutamine-induced heme oxygenase-1 protects small intestine from warm ischemia and reperfusion injury in the rat].

Although it is considered that L-Glutamine (L-Gln) supplementation improves gut morphology and survival in animal models such as radiation and drug-induced enterocolitis, the mechanisms underlying are far from being established. Recently, Gln has been reported to give protection against stress in in vitro intestinal epithelial cell lines through the induction of heat shock proteins (HSPs). This study is designed to examine whether L-Gln may induce cytoprotective molecules such as heme oxygenase-1/HSP32 (HO-1) and reduced glutathione (GSH) in in vivo intestinal tissues, and to clarify whether these molecules may play a role in warm ischemia and reperfusion (I/R) injury. We measured the releases of serotonin and tumor necrosis factor-alpha (TNF-alpha), and graft survival as viability assays following reperfusion of warm ischemically injured intestinal grafts. The substantial expression of HO-1 after L-Gln administration was observed in villous epithelial cells, crypts and muscular layers, and peaked at 6 h, while that of the control group pretreated with lactated Ringer (LR) solution was observed throughout tissues to be slightly similar to those of fresh untreated tissues. Tissue GSH contents slightly increased 24 h after administration and were less reduced through the periods of I/R than those of the LR group. Releases of serotonin and TNF-alpha in L-Gln group were attenuated during the brief periods of warm ischemia, compared with those in the LR group. A significant graft survival rate was also observed between both groups (6/6 of L-Gln group vs. 1/6 of LR group; p < 0.05). In conclusion, the protective effects of L-Gln in small intestines against warm I/R injury were considered to be in part mediated by up-regulation of molecules such as HO-1 and GSH via cellular antioxidant activity. Thus, L-Gln pretreatment may represent an innovative approach to the prevention of complex I/R injury.

Apoptotic and necrotic brain lesions in a fatal case of carbon monoxide poisoning.

A 41-year-old man was accidentally exposed to carbon monoxide (CO) gas and found in a state of cardiopulmonary arrest while he took bath. After admission, he was resuscitated and underwent artificial ventilation in a comatose state and died about 19h later. Computed tomography (CT) examination disclosed bilateral low density area in the basal ganglia and the thalamus, a well-known finding in the CO intoxication. Necropsy, histological examination, DNA ladder assay gave the first line of evidence for the presence of apoptosis as well as necrosis in the human case of CO intoxication. TdT-mediated dUTP-biotin nick-end labeling (TUNEL) positive apoptotic cells were more predominant in the CA2 area than in CA1 area. There is general co-relation between the ratio of TUNEL-positive cells and the DNA laddering on the agarose gel. Basal ganglia and thalamus, which showed bilateral low density area in CT, were revealed to be severe edema. The two types of cell death occurred in the cortex, basal ganglia, hippocampus, thalamus, and cerebellum. Hypoxia caused by CO-hemoglobin formation alone cannot explain the phenomena.

Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits.

Studies in vitro reveal that fluvastatin, an HMG-CoA reductase inhibitor, has a strong DPPH radical scavenging activity and achieves concentration-dependent inhibition of copper- and cell-induced oxidation of low-density lipoprotein (LDL). To further examine the anti-oxidative activity of fluvastatin in vivo, we elucidated the effects of chronic treatment with fluvastatin at a dose insufficient to reduce plasma cholesterol levels (2 mg/kg per day) on vasomotion and vascular oxidative stress in thoracic aortas of 0.5% cholesterol-fed rabbits. After 12 weeks of dietary treatment, aortic segments from rabbits fed cholesterol alone showed impaired endothelium-dependent relaxation responses to acetylcholine and A23187 compared to normal chow-fed rabbits in association with a significant increase in plasma total cholesterol levels. In contrast, although plasma total cholesterol levels were not different from those in control cholesterol-fed rabbits, aortic segments from fluvastatin-treated rabbits showed normal relaxation. Compared with rabbits fed cholesterol alone, fluvastatin treatment decreased susceptibility of LDL to ex vivo copper-induced oxidation, reduced vascular superoxide generation, and atheromatous plaque formation. In conclusion, the potent anti-oxidative properties of fluvastatin in addition to its cholesterol-lowering activity appear to contribute to its anti-atherosclerotic effect in vivo.

Fluvastatin depresses the enhanced lipid peroxidation in vitamin E-deficient hamsters.

Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has recently been reported to have the antioxidative activity in vitro. However, it is still unclear whether chronic treatment with this drug actually leads to amelioration of the redox status in the body. In this study, we investigated the antioxidative effect of fluvastatin in vivo, using a vitamin E-deficient hamster model, an in vivo model of enhanced oxidative stress. After pre-treatment with a vitamin E-deficient diet for 2 months, fluvastatin, pravastatin or probucol was added to the diet for 1 month. Vitamin E deficiency caused a significant increase in the levels of plasma oxidative stress markers such as 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) and hydroperoxides. Furthermore, there was a significant increase in the oxidizability of plasma lipids in the vitamin E-deficient animals, indicating that the oxidative stress was increased in the circulation. Fluvastatin markedly depressed the above oxidative stress markers in plasma, and significantly decreased the oxidizability of plasma lipids without affecting their levels. Probucol, a reference antioxidant, also showed a similar effect while pravastatin, another HMG-CoA reductase inhibitor, showed only a weak improvement. We suggest that the treatment with fluvastatin leads to a reduction of oxidative stress in vivo, which is mainly derived from its antioxidative property rather than its lipid-lowering activity.

Inhibitory effects of fluvastatin and its metabolites on hydrogen peroxide-induced oxidative destruction of hemin and low-density lipoprotein.

Some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are used as hypolipidemic drugs, have been reported to have the potential to reduce the oxidizability of plasma low-density lipoprotein (LDL) when they are administered in vivo. Their in vivo mechanism is believed to be closely related to their hypolipidemic action based on the HMG-CoA reductase inhibitory activity. We hypothesized that some type of HMG-CoA reductase inhibitor has additional mechanism inhibiting LDL oxidation in vivo due not to its hypolipidemic action but to its direct antioxidative effect based on its unique chemical structure. We directly compared in vitro the antioxidative effects of well-known HMG-CoA reductase inhibitors (fluvastatin, pravastatin, simvastatin, cerivastatin and atorvastatin) on the hydrogen peroxide-induced oxidative destruction of hemin and LDL. Fluvastatin but not the others showed the inhibitory effect on this system. Its effect was dose-dependent and almost as strong as the natural antioxidants, alpha-tocopherol and ascorbic acid. Further, M2, which is a hydroxylated metabolite of fluvastatin, showed stronger antioxidative activity than did fluvastatin. We suggest that among these HMG-CoA reductase inhibitors, fluvastatin especially has an ability to retard the LDL oxidation which is based on not only its hypolipidemic action but also its direct antioxidative effect.

Liver weight of adult Japanese, especially recent weight values.

Cases of 445 adult Japanese autopsies of the Tokyo Metropolitan Medical Examiner's Office were used in this study. They were either negative for all hepatitis virus-related markers examined or had little or no histopathological hepatic changes. The maximum liver weight was observed in the fifth decade in both sexes, and after the fifth decade the liver weight decreased markedly with increasing age. The sexual difference in the liver weight was most predominant in the third to fifth decades, but the sexual difference was not marked in the older age groups. The highest liver weight to body weight ratio was observed in the fifth decade of both sexes, and a total decadal pattern of the ratio was similar to a parabola. An interesting finding was that the male liver weights in the third to fifth decades considerably increased in recent years, but the female liver weights in the third decade were almost the same despite the difference in investigation period. We suggest the data of this study may be a standard for Japanese people.

Alcohol enhances characteristic releases of dopamine and serotonin in the central nucleus of the amygdala.

The amygdaloid complex (AMY) is implicated in emotional and motivational aspects of behavior, including the formation of positive reinforcement association. AMY may also associated with brain rewarding circuitry. In the present study, the effect of ethanol (EtOH) on the release of dopamine (DA) and serotonin (5-HT) was studied in the central amygdaloid nucleus (CeAMY), and projecting excitatory afferents to the ventral tegmental area (VTA), of freely moving Wistar rats by brain microdialysis. Within 20 min of i.p. injection of EtOH (2 g/kg), the levels of DA and 5-HT in the CeAMY dialysate increased over the baseline value by 270 and 160% (N = 6-7), respectively. Addition of EtOH (25, 50 and 100 mM) to the microdialysis perfusion medium for 1 h caused a 115-150% dose-related increase in the extracellular level of DA in the CeAMY. 100 mM EtOH-induced CeAMY DA release continued to increase for 1 h after the perfusion medium was returned to normal perfusion medium. In contrast, the CeAMY 5-HT level was increased only by the addition of 100 mM EtOH for 1 h to 130% for 80 min. The stimulation of the CeAMY by EtOH through the microdialysis membrane showed delayed responses of DA and 5-HT compared with the i.p. injection of EtOH. Overall, the present findings are not sufficient to conclude whether EtOH acts directly or indirectly on the major monoamine nerve cells in the CeAMY, but the degree of acute EtOH action affected the differences in time at the peak response on EtOH-induced DA and 5-HT releases in the CeAMY via VTA.

Fluvastatin, an HMG-CoA reductase inhibitor, protects LDL from oxidative modification in hypercholesterolemic rabbits.

The antioxidative effect of fluvastatin sodium (fluvastatin) on low-density lipoprotein (LDL) was evaluated in vivo and in vitro. Since ex vivo measurement of the LDL oxidizability is reported to reflect the response of the atherosclerotic process, LDL isolated from rabbits fed a high cholesterol diet for 4 weeks with or without fluvastatin, pravastatin or alpha-tocopherol administration was oxidized by copper ions to estimate conjugated diene formation. Fluvastatin but not pravastatin significantly prolonged the lag time of LDL oxidized by copper ions ex vivo without affecting plasma cholesterol levels at a dose of 3 mg/kg after four weeks of treatment. Alpha-tocopherol-treated rabbits showed dramatically elongated LDL oxidation lag time at a dose of 150 mg/kg. In order to assess the mechanism, the content of alpha-tocopherol, a major endogenous antioxidant in LDL was measured, and we found that only LDL isolated from alpha-tocopherol-treated rabbits contained a significantly larger amount of alpha-tocopherol than that from high cholesterol control rabbits. To elucidate the mechanism further, the effect of fluvastatin on conjugated diene formation during copper-induced LDL oxidation in vitro was studied. Fluvastatin not only prolonged lag time, but also suppressed the rate of LDL oxidation, both in a dose dependent manner above 1 microM, while pravastatin showed no effect. These results suggest the direct antioxidative effect of fluvastatin on LDL oxidation in vivo. Since oxidation of LDL is an important step in the initiation and progression of atherosclerosis, fluvastatin may reduce the risk of this condition not only by lowering plasma cholesterol but also by protecting LDL from oxidation.

Changes in dopamine transporter and c-Fos expression in the nucleus accumbens of alcohol-tolerant rats.

BACKGROUND: We have shown that neurochemical functions of 5-HT3 receptors in regulating dopamine (DA) release in the nucleus accumbens (ACC) after alcohol exposure compensate for the dysfunction of serotonergic activity to restore the original properties in processing alcohol tolerance, and that the development of alcohol dependence may be mediated by ACC 5-HT3 receptors. In the present study, the effects of chronic alcohol consumption on the functions of the dopamine transporter (DAT) and the expression of c-Fos proteins were investigated using in vivo brain microdialysis and immunocytochemistry. METHODS: Perfusion of cocaine and 1-(2-Bis-(4-fluorophenyl) methoxy) ethyl)-4-(3-phenylpropyl) piperizine (GBR 12909) through the microdialysis probe membrane increased the extracellular levels of DA in ACC of alcohol-treated rats that had developed alcohol tolerance by drinking 10% EtOH for 30 days. RESULTS: The magnitudes of DA reuptake or DAT inhibitors, cocaine, and GBR 12909 that induced DA availability in the ACC were significantly higher in alcohol-treated rats than in controls. When compared with control rats, the alcohol-treated rats exhibited higher levels of DA and its metabolite, DOPAC, in the ACC. Increased expression of the c-Fos-like protein was found in the ACC of alcohol-treated rats. These results show that (1) chronic alcohol consumption desensitizes or decreases the DAT of DA terminals in the ACC and that (2) EtOH causes cellular hyperexcitability of ACC dopaminergic neurons with increased Fos expression during alcohol tolerance. CONCLUSION: The findings suggested that an abnormality of the dopaminergic neurons in the ACC that are involved with DAT dysfunction is associated with the development of alcohol tolerance.

Obesity-sleep apnea (Pickwickian) syndrome: autopsy findings and a medicolegal review.

A 24-year-old obese woman was found dead in her boyfriend's apartment in his absence. She had been admitted to the hospital six times previously because of diminished consciousness, respiratory failure, and pneumonia. A diagnosis of obesity-sleep apnea (Pickwickian) syndrome was made. An autopsy showed that she had an extremely small larynx, intra-alveolar hemorrhage, edema, pulmonary lymphocyte infiltration, and severe focal myocardial fibrosis. No fresh myocardial lesion, coronary arterial lesion, or findings of heart failure were seen. The woman's elder sister had also died of the same disease at the age of 23. The cause of death was diagnosed as respiratory failure and pneumonia with the sleep-apnea syndrome as the underlying cause of death. Although no autopsy reports of the sleep-apnea syndrome have been published in the field of forensic pathology, this syndrome is a predominant cause of sudden death in obese persons and could be a hidden cause of accidental death in such persons.

Superoxide anion scavenging properties of fluvastatin and its metabolites.

We investigated the in vitro superoxide anion scavenging activities of fluvastatin and its metabolites. Fluvastatin showed dose-dependent superoxide anion scavenging activity in the NADH/phenazine methosulphate (PMS)/nitroblue tetrazolium (NBT) system, and the effect was as potent as the reference antioxidant, trolox, which is a water-soluble alpha-tocopherol derivative. The superoxide anion scavenging activities of the major metabolites of fluvastatin (M2, M3, M4, M7) were also determined in this system. All of these metabolites showed the activity. In particular, M2 and M3, which possess a phenolic hydroxyl group at the 5 or 6-position of the indole moiety, respectively, showed 3 times stronger activities than that of fluvastatin. Further, we also determined the effects of fluvastatin, M2 and M3 on phorbol myristate acetate (PMA)-induced superoxide anion generation in human peripheral blood polymorphonuclear leukocytes (PMN). The compounds tested also showed a depressing effect on the amount of superoxide anion in this system. We suggest that fluvastatin and its metabolites have the potential to protect cells or lipids from oxidative modification mediated by superoxide anion.