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Biomedical subjects

Hitoshi Sato

Publications and source records attributed to Hitoshi Sato.

At least 55 records · Page 3Linked to original sources
PubMed2003

Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A.

The mechanism involved in the clinically relevant drug-drug interaction (DDI) between cerivastatin (CER) and cyclosporin A (CsA) has not yet been clarified. In the present study, we examined the possible roles of transporter-mediated hepatic uptake in this DDI. The uptake of [(14)C]CER into human hepatocytes prepared from three different donors was examined. Kinetic analyses revealed K(m) values for the uptake of [(14)C]CER within the range of 3 to 18 microM, suggesting that more than 70% of the total uptake at therapeutic CER concentrations was accounted for by a saturable process, i.e., transporter-mediated uptake. This uptake was inhibited by CsA with K(i) values of 0.3 to 0.7 microM. The uptake of [(14)C]CER was also examined in human organic anion transporting polypeptide-2 (OATP2)-expressing Madin-Darby canine kidney cells (MDCKII). Saturable OATP2-mediated uptake of [(14)C]CER was observed and was also inhibited by CsA, with a K(i) value of 0.2 microM. These results suggest that the DDI between CER and CsA involves the inhibition of transporter-mediated uptake of CER and, at least in part, its OATP2-mediated uptake. The effect of CsA on the in vitro metabolism of [(14)C]CER was also examined. The metabolism of [(14)C]CER was inhibited by CsA with an IC(50) value of more than 30 microM. From these results, we conclude that the DDI between CER and CsA is mainly due to the inhibition of transporter (at least partly OATP2)-mediated uptake in the liver.

Cyclosporine↗
PubMed2003

Varicella-zoster virus open reading frame 21, which is expressed during latency, is essential for virus replication but dispensable for establishment of latency.

Varicella-zoster virus (VZV) open reading frame 21 (ORF21) is one of at least five VZV genes expressed in latently infected human and rodent ganglia. To determine whether ORF21 is required for latent and lytic infection, we deleted 99% of ORF21 from the viral genome. The ORF21 deletion mutant virus could be propagated only in a cell line expressing the ORF21 protein. Insertion of the herpes simplex virus type 1 (HSV-1) homolog of VZV ORF21, HSV-1 UL37, into the ORF21 deletion mutant failed to complement the mutant for growth in cell culture. Inoculation of cotton rats with the ORF21 deletion virus resulted in latent infection in numbers of animals similar to those infected after inoculation with the parental virus. The mean numbers of latent VZV genomes were similar in animals infected with parental and ORF21 deletion viruses. Transcription of ORF63, another latency-associated gene, was detected in ganglia from similar numbers of animals infected with the mutant and parental viruses. Thus, ORF21 is the first VZV gene expressed during latency that has been shown to be dispensable for the establishment of latent infection.

Base Sequence↗
PubMed2003

Varicella-zoster virus ORF47 protein kinase, which is required for replication in human T cells, and ORF66 protein kinase, which is expressed during latency, are dispensable for establishment of latency.

Varicella-zoster virus (VZV) results in a lifelong latent infection in human sensory and cranial nerve ganglia after primary infection. VZV open reading frame 47 (ORF47) and ORF66 encode protein kinases that phosphorylate several viral proteins, including VZV glycoprotein gE and ORF32, ORF62, and ORF63 proteins. Here we show that the ORF47 protein kinase also phosphorylates gI. While ORF47 is essential for virus replication in human T cells and skin, we found the gene to be dispensable for establishment of latent infection in dorsal root ganglia of rodents. ORF66 protein is expressed during latency. Rodents infected with VZV unable to express ORF66 developed latent infection at a rate similar to that for the parental virus. ORF63 transcripts, a hallmark of VZV latency, were also detected in similar numbers of animals infected with the ORF47 and ORF66 mutants and with the parental virus. VZV mutants unable to express four of the six genes that do not have herpes simplex virus (HSV) homologs (ORFs 1, 13, 32, 57) were also unimpaired for establishment of latency. While a truncated HSV VP16 mutant was previously reported to be unable to establish latency in a mouse model, we found that VZV with a deletion of ORF10, the homolog of HSV VP16, was dispensable for establishment of latency. Thus, seven genes, including one expressed during latency, are dispensable for establishing latent VZV infection.

Animals↗
PubMed2003

Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramide.

Disopyramide, a class Ia antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (I(K)) and transient outward current (I(to)), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10-100 microM) and erythromycin (100 microM) led to increases in the APD at 90% repolarization level. Disopyramide reduced I(K) (IC50 = 37.2 +/- 0.17 microM) and I(to) (IC50 = 20.9 +/- 0.13 microM) while erythromycin reduced I(K) (IC50 = 60.1 +/- 0.29 microM) but not I(to). The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.

Action Potentials↗
PubMed2003

[Investigation of the cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injection (2)--Analysis of ethanol eluting materials from catheter].

We studied the cause of cracking of clinically used polyurethane (PU) catheters during the constant infusion of etoposide (VP-16) injection (Lastet inj.) without dilution. After the vehicles used for VP-16 injection, ethanol or polyethylene glycol 400 (PEG400), were infused into the PU catheters at a constant infusion rate (30 ml/h) for 24 h, obvious degradation of the internal wall of the catheter was observed under an electron microscope. When the PU catheter was immersed in ethanol for 24 h, condensed polymers of 1,4-butanediol (BD), contained in PU catheters as an elasticizer, were detected in the ethanol elute using the ESI/MS method. Moreover, time-dependent elution of BD from PU catheters with the infusion of ethanol into the catheter for 24 h at 30 ml/h was observed using the GC/MS method. The cumulative amount of BD eluted from the PU catheter with ethanol vehicle for 24 h was 130 micrograms. In conclusion, degradation and subsequent cracking of PU catheters during the infusion of VP-16 injection were caused by ethanol and PEG400 contained in the injection solution. Furthermore, to prevent the elution of BD from PU catheters, we suggest that PU catheters should not be used for the administration of VP-16 injection without dilution in consideration of safety and efficacy.

Butylene Glycols↗
PubMed2003

Effects of benidipine and candesartan on kidney and vascular function in hypertensive Dahl rats.

We examined the effect of the dihydropyridine calcium channel blocker (CCB) benidipine, the angiotensin II type 1 receptor blocker (ARB) candesartan, and the combination of these drugs on blood pressure and kidney and vascular function in rats with salt-induced hypertension. Dahl salt-sensitive (DS) rats were fed with a high-salt (8% NaCl) diet from 7 weeks of age. Benidipine (1, 3 mg/kg), candesartan (1, 3 mg/kg), benidipine (3 mg/kg) combined with candesartan (3 mg/kg), or vehicle was administered orally after the start of the feeding. Relaxant responses to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator) were measured to examine the vascular function. DS rats fed the high-salt diet showed an increase in systolic blood pressure (SBP), which was accompanied by glomerular sclerosis and an increase in urinary albumin excretion. Relaxant responses to acetylcholine and sodium nitroprusside were impaired in superior mesenteric arterial rings from the hypertensive DS rats. SBP was significantly lower in all of the drug-treated groups than in the vehicle-treated group. The antihypertensive effect of benidipine at 3 mg/kg was more potent than that of candesartan at 3 mg/kg. The albuminuria was significantly decreased in the benidipine and benidipine plus candesartan groups, but not in the candesartan group. The level of SBP in the benidipine plus candesartan group was lower than that by either drug alone. In addition, benidipine alone and benidipine plus candesartan inhibited the glomerular sclerosis and the impairment of relaxant responses in the arteries. These results demonstrate that benidipine is more effective than candesartan in lowering blood pressure and preventing the impairment of kidney and vascular function in salt-sensitive hypertensive rats. In addition, the results suggest that combination therapy with benidipine and an ARB decreases blood pressure more effectively than either drug alone and may be useful for the treatment of hypertension.

Albuminuria↗
PubMed2003

Renoprotective effects of benidipine in combination with angiotensin II type 1 receptor blocker in hypertensive Dahl rats.

We examined the effects of the angiotensin II type 1 receptor blocker candesartan, the calcium channel blockers benidipine and amlodipine, hydralazine, and the combination of candesartan and benidipine or amlodipine on blood pressure and renal function in Dahl salt-sensitive (DS) hypertensive rats. Male DS rats (5 weeks of age) were fed a high-salt (8% NaCl) diet, resulting in hypertension accompanied by glomerular sclerosis and an increased urinary albumin excretion. Drugs were orally administered from 2 to 6 weeks after the start of the feeding. Although candesartan (1 or 10 mg/kg) had little effect on the blood pressure, benidipine (4 mg/kg), amlodipine (4 mg/kg) and hydralazine (5 mg/kg) had similar hypotensive effects. Benidipine, but not amlodipine, hydralazine, or candesartan, significantly inhibited the increase in the albuminuria and glomerular sclerosis. The combination of candesartan (1 mg/kg) and benidipine (4 mg/kg) lowered the levels of blood pressure and albuminuria more effectively than the combination of candesartan (1 mg/kg) and amlodipine (4 mg/kg). These results indicate that benidipine is effective in preventing the impairment of renal function in DS hypertensive rats, and suggest that additional benefits can be expected by combination therapy with benidipine and an angiotensin II type 1 receptor blocker.

Albuminuria↗
PubMed2003

Preventing angiographic progression of coronary atherosclerosis with pravastatin.

We conducted a prospective study to investigate the relationship between the decrease of serum lipid levels during pravastatin therapy and changes of coronary angiography parameters in Japanese patients with coronary atherosclerosis. The patients were predominantly male, aged between 18 and 75 years (mean: 58 years), had at least 25% stenosis of one or more major coronary arteries, and had a serum total cholesterol ( TC) level > or = 200 mg/dl (5.18 mM/l). Treatment with pravastatin (10 mg/day) was continued for 3 years. Coronary angiography was performed before and 3 years after the start of pravastatin therapy to assess the relationship between the mean segment diameter (MSD), the minimal lumen diameter (MLD), and the annual changes of percent stenosis and TC levels. of 265 patients who were initially registered, 129 were followed for an average of 35 months. Consequently, second angiograms were only obtained in 68 patients for various reasons, so this group was used for analysis. During pravastatin therapy, the TC level significantly decreased from 239 mg/dl (6.19 mM/l) to 210 mg/dl (5.44 mM/l) (a 12% reduction; p<0.001). In addition, HDL-cholesterol increased by 5% (p=0.007), but the triglyceride level did not show a significant change. Both MSD and MLD were significantly improved on follow-up angiography, increasing from 2.67 mm to 2.76 mm and from 2.09 mm to 2.13 mm, respectively. However, no change of percent stenosis was observed. The mean TC level during treatment did not show any significant correlation with the changes of angiography parameters. However, a significant correlation was observed between the percent reduction of TC and the annual change of MSD (r=-0.272, p=0.027). A similar relationship was also found between the change of MLD and the percent reduction of TC (r=-0.260, p=0.035). In conclusion, the percent decrease of serum cholesterol may be a better indicator of clinical efficacy than the absolute cholesterol level during pravastatin therapy.

Coronary Angiography↗
PubMed2003

[Differential lung ventilation by use of a combination of a laryngeal mask airway and an endotracheal tube in a pediatric patient with atelectasis of the right lung].

A 5-month-old boy was diagnosed as having complete atelectasis of the right lung due to RS virus infection at the age of 1 month. Conventional respiratory physical therapy, inhalation therapy and mechanical ventilation through an endotracheal tube failed to re-expand the right lung, while the left lung gradually became overinflated. We therefore tried differential lung ventilation by using a combination of a laryngeal mask airway and an extra long endotracheal tube (ID, 3.5 mm; length, 280 mm; Portex Pediatric Tracheal Tube, Extra length; SIMS Portex Co., Ltd. UK). Following induction of anesthesia, a laryngeal mask airway #2 was inserted. Then, an extra long endotracheal tube was inserted through the laryngeal mask airway and was guided to the right main bronchus with the aid of a fiberscope. The right lung was selectively lavaged and inflated with high pressure while ventilation was maintained through the laryngeal mask airway. The SpO2 value was maintained at more than 95% throughout the procedure despite some leakage from the ventilation system. The case demonstrates that differential lung ventilation by use of a combination of a laryngeal mask airway and extra long endotracheal tube is useful for the treatment of a pediatric patient with severe atelectasis.

Humans↗
PubMed2003

[Sevoflurane anesthesia for pancreatectomy in an infant with nesidioblastosis].

We report a case of nesidioblastosis, which is characterized by hyperinsulinism due to a diffuse increase in the number of beta-cells in the pancreas and, consequently, severe hypoglycemia. The patient was a 79-day-old boy. He had been suffering from severe hypoglycemia despite aggressive treatment, including glucose loading and administration of glucocorticoid and diazoxide. Pancreatectomy was performed. Anesthesia was induced by thiamilal 25 mg and vecronium and was maintained by 1 to 2% sevoflurane in 65% nitrous oxide and fentanyl 5 micrograms. No hemodynamic instability was observed during anesthesia. Blood glucose level was maintained around 200 mg.dl-1 without any hyperglycemic event by continuous infusion of 20% glucose at the rate of 14.5 mg.kg-1.min-1, which was calculated from the daily glucose demand to prevent hypoglycemia preoperatively.

Anesthesia, Inhalation↗
PubMed2003

[Wiener spectrum and relative electron density resolution in heavy ion CT based on measurement of residual range distribution].

The relative electron density resolution was discussed by the Wiener spectrum in the heavy ion CT image. The two-dimensional (2D) Wiener spectrum in the CT image was obtained from the one-dimensional (1D) Wiener spectrum of the measured residual range distribution of the water phantom for a single projection angle, and the relative electron density resolution in the CT image was calculated from the 2D Wiener spectrum. To examine the usefulness of this method, the relative electron density resolution was also estimated by other two methods; the calculation using the Wiener spectrum of the reconstructed image of the water phantom, and the estimation by the reconstructed image of the electron density resolution phantom. The result of the first method was similar to those of the other two methods. Therefore, it is useful to estimate the relative electron density resolution by the 1D Wiener spectrum of the measured residual range distribution of the water phantom for a single projection angle.

Electrons↗
PubMed2002

Morphology of physiologically identified otolith-related vestibular neurons in cats.

The morphology of physiologically identified otolith nerve-activated vestibular neurons was investigated using intracellular injections of horseradish peroxidase (HRP). Eleven utricular, 11 saccular and three utricular/saccular nerve-activated vestibular neurons were labeled with HRP. All of these neurons except one were secondary neurons, the exception being a convergent neuron. The labeled neurons were pyramidal, elongated and ovoidal in shape. Most of the labeled cells were medium to large (mean diameter: > or =30 micro m). There was no apparent correlation between morphology and the different types of otolith nerve-activated vestibular neurons. Thus, it seems likely that the functional type of vestibular neurons cannot be presumed on the basis of their morphology alone.

Animals↗
PubMed2002

Treatment with an adenosine uptake inhibitor attenuates glomerulonephritis in mice.

This study evaluated the effects of KF24345 (3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride), a novel adenosine uptake inhibitor, on experimental glomerulonephritis induced in mice by two intravenous injections of rabbit anti-mouse glomerular basement membrane antiserum. Mice with glomerulonephritis showed continuous proteinuria and the histological evaluation revealed glomerular and tubular damage at 7 weeks after the first antiserum injection. KF24345 as well as prednisolone and cyclophosphamide significantly inhibited proteinuria and glomerular damage when it was orally administered once a day from 2 to 7 weeks. Prednisolone elevated plasma bilirubin and glutamic-pyruvic transaminase levels, and cyclophosphamide decreased erythrocytes. Moreover, both prednisolone and cyclophosphamide decreased spleen and thymus weights. KF24345 did not show this kind of side effects. These results demonstrate that KF24345 ameliorates glomerulonephritis with minimal side effects in mice, suggesting that the adenosine uptake inhibitor may be useful for the treatment of glomerulonephritis.

Adenosine↗
PubMed2002

Role of CXC chemokines in the enhancement of LPS-induced neutrophil accumulation in the lung of mice by dexamethasone.

Lipopolysaccharide (LPS)-induced multiple organ injury was mediated in part by a transcription factor, nuclear factor-kappaB (NF-kappaB). Mice were pretreated with dexamethasone (DEX), an inhibitor of NF-kappaB activation, to elucidate its effects on LPS-induced early responses in vivo. Early responses measured 1 h after intraperitoneal LPS administration at a dose of 1 mg/kg were (1) neutrophil accumulation in the tissues, (2) neutrophil degranulation, and (3) protein and mRNA expressions of tumor necrosis factor-alpha (TNF-alpha) and ELR(+) CXC chemokines [macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC)]. Treatment with DEX before LPS administration suppressed NF-kappaB activation and plasma TNF-alpha levels almost to undetectable levels, but enhanced neutrophil accumulation and augmented MIP-2 levels in the lung. The suppression of plasma TNF-alpha levels by pretreatment with an anti-TNF-alpha antibody did not enhance LPS-induced neutrophil accumulation in the lung. These results demonstrate that the enhancement of LPS-induced neutrophil accumulation by DEX might be mediated by MIP-2 and not by TNF-alpha.

Animals↗
PubMed2002

Secretion of interleukin-6 and vascular endothelial growth factor by spindle cell sarcoma complicating Castleman's disease (so-called 'vascular neoplasia').

So-called 'vascular neoplasia' (VN) is a rare tumour of unknown origin that complicates hyaline vascular type Castleman's disease (CD). This paper reports a case of VN complicating CD of hyaline vascular type, in which neoplastic cells were shown to secrete interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). In this case, VN first occurred in the retroperitoneum of a 60-year-old male. The lesion showed typical morphology, with three distinct areas: (1) a lymph node-like area with regressively transformed lymph follicles showing hyaline vascular changes and with a hypervascular interfollicular region filled with slit-like vascular channels; (2) an area composed of spindle cell sarcoma; and (3) an area showing angiolipomatous hamartoma. A proportion of the cells in the spindle cell area showed severe pleomorphism. Subcutaneous recurrence after 8 months was composed purely of pleomorphic spindle cells. A karyotypic analysis of the recurrent tumour showed 47, XXY with some instability. Supernatant from primary culture contained high levels of IL-6 and VEGF, suggesting high secretion of these cytokines from neoplastic cells. Immunohistochemically, p53 overexpression was identified only in the pleomorphic spindle cells of the primary lesion and metastatic tumour. No features suggestive of vascular origin were shown on immunohistochemical or electron microscopic analysis of the neoplastic cells. Human herpesvirus type 8 was not detected by immunohistochemistry or PCR analysis. High levels of IL-6 and/or VEGF have been reported to play a role in CD. This is the first case report that clarifies the site of such cytokine production, showing the possibility of CD as a paraneoplastic phenomenon.

Castleman Disease↗
PubMed2002

Prediction and assessment of extrapyramidal side effects induced by risperidone based on dopamine D(2) receptor occupancy.

In the present study, we attempted to predict the risk of extrapyramidal side effects of a selective monoaminergic antagonist, risperidone, by analyzing the correlation between the dopamine D(2) receptor occupancy and the degree of extrapyramidal side effects of the drug. The occupancies of D(2) and 5-HT(2) receptors at various doses of risperidone were calculated by means of a receptor occupancy theory. The extrapyramidal side effects after administration of risperidone were attempted to predict by theoretical analysis of the correlation between the calculated occupancies and the evidence of extrapyramidal symptoms using a ternary complex model. The pharmacokinetic/pharmacodynamic analysis utilized the data concerning the pharmacokinetics of risperidone and 9-hydroxyrisperidone (active metabolite), their binding affinities with D(2) and 5-HT(2) receptors, and the clinical evidence of extrapyramidal symptoms (Extrapyramidal Symptom Rating Scale: ESRS), gathered from the literature. The mean occupancy of 5-HT(2) receptors after the administration of regular doses of risperidone was suggested to be more than 90%, whereas the mean occupancy of D(2) receptors varied between 50-80%, depending on the dose. The correlation between the occupancy of D(2) receptors and the extrapyramidal symptoms could be successfully analyzed with a ternary complex model, showing the predictability of the model for the extrapyramidal side effects of risperidone. Since the estimated risk of the extrapyramidal side effects varied with the dose, the present method of predicting the extrapyramidal side effects of risperidone may provide a basis for developing a rational dosing regimen for the drug.

Antipsychotic Agents↗
PubMed2002

The peroxisome proliferator-activated receptor alpha-selective activator ciprofibrate upregulates expression of genes encoding fatty acid oxidation and ketogenesis enzymes in rat brain.

Activated peroxisome proliferator activated receptor alpha (PPAR alpha) protects against the cellular inflammatory response, and is central to fatty acid-mediated upregulation of the gene encoding the key ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS). We have previously demonstrated both PPAR alpha and mHS expression in brain, implying that brain-targeted PPAR alpha activators may likewise up-regulate mHS expression in brain. Thus, to attempt pharmacological activation of brain PPAR alpha in vivo, we have administered to rats two drugs with previously defined actions in rat brain, namely the PPAR alpha-selective activator ciprofibrate and the pan-PPAR activator valproate. Using the sensitive and discriminatory RNase protection co-assay, we demonstrate that both ciprofibrate and valproate induce mHS expression in liver, the archetypal PPAR alpha-expressing organ. Furthermore, ciprofibrate potently increases mHS mRNA abundance in rat brain, together with lesser increases in two other PPAR alpha-regulated mRNAs. Thus we demonstrate, for the first time, up-regulation of expression of PPAR alpha-dependent genes including mHS in brain, with implications in the increased elimination of neuro-inflammatory lipids and concomitant increased production of neuro-protective ketone bodies.

Acyl-CoA Dehydrogenase↗