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1.
J Physiol Sci ; 63(4): 235-40, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23588930

ABSTRACT

We recently showed dihydropyridine- and voltage-sensitive Ca(2+) entry in cultured parathyroid cells from patients with secondary hyperparathyroidism. To determine whether normal parathyroid cells have a similar extracellular Ca(2+) entry system, cells were isolated from normal (non-hyperplastic) human parathyroid glands. Fluorescence signals related to the cytoplasmic Ca(2+) concentration ([Ca(2+)]I) were examined in these cells. Cells loaded with fluo-3/AM showed a transient increase in fluorescence (Ca(2+) transient) following a 10-s exposure to a 150 mM K(+) solution in the presence of millimolar concentrations of external Ca(2+). The Ca(2+) transient was reduced by dihydropyridine antagonists or 0.5 mM Cd(2+), but enhanced by FPL-64176, an L-type Ca(2+)-channel agonist. Ca(2+) transients induced by the 10-s exposure to 3.0 mM extracellular Ca(2+) ([Ca(2+)]o) were also inhibited by dihydropyridine antagonists or 0.5 mM Cd(2+). These results provide the first evidence that normal human parathyroid cells express a dihydropyridine-sensitive Ca(2+) entry system that may be involved in the [Ca(2+)]o-induced change in [Ca(2+)]I. This system might provide a compensatory pathway for negative feedback regulation of parathyroid hormone secretion under physiological conditions.


Subject(s)
Calcium Channels/physiology , Calcium Signaling/physiology , Dihydropyridines/metabolism , Parathyroid Glands/metabolism , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/drug effects , Dihydropyridines/pharmacology , Humans , Nicardipine/pharmacology
2.
Anticancer Res ; 30(9): 3509-14, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20944130

ABSTRACT

BACKGROUND: Malignant glioma is one of the most intractable diseases in the human body. Rho-kinase (ROCK) is overexpressed and has been proposed as the main cause for the refractoriness of the disease. Since efficacious treatment is required, this study investigated the effect of inhibition of ROCK isoforms. MATERIALS AND METHODS: The short hairpin RNA transcription vector was transfected into the RT2 rat glioma cell line and the characteristics of the cells were investigated. The effect of nimustine hydrochloride (ACNU) anti-neoplastic agent on cells was also measured. RESULTS: Inhibition of ROCK isoforms did not alter cell growth. Cell cycle analysis revealed that ROCK1 down-regulation reduced the G(0) phase population and ROCK2 down-regulation reduced the G(2)/M phase population. When ROCK1-down-regulated cells were exposed to ACNU, they demonstrated susceptibility to the agent. CONCLUSION: The roles of ROCK1 and ROCK2 may be different in glioma cells. Furthermore, the combination of ROCK1 down-regulation and an anti-neoplastic agent may be useful for the therapy of malignant glioma.


Subject(s)
Glioma/metabolism , rho-Associated Kinases/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Knockdown Techniques , Glioma/genetics , Humans , Immunoblotting , Isoenzymes , Nimustine/pharmacology , RNA, Small Interfering , Rats , Transfection , rho-Associated Kinases/genetics
3.
Psychogeriatrics ; 10(1): 34-8, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20594285

ABSTRACT

BACKGROUND: Elderly patients with Alzheimer's disease (AD) take more medicines, other than those for anti-dementia agents, than healthy people and are sensitive to anticholinergic medications. There are only a few reports, however, on the relationship between cognitive function and anticholinergic activity in AD patients, which is caused by taking prescribed medication. METHODS: We measured serum anticholinergic activity (SAA) in 76 AD patients referred to a Psychogeriatric Unit and separated them into SAA positive group (n= 26, SAA (+) group) and SAA negative group (n= 50, SAA (-) group). The difference in demographic data and cognitive functions were compared between the two groups. RESULTS AND CONCLUSIONS: The total scores of the Mini-Mental State Examination (MMSE), the score of MMSE domain of registration and recall were significantly lower (P < 0.05) and the Functional Assessment Staging (FAST) score, the number of different kinds of prescribed psychotropic medications (the number of prescribed psychotropic medications) were significantly higher (P < 0.05) in the SAA (+) group than in the SAA (-). These results suggest that a higher number of psychotropic medications prescribed leads to a tendency for SAA to be positive and that anticholinergic activity accelerates Alzheimer's pathology and decreases cognitive function, especially memory in AD patients. We should more prudently prescribe psychotropic medications to AD patients, because the prescribed psychotropic medications are one of the important causes of decline in cognitive function of AD patients by way of anticholinergic activity.


Subject(s)
Alzheimer Disease/complications , Alzheimer Disease/physiopathology , Cholinergic Antagonists/adverse effects , Cognition Disorders/chemically induced , Psychotropic Drugs/adverse effects , Aged , Aged, 80 and over , Atropine , Female , Humans , Male , Mental Status Schedule , Receptors, Cholinergic/drug effects , Receptors, Cholinergic/metabolism
4.
Exp Physiol ; 94(7): 847-55, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19346333

ABSTRACT

Patch-clamp and fluorescence measurements of cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) were performed to directly detect extracellular Ca(2+) entry into cultured parathyroid cells from patients with secondary hyperparathyroidism. Cells loaded with fluo-3 AM or fluo-4 AM showed a transient increase in fluorescence (Ca(2+) transient) following 10 s exposure to 150 mm K(+) solution in the presence of millimolar concentrations of external Ca(2+). The Ca(2+) transient was completely inactivated after 30-40 s exposure to the high-K(+) solution, was reduced by dihydropyridine antagonists and was enhanced by FPL-64176, an L-type Ca(2+) channel agonist. The electrophysiological and pharmacological properties of the whole-cell Ca(2+) and Ba(2+) currents were similar to those of L-type Ca(2+) channels. The Ca(2+) transients induced by 10 s exposure to 3.0 mm extracellular Ca(2+) concentration ([Ca(2+)](o)) were inhibited by dihydropyridine antagonists and were partly inactivated following 30-40 s exposure to the high-K(+) solution. These results demonstrate, for the first time, that human parathyroid cells express L-type-like Ca(2+) channels that are possibly involved in the [Ca(2+)](o)-induced change in [Ca(2+)](i). This Ca(2+) entry system might provide a compensatory pathway for the negative feedback regulation of parathyroid hormone secretion, especially in hyperplastic conditions in which the Ca(2+)-sensing receptor is poorly expressed.


Subject(s)
Calcium/metabolism , Dihydropyridines/pharmacology , Parathyroid Glands/metabolism , Barium/physiology , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/physiology , Humans , Parathyroid Glands/cytology , Parathyroid Glands/drug effects , Patch-Clamp Techniques
5.
Biol Pharm Bull ; 31(12): 2250-4, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19043208

ABSTRACT

The effects of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), were studied in normophagic and food-restriction-induced hyperphagic middle-aged Wistar rats. Normophagic intact Wistar rats were given fluvoxamine (100 mg/kg/d, per os (p.o.)) or vehicle for 10 d. Hyperphagic middle-aged Wistar rats were subjected to 10 d of food restriction; they were allowed to refeed for 10 d, with ad libitum food access and administered fluvoxamine (100 mg/kg/d, p.o.) or vehicle during the 10-d refeeding period. Fluvoxamine administration to normophagic middle-aged Wistar rats affected neither their weight nor food intake. However, administration to food-restricted rats showed inhibitory effects of weight gain and food intake during 10 d of refeeding. Fluvoxamine-treated rats showed significantly lower neuropeptide Y (NPY) immunostaining levels in the paraventricular nucleus (PVN) and dorsomedial hypothalamic nucleus (DMH) than untreated controls. Hypophagic and weight-inhibiting effects of fluvoxamine might be mediated via decreased NPY in PVN and DMH. These results suggest that the appetite-controlling effect of fluvoxamine might be responsive to the rats' appetite condition.


Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Eating/drug effects , Fluvoxamine/pharmacology , Hyperphagia/psychology , Weight Gain/drug effects , Animals , Body Weight/drug effects , Hypothalamus/drug effects , Hypothalamus/physiology , Male , Neuropeptide Y/physiology , Rats , Rats, Wistar
6.
Nucleosides Nucleotides Nucleic Acids ; 27(6): 596-600, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18600511

ABSTRACT

Familial juvenile hyperuricemic nephropathy is caused by mutations in the UMOD gene encoding uromodulin. A transgenic mouse model was developed by introducing a human mutant UMOD (C148W) cDNA under control of the mouse umod promoter. Uromodulin accumulation was observed in the thick ascending limb cells in the kidney of transgenic mice. However, the urinary excretion of uromodulin in transgenic mice did not decrease and LC-MS/MS analysis indicated it was of mouse origin. Moreover, the creatinine clearance was not different between wildtype and transgenic animals. Consequently, the onset of the disease was not observed in transgenic mice until 24 weeks of age.


Subject(s)
Mucoproteins/genetics , Mucoproteins/metabolism , Mutation , Animals , Creatinine/metabolism , Disease Models, Animal , Humans , Hyperuricemia/genetics , Hyperuricemia/metabolism , Hyperuricemia/urine , Kidney/metabolism , Kidney/pathology , Mice , Mice, Transgenic , Mucoproteins/urine , Uromodulin
7.
Biol Pharm Bull ; 31(3): 405-11, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18310901

ABSTRACT

Familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease type 2 (MCKD2) are autosomal dominant disorders characterized by juvenile hyperuricemia of the underexcretion type, juvenile gout and chronic renal failure in the adult. FJHN/MCKD2 constitute diseases caused by mutations of the human uromodulin (UMOD) gene that encodes uromodulin, the most abundant glycoprotein in normal human urine. The mutations affect the transport of uromodulin, resulting in the accumulation of uromodulin in the kidneys of FJHN/MCKD2 patients. The purpose of this study was to confirm the accumulation of uromodulin in the kidneys of transgenic mice harboring the mutant human UMOD gene with mouse UMOD gene promoter, and to determine the relationship between its accumulation and the effect on uromodulin transport. The mutant human UMOD mRNA and its protein were expressed in the kidneys of transgenic mice. Moreover, the staining of human uromodulin was colocalized with that of mouse uromodulin. Although the human UMOD mRNA levels increased, the protein levels did not change and the accumulation of human uromodulin was not observed. However, the mouse uromodulin consists of two forms, 103 and 117 kDa, and the 103 kDa protein was gradually increased in the kidneys of transgenic mice. Human and mouse uromodulins in the kidneys of transgenic mice were mainly detected in the Triton X-100 insoluble microsomal fraction. Therefore, the progressive accumulation of uromodulin was observed in the plasma membrane of the kidneys of transgenic mice but the accumulated uromodulin protein was not that encoded by the transgene.


Subject(s)
Kidney/metabolism , Mucoproteins/genetics , Mucoproteins/metabolism , Mutation , Transgenes , Animals , Blotting, Western , Cell Membrane/metabolism , DNA/genetics , Fluorescent Antibody Technique , Humans , Mice , Mice, Transgenic , Promoter Regions, Genetic , Protein Transport , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Uromodulin
8.
Toxicol Appl Pharmacol ; 227(3): 462-7, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-18076961

ABSTRACT

Divalent metal transporter 1 (DMT1) is a mammalian iron (Fe) transporter and also transports Cadmium (Cd) in vitro. This study compared Cd absorption in DMT1-dysfunctional MK/Rej-(mk)/(mk) mice (mk/mk mice) and in DMT1-functional, Fe-deficient wild-type (WT) mice, to clarify the role of DMT1 in intestinal Cd absorption in vivo. Mice were given 1 ppm CdCl2 aq in drinking water for 2 weeks, and the concentrations of Cd and Fe in liver, kidney, and intestinal epithelium were subsequently determined. The Fe concentration in intestinal epithelia of WT mice was decreased in proportion to the level of dietary Fe limitation, while Cd accumulation under the same conditions was increased. DMT1 mRNA expression in the small intestine of Fe-deficient WT mice was clearly increased compared to that in Fe-sufficient WT mice. Iron deficiency resulted in up-regulation of Cd uptake in the intestine of Fe-deficient WT mice. The mk/mk mice have a mutation in DMT1 and loss of its function led to decreased intestinal Fe concentration. However, intestinal Cd accumulation was the same as in WT mice and it was also increased in Fe-deficient situation. There is the possibility that an unknown Cd pathway has taken a role on Cd intestinal absorption in vivo and that this pathway is regulated by food Fe concentrations. Therefore, DMT1 is not the sole transporter of intestinal cadmium absorption in vivo.


Subject(s)
Cadmium/metabolism , Cation Transport Proteins/physiology , Intestinal Absorption , Intestinal Mucosa/metabolism , Alleles , Anemia, Iron-Deficiency/genetics , Animals , Cadmium/analysis , Calcium Chloride/administration & dosage , Cation Transport Proteins/genetics , Intestinal Absorption/genetics , Intestinal Mucosa/chemistry , Iron/analysis , Iron Deficiencies , Mice , Mice, Mutant Strains , Mutation , Tissue Distribution
9.
Life Sci ; 79(22): 2105-11, 2006 Oct 26.
Article in English | MEDLINE | ID: mdl-16889803

ABSTRACT

This study was intended to investigate the effects of chronic exercise on blood adiponectin level. Male Otsuka Long Evans Tokushima Fatty (OLETF) rats (26 weeks old) were divided to undergo either regular 12-week wheel running exercise (EX) or to have food restriction (FR) that resulted in body weight reduction similar to that in EX. Both EX and FR induced similar reductions in body weight, abdominal fat volume and plasma leptin concentration compared with ad libitum control. At the end of the study, although plasma adiponectin level was increased in FR, the adiponectin level did not change in EX. Plasma testosterone level was higher in EX than in either of the other two groups. A significant inverse relationship existed between plasma levels of adiponectin and testosterone for all groups. Our results suggested that 12-week voluntary wheel running exercise induces different effects on plasma adiponectin level than does food restriction, despite similar reduction in body weight, fat tissue mass and plasma leptin concentration. We speculate that the elevated plasma testosterone concentration might offset any hyperadiponectinemic effect of body weight and fat volume reduction in exercising rats.


Subject(s)
Adiponectin/blood , Obesity/blood , Physical Conditioning, Animal , Adipocytes/physiology , Adipose Tissue/anatomy & histology , Animals , Corticosterone/blood , Disease Models, Animal , Epididymis , Estradiol/blood , Insulin/blood , Leptin/blood , Male , Obesity/genetics , Rats , Rats, Inbred OLETF , Running , Testosterone/blood
11.
Diabetes Res Clin Pract ; 72(2): 148-54, 2006 May.
Article in English | MEDLINE | ID: mdl-16325295

ABSTRACT

Glimepiride, a sulfonylurea hypoglycemic agent, is metabolized by cytochrome P450 2C9 (CYP2C9) which is known to have genetic polymorphisms. To examine the effects of CYP2C9 genetic polymorphisms on the safety and efficacy of glimepiride in patients with type 2 diabetes, the responses to the glimepiride were measured in Japanese type 2 diabetic patients with the different CYP2C9 genotype. The reduction in the HbA(1c) was significantly larger (P<0.05) among the CYP2C9*1/*3 subjects than among the CYP2C9*1/*1 subjects. The long-term observations of 2 patients with a CYP2C9*1/*3 suggested that subjects with a CYP2C9*1/*3 respond well to glimepiride during the initial phase of treatment, but 1 patient have shown the weight gain over the long-term treatment. The pharmacokinetic study showed that the area under the concentration-time curve for glimepiride in the CYP2C9*1/*3 subjects was approximately 2.5-fold higher than that of the CYP2C9*1/*1 subjects. The intrinsic clearance of glimepiride by the CYP2C9*3 enzyme was lower than that by the CYP2C9*1 enzyme. These results suggested that the lower hydroxylation activity of glimepiride in the subject with type 2 diabetes and CYP2C9*1/*3 led to a marked elevation in the plasma concentrations of glimepiride and a stronger pharmacological effect of glimepiride.


Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Polymorphism, Genetic , Sulfonylurea Compounds/therapeutic use , Adult , Aged , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP2C9 , Diabetes Mellitus, Type 2/blood , Female , Genotype , Glycated Hemoglobin/metabolism , Humans , Hydroxylation , Hypoglycemic Agents/pharmacokinetics , Japan , Male , Middle Aged , Recombinant Proteins/metabolism , Sulfonylurea Compounds/pharmacokinetics
12.
Oncol Rep ; 14(3): 601-7, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16077962

ABSTRACT

The relationship between the expression level of putative drug resistance factors and sensitivity to anticancer drugs in human normal renal proximal tubule epithelial cells (RPTEC) and 3 kinds of renal cell carcinoma (RCC) cells, VMRC-RCW (RCW), OS-RC-2 (OS2), TUHR14TKB (14TKB), was examined. RPTEC exhibited high expression of P-glycoprotein (Pgp), gamma-glutamyl cysteine synthetase (gammaGCS) and cis-diamminedichloroplatinum (II) (CDDP) resistance-related gene 9 (CRR9), low expression of vacuolar ATPase (V-ATPase) and no expression of multidrug resistance-associated protein 1 (MRP1). 14TKB exhibited high expression of gammaGCS and CRR9, low expression of Pgp and V-ATPase, and no expression of MRP1. OS2 showed high expression of CRR9, low expression of Pgp, gammaGCS and MRP1, and no expression of V-ATPase. RCW exhibited high expression of Pgp, MRP1 and CRR9 and low expression of gammaGCS and V-ATPase. The level of expression of the resistance factors varied among the cells. GST activity and GST-pi expression level of each cell were correlated, and there were high levels in OS2 and RPTEC. When the cytotoxicity of anticancer drugs against each cell was measured at 96 h, the sensitivity to CDDP and Doxorubicin (DXR) in RPTEC and RCW was lower than that in the other cells. Sensitivity to DXR was enhanced by treatment with the Pgp inhibitor, Verapamil, in proportion to the Pgp expression level, and the sensitivity to CDDP was increased by the gammaGCS inhibitor, Buthionine sulfoximine, in proportion to the gammaGCS expression level (corresponding to GSH content). Although a significant increase in sensitivity to CDDP was not observed by treatment of RCC with the V-ATPase inhibitor, Bafilomycin, the sensitivity to DXR in Bafilomycin-treated cells increased about 2-fold. However, no relation between drug sensitivity and V-ATPase expression was observed. The features (such as degree of resistance) varied among the RCC cell lines manifesting many resistance factors or to the contrary, lacking or having lowered resistance factors in comparison with normal cells. Therefore, it is necessary in clinical cancer chemotherapy to determine and measure the level of expression of each resistance factor in respective tumor tissue.


Subject(s)
Carcinoma, Renal Cell/genetics , Epithelial Cells/metabolism , Kidney Neoplasms/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Antineoplastic Agents/pharmacology , Blotting, Western , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Cisplatin/pharmacology , Dose-Response Relationship, Drug , Doxorubicin/pharmacology , Drug Resistance/genetics , Epithelial Cells/cytology , Epithelial Cells/drug effects , Gene Expression/drug effects , Glutamate-Cysteine Ligase/genetics , Glutathione/metabolism , Glutathione Transferase/metabolism , Humans , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Kidney Tubules, Proximal/cytology , Membrane Proteins/genetics , Multidrug Resistance-Associated Proteins/genetics , Neoplasm Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Vacuolar Proton-Translocating ATPases/genetics
13.
J Pharmacol Sci ; 97(2): 234-41, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15684566

ABSTRACT

Decreased expression levels of the glomerular slit membrane proteins, nephrin and podocin, have been reported after the onset of puromycin aminonucleoside (PA) nephrosis. We examined nephrin and podocin expressions prior to the onset of proteinuria of PA nephrosis to elucidate the proteinuria induction mechanism of PA. PA nephrosis was induced by a subcutaneous single injection of 120 mg kg(-1) PA. The mRNA levels of nephrin and podocin in whole kidney total RNA were quantified by the TaqMan real time PCR quantification system. The localization and levels of nephrin and podocin molecules were analyzed by immunofluorescence and Western blotting, respectively. Albuminuria and proteinuria were significant on days 3 and 4 in PA nephrosis rats. The protein levels of nephrin and podocin decreased significantly at day 3. The protein localization of nephrin and podocin changed at day 2 and day 1, respectively. The mRNA level of nephrin increased at day 2 and subsequently decreased at day 4. The podocin mRNA level did not change significantly. In conclusions, the protein level of nephrin and podocin decreased at the onset of albuminuria in the PA nephrosis. However, the first change induced by PA was the change of podocin localization from a linear pattern to a dot-like one prior to the onset of albuminuria.


Subject(s)
Membrane Proteins/biosynthesis , Nephrosis/metabolism , Puromycin Aminonucleoside/toxicity , Animals , Intracellular Signaling Peptides and Proteins , Kidney Glomerulus/drug effects , Kidney Glomerulus/metabolism , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Nephrosis/chemically induced , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley
14.
Clin Exp Nephrol ; 8(2): 117-26, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15235928

ABSTRACT

BACKGROUND: A previous double-blind 24-week clinical trial of mizoribine (MZ) vs placebo in steroid-resistant primary nephrotic syndrome (SRPNS) showed that MZ was more effective than placebo in reducing the rate of deterioration of renal function. The present study was conducted to evaluate the efficacy and safety of MZ in patients with SRPNS after 2 years' treatment. METHODS: A multicenter randomized open-label controlled trial in patients with SRPNS was conducted as a 2-year prospective postmarketing study. RESULTS: There was a significant imbalance in the baseline serum albumin level (s-Alb) between the conventional therapy (CT) and MZ onlay therapy groups. Early dropouts were more frequent in the subset of patients in the CT group having a baseline s-Alb < or =3 g/dl. Therefore, the primary analysis (urinary protein level (UP)-improving effect) was performed using a mixed-effects model, with stratification according to the baseline s-Alb value. The analysis revealed that, in the subset of 34 patients with membranous nephropathy (MN) within the stratum of patients with baseline s-Alb < or =3 g/dl (n = 52), the rate of change (slope of change in the UP level/month), in terms of the log (UP+0.2), was -0.0577 in those allocated to the MZ group and -0.0227 in those allocated to the CT group (P = 0.058). In the stratum of patients with a baseline s-Alb >3 g/dl (n = 97), there were no significant differences in the UP between the two treatment groups. Hence, MZ onlay therapy was not considered to be efficacious in this group of patients. No serious adverse reactions to the drug were observed. CONCLUSIONS: The present study yielded significant results, in that it suggested the possibility that long-term MZ therapy may afford further reduction of the UP, in addition to that obtained following CT, in particular, in MN patients in a severe nephrotic state.


Subject(s)
Immunosuppressive Agents/administration & dosage , Nephrotic Syndrome/drug therapy , Product Surveillance, Postmarketing , Ribonucleosides/administration & dosage , Adult , Drug Resistance , Female , Glomerulonephritis, Membranous/drug therapy , Humans , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Patient Dropouts , Proteinuria/drug therapy , Remission Induction , Ribonucleosides/adverse effects , Steroids/administration & dosage
16.
Neuroreport ; 15(4): 713-6, 2004 Mar 22.
Article in English | MEDLINE | ID: mdl-15094482

ABSTRACT

The purpose of this study was to investigate the effects of exercise on blood leptin concentrations and expression of leptin receptor subtype-b (Ob-Rb) mRNA in the arcuate nucleus of hypothalamus (ARC). Male Wistar rats (26 weeks old) underwent regular wheel exercise for 12 weeks. The expression of Ob-Rb mRNA in the ARC decreased at the end of the study period despite reductions of abdominal fat-pad weight and serum leptin concentration. Serum 1,5-anhydroglucitol levels were higher in exercising rats, suggesting lower serum insulin levels in exercising rats. Our results suggested that 12-week wheel exercise reduced the expression of Ob-Rb mRNA in the ARC probably through improvement in insulin resistance.


Subject(s)
Arcuate Nucleus of Hypothalamus/metabolism , Leptin/blood , Physical Conditioning, Animal/physiology , RNA, Messenger/metabolism , Receptors, Cell Surface/genetics , Adipose Tissue/physiology , Animals , Deoxyglucose/metabolism , Down-Regulation/physiology , Glucose/metabolism , Insulin Resistance/physiology , Male , Muscle, Skeletal/physiology , Rats , Rats, Wistar , Receptors, Leptin , Time
17.
Int Immunopharmacol ; 4(3): 367-75, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15037214

ABSTRACT

BACKGROUND: The effects of the non-impairing, H(1)-receptor antagonist fexofenadine were investigated in in vivo mouse models of eosinophilia and systemic anaphylaxis. METHODS: Eosinophilia was investigated in C57BL/6 mice (n=5 per group) infected with Trichinella spiralis, with and without administration of fexofenadine HCl (5, 10 and 20 mg/kg/day). Eosinophilia was also studied, with and without fexofenadine administration, in mice with a congenital mast-cell deficiency (W/W(v)) and controls (+/+). The effect of fexofenadine HCl (20 mg/kg/day) on IL-5 and eotaxin blood levels was also investigated in C57BL/6 mice. In a separate model, systemic anaphylaxis was induced in C57BL/6 mice using T. spiralis antigen. Fexofenadine HCl (5, 10 and 20 mg/kg) or vehicle was administered 20 min before antigen challenge (n=5 per group). The effect of fexofenadine on systemic anaphylaxis caused by IgE and anti-IgE was also examined in CBF1 mice injected with serum from NC/Nga mice with high IgE levels. Rectal temperature was measured as an indicator of anaphylaxis. RESULTS: In C57BL/6 mice, repetitive oral administration of fexofenadine HCl (5, 10 and 20 mg/kg/day) resulted in dose-dependent suppression of eosinophilia (p<0.05-0.0001). No suppression was observed in mast-cell deficient W/W(v) mice. In addition, single oral administration of fexofenadine HCl (10 and 20 mg/kg) significantly suppressed the decrease in rectal temperature (p<0.01), a marker for systemic anaphylaxis, in C57BL/6 mice. In CBF1 mice injected with serum from NC/Nga mice with high IgE levels, the decrease in rectal temperature was suppressed by single administration of fexofenadine HCl (10 and 20 mg/kg; p<0.01 and p<0.001, respectively). Fexofenadine had no effect on peripheral IL-5 and eotaxin levels. CONCLUSION: These results indicate that fexofenadine suppresses both eosinophilia and systemic anaphylaxis, both of which are fundamental reactions in allergic diseases.


Subject(s)
Anaphylaxis/drug therapy , Eosinophilia/drug therapy , Histamine H1 Antagonists/therapeutic use , Terfenadine/analogs & derivatives , Terfenadine/therapeutic use , Trichinellosis/drug therapy , Anaphylaxis/etiology , Animals , Antigens, Helminth/chemistry , Chemokine CCL11 , Chemokines, CC/blood , Dose-Response Relationship, Drug , Endotoxins/analysis , Eosinophilia/etiology , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/pharmacology , Interleukin-5/blood , Intestine, Small/drug effects , Intestine, Small/pathology , Male , Mast Cells/drug effects , Mast Cells/pathology , Mice , Species Specificity , Terfenadine/administration & dosage , Terfenadine/pharmacology , Trichinella spiralis , Trichinellosis/complications , Trichinellosis/immunology
18.
Toxicol Appl Pharmacol ; 187(3): 162-7, 2003 Mar 15.
Article in English | MEDLINE | ID: mdl-12662899

ABSTRACT

Using the Xenopus oocyte expression system, human Nramp2, a human intestinal iron transporter, was shown to work as a cadmium transporter. An 1824-bp human Nramp2 cDNA was constructed by PCR cloning from reverse transcription products of human kidney mRNA. When the pH of the extracellular solution was 6.0, human Nramp2 transported (109)Cd(2+). Substitution of external Cl(-) with NO3- had no effect on human Nramp2-dependent cadmium uptake. The concentration-dependent Cd(2+) transport of human Nramp2 indicated Michaelis-Menten type transport with an average K(m) value of 1.04 +/- 0.13 microM and an average V(max) of 14.7 +/- 1.9 pmol/oocyte/h (n = 3). Cd(2+) transport via human Nramp2 was inhibited significantly by Cd(2+), Fe(2+), Pb(2+), Mn(2+), Cu(2+), and Ni(2+), while it was not inhibited by Hg(2+) and Zn(2+). Transport of 0.1 microM Cd(2+) by human Nramp2 was inhibited by metallothionein (IC50 = 0.14 microM). Therefore, human Nramp2 is suggested to function as a pH-dependent cadmium absorption transporter on the luminal membrane of human intestinal cells.


Subject(s)
Cadmium/metabolism , Cation Transport Proteins/metabolism , Iron-Binding Proteins/metabolism , Oocytes/metabolism , Animals , Cadmium Radioisotopes/metabolism , Cation Transport Proteins/genetics , Cations, Divalent/pharmacology , Dose-Response Relationship, Drug , Gene Expression , Humans , Hydrogen-Ion Concentration , Ion Transport/drug effects , Iron-Binding Proteins/genetics , Metallothionein/pharmacology , Oocytes/drug effects , Time Factors , Xenopus laevis
19.
Jpn J Antibiot ; 55(1): 77-88, 2002 Feb.
Article in Japanese | MEDLINE | ID: mdl-11977923

ABSTRACT

Complication by secondary infection is observed in not only bacterial pleurisy but also other pleurisy, and the appropriate administration of antibacterial agents is necessary. It is very important to secure a smooth penetration of systemically administered antibacterial agents to pleural effusion in infection therapy. In this study, we investigated the pharmacokinetics of a carbapenem antibiotic, meropenem (MEPM), in blood and pleural effusion in patients with an accumulation of pleural effusion caused by pleurisy, who underwent placement of an indwelling thoracic drain and received intravenous drip administration of MEPM for pneumonia or other respiratory tract infection. The blood pharmacokinetic parameters of MEPM after an intravenous drip administration of 0.5 g MEPM in six patients were: area under the blood concentration-time curve (AUCx), 37.9 +/- 6.2 (hr.mg/L); volume of distribution (Vd), 27.3 +/- 4.4 (L); total clearance (CLtotal), 13.4 +/- 1.8 (L/hr); elimination half life (t1/2), 0.50 +/- 0.08 (hr-1); and elimination rate constant (kel), 1.42 +/- 0.22 (hr). The pharmacokinetic parameters in pleural effusion were: AUCx, 35.7 +/- 7.1 (hr.mg/L); mean retention time (MRT), 5.00 +/- 3.25 (hr); variance of retention time (VRT), 29.9 +/- 44.6 (hr2); kel, 0.34 +/- 0.27 (hr-1); and t1/2, 3.14 +/- 2.36 (hr). The penetration rate calculated from the ratio of pleural concentration to blood concentration in each patient was 46.5 +/- 26.1%, showing good penetration comparable or superior to those of other antibacterial agents previously reported. From these results, it was suggested that MEPM was rapidly penetrated to the pleural effusion and was retained for a more prolonged time in the pleural effusion than in the blood of patients with accumulated pleural effusion, and it suggested the usefulness of MEPM in antibacterial therapy for patients with pleurisy causing accumulation of pleural effusion.


Subject(s)
Pleural Effusion/metabolism , Pleurisy/metabolism , Thienamycins/pharmacokinetics , Aged , Female , Humans , Male , Meropenem , Middle Aged , Thienamycins/administration & dosage
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