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Background: Glucose dysmetabolism is an important risk factor for dementia.Objective: We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study.Methods: In this study, 10,214 community-dwelling participants were enrolled. Hemoglobin A1c (HbA1c), the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), the HOMA of percent β-cell function (HOMA-β), and the glycated albumin (GA) was evaluated. The associations of each measure with Alzheimer's disease (AD) and vascular dementia (VaD) were investigated.Results: The multivariable-adjusted odds ratios (ORs) of AD were significantly higher in participants with diabetes mellitus than in those without diabetes (1.46 [95% CI: 1.08-1.97]). Higher HbA1c levels were significantly associated with AD at diabetes (≥6.5%) and even at prediabetes (5.7 %-6.4 %) levels; multivariable-adjusted ORs for AD in participants at the diabetes level were 1.72 (95% CI: 1.19-2.49), and those in participants at the prediabetes level were 1.30 (95% CI: 1.00-1.68), compared with those in normal participants. Moreover, higher GA levels were associated with AD. No associations were observed between the diabetic status or the levels of glycemic measures and VaD. In addition, no significant relationships were observed between insulin resistance and secretion measurements and AD and VaD.Conclusion: Our findings indicate that diabetes mellitus and hyperglycemia are significantly associated with AD, even in individuals at the prediabetes level. [ABSTRACT FROM AUTHOR]

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case–control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05–3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05–5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58–6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain. [ABSTRACT FROM AUTHOR]

Lambert‐Eaton myasthenic syndrome (LEMS) is characterized by muscle weakness, amyotrophy, easy fatigability, and depressed tendon reflexes. 3,4‐Diaminopyridine (3,4‐DAP) is the recommended therapy for the treatment of LEMS. However, estimations of 3,4‐DAP pharmacokinetics in human and animals, such as rats, are rarely reported because 3,4‐DAP is an orphan drug for the treatment of a very rare disease (LEMS). In particular, little is known about its tissue distribution. Therefore, the pharmacokinetics of 3,4‐DAP were studied, with particular focus on tissue distribution, in rats. After intravenous administration of 3,4‐DAP to rats, the half‐life of 3,4‐DAP was 15.9 ± 3.9 min and the volume of distribution at steady‐state was 2.8 ± 0.7 L/kg. The tissue‐to‐plasma partition coefficient (Kp) was high in the kidney, heart, and muscle. In addition, with increased steady state plasma concentration (Css), a tendency toward increased Kp was found in most tissues. In the muscle, a likely target region of 3,4‐DAP in LEMS patients, the Kp was higher than in the plasma. Furthermore, more than 68% of 3,4‐DAP was distributed to the muscle as determined by the ratio of 3,4‐DAP distribution calculated from the apparent volumes of distribution. Hence, 3,4‐DAP may provide for more effective and long‐lasting effects. [ABSTRACT FROM AUTHOR]

Dysthymia is a depressive mood disorder characterized by chronic and persistent but mild depression. It is often difficult to be distinguished from major depression, specifically in its partially remitted state because "loss of interest" or "apathy" tends to prevail both in dysthymia, and remitted depression. Apathy may also occur in various psychiatric and neurological disorders, including schizophrenia, stroke, Parkinson's disease, progressive supranuclear palsy, Huntington's disease, and dementias such as Alzheimer's disease, vascular dementia, and frontotemporal dementia. It is symptomatologically important that apathy is related to, but different from, major depression from the viewpoint of its causes and treatment. Antidepressants, especially noradrenergic agents, are useful for depression-related apathy. However, selective serotonin reuptake inhibitors (SSRIs) may be less effective for apathy in depressed elderly patients and have even been reported to worsen apathy. Dopaminergic agonists seem to be effective for apathy. Acetylcholine esterase inhibitors, methylphenidate, atypical antipsychotics, nicergoline, and cilostazol are another choice. Medication choice should be determined according to the background and underlying etiology of the targeting disease. [ABSTRACT FROM AUTHOR]

Objective Reversible/irreversible abnormalities of regional cerebral blood flow (rCBF) are seen in patients with depression. However, in late-life depression there is little evidence of a longitudinal change in rCBF through remission. We examined whether the decreased rCBF in individuals with late-life depression resolves following treatment. Methods Twenty-five depressed patients older than 55 years completed the Hamilton Rating Scale for Depression and single photon emission computed tomography before and after a mean of 13.7 weeks of pharmacotherapy. Quantitative analyses were performed using the Statistical Parametric Mapping procedure. Results Patients with depression demonstrated decreased rCBF in the anterior ventral and dorsal medial prefrontal cortex (PFC), including anterior cingulate cortices, bilateral ventrolateral PFC to temporal cortices, and bilateral medial to lateral parieto-occipital lobes relative to healthy controls. No particular areas showed increased rCBF. Following pharmacotherapy, rCBF significantly increased in the left dorsolateral PFC to precentral areas and the right parieto-occipital regions. However, decreased rCBF at baseline in the anterior ventral/dorsal medial PFC, bilateral ventrolateral PFC, bilateral temporal lobes, and bilateral parietal lobes did not show significant improvement after treatment. Conclusions Remarkable improvements in rCBF in the left dorsolateral PFC to precentral regions are consistent with the hypothesis that neuronetworks including the left frontal cortex may be functionally and reversibly involved in late-life unipolar major depression (state-dependent). In contrast, neural circuits including bilateral medial, dorsolateral, and parietal areas may reflect underlying and continuous pathognomonic brain dysfunction of depression (trait-dependent). Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer patients receiving methotrexate, vinblastine, adriamycin and cisplatin (MVAC) chemotherapy are co-administered with dexamethasone as an anti-emetic. We examined whether or not dexamethasone affects the severity and onset day of MVAC-induced severe neutropenia., Methods: This was a retrospective study of bladder cancer patients treated with MVAC chemotherapy with or without dexamethasone as an antiemetic at Kanazawa University Hospital during January 2005 - December 2009. Patients were categorized into three groups; no dexamethasone use (Dex (-)), dexamethasone on day 2 (Dex 1 day), and dexamethasone on days 2, 3 and 4 (Dex multiday). We evaluated the incidence of grade 3/4 neutropenia and the day of onset of first severe neutropenic episode during the first course of MVAC chemotherapy. Logistic regression was used to investigate whether co-administration of dexamethasone was a risk factor for severe neutropenia., Results: Episodes of grade 3/4 neutropenia occurred in 3 out of 6 (50.0%), 11 out of 12 (91.7%) and 6 out of 6 (100%) patients in the Dex (-), Dex 1 day, and Dex multiday groups, respectively. The appearance day of first severe neutropenia in the Dex multiday group (13.2 ± 1.0) was significantly accelerated compared to the Dex (-) group (17.7 ± 2.1). Univariate logistic regression analysis revealed that dexamethasone is a risk factor for severe neutropenia (OR 17.0; 95%CI: 1.3-223.1)., Conclusions: Co-administration of dexamethasone for anti-emesis brings forward the first appearance of neutropenia, and increases the severity of neutropenia, in bladder cancer patients receiving MVAC chemotherapy.

Changes of mycophenolic acid (MPA) pharmacokinetics with aging were investigated in rats. We also compared the effect of concomitant amoxicillin/clavulanate combination (CVA/AMPC) on the pharmacokinetics of MPA in 4-week-old and 12-week-old rats (the package insert of CVA/AMPC warns of possible interaction with MPA). Four-week-old rats showed a 1.4-fold higher total body clearance of MPA and a lower volume of distribution of MPA (65%), compared to the values in 12-week-old rats. However, the difference in MPA pharmacokinetics disappeared when enterohepatic circulation was eliminated by bile duct cannulation (BDC). Concomitant CVA/AMPC significantly reduced plasma MPA concentration in intact rats of both age groups, and the age-dependent difference of MPA pharmacokinetics was no longer apparent. The effect of CVA/AMPC was not seen in rats that had undergone BDC, suggesting that the drug-drug interaction can be attributed to inhibition of enterohepatic circulation by CVA/AMPC. These results indicate that the aging-related alteration of MPA pharmacokinetics is a consequence of immature enterohepatic circulation in 4-week-old rats. Higher doses of MPA may be necessary in juveniles.

Accumulation of visceral fat induces various symptoms of metabolic syndrome such as insulin resistance and abnormal glucose/lipid metabolism and eventually leads to the onset of ischemic cerebrovascular diseases. Geniposide, which is iridoid glycoside from the fruit of Gardenia jasminoides ELLIS, is recognized as being useful against hyperlipidemia and fatty liver. In order to clarify the effect of geniposide on metabolic disease-based visceral fat accumulation and the relevant molecular mechanism, experiments were performed in spontaneously obese Type 2 diabetic TSOD mice and the free fatty acid-treated HepG2 cells. In the TSOD mice, geniposide showed suppression of body weight and visceral fat accumulation, alleviation of abnormal lipid metabolism and suppression of intrahepatic lipid accumulation. In addition, geniposide alleviated abnormal glucose tolerance and hyperinsulinemia, suggesting that geniposide has an insulin resistance-alleviating effect. Next, in order to investigate the direct effect of geniposide on the liver, the effect on the free fatty acid-treated HepG2 fatty liver model was investigated using genipin, which is the aglycone portion of geniposide. Genipin suppressed the intracellular lipid accumulation caused by the free fatty acid treatment and also significantly increased the intracellular expression of a fatty acid oxidation-related gene (peroxisomal proliferator-activated receptor: PPARα). From these results, it was confirmed that geniposide has an anti-obesity effect, an insulin resistance-alleviating effect and an abnormal lipid metabolism-alleviating effect, and the metabolite genipin shows a direct effect on the liver, inducing expression of a lipid metabolism-related gene as one of its molecular mechanisms.

We examined the binding of various basic drugs to the F(1)S and A genetic variants of alpha(1)-acid glycoprotein (AGP), which were isolated from native human commercial AGP (total AGP) by chromatography on an immobilized copper(II) affinity adsorbent. The values of the dissociation constant (K(d)) of some basic drugs with the F(1)S variant in equilibrium dialysis differed characteristically from those with the A variant. The selective binding to these variants was evaluated by measuring the displacement ratio of dicumarol bound to the F(1)S variant or that of acridine orange bound to the A variant, using circular dichroism spectroscopy. There was reasonably good agreement between the K(d) values and displacement ratios. There was a characteristic difference between the values of inhibition constant (K(i)) of basic drugs towards dipyridamole binding to F(1)S and towards disopyramide binding to A in total AGP. We found that the K(i) values for dipyridamole binding were well correlated with the K(d) values for the F(1)S variant, whereas those for disopyramide binding were well correlated with the K(d) values for the A variant. In conclusion, the higher the affinity of basic drugs for AGP, the more they inhibit the binding of other basic drugs, and further, the inhibitory potency depends on the selectivity of binding to the AGP variants.

Background: The object of this study was to investigate the safety and clinical response of immunotherapy targeting the WT1 (Wilms' tumor 1) gene product in patients with gynecological cancer., Patients and Methods: Twelve patients with WT1/human leukocyte antigen (HLA)-A*2402-positive gynecological cancer were included in a Phase II clinical trial of WT1 vaccine therapy. In all the patients, the tumors were resistant to standard therapy. The patients received intradermal injections of a HLA-A*2402-restricted, modified 9-mer WT1 peptide every week for 12 weeks. Tumor size, which was measured by computed tomography (CT), was determined every 4 weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors (RECIST)., Results: The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The clinical responses were as follows: stable disease (SD) in 3 patients and progressive disease (PD) in 9 patients. No patients had a complete (CR) or partial response (PR). The disease control rate was 25.0%., Conclusion: Although a small, uncontrolled, nonrandomized trial, this study showed that WT1 vaccine therapy for patients with gynecological cancer was safe and produced a clinical response.

The influence of drug interaction and protein variants on the binding disposition of ropivacaine to alpha1-acid glycoprotein (AGP) was examined. The subjects were five patients who received epidural infusion of ropivacaine for 24-54 h in off-pump coronary artery bypass grafting followed by drug combination therapy, and 10 healthy volunteers. The post-operation plasma albumin concentration showed little overall change, while the AGP concentration in the five patients decreased for 6 h, then increased gradually to about 3-times the initial value by 54 h. The unbound fraction in plasma (fu) of ropivacaine gradually decreased as the AGP concentration increased, but there was large inter-individual variation among the five patients. In contrast, there was a good correlation between the fu value and AGP concentration when ropivacaine was added to blood samples from the 10 healthy volunteers. Among the volunteers, eight showed F1S variants and two showed F1 variant without S variant of AGP. The fu value of ropivacaine did not differ between these two groups. However, when ropivacaine was added in combination with dipyridamole, the fu values of ropivacaine in blood from volunteers with F1S variants were greater than those in blood from volunteers without S variant. In the case of co-administration of disopyramide or lidocaine, there was no such difference. Among the patients, one showed F1S variants and four showed F1 variant without S variant. The results indicate that variability in the side-effects of therapy with ropivacaine alone is caused by the change of the unbound concentration upon changes in the AGP concentration. However, in combination therapy, it is also important to consider the AGP variant-dependence of the inhibitory effect of concomitantly administered drugs.

The levels of serum aminotransferase activity, including aspartate aminotransferase (AST), in rats with acute hepatic failure at 24 h after an oral administration of CCl4 (0.01-0.5 ml/kg) were about 15-50 times higher (up to nearly 5000 IU/l) than those of vehicle control rats (about 85 IU/l). The values of total clearance (CL(tot)) of cyclosporin A, doxorubicin, tacrolimus and zonisamide in the CCl4-treated rats were decreased to about 1/2-1/3 of those in control rats. There were good correlations between AST activity and hepatic intrinsic clearance (CL(int)) (r=0.733-0.949) for the above drugs, as well as for chlorzoxazone, caffeine, lidocaine and tolbutamide after the intravenous administration of each drug in rats with acute hepatic failure. However, the slope of the linear regression equation, i.e., the ratio of decrease of CL(int) against increase of AST activity, differed markedly among these drugs. We found that there is a good correlation (r=0.953) between the values of the slope and the CL(int) of normal rats for these drugs, except for caffeine. In summary, the linear regression equation enables us to predict the decrease of CL(tot) in rats with acute hepatic failure to be predicted from the increase in serum AST activity. This approach may be useful as a guide for the dose modification of drugs for patients with acute hepatic failure.

Rats were intraperitoneally administered 40 mg x kg(-1) of paclitaxel or docetaxel dissolved in various drug solutions. The drug solutions were prepared using 20 mL of saline, adding 4.2% Cremophor EL (crEL) for paclitaxel (TXL), and 1.5% Polysorbate-80 (PS-80) (TXT), 7.5% PS-80 (TXT+PS-80) or 4.2% crEL (TXT+crEL) for docetaxel. The apparent first-order absorption rate constant from the peritoneal cavity (k(a)) of TXL was about one-twentieth of that of TXT. The ratio of the area under the concentration-time curve of drug in plasma over that in ascites for TXL was about one-third of that of TXT. The values of the above ratio and the k(a) of TXT+PS-80 and TXT+crEL were similar to those of TXL. After intraperitoneal administration, the values of the blood-to-plasma concentration ratio in the four groups were similar and independent of time. In the in-vitro study, PS-80 and crEL caused similar, concentration-dependent decreases of drug permeation into red blood cells after a 15-min incubation of rat blood with 10 microg x mL(-1) of TXL. We demonstrated that the disposition kinetics of taxanes after intraperitoneal administration to rats was strongly influenced, in a concentration-dependent manner, by the surfactant vehicle used, crEL or PS-80.