To determine the mechanism involved, the incorporation rate (ICR) of drugs into hair was compared to melanin affinity, lipophilicity and membrane permeability. The following 20 drugs were tested; amphetamine, methamphetamine, p-hydroxyamphetamine, p-hydroxymethamphetamine, cocaine, benzoylecgonine, ecgonine methyl ester, morphine, 6-acetylmorphine, phencyclidine, 1-(1-phenyl)-piperidinyl-cyclohexanol, methylenedioxyamphetamine, methylenedioxymethamphetamine, methoxyphenamine, O-desmethyl methoxyphenamine, benzphetamine, norbenzphetamine, deprenyl, lysergic acid diethylamide (LSD) and 11-nortetrahydrocannabinol-9-carboxylic acid (THCA). Their ICRs were represented as the ratios of the drug concentrations in rat hair to AUCs (the areas under the concentration vs. time curves) in rat plasma. Cocaine had the highest incorporation rate understood and there was a 3600 fold difference between the ICR of cocaine and that of THCA, the lowest drug. The melanin affinity of these drugs was determined by incubating a test solution with melanin at 36 degrees C in the dark for 2 h. After incubation and centrifugation, the drug concentration in the filtrate was determined by GC/MS or LC. The drug most affinitive to melanin was cocaine, followed by benzphetamine, phencyclidine, methylenedioxymethamphetamine and LSD. The correlation coefficient between ICR and melanin affinity of the 20 drugs was 0.947 (0.949 excluding THCA). Lipophilicity was calculated from the retention times of HPLC according to Kaliszan's method. Although the correlation coefficient between ICR and lipophilicity was very low (0.201), it rose to 0.770 by removing only THCA. The combination of melanin affinity and lipophilicity brought about a higher correlation (0.979) with the ICRs. Our data also suggested that the higher ICRs of basic drugs than neutral or acidic ones are strongly related to the membrane permeability of the drug based on the pH gradient between blood (pH 7.4) and hair matrix (acidic).

OBJECTIVEDeficits of b-cells characterize the islet pathology in type 2 diabetes. It is yet to be clear how the b-cell loss develops in type 2 diabetes. We explored the implication of oxidative stress, endoplasmic reticulum (ER)-induced stress, and autophagy deficit in the b-cell decline in Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODSPancreases from recent autopsy cases of 47 type 2 diabetic and 30 nondiabetic subjects were investigated on the islet structure with morphometric analysis. Volume densities of islet (Vi), b-cell (Vb), and a-cell (Va) were measured. To evaluate cell damage of endocrine cells, immunohistochemical expressions of oxidative stress-related DNA damage as expressed by gH2AX, ER stress-related cell damage as CCAAT/enhancer 1 binding protein-b (C/EBP-b), and autophagy deficit as P62 were semiquantified, and their correlations to islet changes were sought. RESULTSCompared with nondiabetic subjects, Vb was reduced in diabetic subjects. Contrariwise, there was an increase in Va. There was a significant link between reduced Vb and increased HbA 1c levels (P < 0.01) and a trend of inverse correlation between Vb and duration of diabetes (P = 0.06). Expressions of gH2AX, P62, and C/EBP-b were all enhanced in diabetic islets, and reduced Vb correlated with the intensity of gH2AX expression but not with C/EBP-b or P62 expressions. Combined expressions of gH2AX, P62, and C/EBP-b were associated with severe reduction of Vb. CONCLUSIONSb-Cell deficit in type 2 diabetes was associated with increased oxidative stress and may further be augmented by autophagic deficits and ER stress.

MCC-465 was well tolerated. The recommended dose for a phase II study of MCC-465, for a 3-week schedule, is considered to be 32.5 mg/m2 in an equivalent amount of DXR.

Aims/Introduction: Impaired growth and premature death of b-cells are implicated in the progression of islet pathology in type 2 diabetes. It remains unclear, however, how aging affects islet cells, or whether the islet change in diabetes is an augmented process of aging. We studied age-related changes of the islet structure in Japanese non-diabetic subjects and explored the underlying mechanism of the changes. Materials and Methods: A total of 115 non-diabetic autopsy cases were subjected to morphometric analysis for volume densities of islets, b-and non-b-cells, as well as their masses. Proliferation activity identified by Ki67, and expressions of pancreatic and duodenal homeobox (PDX)-1, cell cycle inhibitor P16, and oxidative stress marker cH2AX were also examined.Results: There was a gradual and marginal decline of volume densities of islets, b-and non-b-cells with aging, while masses of these components were increased during maturation and slowly decreased after the 40s. Islet density was high in the young, but reduced after maturation. There was only a minimal influence of increased body mass index (BMI) on the increase in b-cell mass, but not on the other variables. Ki67 positivity and PDX-1 expressions were high in the young, but low after maturation, whereas expressions of P16 and cH2AX were elevated in the aged. Conclusions: Age-associated decline of b-cell mass is marginal after maturation, and the reduction of b-cell mass could be a specific process in diabetes. The impact of BMI on the islet structure is limited in Japanese with normal glucose tolerance.

Determination of methamphetamine and amphetamine in hair was performed by gas chromatography/mass spectrometry using stable isotope-labeled internal standards, 2-methylamino-1-phenylpropane-2,3,3,3-d4 and 2-amino-1-phenylpropane-2,3,3,3-d4. Extraction of hair with methanol/5M hydrochloric acid (20:1) using ultrasonication was chosen as the standard method. The calibration curves for amphetamines in the hair were linear from 1 to 100 ng/mg (r &gt; 0.99). The detection limit was 0.5 ng/mg at the 95% confidence level. The coefficients of variation (CV) (n = 8) of analysis using the spiked hair with methamphetamine were from 0.7 to 6%. The CV (n = 8) of analysis of the methamphetamine abuser's hair was 17.5%. Sectional analysis of monkey and human hair after methamphetamine ingestion suggested a good correlation between the duration of drug use and drug distribution in the hair.

The morning surge in blood pressure (BP) is related to the morning occurrence of lethal cardiovascular events. We tested the hypothesis that salt intake may be associated with the morning surge in BP in essential hypertension. Seventy-six patients were admitted and placed on a low salt diet (2 g/day) for 7 days followed by a high salt diet (20-23 g/day) for another 7 days. At the end of each salt diet, 24-h ambulatory BP and heart rate monitorings and head-up tilt (HUT) test were performed. Patients whose average mean BP (MBP) was increased by more than 10% by salt loading were assigned to the salt-sensitive (SS) group (n ‫؍‬ 37); the remaining patients, whose MBP was increased by less than 10%, were assigned to the non-salt-sensitive (NSS) group (n ‫؍‬ 39). The increase in ambulatory MBP during 6.30-8.00 am above the baseline (2.00-4.00 am) was significantly

Abstract. Although a loss-of-function type mutation was identified in familial Parkinson's disease PARK7, the wild-type of DJ-1 is known to act as an oxidative stress sensor in neuronal cells. Recently, we found a DJ-1 modulator UCP0054278 by in silico virtual screening. In this study, we determined the neuroprotective effects of UCP0054278 against focal ischemia-induced neurodegeneration in rats. Hydrogen peroxide-induced cell death and the production of reactive oxygen species were significantly inhibited by UCP0054278 in normal SH-SY5Y cells, but not in DJ-1-knockdown cells. These results suggest that UCP0054278 interacts with endogenous DJ-1 and then exhibits antioxidant and neuroprotective responses.

This study suggested that correction of impaired neural signalling of PKC and oxidative stress-induced damage may be a major attribute to the beneficial effects of MC on diabetic nerve.