Butyrylcholinesterase activity and metabolic syndrome in obese patients.

Total butyrylcholinesterase activity (EC 3.1.1.8) was previously suggested as a marker for metabolic syndrome. The present study examined total butyrylcholinesterase activity and the relative and absolute activities of two butyrylcholinesterase electrophoretic bands (C(4/5) and C(OF) in 99 obese individuals (body mass index > or = 30 kg/m2) presenting the CHE2 C5- phenotype of the CHE2 gene. Anthropometric, hormonal and biochemical variables already associated with metabolic syndrome were also examined. The data from these obese individuals of the CHE2 C5- phenotype show that total butyrylcholinesterase activity and the absolute activities of the C(4/5) and C(OF) electrophoretic bands are associated with metabolic syndrome and with variables related to it. These butyrylcholinesterase activities do not behave as independent risk factors for metabolic syndrome, but can be considered as secondary markers for this syndrome in obese individuals with the CHE2 C5- phenotype.     

Morphine in combination with metabotropic glutamate receptor antagonists on schedule-controlled responding and thermal nociception

The present study examined the interactive effects of morphine in combination with metabotropic glutamate (mGlu) receptor antagonists on schedule-controlled responding and thermal nociception. Drug interaction data were examined with isobolographic and dose-addition analysis. Morphine, the mGlu1 receptor antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone], the mGlu5 receptor antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride], and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] all decreased rates of schedule-controlled responding. JNJ16259685/morphine, MPEP/morphine, and LY341495/morphine mixtures produced additive effects on this endpoint. Morphine also produced dose-dependent antinociception in the assay of thermal nociception, whereas JNJ16259685, MPEP, and LY341495 failed to produce an effect. In this assay, JNJ16259685 and LY341495 potentiated the antinociceptive effects of morphine, whereas MPEP/morphine mixtures produced additive effects. These results suggest that an mGlu1 and an mGlu2/3 receptor antagonist, but not an mGlu5 receptor antagonist, selectively enhance the antinociceptive effects of morphine. In addition, these data confirm that the behavioral effects of drug mixtures depend on the endpoint under study.     

Comparisons between basal metabolic rate and diet-induced thermogenesis in different types of chronic obstructive pulmonary disease.

1. Some patients with the emphysematous type of tobacco-related chronic obstructive pulmonary disease are hypermetabolic. Since the likely mechanism is the increased work of breathing, other groups of patients with chronic obstructive pulmonary disease should be similar. We have now measured basal metabolic rate and diet-induced thermogenesis in six patients with chronic obstructive pulmonary disease with an arterial partial pressure of CO2 of less than 5 kPa (emphysematous), nine patients with chronic obstructive pulmonary disease with an arterial partial pressure of CO2 of greater than 6 kPa (bronchitic), eight patients with chronic obstructive pulmonary disease due to chronic asthma and seven control subjects. Diet-induced thermogenesis was measured for 4h after a meal of 87% carbohydrate, 11% protein and 2% fat as energy, with a total energy content of 40% of basal metabolic rate. 2. There was no difference between measured and predicted basal metabolic rate in the control (5541 +/- 272 versus 5881 +/- 245 kJ/24h) or emphysematous (5552 +/- 370 versus 6239 +/- 197 kJ/24h) groups, but measured basal metabolic rate was significantly higher than predicted in the bronchitic (6126 +/- 387 versus 5405 +/- 250 kJ/24h) and asthmatic (6293 +/- 197 versus 5701 + 245, mean +/- SEM, P less than 0.01) groups. All the control subjects had measured basal metabolic rates within 10% of predicted, whereas two out of six emphysematous patients, four out of nine bronchitic patients and five out of eight asthmatic patients were hypermetabolic. The contributions of fat, carbohydrate and protein oxidation rates to the overall basal metabolic rate were similar between groups. 3. Diet-induced thermogenesis was similar between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of caspofungin on metabolite profiles of Aspergillus species determined by nuclear magnetic resonance spectroscopy

Invasive aspergillosis remains a potentially life-threatening infection, the incidence of which is increasing. Current methods used to determine the susceptibilities of Aspergillus strains to antifungal drugs are often unreliable. Nuclear magnetic resonance (NMR) spectroscopy can identify the metabolic complement of microorganisms while monitoring nutrient utilization from the incubation medium. We used 600-MHz (1)H NMR spectroscopy to monitor the metabolic responses of five Aspergillus species cultured in RPMI 1640-2% glucose-morpholinepropanesulfonate buffer to various concentrations of the antifungal drugs amphotericin B (AMB) and caspofungin. The metabolic endpoint (MEP) was determined from nutrient and metabolite resonances, measured as a function of the drug concentration, and was defined as a > or =50% reduction in nutrient consumption or metabolite production. MICs were evaluated by a modification of Clinical and Laboratory Standards Institute broth microdilution method M27-A, and minimal effective concentrations (MECs) were determined by microscopic examination of fungal hyphae. For AMB, the MEPs coincided with the MICs. For caspofungin, the MEPs agreed with the MECs for several Aspergillus strains, but the effect of drug pressure was more complex for others. Expansion of the MEP definition to include any significant changes in metabolite production resulted in agreement with the MEC in most cases. Paradoxical metabolic responses were observed for several Aspergillus strains at either high or low caspofungin concentrations and for one Aspergillus terreus strain with AMB. NMR spectroscopy proved to be a powerful tool for detecting the subtle effects of drug pressure on fungal metabolism and has the potential to provide an alternative method for determining the susceptibilities of Aspergillus species to antifungal drugs.     

Beta(3)-adrenoceptor agonist-induced increases in lipolysis, metabolic rate, facial flushing, and reflex tachycardia in anesthetized rhesus monkeys

The effects of two beta(3)-adrenergic receptor agonists, (R)-4-[4-(3-cyclopentylpropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]benzenesulfonamide and (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)- ethyl]amino]ethyl]phenyl]-1-(4-octylthiazol-2-yl)-5-indolinesulfonamide, on indices of metabolic and cardiovascular function were studied in anesthetized rhesus monkeys. Both compounds are potent and specific agonists at human and rhesus beta(3)-adrenergic receptors. Intravenous administration of either compound produced dose-dependent lipolysis, increase in metabolic rate, peripheral vasodilatation, and tachycardia with no effects on mean arterial pressure. The increase in heart rate in response to either compound was biphasic with an initial rapid component coincident with the evoked peripheral vasodilatation and a second more slowly developing phase contemporaneous with the evoked increase in metabolic rate. Because both compounds exhibited weak binding to and activation of rhesus beta(1)-adrenergic receptors in vitro, it was hypothesized that the increase in heart rate may be reflexogenic in origin and proximally mediated via release of endogenous norepinephrine acting at cardiac beta(1)-adrenergic receptors. This hypothesis was confirmed by determining that beta(3)-adrenergic receptor agonist-evoked tachycardia was attenuated in the presence of propranolol and in ganglion-blocked animals, under which conditions there was no reduction in the evoked vasodilatation, lipolysis, or increase in metabolic rate. It is not certain whether the beta(3)-adrenergic receptor-evoked vasodilatation is a direct effect of compounds at beta(3)-adrenergic receptors in the peripheral vasculature or is secondary to the release or generation of an endogenous vasodilator. Peripheral vasodilatation in response to beta(3)-adrenergic receptor agonist administration was not attenuated in animals administered mepyramine, indomethacin, or calcitonin gene-related peptide(8-37). These findings are consistent with a direct vasodilator effect of beta(3)-adrenergic receptor agonists.     

Nutritional monitoring in the ICU: rational and practical application

The metabolic response to injury can induce a state of hypermetabolism that results in the rapid loss of the body nitrogen, so that a critical reduction in lean body mass that affects morbidity and mortality can occur in a short period of time. The process also induces a redistribution of the body nitrogen away from the skeletal mass and toward the viscera and areas of increased metabolic activity, such as the surgical wound, the zone of inflammation, and toward cells producing mediators. Exogenously administered nitrogen is not very effective in reducing the rate of catabolism. It can, however, increase the rate of protein synthesis. In so doing, the rate of net catabolism is reduced. The modified amino acids appear to be much more effective in achieving these ends than do the standard amino acid formulas. Visceral protein synthesis is difficult to use as an index of visceral protein malnutrition in the settings where the metabolic response to injury is also present. These proteins and the acute-phase reactants may not have the sensitivity and specificity to discriminate between visceral protein malnutrition and the changes induced by the metabolic response to injury. The practical clinical endpoint, then, in managing the nitrogen economy during the metabolic response to injury is to provide adequate nitrogen intake, achieving 2 to 4 gm of positive nitrogen balance whenever possible. Caloric (energy) equilibrium can be achieved. Calories in excess of demand or glucose in excess of the ability to effectively oxidize, however, can have detrimental effects in some settings. Expired gas analysis can be useful in this context. Achieving caloric equilibrium does not appear to be essential. The reduction in malnutrition as a cofactor in morbidity and mortality appears to come from achieving nitrogen equilibrium. These alterations in metabolism induced by metabolic stress and the changes in nutrient requirements have been called metabolic support and are summarized in Table 3. The end-points of metabolic support, whenever possible, become 2 to 4 gm of positive nitrogen balance with an amino acid load that will achieve that balance; support of visceral protein synthesis as judged by acute-phase reactant and hepatic protein (e.g., transferrin) synthesis; and avoiding complications of excess VCO2 and urea production (BUN less than 110 mg per cent) (Fig. 5).     

The effects of affinity-purified anti-DNA antibodies from patients with systemic lupus erythematosus on the fluorescent antinuclear antibody assay using HEp-2 cells.

The aim of this study was to clarify the effects of anti-dsDNA antibodies on the titer and the nuclear staining pattern(s) in a fluorescent antinuclear antibody (FANA) assay using HEp-2 cells. Anti-dsDNA derived from 14 patients with systemic lupus erythematosus (SLE) was individually affinity-purified. The anti-dsDNA titer of the purified anti-dsDNA solution was measured by radioimmunoassay (RIA) or by enzyme-linked immunosorbent assay (ELISA). In the FANA assay, the anti-dsDNA solution was diluted in a stepwise manner and its titer was expressed by the endpoint dilution. The nuclear staining pattern in the anti-dsDNA solution was examined at the 1:5 and 1:20 dilutions and at the endpoint dilution. The anti-dsDNA titers of the affinity-purified anti-dsDNA solution were high enough (13 to 126 IU/ml) to be measured by RIA. However, the antinuclear antibody (ANA) titers of this solution were relatively low: 1:20 to 1:320. In the study of nuclear staining the peripheral pattern was observed in nine of the 14 cases at a 1:5 dilution. However, at the endpoint dilution, all cases exhibited the homogeneous pattern. These findings indicate that in the FANA assay using HEp-2 cells, 1) although serum samples show high anti-dsDNA titers by RIA or by ELISA, the antibodies' direct contribution to ANA titers is limited, and 2) when samples reveal a homogeneous staining pattern at the endpoint dilution, this suggests the presence of anti-dsDNA.     

Concentration-dependent effects of caspofungin on the metabolic activity of Aspergillus species

The minimum effective concentration (MEC) used to assess the in vitro antifungal activity of caspofungin against Aspergillus spp. is a qualitative endpoint requiring microscopic examination of hyphae. We therefore developed a tool for the quantitative assessment of caspofungin activity against Aspergillus spp. at clinically applicable concentrations. Susceptibility to caspofungin (0.008 to 8 microg/ml) was studied for 9 A. fumigatus, 8 A. flavus, and 12 A. terreus isolates based on the Clinical and Laboratory Standards Institute M38-A protocol. After 48 h of incubation, the MEC was defined microscopically, and metabolic activity assessed with a modified XTT assay, using 100 microg of the tetrazolium salt XTT/ml and 6.25 muM menadione. A significant reduction in metabolic activity was demonstrated at the MEC (0.25 to 0.5 microg/ml) for all Aspergillus spp. and was more pronounced for A. flavus (median metabolic activity, 25% of control) compared to A. fumigatus and A. terreus (median metabolism, 42 and 53%, respectively), allowing determination of MEC with the XTT assay (93 to 100% agreement with microscopic MEC). Fungal metabolism tended to reach the lowest levels (median, 17 to 38% of control) one to two dilutions higher than the MEC, at the minimum metabolic activity concentration (MMC). For 5 of 9 A. fumigatus isolates, 6 of 12 A. terreus isolates, and 1 of 8 A. flavus isolates, a paradoxical increase in metabolism was observed at concentrations greater than the MMC. Sigmoid (E(max)) or bell-shaped models described accurately (median R(2) = 0.97) the concentration-dependent metabolic changes in the absence or presence, respectively, of paradoxical response. Assessment of metabolic activity may provide useful quantitative endpoints for in vitro studies of caspofungin against Aspergillus spp.     

Expression of rat renal Na/H antiporter mRNA levels in response to respiratory and metabolic acidosis.

The mammalian proximal tubule is an important mediator of the renal adaptive response to systemic acidosis. In chronic metabolic and respiratory acidosis the bicarbonate reabsorptive (or proton secretory) capacity is increased. This increase is mediated, at least in part, by an increase in Vmax of the luminal Na/H antiporter. To determine whether this adaptation involves increased mRNA expression, Na/H antiporter mRNA levels were measured by Northern analysis in renal cortex of rats with metabolic (6 mmol/kg body wt NH4Cl for 2 or 5 d) and respiratory (10% CO2/air balanced for 2 or 5 d) acidosis and of normal, pair-fed rats. Na/H antiporter mRNA levels were unchanged after 2 d of both metabolic and respiratory acidosis. After 5 d, however, Na/H antiporter mRNA expression was increased 1.76 +/- 0.12-fold in response to metabolic acidosis (P less than 0.005, n = 8), but was not different from normal in response to respiratory acidosis: 1.1 +/- 0.2 (NS, n = 8). Thus, the renal adaptive response to metabolic acidosis involves increased cortical Na/H antiporter mRNA levels. In contrast, the enhanced proximal tubule Na/H antiporter activity and bicarbonate reabsorption in respiratory acidosis seem to involve mechanisms other than increased Na/H antiporter gene expression.     

Electrocardiographic Criteria of True Left Bundle Branch Block: A Simple Sign to Predict a Better Clinical and Instrumental Response to CRT

Background: Cardiac resynchronization therapy (CRT) has proved to be very effective in improving morbidity and mortality in patients affected with severe congestive heart failure. Its efficacy has been shown to be greater in patients with left bundle branch block (LBBB). The aim of our study was to verify if newly proposed criteria for true LBBB identify patients with a better clinical and instrumental response to CRT. Methods: Between May 2007 and April 2011, 111 patients with left ventricular ejection fraction (LVEF) ≤ 35% and LBBB morphology received a CRT device and were divided into two groups according to QRS morphology. Group 1 (61 patients) consisted of patients with "true" LBBB morphology; group 2 (50 patients) consisted of patients with "false" LBBB. The primary endpoint was the utility of criteria for true LBBB to predict a composite endpoint of all-cause mortality and hospital admission with heart failure. The secondary endpoint was the utility of the same criteria to predict an absolute increase in LVEF ≥ 10%. Results: "False" LBBB morphology and a dose of bisoprolol <5 mg at last follow-up were the only parameters related to clinical outcome in multivariate analysis (respectively: hazard ratio [HR] 3.98, confidence interval [CI] 95% 1.51-10.48; HR 0.15, CI 95% 0.05-0.43). "True" LBBB morphology was the only variable significantly related to a greater increase in LVEF (HR 4.57, CI 95% 1.36-8.28). Conclusion: True LBBB morphology is related to a higher event-free survival rate in CRT patients and better echocardiographic response. (PACE 2012; 35:927-934).     

The National Cholesterol Education Program - Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes

OBJECTIVE: The clinical value of metabolic syndrome is uncertain. Thus, we examined cardiovascular disease (CVD) and diabetes risk prediction by the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATPIII), International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome. RESEARCH DESIGN AND METHODS: We analyzed the risks associated with metabolic syndrome, the NCEP multiple risk factor categories, and 2-h glucose values in the San Antonio Heart Study (n = 2,559; age range 25-64 years; 7.4 years of follow-up). RESULTS: Both ATPIII metabolic syndrome plus age > or = 45 years (odds ratio 9.25 [95% CI 4.85-17.7]) and multiple (two or more) risk factors plus a 10-year coronary heart disease (CHD) risk of 10-20% (11.9 [6.00-23.6]) had similar CVD risk in men without CHD, as well as CHD risk equivalents. In women counterparts, multiple (two or more) risk factors plus a 10-year CHD risk of 10-20% was infrequent (10 of 1,254). However, either a 10-year CHD risk of 5-20% (7.72 [3.42-17.4]) or ATPIII metabolic syndrome plus age > or = 55 years (4.98 [2.08-12.0]) predicted CVD. ATPIII metabolic syndrome increased the area under the receiver operating characteristic curve of a model containing age, sex, ethnic origin, family history of diabetes, and 2-h and fasting glucose values (0.857 vs. 0.842, P = 0.013). All three metabolic syndrome definitions imparted similar CVD and diabetes risks. CONCLUSIONS: Metabolic syndrome is associated with a significant CVD risk, particularly in men aged > or = 45 years and women aged > or = 55 years. The metabolic syndrome predicts diabetes beyond glucose intolerance alone.     

Teicoplanin metabolism in humans.

Teicoplanin, a lipoglycopeptide antibiotic, consists of five major components (A2-1 through A2-5), one hydrolysis component (A3-1), and four minor components (RS-1 through RS-4). All the major components contain an N-acyl-beta-D-glucosamine, but they differ in the lengths and branchings of their acyl-aliphatic chains. Previous studies with radiolabeled teicoplanin in rats and humans have shown that the drug is eliminated by the renal route and that metabolic transformation is very minor, about 5%. A possible metabolic transformation of teicoplanin into A3-1 was also suggested. In the present study in humans, two metabolites (metabolites 1 and 2; 2 to 3% of total teicoplanin) were isolated after intravenous administration of radiolabeled teicoplanin. After purification, their structures were determined by fast atom bombardment mass spectroscopy and 1H nuclear magnetic resonance spectroscopy on the basis of the well-known correlations established in this field, and they were found to be new teicoplaninlike molecules, bearing 8-hydroxydecanoic and 9-hydroxydecanoic acyl moieties. This metabolic transformation is likely due to hydroxylation in the omega-2 and omega-1 positions for metabolites 1 and 2, respectively, of the C-10 linear side chain of component A2-3. This might explain the low extent of metabolism of teicoplanin if we consider that only component A2-3 has a linear chain that is susceptible to such oxidation.     

Effects of malnutrition on cytochrome P450 1A2 activity in elderly patients

Little is known of the influence of nutritional status on cytochrome P450 (CYP) 1A2 activity in elderly patients. Thirty elderly institutionalised patients with malnutrition (group A, aged 88 +/- 5 years) and 24 without (group B, aged 81 +/- 9 years) were included. Malnutrition was defined as weight loss of >10% over the previous 6 months and/or a body mass index (BMI) <21 kg/m2 and albuminaemia < or = 32 g/L. CYP1A2 activity was evaluated by the plasma paraxanthine/caffeine (PAX/CAF) metabolic ratio. The plasma PAX/CAF metabolic ratio was similar in both groups regardless of nutritional status (0.34 +/- 0.13 [A] versus 0.30 +/- 0.11 [B]; p = 0.11). The CYP1A2 metabolic ratio was not correlated to either BMI, serum albumin or renal clearance. CYPI A2 activity, as measured by the plasma PAX/CAF ratio, was not influenced by nutritional status in elderly patients.     

BAY 59-7939: an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study

BACKGROUND: BAY 59-7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery. METHODS: In a multicenter, parallel-group, double-blind, double-dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59-7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12-24 h postsurgery). Treatment was continued until mandatory bilateral venography 5-9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non-fatal pulmonary embolism and all-cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment. RESULTS: Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59-7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59-7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5-10 mg b.i.d. doses compared with higher doses of BAY 59-7939. CONCLUSIONS: Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.     

A metabolic screening study of trichostatin A (TSA) and TSA-like histone deacetylase inhibitors in rat and human primary hepatocyte cultures

Hydroxamic acid (HA)-based histone deacetylase (HDAC) inhibitors, with trichostatin A (TSA) as the reference compound, are potential antitumoral drugs and show promise in the creation of long-term primary cell cultures. However, their metabolic properties have barely been investigated. TSA is rapidly inactivated in rodents both in vitro and in vivo. We previously found that 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxyamide or 4-Me2N-BAVAH (compound 1) is metabolically more stable upon incubation with rat hepatocyte suspensions. In this study, we show that human hepatocytes also metabolize TSA more rapidly than compound 1 and that similar pathways are involved. Furthermore, structural analogs of compound 1 (compounds 2-9) are reported to have the same favorable metabolic properties. Removal of the dimethylamino substituent of compound 1 creates a very stable but 50% less potent inhibitor. Chain lengthening (4 to 5 carbon spacer) slightly improves both potency and metabolic stability, favoring HA reduction to hydrolysis. On the other hand, Calpha-unsaturation and spacer methylation not only reduce HDAC inhibition but also increase the rate of metabolic inactivation approximately 2-fold, mainly through HA reduction. However, in rat hepatocyte monolayer cultures, compound 1 is shown to be extensively metabolized by phase II conjugation. In conclusion, this study suggests that simple structural modifications of amide-linked TSA analogs can improve their phase I metabolic stability in both rat and human hepatocyte suspensions. Phase II glucuronidation, however, can compensate for their lower phase I metabolism in rat hepatocyte monolayers and could play a yet unidentified role in the determination of their in vivo clearance.     

The intracellular pH of human leucocytes in response to acid-base changes in vitro.

1. Viable human leucocytes were isolated from venous blood and suspended in artificial media. Intracellular pH measurements were made by the dimethyloxazolidinedione technique in conditions simulating "respiratory" or "metabolic" acid-base disturbances. 2. Normal intracellular pH was 7-11 +/- 0-02 (mean +/- 2 SD) at an extracellular PCO2 of 5-8 kPa and a bicarbonate concentration of 25 mmol/l. 3. "Respiratory" and "metabolic" acidosis caused little change in pHi although increases in PCO2 led to relatively greater falls in pHi than did reduction in external bicarbonate concentration. 4. "Respiratory" and "metabolic" alkalosis caused similar and relatively greater increases in the pHi when compared with the response to an external acidosis.     

Five-year follow-up study on plasma insulin levels in newly diagnosed NIDDM patients and nondiabetic subjects

A representative group of middle-aged (45- to 64-yr-old) patients with non-insulin-dependent diabetes mellitus (NIDDM) (n = 133; 70 men, 63 women) were examined at the time of diagnosis and 5 yr afterward for metabolic control and insulin response to oral glucose; 144 nondiabetic control subjects (62 men, 82 women) were similarly examined twice between 5-yr intervals. At the 5-yr examination, 56 of the diabetic patients (36 men, 20 women) were on diet therapy only, 60 (27 men, 33 women) received oral antidiabetic drugs, and 5 were treated with insulin. The metabolic control of diabetic patients was poor at the time of diagnosis and 5-yr examination. Fasting plasma insulin levels were higher in diabetic patients than in control subjects both at baseline (23 +/- 2 vs. 14 +/- 1 mU/L, P less than 0.01, for men; 26 +/- 2 vs. 15 +/- 1 mU/L, NS, for women) and 5-yr examination (19 +/- 1 vs. 16 +/- 2 mU/L, NS, for men; 29 +/- 5 vs. 15 +/- 1 mU/L, P less than 0.05, for women). The frequency of insulin deficiency in diabetic patients based on a postglucagon (1 mg i.v.) C-peptide level less than 0.60 nM was 3.3% at the 5-yr examination, indicating that true insulin deficiency was uncommon during the first years after diagnosis of diabetes in middle-aged subjects.     

A novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), potently decreases plasma triglyceride and glucose levels and modifies lipoprotein profiles in KK-Ay mice

2-Methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220) was newly synthesized and demonstrated to be a novel potent peroxisome proliferator-activated receptor alpha (PPARalpha) agonist with high subtype selectivity. In cell-based reporter gene assays, the EC(50) values of NS-220 for human PPARalpha, PPARgamma, and PPARdelta were 1.9 x 10(-8), 9.6 x 10(-6), and >10(-4) M, respectively, and for mouse PPARalpha, PPARgamma, and PPARdelta were 5.5 x 10(-8), 3.3 x 10(-5), and >10(-4) M, respectively. In addition, [(3)H]NS-220 bound to the ligand-binding domain of human PPARalpha with a K(D) value of 1.85 x 10(-7) M. Fenofibric acid and bezafibrate showed weak agonist activity for PPARalpha (EC(50), 2-8 x 10(-5) M), with poor subtype selectivity. NS-220 (0.1-3 mg/kg p.o.) decreased plasma triglyceride levels in ddY mice in a dose-dependent manner, but its hypolipidemic activity was abolished in PPARalpha-deficient mice. In KK-A(y) mice, an animal model of type-2 diabetes, NS-220 (0.3-1 mg/kg p.o.; 4 days) and fenofibrate (100-300 mg/kg p.o.; 4 days) decreased plasma triglyceride and glucose levels in a dose-dependent manner. In a 2-week repeated administration test, NS-220 (0.3-1 mg/kg p.o.) decreased plasma glucose levels markedly without increasing in plasma insulin levels. Furthermore, NS-220 increased high-density lipoprotein levels and decreased triglyceride-rich lipoprotein levels. In conclusion, a newly synthesized dioxanecarboxylic acid derivative, NS-220, is a potent and highly selective PPARalpha agonist that ameliorates metabolic disorders in diabetic mice. These results strongly suggest that it will be a promising drug for the treatment of hyperlipidemia or metabolic disorders in type-2 diabetes.     

Effect of glucoprivation on serotonin neurotoxicity induced by substituted amphetamines

The present studies were conducted to further explore the potential role of metabolic compromise in substituted amphetamine-induced serotonin (5-HT) neurotoxicity. To this end, we examined the glucoprivic effects of 2-deoxy-D-glucose (2-DG) on the 5-HT neurotoxic effects of fenfluramine (FEN) and methylenedioxymethamphetamine (MDMA). Rats were treated with either FEN or MDMA, alone and in combination, with doses of 2-DG known to produce glucoprivic effects at either 22 +/- 1 or 28 +/- 1 degrees C. At 22 +/- 1 degrees C, FEN produced hypothermia, MDMA induced hyperthermia, and both drugs produced significant long-term reductions in regional brain 5-HT neuronal markers. 2-DG did not enhance 5-HT neurotoxicity induced by either FEN or MDMA; indeed, in some instances, it afforded partial neuroprotection. Although 2-DG afforded partial protection from both FEN and MDMA-induced 5-HT neurotoxic changes, it also caused significant hypothermia, raising the possibility that protection was due to a lowered temperature. Increasing the ambient temperature to 28 +/- 1 degrees C largely eliminated drug-induced hypothermia and eliminated the neuroprotective effects of 2-DG. Thus, even without the confounding effect of temperature, 2-DG still did not potentiate FEN or MDMA-induced 5-HT neurotoxicity. These findings suggest that the role of metabolic compromise in amphetamine-induced 5-HT neurotoxicity merits further study.     

葡萄糖氧化酶双试剂终点法测量模式的系统分析

目的通过系统地评价葡萄糖氧化酶双试剂终点法不同参数设置,寻求终点法最佳参数设置模式。方法比较葡萄糖氧化酶终点法5种模式对4个不同浓度样品的分析结果,评价不同参数限制所起作用的实际表现。结果终点法5种模式中模式1（有效的线性和吸光度限制）能够对不同浓度样品进行准确地分析测量,并能对高值标本的底物耗尽现象进行有效地识别判断,其余4种模式均存在一些缺陷。结论葡萄糖氧化酶双试剂终点法在岛津CL-8000全自动生化分析仪上应用时要重视参数模式的正确选择和运用,尤其是终点吸光度A值的最高检测限额要设置在1300~1400mAbs,线性范围设置在24.5mmol/L左右,才能与实际情况相符。