Effects of alcohol on the hypothalamic-pituitary-gonadal axis in the developing male rat.

The ontogeny of the effects of alcohol on serum testosterone levels was examined in male rats throughout sexual maturation (25-70 days). Alcohol decreased serum testosterone levels in rats 45 days or older as expected. In contrast to these results, we found precisely the opposite effects in prepubescent male rats (25-30 days old): namely, a marked stimulation of serum testosterone. Alcohol produced dose-dependent increases in serum testosterone levels in the prepubescent animal with increases of over 300% observed. In contrast to the biphasic effects of alcohol on serum testosterone levels in the developing animal, we found either no changes or modest decreases in serum luteinizing hormone levels at all ages tested. These data indicate that the increase in testosterone occurred independently of changes in luteinizing hormone in the prepubescent animal. Thus, it appears that the primary site of action of alcohol on the hypothalamic-pituitary-gonadal axis in prepubescent male rats is the testes and that alcohol acts to directly stimulate testosterone's biosynthesis. In contrast, alcohol appears to act at both central and testicular sites in rats 45 days or older to depress the synthesis and release of testosterone. The mechanisms underlying these age-dependent, biphasic effects of alcohol on serum testosterone levels are unknown at the present time, but it seems unlikely that differences in the biodisposition of alcohol were involved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Castration-induced changes in the response of the hypothalamic-pituitary axis to alcohol in the male rat

In an attempt to determine the direct effects of alcohol on the hypothalamic-pituitary aspect of the hypothalamic-pituitary-gonadal axis, we examined the effects of alcohol on serum luteinizing hormone (LH) levels in the normal and testosterone-depleted castrated male rat. We found that within several days after castration (2-4 days) alcohol, at low to moderate doses, was only modestly effective in suppressing serum LH levels, whereas in sham-operated controls it was maximally effective at all doses tested. Surprisingly, at very high doses (4-6 g/kg), alcohol not only did not depress serum LH levels in long-term castrated rats, but elevated them by 2- to 4-fold when compared to saline-injected controls. The loss of sensitivity of the hypothalamic-pituitary axis to alcohol observed in castrated rats appeared to be selective, inasmuch as the mortality rate at high doses of alcohol was significantly (P less than .01) greater in castrated rats, when compared to sham-operated controls, and other measures of central nervous system impairment were equivalent in both groups. At the present time, it is difficult to explain this biphasic effect of alcohol on serum LH in the castrated animal, but our results are consistent with the hypothesis that the effects of alcohol on gonadotropin release may be dependent to a significant degree on the steroid milieu at the time of the experiments.     

Influence of morphine exposure during adolescence on the sexual maturation of male rats and the development of their offspring

The effects of adolescent morphine exposure on the sexual maturation of male rats, their reproductive capacity and the development of their progeny were examined. Groups of prepubescent male rates (25-27 days of age) were implanted with morphine- or placebo-pellets (one on Day 1, then two pellets on Days 4, 7 and 10); the pellets were not removed to assure the sustained release of morphine for 3 to 4 weeks and to avoid the confounding effects of a precipitated withdrawal syndrome. Groups of animals were sacrificed at weekly intervals through adulthood for an assessment of reproductive endocrine function. A large group, however, was also bred with drug-naive primiparous females at 85 days of age (8 weeks after morphine or placebo pellet implantation), when the acute and chronic effects of morphine on reproductive endocrine parameters had dissipated; their fertility and the development of the male and female progeny was characterized. Our results indicated that morphine exposure during adolescence led to a pronounced inhibition of a number of indices of sexual maturation (e.g., serum testosterone and luteinizing hormone levels and reduced weights of the testes and seminal vesicles). Breeding morphine- and placebo-implanted male rats with drug-naive females resulted in smaller liters derived from morphine-treated fathers when compared to controls, but in all other respects the development of the offspring in the two groups were equivalent. However, upon reaching adulthood, a number of selective endocrine differences were detected in morphine-derived offspring when compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term effect of glimepiride and rosiglitazone on non-conventional cardiovascular risk factors in metformin-treated patients affected by metabolic syndrome: a randomized, double-blind clinical trial

We evaluated the effect of glimepiride plus metformin and rosiglitazone plus metformin on glucose, and on cardiovascular risk parameters such as lipoprotein(a) (Lp[a]) and homocysteine (HCT) in patients with type 2 diabetes and metabolic syndrome. Ninety-nine patients in the multicentre, randomized, double-blind study took metformin (1500 mg/day) plus glimepiride (2 mg/day) or rosiglitazone (4 mg/day) for 12 months. Changes in body mass index, glycosylated haemoglobin (HbA1c), Lp(a) and HCT were primary efficacy variables. Fasting plasma glucose (FPG), post-prandial plasma glucose (PPG) and homeostasis model assessment index were also used to assess efficacy. On average, HbA1c decreased by 9.1% and 8.1%, FPG decreased by 7.3% and 10.9%, and PPG decreased by 7.6% and 10.5%, respectively, in the glimepiride and rosiglitazone groups after 12 months. Patients receiving rosiglitazone experienced more rapid improvement in glycaemic control than those on glimepiride, and showed a significant improvement in insulin resistance-related parameters. There was a statistically significant decrease in basal homocysteinaemia in glimepiride-treated patients (-27.3%), but not in rosiglitazone-treated patients. Rosiglitazone plus metformin significantly improved long-term control of insulin resistance-related parameters compared with glimepiride plus metformin, although glimepiride treatment was associated with a slight improvement in cholesterolaemia, not observed in the rosiglitazone-treated patients, and with significant improvements in non-traditional risk factors for cardiovascular disease, such as basal homocysteinaemia and plasma Lp(a) levels.     

Long-term effects of glimepiride or rosiglitazone in combination with metformin on blood pressure control in type 2 diabetic patients affected by the metabolic syndrome: a 12-month, double-blind, randomized clinical trial

BACKGROUND: Some evidence suggests that antihyperglycemic drugs might have a small but clinically significant beneficial effect on blood pressure in patients with diabetes mellitus. Based on a literature search, few direct comparisons of different antihyperglycemic treatments on blood pressure have been reported. OBJECTIVES: The primary aim of the present study was to compare the effect of long-term (12-month) combination treatment with glimepiride or rosiglitazone plus metformin on blood pressure in patients with type 2 diabetes mellitus (DM-2) and the metabolic syndrome. Secondary end points were glycemic control and improvement in insulin sensitivity. METHODS: This randomized, double-blind study was conducted at 2 centers in Italy. Patients aged > or =18 years with DM-2 and the metabolic syndrome and poor glycemic control (insulin resistance) with monotherapy with the maximum tolerated dose of an antihyperglycemic agent (eg, a sulfonylurea, metformin) were enrolled. All patients received 12 months of oral treatment with metformin 500 mg TID plus glimepiride 2 mg QD (G + M) or rosiglitazone 4 mg QD (R + M). Blood pressure, heart rate (HR), and body mass index (BMI); plasma levels of fasting and postprandial glucose and insulin (FPG, PPG, FPI, and PPI, respectively) and glycosylated hemoglobin (HbA(1c)); and homeostasis model assessment (HOMA) index were determined at 0 (baseline), 3, 6, 9, and 12 months of treatment. Adverse effects (AEs) were assessed using spontaneous reporting, patient interview, and laboratory analysis. RESULTS: Ninety-nine patients were enrolled in the study; 95 completed it (48 men, 47 women; mean age, 54 years [range, 47-58 years]; G + M, 47 patients; R + M, 48 patients). Four patients did not complete the study due to noncompliance (2 patients in the R + M group), protocol violation (1 patient in the G + M group), and loss to follow-up (1 patient in the G + M group). Mean blood pressure values were not significantly improved in the G + M group at any time point, whereas these values were significantly improved at 12 months in the R + M group. Mean BMI, HbA(1c), FPG, and PPG were significantly decreased from baseline in both groups at 12 months (all, P < or = 0.05). Mean FPI, PPI, and HOMA index were significantly improved at 12 months only in the R + M group (all, P < or = 0.05 vs baseline); these changes were not found in the G + M group. No significant changes in HR were found. Headache and flatulence were reported in both groups (G + M, 2 patients each; R + M, 1 and 2 patients, respectively), but these AEs were mild and transient. In the R + M group, liver enzyme levels were increased to 1.5-fold the upper limit of normal in 3 patients, but were normalized by study end. CONCLUSIONS: In this study in patients with DM-2 and the metabolic syndrome, long-term (12-month) combination treatment with R + M, but not G + M, was associated with a significant improvement in blood pressure control. Improvements in glycemic control and insulin resistance-related parameters were found at 9 months with R + M, compared with 12 months with G + M. Both treatments were well tolerated.     

Addition of L-carnitine to additive solution-suspended red cells stored at 4 degrees C reduces in vitro hemolysis and improves in vivo viability

BACKGROUND: The role of L-carnitine (LC) as the requisite carrier of long-chain fatty acids into mitochondria is well established. Human red cells (RBCs), which lack mitochondria, possess a substantial amount of LC and its esters. In addition, carnitine palmitoyl transferase, an enzyme that catalyzes the reversible transfer of the acyl moiety from acyl-coenzyme A to LC is found in RBCs. It has recently been shown that LC and carnitine palmitoyl transferase play a major role in modulating the pathway for the turnover of membrane phospholipid fatty acids in intact human RBCs, and that LC improved the membrane stability of RBCs subjected to high shear stress. RBC membrane lesions occur during storage at 4 degrees C; this study investigated whether the addition of LC (5 mM) to a standard RBC preservative solution (AS-3) affected cellular integrity with 42 days' storage. STUDY DESIGN AND METHODS: A paired (n = 10) crossover design was used for RBCs stored in AS-3 with and without LC. Both in vitro RBC properties reflective of metabolic and membrane integrity and in vivo measures of cell viability (24-hour percentage of recovery and circulating lifespan) were measured at the end of the storage. In addition, the turnover of membrane phospholipid and long-chain acylcarnitine fatty acids and the carnitine content of control and LC-stored RBCs were measured. RESULTS: It was shown that LC was irreversibly taken up by RBCs during storage, with a fourfold increase at 42 days. Furthermore, as found by the use of radiolabeled palmitate, the stored RBCs were capable of generating long-chain acylcarnitine. The uptake of LC during storage was associated with less hemolysis and higher RBC ATP levels and by a significantly greater in vivo viability for LC-stored RBCs than for control-stored RBCs: a mean 24-hour percentage of recovery of 83.9 +/? 5.0 vs. 80.1 +/? 6.0 percent and a mean lifespan of 96 +/? 11 vs. 86 +/? 14 days, respectively (p < 0.05). CONCLUSION: A beneficial effect of the addition of LC to RBCs stored at 4 degrees C was evident. This effect may be related to both biophysical and metabolic actions on the cell membrane.     

低血糖指数膳食改善超重老年糖尿病患者氧化应激水平

目的:观察低血糖指数的膳食对2型糖尿病患者氧化应激状态的影响。方法:2004-10/11在上海市静安区二个社区卫生服务中心招募受试者,经医生明确诊断为2型糖尿病、病程超过6个月,体质量指数≥24kg/m2的老年糖尿病志愿者43名,受试者对试验知情同意。采用随机交叉试验随机分配至低血糖指数饮食组和高血糖指数饮食组,每种膳食分别连续使用4周,间隔洗脱期4周,比较试验前后患者超氧化物歧化酶、脂质过氧化产物丙二醛和谷胱甘肽过氧化物酶含量的变化。结果:受试者依从性好,除1人因试验期间发现肿瘤而退出试验,42名志愿者按设计要求完成试验。膳食干预后低血糖指数饮食组和高血糖指数饮食组的超氧化物歧化酶活力分别升高了15.68%和21.33%,丙二醛水平分别下降23.94%和21.55%,谷胱甘肽过氧化物酶活力分别升高了15.74%和17.09%;干预后低血糖指数饮食组丙二醛下降水平与高血糖指数饮食组比较差异有显著性意义(P<0.05),而超氧化物歧化酶和谷胱甘肽过氧化物酶活性两组间差异无显著性意义(P>0.05)。结论:在控制总能量的基础上给予平衡膳食能够改善其氧化应激水平,采用低血糖指数食物有助于氧化应激水平的改善。     

Possible role of ubiquinone in the treatment of massive hypertriglyceridemia resistant to PUFA and fibrates.

OBJECTIVE: To describe the effect of Coenzyme Q10 (CoQ10) (added to either a fibrate, or polyunsaturated fatty acids (PUFA) or association of both) in patients affected by massive hypertriglyceridemia (MHTG) resistant to fibrates and PUFA. DESIGN: Open, sequential, comparative intervention study. SETTING: Specialised centres for dyslipidemia management. SUBJECTS: Fifteen subjects (mean age: 45.1+/-12.5 years) affected by MHTG and hyporesponsive to either fibrates, or PUFA, or fibrates-PUFA association, and 15 age-matched subjects regularly responders to PUFA and fenofibrate treatment. INTERVENTIONS: Treatment for periods of 6 weeks each with the following consecutive treatments: CoQ10 150 mg/day, PUFA 3000 mg/day, fenofibrate 200 mg/day, PUFA 3000 mg/day+fenofibrate 200 mg/day, PUFA 3000 mg/day+CoQ10 150 mg/day, fenofibrate 200 mg/day+CoQ10 150 mg/day, and finally, fenofibrate 200 mg/day+PUFA 3000 mg/day + CoQ10 150 mg/day. RESULTS: CoQ10 supplementation did not improve any monitored parameter in the control group except for systolic and diastolic blood pressure, creatinine and Lp(a) plasma levels, both during fenofibrate and/or PUFA treatment. In MHTG group, CoQ10 supplementation significantly improved TG, TC, Lp(a), uric acid and blood pressure during fenofibrate treatment, but only Lp(a) and blood pressure during PUFA treatment. Fenofibrate appeared to have better effect on hsCRP and gamma-GT plasma levels than PUFA. No significant change was observed in any group and under any treatment in regards to homocysteinemia, PAI-1, or t-PA. CONCLUSION: Even though the mechanism of action through which the effects were obtained is yet to be elucidated, adding CoQ10 to fenofibrate could improve the drug's efficacy in MHTG patients not responding to fenofibrate alone.     

Emerging biologic therapies for hypercholesterolaemia

Introduction: LDL-cholesterol (LDL-C) is one of the most well-established risk factors for CV disease. Indeed, therapies that decrease LDL-C are proven to effectively reduce the risk of atherosclerotic CV disease. Monoclonal antibodies (mAbs) that target proprotein convertase subtilisin/kexin type 9 (PCSK9) have recently gained traction as a promising therapeutic strategy.

Areas covered: In this review, the authors discuss the effectiveness of mAbs against PCSK9 in lowering low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipid fractions. The discontinuation in the development of bococizumab due to efficacy and safety concerns, and the initial promising data about inclisiran, a long-acting small inhibiting RNA molecule against PCSK9 synthesis, is also discussed.

Expert opinion: Initial data about cardiovascular (CV) outcomes in large scale, long-term studies suggest a possible further therapeutic pathway for LDL-C reduction, and currently support the notion that further LDL-C reduction, obtained with PCSK9 inhibition on top of best available therapy, provides increased CV protection in subjects at very high CV risk. The development and marketing of mAbs against PCSK9 could help to redefine current therapeutic strategies aimed at reducing cardiovascular (CV) morbidity and risk, through the reduction of LDL-C concentrations. The cost-effectiveness of these emerging drugs is yet to be established.