Carnitine and Coenzyme A Decrease Valproic Acid-Induced Neural Tube Defects in Mice

Abstract The effects of the administration of L-carnitine or coenzyme A (Co A) on valproic acid (VPA)-induced teratogenesis were examined in mice. VPA (300, 400, 500, 600, and 700 mg/kg, s. c.), L-carnitine (100, 200, and 400 mg/kg, s. c.), or Co A (10, 100, 200 mg/kg, i. v.) was injected on day 8 of gestation (plug day = day 0). Exencephaly was induced dose-dependently by single injections of VPA. Administration of L-carnitine or Co A alone at any of the dose levels tested did not induce embryocidal or teratogenic effects. In combined treatment experiments, L-carnitine (400 mg/kg) significantly reduced VPA (500 and 600 mg/kg)-induced exencephaly, while L-carnitine did not decrease VPA-induced open eyelids. Co A (200 mg/kg) also significantly reduced VPA-(600 mg/kg) induced exencephaly. The results demonstrate the attenuation of VPA teratogenicity by L-carnitine and Co A.     

白蔹配伍乌头对大鼠肝脏CYP450的调节作用

［摘要］目的研究乌头、白蔹配伍对主要药物代谢酶CYP1A2、CYP2E1、CYP3A1/2在酶活性、mRNA水平和蛋白质水平的影响。方法采用高效液相色谱法测定CYP1A2、CYP2E1活性；采用紫外 可见分光光度法测定CYP3A1/2活性；分别采用逆转录 聚合酶链反应（RT PCR）和Western Blot方法评价药物对CYP1A2、CYP2E1、CYP3A1、CYP3A2 mRNA及蛋白水平的影响。结果乌头、白蔹配伍后CYP1A2、CYP2E1、CYP3A1/2的酶活性均有下降；Western Blot检测显示CYP1A2、CYP3A1的蛋白质表达水平上升；CYP2E1、CYP3A2的蛋白质表达水平下降。RT PCR检测显示CYP1A2、CYP2E1、CYP3A1、CYP3A2的mRNA水平均上升。结论乌头、白蔹配伍后抑制CYP1A2、CYP2E1、CYP3A1/2的酶活性，CYP2E1酶活性下降可能主要通过影响基因转录进而影响其蛋白水平来实现；CYP1A2、CYP3A1/2酶活性下降则与基因和蛋白水平不相关。     

Naloxone prolongs cutaneous nociceptive block by lidocaine in rats

We aimed to investigate the local anesthetic properties of naloxone alone or as an adjunct for the local anesthetic lidocaine. After the block of the cutaneous trunci muscle reflex (CTMR) with drugs delivery by subcutaneous infiltration, cutaneous nociceptive block was tested on the rats? backs. We demonstrated that naloxone, as well as lidocaine, elicited cutaneous analgesia dose‐dependently. The relative potency in inducing cutaneous analgesia was lidocaine [22.6 (20.1 – 25.4) μmol/kg] > naloxone [43.2 (40.3 – 46.4) μmol/kg] (P < 0.05). On an equianesthetic basis [50% effective dose (ED₅₀), ED₂₅, and ED₇₅], naloxone displayed a greater duration of cutaneous analgesic action than lidocaine (P < 0.01). Coadministration of lidocaine (ED₉₅ or ED₅₀) and ineffective‐dose naloxone (13.3 μmol/kg) intensifies sensory block (P < 0.01) with prolonged duration of action (P < 0.001) compared with lidocaine (ED₉₅ or ED₅₀) alone or naloxone (13.3 μmol/kg) alone on infiltrative cutaneous analgesia. The preclinical data showed that naloxone is less potent than lidocaine as an infiltrative anesthetic, but its analgesic duration was longer than that of lidocaine. Furthermore, naloxone prolongs lidocaine analgesia, acting synergistically for nociceptive block.     

Ezetimibe: a novel option for lowering cholesterol

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease but lowering LDL-cholesterol to levels established in current National Cholesterol Education Program (NCEP) guidelines provides significant risk reduction. Nevertheless, many patients receiving lipid-lowering therapy, particularly those at highest coronary heart disease risk, do not reach LDL-cholesterol goals with their current medications. Ezetimibe (Zetia^®, Merck Schering-Plough) is the first of a new class of lipid-lowering drugs known as cholesterol absorption inhibitors. Ezetimibe has a favorable pharmacokinetic profile, which allows it to be administered once daily and to be given in conjunction with statins. In a series of randomized, controlled, multicenter studies, ezetimibe produced significant improvements in levels of LDL-cholesterol and other lipid parameters when used as monotherapy, with a safety profile comparable with that of placebo. Furthermore, coadministration of ezetimibe with a statin (simvastatin, atorvastatin, lovastatin, or pravastatin) was more effective than statin monotherapy in lowering LDL-cholesterol and improving other lipid parameters. Moreover, coadministration of ezetimibe with a statin allowed a greater percentage of patients to achieve treatment goals established in NCEP guidelines. The safety and side-effect profile of ezetimibe plus statin coadministration therapy was generally comparable with that of statin monotherapy. These studies establish ezetimibe as an effective lipid-lowering agent, which will likely be useful in the management of a broad range of patients with hypercholesterolemia. Ezetimibe can be used in conjunction with a statin at the beginning of therapy, or it can be added if patients do not achieve their LDL-cholesterol goal with statins alone.     

Effect of Rifampin on the Pharmacokinetics of Ertugliflozin in Healthy Subjects

Purpose

Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor being developed for the treatment of type 2 diabetes mellitus. The primary enzyme involved in the metabolism of ertugliflozin is uridine diphosphate-glucuronosyltransferase (UGT) 1A9, with minor contributions from UGT2B7 and cytochrome P450 (CYP) isoenzymes 3A4, 3A5, and 2C8. Rifampin induces UGT1A9, UGT2B7, CYP3A4, and CYP3A5. Because concurrent induction of these enzymes could affect ertugliflozin exposure, this study assessed the effect of multiple doses of rifampin on the pharmacokinetic properties of single-dose ertugliflozin.

Effect of Coadministered Uridine on Intestinal First-Pass Metabolism of 5′-Deoxy-5-Fluorouridine in Conscious Rats—An Evaluation by Method of Portal-Systemic Concentration Difference

Purpose. The effect of uridine (UR) coadministration on the intestinal metabolism from 5-deoxy-5-fluorouridine (5-DFUR) to 5-fluorouracil (5-FU) was evaluated by a method of concentration difference between portal and systemic bloods in conscious rats (PS method). Methods. 5-DFUR (100 mg/kg) alone (Group A), or 5-DFUR + UR (100 mg/kg each) (Group B) was orally administered to conscious rats. The portal and arterial bloods were simultaneously withdrawn from two canulas at appropriate time intervals, and blood concentrations of 5-DFUR, 5-FU, UR and uracil (U) were assayed by HPLC. The concentration-time profiles of these drugs and its metabolites were analyzed by local moment analysis. Results. UR coadministration made the local absorption ratio (F_a) of 5-DFUR decrease significantly from 60.1 ± 10.5% to 38.0 ± 18.6% of dose. Though the local absorption ratios (F_a ^m) of the metabolite (5-FU) were the same between Group A and Group B (8.3 ± 1.9 and 8.7 ± 4.0% of 5-DFUR, respectively), AUC of arterial 5-FU in Group B was 5 times greater than that in Group A. UR was not detected in the portal blood, and F_a ^m of U was estimated to be 41.9 ± 26.8% of UR in Group B. Conclusions. It is predicted that a large portion of 5-FU generated from 5-DFUR is further degraded in the intestine in Group A, and U generated from UR blocks 5-FU degradation in the intestine and the systemic circulation in Group B.     

Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.     

唑吡坦与咖啡因药动学相互作用研究

 目的 研究咖啡因与唑吡坦之间的药动学相互作用.方法 经双盲、单剂量、6批次、轮换式志愿者人体试验评价了咖啡因与唑吡坦同时口服药动学相互作用.结果 咖啡因可中度增加唑吡坦最大血浆浓度(coadministration modestly increased maximum,Cmax)和血浆浓度一时间曲线下面积(area under the plasma concentration-time,AUC)约30%～40%,而唑吡坦并不明显影响咖啡因及其代谢物的药动学特点.结论 实验研究表明,咖啡因能够减弱唑吡坦的药理作用.