一类创新药苯胺洛芬注射液急性毒性研究

目的 研究一类创新药苯胺洛芬的急性毒性,并与日本同类上市产品联苯乙酸乙酯注射液的急性毒性实验结果进行比较,为新药研发提供依据。方法选用NIH小鼠和Beagle犬为研究对象,采用最大耐受量法和近似致死量法考察一类创新药苯胺洛芬的急性毒性情况。结果苯胺洛芬NIH小鼠静脉注射给药最大耐受量为900 mg/kg,Beagle犬...     

一类创新药苯胺洛芬注射液安全性药理研究

目的:研究一类创新药苯胺洛芬的安全性药理,为新药研发提供依据。方法:通过小鼠自发活动试验、协调力实验和戊巴比妥钠催眠实验来考察苯胺洛芬对中枢神经系统的影响;通过麻醉Bealge犬实验考察苯胺洛芬对呼吸系统和循环系统的影响;通过正常大鼠和胃溃疡大鼠来考察苯胺洛芬对胃黏膜的影响。结果:苯胺洛芬剂量为临床拟用剂量的18倍时(小鼠216 mg.kg-1、大鼠162 mg.kg-1、犬45 mg.kg-1)单次给药后会导致麻醉Beagle犬血压一过性升高、小鼠自主活动降低、协调能力降低、与戊巴比妥钠具有协同作用;其余各剂量组和各观察指标均未见异常。结论:苯胺洛芬在剂量为临床拟用剂量的18倍时对中枢神经系统和心血管系统具有明显的影响;苯胺洛芬在剂量为临床拟用剂量的6倍时对中枢神经系统、呼吸系统和心血管系统未见明显影响;各剂量组对大鼠胃黏膜均未见明显影响。     

一类创新药苯胺洛芬注射液急性毒性研究

目的研究一类创新药苯胺洛芬的急性毒性,并与日本同类上市产品联苯乙酸乙酯注射液的急性毒性实验结果进行比较,为新药研发提供依据。方法选用NIH小鼠和Beagle犬为研究对象,采用最大耐受量法和近似致死量法考察一类创新药苯胺洛芬的急性毒性情况。结果苯胺洛芬NIH小鼠静脉注射给药最大耐受量为900 mg/kg,Beagle犬静脉滴注给药的近似致死剂量范围为405～608mg/kg(均以联苯乙酸计);联苯乙酸乙酯小鼠LD50分别为雄性337 mg/kg(294.5～347.4),雌性433 mg/kg(392.3～462.9);Beagle犬静脉滴注近似致死量为250～500 mg/kg(均以联苯乙酸计)。结论与联苯乙酸乙酯注射液相比,一类创新药苯胺洛芬注射液的安全性较好,安全范围较大,具有较好的应用前景。     

苯胺洛芬注射液镇痛作用及镇痛部位研究

目的研究苯胺洛芬注射液对大鼠单足致炎急性炎症模型和大鼠单发性关节慢性病理性炎症模型的镇痛作用,并对其镇痛部位进行分析。方法通过角叉菜胶致大鼠单足致炎后的后肢压痛实验和完全弗氏佐剂致大鼠单发性关节炎性疼痛实验,测定致炎足和非致炎足痛阈值和屈伸关节评分。结果在大鼠急性炎症模型和慢性病理性炎症模型中,苯胺洛芬注射液25.2、75.6 mg·kg-1可提升致炎足的痛阈值,但对非致炎足的痛阈值无明显影响,致炎足和非致炎足痛阈值变化情况与氟比洛芬酯注射液相当,而喷他佐辛注射液对致炎足和非致炎足均有镇痛作用。结论苯胺洛芬注射液发挥镇痛作用的部位主要在外周,这与非甾体类抗炎镇痛药的作用部位相似。     

进口精氨洛芬颗粒剂人体生物等效性研究

目的:研究进口精氨洛芬颗粒剂在健康人体内的生物等效性.方法:20例健康男性志愿者按双周期随机交叉口服单剂量400mg试验药精氨洛芬颗粒剂与对照药布洛芬颗粒剂两种制剂.用HPLC-UV法测定血清中布洛芬的浓度,利用3p97软件处理数据,对2种制剂的生物等效性进行评价.结果:单剂量口服精氨洛芬颗粒剂及布洛芬颗粒剂后,布洛芬的Cmax分别为(54.747±9.888)和(44.032±7.046)μg·mL-1;Tmax分别为(0.53±0.39)和(1.69±0.81)h;t1/2ke分别为(1.83±0.27)和(1.82±0.26)h;AUC0～8h分别为(145.927±30.114)和(139.444±23.709)μg·h·mL-1;AUC0～∞分别为(155.144±34.458)和(150.000±26.987)μg·h·mL-1;精氨洛芬颗粒剂的相对生物利用度为(105.72±18.17)%.结论:精氨洛芬颗粒剂与布洛芬颗粒剂具有生物等效性.     

人体关键药代动力学参数预测方法

分布容积、清除率、半衰期和生物利用度是重要的药物代谢动力学参数,决定着药物在体内的暴露程度与暴露时间,在新药开发过程中尽早预测人体内这些参数对选择与优化潜在新药有重要价值。本文综述了采用临床前药代动力学实验数据、体外吸收与代谢数据、化合物理化性质、计算机模拟等多种方法预测人体内关键药代动力学参数的研究及其进展。     

洛索洛芬钠大鼠在体肠吸收动力学研究

目的:研究洛索洛芬钠大鼠在体肠吸收动力学,为剂型设计提供依据。方法:采用大鼠在体肠灌流方法,采用高效液相色谱法-紫外检测器测定洛索洛芬含量,取麻醉后大鼠的十二指肠、空肠、回肠和结肠段作为受试肠段建立在体肠灌流模型,计算洛索洛芬的吸收速率常数和吸收百分率。结果:洛索洛芬在大鼠各肠段吸收百分率和吸收速率常数均无显著性差异(P>0.05),无特异吸收部位。洛索洛芬在不同质量浓度及pH范围内的肠吸收速率常数基本不变。结论:洛索洛芬大鼠肠吸收为一级动力学过程,各肠段均有吸收,吸收机制为被动扩散,适合制成缓控释制剂。     

药物与肝脏(合理用药讲座)

肝脏是人体内最重要的代谢器官,几乎参与体内的一切代谢过程,故有“物质代谢中枢”之称。绝大多数药物的代谢也在肝脏中进行。近年来临床药学也从事研究药物在人体中从摄入到排出体外,称作研究“药物体内命运”问题,肝脏是“药物体内命运”中重要环节。本文从三个方面谈药物与肝脏的关系。     

非诺洛芬钙亲水凝胶缓释骨架片释药机理的研究

目的　研究非诺洛芬钙亲水凝胶缓释骨架片的释放机理。方法　以羟丙基甲基纤维素(HPMC)为亲水骨架材料,通过对Peppas经验式中n值的详细考察,研究非诺洛芬钙缓释骨架片在不同条件下的溶蚀度与释放度。结果　在各种条件下,非诺洛芬钙骨架片的释放与溶蚀均呈零级动力学过程,且二者间呈线性关系。结论　非诺洛芬钙骨架片的释放机理为:前40min,以扩散和溶蚀协同作用方式释放;50min后,以溶蚀机制释放。     

口服药物的奇妙“旅程”

在日常生活中,一些小毛病在所难免,需要服用药物的情况也不少,那么大家知道药物吃进去之后,在人体内的“旅程”是什么样子吗?今天就来聊一聊口服药物在人体内的奇妙“旅程”。口服药物在人体内主要经过吸收、分布、代谢和排泄四个过程。     

Pharmacokinetics of felbinac after intravenous administration of felbinac trometamol in rats

Felbinac trometamol (trishydroxymethylaminomethane 4-biphenylacetate) is a new water-soluble salt of felbinac currently undergoing clinical evaluation as an intravenous (i.v.) formulation for the treatment of severe post-operative pain. This article reports the pharmacokinetics of felbinac after i.v. administration of felbinac trometamol in Sprague-Dawley rats. The maximum plasma concentration (C(0)) and area under the plasma concentration-time curve (AUC) of felbinac administered at doses of 3.36, 8.40 and 21.0?mg/kg felbinac trometamol increased linearly with dose. Felbinac was highly protein bound (~95%) at plasma concentrations up to 75?μg/ml and extensively metabolized with only small amounts being excreted unchanged in urine (0.318%), feces (0.530%) and bile (0.465%). 4'-Hydroxyfelbinac was the principal metabolite in urine, feces and bile together with felbinac glucuronide, 4'-hydroxyfelbinac glucuronide and sulfate. The majority of the administered dose was excreted in urine (63.6%) mostly as 4'-hydroxyfelbinac. Total drug in urine and feces accounted for about 72% of the dose. It would appear that felbinac trometamol has the potential to replace lipid-based NSAID formulations and progress to clinical evaluation.     

Pharmacokinetics of felbinac after intravenous administration of felbinac trometamol in rats

1. Felbinac trometamol (trishydroxymethylaminomethane 4-biphenylacetate) is a new water-soluble salt of felbinac currently undergoing clinical evaluation as an intravenous (i.v.) formulation for the treatment of severe post-operative pain. This article reports the pharmacokinetics of felbinac after i.v. administration of felbinac trometamol in Sprague–Dawley rats.

2. The maximum plasma concentration (C₀) and area under the plasma concentration-time curve (AUC) of felbinac administered at doses of 3.36, 8.40 and 21.0?mg/kg felbinac trometamol increased linearly with dose.

3. Felbinac was highly protein bound (~95%) at plasma concentrations up to 75?μg/ml and extensively metabolized with only small amounts being excreted unchanged in urine (0.318%), feces (0.530%) and bile (0.465%).

4. 4′-Hydroxyfelbinac was the principal metabolite in urine, feces and bile together with felbinac glucuronide, 4′-hydroxyfelbinac glucuronide and sulfate. The majority of the administered dose was excreted in urine (63.6%) mostly as 4′-hydroxyfelbinac. Total drug in urine and feces accounted for about 72% of the dose.

5. It would appear that felbinac trometamol has the potential to replace lipid-based NSAID formulations and progress to clinical evaluation.

     

通天口服液抗炎镇痛作用研究

目的观察通天口服液的抗炎镇痛作用和对血流变学的影响。方法用二甲苯所致小鼠耳廓及乙酸引起小鼠毛细血管通透性的增高试验,观察该药的抗炎作用,用乙酸扭体法研究其镇痛作用;用WTP-B1型毛细血管血液黏度计测定血液流变学指标。结果通天口服液对二甲苯所致小鼠耳廓肿胀有明显的抑制作用,并抑制乙酸所致小鼠毛细血管通透性的增高,对乙酸扭体法和热板法镇痛实验的研究显示通天口服液具有明显的镇痛效应,并能降低小鼠全血高切?低切的血黏度。结论通天口服液具有明显的抗炎镇痛作用。     

Metabolism of nabumetone (BRL 14777) by various species including man

Radiotracer methodology was used to study the metabolic fate of 4-(6-methoxy-2-naphthyl)-butan-2-one (nabumetone) after oral administration to rats, mice, rabbits, dogs, rhesus monkeys and healthy human subjects. Parent compound was not detected in plasma and urine and the major circulating metabolite in all species was identified as 6-methoxy-2-naphthylacetic acid, a compound known to possess anti-inflammatory activity. Metabolites were mainly excreted in urine from which four principal metabolites were isolated and identified by mass spectrometry and independent synthesis. Pathways involving O-demethylation, reduction of the ketone group and oxidation of the butanone side-chain to acetic acid occurred in all species, but the ratios of the metabolic end-products tended to be species dependent. In the rat about half of the administered nabumetone was oxidized to the pharmacologically active acid metabolite.     

Effect of enoxacin, felbinac, and sparfloxacin on fatty acid metabolism and glucose concentrations in rat tissues

Multiple changes in metabolic levels could be useful for understanding physiological toxicity. To explore further risk factors for the convulsions induced by the interaction of nonsteroidal anti-inflammatory and new quinolone antimicrobial drugs, the effect of sparfloxacin, enoxacin, and felbinac on fatty acid metabolism and glucose concentrations in the liver, brain, and blood of rats was investigated. The levels of long-chain acyl-CoAs (C(18:1) and C(20:4)) in the liver and brain were decreased at the onset of convulsions induced by the coadministration of enoxacin with felbinac. Then, glucose concentrations in the liver and blood were decreased, whereas they were increased in a dose-dependant manner in the brain. However, the formation of acyl-CoAs and glucose levels in the liver, brain, and blood was not significantly influenced by enoxacin, felbinac, and sparfloxacin alone, respectively. The disturbance of both fatty acid metabolism and glucose levels might be associated with the increased susceptibility to convulsions, which may contribute to further understanding of the toxic effects associated with these drugs.     

Bioavailability and pharmacokinetics of oral dopamine in dogs

The bioavailability and pharmacokinetics of oral dopamine (DA) were studied in dogs. Plasma concentrations of DA and its main metabolites, such as dopamine-3-O-sulfate (DA-SO4) and 3,4-dihydroxyphenyl acetic acid (DOPAC) were determined after intravenous or oral administration of DA using high-performance liquid chromatography with electrochemical detector (HPLC-ECD). Following the intravenous administration, plasma DA-SO4 and DOPAC concentrations were lower than the plasma DA concentration. On the other hand, following the oral administration, plasma DA-SO4 and DOPAC concentrations were much higher than the plasma DA concentration. The absolute bioavailability of DA after oral administration was calculated to be approximately 3%. Intraduodenal and mesenteric venous administration of DA revealed that DA-SO4 was mainly produced in the intestine and DOPAC was produced in the intestine and liver. On the basis of these observations, the bioavailability and pharmacokinetics of oral DA are discussed in connection with the metabolic inactivation due to first-pass metabolism.     

Quantitative comparison of the analgesic and anti-inflammatory activities of aspirin, phenacetin and acetaminophen in rodents.

The mild analgesic activities of aspirin, phenacetin and acetaminophen have been compared in the trypsin, kaolin and carrageenan hyperalgesic assays as well as in the acetic acid writhing test. The trypsin and kaolin hyperalgesic assays were designed to be unaffected by drugs with anti-inflammatory activity. Aspirin and acetaminophen were inactive in these two tests at dose levels devoid of side effects. Phenacetin was active in the trypsin and kaolin assays with oral ED50's of 114 +/- 36.2 and 107 +/- 11.5 mg/kg, respectively. Non-steroidal anti-inflammatory drugs as well as phenacetin and acetaminophen were active in the acetic acid writhing and carrageenan hyperalgesic assays. This led to evaluation of phenacetin and acetaminophen as anti-inflammatory agents. Both of these latter drugs were active in the carrageenan pleurisy and adjuvant arthritis models of inflammation. In all studies phenacetin was equipotent to or more potent than acetaminophen. The data suggest that the analgesia produced by aspirin and acetaminophen results from their anti-inflammatory activity whereas the analgesia produced by phenacetin has two components, one dependent on and one independent of anti-inflammatory activity.     

Clinical pharmacokinetics of dexketoprofen

Dexketoprofen trometamol is a water-soluble salt of the dextrorotatory enantiomer of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen. Racemic ketoprofen is used as an analgesic and an anti-inflammatory agent, and is one of the most potent in vitro inhibitors of prostaglandin synthesis. This effect is due to the (S)-(+)-enantiomer (dexketoprofen), while the (R)-(-)-enantiomer is devoid of such activity. The racemic ketoprofen exhibits little stereoselectivity in its pharmacokinetics. Relative bioavailability of oral dexketoprofen (12.5 and 25mg, respectively) is similar to that of oral racemic ketoprofen (25 and 50mg, respectively), as measured in all cases by the area under the concentration-time curve values for (S)-(+)-ketoprofen. Dexketoprofen trometamol, given as a tablet, is rapidly absorbed, with a time to maximum plasma concentration (tmax) of between 0.25 and 0.75 hours, whereas the tmax for the (S)-(+)-enantiomer after the racemic drug, administered as tablets or capsules prepared with the free acid, is between 0.5 and 3 hours. The drug does not accumulate significantly when administered as 25mg of free acid 3 times daily. The profile of absorption is changed when dexketoprofen is ingested with food, reducing both the rate of absorption (tmax) and the maximal plasma concentration. Dexketoprofen is strongly bound to plasma proteins, particularly albumin. The disposition of ketoprofen in synovial fluid does not appear to be stereoselective. Dexketoprofen trometamol is not involved in the accumulation of xenobiotics in fat tissues. It is eliminated following extensive biotransformation to inactive glucuroconjugated metabolites. No (R)-(-)-ketoprofen is found in the urine after administration of dexketoprofen, confirming the absence of bioinversion of the (S)-(+)-enantiomer in humans. Conjugates are excreted in urine, and virtually no drug is eliminated unchanged. The analgesic efficacy of the oral pure (S)-(+)-enantiomer is roughly similar to that observed after double dosages of the racemic compound. At doses above 7mg, dexketoprofen was significantly superior to placebo in patients with moderate to severe pain. A dose-response relationship between 12.5 and 25mg could be seen in the time-effects curves, the superiority of the 25mg dose being more a result of an extended duration of action than of an increase in peak analgesic effect. A plateau in the analgesic activity of dexketoprofen trometamol at the 25mg dose is suggested. The time to onset of pain relief appeared to be shorter in patients treated with dexketoprofen trometamol. The drug was well tolerated.     

The pharmacokinetics of meprobamate following its oral and rectal administration as a series of combinations with diphenhydramine, acetylsalicylic acid, codeine and pentaerythritol tetranitrate

Studies in human volunteers of the pharmacokinetics of the active drugs in the formulations Visano-mini (meprobamate and diphenhydramine HCl), DoloVisano (meprobamate, diphenhydramine HCl, acetylsalicylic acid and codeine phosphate) and VisanoCor (meprobamate, diphenhydramine HCl and pentaerythritol tetranitrate (PETN], have demonstrated systemic absorption of each of the drugs from all of the formulations. Bioequivalence of meprobamate is indicated despite the drug combinations involved. Some differences in diphenhydramine pharmacokinetics are, however, apparent. The bioavailability of meprobamate administered rectally to human volunteers as the marketed preparations DoloVisano Suppositories and Dolo-Visano Suppositories sine codeino, is similar to that observed following oral administration.