Paracetamol potentiates acetylsalicylate in inhibiting prostaglandin synthesis

Lower concentrations of paracetamol stimulated, but a higher concentration inhibited prostaglandin synthesis by bull seminal vesicle homogenate in the absence of added co-factors. Admixed with acetylsalicylate or indomethacin, paracetamol strongly potentiated the inhibition of prostaglandin synthesis in vesicle homogenate, and weakly potentiated inhibition in rat gastric fundus strip. We propose that, by acting as a phenolic co-factor, paracetamol stimulates prostaglandin synthesis and thus renders the cyclo-oxygenase more vulnerable to acetylsalicylate or indomethacin.     

布洛芬、赖氨匹林和对乙酰氨基酚治疗小儿发热的疗效比较

目的：比较布洛芬混悬液（美林）、注射用赖氨匹林、对乙酰氨基酚栓对急性呼吸道感染伴高热患儿的退热效果。方法：选择有急性呼吸道感染伴有发热症状的患儿170例,随机分为三组,分别给予布洛芬混悬液f美林）、赖氨匹林注射液、对乙酰氨基酚栓治疗。结果：在1h内,赖氨匹林注射液退热速度最快,布洛芬混悬液次之,对乙酰氨基酚栓最慢,三者两两间有非常显著性差异（S〉S0.01）。在1～2h,布洛芬混悬液退热速度最快,其次是对乙酰氨基酚栓,赖氨匹林注射液的退热速度最慢（P〈0．01）。在2～3h,布洛芬混悬液与赖氨匹林注射液的退热速度无显著性差异（P〉0．05）,两者快于对乙酰氨基酚栓（P〈0．01）,对乙酰氨基酚栓组的体温呈回升趋势。在3～8h,布洛芬混悬液仍有退热效果,与赖氨匹林注射液和对乙酰氨基酚栓有非常显著性差异（P〈0．01）,赖氨匹林注射液组和对乙酰氨基酚栓组的体温均呈现回升。布洛芬混悬液能在2h内使患儿体温降至正常,并能维持8h。赖氨匹林注射液能在2h内使患儿体温降至正常,并能维持3h,3-6h后体温呈回升趋势。对乙酰氨基酚栓给药后2～3h体温呈回升趋势。布洛芬混悬液、赖氨匹林注射液的总有效率均为100．0％,对乙酰氨基酚栓的总有效率为94．0％。布洛芬混悬液退热的显效率为90．0％．赖氨匹林注射液为92．0％,对乙酰氨基酚栓为36．0％：布洛芬混悬液和赖氨匹林注射液的疗效比较无显著性差异（P〉0．05）,两者优于对乙酰氨基酚栓（P〈0．01）。结论：布洛芬混悬液和赖氨匹林注射液的退热作用强,布洛芬混悬液的维持时间长,赖氨匹林注射液的维持时间中等,对乙酰氨基酚栓的退热作用较弱,维持时间短。     

The effect of prostaglandin synthesis inhibition of the acute blood pressure reduction by captopril in pentobarbital-anaesthetized rats

Treatment of pentobarbital-anaesthetized rats with captopril (SQ 14225) caused a reduction in mean arterial blood pressure (MAP), which lasted for over 1 h when a dose of 5 mg/kg i.p. was used. Pretreatment with the prostaglandin synthesis inhibitors indometacin (IND, 5 mg/kg i.p.) or acetylsalicylic acid (ASA, 100 mg/kg i.p.) did not prevent the initial decrease in MAP after captopril. However, the recovery of the MAP was much faster than after captopril alone. In rats pretreated with IND, the MAP after captopril was significantly higher than after captopril alone from 30 min onwards. With ASA pretreatment the same was observed after 45 min. These data indicate that the subacute blood pressure lowering effect of captopril in pentobarbital-anaesthetized normotensive rats may be at least partly dependent on the presence of an intact prostaglandin biosynthetic pathway. This may be due to activation of prostaglandin synthesis by the accumulation of bradykinin and angiotensin I after captopril.     

Paracetamol pharmacokinetics during the first trimester of human pregnancy

Paracetamol pharmacokinetics was evaluated in groups of pregnant (8–12 weeks) and non pregnant women given the standard oral dose of 650 mg.The mean half-life was significantly lower and oral clearance was significantly higher in the first trimester group compared to the control group. The AUC was lower in the first trimester but the difference was not significant. The maximum serum concentration (C_max) was reached 48 min after administration in both groups, and the mean maximal serum concentration was similar in the pregnant and non-pregnant women (11.16 and 11.58 g·ml^–1). A correlation of r=0.85 was found between C_max and the weight of the pregnant women (P<0.01) but not with the weight of the control women, this suggests that weight gain might be used to determine the women in whom dosage adjustment is needed.     

对乙酰氨基酚/MCM-41载药体系的制备及其缓释性能的研究

目的制备对乙酰氨基酚/MCM-41缓释体系,并考察其体外释放行为。方法在碱性和室温条件下制备MCM-41介孔材料;采用浸渍法将解热镇痛药物对乙酰氨基酚组装到MCM-41的孔道中,通过XRD、IR、低温N2吸附对MCM-41介孔材料及药物组装体进行表征;测定组装体的载药量、载药时间以及在人工胃液中的释放行为。结果介孔材料MCM-41作为药物载体具有较短的载药时间(7 h)、较大的载药量(46.65%)、较低的释放速率(6 h仅释放35.6%)。结论通过测定组装体在体外模拟人工胃液和人工肠液中的释放速率,结果表明制得了对乙酰氨基酚/MCM-41缓释释放体系。     

RP-HPLC法测定氨酚伪麻片中对乙酰氨基酚和盐酸伪麻黄碱含量

摘要：目的 测定氨酚伪麻片中对乙酰氨基酚和盐酸伪麻黄碱含量。方法 采用十八烷基硅烷键合硅胶柱；流动相为甲醇—0.05mol/L磷酸二氢钾(18:82)为流动相，检测波长为254nm；流速为1.0ml/min。结果 对乙酰氨基酚线性范围2.016～6.048mg平均回收率为99.6%，RSD=0.8%(n=5)；盐酸伪麻黄碱线性范围0.2110～0.633mg，平均回收率为100.5%，RSD=1.0% (n=5)结论：方法简便，结果准确。     

(+)-Cyanidanol-3 as inhibitor of prostaglandin synthetase

Summary (+)-Cyanidanol-3 inhibits the prostaglandin synthetase of the renal medulla and of the liver of rats in vitro and after treatment of the animals with 200 mg/kg. A half-maximal inhibition of the enzyme was obtained with 5·10^–5 M cyanidanol. If the microsomal inhibitor CFT1201 is first applied, the inhibitory effect in vivo of 50% is increased to 80%. It is supposed that cyanidanol is converted to metabolites which, according to our earlier studies, activate the enzyme system. An enzyme activity of the rat liver was measured which — with a turnover of 18–20% — was significantly higher than the values obtained by other authors.     

Local nitric oxide release does not affect tachyphylaxis to angiotensin II in dorsal hand veins in man in the presence of prostaglandin synthesis inhibition

AIMS: Local prostaglandin (PG) production contributes to tachyphylaxis to angiotensin II (ANGII) in veins. Our aim was to assess the hypothesis that local nitric oxide (NO) generation is also, in part, responsible for tachyphylaxis to ANGII in veins, using the Aellig dorsal hand vein technique. METHODS: Eight healthy male volunteers received 600 mg of aspirin (orally) to inhibit PG production. The venoconstrictor effects of ANGII and noradrenaline (NA) were then compared in dorsal hand veins during co-infusion of the NO synthase inhibitor L-NMMA or saline, on separate occasions. RESULTS: ANGII and NA produced a similar degree of initial venoconstriction. However, the response to ANGII was significantly attenuated by 12 min compared with NA (AUC 147 +/- 38 vs 196 +/- 40, respectively; [95% confidence interval for difference: 7, 92], P = 0.02). Infusion of L-NMMA did not influence the response to ANGII or NA (P = 0.2 and P = 0.3, respectively). CONCLUSIONS: Tachyphylaxis to ANGII in dorsal hand veins is not dependent on local NO release.     

Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study

AIM

The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H₁-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg.

METHODS

Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg.

RESULTS

Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated.

CONCLUSION

Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations.     

布洛芬与对乙酰氨基酚治疗早产儿症状性动脉导管未闭对患儿血浆和尿前列腺素E_2水平的影响

目的分析布洛芬与对乙酰氨基酚治疗早产儿症状性动脉导管未闭(sPDA)对患儿血浆和尿前列腺素E_2(PGE_2)水平的影响。方法纳入2014年7月至2016年12月我院出生的患有sPDA的84例早产儿作为观察对象。随机纳入42例给予布洛芬进行治疗(A组),另外42例给予对乙酰氨基酚治疗(B组)。对比两组治疗疗效,治疗前后血浆和尿PGE_2水平以及不良反应。结果两组患儿在各时段的关闭率以及总关闭率的组间差异均无统计学意义(P>0.05)。经治疗,两组患儿血浆PGE_2和尿PGE_2水平均较治疗前下降,与治疗前比较差异有统计学意义(P<0.05);A组下降程度稍大于B组,但组间差异均无统计学意义(P>0.05)。经治疗,两组患儿肝肾功能指标血肌酐(SCr)和丙氨酸氨基转移酶(ALT)水平均较治疗前略有上升(P>0.05),血小板(PLT)较治疗前有所下降,但差异无统计学意义(P>0.05);两组SCr、ALT及PLT水平比较差异无统计学意义(P>0.05)。B组高胆红素血症比例低于A组,组间差异有统计学意义(P<0.05),其他不良反应上,组间差异均无统计学意义(P>0.05)。结论布洛芬与对乙酰氨基酚的疗效相当,其对血浆PGE_2和尿PGE_2水平的影响略强于对乙酰氨基酚,但对乙酰氨基酚高胆红素血症的比例低于布洛芬。     

紫外分光光度法测定对乙酰氨基酚片含量的测量不确定度评估

摘 要 目的：评定紫外分光光度法测定对乙酰氨基酚片含量的测量不确定度。方法: 建立紫外分光光度法测定乙酰氨基酚片含量的数学模型,分析测量不确定度的来源并对各分量进行量化分析和评估,合成标准测量不确定度,给出扩展测量不确定度报告。结果: 紫外分光光度法测定对乙酰氨基酚片含量的扩展测量不确定度为1.2%,测量结果表示为（97.0±1.2）%,k=2。结论:通过分析产生不确定度的主要来源,为有效控制该含量测定方法的准确性提供可靠的理论依据。     

Tyramine does not release noradrenaline from splenic nerve by exocytosis

Summary The release of noradrenaline by tyramine from bovine splenic nerves was found to be dose dependent. No dopamine--hydroxylase could be detected in perfusates from tyramine stimulated spleens in contrast to results obtained by electrical stimulation. It is concluded that the releasing action of tyramine differs fundamentally from that of electrical stimulation in that exocytosis is not involved.     

Phenobarbital induction does not potentiate hepatotoxicity but accelerates liver cell necrosis from acetaminophen overdose in the rat

Rats were pretreated with phenobarbital to induce hepatic cytochrome P-450. Compared to noninduced rats, a similar relation between the dose of acetaminophen and mortality, and between dose and changes in liver function (prothrombin index) and identical time courses, was found. The urinary excretion of acetaminophen mercapturate and acetaminophen cysteine was identical in induced and noninduced rats. The metabolism of acetaminophen in terms of blood levels and excreted metabolites was not influenced by phenobarbital induction. At the same dose level, hepatic necrosis was accelerated (maximum 24 h) compared to noninduced animals (maximum 72 h), but no difference in the maximum extent was found. These data cannot support the concept that induction of cytochrome P-450 leads to greater formation of the hypothetical toxic metabolite of acetaminophen, or that induction enhances its hepatotoxicity, in the rat. Several factors may contribute to accelerate the necrotic changes which make it possible to histologically identify cell damage and death. In that case, functional studies are more relevant than morphological evaluation in quantitative assessment of liver damage.     

The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages

BACKGROUND AND PURPOSE

Zileuton is the only 5-lipoxygenase (5-LOX) inhibitor marketed as a treatment for asthma, and is often utilized as a selective tool to evaluate the role of 5-LOX and leukotrienes. The aim of this study was to investigate the effect of zileuton on prostaglandin (PG) production in vitro and in vivo.

EXPERIMENTAL APPROACH

Peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon γ (LPS/IFNγ), J774 macrophages and human whole blood stimulated with LPS were used as in vitro models and rat carrageenan-induced pleurisy as an in vivo model.

KEY RESULTS

Zileuton suppressed PG biosynthesis by interference with arachidonic acid (AA) release in macrophages. We found that zileuton significantly reduced PGE2 and 6-keto prostaglandin F1α (PGF1α) levels in activated mouse peritoneal macrophages and in J774 macrophages. This effect was not related to 5-LOX inhibition, because it was also observed in macrophages from 5-LOX knockout mice. Notably, zileuton inhibited PGE2 production in LPS-stimulated human whole blood and suppressed PGE2 and 6-keto PGF1α pleural levels in rat carrageenan-induced pleurisy. Interestingly, zileuton failed to inhibit the activity of microsomal PGE2 synthase1 and of cyclooxygenase (COX)-2 and did not affect COX-2 expression. However, zileuton significantly decreased AA release in macrophages accompanied by inhibition of phospholipase A2 translocation to cellular membranes.

CONCLUSIONS AND IMPLICATION

Zileuton inhibited PG production by interfering at the level of AA release. Its mechanism of action, as well as its use as a pharmacological tool, in experimental models of inflammation should be reassessed.     

Prevention of clofilium-induced torsade de pointes by prostaglandin E2 does not involve ATP-dependent K+ channels

Drugs that prolong the QT interval can trigger the life-threatening arrhythmia, torsade de pointes, but there is a poor correlation between the extent of QT prolongation and the occurrence of torsade de pointes. The clinical status of a patient may modify the arrhythmogenicity of drugs; thus, we have investigated whether a mediator of fever and inflammation, prostaglandin E(2), alters the proarrhythmic effects of clofilium. In pentobarbitone-anaesthetized, open-chest, alpha-adrenoceptor-stimulated rabbits, prostaglandin E(2) 0.28, 0.84 and 2.80 nmol kg(-1) min(-1), infused into the left ventricle, reduced the incidence of torsade de pointes from 50% in controls to 20%, 20% and 0%, respectively (n=10 per group). Pretreatment with glibenclamide (10 micromol kg(-1)) did not alter the antiarrhythmic effect of prostaglandin E(2) (2.80 nmol kg(-1) min(-1)). These results indicate that prostaglandin E(2) prevents drug-induced torsade de pointes and that this action of prostaglandin E(2) is not mediated via opening of ATP-dependent K(+) channels (K(ATP)).     

Block of electrically induced contractions of guinea pig longitudinal muscle by prostaglandin synthetase and receptor inhibitors.

Inhibitors of prostaglandin synthetase as well as prostaglandin receptor inhibitors block electrically induced contractions of the longitudinal muscle of the guinea pig ileum. This blockade is selectivety reversed by some prostaglandins, particularly those of the E series. There is a very close parallel between the potency with which the synthetase inhabitors block transmission and inhibit the enzyme. That blockade is actually accompanied by inhibition of synthesis of PG was shown by inhibition of arachidonic acid contractions of the tissue by indomethacin. The inhibition of transmission by indomethacin involves block of acetylcholine release as shown by direct assay and by the fact that physostigmine can reverse the block. Physostigmine also reverses block of transmission by prostaglandin receptor inhibitors and by morphine but not that produced by chlorpromazine or papaverine. Other evidence for a presynaptic site of action for the synthetase and PG receptor inhibitors is indicated by lack of effect of blocking concentrations on response of the tissue to exogenous acetylcholine. That prostaglandin reverses block of transmission by a presynaptic effect was shown by lack of reversal of atropine and papaverine inhibition of electrically induced contractions; both of these drugs produce this effect directly on the smooth muscle. These results are compatible with the previous postulate that a prostaglandin system, comprised of prostaglandin, its synthesizing enzyme and its receptor, is directly involved with the release of acetylcholine in the ileum.     

Protection of the ischemic myocardium from reperfusion injury by prostaglandin E1 inhibition of ischemia-induced neutrophil activation

Summary This study investigates the action of intravenous PGE₁ on myocardial reperfusion injury and the possible involvement of antineutrophil activities. Cats were subjected to 3 h of temporary ligation of the left anterior descending coronary artery, followed by 2 h of reperfusion. Animals were treated with PGE₁ (5 g/kg x min) or vehicle (saline solution), starting 0.5 h after coronary artery occlusion. Vehicle-treated cats exhibited a significant loss of cardiac creatine phosphokinase specific activity at 5 h, accompanied by a significant ischemia-induced rise in the ST segment of the ECG and development of a Q wave after starting reperfusion. All of these alterations were largely prevented by PGE₁ treatment. PGE₁ exerted some blood-pressurelowering activity at 5 h (P > 0.05) but did not reduce myocardial contractile force and oxygen consumption. PGE₁ modestly antagonized ischemia-induced formation of platelet aggregates. However, PGE₁ prevented the rise in peripheral white blood cell count during ischemia and reperfusion and inhibited the generation of reactive oxygen species (myeloperoxidase assay) from zymosan-stimulated whole blood ex vivo. The ratio of generation of reactive oxygen species/white blood count remained unchanged. It is concluded that PGE₁ protects the ischemic myocardium from acute reperfusion injury and that this effect involves an action of the compound on neutrophils, probably by improved myocardial tissue preservation, resulting in reduced formation of chemotactic products and, consequently, less local neutrophil accumulation and release of noxious metabolites.Parts of these results have been presented to the 29th Spring meeting of the Deutsche Gesellschaft für Pharmakologie und Toxikologie, Mainz, 1988 Send offprint requests to K. Schrör at the above address