Effect of malotilate on paracetamol-induced hepatotoxicity

Malotilate (diisopropyl-1,3-dithiol-2-ylidenemalonate) prevented liver damage induced by paracetamol in male mice only when given 1 h prior to the hepatotoxic agent. Furthermore, it partially inhibited paracetamol-induced glutathione depletion in mouse liver, indicating that the antihepatotoxic activity of malotilate is related to an interaction with the bioactivation of paracetamol.     

Effect of sulphydryl drugs on paracetamol-induced hepatotoxicity in mice

It has been shown that the major in vivo biotransformation of thiol-containing drugs such as captopril (CP) and penicillamine (PA) involve mixed disulphide formation with endogenous thiols derived from cysteine. At high doses, both drugs produced a dose-dependent depletion of glutathione (GSH) and may perturb GSH and related GSH-enzymes. In this study the possible interactions of these drugs with paracetamol, which produce hepatotoxicity after GSH depletion, were investigated. Following co-administration of CP (50-250 mg/kg) or PA (43-257 mg/kg) with paracetamol (300 mg/kg), the hepatotoxic effect produced by paracetamol was diminished. The protective effect was comparable to that produced by N-acetylcysteine (500 mg/kg) and L-cysteine (500 mg/kg). However, pre-treatment with buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, abolished the protective effects of CP, N-acetylcysteine and L-cysteine while the protective effect of PA was unaffected. This suggests that, although both CP and PA may act as alternative sulphydryl nucleophiles to GSH to prevent arylation of essential cellular macromolecules by the reactive metabolite of paracetamol, the underlying mechanisms of these drug interactions may be distinctly different.     

Effect of Teucrium stocksianum on paracetamol-induced hepatotoxicity in mice

• 1.1. Hepatoprotective activity of an ethanolic extract of Teucrium stocksianum was investigated against paracetamol-induced hepatic damage in mice.
• 2.2. Paracetamol at an oral dose of 0.6 g/kg produced about 94% mortality in mice while pretreatment with the plant extract (0.5 and 1 g/kg for 5 days) reduced the death rate to 0%.
• 3.3. Paracetamol (0.6 g/kg, orally) produced liver damage as manifested by significant rises in liver weight, plasma aspartate aminotransferase (AST) activity and bilirubin concentration, pentobarbitone-induced sleeping time, and by the significant depletion of reduced glutathione (GSH) in the liver.
• 4.4. Pretreatment of mice with T. stocksianum at the above doses significantly ameliorated all the paracetamol-induced signs of liver damage described above.
• 5.5. T. stocksianum did not produce any lethality or adverse effects in the livers of treated mice.
• 6.6. These results indicate that T. stocksianum ethanolic extract contains hepatoprotective constituents, and suggest further work on the isolation and characterization of these constituents which may potentially be used as hepatoprotective agents.

     

Combined antihypertensive therapy: vasodilatation using prazosin in combination with beta-adrenoceptor blockers and diuretics

An open study was carried out in 20 hypertensive patients, who had inadequate blood pressure control with beta-adrenoceptor blocking drugs and diuretics, to investigate the effects of adding prazosin to their existing treatment regimen. Patients received a mean daily dose of prazosin of 8.7 +/- 4.4 mg over a period of 12 weeks. The results showed that there was a significant reduction in systolic and diastolic blood pressures in the resting position. Only a few side-effects were reported and these occurred during the first 4 weeks whilst prazosin dosage was being adjusted. Weight increase, however, was noted in all but 4 of the patients. It is suggested that this may have been due partly to fluid retention, even though the majority were receiving diuretics, or possibly to changed carbohydrate-insulin metabolism.     

Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity

AIMS

Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported.

METHODS

Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit.

RESULTS

Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P < 0.001). The King''s College poor prognostic criteria had reduced sensitivity in unintentional overdoses (77.8%, 95% confidence intervals (CI) 62.9, 88.8) compared with intentional overdoses (89.9%, 95% CI 83.4, 94.5). Unintentional overdose was independently predictive of death or liver transplantation on multivariate analysis (odds ratio 1.91 (95% CI 1.07, 3.43), P= 0.032).

CONCLUSIONS

Unintentional paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses.     

曲尼司特对小鼠对乙酰氨基酚肝损伤的保护作用及其机理

曲尼司特对小鼠对乙酰氨基酚肝损伤的保护作用及其机理１傅阳平王键吴若（中国医学科学院，中国协和医科大学药物研究所，北京１０００５０）近来发现某些肝炎患者的肝损伤可能有过敏反应的因素参与［１］．我们观察了几种抗过敏药对不同原因引起小鼠肝损伤的作用，发现...     

Effect of calcium channel blockers on adrenergic and nonadrenergic vascular responses in man

There is evidence that responses mediated via alpha adrenoceptors are dependent on calcium fluxes and it has been suggested that the alpha 2 adrenoceptor is particularly associated with the increased entry of extracellular calcium ions, which is preferentially antagonised by calcium channel blocking drugs. This study investigates in normotensive men the effects of calcium antagonism with verapamil and the dihydropyridine nisoldipine on the pressor responses to adrenergic and nonadrenergic vasoconstriction. Phenylephrine and alphamethylnoradrenaline were intravenously infused to assess respectively alpha 1 and alpha 2 adrenoceptor-mediated peripheral vascular responsiveness and angiotensin II was used to assess nonadrenergic responsiveness. After 4 days oral treatment, both verapamil and nisoldipine significantly attenuated the responses to angiotensin II with three- to fivefold rightward shifts of the mean pressor dose-response curves. Rightward shifts of comparable magnitude were obtained for phenylephrine but with alphamethylnoradrenaline, although the overall trend was similar, only nisoldipine caused a significant twofold rightward shift. These data demontrate, in humans, that peripheral vascular adrenergic responses mediated via both alpha 1 and alpha 2 adrenoceptors are affected by calcium channel blocking drugs. There was no evidence that this effect was specifically linked to the alpha 2 adrenoceptor.     

Studies on the mechanism of paracetamol-induced protection against paracetamol hepatotoxicity.

In rats, 3 days treatment with paracetamol (1 oral dose of 1 g/kg daily) produced a complete protection against the hepatotoxic actions of a further dose of paracetamol as documented by determination of serum enzyme activities (glutamic-oxaloacetic transaminase, (GOT), glutamic-pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), bromsulphthalein retention and histological investigations. Subacute paracetamol treatment decreased liver glutathione levels by 46%, liver microsomal cytochrome P-450 content by 23%, hepatic hydroxylation of aniline by 29% and hepatic demethylation of aminopyrine by 46%. It afforded also some protection against the hepatotoxic actions of carbon tetrachloride, bromobenzene and thioacetamide, but did not influence the antiphlogistic activity of paracetamol (carrageenan paw edema test). Plasma and liver concentrations of free paracetamol after oral administration of 1 g/kg paracetamol were somewhat higher in the subacutely paracetamol-pretreated rats than in the non-pretreated control animals whereas no differences in the concentrations of conjugated paracetamol were found between the 2 groups. Pretreatment with paracetamol did not influence the urinary excretion of free paracetamol but caused some shift in the urinary excretion of paracetamol conjugates: pretreated rats excreted 23% less of the paracetamol glucuronide and sulfate and 33% more of the paracetamol mercapturate than the control animals. A depression of the microsomal mixed-function oxidase activity is presumed to be the main cause of the paracetamol-induced protection against paracetamol hepatotoxicity.     

Selective protective effect of an extract from Fumaria parviflora on paracetamol-induced hepatotoxicity

• 1.1. The hepatoprotective activity of an aqueous-methanolic extract of Fumaria parviflora was investigated against paracetamol- and CCl₄-induced hepatic damage.
• 2.2. Paracetamol (1 g/kg; orally) produced 100% mortality in mice; pretreatment of animals with the plant extract (500 mg/kg; orally) reduced the death rate to 50%.
• 3.3. Pretreatment of rats with plant extract (500 mg/kg, orally twice daily for 2 days) prevented (P<0.001) the paracetamol (640 mg/kg)-induced rise in serum enzymes alkaline phosphatase (ALP) and transaminases (GOT and GPT), whereas the same dose of the extract was unable to prevent (P>0.05) the CCl₄-induced rise in serum enzyme levels.
• 4.4. Posttreatment with 3 successive doses of the extract (500 mg/kg, 6 hourly) also restricted the paracetamol-induced hepatic damage.
• 5.5. The plant extract (500 mg/kg; orally) caused significant prolongation in pentobarbital (75 mg/ kg)-induced sleep as well as increased strychnine-induced lethality in mice (P<0.05), suggestive of an inhibitory effect on microsomal drug metabolizing enzymes (MDME).
• 6.6. It is conceivable therefore, that Fumaria parviflora extract exhibits a selective protective effect against paracetamol-induced hepatotoxicity, probably mediated through MDME inhibition.

     

Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium

1. Clinical studies have shown different effects of beta-blockers on the beta-adrenergic system, tolerability and outcome in patients with heart failure. 2. The study examines beta-adrenoceptor-G-protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. 3. Radioligand binding studies ([(125)I]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts. 4. Bucindolol and carvedilol bound non-selectively to beta(1)- and beta(2)-adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold beta(1)-selective and lacked guanine nucleotide modulatable binding. 5. All beta-blockers antagonized isoprenaline-induced enhancement of contractility. 6. In preparations in which the coupling of the stimulatory G-protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in five experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89. 4+/-2.2% (P<0.01 metoprolol vs carvedilol and bucindolol). The negative inotropic effect of metoprolol was antagonized by bucindolol. 7. It is concluded that differences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue. 8. Differences in intrinsic activity may contribute to differences in beta-adrenoceptor regulation and possibly to differences in tolerability and outcomes of patients with heart failure.     

卡维地洛在慢性心力衰竭中的对照研究

目的：探讨卡维地洛在慢性心力衰竭中的应用，并与美托洛尔进行对照。方法：202例慢性心力衰竭患者随机分成2组，分别在常规治疗的基础上合用卡维地洛或美托洛尔治疗13周，观察慢性心力衰竭的改善情况。结果：卡维地洛治疗102例，心功能改善总有效率为89．2％，美托洛尔治疗组100例，心功能改善总有效率77％。结论：卡维地洛在慢性心衰中，对心功能的改善及左室舒张功能的好转优于美托洛尔。     

Protective effects of Swertia longifolia Boiss. and its active compound, swerchirin, on paracetamol-induced hepatotoxicity in mice

Aerial parts of Swertia longifolia Boiss. (Gentianaceae), which grows in the north of Iran, were screened for hepatoprotective activity against paracetamol (acetaminophen)-induced hepatotoxicity in Swiss mice. Pretreatment with total plant extract and swerchirin, the major component of the plant, significantly reduced the elevation of biochemical parameters, AST (aspartate aminotransferase), ALT (alanine aminotransferase) and ALP (alkaline phosphatase), the enzymes that are increased by liver damage (P < 0.001). Our results indicated that total plant extract and swerchirin were hepatoprotective in the range of 6-50 mg kg(-1) orally.     

A comparison of carvedilol and metoprolol antioxidant activities in vitro

Carvedilol is a vasodilating beta-blocker and antioxidant approved for treatment of mild to moderate hypertension. angina, and congestive heart failure. Metoprolol is a beta1-selective adrenoceptor antagonist. When carvedilol and metoprolol were recently compared in clinical trials for heart failure, each showed beneficial beta-blocker effects such as improved symptoms, quality of life, exercise tolerance, and ejection fraction, with no between-group differences. When thiobarbituric acid reactive substance (TBARS) levels were measured in serum as an indirect marker of free radical activity, there were also no between-group differences. However, we had noted superior cardioprotection by carvedilol in comparison to metoprolol in ischemia and reperfusion models. We therefore examined antioxidant activity directly in cells and tissues. Here we show that in cultured rat cerebellar neurons, and in brain and heart membranes, carvedilol has far greater antioxidant activity than metoprolol, which is essentially inactive as an antioxidant in these model systems. The antioxidant activity of carvedilol could be explained by a greater degree of lipophilicity, as measured by its ClogP value of 3.841 as contrasted to a ClogP value of 1.346 for metoprolol. Alternatively, the molecular structure of carvedilol favors redox recycling, which the structure of metoprolol does not. Therefore, carvedilol could have additional pharmacologic effects that are favorable for long-term therapy.     

卡维地洛与美托洛尔治疗高血压的临床观察

目的 比较卡维地洛与美托洛尔治疗高血压的临床效果与安全性.方法 选取原发性高血压患者84例,随机分为对照组与观察组各42例,对照组患者接受美托洛尔治疗,观察组患者接受卡维地洛治疗,治疗6个月后比较两组临床疗效与不良反应发生情况.结果 观察组的总有效率（90.48％）显著高于对照组（76.19％）（P＜0.05）,观察组的治疗方法可有效降低患者TG、Ins、LDL、GLU水平,促使HDL-C显著提高,治疗前后比较,差异均有统计学意义（P＜0.05）;观察组不良反应发生率（19.05％）显著低于对照组（42.86％）（P＜0.05）.结论 在对高血压的治疗中卡维地洛与美托洛尔均可发挥显著疗效,但卡维地洛能显著改善患者各项指标,且不良反应发生率较低,因此更值得在临床中推广应用.     

Comparison of the effects of ascorbyl palmitate and L-ascorbic acid on paracetamol-induced hepatotoxicity in the mouse

The effects of ascorbyl palmitate (ASCP) and free L-ascorbic acid (LAA) on the hepatotoxicity of paracetamol (acetaminophen) and the in vivo covalent binding of reactive paracetamol metabolites to hepatic proteins has been studied in male MF1 mice. The oral administration of [3H(G)]paracetamol (600 mg/kg) resulted in covalent binding to hepatic proteins, a depletion of hepatic non-protein sulphydryl (NPS) groups after 2 h, and a marked elevation of plasma alanine aminotransferase (ALAT) activity after 24 h. The co-administration of paracetamol and ASCP (1412 mg/kg, equivalent to 600 mg/kg free LAA), but not paracetamol and LAA (600 mg/kg), significantly reduced covalent binding of paracetamol metabolites at 2 and 4 h after treatment. In addition ASCP, but not LAA, significantly reduced the depletion of NPS groups and the elevation of plasma ALAT activity. ASCP also completely prevented the 35% mortality observed at 24 h in paracetamol treated mice. These results demonstrate that ASCP, but not LAA, when co-administered orally with the analgesic is an effective inhibitor of paracetamol-induced hepatotoxicity in the mouse. The mechanism by which ASCP prevents liver injury appears to involve destruction of reactive paracetamol metabolites which is associated with a sparing action on hepatic reduced glutathione levels.     

Effects of prazosin on metabolism and body temperature in normothermic rabbits

An attempt was made to study the influence of prazosin on thermoregulatory parameters. Two sets of experiments were carried out in rabbits. In the first set of experiments prazosin was given as 3 h infusion intravenously, (iv) (0.1, 0.25 and 0.5 mg/kg/h) or intracerebroventricularly, (icv) (20, 50 and 100 micrograms/animal) at an ambient temperature of 22 degrees C. Iv infusion caused a fall while icv administration a rise in body temperature. In the second set of experiments at different ambient temperatures (Ta = 4, 22, 28 degrees C) the following thermoregulatory parameters were recorded: rectal (Tre) and ear skin (Te) temperatures, metabolic rate (M), respiratory heat loss (Eres). The most evident result of iv infusion of prazosin in a dose of 0.25 mg/kg/h was a fall in Tre accompanied by a decrease in metabolic rate at ambient temperature of 4 degrees C. At Ta of 22 degrees C and 28 degrees C prazosin iv (0.25 mg/kg/h) induced only minimal changes in measured parameters. The results of the experiments may suggest that prazosin given peripherally induced hypothermia at Ta of 4 degrees C by inhibition of non-shivering thermogenesis.     

Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium

1. The present study investigated whether or not there may be differences in the direct cardiac actions of the novel, highly beta(1)-selective adrenoceptor antagonist nebivolol (NEB) in comparison to metoprolol (MET), bisoprolol (BIS), carvedilol (CAR) and bucindolol (BUC) in human myocardium (n=9). 2. The rank order of beta(1)-selectivity as judged by competition experiments to (3)H-CGP 12.1777 in the presence of CGP 207.12 A (300 nmol l(-1), K(i)beta(2)) or ICI 118.551 (50 nmol l(-1), K(i)beta(1)) were NEB(K(i)beta(2)/K(i)beta(1): 40.7) > BIS(15.6) > MET(4.23) > CAR(0.73) > BUC(0.49). 3. The rank order of the negative inotropic potency of the beta-adrenoceptor antagonists measured in left ventricular trabeculae (dilated cardiomyopathy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (1 micromol l(-1))-stimulated force (IC(50)) was: MET (0.6 micromol l(-1)) > CAR (4.1 micromol l(-1)) > NEB (7.0 micromol l(-1)). 4. NEB, BUC, MET and CAR did not not exert an intrinsic sympathomimetic activity (ISA) as determined by measurements of force development in forskolin (0.3 micromol l(-1)) pre-treated left ventricular trabeculae, nor by measuring adenylate cyclase activity in forskolin (0.3 micromol l(-1))-stimulated assays (crude membranes). This also holds true for radioligand binding assays with or without guanine nucleotide guanyl-5'-yl imidodiphosphate (Gpp(NH)p). 5. Although all studied beta-adrenoceptor antagonists lack intrinsic sympathomimetic activity (ISA), they differ in the beta(1)-selectivity as well as in their direct negative inotropic action. These differences as well as the mode of extracardiac action may have an impact on outcome of patients treated with beta-adrenoceptor antagonists.