Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients

Objective N-acetylcysteine (NAC) is a mucolytic agent with anti-oxidant properties. It might have potential positive effects in renal patients and, therefore, its pharmacokinetics and safety in haemodialysis was investigated.Methods Twelve dialysis patients received 2 g NAC (10 ml NAC 20% solution i.v.) mixed with 500 ml saline during the first 3 h of the session for six dialysis sessions. A bolus of heparin was injected intravenously as LWH-heparin. In six patients, one session was repeated with NAC mixed with heparin and infused through the heparin pump.Results Baseline NAC was on average 454 ng ml^–1; its concentration increased to 9,253 ng ml^–1 at the second infusion and attained a steady state between 14,000 ng ml^–1 and 17,000 ng ml^–1 at the fourth dose. We observed a C _max of 53,458 ng ml^–1 with a t _max of 3.0 h. Plasma clearance was 1.25 l h^–1 and dialytic clearance 5.52 l h^–1. No side effects were observed.Conclusion In the case of repeated doses, the NAC pre-dose concentration after repeated infusion of 2 g of the drug during the first 3 h of a dialysis session reached the steady state at the fourth infusion, without further accumulation. The dialytic clearance is effective, the total body clearance being reduced to 1.25 l h^–1. In dialysis patients, 2 g NAC given intravenously over 3 h is a safe dosage, with no short-term side effects.The study was conducted in accordance with the guidelines for Good Clinical Practice and all current Swiss laws concerning clinical research. The protocol was approved by the Ethics Committee of the Canton Ticino, Switzerland.     

Effects of Montelukast on free radical production in whole blood and isolated human polymorphonuclear neutrophils (PMNs) in asthmatic children

Montelukast is a highly selective leukotriene-receptor antagonist (LTRA). It is widely used in the treatment of bronchial asthma, primarily as an adjunct to corticosteroids. Reactive oxygen species (ROSs) play an important role in the pathogenesis of asthma and oxidative stress contributing to the initiation and worsening of inflammatory respiratory disorders, such as asthma. Antioxidant drugs may have a role in minimizing or preventing damage in asthmatic children. The aim of this study was to assess the antioxidant effect of montelukast on the production of free radicals in the whole blood and polymorphonuclear neutrophils (PMNs) in asthmatic children. A group of 48 (38 males and 10 females), apparently healthy asthmatic children were recruited with ages ranging between 6 and 14 years. In asthmatic children, base line (premedication) and post medication free radicals activity in the whole blood and polymorphonuclear neutrophils (PMNs) was determined by measuring chemiluminescence (CL) response through chemiluminescence luminometer. Free radical productions were significantly decreased in the whole blood, when stimulated with Phorbol Myristate Acetate (p < 0.04) and Opsonised Zymosan (p < 0.05). The free radicals were also significantly decreased in isolated polymorphonuclear neutrophils (PMNs) when stimulated with Opsonised Zymosan (p < 0.05) after the post medication treatment of montelukast in asthmatic children. Montelukast decreased the reactive oxygen species production, both in the whole blood as well as isolated PMNs in asthmatic children.     

Pharmacokinetics of N-acetylcysteine in man

Summary N-Acetylcysteine was given intravenously and as three fast dissolving and one slow-release formulation, on separate occasions, as a single dose of 600 mg to 10 fasting (5 men and 5 women) healthy volunteers. Blood and urine were sampled for the following 12 h.Renal clearance constituted around 30% of total body clearance, which was 0.21 l/h/kg. Volume of distribution was 0.33 l/kg, consistent with distribution mainly to extracellular water. The late elimination half-life was 2.27 h and the mean residence time 1.62 h.The slow-release tablet resulted in a flattened plasma concentration-time curve typical of slow release formulations, while the other three oral formulations were rapidly absorbed.The oral availability of N-acetylcysteine varied between 6 and 10%, with the slow-release tablet having the lowest and the fast dissolving tablet the highest availability.     

Garlic oil as a modulating agent for oxidative stress and neurotoxicity induced by sodium nitrite in male albino rats

In the present study, we investigated the neurobiochemical alterations and oxidative stress induced by food preservative; sodium nitrite (NaNO₂) as well as the role of the garlic oil in amelioration of the neurotoxicity in male albino rats. Serum and brain homogenates of the rats received NaNO₂ (80 mg/kg body weight) for 3 months exhibited significant decrease in acetylcholine esterase (AChE) activity as well as the levels of phospholipids, total protein and the endogenous antioxidant system (glutathione; GSH and superoxide dismutase; SOD). In contrast, lactic dehydrogenase (LDH) activity, brain thiobarbituric acid reactive substances (TBARS) and nitric oxide (NO) levels were significantly increased. On the other hand, the oral administration of garlic oil (5 ml/kg body weight) daily for 3 months significantly improved the neurobiochemical disorders and inhibited the oxidative stress induced by NaNO₂ ingestion. So, this study reveals the neural toxic effects of NaNO₂ by exerting oxidative stress and retrograde the endogenous antioxidant system. However, garlic oil has a promising role in attenuating the obtained hazard effects of sodium nitrite by its high antioxidant properties which may eventually be related with the preservation of SOD activity and primary mitochondrial role against nitrite-induced neurotoxicity in rats.     

别克参提取物抗氧化活性研究

目的：研究别克参提取物的体外抗氧化活性。方法：采用清除二苯代苦味酰基（DPPH）自由基、2,2’-氨基-（3-乙基-苯并噻唑啉-6-磺酸）二氨盐（ABTS）自由基与超氧阴离子（O2^-）自由基法,对别克参不同提取物的体外抗氧化活性进行评价。结果：别克参不同提取物清除DPPH·自由基、ABTS·自由基的能力强弱顺序为：乙酸乙酯提取物〉石油醚提取物〉正丁醇提取物〉水提取物。别克参不同提取物对O2^-自由基有一定的清除能力,但不明显。结论：别克参不同提取物抗氧化活性差异可能与各部位中所含抗氧化成分的种类和结构有关。     

Pharmacokinetics of ornidazole in neonates and infants after a single intravenous infusion

Summary The single dose pharmacokinetics of ornidazole has been evaluated in 12 neonates or infants (aged 1 to 42 weeks) after the infusion of 20 mg/kg over 20 min. Plasma disposition was described by a two-compartment open model. The distribution phase was short (T_1/2 (1)=0.31 h) and was followed by an elimination phase (t_1/2 (2)=14.67 h). The mean apparent volume of distribution was 0.96 l/kg^–1. These results did not differ from data previous by reported in adults. Total plasma clearance was between 0.4 and 1.4 ml·min^–1·kg^–1. The plasma concentration 24 h after the infusion was 7.32 mg·l^–1, which was above the minimum inhibitory concentration for clinically significant anaerobic bacteria. Based on the pharmacokinetic results and residual concentrations at 24 h, a single daily infusion of ornidazole 20 mg·kg^–1 appears adequate for therapy in neonates and infants.     

单宁急性毒性及其对小鼠丙二醛和抗氧化酶的影响

目的探讨单宁的急性毒性以及其体内抗氧化作用。方法120只二级昆明鼠随机分成6组，设溶剂对照组和5个单宁处理组，分别经一次性灌胃给予剂量为0．00、1．25、2．50、5．00、10．00和20．00g／kg的单宁水溶液。观察10d动物的存活情况，计算昆明小鼠单宁经口半数致死量(LD50)。给药后第11天，处死存活小鼠，检测全血过氧化氢酶(CAT)活力、血清和肝脏丙二醛(MDA)含量和超氧化物歧化酶(SOD)活力。结果各组动物的死亡率依次分别为0、0、5％、5％、10％和85％，用改良的寇氏法计算，昆明种小鼠单宁经口LD50为13．2g／k，其95％可信限范围为10．6～16．4g／kg。各给药组血清MDA含量较对照组均有不同程度的升高，且存在着一定的剂量一效应关系。肝脏MDA变化趋势与血清MDA的变化基本一致。低剂量给药组血清SOD活力较阴性对照组升高，而高剂量组血清SOD活力反而降低。单宁给药各组全血CAT活力较对照组降低，并且与剂量呈正相关。结论单宁为实际无毒级，但大剂量单宁可以引起正常小鼠机体的氧化损伤。     

Improvements of cellular stress response on resveratrol in liposomes

Resveratrol (RSV) has proven potential in prophylaxis and treatment of various disorders mediated by free radicals and oxidative stress. RSV solubility, stability, and cytotoxicity must be regulated for satisfactory bioavailability. Here, RSV was loaded into liposomes, characterized by PCS and TEM and evaluated on HEK293 cell line by metabolic activity assay, electron paramagnetic resonance, and fluorescence microscopy.RSV at 10 μM induced changes in cell metabolic activity and significantly improved antioxidative capacity. At 100 μM it showed concentration-dependent cytotoxicity. Oligolamellar liposomes with mean diameter 84 nm, polydispersity index 0.2, and zeta potential −40 mV showed high entrapment of RSV and rapid cellular internalization. Cell stress caused by UV-B irradiation diminished cell metabolic activity by 50%. RSV loaded into them showed no cytotoxicity at 100 μM and stimulated cellular metabolic and antioxidant activity levels to eliminate the harmful effect of the stress. Localization of RSV within liposomal bilayer is crucial for stimulation of cell-defense system, prevention of RSV cytotoxicity, and its long-term stability. In summary, evidence of different metabolic activity using free RSV and LIP–RSV is presented indicating that liposome-mediated uptake of RSV is more effective for improvement of the cell-stress response.     

In vitro evaluation of quercetin cutaneous absorption from topical formulations and its functional stability by antioxidant activity

Recently, it was demonstrated that two different formulations containing quercetin inhibit the UVB-induced cutaneous oxidative stress and inflammation. Therefore, in the present study it was evaluated the functional stability of those formulations by the antioxidant activity, the release of quercetin from the formulations, and its skin retention using modified Franz diffusion cells. Both formulations tested ((1) non-ionic emulsion with high lipid content and (2) anionic emulsion with low lipid content) remained functionally (hydrogen-donating ability) stable during 180 days. Furthermore, quercetin was released from both formulations as determined using nitrocellulose membrane. In vitro antioxidant activity of retained quercetin into the skin was observed for both formulations as detected by the inhibition of malondialdehyde formation. The effect of quercetin retention was time-dependent for formulation 1. Concluding, this study demonstrates that quercetin remains functionally stable in formulations, and measuring the antioxidant activity is an efficient approach to evaluate quercetin skin retention with minimal interference of the tissue products. Furthermore, the present results on skin retention explain the previous study on quercetin in vivo activities, and together, these data suggest that formulations containing quercetin may be used as topical active products to control UVB-mediated oxidative damage of the skin.     

Pharmacokinetics of ethylene in man by on-line laser photoacoustic detection

The pharmacokinetics of ethylene are determined using laser-based photoacoustic detection and a closed chamber setup. Concentration-time data are analyzed using a two-compartment and a physiologically based pharmacokinetic (PBPK) model. Endogenous production was 92 +/- 13 pmol/h/kg for the two-compartment model and 75 +/- 10 pmol/h/kg for the PBPK model. These values agree with previous work at our department but are significantly lower than published values based on gas chromatography. The blood:air partition coefficient in the PBPK model was determined by curve fitting, because simulations based on published values did not agree well with data. Curve fitting gave a value of 0.092 +/- 0.029. The real-time nature and high sensitivity of photoacoustic detection make it a useful addition to gas chromatography in closed chamber studies.     

N-乙酰半胱氨酸对高糖环境中胰岛细胞的影响

目的探讨N-乙酰半胱氨酸(NAC)对高糖环境下胰岛细胞的影响。方法体外培养胰岛细胞INS-1,分为正常对照组,高糖组(葡萄糖25mmol/L),NAC作用组(浓度分别为50、100、200μmol/L),培养24h后,取上清测定胰岛素水平及谷胱甘肽过氧化物酶(GSH-Px)、丙二醛(MDA)含量。结果高糖可使胰岛素分泌量减少,GSH-Px浓度下降,MDA含量增加,NAC可以明显抑制高糖引起的上述变化,抑制作用随NAC浓度的增加而增强。结论抗氧化剂NAC对高糖导致的胰岛细胞损伤有一定的保护作用,并且呈浓度依赖性。     

Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine

Summary The pharmacokinetics and bioavailability of N-acetylcysteine (NAC) have been determined after its intravenous and oral administration to 6 healthy volunteers.According to a randomized cross-over design each subject received NAC 200 mg i.v. and 400 mg p.o., and blood samples were collected for 30 h.Reduced NAC had a volume of distribution (V_SS) of 0.59 l·kg^–1 and a plasma clearance of 0.84 l·h^–1·kg^–1. The terminal half-life after intravenous administration was 1.95 h. The oral bioavailability was 4.0%.Based on total NAC concentration, its volume of distribution (V_SS) was 0.47 l·kg^–1 and its plasma clearance was 0.11 l·h^–1·kg^–1. The terminal half-life was 5.58 h after intravenous administration and 6.25 h after oral administration. Oral bioavailability of total NAC was 9.1%.     

Pharmacokinetics of intravenous isosorbide-dinitrate

The kinetics of isosorbide dinitrate (ISDN) after i.v. administration and the absolute availability of an oral slow release preparation (SR) were studied in young healthy volunteers. ISDN and the 2- and 5-mononitrates of isosorbide (2-MN, 5-MN) were determined by GLC. After i.v. administration plasma levels of ISDN declined biexponentially and could be adequately described by an open two compartment body model. Distribution half-life was extremely rapid (2–5 min). Terminal disappearance had a half-life of 67 (62–75) min (mean, range). Total plasma clearance was 1.6 (1.2–2.2) litres · min^–1, thus approaching liver blood flow. Nevertheless, absolute systemic availability (F) or oral ISDN amounted to 22% (16–29%). Assuming that oral ISDN is completely absorbed and blood levels do not exceed serum levels, an upper limit of hepatic clearance (liver blood flow 1.5 litres·min^–1 · (1-F/100)) can be estimated, which is significantly smaller (p<0.05) than the measured clearance. This finding is best interpreted by assuming that ISDN is partly eliminated by extrahepatic routes, which is further substantiated by a different pattern of metabolites after i.v. and oral dosing. Whereas after i.v. administration more 2-MN is produced, 5-MN is the main metabolite after oral ISDN. Since the glutathione-S-transferases are found in the cytosol of most cells, it seems likely that other organs than the liver contribute to the metabolism of ISDN.This work was supported in part by a grant from the Swiss National Science Foundation and by a grant-in-aid of the Globopharm AG, Küsnacht, Switzerland.     

山莨菪碱在体外清除超氧阴离子自由基保护大鼠红细胞膜蛋白巯基

<正> 山莨菪碱(anisodamine,Ani)为M胆碱受体阻断剂,对感染中毒性休克等有显著疗效。近年来的研究表明,该药具有抗氧化作用,为进一步了解其抗氧化机理,本文采用化学发光法探讨了Ani对超氧阴离子自由基O_2~-的体外清除作用,并观察了Ani对外源性H_2O_2损伤大鼠红细胞膜蛋白巯基的保护作用。     

Pharmacokinetics of intravenous erythromycin

Erythromycin pharmacokinetics were examined following intravenous infusion to male subjects. The biological half-life of erythromycin in serum was 2 hr in individuals with normal renal function. The half-life varied in cases of reduced renal function, with values of 3.9 and 7.0 hr occurring in two subjects with severe renal impairment. Postinfusion serum erythromycin levels were adequately described by two-compartment model kinetics, and values for the distribution volume of the central compartment and the overall distribution are described. Estimated erythromycin distribution volumes in normal individuals may facilitate calculation of absorption efficiencies of erythromycin and its salts after oral doses.     

Pharmacokinetics of intravenous alendronate

Alendronate is a potent bisphosphonate that has been studied for the treatment of osteoporosis and Paget's disease of the bone. To examine the pharmacokinetics of this drug, several groups of postmenopausal women were dosed intravenously in several studies. Twelve patients with metastatic bone disease were administered an intravenous dose of 10 mg of 14C-labeled alendronate (approximately 26 muCi), and plasma, feces, and urine samples were collected for 72 hours. Radioactivity was excreted almost exclusively in urine, and all of it was accounted for by alendronate. Overall recovery accounted for 47% of dose, with the remainder presumed to be retained in bone. Metabolism of alendronate was not observed. Renal clearance of alendronate was 71 mL/min. An additional 10 subjects were given repeated i.v. administrations of alendronate to demonstrate that previous exposure does not alter the pharmacokinetic behavior of the drug. Examination of the findings from these and other studies in which alendronate was administered intravenously revealed that disposition of single doses is linear in the range of 0.125 to 10 mg. With the possible exception of a somewhat greater skeletal retention of a systemically administered dose, the pharmacokinetics of i.v. alendronate were found to be similar to those of other bisphosphonates.     

Zingiber officinale Roscoe alone and in combination with alpha-tocopherol protect the kidney against cisplatin-induced acute renal failure.

Oxidative stress due to abnormal production of reactive oxygen molecules (ROM) is believed to be involved in the etiology of toxicities of many xenobiotics. Evidences suggested that ROM is involved in the nephrotoxicity of a widely used synthetic anticancer drug cisplatin. The nephroprotective effects of ethanol extract of Zingiber officinale alone and in combination with vitamin E (alpha-tocopherol) were evaluated using cisplatin (single dose of 10 mg/kg body wt, i.p) induced acute renal damage in mice. The results of the study indicated that Z. officinale significantly and dose dependently protected the nephrotoxicity induced by cisplatin. The serum urea and creatinine levels in the cisplatin alone treated group were significantly elevated (P<0.01) with respect to normal group of animals. The levels were reduced in the Z. officinale (250 and 500 mg/kg, p.o) plus cisplatin, vitamin E (250 mg/kg) plus cisplatin, and Z. officinale (250 mg/kg) with vitamin E plus vitamin E treated groups. The renal antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and level of reduced glutathione (GSH) were declined; level of malondialdehyde (MDA) was elevated in the cisplatin alone treated group. The activities of SOD, CAT GPx and level of GSH were elevated and level of MDA declined significantly (P<0.05) in the Z. officinale (250 and 500 mg/kg) plus cisplatin and Z. officinale (250 mg/kg) with vitamin E plus cisplatin treated groups. The protective effect of Z. officinale (250 mg/kg body wt) was found to be better than that of vitamin E (250 mg/kg body wt). The results also demonstrated that combination of Z. officinale (250 mg/kg) with vitamin E (250 mg/kg) showed a better protection compared to their 250 mg/kg alone treated groups. This study concluded that ethanol extract of Z. officinale alone and in combination with vitamin E partially ameliorated cisplatin-induced nephrotoxicity. This protection is mediated either by preventing the cisplatin-induced decline of renal antioxidant defense system or by their direct free radical scavenging activity.     

Pharmacokinetics of famotidine in infants

BACKGROUND: Although famotidine pharmacokinetics are similar in adults and children older than 1 year of age, they differ in neonates owing to developmental immaturity in renal function. Little is currently known about the pharmacokinetics of famotidine in infants aged between 1 month and 1 year, a period when renal function is maturing. OBJECTIVE: To characterise the pharmacokinetics of famotidine in infants. DESIGN: This was a two-part multicentre study with both single dose (Part I, open-label) and multiple dose (Part II, randomised) arms. PATIENTS: Thirty-six infants (20 females and 16 males) who required treatment with famotidine and who had an indwelling arterial or venous catheter for reasons unrelated to the study. METHODS: Infants in Part I were administered a single dose of famotidine 0.5 mg/kg; the dose was intravenous or oral according to the judgement of the attending physician. Infants receiving 0.5 mg/kg intravenously were divided into two groups by age, and pharmacokinetic parameters in infants 0-3 months and >3 to 12 months of age were compared. Infants in Part II were randomised to one of the following treatments: 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 and subsequent days, or 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 followed by doses of either 0.5 mg/kg/dose intravenously or 1 mg/kg/dose orally on subsequent days. From day 2 onwards, age-adjusted dose administration regimens (once daily in infants <3 months of age and every 12 hours in infants >3 months of age) were used; the total number of famotidine doses ranged from 3 to 11 and the total number of days of dose administration ranged from two to eight. RESULTS: In infants <3 months of age, plasma and renal clearance of famotidine were decreased compared with infants >3 months of age. Pharmacokinetic parameters for the older infants (i.e. those >3 months) were similar to those previously reported for children and adults. Approximate dose-proportionality, no accumulation on multiple dosing and an estimated bioavailability similar to adult values were also observed. CONCLUSION: A short course of famotidine therapy in infants appears generally well tolerated, and the characteristics of famotidine pharmacokinetics during the first year of life are explained to a great degree by the development of renal function, the primary route of elimination for this drug.