氧氟沙星在肾功能障碍大鼠唾液中的分布

目的 :研究肾功能障碍时氧氟沙星 (OFLX)在唾液中分布的变化规律。方法 :通过 5 / 6肾摘除术 ,制成大鼠肾功能障碍模型 ,以模拟手术为对照。OFLX( 10mg·kg-1)静脉注射后 ,经时采血及腮腺 (Pr)、颌下腺 (M )唾液。采用HPLC法测定各样品中的OFLX浓度。结果 :肾功能障碍使大鼠OFLX血浆浓度显著增高 ,全身清除率下降约 4 0 %。肾障碍组Pr唾液中浓度明显增高 ,而M唾液中浓度与对照组之间差异无显著性。在肾功能障碍组及对照组 ,消失相的OFLX唾液中浓度及唾液 /血浆浓度比 (S/P比 ) ,在Pr唾液均比M唾液高约 2和 3倍。肾功能正常大鼠的S/P比与Pr唾液中药物浓度之间呈良好正相关。结论 :OFLX在大鼠唾液中的分布存在腺差。肾功能低下 ,导致了OFLX向Pr唾液中的移行性增大 ,但对M唾液的影响不明显。而OFLX向Pr唾液中分布的量与该唾液中药物浓度有关。     

Reduced hepatic uptake of propranolol in rats with acute renal failure

The effect of acute renal failure (ARF) on the hepatic uptake and metabolism of propranolol was investigated in relation to the hepatic clearance of the drug. ARF was induced by the subcutaneous injection of uranyl nitrate to rats. The uptake rate of propranolol in the isolated perfused liver was determined by the multiple-indicator dilution method and was found to decrease from 43.6 +/- 2.0 min-1 (mean +/- S.E.) in control to 29.4 +/- 1.7 min-1 in ARF (P less than 0.001). The recovery fraction of propranolol in effluent venous blood increased about twofold in ARF compared to control (P less than 0.05). The metabolic activity for propranolol was examined using the hepatic microsomal fraction prepared from control and ARF rats. There was no significant difference in the kinetics of oxidative metabolism of propranolol between two groups. These results suggest that the previously reported decrease in the hepatic clearance of propranolol in ARF is due to decreased hepatic uptake of the drug from the blood into the liver cells.     

Pharmacokinetics and hepatic extraction of metoprolol in rats with glycerol-induced acute renal failure

The aim of the present study was to evaluate the effect of glycerol-induced acute renal failure (ARF) on the pharmacokinetics and hepatic extraction of metoprolol in rats. Experimental ARF in rats was induced by injections of 50% glycerol into the leg muscle (10 ml/kg). Pharmacokinetics and hepatic extraction of metoprolol was evaluated by means of intravenous, intra-intestinal, and intra-portal administration of the drug. The blood metoprolol concentration following intravenous infusion in ARF rats was similar to that in control rats. On the other hand, the blood metoprolol concentration at 5--10 min after intra-intestinal administration in ARF rats was significantly higher than that in control rats, and the oral clearance (CL/F) of the drug was significantly decreased in ARF rats. Hepatic extraction following intra-portal infusion was not altered by glycerol-induced ARF; however, hepatic first-pass extraction of metoprolol was dose-dependent and saturable in both ARF and control rats. These results suggested that the decreased CL/F of metoprolol in rats with glycerol-induced ARF is mainly a result of the increased initial absorption rate in the intestine followed by partial saturation of hepatic first-pass metabolism.     

Cardiac function in rats with acute renal failure.

Inotropic responses of isolated cardiac preparations from rats with glycerol-induced acute renal failure (ARF) were recorded, following a range of cardiac stimulants. Left atria of rats with ARF showed diminished inotropic responses only to the calcium agonist Bay K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl-phenyl)-pyridine-5 -carboxylate) whilst right ventricular strips exhibited reduced responses to isoprenaline, 3-isobutyl-1-methylxanthine, Ca2+ and Bay K 8644. Investigations of cardiac mitochondrial respiration indicated that there is a site-unspecific 'pseudo' uncoupling of oxidative phosphorylation in ARF but that electron transport is unaffected. This uncoupling of oxidative phosphorylation did not have any detectable effect on either levels of total adenine nucleotides and creatine phosphate or cellular energy charge. Measurements were also made of the activity of pyruvate dehydrogenase which provides an index of mitochondrial Ca2+ levels. The proportion of pyruvate dehydrogenase in its active form was threefold higher following isoprenaline injection in hearts of rats with ARF compared with controls. The results suggest that in hearts of rats with ARF there is a change in the number, affinity, efficacy or coupling of the dihydropyridine receptor on the L-type calcium channel. Moreover, in the ventricle, a defect in cellular Ca2+ control, resulting in an increase in mitochondrial Ca2+ uptake, may contribute to the depression of inotropic response to the range of cardiac stimulants tested.     

The role of renal sympathetic nervous system in the pathogenesis of ischemic acute renal failure

We investigated the role of renal sympathetic nervous system in the progression of ischemia/reperfusion-induced acute renal failure in rats. Acute renal failure was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after the contralateral nephrectomy. Renal venous plasma norepinephrine concentrations markedly and significantly increased immediately after reperfusion, thereafter, the increased level declined but remained higher even at 24 h after reperfusion. Renal sympathetic nerve activity was significantly augmented during the renal ischemia. Renal denervation or the administration of pentolinium, a ganglion blocking agent, (5 mg/kg i.v.) at 5 min before ischemia attenuated the ischemia/reperfusion-induced renal dysfunction and histological damage, such as proteinaceous casts in tubuli and tubular necrosis. The elevation of renal venous norepinephrine levels after reperfusion was suppressed by renal denervation or pentolinium treatment. Thus, a surgical or pharmacological blockade of renal sympathetic nerve prevents the progression of ischemia/reperfusion-induced acute renal failure, thereby suggesting that renal sympathetic nervous system plays an important role in the development of the ischemic acute renal failure.     

慢性肾功能衰竭患者使用头孢菌素致中枢神经系统不良反应病例分析

目的了解头孢菌素应用于慢性肾功能衰竭患者导致精神症状的临床特点,探讨其防治措施。方法对2010年5月至2013年8月本院收治的慢性肾衰竭患者使用头孢菌素治疗中出现神经精神症状的病例进行临床特点和用药情况分析。结果共9例患者,使用常规剂量的头孢菌素3¹2 d出现神经精神症状,颅脑CT检查排除急性病变,经停药、对症治疗和加速药物排出后,9例患者症状均得到缓解。结论慢性肾功能衰竭患者使用头孢菌素类药物可导致药物在中枢神经系统内蓄积,出现中枢神经系统不良反应,故根据患者的肌酐清除率及药物的动力学特点制定个体化给药方案是预防的关键,有效的治疗措施为及时停药和充分透析。     

Interaction between ciprofloxacin and thiopental in the central nervous system of the male rat.

The effect of intravenous ciprofloxacin (CPX) pretreatment on the kinetics and brain sensitivity for thiopental was studied in male rats using a previously developed electroencephalographic (EEG) threshold method. Thiopental was administered intravenously with constant infusion rate. Immediately after the appearance of the first burst suppression of 1 sec. or more (the "silent-second") in the EEG the infusion was stopped and the rats were killed by decapitation. The dose of thiopental needed to reach the criterion of silent-second was slightly reduced in ciprofloxacin pretreated rats when compared with saline pretreated controls. One rat that developed seizures after CPX pretreatment needed a considerably reduced dose of thiopental to induce the silent-second. The serum concentrations of thiopental were markedly reduced in the experimental group while no significant differences were found in the concentrations of thiopental in the different parts of the central nervous system (CNS), fat or muscle tissue. The kinetics of CPX were also affected. The experimental group (CPX + thiopental treated) had significant higher brain concentrations of CPX than the corresponding only CPX treated control group while no differences were found in the serum concentrations of CPX between the groups. As previously suggested, the distribution of thiopental in the CNS is not only dependent on its lipid solubility, but also as a weak organic acid, on the transport system for organic acids out of the CNS which both thiopental and ciprofloxacin seem to use and mutually compete for it.     

Effect of aminophylline on aspirin penetration into the central nervous system in rats

This study investigated with the effect of aminophylline on the penetration of aspirin through the blood-brain barrier (BBB) into the central nervous system (CNS) in rats. Acetylsalycylic was injected into the right axillary artery, to avoid the drug affecting the peripheral organs before it reached the CNS. The test animals received subcutaneously (s.c.) aminophylline 30 min before aspirin injection, while the control animals received an equimolar dose of physiological solution s.c. At time intervals of 30, 60, 90, 120, and 240 s after aspirin injection, the animals were decapitated and blood samples from the left jugular vein, as well as samples from the brainstem, cerebellum and left and right cerebral hemispheres, were taken to determine aspirin concentrations in all of them by a standard method. It was found that aspirin concentrations in the CNS were even 30 times lower than in the blood, with the concentrations being higher in the brainstem and cerebellum than in the left and right hemispheres. The presence of aminophylline did not alter aspirin concentrations either in the blood or the brain, and therefore did not affect significantly the aspirin penetration through the BBB into the CNS.     

Dibromosulphophthalein: its pharmacokinetics and binding to hepatic cytosol proteins in rats with acute renal failure.

1. The pharmacokinetics, biliary excretion and binding of dibromosulphophthalein (DBSP) to plasma proteins and hepatic cytosol proteins have been studied in male rats with glycerol-induced acute renal failure (ARF). 2. The rate constants for hepatic uptake, efflux from liver to plasma and excretion into bile were all significantly decreased in rats with ARF. Furthermore, the plasma clearance of DBSP was also reduced. 3. The initial (0-10 min) and maximum biliary excretion rates of DBSP were both diminished in animals with ARF. The maximum excretion rate occurred between 5-10 min in control rats and 10-15 min in rats with ARF. However, there was no statistically significant change in the percentage dose recovered from bile after 30 min. 4. The plasma-protein binding of DBSP was decreased in rats with ARF and this change was due to a significant reduction in the association constant for the primary binding sites. 5. The binding of DBSP to ligandin (Y protein) was reduced by about 38% in rats with ARF but no change was noted in binding to Z protein. Reduced binding to ligandin was accompanied by decreased total liver glutathione S-transferase (GST) activity and a 36% reduction in the GST activity of ligandin. 6. The results support the contention that altered hepatic handling of cholephilic dyes in rats with ARF may be due to reduced binding to ligandin.     

Pharmacokinetics of bicyclol in rats with acute hepatic failure

The aim of present study is to evaluate the pharmacokinetics of bicyclol in carbon tetrachloride (CCl(4))-intoxicated rats. The plasma concentration of bicyclol was detected in rats after a single oral or intravenous administration by high-performance liquid chromatography (HPLC) analysis. Rat intestinal and hepatic perfusion models were employed to clarify the respective effect of gut and liver on the pharmacokinetics of bicyclol in acute hepatic failure (AHF) rats. Rat in vitro microsomal incubation was also conducted. The bioavailability of bicyclol was increased 3.1-fold after CCl(4) intoxication in rats. The area under the curve (AUC)((0-infinity)), C(max), and clearance (CL) of bicyclol after intravenous administration were 13.4 mg h l(-1), 18.8 mg l(-1), and 1.8 l h(-1) kg(-1) in control rats, and 130 mg h l(-1), 33.1 mg l(-1), and 0.15 l h(-1) kg(-1) in AHF rats, respectively. In the present study we investigated the pharmacokinetics of bicyclol in CCl(4)-intoxicated rats and differentiated the respective role of intestine and liver by using in situ intestinal and hepatic perfusion in rats, and in vitro rat microsomes incubation. The studies are expected to provide a better understanding related to the alteration of pharmacokinetics of bicyclol in pathological situation.     

Pharmacokinetics of bicyclol in rats with acute hepatic failure

The aim of present study is to evaluate the pharmacokinetics of bicyclol in carbon tetrachloride (CCl₄)-intoxicated rats. The plasma concentration of bicyclol was detected in rats after a single oral or intravenous administration by high-performance liquid chromatography (HPLC) analysis. Rat intestinal and hepatic perfusion models were employed to clarify the respective effect of gut and liver on the pharmacokinetics of bicyclol in acute hepatic failure (AHF) rats. Rat in vitro microsomal incubation was also conducted. The bioavailability of bicyclol was increased 3.1-fold after CCl₄ intoxication in rats. The area under the curve (AUC)_(0–∞), C_max, and clearance (CL) of bicyclol after intravenous administration were 13.4 mg h l^?1, 18.8 mg l^?1, and 1.8 l h^?1 kg^?1 in control rats, and 130 mg h l^?1, 33.1 mg l^?1, and 0.15 l h^?1 kg^?1 in AHF rats, respectively. In the present study we investigated the pharmacokinetics of bicyclol in CCl₄-intoxicated rats and differentiated the respective role of intestine and liver by using in situ intestinal and hepatic perfusion in rats, and in vitro rat microsomes incubation. The studies are expected to provide a better understanding related to the alteration of pharmacokinetics of bicyclol in pathological situation.     

Pharmacokinetics of intravenously administered ciprofloxacin in intensive care patients with acute renal failure

The pharmacokinetics of ciprofloxacin after a single intravenous administration of 100 mg were studied in intensive care patients with an acute renal impairment. There was no correlation found between the creatinine clearance and the renal clearance of ciprofloxacin. This applies to the entire group of patients. The decrease in renal clearance of ciprofloxacin was, however, more pronounced than the change in the elimination half-life, suggesting an important extra-renal elimination of the drug.     

Cardiac reactivity in rats with acute renal failure

Cardiac reactivity has been determined in rats with acute renal failure (ARF) induced by either bilateral nephrectomy or intramuscular glycerol injection. Rats with bilateral nephrectomy showed reduced chronotropic responses to cervical sympathetic stimulation but no appreciable alteration in the chronotropic responses to vagal stimulation. By contrast, we have previously noted that rats with glycerol-induced ARF show diminished chronotropic responses to stimulation of both nerves. The negative chronotropic and inotropic responses to carbachol in isolated atria from both nephrectomized and glycerol-injected rats were not significantly different from their respective controls. In both models of ARF the atrial positive chronotropic responses to isoprenaline were significantly decreased whilst positive inotropic responses were not significantly different from controls. The results indicate that the cause of the reduced chronotropic response to vagal stimulation observed in glycerol-injected rats is of presynaptic origin whilst the reduced chronotropic response to cervical sympathetic stimulation noted in both models of ARF may be due to an impaired postsynaptic response.     

反式曲马朵及反式氧去甲基曲马朵对映体在大鼠中枢神经系统的分布

目的：研究反式曲马朵（trans-T)及其活性代谢产物反式氧去甲基曲马朵（M1）对映体的中枢神经系统分布。方法：大鼠ip单剂量的盐酸trans-T或M1后,采用高效毛细管电泳（HPCE）法测定血清和不同脑组织中trans-T及M1对映体的浓度,脑组织包括脑脊液、大脑皮层、纹状体、下丘脑、小脑、延髓。结果：大鼠ip盐酸trans-T后,在血清及所有测试脑组织中,（＋）－trans-T的浓度均高于（－）－trans-T的浓度;在所有测试脑组织中,（＋）－M1的浓度均低于（－）－M1的浓度;trans-T和（＋）－M1对映体的浓度以大脑皮层中最高,脑脊液中最低。大鼠ip M1后,在血清及所有测试脑组织中,（＋）－M1的浓度均高于（－）－M1的浓度;M1对映体的浓度以大脑皮层中最高,脑脊液中最低。结论：在血清和不同脑组织中,trans-T及M1对映体的浓度是有区别的;trans-T及M1在中枢神经系统的分布具有立体选择性;大鼠ip M1与trans-T后,M1在中枢神经系统分布的立体选择性是不同的。     

Down-regulation of hepatic cytochrome P450 enzymes associated with cisplatin-induced acute renal failure in male rats

Hepatic drug metabolism is impaired in experimental animals and humans with renal diseases. An anticancer drug, cisplatin induces acute renal failure (ARF) in rats. Under the same experimental conditions, cisplatin causes down-regulation of hepatic cytochrome P450 (P450) enzymes in an isozyme selective manner. The present study examined the pathological role of ARF in the down-regulation of hepatic P450 enzymes in the cisplatin-treated rats. Male rats with single dose of intraperitoneally cisplatin (5 mg/kg) caused marked changes in renal parameters, BUN and serum creatinine but not hepatic parameters, serum alanine aminotransferase or aspartate aminotransferase. The rats also suffered from down-regulation of hepatic microsomal CYP2C11 and CYP3A2, male specific P450 isozymes, but not CYP1A2, CYP2E1, or CYP2D2. The decrease in serum testosterone level was also observed in injured rats, which was consistent with the selective effects on male specific P450 enzymes. Protection of rats against cisplatin-induced ARF by dimethylthiourea, a hydroxyl radical scavenger, also protected rats against the decrease in serum testosterone levels and the down-regulation of CYP2C11 and CYP3A2. Carboplatin, an analogue to cisplatin but no ARF inducer, did not cause decrease in serum testosterone levels and down-regulation of hepatic male specific P450 enzymes. These results suggest that down-regulation of hepatic P450 enzymes in male rats given cisplatin is closely related to the cisplatin-induced ARF and the resultant impairment of testis function.     

The effects of apamin in rats with pretrigeminal or high spinal transsection of the central nervous system

P. Janicki, S.W. Gumulka, P. Krza?cik and E. Habermann. The effects of apamin in rats with pretrigeminal or high spinal transsection of the central nervous system. Toxicon23, 993–996, 1985. — Rats were injected in one lateral cerebral ventricle (i.c.v.) with apamin (100 ng per animal). The resulting desynchronisation pattern in the electrocorticogram (ECoG) and the symptoms of poisoning were monitored before and after transsection at different levels, and following morphine. Apamin acts primarily on the brain stem and spinal cord, i.e. structures possessing a sensory input, and then indirectly on the higher integrating systems. There is no general parallelism between receptor density and locus of action.     

Cardiovascular responses in rats with glycerol-induced acute renal failure

Autonomic and cardiovascular function were assessed in rats with glycerol-induced acute renal failure (ARF). Rats with ARF had significantly lower mean arterial blood pressure and heart rates and significantly elevated plasma noradrenaline concentrations. The chronotropic responses to right cervical sympathetic and vagal stimulation were diminished in rats with ARF. The pressor and depressor responses to noradrenaline and nitroprusside respectively when expressed as a change in mmHg pressure were significantly reduced in rats with ARF when compared to controls. However, when the depressor responses to nitroprusside were expressed as a percentage fall in basal mean arterial pressure, with the exception of the response to a dose of 10 micrograms kg-1, there were no significant differences between control and uraemic rats. The present findings show that in the rat, changes in cardiovascular responsiveness occur after a brief period of uraemia which are similar to those observed in patients and rats with chronic renal failure.     

Infiltration of central nervous system in adult acute myeloid leukaemia.

Out of 64 consecutive unselected patients with acute myeloid leukaemia studied during 1973-6, five developed clinical evidence of spread to the central nervous system (CNS). Neuroradiological examination showed cerebral deposits in three, in whom rapid symptomatic relief was obtained with radiotherapy. In two of these patients who developed solid intracranial deposits haematological remission could be reinduced or maintained; they were still alive 86 and 134 weeks later. When patients presented with spread to the CNS complicating generalised uncontrolled leukaemia they had short survivals. CNS infiltration may respond dramatically to appropriate treatment provided that it is not associated with generalised uncontrolled leukaemia, which has a poor prognosis. In view of this, routine "prophylaxis" of the CNS in adult acute myeloid leukaemia does not seem justified at present.     

Quantitative estimation of renal clearance of N-acetylprocainamide in rats with various experimental acute renal failure.

The dosage regimen of a drug eliminated predominantly through the kidney need to be adjusted for the patients with renal disease. The objective of the present study was to establish a quantitative approach to precisely predicting the renal clearances of basic drugs using N-1-methylnicotinamide (NMN). A variety of experimental acute renal failure (ARF) in rats were prepared and N-acetylprocainamide (NAPA) was used as a model drug. The renal clearances of NAPA were significantly decreased in rats with ARF, resulting in significantly increased plasma concentrations. Remarkable reduction in clearance ratios (CL(ratio)) was observed, indicating that the impairment in tubular and glomerular function did not proceed in a parallel manner. The renal clearance of NAPA (CL(rNAPA)) was better predicted from the renal clearance of NMN (CL(rNMN)) than from GFR. A mathematical equation was also constructed to estimate the CL(rNMN) from the NMN plasma concentration. Therefore, the renal clearance of basic drugs excreted predominantly from the kidney can be easily and more accurately estimated based on the concentrations of endogenous NMN to provide a precise dosage regimen for patients with renal failure.