藥學(xué)專(zhuān)業(yè)畢業(yè)論文外文翻譯--實(shí)驗(yàn)性腎衰竭對(duì)頭孢噻利誘導(dǎo)大鼠癲癇發(fā)作的藥效學(xué)影響(英文）

1、Cefoselis (CFSL), a fourth-generation parenteral cephalo- sporin, has been marketed in Japan since September 1998. In December 1998, warnings of central nervous system (CNS) adverse effects such as seizures and confusion

2、al states were added to the labeling of CFSL. In many cases, these adverse effects were observed in patients who were elderly and/or had renal failure. Therefore renal failure is considered as one of the risk factors for

3、 neurotoxicity of CFSL. Since CFSL is mainly eliminated by renal excretion,1) renal failure would be associated with increased serum concentrations of CFSL. On the other hand, it is still unknown whether renal failure ca

4、n alter the pharmacodynamics of CFSL-induced seizures. Drug administration can be divided into two phases: a pharmacokinetic phase in which dose, dosage form, fre- quency, and route of administration are related to drug

5、con- centration–time relationships in the body; and a pharmacody- namic phase in which the concentration of drug at the site(s) of action is related to the magnitudes of the effect(s) pro- duced.2) The pathophysiologic s

6、tatus of patients can affect both the pharmacokinetics and the pharmacodynamics of a drug. Our knowledge of the effects of disease on the pharma- cokinetics of a drug cannot be used to optimize the drug dosage of a patie

7、nt without information on disease effects on the pharmacodynamics.3) Therefore it is important to distin- guish the effects of disease on the pharmacokinetics from those on the pharmacodynamics. Danhof and Levy3) reporte

8、d an experimental strategy to assess the effects of disease and other variables on the pharmacodynamics of drugs with CNS activity. The effects of experimental renal failure on the pharmacodynamics of CNS stimulant drug

9、s such as theo- phylline,4) pentylentetrazole,5) and cimetidine6) were investi- gated previously. There have been clinical case reports of seizures caused by various b-lactam antibiotics such as penicillin,7) cefazoline,

10、8)ampicillin,9) and imipenem.10) However, to our knowledge, there have been no reports that clarifi ed the effect of renalfailure on the pharmacodynamics of b-lactam antibiotic-in- duced seizures. To assure safe and effe

11、ctive antibiotic drug therapy, it must be determined if renal failure can change the relationship between the concentration and intensity of phar- macologic activity of drugs. The present study was designed to determine:

12、 1) the suit- ability of the rat as an animal model of CFSL-induced seizures; 2) the sampling site where CFSL concentrations re- fl ect the drug concentration at the site of neurotoxic action; and 3) the effect of renal

13、failure on the pharmacodynamics of CFSL-induced seizures.MATERIALS AND METHODSAnimals Male Wistar rats weighing 240 to 300 g were used in this investigation. The rats had an indwelling cannula implanted in the left jugla

14、r vein under light ether anesthesia one day before the experiment and they were fasted until the CFSL infusion began. Chemicals CFSL sulfate (Wincef ® for infusion) used for animal experiments was obtained from Fuji

15、sawa Pharma- ceutical Co., Ltd. Cefpirome sulfate (Broact® injection) used as an internal standard was obtained from Shionogi Co., Ltd. All other chemicals were purchased from commercial sources and used without fu

16、rther purifi cation. Effect of Infusion Rate on the Concentrations of CFSL in Serum, Brain, and CSF at Onset of Maximal Seizures CFSL was infused through the cannula at one of three different rates (1.4, 2.9, or 5.8 g/h

17、) in rats. The infusion was stopped immediately at the onset of maximal seizures. The rats were then lightly anesthetized with ether, and samples of CSF, blood, and brain were obtained, in that order. CSF was obtained by

18、 cisternal puncture. Blood was obtained from the abdominal aorta and centrifuged to obtain serum. The whole brain was removed and the right half of the cerebrum was used for drug assay.September 2001 Biol. Pharm. Bull. 2

19、4(9) 1049—1052 (2001) 1049? To whom correspondence should be addressed. e-mail: yasuhara.mpha@med.tmd.ac.jp © 2001 Pharmaceutical Society of JapanEffect of Experimental Renal Failure on the Pharmacodynamics of Cefos

20、elis-Induced Seizures in RatsMasashi NAGATA and Masato YASUHARA*Department of Hospital Pharmacy, School of Medicine, Tokyo Medical and Dental University, 1– 5– 45 Yushima, Bunkyo- ku, Tokyo 113– 8519, Japan. Received Apr

21、il 17, 2001; accepted June 12, 2001We investigated the effect of infusion rate and experimental renal failure on the pharmacodynamics of cefos- elis (CFSL)-induced seizures. As an animal model of CFSL-induced seizures, m

22、ale Wistar rats received an intra- venous infusion of CFSL at one of three different rates (1.4—5.8 g/h/rat) until the onset of maximal seizures (which occurred after 8.0 to 36.0 min of infusion). Samples of cerebrospina

23、l fl uid (CSF), blood (for serum), and brain were obtained immediately after stopping infusion of CSFL. The serum concentration of CFSL at the onset of seizures increased with increasing infusion rate, but brain and CSF

24、concentrations of CFSL at the onset of seizures were not affected by the infusion rate. Ureter-ligated (UL) and control rats received an intravenous in- fusion of CFSL at 1.4 g/h/rat until the onset of seizures. Then the

25、 same procedure as used to determine the effect of infusion rate on the concentrations of CFSL was carried out. Renal failure was associated with a signifi cant decrease in the amount of CFSL required to induce seizures.

26、 Serum, brain, and CSF concentrations of CFSL in UL rats were signifi cantly lower than those in control rats. These results indicate that the experimental strategy and animal model in this investigation would be useful

27、to assess the effects of diseases and other variables on the pharmacodynamics of CFSL-induced seizures and that renal failure is one of the risk factors for neurotoxicity of CFSL.Key words cefoselis; renal failure; seizu

28、re; pharmacodynamicsDISCUSSIONDrugs that act directly and reversibly, have no pharmaco- logically active metabolites, and are not subject to the devel- opment of acute tolerance may be expected to produce their apparent

29、pharmacologic effect(s) when their concentration(s) at the site of action reach and exceed the minimum effective concentration. We need to determine the sampling site that refl ects drug concentrations in the site of act

30、ion because it is technically impossible to measure drug concentrations in the immediate environment of the site of action. For this pur- pose, the drug is administered by constant-rate intravenous infusion at different

31、rates until the onset of a suitable phar- macologic endpoint and drug concentration in various fl uids and tissues (serum, brain, and CSF) at that time are deter- mined. Sites at which the drug concentration at the onset

32、 of action is dependent on infusion rate (the concentration tends to increase with increasing infusion rate) can be considered to be in slow equilibrium with the site of action. Any fl uid or tissue that yields the same

33、drug concentration at onset of ac- tion, independent of the rate of drug administration, must be considered as being in “ instantaneous” distribution equilib- rium with the site of action.3)The results of this study show

34、 that CFSL concentration in the serum at the onset of maximal seizures is signifi cantly af- fected by the rate of drug infusion, whereas CFSL concentra- tions in the brain and CSF at the pharmacologic endpoint are indep

35、endent of infusion rate. These results suggest that CFSL equilibrates slowly between serum and the site of ac- tion, and drug concentrations in the brain and CSF are more appropriate indices of the drug concentration in

36、the site of action. We also investigated the effect of experimental renal fail- ure on the pharmacodynamics of CFSL-induced seizures in rats. In the present study, renal failure was associated with a signifi cant decreas

37、e in the amount of CFSL required to in- duce seizures. This result suggests that renal failure is one of the risk factors for CFSL-induced seizures, and this is con- sistent with recent clinical fi ndings of a higher inc

38、idence of CFSL-induced neurotoxicity in patients with renal failure.11)In addition, serum, brain, and CSF concentrations of CFSL in UL rats were signifi cantly lower than those in control rats. This indicates that renal

39、failure is associated with changes in the pharmacodynamics of CFSL-induced seizures. Renal failure could change the pharmacokinetics of CFSL because CFSL is mainly eliminated by renal excretion.1) The permeability of the

40、 blood-CSF barrier may be increased as refl ected by increased protein concentration in the CSF. If renal failure affected only the pharmacokinetics of CFSL and/or the permeability of CFSL at the blood-CSF barrier, there

41、 would be no differences in the CFSL concentration in the brain and CSF at the onset of seizures between control and UL rats. In this study, however, UL rats had lower brain and CSF concentrations of CFSL at the onset of

42、 seizures compared with the corresponding results in control rats. This indicates that the cause of the change in drug effect with renal failure is not only the delay in CFSL elimination and the increased permeability of

43、 CFSL at the blood-CSF barrier but also the increased CNS sensitivity to CFSL-induced seizures. The effects of experimental renal failure on the pharmaco-dynamics of other CNS-active drugs were investigated previ- ously.

44、4—6,12,13) Ramzan and Levy4) reported that the theo- phylline concentrations in the serum, brain, and CSF at the onset of maximal seizures in rats with renal failure by ureter ligation were lower than those in control ra

45、ts. Hoffman and Levy14) reported that the potentiation of the convulsive effect of theophyline in rats with renal failure was counteracted by oral administration of activated charcoal that presumably in- terrupts the cyc

46、ling of the endogenous substance(s) between blood and the gastrointestinal tract. These indicate that changes in drug effects under renal impairment may be due to, at least in part, an increase in levels of one or more e

47、n- dogenous substance(s) that alter the pharmacological effects of certain drugs in uremic rats. The uremic blood apparently contains elevated concentra- tions of one or more endogenous substances, the so-called uremic t

48、oxins, and these retained substances probably play a major role as toxins in the pathogenesis of uremia, either working singly or in combination.15) Guanidino compounds are believed to be toxic agents in patients with re

49、nal insuffi - ciency. Gamma-guanidinobutyric acid was shown to induce tonic and clonic seizures following intracisternal injection in rabbits.16) De Deyn et al. reported that guanidino compounds were found to be increase

50、d in the serum and CSF of uremic patients17) and guanidinosuccinic acid induced behavioral convulsions after intraperitoneal injection in mice.18) In addi- tion, four guanidino compounds (guanidinosuccinic acid, cre- ati

51、nine, guanidine, and methylguanidine) were shown to in- hibit gamma-aminobutyric acid and glycine responses on mouse neurons in cell culture.19) These suggest that guani- dino compounds can contribute to increased neurot

52、oxic ac- tion of certain drugs in uremia. We used UL rats as a model of renal failure in this study. Ramzan and Levy5) reported that the effect of impaired renal function on the convulsant activity of pentylentetrazol in

53、 UL rats was different from that in uranyl nitrate-treated rats. Fur- ther investigation using more than one experimental model of disease is thus warranted. In conclusion, renal failure is associated with increased CNS

54、sensitivity to CFSL-induced seizures, and the experi- mental strategy and animal model in this investigation would be useful to assess the effects of disease and other variables on the pharmacodynamics of CFSL-induced se

55、izures.Acknowledgment This work was supported in part by a Grant-in-Aid for Scientifi c Research (C) from the Japan So- ciety for the Promotion of Science.REFERENCES1) Sakamoto H., Hatano K., Higashi Y., Mine Y., Nakamot

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57、vy G., J. Pharmacol. Exp. Ther., 229, 44—50 (1984). 4) Ramzan I. M., Levy G., J. Pharmacol. Exp. Ther., 240, 584—588 (1987). 5) Ramzan I., Levy G., J. Pharm. Sci., 78, 142—145 (1989). 6) Nakada Y., Yamamoto K., Kawakami

58、J., Sawada Y., Iga T., Pharm. Res., 12, 1953—1957 (1995). 7) Johnson H. C., Walter A. E., JAMA, 127, 217—219 (1945). 8) Bechtel T. P ., Slaughter R. L., Moore T. D., Am. J. Hosp. Pharm., 37, 271—273 (1980).September 2001