大鼠静注苯妥英钠的毒代动力学研究

目的：探讨苯妥英钠（DPH—Na）在大鼠血液的毒代动力学规律及组织分布。方法：大鼠静注中毒剂量DPH-Na后采集血液及组织样品,HPLC法测定其血浆及组织中药物浓度,分别用隔室模型拟合和米曼氏方程计算毒代动力学参数,并比较各组织中药物浓度。结果：DPH-Na静注中毒剂量后,在大鼠体内符合二室模型过程,主要毒代动力学参数：Cmax=（61．31±7．09）ug·ml^-1,t1／2a：（0．18±0．08）h,t1／2 B：（2．60±0．52）h,AUC=（147．22±29．16）（ug·ml^-1）·h,CL=（0．15±0．02）L·h^-1。按米曼氏方程解析所得主要毒代动力学参数：Vm=（10．42±5．33）ug·ml^-1·h^-1,Km=（66．65±13．71）ug·ml^-1,其余毒代动力学参数与二室模型拟合结果无明显差异（P〉0．05）。DPH-Na在各组织中的浓度顺序依次为：肺〉肾〉肝〉心〉脑。结论：DPH-Na在大鼠体内的毒代动力学与药物动力学规律有差异,其中毒后在体内消除减慢,血液及组织中可能大量蓄积。     

Venous Irritation,Pharmacokinetics, and Tissue Distribution of Tirilazad in Rats Following Intravenous Administration of a Novel Supersaturated Submicron Lipid Emulsion

Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [¹⁴C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p > 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower V_ss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p < 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.     

The Safety,Tolerability, and Pharmacokinetics of Fosphenytoin after Intramuscular and Intravenous Administration in Neurosurgery Patients

Study Objective . To evaluate the safety, tolerability, and pharmacokinetic profile of fosphenytoin, a water-soluble phenytoin prodrug, after intramuscular and intravenous administration. Design . Open-label study of intramuscular administration, and double-blind, randomized study of intravenous administration. Setting . Six and ten hospitals throughout the United States for the intramuscular and intravenous multicenter studies, respectively. Patients . Neurosurgical patients who required anticonvulsant prophylaxis or treatment. Interventions . In the intramuscular study, 118 patients received loading doses ranging from 480–1500 mg phenytoin equivalents (PE) and daily maintenance doses ranging from 130–1250 mg PE for 3–14 days. In the intravenous study, 88 patients received fosphenytoin and 28 received phenytoin sodium for 3–14 days. Mean ± SD loading doses and maintenance doses of intravenous fosphenytoin and phenytoin were 1082 ± 299 mg PE and 411 ± 221 mg PE, and 1082 ± 299 mg and 422 ± 197 mg, respectively. Trough phenytoin concentrations were measured daily in all patients. Measurements and Main Results . Intramuscular fosphenytoin was safe and well tolerated, with no irritation found for 99% of all injection site evaluations. Adverse events associated with the drug occurred in 9% of patients, commonly those typical of the parent drug. For intravenous treatment, the frequency of mild irritation at the infusion site was significantly lower in the fosphenytoin group (6%) than in the phenytoin group (25%, p<0.05). Reductions in infusion rates were required in 17% and 36% of fosphenytoin and phenytoin recipients, respectively. No significant difference was observed relative to adverse events or seizure frequency between the groups. Trough plasma phenytoin concentrations were approximately 10 μg/ml or greater in patients receiving at least 3 days of intramuscular and intravenous fosphenytoin. Trough phenytoin concentrations were similar between patients receiving intravenous phenytoin and fosphenytoin on all study days. Conclusion . Fosphenytoin can be administered intramuscularly and intravenously in neurosurgical patients to achieve and maintain therapeutic phenytoin concentrations for up to 14 days. Both routes are safe and well tolerated. Intravenous fosphenytoin is significantly better tolerated than intravenous phenytoin sodium in this patient subset.     

注射剂处方筛选中血管刺激性评价研究进展

对于具有较强血管刺激性的药物,使用合理的刺激性评价指标,筛选出合适的制剂处方,以降低其血管刺激性,对于提高注射剂临床用药安全性和患者顺应性具有重要意义.本文从静脉给药导致血管刺激性的机制出发,综述了处方筛选中注射剂血管刺激性的评价体系,以期为研制刺激性小、耐受性好的注射剂提供参考.     

Bioavailability of Phenytoin Following Oral Administration of Phenytoin-lipid Conjugates to Rats

The bioavailability of phenytoin was evaluated in rats upon oral administration of phenytoin-lipid conjugates obtained by covalent binding of 3-hydroxymethylphenytoin to 1,3-dimyristoylglyceride via a succinidyl linkage, to 2-(1,3-dimyristoyl-2-glyceryl)butyric acid and to 3-myristoyloxy-2-myristoyloxy-methylpropionic acid. Despite differences of the phenytoin plasma concentrations all three compounds approximately doubled the AUC compared with the dosing of phenytoin itself. The early onset and the long duration of the anticonvulsant activity after administration of the triglyceride-derived conjugate could be correlated to the increased phenytoin plasma levels. It is concluded that drug-lipid conjugates may be useful prodrugs for the oral delivery of poorly watersoluble drugs.     

Comparison of in vitro and In vivo Models to Assess Venous Irritation of Parenteral Antibiotics

Comparison of in vitro and In vivo Models to Assess Venous Irritationof Parenteral Antibiotics. HOOVER, D. M., GARDNER, J. B., TIMMERMAN,T. L., KLEPFER, J. A., LASKA, D. A., WHITE, S. L., MCGRATH,J. P., BUENING, M. K., AND WILLIAMS, P. D. (1990). Fundam. Appl.Toxicol. 14, 589–597. The venous irritation potentialof four parenteral antibiotics, tetracycline hydrochloride (TET),erythromycin lactobionate (ERY), amphotericin B (AMP), and cephalori-dine(CEP), was evaluated in an In vivo model using the rabbit earvein. Lateral ear veins of New Zealand White rabbits were infusedfor 1 hr with test solutions containing TET (0.25, 2.5, or 10mg/ml), ERY (2.5, 5, or 25 mg/ml), AMP (0.05, 0.1, or 0.5 mg/ml),or CEP (4 or 20 mg/ml). Control rabbits received comparablevolumes of 0.9% NaCl or 5% dextrose. Approximately 24 hr postinfusion,the rabbits were evaluated for visually evident changes in thetreated ears. Pathologic evaluation of the veins was performedusing histologic sections and scanning electron microscopy.TET, ERY, and AMP caused concentration-dependent changes inveins characterized primarily by loss of endothelium with associatedinflammation and thrombus formation, consistent with the knownclinical irritancy of these antibiotics. CEP, on the other hand,was well tolerated in the rabbit ear vein, paralleling its lowirritancy potential in man. Test solutions identical to thoseused In vivo in rabbits were also evaluated in established invitro assays for hemolytic potential when mixed with whole bloodfrom monkeys and for damage to L6 muscle cells as determinedby loss of creatine phosphokinase. Results of the in vitro testsystems paralleled those of the rabbit ear model, with TET,ERY, and AMP exhibiting dose-dependent hemol-ysis and musclecell toxicity, while CEP was comparatively nontoxic. Of thethree models, the rabbit ear vein had the greatest sensitivitywhen histopathologic evaluation was employed. The in vitro musclecell toxicity test was slightly less sensitive than the In vivomodel, followed by the in vitro hemolysis test. Results indicatethat the use of these in vitro and In vivo models to evaluatevenous irritancy may assist prec.linical assessment of potentialclinical reactions to new parenteral drug formulations.     

Bioavailability of Phenytoin and Anticonvulsant Activity after Oral Administration of Phenytoin-bis-hydroxyisobutyrate to Rats

Pharmaceutical Research -     

Fatal Toxic Epidermal Necrolysis Related to Lamotrigine Administration

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe life-threatening dermatologic conditions. To date, eight cases of TEN and one of SJS related to lamotrigine administration have been reported in the literature. Most patients were also taking concomitant valproic acid. It was hypothesized that valproic acid may interfere with glucuronidation of lamotrigine, leading to increased serum lamotrigine levels, or perhaps alter the drug's metabolism, resulting in accumulation of a toxic intermediate metabolite. Ultimately, this may possibly predispose a patient to increased dermatologic reactions, including TEN. A 54-year-old man developed TEN 4 weeks after beginning lamotrigine for complex partial seizures related to a glioblastoma multiforme brain tumor. The patient had also been taking concomitant allopurinol and captopril for more than 4 years with no complications, and valproic acid 3 months before the cutaneous event. Despite aggressive intensive care management, the patient died 17 days from the onset of symptoms due to multiple organ failure. Administration of lamotrigine, especially in combination with valproic acid, may lead to the development of TEN.     

Pharmacodynamics of Methylprednisolone Phosphate After Single Intravenous Administration to Healthy Volunteers

The pharmacokinetics and pharmacodynamics of methylprednisolone were investigated after intravenous administration of methylprednisolone phosphate to healthy subjects at seven different doses (16 to 1000 mg). Forty different pharmacodynamic parameters were followed for 1 week. The pharmacodynamic data were analyzed as a function of time as well as cumulative effects in form of the areas under the effect–time curves. Statistically significant dose-dependent effects of methylprednisolone were observed for 15 pharmacodynamic parameters. Highly significant (P 0.0001) effects were increases in glucose levels, number of white blood cells, and segmented granulocytes as well as a decrease in the number of lymphocytes. For these pharmacodynamic effects an integrated pharmacokinetic/pharmacodynamic model was derived that translates the methylprednisolone plasma concentration–time profiles into effect– time profiles. This model allows prediction of pharmacodynamic effects for any single dose in the range studied at any time point.     

Pilocarpine Disposition and Salivary Flow Responses Following Intravenous Administration to Dogs

Oral doses of pilocarpine increase salivary flow rates in patients afflicted with xerostomia (dry mouth). This study examined the pharmacokinetics of and a pharmacodynamic response (salivation) to intravenous pilocarpine nitrate administration in dogs. Disposition was linear over a dose range of 225–600 µg/kg; plasma concentrations were 10–120 µg/L. Elimination was rapid and generally biphasic, with a terminal elimination half-life of approximately 1.3 hr. The systemic clearance of pilocarpine was high (2.22 ± 0.49 L/kg/hr) and its steady-state volume of distribution (2.30 ± 0.64 L/kg) was comparable to that of many other basic drugs. All doses of pilocarpine induced measurable submaxillary and parotid salivary flow rates which could be maintained constant over time. Cumulative submaxillary saliva flow was linearly related to total pilocarpine dose. Plasma pilocarpine concentration was linearly related to both steady-state and postinfusion submaxillary salivary flow rates.     

Mandibular and Parotid Salivary Levels of Indomethacin Following Intravenous Administration to Rabbits

Indomethacin was measured in mandibular and parotid saliva, obtained from separate cannulas in the salivary ducts, after bolus intravenous administration (15 mg/kg) to male white rabbits that were stimulated for salivation with pilocarpine given subcutaneously. There was a significant correlation between each salivary drug concentration and plasma drug concentration. Saliva to plasma drug concentration ratio (S/P ratio) and pH were higher in mandibular saliva than in parotid saliva. These gland specific differences were in contrast with the previously reported differences in dogs. Matin's equation was found to predict approximately the mean observed S/P ratio of indomethacin for each saliva sample.     

局部使用苯妥英钠对皮肤伤口愈合影响的Meta分析

摘 要 目的：评价局部使用苯妥英钠对各种类型皮肤伤口的临床疗效。 方法: 计算机检索PubMed和Cochrane图书馆临床对照试验资料库,检索时间均从建库至2016年5月,收集所有皮肤伤口愈合与局部使用苯妥英钠有关的临床对照研究文献。采用RevMan 5及Stata12.0软件进行Meta分析。结果: 共纳入15项符合要求的研究,合计1 048例受试者。Meta分析显示,局部使用苯妥英钠与伤口愈合率（OR=3.28, 95%CI：1.23~8.75,P=0.02）、与健康肉芽组织生成率（OR=2.18,95% CI：1.33~3.59, P=0.002）、平均伤口表面积百分率减少（SMD=1.77, 95%CI:0.53~3.02, P<0.000 01）均显著相关。但伤口愈合率的研究间以及伤口平均表面积百分率减少的研究间均存在异质性。Meta回归结果显示,伤口类型与伤口愈合率的研究间异质性显著相关(P=0.02),治疗时间也与其有一定的相关性(P=0.08);平均年龄与伤口平均表面积百分率减少的研究间异质性有一定相关性(P=0.07)。结论:局部使用苯妥英钠对多种皮肤伤口愈合有积极作用,但由于研究间存在异质性,该结论在临床实践中需要谨慎使用。     

犬无束缚静脉输注给药的实现

目的建立犬无束缚静脉给药方法。方法将犬无束缚静脉给药装置(背心,输液保护套管,套管连接构件,精密微量输液监控器)组装,然后将该装置与埋植好留置针的犬连接,建立完整的输液通路给药开始。结果成功建立了犬无束缚静脉给药方法。结论设计合理、动物穿着舒适的给药装置,是犬无束缚静脉给药成败的关键因素。     

Clinical Pathology Changes Related to Cutaneous Irritation in the Fischer 344 Rat and New Zealand White Rabbit

Abstract

An evaluation of 27 repeated dose cutaneous application studies (9 applications of 6 h over an 11-day period) indicated that several hematologic and clinical chemistry parameters may be altered by chemically induced skin irritation. Irrespective of species, values that were generally decreased included hemoglobin concentration, hematocrit, erythrocyte count, and serum concentrations of calcium, potassium, inorganic phosphorus, and creatinine. Values that were increased included the neutrophil and total leukocyte counts. Some species differences were seen; for example, while the platelet count and serum globulin concentration were increased in rabbits only, the serum glucose, sodium, and chloride concentrations were increased in rats only. The mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and serum albumin and total protein concentrations were variably affected. Changes were generally well associated with the degree of cutaneous irritation, but did not appear to be related to the chemical class of the test substances, decreased food consumption, loss of body weight, or systemic toxicity of the chemical. However, the relationship of the changes in the clinical pathology measurements to cutaneous irritation or secondary effects was not always clear. Some measurements were considered to be secondary to the cutaneous inflammation while others may be related to vascular and fluid balance alterations. Regardless of the cause of these changes, their frequent occurrence and consistent direction of change suggest a relationship to cutaneous irritation rather than systemic toxicity of the test substances. It is considered important that the interpreter of toxicologic studies be aware of these irritation-induced changes when evaluating the findings of repeated cutaneous application studies.     

Trimedoxime and HI-6: Kinetic Comparison after Intravenous Administration to Mice

Abstract: The intravenous pharmacokinetics of the oximes HI-6 (pyridinium-1-(((4-carbamoi 1-pyridinio)metoxy)rnethyl)-2-(hydroxyiminomethyl)dichloride monohydrate), (132.54 μmol/kg) and trimedoxime (1,1′-(1,3′-propanedyl)bis((4-hydroxyimino) methyl)-pyridinium dibromide), (55,98 μmol/kg) in mice was investigated. The concentrations of oximes in plasma determined by high pressure liquid chromatography (HPLC) corresponded to a two-compartment pharmacokinetic open model. The oximes were rapidly eliminated from mice plasma, with half-times of 57.93 min. for HI-6 and 108.08 min. for trimedoxime. Although the oximes passed from circulation into the tissues at approximately the same rate, their transport back to the central compartment was two-times slower in the case of trimedoxime: t_1/2k21 was 77.9 min. for trimedoxime and 41.7 min. for HI-6. The total body clearance (CI_tot) of HI-6 was about 25% higher than that of trimedoxime. The central compartment volume of HI-6 distribution (V₁) was greater, whereas the volume of distribution of the peripheral compartment (V₂) was lower for about 35% with respect to the corresponding parameters of trimedoxime. The calculated pharmacokinetic parameters for the oxime HI-6 and trimedoxime show that trimedoxime is eliminated more slowly in mice, and penetrates better into the peripheral comparment where it remains longer.     

Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep

Abstract— Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0·45 ± 0·05 L h^?1 kg^?1), distribution volume (4·4 ± 2·0 L kg^?1), mean residence time (9·6 ± 4·1 h) and half-life (12·1 ± 3·1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26·3 mg kg^?1, but was curvilinear above this dose. Abomasal bioavailability at 6·4 mg kg^?1 was 0·26 ± 0·09, and mean absorption time was 4·7 ± 11·1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.     

静脉药物配置中心临床用药批次的程序化运行模式

目的 设计一套优化静脉药物配置中心用药批次的工作流程,提高工作效率.方法 对临床医嘱特点进行总体分析,设计输液批次方案.结果 采用程序自动分批、前台有条件调整的批次决策方案,科学合理地分配不同时段的工作量.结论 药物批次程序化设计优化了静脉药物配置中心的工作流程,提高了工作效率.     

Percutaneous Absorption and Excretion of Xenobiotics after Topical and Intravenous Administration to Pigs

Interspecies comparisons suggest that the weaning pig is a suitablesurrogate for man in percutaneous absorption studies. Despiteknown anatomical and physiological similarities between porcineand human skin, very few investigations of percutaneous absorptionphenomena have been conducted in pigs. This study examined radiolabelexcretion patterns after intravenous (iv) and topical administrationof six ¹⁴C-radioIabeled compounds in weanling Yorkshire sows.Radiolabel recovery from excrement collected over 6 days followingiv doses in physiological saline (200 µg, 10 µCi)showed that malathion (M), parathion (P), caffeine (C), andbenzoic acid (B) were primarily excreted into urine (>80%),while greater fractions of testosterone (T, 72%) and progesterone(R, 35%) were fecally eliminated. Percutaneous absorption wasdetermined from total urine and fecal excretion of radiolabelafter topical application, corrected for incomplete excretionfollowing iv administration. Topical doses in ethanol (200 µg,10 µCi) were applied at a surface concentration of 40µg cm^–2 and penetrated in the following rank order(percentage dose): B (25.7%) > R (16.2%) > C (11.8%) >T (8.8%) > P (6.7%) > M (5.2%). Fecal clearances of radiolabel,expressed as a percentage of total excretion, were greater aftertopical administration for four of the six compounds (B, C,P, and T, p < 0.05). Calculations based on urinary excretionalone underestimated percutaneous absorption determined fromtotal excretion by 5–30%, although the difference betweenthe two estimates was statistically significant only for C (p< 0.05). These results suggest that percutaneous absorptionestimates based on urinary radiolabel excretion alone shouldbe interpreted with caution whenever compounds with unknownpenetration characteristics arc used. Factors known to affecthuman skin absorption, such as applied dose, anatomical region,sex, age, various vehicles and solvents, and differences incutaneous metabolism, should be more closely examined in allanimal species used to model percutaneous absorption phenomenain man.     

Receptor-Mediated Gene Targeting to Tissues In Vivo Following Intravenous Administration of Pegylated Immunoliposomes

Purpose. Gene therapy has been limited by the immunogenicity of viral vectors, by the inefficiency of cationic liposomes, and by the rapid degradation in vivofollowing the injection of naked DNA. The present work describes a new approach that enables the non-invasive, non-viral gene therapy of the brain and peripheral organs following an intravenous injection. Methods. The plasmid DNA encoding -galactosidase is packaged in the interior of neutral liposomes, which are stabilized for in vivo use by surface conjugation with polyethyleglycol (PEG). The tips of about 1% of the PEG strands are attached to a targeting monoclonal antibody (MAb), which acts as a molecular Trojan Horse to ferry the liposome carrying the gene across the biological barriers of the brain and other organs. The MAb targets the transferrin receptor, which is enriched at both the blood-brain barrier (BBB), and in peripheral tissues, such as liver and spleen. Results. Expression of the exogenous gene in brain, liver, and spleen was demonstrated with -galactosidase histochemistry, which showed persistence of gene expression for at least 6 days after a single intravenous injection of the pegylated immunoliposomes. The persistence of the transgene was confirmed by Southern blot analysis. Conclusions. Widespread expression of an exogenous gene in brain and peripheral tissues is induced with a single intravenous administration of plasmid DNA packaged in the interior of pegylated im- munoliposomes. The liposomes are formulated to target specific receptor systems that enable receptor-mediated endocytosis of the complex into cells in vivo. This approach allows for non-invasive, non-viral gene therapy of the brain.