Increased peritoneal permeability in patients with peritonitis undergoing continuous ambulatory peritoneal dialysis

Summary The distribution of cefuroxime (250 mg) was studied in patients with renal failure undergoing continuous ambulatory peritoneal dialysis (CAPD). 10 uninfected patients received the drug intravenously and intraperitoneally, while 9 patients with peritonitis were randomly allocated to intravenous or intraperitoneal administration. Samples were taken over the first 6 hour dialysis period. In the infected patients, more drug (p<0.01) crossed into the peritoneal cavity following intravenous injection and reached the systemic circulation following intraperitoneal administration than in the uninfected group. This increased permeability of the peritoneal membrane during infection may result in unexpected systemic toxicity in patients treated with intraperitoneal antibiotics.     

Pharmacokinetics of fluconazole and fosfluconazole after intraperitoneal administration to peritoneal dialysis rats

Fluconazole (FLCZ) is an antifungal agent that is efficacious in the treatment of fungal peritonitis. Fosfluconazole (F-FLCZ) is the phosphate prodrug of FLCZ, which is highly soluble compared with FLCZ. F-FLCZ is useful against fungal peritonitis in continuous ambulatory peritoneal dialysis (CAPD) patients because it has a high water solubility. The aims of the present study were to characterize the peritoneal permeability of FLCZ and the pharmacokinetics of FLCZ and F-FLCZ after intraperitoneal (i.p.) administration to peritoneal dialysis rats. FLCZ or F-FLCZ was administered intravenously and intraperitoneally. After the i.p. administration of F-FLCZ, FLCZ was detected in circulating blood and the dialyzing fluid in peritoneal dialysis rats. The concentration of plasma FLCZ after the i.p. F-FLCZ administration was lower than that after the intravenous (i.v.) F-FLCZ administration. It is considered that the dose should be increased appropriately when F-FLCZ is administered intraperitoneally. The profiles of plasma FLCZ after i.v. and i.p. administrations were analyzed using a two-compartment model in which the distribution volume of the peripheral compartment was fixed at a volume of the dialyzing fluid (peritoneal dialysis PK model). The peritoneal dialysis PK model could describe the profiles of plasma and dialyzing fluid FLCZ. These results suggest that FLCZ and F-FLCZ could be administered intraperitoneally for the treatment of fungal peritonitis in CAPD patients.     

异搏定注射液对大鼠腹膜透析效能的影响

目的动物实验观察异搏定注射液对腹膜透析效能的影响,并初步探讨其作用机理。方法将48只SD大鼠平均分为单纯腹透组、异搏定低、中、高剂量组4组,观察不同剂量异搏定加入腹透液对大鼠血尿素、肌酐、透析液尿素氮、肌酐、尿素氮D/P值、肌酐D/P值、排液量及透出液蛋白质浓度的影响。结果异搏定中、高剂量能明显降低透析大鼠血中肌酐和尿素氮含量,升高透析液中肌酐和尿素氮含量,升高BUND/P、CrD/P,中剂量能增加的排液量,但对透出液蛋白质浓度无明显影响。结论异搏定注射液确能提高大鼠腹膜透析效能,提高小分子物质的清除率,对透出液中蛋白质浓度无明显影响,其作用与增加超滤量与腹膜毛细血管血流量均有关。     

Femoxetine and cimetidine: Interaction in healthy volunteers

Summary The kinetics of moxalactam has been investigated in 10 subjects undergoing continuous ambulatory peritoneal dialysis (CAPD). A single 1 g dose was injected i.v. and a 1 g dose was given intraperitoneally in the CAPD fluid during a 4 h dwell-time. Moxalactam was assayed by HPLC. After i.v. injection, the serum kinetics of moxalactam were: plasma t 1/2=17.9 h; volume of distribution at steady-state, 0.27 l/kg; total plasma clearance, 12.8 ml/min; peritoneal clearance, 2.1 ml/min. Dialysate moxalactam concentrations rose rapidly but only 20% of the dose was eliminated by the peritoneal route. After intraperitoneal instillation, moxalactam appeared in the serum rapidly and the peak serum concentration ranged from 21 to 49 µg/ml after between 4 and 5 h. The absorption of moxalactam from the peritoneal space was 57±16%. The data suggest that moxalactam has bidirectional exchange characteristics through the peritoneal membrane. Instillation of moxalactam in CAPD fluid may permit rapid absorption and the appearance of a therapeutic serum concentration.     

Urethane anesthesia in rats. Altered ability to regulate hydration

Anesthesia in rats produced by urethane administered intraperitoneally caused (1) peritoneal fluid accumulation; (2) inability to undergo a renal response to NaCl or water loading, and (3) pronounced hyperosmolality of body fluids without affecting plasma [Na+]. The impairment of the renal function appears not to be due to anesthesia per se, angiotensin, aldosterone, vasopressin or renal nerves. It probably is attributable to osmotoxicity of the mesenteric vasculature. By contrast, urethane administered intravenously evokes a brisk osmotic diuresis without fluid leakage into the peritoneum. Plasma osmolality is still increased. The osmotic toxicity to the mesenteric vasculature, poor renal function and altered composition of body fluids that occur after intraperitoneal urethane may complicate the interpretation of data obtained in rats anesthetized in this manner.     

PERITONEAL DIALYSIS SOLUTIONS AND FELINE SPLANCHNIC BLOOD FLOW

Splanchnic blood flow is generally considered to be one of the major factors governing the efficiency of peritoneal dialysis; however, few direct measurements of blood flow have been made during peritoneal dialysis. The radioactive microsphere technique was used to assess the effects of 1.5 and 4.25 g/100 ml dextrose-Dianeal solutions on blood flow to various tissues in the abdominal cavity. The effects of dialysis solution on blood flow through the superior mesenteric and coeliac arteries were measured by electromagnetic flowmetry. The results indicate that the commercial peritoneal dialysis solutions dramatically increase blood flow to the mesentery, omentum, intestinal serosa and parietal peritoneum. These changes are not accompanied by significant alterations in blood perfusion in the major abdominal organs (liver, stomach, intestine, pancreas, spleen). Peritoneal dialysis solutions do not significantly alter blood flow through the coeliac and superior mesenteric arteries. These findings indicate that commercial dialysis solutions improve perfusion to the peritoneum without significantly altering splanchnic blood flow.     

Extracellular Vesicles and Their Relationship with the Heart–Kidney Axis,Uremia and Peritoneal Dialysis

Cardiorenal syndrome (CRS) is described as primary dysfunction in the heart culminating in renal injury or vice versa. CRS can be classified into five groups, and uremic toxin (UT) accumulation is observed in all types of CRS. Protein-bound uremic toxin (PBUT) accumulation is responsible for permanent damage to the renal tissue, and mainly occurs in CRS types 3 and 4, thus compromising renal function directly leading to a reduction in the glomerular filtration rate (GFR) and/or subsequent proteinuria. With this decrease in GFR, patients may need renal replacement therapy (RRT), such as peritoneal dialysis (PD). PD is a high-quality and home-based dialysis therapy for patients with end-stage renal disease (ESRD) and is based on the semi-permeable characteristics of the peritoneum. These patients are exposed to factors which may cause several modifications on the peritoneal membrane. The presence of UT may harm the peritoneum membrane, which in turn can lead to the formation of extracellular vesicles (EVs). EVs are released by almost all cell types and contain lipids, nucleic acids, metabolites, membrane proteins, and cytosolic components from their cell origin. Our research group previously demonstrated that the EVs can be related to endothelial dysfunction and are formed when UTs are in contact with the endothelial monolayer. In this scenario, this review explores the mechanisms of EV formation in CRS, uremia, the peritoneum, and as potential biomarkers in peritoneal dialysis.     

Pharmacokinetic advantage of intraperitoneal injection of docetaxel in the treatment for peritoneal dissemination of cancer in mice

Intraperitoneal administration of docetaxel has been used to treat peritoneal dissemination of cancer, but its safety has not yet been confirmed. We have compared the pharmacokinetic behaviour of docetaxel after intravenous and intraperitoneal administration in CD-1-nu/nu mice bearing MKN45P, a gastric cancer variant line producing peritoneal dissemination. Docetaxel (8 mg kg(-1)) was intravenously or intraperitoneally injected into the mice and at designated times the drug concentration was measured in plasma, ascites fluid, and abdominal tissues (liver, kidney, intestine and spleen, solid cancer, and suspended free cancer). The pharmacokinetic behaviour of docetaxel was similar in control mice and cancer-bearing mice after administration via either route, except that the transfer of docetaxel from the abdominal cavity to systemic blood (plasma) was slower in cancerbearing mice than in control mice. As expected, the intraperitoneal drug concentration was much higher (approximately 100-fold) and was maintained for a longer time in the intraperitoneal injection group than in the intravenous injection group. The drug concentrations in peritoneal solid cancer tissue and suspended free cancer cells were also significantly higher for a longer time in the intraperitoneal injection group than in the intravenous injection group. The values of the plasma area under concentration-time curves (AUC) were similar for both administration routes. The ratio of AUC ascite/AUC plasma after intraperitoneal administration was higher than after intravenous administration. The drug concentration in abdominal organs after intraperitoneal injection was lower during the first 2 h, then became similar to those after intravenous injection. These results indicated that the intraperitoneal administration of docetaxel for peritoneal dissemination was likely to be an effective treatment method, without causing any increase in systemic toxicity.     

Pharmacokinetics of intravenous and intraperitoneal ceftriaxone in chronic ambulatory peritoneal dialysis

Summary The kinetics of ceftriaxone was investigated in 8 patients without infection, who were receiving continuous ambulatory peritoneal dialysis (CAPD). Ceftriaxone 1 g was injected i.v. and 1 g was given intraperitoneally in the CAPD fluid during a 4-h dwell time. Ceftriaxone was assayed by HPLC. After intravenous administration, the kinetic parameters of ceftriaxone were: plasma t_1/2, 12.3 h, total plasma clearance, 14.0 ml/min, volume of distribution at steady state 0.18 l/kg, and peritoneal clearance 0.59 ml/min. Over 72 hours only 5.5% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftriaxone rapidly appeared in serum; the absorption t_1/2 was 1.1 h and the mean peak concentration was 38.8 µg/ml. The absorption of ceftriaxone from the peritoneal space was 39%. A single 1.0 g IP dose led to serum and dialysate concentrations of ceftriaxone above the minimum inhibitory concentration for susceptible pathogens for 24 hours.     

Drug therapy in patients undergoing continuous ambulatory peritoneal dialysis. Clinical pharmacokinetic considerations

Continuous ambulatory peritoneal dialysis (CAPD) is an accepted alternative to haemodialysis in the treatment of end-stage renal failure. The frequently used intraperitoneal administration of antibiotics to treat peritonitis and the possible role of CAPD in the elimination of drugs has stimulated pharmacokinetic research in this field. The 2 principal results derived from these studies are: (1) the elimination capacity of CAPD for drugs given systemically or orally is very low, and (2) drugs administered intraperitoneally rapidly enter the circulation, a significant amount of drug being absorbed from the peritoneal cavity. This pharmacokinetic behavior is easily understood considering some basic and simple pharmacokinetic principles: the higher the volume of distribution of a substance, the lower will be the percentage of drug present in the peritoneal cavity. Thus, a prerequisite for rapid drug elimination by CAPD is a low body volume of distribution of a particular drug. Only in such a case will the drug diffuse into the peritoneal space to a significant extent. For dosing regimens in CAPD patients, the fraction of the dose eliminated by the peritoneal route should be known or estimated. This fraction depends on the relation of the peritoneal clearance to the total body clearance, and on the protein binding of the drug. The low flow rate of the peritoneal effluent (approximately 10 L/day = 7 ml/min) appears to be the most important limiting factor for the low extraction capacity of CAPD. The list of drugs that have been found to be significantly eliminated by CAPD is short: particular mention should be made of the aminoglycosides and some cephalosporins. The data on the peritoneal elimination of vancomycin are inconsistent. Although the intravenous and oral routes have been successfully used for the treatment of peritonitis, the time course of antibiotic concentrations in the peritoneal space appears to favour the peritoneal route of drug administration. During peritonitis, intraperitoneally administered drugs enter the circulation more rapidly and completely, due to the increased permeability of the peritoneal membrane. As long as the dialysate outflow rate and protein binding of the drug are not extensively altered by peritoneal inflammation, however, the extraction capacity of CAPD appears to remain low.     

头孢噻吩在腹膜透析和血液透析病人中的药物动力学

本实验测定了4例腹膜透析和3例血液透析病人,在静注头孢噻吩后的药物动力学过程,并观察了7例腹膜透析病人,从腹腔途径给药后的吸收情况.资料提示;腹膜约能吸收50-60％的头孢噻吩;血液透析可有效地清除之,透析半衰期约2h,但腹膜透析对该药从血浆中的清除并无显著影响,8h透析仅排出给药量的10％左右.     

Long-term methylglyoxal intake aggravates murine Th2-mediated airway eosinophil infiltration

Asthma outcomes is aggravated in obese patients. Excess of methylglyoxal (MGO) in obese/diabetic patients has been associated with diverse detrimental effects on cell function. This study aimed to evaluate the effects of long-term oral intake of MGO on ovalbumin-induced eosinophil inflammation. Male C57/Bl6 mice received 0.5% MGO in the drinking water for 12 weeks. Mice were sensitized and challenged with ovalbumin (OVA), and at 48 h thereafter, bronchoalveolar lavage (BAL) fluid and lungs were collected for cell counting, morphological analysis, and ELISA, mRNA expressions and DHE assays. In MGO-treated mice, OVA challenge significantly increased the peribronchiolar infiltrations of inflammatory cells and eosinophils compared with control group. Higher levels of IL-4, IL-5, and eotaxin in BAL fluid were also detected in MGO compared with control group. In addition, lung tissue of MGO-treated mice displayed significant increases in mRNA expressions of NF-κB and iNOS whereas COX-2 expression remained unchanged. The high TNF-α mRNA expression observed in lungs of OVA-challenged control mice was not further increased by MGO treatment. In MGO group, OVA-challenge increased significantly the NOX-2 and NOX-4 mRNA expressions, without affecting the NOX-1 expression. Levels of reactive-oxygen species (ROS) were significantly higher in lungs of MGO-treated mice, and no further increase by OVA-challenge was observed. In conclusion, 12-week intake of MGO exacerbates Th2-mediated airway eosinophil infiltration by activation of NF-kB/iNOS-dependent signaling pathway and positive regulation of NOX-2 and NOX-4 in the lung tissues. Scavengers of MGO could be an option to prevent obesity-related asthma.     

Effect of the memory-improving substance methylglucamine orotate on paradoxical sleep in rats

The effects of methylglucamine orotate (MGO) were studied on polygraphic sleep recordings in rats for 8 h per day between 8 a.m. and 4 p.m. MGO (225 mg/kg) was injected intraperitoneally immediately prior to the onset of recording. In the acute experiment, the effect of MGO was compared to pre- and post-drug control days. In the chronic experiment, a sequence of 5 control days, 10 days of MGO treatment, and a further 8 control days was tested. Both acute and chronic administration of MGO resulted in increased paradoxical sleep (PS) latency and a small, but significant, decrease in PS during the first 4 h after injection. This effect seems to be specific to PS, as no effects of MGO on waking or total sleep were found. With chronic administration, no PS rebound occurred within the 8-h recording time during the 8-day post-treatment control period. How the RNA precursor can decrease PS and whether this effect may play a role in the memory-improving action of the substance is discussed in terms of an interrelationship between macromolecular synthesis, sleep, and memory, respectively.     

THE ACE INHIBITOR, QUINAPRIL, AMELIORATES PERITONEAL FIBROSIS IN AN ENCAPSULATING PERITONEAL SCLEROSIS MODEL IN MICE

Encapsulating peritoneal sclerosis (EPS) is a serious complication of patients on continuous ambulatory peritoneal dialysis. In the present study, the inhibitory effect of angiotensin-converting enzyme inhibitor, quinapril, on the peritoneal fibrosis was examined in an experimental EPS model in mice. C57BL/6 mice were divided into three groups. Group 1 (n=20) mice received daily intraperitoneal injection of 0.3 ml of SH solution which consists of 0.1% chlorhexidine gluconate and 15% ethanol dissolved in saline. Group 2 (n=20) and group 3 (n=20) mice received SH solution by the same manner of group 1 mice, and were given orally 1 or 3 mg kg(-1) of quinapril, respectively, on daily basis. Five mice from each group were sacrificed on day 3, 7, 21, and 56, and evaluated macroscopically and histologically. Macroscopic examination revealed that fibrotic change in parietal peritoneum in group 1 was more severe than in group 2 and 3, accompanied with statistical significance. Histological examination demonstrated that peritoneal thickening in group 2 and 3 were markedly ameliorated than in group 1. Semi-quantitative analysis showed that histological fibrotic score was significantly higher in group 1 than in group 2 and 3. These results suggest that quinapril ameliorate the fibrotic change in parietal peritoneum in experimental EPS model in mice, and may have a clinical utility for the prevention of EPS.     

扶肾方对尿毒症腹膜透析大鼠腹膜超滤功能及VEGF-Notch信号通路的影响

目的探讨扶肾方对尿毒症腹膜透析大鼠的腹膜超滤功能及腹膜组织Notch1、delta-样配体4(Dll4)、Notch胞内域(NICD)、Hes1、血管内皮生长因子(VEGF)及血管内皮生长因子受体-2(VEGFR-2)的影响。方法采用随机数字表法将50只雄性SD大鼠分为正常组、模型组、扶肾方低剂量组(模型+扶肾方324 g/L灌胃)、扶肾方高剂量组(模型+扶肾方648 g/L灌胃)和塞来昔布组(模型+塞来昔布1.8 g/L灌胃),每组10只。规律腹腔注射腹膜透析液4周,行腹膜平衡实验计算超滤量后处死大鼠,取腹膜组织,HE染色观察腹膜形态学变化,采用实时荧光定量PCR(q PCR)和蛋白印迹法检测Notch1、Dll4、NICD、Hes1、VEGF、VEGFR-2的mRNA和蛋白表达,蛋白印迹法检测p-VEGFR-2的蛋白水平。结果模型组、扶肾方低剂量组、扶肾方高剂量组及塞来昔布组大鼠腹膜超滤量明显低于正常组,扶肾方高剂量组与塞来昔布组超滤量高于模型组和扶肾方低剂量组,塞来昔布组超滤量低于扶肾方高剂量组(P<0.05)。腹膜HE染色显示,扶肾方低剂量组与高剂量组大鼠腹膜新生血管较模...     

Pharmacokinetics of piperacillin in patients on peritoneal dialysis with and without peritonitis

The pharmacokinetics of piperacillin given intravenously (1 or 2 g) to nine patients with chronic renal failure and undergoing continuous ambulatory peritoneal dialysis was intermediate between values obtained in healthy volunteers and in patients with renal insufficiency studied between dialyses: half-life, 2.4 h; total clearance, 100 mL/min; urinary or peritoneal clearance, 3 mL/min. The intraperitoneal administration of piperacillin in dialysis fluid (400 mg or 1 g to five patients) increased the half-life (6 to 7 h) and decreased the volume of distribution of about two thirds. In both instances, the area under the curve was well correlated with dosage. The absorption of piperacillin by an inflamed peritoneum in eight patients suffering from peritonitis and treated with 400 mg, 1 g, or 2 g, was increased and returned to normal concurrently with care. Consequently, the recommended dosage is intravenous administration of 2 g of piperacillin every 8 h or intraperitoneal administration of 1 g every 6 h in the dialysate. With such conditions, serum concentrations greater than minimal inhibitory concentrations and sufficient to avoid dissemination of piperacillin-susceptible organisms without risk of accumulation are obtained.     

Co-trimoxazole (sulphamethoxazole plus trimethoprim) peritoneal barrier transfer pharmacokinetics

The pharmacokinetics of co-trimoxazole (sulphamethoxazole plus trimethoprim) were studied in end-stage renal disease in patients undergoing treatment with continuous ambulatory peritoneal dialysis (CAPD) and free of peritonitis. Plasma and dialysate concentrations were monitored for 1 exchange after administration of a single oral or intraperitoneal dose of co-trimoxazole, and were fitted by a pharmacokinetic model that took into account the equilibrium nature of CAPD by including return from the peritoneum in oral studies and from the plasma in intraperitoneal studies. Clearances were calculated and compared by analysis of variance. There was a significant effect of direction of flow (p less than 0.01), plasma-peritoneal clearances being larger than peritoneal-plasma clearances for both drugs. In addition, there was a significant difference (p less than 0.0001) between sulphamethoxazole clearances and trimethoprim clearances, with the latter being greater in both directions.     

Site of analgesic action of a non-steroidal, anti-inflammatory drug, tolmetin sodium, in rats.

1 The site of the analgesic action of tolmetin sodium was investigated by use of the acetic acid writhing test in rats. 2 Tolmetin sodium was administered to the rat between 15 and 60 min after intraperitoneal injection of 1 ml of a 1% acetic acid aqueous solution. Number of writhing was counted for 20 min beginning from 60 min after acetic acid injection. 3 When the rat was given tolmetin sodium 5 mg/kg orally, a relatively large quantity of tolmetin was found in the peritoneal exudate and there was a rough correlation between anti-writhing activity and the exudate tolmetin content. 4 Anti-writhing ED50 of tolmetin sodium was 1.42 (0.82-2.91) and 92.0 (57.0-140) microgram/kg when given intraperitoneally and intravenously, respectively, and the potency ratio of intraperitoneal to intravenous tolmetin sodium was 40.0 (18.5-80.2). This potency ratio for salicylic acid and morphine hydrochloride was 19.4 and 1.0, respectively. 5 When equipotent doses ( 5 microgram/kg i.p.; 200 microgram/kg i.v.) of tolmetin sodium were administered to the rat, the plasma tolmetin level after the intraperitoneal administration was less than one-fortieth that after the intravenous administration during the counting time of 20 min, while both the peritoneal exudate contents of tolmetin were nearly equal. 6 From these results, it is concluded that the site of anti-writhing action of tolmetin sodium is in the peritoneum and that tolmetin sodium produces its anti-writhing action mainly by a peripheral mechanism in the rat.     

Pharmacokinetics of cefoperazone in end-stage renal failure patients on peritoneal dialysis

Pharmacokinetics of cefoperazone (CPZ) was examined in 5 patients with end-stage renal failure on maintenance intermittent peritoneal dialysis. Blood levels of CPZ given as a 1 g intravenous bolus injection were not different whether a patient was on or off peritoneal dialysis. Peritoneal clearance of CPZ was 1.6-1.9 ml/min. Blood CPZ levels reached the therapeutic level within 30-120 minutes after an intraperitoneal administration of 1 g CPZ, and remained at the level at least for 3-5 hours. Side effects of CPZ were not observed in any patient. These data indicate that the peritoneal dialysis does not affect blood CPZ levels given intravenously and that effective blood levels of CPZ can be maintained for several hours after an intraperitoneal injection of the drug. Thus, CPZ is considered useful in renal failure patients on peritoneal dialysis.     

持续性不卧床式腹膜透析患者腹腔内使用万古霉素的治疗药物监测

目的:对持续性不卧床式腹膜透析患者腹腔内使用万古霉素进行监测,为万古霉素用药方案调整提供依据。方法:6名持续性不卧床式腹膜透析腹膜炎患者腹腔内使用万古霉素后,采集不同时间点的血浆和腹膜透析液样品,用高效液相色谱法测定血药浓度和腹膜透析液中药物浓度。结果:万古霉素加入腹膜透析液中给药的生物利用度为93.27%。给药后10h(第1次腹膜透析液放出来前)患者血药浓度约为21.71μg·mL-1,最低血药浓度(下次给药前)为11.39μg·mL-1;腹膜透析液中药物谷浓度为5.62μg·mL-1。结论:万古霉素加入腹膜透析液中给药,能够确保万古霉素有效吸收,且使腹腔局部保持有效的抑菌浓度,未造成万古霉素蓄积。