Pretransplantation Cystatin C, but not Creatinine, Predicts 30-day Cardiovascular Events and Mortality in Liver Transplant Recipients With Normal Serum Creatinine Levels.

BACKGROUND: The connection between renal dysfunction and cardiovascular dysfunction has been consistently shown. In patients with liver cirrhosis, renal dysfunction shows a tight correlation with prognosis after liver transplantation (LT); therefore, precise renal assessment is mandatory. Cystatin C, a sensitive biomarker for assessing renal function, has shown superiority in detecting mild renal dysfunction compared to classical biomarker creatinine. In this study, we aimed to compare cystatin C and creatinine in predicting 30-day major cardiovascular events (MACE) and all-cause mortality in LT recipients with normal serum creatinine levels. PATIENTS AND METHODS: Between May 2010 and October 2015, 1181 LT recipients (mean Model for End-stage Liver Disease score 12.1) with pretransplantation creatinine level ≤1.4 mg/dL were divided into tertiles according to each renal biomarker. The 30-day MACE was a composite of troponin I >0.2 ng/mL, arrhythmia, congestive heart failure, death, and cerebrovascular events. RESULTS: The highest tertile of cystatin C (≥0.95 mg/L) was associated with a higher risk for a 30-day MACE event (odds ratio: 1.62; 95% confidence interval: 1.07 to 2.48) and higher risk of death (hazard ratio: 1.96; 95% confidence interval: 1.04 to 3.67) than the lowest tertile (<0.74 mg/L) after multivariate adjustments. However, the highest tertile of creatinine level showed neither increasing MACE event rate nor worse survival rate compared with the lowest tertile (both insignificant after multivariate adjustment). CONCLUSIONS: Pretransplantation cystatin C is superior in risk prediction of MACE and all-cause mortality in LT recipients with normal creatinine, compared to creatinine. It would assist further risk stratification which may not be detected with creatinine.

Application of the Revised Cardiac Risk Index to the Model for End-Stage Liver Disease Score Improves the Prediction of Cardiac Events in Patients Undergoing Liver Transplantation.

INTRODUCTION: Although the revised cardiac risk index (RCRI) is a useful tool for estimating the risk of postoperative cardiac events, whether it improves the prediction of cardiac events in patients undergoing liver transplantation (LT) has not been sufficiently demonstrated. METHODS: We retrospectively analyzed 1429 patients who underwent LT. Cardiac events were defined as myocardial infarction, death, or combined events within 30 days after surgery. The RCRI was defined as the number of independent predictors including high-risk surgery, ischemic heart disease, congestive heart failure, cerebrovascular disease, insulin treatment, and creatinine level >2 mg/dL. Multivariate logistic regression analysis was performed to identify factors independently associated with cardiac events. The additive predictability of RCRI for the Model for End-Stage Liver Disease (MELD) score was assessed using receiver operating characteristic curve analysis. RESULTS: Forty-four (3.1%) cardiac events occurred within 30 days after surgery. Both the MELD score (adjusted odds ratio [aOR], 1.05; P = .005) and RCRI (aOR, 4.35; P < .001 for RCRI score 2; aOR, 6.27; P = .009 for RCRI score 3 compared with RCRI score 1) independently predicted postoperative 30-day cardiac events. The model with MELD score plus RCRI was significantly more predictive for postoperative 30-day cardiac events than the model with MELD score alone (C-statistics 0.800 vs 0.757; P = .030). CONCLUSIONS: For preoperative risk stratification, RCRI showed additive value to MELD score in predicting postoperative 30-day cardiac events after LT.

Diabetes With or Without Hypertension Does Not Affect Graft Survival and All-cause Mortality After Liver Transplant: A Propensity Score Matching Analysis.

BACKGROUND: Many studies have reported the negative influence of diabetes and hypertension on morbidity and mortality in the general population. In liver transplantation (LT) recipients, prevalence of nonalcoholic fatty liver disease and metabolic syndrome is increasing. Hence, concerns over the negative influence of metabolic syndrome, including diabetes and hypertension, are growing. However, there have been few studies about the outcomes of LT recipients with diabetes with/without hypertension. We aimed to evaluate the impact of diabetes with/without hypertension on the outcomes of LT. METHODS: Between May 2010 and October 2015, 814 LT recipients (median age, 51 [46-55] years; median MELD score, 13 [9-18]), without overt cardiovascular disease were retrospectively evaluated. To rigorously adjust for clinically confounding factors, a 1:2 propensity score matching analysis was performed. Kaplan-Meier survival curves and Cox proportional hazard regression analysis were performed to examine the association between diabetes with/without hypertension and all-cause mortality or graft survival rate. RESULTS: There were 77 (9.5%) graft failures and 71 (8.7%) deaths during a median follow-up of 2.4 years. After 1:2 matching of 173 (21.3%) diabetic patients, no significant differences were evident in graft survival rate (log-rank test, P = .46; and hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.55-2.06; P = .865) and all-cause mortality (log-rank test, P = .59; and HR, 1.06; 95% CI, 0.55-2.06; P = .727). Separate 1:2 matching was applied to a subgroup of 43 (5.3%) patients with diabetes and hypertension. This matching also showed no difference in graft survival rate (log-rank test, P = .45; and HR, 1.35; 95% CI, 0.43-4.27; P = .613) and all-cause mortality (log-rank test, P = .25; and HR, 1.87; 95% CI, 0.54-6.50; P = .325). CONCLUSION: Diabetes with/without hypertension does not have an impact on graft survival rate or all-cause mortality in LT recipients.

Prevalence of Antiphospholipid Antibody Positivity and Association of Pretransplant Lupus Anticoagulant Positivity With Early Allograft Dysfunction in Liver Transplantation.

BACKGROUND: Antiphospholipid antibodies (aPL), including anticardiolipin (aCL), anti-ß2-glycoprotein I (anti-ß2GPI), and lupus anticoagulant (LA) antibodies, are frequently found in liver cirrhosis and associated with splanchnic vein thrombosis. Although the risk factors of early allograft dysfunction (EAD) are known, the association between EAD and aPL has been poorly investigated. We hypothesized that LA, potent aPL with thrombotic potential, may be associated with EAD development after living donor liver transplantation (LDLT). METHODS: Data of 719 patients who underwent LDLT from February 2014 to June 2016 at our center were retrospectively collected and analyzed. Patients were divided into 2 groups according to the positivity of LA screening test (LA group [n = 148] vs no-LA group [n = 571]). Risk factors for EAD were investigated using multivariable regression analysis and inverse probability of treatment weighting (IPTW) of propensity scores. RESULTS: The prevalence of LA screening positivity, confirmatory test positivity, and EAD was 20.6%, 1.1%, and 11.3%, respectively. aCL positivity rate was 7.5% and anti-ß2GPI positivity rate was 7.0%. The EAD prevalence in LA and no-LA group was 25.7% and 7.5%, respectively. However, multivariable and IPTW analyses showed no association between EAD and LA screening positivity (P = .263 and P = .825, respectively), although a significant association was found in univariate analysis (odds ratio, 4.242; P < .001). Model for End-stage Liver Disease score, operation time, and C-reactive protein level remained significant after multivariable analysis. CONCLUSION: A positive LA screening test result was associated with EAD only in the univariate analysis. Inflammation, based on C-reactive protein level, was more important for EAD development.

Brief Episodes of Newly Developed Intraoperative Atrial Fibrillation Predicts Worse Outcomes in Adult Liver Transplantation.

BACKGROUND: Although patients undergoing liver transplantation (LT) are frequently exposed to predisposing factors of atrial fibrillation (AF) such as autonomic imbalance, surgical stress, and elevated catecholamine levels, the occurrence of intraoperative AF (IOAF) has not been fully examined in LT candidates. METHODS: Data from 1059 patients who underwent adult LT from 2006 to 2010 were analyzed. Among patients with preoperative normal sinus rhythm, the incidence, prognosis, and detailed characteristics of newly developed IOAF were assessed. Their risk factors and clinical implication, including hepatic graft survival and mortality, were also examined. RESULTS: Thirteen (1.2%) cases of AF newly developed intraoperatively. A higher Model for End-Stage Liver Disease score (adjusted odds ratio, 1.077 [95% confidence interval, 1.015-1.143]; P = .015) and fulminant hepatic failure (adjusted odds ratio, 6.844 [95% CI, 1.944-24.096]; P = .003) were associated with its occurrence. Eight cases of newly developed AF occurred immediately after hepatic graft reperfusion; the other 3 cases occurred during the pre-anhepatic or anhepatic phase. The majority of patients (9 cases) experienced only brief episodes of AF lasting <1 hour. Despite all patients with newly developed AF eventually converting to sinus rhythm within 1 week after surgery, the episode of IOAF was independently associated with mortality (adjusted hazard ratio, 5.097 [95% confidence interval, 2.189-11.868]; P < .001) after adjustment for Model for End-Stage Liver Disease score. CONCLUSIONS: For LT recipients, even a brief episode of newly developed IOAF seems to be an important prognosticator, regardless of AF duration.

Does Activated Clotting Time Help to Predict Innate Coagulopathy in End-Stage Liver Disease Patients?

BACKGROUND: Measuring activated clotting time (ACT) is widely performed to monitor heparin therapy. Regardless of anticoagulant use, ACT is affected by coagulopathies such as coagulation factor deficiency and thrombocytopenia. However, its use in end-stage liver disease (ESLD) with complex coagulopathy is not well characterized. We evaluated whether ACT could be used to detect innate coagulopathy in ESLD patients. METHODS: We retrospectively assessed Hemochron (International Technidyne, Edison, NJ, USA) ACT (FTCA 510, normal range 105-167 seconds) and INTEM clotting time (CT) of rotational thromboelastometry (ROTEM; ROTEM delta, Pentapharm GmbH, Munich, Germany) (100-240 seconds) in 366 liver transplantation (LT) recipients, simultaneously measured before anesthetic induction for LT. Multiple linear regression analyses helped identify the factors related to ACT in ESLD patients. The relationship between ACT and INTEM CT was evaluated by Spearman rank correlation analysis and receiver operating characteristic curve. RESULTS: Median ACT was 143 seconds (range 73-295 seconds), and 60 patients (16.4%) had ACTs of >167 seconds. Multiple regression analyses revealed that prolonged prothrombin time, activated partial thromboplastin time, low antithrombin III, and young age were associated with high ACT levels. INTEM CT was associated with ACT independent of liver disease severity, while EXTEM CT was not. ACT was moderately correlated with INTEM CT (r = 0.535), and the optimal cutoff value of ACT for predicting INTEM CT >240 seconds was 151 seconds (area under the curve = 0.787). CONCLUSIONS: In ESLD patients, ACT is effective in detecting prolonged INTEM CT. Therefore, ACT may be used to predict intrinsic pathway defects with a cutoff value of 151 seconds, suggesting feasibility when ROTEM is unavailable.

Prediction of Fluid Responsiveness by a Non-invasive Respiratory Systolic Time Interval Variation Using Heart Sound Signals in Recipients Undergoing Liver Transplantation.

BACKGROUND: The fluid management of cirrhotic patients undergoing liver transplantation (LT) is challenging. Phonocardiography, a graphic recording of heart sounds, provides valuable information concerning heart function and hemodynamic condition. We assessed whether the systolic time interval (STI) and its respiratory variation could predict fluid responsiveness in cirrhotic patients undergoing LT. METHODS: Thirty LT recipients who needed volume expansion were included. The fluid challenge consisted of 500 mL 5% albumin administered over a period of 10 minutes. STI was measured as the time interval between the maximal amplitude of each heart sound corrected with the corresponding RR interval (cSTI). The respiratory variation in STI (STV) induced by mechanical ventilation was calculated. Responders were defined as those showing a ≥10% increase in stroke volume index after volume expansion. RESULTS: In all, 14 of the 30 patients were responders. Significant increases in cSTI were observed after volume expansion in both responders (P < .001) and non-responders (P = .008). Responders showed significant decreases in STV (11.1% ± 4.3% vs 6.1% ± 2.6%, P < .001) after fluid loading, whereas STV in non-responders remained unchanged (6.4% ± 2.6% vs 6.4% ± 4.2%, P = .86). A cut-off value of ≥7.5% STV from baseline could predict fluid responsiveness with an area under the receiver operating characteristic curve of 0.804 (95% confidence interval, 0.618-0.925). CONCLUSIONS: Intra-operative STV can predict fluid responsiveness in patients undergoing LT. Beat-to-beat monitoring of STI and STV may be useful as a non-invasive hemodynamic index and for fluid management.

Pretransplant Resting Heart Rate and Its Association With All-Cause Mortality in Liver Transplant Recipients.

BACKGROUND: The importance of heart rate (HR) measurement as a prognostic factor has been recognized in many clinical conditions, such as hypertension, coronary artery disease, or heart failure. Patients with liver cirrhosis tend to have increased resting HR as consequence of hyperdynamic circulation. In the current study, we examined whether pretransplant resting increased HR is associated with overall mortality in cirrhotic patients following liver transplantation (LT). PATIENTS AND METHODS: We retrospectively collected and analyzed the data of 881 liver recipients who underwent LT surgery between October 2009 and September 2012. Patients were categorized into 3 groups by tertile of resting HR as follows: tertile 1 group, HR ≤ 65 beats per minute (bpm); tertile 2 group, HR 66 to 80 bpm; and tertile 3 group, HR > 80 bpm. RESULTS: Kaplan-Meier analysis showed that the all-cause mortality rate was significantly different according to tertiles of HR (P = .016, log-rank test). The multivariate Cox regression analysis showed that tertile 3 group was significantly associated with higher risk for all-cause mortality (hazard ratio 1.83, 95% confidence interval, 1.10-3.07; P = .021) compared with tertile 1 group, after adjusting for clinically significant variables in univariate analysis. CONCLUSIONS: Our results demonstrate that pretransplant resting tachycardia can identify patients at high risk of death in cirrhotic patients following LT, suggesting that further study will be need to clarify relationship between HR burden and sympathetic cardiac neuropathy.

Pretransplant Left Ventricular Dysfunction Adversely Affects Perioperative Outcomes in Pediatric Liver Transplantation: A Retrospective Observational Study.

BACKGROUND: Although left ventricular diastolic dysfunction (LVDD) is a pronounced feature of adult cirrhotic cardiomyopathy and a major predictor of poor outcomes following liver transplantation (LT), little is known about if pretransplant cardiac dysfunction affects perioperative outcomes in pediatric LT. METHODS: We retrospectively evaluated pretransplant clinical and Doppler echocardiographic data for 45 consecutive pediatric LT recipients who were treated between 2007 and 2013 (median age = 15 months; interquartile range = 9 to 78 months). LVDD was defined according to the cirrhotic cardiomyopathy criteria, and the myocardial performance index (MPI) was measured using tissue Doppler imaging. Intraoperative data and hospitalization days following LT were compared. RESULTS: LVDD and MPI ≥0.5 (defined as a z score ≥2) were observed in 13% and 27% of patients, respectively. Patients with an MPI ≥0.5 demonstrated the increased accumulation of lactate at the end of their LT operation (mean = 2.48 vs 0.82; P = .026) compared with patients with an MPI <0.5. The hospital stay was longer in patients with LVDD (median = 46 days vs 30 days; P = .041) and patients with an MPI ≥0.5 (median = 38 days vs 29 days; P = .014) compared with patients without LVDD and MPI <0.5, respectively. CONCLUSIONS: LVDD might be less prevalent (13%) in pediatric patients compared with adults. However, pretransplant cardiac dysfunction in patients with LVDD and an MPI ≥0.5 adversely affects perioperative outcomes, necessitating that such pediatric LT recipients be cautiously observed perioperatively.

Two-step forecast of geomagnetic storm using coronal mass ejection and solar wind condition.

To forecast geomagnetic storms, we had examined initially observed parameters of coronal mass ejections (CMEs) and introduced an empirical storm forecast model in a previous study. Now we suggest a two-step forecast considering not only CME parameters observed in the solar vicinity but also solar wind conditions near Earth to improve the forecast capability. We consider the empirical solar wind criteria derived in this study (Bz ≤ -5 nT or Ey ≥ 3 mV/m for t≥ 2 h for moderate storms with minimum Dst less than -50 nT) and a Dst model developed by Temerin and Li (2002, 2006) (TL model). Using 55 CME-Dst pairs during 1997 to 2003, our solar wind criteria produce slightly better forecasts for 31 storm events (90%) than the forecasts based on the TL model (87%). However, the latter produces better forecasts for 24 nonstorm events (88%), while the former correctly forecasts only 71% of them. We then performed the two-step forecast. The results are as follows: (i) for 15 events that are incorrectly forecasted using CME parameters, 12 cases (80%) can be properly predicted based on solar wind conditions; (ii) if we forecast a storm when both CME and solar wind conditions are satisfied (∩), the critical success index becomes higher than that from the forecast using CME parameters alone, however, only 25 storm events (81%) are correctly forecasted; and (iii) if we forecast a storm when either set of these conditions is satisfied (∪), all geomagnetic storms are correctly forecasted.

Effect of laser-induced temperature field on the characteristics of laser-sintered silver nanoparticle ink.

Laser sintering of metal nanoparticles is a key technology for high-performance printed electronics fabricated on heat-sensitive substrates such as glass or plastic. Although laser-sintered electronic devices have been successfully fabricated, the role of the induced temperature field in the laser sintering process has not been reported thus far. In this work, the effect of temperature on the laser sintering process is described for the first time using a two-dimensional transient heat conduction equation for inkjet-printed silver nanoparticle ink. The in situ electrical resistance was measured to estimate the transient thermal conductivity and hence the temperature of the sintered ink during the laser sintering process. To verify the estimated laser sintering temperature, the morphology of furnace-sintered silver nanoparticle ink was compared with that of laser-sintered ink. The electrical characteristics and surface morphology of laser-sintered ink are found to be related to the process temperature.

Intracellular lipid accumulation inhibitory effect of Weissella koreensis OK1-6 isolated from Kimchi on differentiating adipocyte.

AIMS: To investigate the intracellular lipid accumulation inhibitory effect of spent culture medium extract and the cytoplasmic fraction of Weissella koreensis OK1-6 cells isolated from kimchi in differentiating 3T3-L1 cells. METHODS AND RESULTS: Differentiating 3T3-L1 cells were treated with either cytoplasmic fraction of W. koreensis OK1-6 cells or its spent media for 4 days. Both the spent culture medium extract and cytoplasmic fraction of W. koreensis OK1-6 cells significantly decreased the triglyceride concentration and intracellular lipid accumulation in the treated groups compared with the control group. The mRNA expression levels of C/EBP-α, one of the major transcriptional factors involved in adipocyte differentiation, were significantly less expressed in 3T3-L1 cells treated with the spent medium and cytoplasmic fraction. The expressions of aP2, fatty acid synthase (FAS) and SREBP1 genes were also decreased significantly. CONCLUSIONS: These results suggested that W. koreensis OK1-6 could play a crucial role in preventing intracellular lipid accumulation by down-regulating the expression of adipocyte-specific genes C/EBPα, aP2, SREBP1 and FAS. SIGNIFICANCE AND IMPACT OF THE STUDY: These results may contribute to nutraceutical and food industries in developing probiotic-based therapies for the treatment and prevention of obesity.

Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review.

Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ dysfunction, age, genetics) and extrinsic (e.g., drug-drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision-making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.

Multipotent progenitor cells derived from human umbilical cord blood can differentiate into hepatocyte-like cells in a liver injury rat model.

Umbilical cord blood (UCB), a rich source of hematopoietic stem cells, offers practical and ethical advantages. It has been reported that various adult stem cells transplanted into a damaged liver show characteristics of a hepatic lineage. In a previous study, we reported on novel UCB-derived adult stem cells, termed umbilical cord blood-derived multipotent progenitor cells (UCB-MPCs). We demonstrated that these cells were capable of differentiating into hepatocyte- like cells in vitro. To assess the hepatic differentiation capacity of UCB-MPCs, rat models of hepatic injury were generated using carbon tetra-chloride (CCl(4)) with transplantation of cells into the liver. The transplanted cells successfully incorporated into the liver of the recipient animal differentiated into functional hepatocyte-like cells that expressed hepatocyte-specific markers, such as CK-18 and albumin. Moreover, human albumin was detected in the serum of the recipient rat model. These data indicated that UCB-MPCs were capable of displaying similar characteristics to those of functional hepatocytes in a recipient liver. UCB-MPCs may prove to be a useful, transplantable alternative for hepatic progenitor cells in both experimental and therapeutic applications.

Ten-year survival of patients with locally advanced, stage ib-iib cervical cancer after neoadjuvant chemotherapy and radical hysterectomy.

OBJECTIVE(S): The aim of this study was to evaluate the effects of neoadjuvant chemotherapy and radical hysterectomy on long-term survival in stage IB-IIB locally advanced cervical cancer by conducting a 10-year follow-up. METHODS: Between August 1983 and May 1990, 80 locally advanced, stage IB-IIB cervical cancer patients with tumor diameter greater than or equal to 4 cm were treated with neoadjuvant VBP chemotherapy (cisplatin, vinblastine, and bleomycin) followed by radical hysterectomy with pelvic lymphadenectomy. After this therapeutic modality, patients were followed for more than 10 years. Ten-year survival rates and factors affecting recurrence after this therapy were evaluated. RESULTS: Of 80 patients, 75 (93.7%) showed a reduction in tumor size after neoadjuvant chemotherapy. At pathologic examination, stage reduction was noted in 53 (66.2%) patients and 20 patients (25%) showed no residual or microinvasive cervical tumor. Pelvic lymph node metastases were found in 17 patients (21.3%). During the 10-year follow up, 2 patients were lost and 16 patients recurred. Overall 5-year and 10-year disease-free actual survival rates were 82.0 (64/78) and 79.4% (62/78), respectively. Clinical stage, initial tumor size, clinical response, and residual tumor size were not risk factors for recurrence after this therapy. However, pelvic lymph node metastasis was a significant risk factor for recurrence. CONCLUSION(S): Neoadjuvant VBP chemotherapy followed by radical hysterectomy in locally advanced, stage IB-IIB cervical cancer patients seemed to improve the long-term survival rate for these patients compared to that of conventional therapy. However, randomized controlled trials are needed to confirm this result.

ctr1, a gene involved in a signal transduction pathway of the gliding motility in the cyanobacterium Synechocystis sp. PCC 6803.

We generated random Tn5 mutations in Synechocystis sp. PCC 6803 in search for genes involved in the signal transduction cascade for the cyanobacterial gliding motility. One of the non-gliding Tn5 mutants, S1-105, had an insertional inactivation in the slr1044 gene encoding a putative methyl-accepting chemotaxis protein. Interposon mutation on the slr1044 (named ctr1) in the bacterium also eliminated gliding motility. In the interposon mutant, the expression of pilA1 was 5-fold decreased compared with that of wild-type and thick pili, that are believed to be the motor for gliding, could not be observed by an electron microscope. Therefore, we suggest that the Ctr1 protein functions as a transducer that regulates the expression of pilA1, and thus is required for the biogenesis of thick pili.

Primary peritoneal pregnancy implanted on the uterosacral ligament: a case report.

Peritoneal pregnancies are classified as primary and secondary. Primary implantation on the peritoneum is extremely rare in extrauterine pregnancy and is a potentially life-threatening variation of ectopic pregnancy within the peritoneal cavity, representing a grave risk to maternal health. Secondary abdominal pregnancies are by far the most common and result from tubal abortion or rupture, or less often, after uterine rupture with subsequent implantation within abdomen. Early diagnosis and appropriate surgical management, regardless of stage of gestation, appear to be important in achieving good results. We report a case of primary peritoneal pregnancy in a 28-year-old woman, who had severe lower abdominal pain one day before laparotomy for a preoperative diagnosis of ectopic pregnancy. The conceptus was implanted on the left uterosacral ligament. A fresh embryo of approximately 8 weeks' gestation was found in the conceptus.

Pharmacokinetic changes of intravenous tacrolimus in rats with uranyl nitrate-induced acute renal failure.

Because the physiological changes that occur in patients with acute renal failure could alter the pharmacokinetics of the drugs, the pharmacokinetics of tacrolimus were investigated after 1-min intravenous administration of the drug (1 mg kg(-1)) to control rats and rats with uranyl nitrate-induced acute renal failure (rats with U-ARF). The impaired kidney and hepatic functions were observed in rats with U-ARF on the basis of physiological parameters and by microscopy of the tissues. After intravenous infusion of tacrolimus, the total area under the blood concentration-time curve from time zero to time infinity was significantly greater in rats with U-ARF than that in control rats (35.8 versus 29.2 microg min mL(-1)) due to significantly slower total body clearance of tacrolimus (27.9 versus 34.3 mL min(-1) kg(-1)), and this could be due to significantly slower nonrenal clearance (because of impaired hepatic function). The urinary excretion of unchanged tacrolimus was almost negligible for both groups of rats, therefore, effects of kidney impairment on the pharmacokinetics of tacrolimus seemed to be minor.

Pharmacokinetics, stability, and blood partition of 7-anilino-5,8-isoquinolinedione, a new isoquinonlinedione derivative.

Pharmacokinetics of IQO4, a new isoquinolinedione derivative, after 30-min intravenous administration of the drug, 5 mg/kg, to rats, the stability, and the blood partition between plasma and blood cells of IQO4 were evaluated. After intravenous administration, IQO4 was eliminated fast with the mean total body clearance of 105 ml/min/kg. IQO4 was almost completely metabolized in rats; 5.18% of intravenous dose of IQO4 was excreted in 24-hr urine and IQO4 was under detection limit in whole gastrointestinal tract as 24 hr. IQO4 has a good affinity to liver, small intestine, heart, lung, and kidney as reflected to greater-than-unity tissue-to-plasma ratios. IQO4 was unstable in rat whole blood, plasma, and liver homogenates when incubated in a water-bath shaker for 24 hr kept at 37 degrees C and at a rate of 50 oscillations per min. The disappearance rate constants of IQO4 were 0.0611, 0.O436, and 0.174 hr(-1) for rat whole blood, plasma, and liver homogenates, respectively. However, IQO4 was stable for up to 3-hr incubation in human gastric juices. The plasma-to-blood cell concentration ratios of IQO4 were independent of initial blood concentrations of IQO4, 0.5, 2, and 10 microg/ml, when the rabbit whole blood was incubated for up to 120 min; the ratios were in the range of 1.56-3.60. Since IQO4 was unstable in blood, considerable in vitro 'blood storage effect' in the plasma concentration of IQO4 was observed.