C0 Concentrations Research Articles

Flocculation mechanism of the acquisition of remanent magnetization by sedimentary rocks

Coagulation of particles into aggregates during their deposition in a reservoir is numerically simulated with regard for Brownian motion, Van der Waals forces, gravitation, Stokes friction, and magnetostatic interaction, and the effect of this process on the depositional magnetization (DRM) is estimated. Clusters obtained due to random aggregation of smaller clusters have a loose and branching structure. The average fractal dimension of the clusters is d = 1.83 ± 0.23. In the process of coagulation, magnetic particles do not form chains or clusters, as was supposed in a number of preceding works, but become rather uniformly distributed among nonmagnetic particles, which provides an additional argument in favor of the fact that chains of magnetite particles in marine sediments are of biogenic origin rather than a result of mutual attraction of magnetic particles due to magnetostatic interaction. The deposition process is shown to obey a kind of the principle of scale invariance: the number of clusters and their average number of particles do not change if the basin depth H and the surface concentration of initial material c 0 simultaneously change (provided that temperature and the initial particle size r are constant) in such a way that Hc 0 = const. Coagulation is the most important factor forming the bottom layer structure and the magnetization of the suspension at a relatively high concentration c 0 Typical of redeposition conditions, lakes, and shelf seas. Coagulation virtually does not influence oceanic sediments because of the smallness of c 0.

Effect of Chronic Ammonia Exposure on Energy Budget of Juvenile Soft‐shelled Turtle, Pelodiscus sinensis

Abstract.— The present work investigated the effect of chronic ammonia exposure on energy budget of juvenile soft‐shelled turtle, Pelodiscus sinensis. Turtles (87.14 ± 4.00 g) were exposed to external total ammonia nitrogen (TAN) concentrations of C0 (11.01 mg/L), C1 (46.32 mg/L), C2 (68.71 mg/L), and C3 (97.0 mg/L), respectively, for 97 d at 29.5 C, pH 7.76. The ambient ammonia showed no significant influence on any component of the energy budget such as feed consumption, fecal production, excretion, standard metabolism, and growth. There were also no significant differences in body composition of the turtles among different treatments. Chronic exposure to ambient ammonia as high as 97 mg/L TAN did not affect energy budget of juvenile soft‐shelled turtle. The average energy budget for all turtles can be described as follows: 100 C = 9.3 F + 3.0 U + 74.6 R + 13.1 G, where C, F, U, R, and G represent energy intake, fecal energy, excretory energy loss, metabolism energy, and growth energy, respectively.

Efikasnost terapijskog monitoringa ciklosporina odredjivanjem C2 i PIK0−4 tokom prva 24 meseca posle transplantacije bubrega

Cyclosporine (CyA) therapeutic drug monitoring (TDM) through the measurement of drug concentration in blood two hours after the administration (C2), and/or according to the calculated value of the area under the concentration-time curve during the first four hours following administration (AUC(0-4)) shows favourable correlation with clinical manifestations in patients with kidney transplantation (Tx). The aim of this study was to analyze clinical efficiency and usability of TDM CyA through C2 and AUC(0-4) in the group of our kidney transplanted patients during the first 24 months following Tx. The study included 50 patients who had undergone kidney Tx using living donors at the Clinic of Nephrology Military Medical Academy, from 1996 to 2003. The first group (group C2) consisted of 25 patients in whom CyA dose was adjusted according to the target C2 and AUC(0-4) (calculated by the regression formula based on C1, C2 and C3), while the second group (group CO) consisted of 25 "historical" patients in whom the dose of this drug was adjusted according to CO. On the 6th day the average daily dose of CyA in the group C2 was 10.1 +/- 0.8 mg/kg, while in the group CO it was 7.6 +/- 1.6 (p < 0.05). One month following the Tx, daily drug doses were quite similar in the two observed groups (6.2 mg/kg in CO and 6.6 mg/kg in group C2, p = NS). In the group C2, target C2/AUC(0-4) (C2 1700 ng/ml, AUC(0-4) 4400 ng h/ml) on the sixth day was achieved in 36.3%, and on day 14 in 76% of the patients. The target AUC(0-4), in relation with C2, in each observed time interval was reached in the higher number of patients. Maximum CyA concentrations in the group C2 were registered 2 hours following the administration (C2), when compared with the concentrations registered after the first and the third hour (C1 and C3). In relation with C1 and C3, C2 concentration correlated most favorably with AUC(0-4), both on the 6th (r = 0.85) and on the 9th day (r = 0.87). During the first three months following the Tx, in the group CO, 10 episodes (40%) of acute cell rejection (AR) were registered, while in the group C2, two episodes (8%, p = 0.07) were registered; in the observed period covering the first two years, a total of 13 (52%) AR episodes in the group CO and 5 AR episodes (20%) in the group C2 (p = 0.03) were registered. All of five episodes of steroid resistant AR were registered in the group CO. In the group C2, all five patients with AR had lower C2 during AR: the average C2 at the moment of AR was 933.8 ng/ml, and in the patients without rejections was 1364.2 ng/ml (p = 0.008). In the same group, the average C0 at the moment of AR was 263.2 ng/ml, and 240.0 ng/ml (p = 0.486) in the patients without AR. In the C0 group, average C0 concentration at the moment of AR was 227.1 ng/ml, while in the patients without AR it was 227.7 ng/ml (p = 0.95). Totally 68% of the patients showed signs of acute CyA nephrotoxicity during the first year in the group C2, and 52% in the group CO (p = 0.38). In seven patients (28%) of the group C2 and six patients of the group C0 (24%, p = 0.96) in the first two years following Tx, administration of CyA was interrupted due to nephrotoxicity. Overall graft function was good in both groups during the period of two years. One graft was lost in the group CO due to chronic allograft nephropathy. The patients in the group C2 had better early and the same late graft function. Five patients in the group C2 who did not reach the target C2/AUC during the first 30 days, did not have more AR or worse graft function, comparing with the patients who reached the target concentrations. In the patients with CyA TDM through with the C2 and AUC(0-4), AR frequency was considerably lower, and AR episodes had a milder flow than in those with CyA TDM through the CO. The drug concentration in blood two hours after administration (C2) was a good predictor of acute graft rejection, while CO failed to point to the patients with the insufficient drug concentration. Higher drug doses were administered in the group C2 during the first month following Tx, and these patients did not show significantly higher frequency of acute nephrotoxicity and more frequent requirement of the drug use interruption. Graft function in both groups was good during the period of two years. CyA dose determination through C2 and AUC(0-4) is efficient TDM method, relatively simple for use in day to day clinical practice.

Automated monitoring of C2 and C0 blood levels of mycophenolic acid and cyclosporine on the Abbott Architect c8000

Objectives: Evaluation of the performance of the EMIT 2000 Cyclosporin assay using 2 sets of assay calibrators and the EMIT 2000 mycophenolic acid assay to measure C0 and C2 concentrations on the Abbott Architect c8000 analyzer. Design and methods: Imprecision studies were performed. Cyclosporin concentration was assayed by EMIT on the c8000, by ACMIA on the Dimension and by LC-MS/MS while mycophenolic acid was analyzed by EMIT on c8000 and on Dimension and by HPLC. Results: Agreement between cyclosporin and mycophenolic acid concentrations assayed on the c8000 and on the Dimension was very good. Method comparison between the c8000 and LC-MS/MS resulted in a relative bias of 15.7% for C0 and 11.5% for C2 concentrations. Relative bias of the mycophenolic acid concentrations assayed on the c8000 and the HPLC was 37.7%. Conclusions: When reported properly to the clinician mycophenolic acid and cyclosporine blood levels can be monitored using the EMIT assays on the c8000 consolidating standard routine workflow and reducing reagent costs significantly.

Cyclosporine drug monitoring with C0 and C2 concentrations in children with stable renal allograft function

Cyclosporin A (CsA) has a narrow therapeutic window and necessitates monitoring of blood concentration. We aimed to evaluate trough (C0) and second hour (C2) level after ingestion of drug monitoring in renal allograft recipients. In this retrospective study, 12 children eight boys and four girls; mean age at transplantation 14.6 +/- 3.7 yr (ranges: 7.0-19.0), mean age post-transplant 17.8 +/- 4.9 yr (ranges: 9.0-24.0) who were transplanted >6 months were enrolled in this evaluation. Ten were recipients of a living related donor and two deceased donor grafts. While six children were receiving CsA, steroids and azathioprine, the other six received CsA, steroids and mycophenolate mofetil. Clinical course, blood pressure, renal and liver function tests were recorded. Mean C0 and C2 were 96.2 +/- 59.5 and 504 +/- 305.4 ng/mL respectively. Mean serum creatinine level was 1.2 +/- 0.45 mg/dL and mean creatinine clearance (CrCl) was 89.2 +/- 36.8 mL/min/1.73 m2. There was a correlation between serum creatinine level, CsA dose and C2 levels,whereas,there was no correlation between age, blood pressure, CrCl and C2 levels. However, no correlation was found between C0 levels and any of the above parameters. In conclusion, our data suggest that C2 levels are correlated better with dose and serum creatinine level.

Microemulsion cyclosporine with C2 monitoring and tacrolimus in liver transplantation with or without hepatitis C virus infection

The introduction of calcineurin inhibitors has improved graft survival in the last 25 years. The superiority of tacrolimus over cyclosporine (CsA) was well established in preventing acute rejection and corticosteroid-resistant rejection from 3 large randomized trials after liver transplantation. However, these differences were studied with a conventional formulation of CsA and CsA monitoring with trough (C0) concentrations. 4-6 In addition, in those three studies, the indication of hepatitis C virus (HCV)-related end-stage liver disease is relatively low: it accounts for more than 40% of liver transplantations in the United States. It is now clear that C2 monitoring of CsA better reflects the area under the concentration curve of the drug and has a better safety and efficacy profile in renal transplantation. Also, the microemulsion formulation of CsA (CsA ME) provides more predictable area under the concentration curve, and day-to-day fluctuations in concentration are less common. In liver transplantation, diversion of bile affects the absorption of CsA, which is less affected with CsA ME formulation. In vitro studies have shown anti-HCV activity of CsA at higher concentrations. Thus, several questions emerge. Does microemulsion formulation of CsA with C2monitoring provides better safety and efficacy in liver transplant patients as compared with tacrolimus? And is there any benefit of CsA ME with C2 monitoring over tacrolimus in HCV-positive patients undergoing liver transplantation? Both of these questions are important to clinicians in order to provide the best possible options for their patients. In a U.S. multicenter trial, Wiesner showed that the survival benefit of tacrolimus over CsA was maintained even in patients who were HCV positive with up to a 5-year follow-up. Ghobrial et al. reported the results of a retrospective data analysis of 190 CsA-treated and 132 tacrolimus-treated HCV-positive liver transplant recipients, with median follow-up of 22 months, and found no difference in patient or graft survival. In their study, conventional CsA and CsA ME were grouped together. A randomized study by Martin et al. of 77 patients examined the difference between CsA-treated or tacrolimus-treated HCV-positive liver transplant recipients. Although HCV RNA viral load in the CsA group were higher, histologically diagnosed HCV recurrence rate and survival rate were not different. However, CsA dose was not based on C2 monitoring. Similarly, Zervos et al. reported the results of a prospective study of tacrolimus-treated HCV-positive liver transplant recipients (n 25) with CsA ME–treated HCV-positive liver transplant recipients (n 24) with a median follow-up of 14 months. They found an increased incidence of acute rejection with CsA ME compared with tacrolimus but did not find any difference in patient survival or graft survival. A prospective study conducted in Europe, which included more than 600 cases, found a benefit with tacrolimus over CsA ME. However, in both studies, C0 concentrations were measured. 22,23

STARK EFFECTS FROM GLOBAL WARMING

THE CLEAREST EVIDENCE YET THAT Earth is warming and that C0 2 emissions are largely responsible was presented by researchers in February at the annual meeting of the American Association for the Advancement of Science (AAAS), in Washington, D.C. The researchers also presented evidence that increasing concentrations of atmospheric C0 2 may be causing some biosystems, such as coral reefs, to approach the threshold for damage. If global temperatures rise more than 1.5 °C over today's level, the world's tropical coral reefs may be irreversibly destroyed, they said. Beginning in the 1960s, the average temperatures of surface waters in all of the world's major oceans began to rise, said Tim P. Barnett, research marine physicist at Scripps Institution of Oceanography The results of computer models simulating the rise in ocean temperatures from increasing levels of atmospheric C0 2 are nearly identical to temperature measurements taken since I960 at various oceanic depths, he said. This is perhaps ...

Synthesis of Spinel LiMn2O4 Powders by the Drip Pyrolysis in Fluidized Bed Reactor

A simple technique has been developed to directly produce fine ceramics powders from liquid solution by drip pyrolysis in a fluidized bed reactor. Using this technique, the preparation of lithium manganese oxides LiMn2O4, which are the most promising cathode materials for lithium ion battery, has been carried out for various superficial gas velocities U0 = 0.30–0.91 m/s, concentrations of precursor solution C0 = 0.45–4.50 mol/dm3 and static bed heights Ls = 50–150 mm. The as-prepared samples exhibited a pure cubic spinel structure without any impurities in the XRD patterns, and the chemical composition of as-prepared powders showed in a good agreement with the one of precursor solution.The as-prepared sample was used as cathode active materials for lithium-ion battery and their charge/discharge properties have been investigated. Test experiments in the electrochemical cell Li|1M LiClO4 in PC|LiMn2O4 demonstrated that the sample, prepared by the drip pyrolysis method and then calciend at 750°C for 4 h in the air, was a promising cathode material for 4 V lithium-ion batteries.

Preliminary evaluation of a new chemiluminescence assay (liaison cyclosporine; diasorin laboratories) allowing both C0 and C2 cyclosporine levels determination: Comparison with RIA method

Cyclosporine (CsA) monitoring is generally assessed by trough concentration determinations (C0). Recently, the 2-hour postdose CsA level (C2) has been proposed to be a better measurement to predict graft outcome and prevent toxicity. However, using the available methods, C2 determinations require external dilution, which impairs the precision and practicability of the assay. This study assessed the performance characteristics of a new competitive chemiluminescence immunoassay (CLIA, DiaSorin Laboratories, Anthony, France) for the determination of both C0 and C2 CsA concentrations in whole blood on a Liaison analyzer. The results were compared with the RIA method (DiaSorin) used in our laboratory as a refereence technique. Analytical performances showed that the total intra-assay variation coefficients (CVs) on the CLIA Liaison ranged from 7.6% to 11.3%, while the between-day imprecision was 11% (15.2%, 11.5%, and 6.5%). The linearity of the method was estimated over the range of 30 to 2400 ng/mL as a correlation coefficient of r = .997. Recoveries, which were checked by adding pure CsA to CsA-free blood, showed a mean value of 86%. A total of 236 whole-blood samples (31% women, 69% men of mean age 45 ± 17 years) were subjected to a comparative study of CLIA-CsA versus RIA (radioimmunoassay) values, yielding a correlation coefficient >0.90 (CLIA = 0.825RIA+21.611; r 2 > .90). In conclusion, the CLIA Liaison CsA kit represents an alternative to the radioisotopic method, which allows both C0 and C2 determinations without any preanalytical step. The chemiluminescence method demonstrated good analytical performance and practicability in routine use.

A CONCENTRATION-CONTROLLED REGIMEN OF HIGH SIROLIMUS EXPOSURE SUPPORTS FUNCTIONAL RECOVERY OF HUMAN RENAL ALLOGRAFTS FROM DECEASED DONORS

O83 Aim: To assess the benefit of a concentration-controlled strategy of de novo sirolimus (SRL) administration, the evolution of renal function among a cohort of deceased donor kidneys at high risk for delayed graft function (DGF) was compared with the outcomes in the Scientific Registry of Transplant Recipients (SRTR). Methods: Between 3/22/1999 and 12/31/2001, 200 local recipients (Group I) were deemed to be at high risk for DGF, due to use of extended donors (n=197) or high PRA/presensitization (n=3). In addition to SRL (target C0=10-20ng/mL), induction therapy included steroids plus either basiliximab (20mgx2; low immune responder: primary graft in Caucasian/Hispanic; n=141 [70%]) or rabbit antihuman thymocyte globulin (1.5mg/kg/dx7; high responder: African American, re-transplant, >50% PRA; n=59 [30%]). When the serum creatinine (Scr) fell to 2.5mg/dL, cyclosporine (CsA; 1.5mg/kg/d) was initiated and adjusted to C2=200ng/mL for low- or 400ng/mL for high-risk patients. CsA exposure was tapered based upon renal function. The 12-mo evolutions of Scr and glomerular filtration rate (GFR; MDRD calculation) among Group I patients were compared with contemporaneous cohorts in the SRTR, who had been induced with (Group IIA; n=2674 including 15% expanded donors and 11.4% African Americans) or without (Group IIB; n=2752 including 13.9% expanded donors and 10.3% African Americans) SRL. SRTR groups were matched within centers by age and year of transplant, excluding centers not using SRL. Differences were evaluated for statistical significance by chi-square tests. Logistic regression models were used to assess the impact of drug concentrations on GFR. Results: Group I patients displayed superior function to Group IIA and equal to group IIB patients. The incidences of Scr <1.5mg/dL at 12 mo were 63.3 vs 52.8 (p=0.01) vs 61.8 (p=NS); of GFR >70mL/min, 25.2 vs 19.8 vs 21.9, and of GFR >55mL/min, 54.5 vs 42.5 vs 47.2, respectively. These results were observed despite Group I patients showing demographic features that forecast poorer allograft function—a higher incidence of DGF (44.9 vs 31.7; p=0.002 or 23.7; p<0.0001), older age, higher body mass index, and longer time on dialysis. Also, among Group I patients the frequencies of Scr <1.5mg/dL and GFR >55mL/min were similar at 1 and 12 mo; namely, 60.3 vs 63.3 and 51.8 vs 54.5, respectively. A high % coefficient of variation (%CV) of SRL C0 (>30%) produced no detriment in GFR values. Logistic models revealed a positive impact of increasing SRL concentrations (odds ratio [OR])=1.31 per ng/mL SRL C0 (p=0.003) on the odds of GFR >40 at 1 mo. An OR of 3.09 for GFR >40 at 1 mo was determined for patients with mean SRL concentrations ≥16ng/mL (p=0.02). Logistic models revealed a significant interaction between mean SRL C0 and CsA average concentrations. Conclusion: Our single-center experience with tailored antibody induction and delayed introduction of markedly reduced CsA exposure demonstrates that high SRL concentrations are associated with increased GFRs among deceased donor kidneys at increased risk of DGF.

Therapeutic drug monitoring of cyclosporine

The introduction of cyclosporine into clinical practice improved transplant outcome. However, the use of cyclosporine is not without problems. A narrow therapeutic index (the drug causes irreversible kidney damage when given in too high a dose) coupled with variable absorption and unpredictable pharmacokinetics has resulted in the need to measure cyclosporine blood concentrations to enable the dose of the drug to be individualised to the patient. When this is done correctly therapeutic efficacy can be maximised while toxicity is kept to a minimum. The evolution of cyclosporine dose optimisation started with the adjustment of empirical fixed doses by clinical “judgement;” progressed to therapeutic drug monitoring of trough, predose, C0 concentration with non specific assays that measured parent drug and metabolite; then on to “specific” cyclosporine C0 measurements; through area under curve monitoring using full profile measurements and limited sampling scheme procedures; and finally ending up with absorption profiling that targets AUC in the first 4 hours or the 2 hour blood cyclosporine concentration, C2. At the same time the formulation of cyclosporine has changed from Sandimmune to Neoral and now generic forms of the latter are available. The evidence base supporting C2 monitoring continues to grow and the technique will need to be customised as new combination therapies emerge. Therapeutic drug monitoring of cyclosporine may also need to be tailored to avoid the potential negative impact of switching patients to generic forms of the drug.

Experience with cyclosporine

The concentration at 2 hours after drug intake (C2) is proposed to optimise clinical outcomes in organ transplantation and for adjustment of the regimen of cyclosporine. A population based pharmacokinetic study was undertaken during the first 30 days post-liver transplantation. Preliminary results observed during this study on C0 and C2 values are described here. Thirty-seven patients with first hepatic transplantation were included in a single center, prospective study conducted under conditions of normal practice. Dose adjustments were made according to C0. Cyclosporine C0 and C2 were assayed by an immunoassay (EMIT) and by a HPLC technique. Clinical outcome was assessed by occurrence and severity of acute rejection. Our data shows that average blood C0 and C2 concentrations are significantly different with the two techniques. From the third day to the end of the study, mean C2 (EMIT) were within or near the recommended values. This was associated with a low rejection rate (8.8%). Nevertheless, individual values are largely dispersed and low cyclosporine absorption profiles are identified. Mean cyclosporine dose was low compared to a previous study (7.65 ± 4.28 mg/kg/day). Our data suggest that the target ranges need to be adjusted when different techniques are applied and that optimal cyclosporine regimen to achieve the C2 goal and low rejection rate remains to be defined. Pharmacokinetic models based on population study are needed to describe normal and abnormal cyclosporine absorption profiles with higher accuracy.

Long-term changes in mycophenolic acid exposure in combination with tacrolimus and corticosteroids are dose dependent and not reflected by trough plasma concentration: a prospective study in 100 de novo renal allograft recipients.

Tacrolimus and cyclosporine A have different effects on exposure to concomitantly administered mycophenolate mofetil (MMF), measured as the mycophenolic acid (MPA) dose interval area under the plasma concentration versus time curve (AUC0-12 h) or the plasma MPA predose concentration (C0). This has led to recommendations in using a 50% lower dose of MMF in combination with tacrolimus compared to cyclosporin A. At present, no long-term data are available regarding the pharmacokinetics (PK) of different dosages of MMF in combination with tacrolimus and the clinical variables that influence the dose-exposure relationship of MPA. A prospective 12-month pharmacokinetic study was performed in 100 de novo renal transplant recipients treated with two different MMF dosages (1 g/day vs. 2 g/day) in combination with tacrolimus and corticosteroids. MPA AUC data were collected 7 days, 6 weeks, and 3 and 12 months posttransplantation, and model-independent PK parameters were calculated. Clinical variables that could possibly influence MPA PK were evaluated. The MPA AUC0-12 h significantly increased toward 6 weeks (p < 0.05) but only in the 2-g MMF dosing group. The MPA AUC0-12 h in the 1-g MMF group reached its nadir at 3 months, while in the 2-g MMF group, it remained elevated until 3 months, returning to baseline values by 12 months. This differential evolution in exposure was not only inadequately reflected by the corresponding MPA C0 concentrations, but the MPA C0 concentrations also were not significantly different between the two dosing groups at early postgrafting (day 7) and at 12 months. Using multiple stepwise regression analysis, C0 (r = 0.51, p < 0.0001) and end-of-dose interval MPA plasma concentration (C12: r2 = 0.61, p < 0.0001) were found to poorly predict MPA AUC0-12 h, while MPA plasma concentrations at 4 hours (C4: r2 = 0.85, p < 0.0001) and 6 hours postdosing (C6: r2 = 0.83, p < 0.0001) were superior but hampered by a large prediction bias and imprecision. An abbreviated 2-hour AUC measurement (r2 = 0.78), using three sampling points (C0, C40 [MPA plasma concentration 40 min postdosing], C2), provided the best compromise between a monitoring tool that is theoretically ideal and practically feasible. MPA pharmacokinetics were not influenced by recipient age, gender, and body weight or by serum albumin concentrations, allograft function, or corticosteroid or tacrolimus dose. Mild hepatic dysfunction early after grafting did result in significantly reduced MPA exposure (MPA AUC0-12 h, p = 0.01 and C0, p = 0.03). In this study, it was demonstrated for the first time that the dynamics of long-term MPA pharmacokinetics in combination with tacrolimus differ according to the daily MMF dose and that this effect is not adequately reflected by MPA trough concentrations. Using the latter as a routine measure for therapeutic drug monitoring might mislead clinicians into drawing wrong conclusions in terms of relating questions of efficacy or toxicity to MPA exposure.

Effects of biodegradation on the distribution of alkylcarbazoles in crude oils

We have investigated the distributions of alkylcarbazoles in a series of crude oils with different biodegradation extents, in combination with biomarker parameters, stable carbon isotopic ratios and viscosities. The analyses showed that slight biodegradation has little effect on alkylcarbazoles. The concentrations of C0-, C1-, and C2-carbazoles seem to display a slight decrease with biodegradation through the moderately biodegraded stage, and an abrupt decrease to the heavily biodegraded stage. The relative concentrations of C0-, C1-, and C2-carbazoles do not show any apparent change in the non-heavily biodegraded stages, but through non-heavily biodegraded to heavily biodegraded stages, the percentages of C0- and C1-carbazoles decrease, and those of C2-carbazoles increase significantly, which may indicate that C2-carbazoles are more resistant to biodegradation than lower homologous species. As to C2-carbazole isomers, the relative concentrations of the pyrrolic N-H-shielded, pyrrolic N−H partially shielded and pyrrolic N-H-exposed isomers do not show any obvious variation in the non-heavily biodegraded oil, but there is an abrupt change through the mid-biodegraded stage to the heavily biodegraded stage.

Predictive value of cyclosporine blood levels during the absorption phase to estimate the area under the curve in stable renal transplant patients

THE AREA UNDER the CsA concentration time curve (AUC) is a better measure of systemic drug exposure than trough concentrations (C0) and has been shown to correlate better with clinical outcome. However, therapeutic monitoring of CsA based on AUC is impractical because collection of multiple blood samples is required. For this reason C0 concentrations are used in most centers for the adjustment of CsA dosage. Recently, several reports suggest that monitoring of markers of neoral absorption such as AUC0–4h are more sensitive than C0 for optimizing the effect of CsA. 3–4

Invasion and distribution of methanol.

After the enzyme systems responsible for methanol oxidation were blocked by ethanol, five test persons were given methanol at a dose of approximately 10 mg/kg weight, once orally and once parenterally. Taking into account the endogenous blood methanol levels detectable before the administration of methanol, C0 concentrations of 11.1-15.9 mg/kg were reached. This corresponds to a distribution volume of approximately 0.77 +/- 0.07 l/kg, which is comparable to the 0.78 +/- 0.09 l/kg obtained for ethanol. After parenterally administering methanol as a bolus, the distribution half-life was on average 8 min (range: 3.8-13.8 min). After oral administration of methanol diluted in 100 ml water on an empty stomach, invasion took place with a half-life of approximately 5 min (3.8-6.9 min). In one case, however, due to vegetative disturbances the invasion half-life was 23.1 min.

Cyclosporine A blood concentration during pregnancy in renal allograft recipients.

Pregnancy-induced changes increase hazards associated with cyclosporine (CsA) treatment. Blood CsA trough levels (C0) were estimated in 15 pregnant renal allograft recipients treated with prednisolone + CsA + azathioprine using the TDx Abbott fluorescent polarization immunoassay. Despite therapeutical dose levels of CsA administered during pregnancy (3.52-3.67 and 3.59 mg/kg body weight in the first, second, and third trimesters, respectively), C0 significantly decreased (first trimester 130.8 +/- 36.9, second 92.0 +/- 32.7, and third 99.0 +/- 36.9 ng/ml). The mean increase of patient's body weight in mid-pregnancy was 3.0 +/- 2.19 kg and was associated with a significant (P < 0.05) fall in a hematocrit value (from 42 +/- 4.9% prior to pregnancy to 34 +/- 6% at the 20th week). We postulate that C0 concentration does not reflect the true exposure to CsA as no episodes of acute graft rejection were observed during pregnancy.

Cyclosporine A blood concentration during pregnancy in renal allograft recipients

Abstract Pregnancy-induced changes increase hazards associated with cyclosporine (CsA) treatment. Blood CsA trough levels (C0) were estimated in 15 pregnant renal allograft recipients treated with prednisolone + CsA + azathioprine using the TDx Abbott fluorescent polarization immunoassay. Despite therapeutical dose levels of CsA administered during pregnancy (3.52-3.67 and 3.59 mg/kg body weight in the first, second, and third trimesters, respectively), C0 significantly decreased (first trimester 130.8 ± 36.9, second 92.0 ± 32.7, and third 99.0 ± 36.9 ng/ml). The mean increase of patient's body weight in miD-pregnancy was 3.0 ± 2.19 kg and was associated with a significant (P < 0.05) fall in a hematocrit value (from 42 ± 4.9 % prior to pregnancy to 34 ± 6% at the 20th week). We postulate that C0 concentration does not reflect the true exposure to CsA as no episodes of acute graft rejection were observed during pregnancy.

Simple Scaling Rules on Swollen and Shrunken Polymer Gels

The equilibrium swelling ratios of temperature sensitive polymer gels have been studied as a function of the initial monomer concentration at preparation in both the swollen and the shrunken states. The linear swelling ratio, d/d0, was independent of the initial monomer concentration of N-isopropylacrylamide, C0, where d and d0 are the diameters of gels at observation and at preparation, respectively. On the other hand, d/d0 was proportional to C0 in the shrunken state. The swelling curves of gels with different C0's were successfully reproduced with a modified Flory−Rehner equation, where the effective cross-link density was modified to be proportional to C0 by taking account of the contribution of “excess cross-linking” by entanglement. Scaling rules for the polymer fractions were derived for both the swollen and the shrunken states; i.e., φsw ∼ C01 and φsh ∼ C00, where φsw and φsh are the equilibrium volume fractions of the network at the swollen and shrunken phases, respectively.

Elastic Modulus and Equilibrium Swelling of Polyelectrolyte Gels

We present a scaling theory for the modulus G of polyelectrolyte gels as a function of strand length between cross-links, monomer concentration c, salt concentration cs, and preparation conditions (monomer concentration c0 and salt concentration cs°). The theory assumes affine displacement of the junction points when the concentration is changed. With no added salt (cs = cs° = 0), we predict a new concentration dependence of the modulus G ∼ c5/6. In the high-salt limit, we predict the usual concentration dependence for uncharged polymers but a novel dependence on salt concentration, G ∼ c7/12cs1/4. We also predict the modulus to decrease as charge is added to the gel strands. The predicted effects of added salt and charge on modulus have recently been observed by Candau and co-workers. At low concentrations, we discuss the strong stretching of network strands and its effect on modulus and equilibrium swelling.