Cyclosporin is an immunosuppressive agent with a narrow therapeutic index. The total concentration of cyclosporin in blood is usually monitored to guide dosage adjustment and to compensate for ...substantial interindividual and intraindividual variability in cyclosporin pharmacokinetics. Cyclosporin is a highly lipophilic molecule and widely distributes into blood, plasma and tissue components. It mainly accumulates in fat-rich organs, including adipose tissue and liver. In blood, it binds to erythrocytes in a saturable fashion that is dependent on haematocrit, temperature and the concentration of plasma proteins. In plasma, it binds primarily to lipoproteins, including high-density, low-density and very-low-density lipoprotein, and, to a lesser extent, albumin. The unbound fraction of cyclosporin in plasma (CsA(fu)) expressed as a percentage is approximately 2%. It has been shown that both the pharmacokinetic and pharmacodynamic properties of cyclosporin are related to its binding characteristics in plasma. Furthermore, there is some evidence to indicate that the unbound concentration of cyclosporin (CsA(U)) has a closer association with both kidney and heart allograft rejection than the total (bound + unbound) concentration. However, the measurement of CsA(fu) is inherently complex and cannot easily be performed in a clinical setting. Mathematical models that calculate CsA(fu), and hence CsA(U), from the concentration of plasma lipoproteins may be a more practical option, and should provide a more accurate correlate of effectiveness and toxicity of this drug in transplant recipients than do conventional monitoring procedures. In conclusion, the distribution characteristics of cyclosporin in blood, plasma and various tissues are clinically important. Further investigations are needed to verify whether determination of CsA(U) improves the clinical management of transplant recipients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Two simple, sensitive and reproducible methods for determination of total mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) as well as unbound MPA (fMPA) was developed by the use of ...HPLC-UV and LC–MS/MS methods, respectively. For the total MPA/MPAG method, the analytes were extracted using Isolute C
2 solid-phase extraction (SPE) cartridges and analyzed at 254
nm over a Zorbax Rx C
8 column (150
mm
×
4.6
mm, 5
μm). The mobile phase was a gradient mixture of methanol and water (containing 0.1% (v/v) phosphoric acid). The total run time was 18
min and the extraction recovery was 77% for MPA and 84% for MPAG. The method was precise and accurate with a lower limit of quantification (LLOQ) of 0.5
mg/l for MPA and 5.0
mg/l for MPAG. For the fMPA method, plasma was subjected to ultrafiltration followed by SPE using C
18 cartridges. Analytical column was the same as the HPLC-UV method and the mobile phase was a gradient composition of methanol:0.05% formic acid with a flow rate of 0.6
ml/min for the first 3
min and 0.7
ml for the last 4
min. The chromatographic method separated MPA from its metabolites MPAG and Acyl-MPAG. Mass transitions in negative ionization mode for MPA and the internal standard, indomethacin were
m/
z: 319
→
190.9 and
m/
z: 356
→
312.2, respectively. The assay was linear in the concentration range of 1–1000
μg/l for fMPA with a LLOQ of 1
μg/l and an accuracy of >95%. The two methods reported have an adequate degree of robustness and dynamic concentration range for the measurement of MPA, MPAG and fMPA for therapeutic drug monitoring purposes or pharmacokinetics investigations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Previous research has shown that sexual minority (i.e., nonheterosexual) individuals report increased problematic substance use involvement, compared with their sexual majority counterparts. We ...hypothesize that feelings of an unstable sense of self (i.e., identity disturbance) may potentially drive problematic substance use. The purpose of the current study is to examine identity disturbance among sexual minorities as a potential explanatory mechanism of increased sexual minority lifetime rates of substance dependence. Measures of identity disturbance and three indicators of sexual orientation from lifetime female (n = 16,629) and male (n = 13,553) alcohol/illicit drug users in Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were examined. Findings generally showed that the increased prevalence of alcohol dependence, illicit drug dependence, and combined alcohol/illicit drug dependence as well as a younger age of alcohol use initiation among sexual minority women was associated with elevated levels of identity disturbance. The results were consistent with a mediational role for identity disturbance in explaining the association between sexual minority status and substance dependence and were generally replicated among male sexual minority respondents. The current research suggests that identity disturbance, a predictor of substance use, may contribute to heightened risk for substance dependence among certain subgroups of sexual minority individuals.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
The objective of this study was to investigate the relationship between cyclosporine (CsA) pharmacokinetic parameters and clinical outcomes after lung transplantation.
Data from 48 lung or heart/lung ...transplant recipients originally recruited to a randomized, prospective clinical trial of Sandimmune vs Neoral and followed for 12 months were included in this study. CsA dosing was based on the trough concentration. CsA concentrations at 0 (C0), 2 (C2), and 6 (C6) hours post-dosing were obtained at 1, 2, 3, 4, 13, 26, 39, and 52 post-operative weeks. Based on their average C2 levels in the first post-transplant month, patients were stratified retrospectively into Low C2 (<1,000 microg/liter, n = 18), Intermediate C2 (1,000-1,500 microg/liter, n = 16) and High C2 (>1,500 microg/liter, n = 14) Groups.
Cyclosporine C2 was the best single-point determinant (r2 = 0.934) for area-under-the-concentration-time curve (AUC(0-6 hours)) compared with C0 (r2 = 0.267) or C6 (r2 = 0.304). The mean +/- SD values of CsA C2 and AUC(0 to 6 hours) in the first year post-transplant were significantly lower in patients with >2 rejection episodes compared with those with < or =2 rejection episodes (C2: 875 +/- 546 microg/liter vs 1,114 +/- 633 microg/liter, p = 0.01; AUC(0-6 hours): 4,036 +/- 1,904 microg x hour/liter vs 4,870 +/- 2,182 microg x hour/liter; p = 0.01) whereas C0 and C6 did not differ. Patients in the Intermediate C2 Group were free from rejection episodes for a significantly longer duration (p < 0.001) and had significantly higher predicted forced expiratory volume in 1 second (%) values (p < 0.001) compared with the Low and High C2 Groups. The percentage of increase in serum creatinine concentration by the end of first month post-transplant was significantly higher in the Intermediate C2 Group (p < 0.003).
CsA C2 concentrations correlated better with the incidence of multiple rejections after lung transplantation than did C0 or C6. C2 concentrations between 1,000 and 1,500 microg/liter within the first post-operative month may be associated with better graft outcomes and improved pulmonary function and worsened renal function.
A population pharmacokinetic analysis of cyclosporine (CsA) was performed, and the influence of covariates on CsA oral clearance and relative bioavailability was investigated. Data from 48 recipients ...of heart-lung (n = 21) or single (n = 18) or double (n = 9) lung transplant were included in the study. Patients received oral CsA as either a conventional formulation (Sandimmune) or a microemulsion (Neoral). Steady-state CsA concentrations were measured before and at approximately 2 and 6 hours after the morning dose of CsA at the end of weeks 1, 2, 3, 4, 13, 26, 39, and 52 posttransplantation. A total of 1004 CsA concentration observations were analyzed using mixed effects-modeling (NONMEM). A 1-compartment pharmacokinetic model and first-order oral absorption were used to fit the data. The absorption rate constants were fixed at 0.25 L/h for Sandimmune and 1.35 L/h for Neoral formulations. Oral clearance (CL/F) was estimated to be 22.1 L/h (95% confidence intervals CI 19.5-24.7 L/h). Itraconazole (ITRA), cystic fibrosis (CF), and weight (WT) were identified as significant covariates for CL/F according to the final model: CL/F = 22.1 - 11.3 x ITRA + 23.5 x CF + 0.129 x (WT - 58.7) L/h; where ITRA = 1 if the patient was taking concomitant itraconazole, otherwise 0; CF = 1 if the patient had cystic fibrosis, otherwise CF = 0; and WT is patient weight in kilograms. The relative oral bioavailability of Sandimmune to Neoral was 0.82. The bioavailability of both preparations increased during the first month posttransplantation. Age, gender, and type of transplant (single, double, or heart-lung) were not identified as significant covariates for CsA clearance. The population pharmacokinetic model developed identified some sources of variability in CsA pharmacokinetics; however, an appreciable degree of variability is still present in this patient population.
Hyperlipidemia is an important complication after organ transplantation and contributes to the development of posttransplant accelerated coronary artery diseases.
We have retrospectively evaluated ...the relative contribution of various risk factors associated with the development and progression of hyperlipidemia in 194 heart transplant recipients by the use of mixed effects multiple linear regression analysis. The demographic characteristics evaluated were primary diagnosis of ischemic heart disease (IHD), gender, and age. Postoperative characteristics included number of treated rejections, dosage of cyclosporine (CYA), tacrolimus (TAC), prednisolone and azathioprine, and concentration of serum creatinine and glucose. The effects of administration of antihypertensive agents, diuretics, and lipid lowering agents were also studied.
The total cholesterol concentration increased significantly in the first 3 months posttransplant but gradually decreased thereafter. Total cholesterol and the ratio of low density lipoprotein (LDL) cholesterol to high density lipoprotein (HDL) cholesterol (LDL-C/HDL-C) increased to a greater extent in patients with IHD although female transplant recipients had a greater increase in the total cholesterol concentration. Each episode of rejection increased serum cholesterol by 0.306 mmol/liter (0.258, 0.355) mean (95% C.I.) and serum triglyceride by 0.164 mmol/liter (0.12, 0.209) although switching to TAC improved total cholesterol and LDL-C/HDL-C. Administration of frusemide, increased the total cholesterol and LDL-C/HDL-C whereas administration of bumetanide or metolazone increased the concentration of serum triglyceride. Serum glucose was associated with hypertriglyceridemia whereas serum creatinine was associated with increases in the total cholesterol, LDL-C/HDL-C and triglyceride.
We have identified demographic and postoperative covariables that predispose heart transplant recipients to hyperlipidemia. Some of these risk factors, such as the effect of diuretics, have not been identified before in this group of patients and may be amenable to modification or closer control. TAC rather than CYA may be the immunosuppressive of choice for patients who are at greater risk of developing hyperlipidemia.
Increased susceptibility to bacterial infection is a recognized side-effect of sirolimus treatment after transplantation, which could be caused by inhibition of neutrophil activation. Blood from 24 ...healthy subjects was equilibrated with 0 to 50 ng/mL sirolimus or 60 microg/mL propofol. Blood was also collected from 23 transplant recipients (13 kidney, 10 liver) with renal impairment, randomized to remain on calcineurin inhibitors (n=12) or to be switched to sirolimus monotherapy (n=11). Phorbol myristate acetate (PMA)-stimulated oxidative burst was measured by flow cytometry at 0 and 3 months after randomization. There was a linear relationship between inhibition of neutrophil activation in vitro and sirolimus concentrations spanning the therapeutic range (P=0.01). Neutrophil activation was decreased significantly in transplant recipients 3 months after switching from calcineurin inhibitors to sirolimus therapy (mean percentage change -24.4%; 95% confidence interval -7.5, -41.2%, P=0.009), but no changes were observed in patients who remained on calcineurin inhibitors.
Background: The proteins of the complement cascade play an important role in inflammation and the immune response. They have been shown to be activated during cardiopulmonary bypass (CPB), and may be ...responsible for the inflammatory response to CPB. We looked at the effect of APT070, an anti-complement agent, on human blood during in vitro CPB. Materials and methods: Four hundred millilitres of blood was venesected from healthy human volunteers and heparinised. To the blood was added either APT070 to a concentration of 50 μg/ml (n = 5) or vehicle control (n = 4). The blood was entered into an in vitro CPB circuit and circulated for 90 min. Results: Our results showed that after 90 min of in vitro bypass APT070 significantly inhibited the activation of compliment as demonstrated by C3a (p = 0.03) and sC5b-9 (p = 0.01) levels, and reduced neutrophil stimulation as measured by CD11b expression (p = 0.04 at 90 min). Conclusion: APT070 significantly inhibits complement and neutrophil activation. This result may have considerable implications, especially if it can be shown to decrease the inflammatory sequelae of CPB.
Artificial neural networks (ANNs) are techniques of nonlinear data modeling that have been studied in a wide variety of medical applications. An ANN was developed to assist in the diagnosis of acute ...rejection in liver transplant recipients. We investigated the diagnostic accuracy of this ANN on a new data set of patients from the same hospital. In addition, we compared the diagnostic accuracy of the ANN with that of the individual input variables (alanine aminotransferase ALT and bilirubin levels and day posttransplantation). Clinical and biochemical data were collected retrospectively for 124 consecutive liver transplantations (117 patients) over the first 3 months after transplantation. Diagnostic accuracy was calculated using receiver operating characteristic (ROC) curve analysis. The ANN differentiated rejection from rejection-free episodes in the new data set over the first 3 months posttransplantation with an area under the ROC curve of 0.902 and sensitivity and specificity of 80.0% and 90.1% at the optimum decision threshold, respectively. The ANN was significantly more specific than ALT or bilirubin level or day posttransplantation at their corresponding optimum decision thresholds (P < .0001). Peak ANN output occurred 1 day earlier than peak values for either ALT or bilirubin (P < .005). The diagnostic accuracy of the ANN was greater than that of any of the individual variables that had been used as inputs. It would be a useful adjunct to conventional liver function tests for monitoring liver transplant recipients in the early postoperative period. (Liver Transpl 2001;7:496-503.)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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