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Biomedical subjects

D Czock

Publications and source records attributed to D Czock.

18 recordsLinked to original sources
PubMed2006

High-dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: a long-term follow-up.

In progressive immunoglobulin A nephropathy (IgAN), intravenous immunoglobulin (IVIg) treatment has been used to delay disease progression, but the long-term efficacy is largely unknown. We report the clinical outcomes after IVIg therapy in six male patients with progressive IgAN [median glomerular filtration rate (GFR) 31 ml/min per 1.73 m(2)] followed for a median observation period of 8 years. In this single-arm, non-randomized study, IVIg was given monthly at a dose of 2 g/kg body weight for 6 months. The course of renal function was assessed by linear regression analysis of GFR and proteinuria, and was compared to eight patients with IgAN (median GFR 29 ml/min per 1.73 m(2)) without IVIg as a contemporaneous control group. IgAN disease progression was delayed after IVIg therapy on average for 3 years. The mean loss of renal function decreased from -1.05 ml/min per month to -0.15 ml/min per month (P = 0.024) and proteinuria decreased from 2.4 g/l to 1.0 g/l (P = 0.015). The primary end-point (GFR < 10 ml/min or relapse) occurred 5.2 years (median; range 0.4-8.8) after the first IVIg pulse, and after 1.3 years (median; range 0.8-2.4) in the control group (P = 0.043). In Kaplan-Meier analysis, the median renal survival time with IVIg was prolonged by 3.5 years (IVIg 4.7 years versus control 1.2 years; P = 0.006). IVIg pulse therapy may be considered as a treatment option to reduce the loss of renal function and improve proteinuria in patients with progressive IgAN.

Adult↗
PubMed2006

Pharmacodynamic dose adjustment in renal failure: importance of the Hill coefficient.

OBJECTIVE: The most commonly applied pharmacodynamic model is the sigmoid E(max) model which can be applied for evaluation of dose adjustment schemes in renal failure. It is not known whether the Hill coefficient (H) is a shape factor that only improves the mathematical fit or whether the Hill coefficient is a pharmacodynamic parameter that independently affects drug effects and drug dosage adjustment. METHODS: We performed simulations applying a mechanism-based mathematical pharmacokinetic-pharmacodynamic model for antimicrobial drugs. For the case of renal failure, two dose adjustment rules were evaluated. RESULTS: Administering the drug as 3 dose fractions per day increased the predicted total effect in the case of H = 1 but decreased the predicted total effect in the case of H = 2 compared to once-daily dosing. In renal failure, administration of the normal dose and prolongation of the interval leads to an increased total effect for the simulated drugs for both cases, namely H = 1 and H = 2. However, reducing the dose in renal failure might produce underdosage for a drug with a high Hill coefficient. CONCLUSION: The predicted effects of once- versus thrice-daily dose fractions as well as the predicted effects of dose reduction versus interval prolongation in renal failure critically depend on the Hill coefficient. Methods to estimate the Hill coefficient more precisely should be explored.

Anti-Infective Agents↗
PubMed2003

Pharmacokinetics and pharmacodynamics of lispro-insulin in hemodialysis patients with diabetes mellitus.

OBJECTIVE: Lispro-insulin, after subcutaneous injection in patients with normal renal function, is absorbed faster and has a faster onset of action when compared to regular insulin. However, the pharmacokinetics and pharmacodynamics of lispro-insulin in renal failure have not yet been investigated. PATIENTS AND METHODS: Eight patients with diabetes mellitus on long-term hemodialysis received an individualized dose of regular insulin or lispro-insulin in a crossover design. Blood glucose and insulin concentrations were measured before and after the subcutaneous insulin injections. RESULTS: Plasma insulin concentrations increased faster (time of maximum concentration tmax 20 vs 40 minutes, p = 0.01) and were higher (standardized maximum concentration Cmax/D 13.6 vs 6.1 microU/ml/U, p = 0.01) after lispro-insulin compared to regular insulin. The area under the curve, clearance and parameters of the hypoglycemic action for the 2 insulin products did not differ significantly, but there was a trend to minimum blood glucose level (time of the blood glucose minimum, Gtmin) to occur earlier with lispro-insulin (120 vs 210 minutes, p > 0.05). Differences in elimination half-life and volume of distribution were explained by flip-flop pharmacokinetics in the case of regular insulin. CONCLUSIONS: In hemodialysis patients with diabetes mellitus, lispro-insulin is absorbed faster than regular insulin. Differences in the effects of lispro-and regular insulin can be explained by the differences in pharmacokinetics.

Area Under Curve↗
PubMed2003

Determination of the pharmacokinetics of cerivastatin when administered in combination with sirolimus and cyclosporin A in patients with kidney transplant, and review of the relevant literature.

OBJECTIVE: Therapy of elevated cholesterol serum concentrations is often necessary in patients with kidney transplants. However, the pharmacokinetics of HMG-CoA reductase inhibitors when administered in combination with sirolimus and cyclosporin A (CsA) have not been determined. The aim of this study was to investigate the pharmacokinetics of cerivastatin when administered in combination with sirolimus in patients with kidney transplants, and to review the literature with regard to the differences in pharmacological behavior between sirolimus, CsA and tacrolimus. METHODS: Patients (n = 7) with a stable and functioning kidney transplant and elevated LDL cholesterol serum concentrations were included in the study. After an observation period of 3 months, and whilst receiving sirolimus and CsA, cerivastatin (0.2 mg daily) was administered for a period of 3 months. Pharmacokinetic parameters were calculated on Day 1 and 3 months after initiation of cerivastatin therapy. Routine laboratory parameters and clinical adverse events were monitored throughout the study period. RESULTS: Single-dose cerivastatin AUC was 2 to 3-fold higher in comparison to published values obtained in healthy subjects. The accumulation ratio of cerivastatin (after 3 months/ Day 1) was 1.6. Sirolimus and CsA trough levels, and the sirolimus AUC did not differ after single dose and multiple doses of cerivastatin. CONCLUSIONS: The combination therapy of cerivastatin with sirolimus and CsA leads to a significant increase in cerivastatin exposure. Additional drug monitoring of sirolimus and CsA is not necessary.

Adult↗
PubMed2002

Pharmacokinetics and pharmacodynamics of methylprednisolone after one bolus dose compared with two dose fractions.

OBJECTIVE: Although the elimination half-life of most glucocorticoids is short, they are usually administered once daily, or even on alternate days. Our hypothesis was that this practice might compromise the immunosuppressive effect of those drugs during the second part of the administration interval. METHODS: Eight healthy male volunteers were randomly assigned to receive intravenous methylprednisolone either 32 mg in the morning, or 16 mg in the morning and 16 mg in the evening in a cross-over design. Methylprednisolone concentrations were determined in plasma by high-pressure liquid chromatography. The total number of CD3+ lymphocytes, and CD4+ and CD8+ T-cell subpopulations was measured in blood. The suppression of these cells was used as a surrogate parameter for the immunosuppressive response, and expressed as reduction of the area under the effect time curve (AUETC). Possible adverse effects on blood pressure, glucose, insulin, and endogenous cortisol levels were monitored. RESULTS: There were no significant differences in methylprednisolone half-life (2.2 +/- 0.4 h), clearance (575 +/- 113 mL/min), volume of distribution (106 +/- 22 l), concentration producing the half-maximum effect on CD4+ T-cells (1.5 +/- 0.7 ng/mL), and Hill-coefficient (1.2 +/- 0.1), after single or divided dose. However, the total 24 h effect area (AUETC) of lymphocytes, and mainly CD4+ T-cells was significantly more suppressed (P = 0.008) with the divided dosage regimen than after the single dose (8422 +/- 2163 vs. 11,545 +/- 3020 h cells/microL). The surrogate markers for adverse events were not different, except for cortisol. CONCLUSION: Within a 24-h interval, two dose fractions of methylprednisolone produce a stronger and more sustained immunosuppressive response than one single bolus dose.

Adult↗
PubMed2002

PK-PD curve-fitting problems with the Hill equation? Try one of the 1-exp functions derived from Hodgkin, Douglas or Gompertz.

UNLABELLED: Non-linear phenomena are observed with enzyme kinetics, protein binding, pharmacokinetics or pharmacodynamics. The Hill equation, the Michaelis-Menten equation extended by a power coefficient, is traditionally used for sigmoid curve fitting. Sigmoid saturation phenomena can also be described by exponential functions (1-exp), extended by a power coefficient such as those derived by Hodgkin, Douglas or Gompertz. Comparing the 4 equations, the sigmoid 1-exp function in the form of Hodgkin and Huxley comes closest to the principle of simplicity and succinctness with regard to definition, slope and flexibility of the inflection point. To compare the applicability, a standardized sample of 250 curves was generated by each I of the 4 equations and mutually fitted with the remaining 3. The Hill equation gives the closest fit with the data generated by the other functions. The Douglas variant exhibits the highest rate of convergence. The Gompertz function provides the basic feature of a baseline effect. CONCLUSION: The sigmoid functions investigated (Hill, Hodgkin, Douglas, Gompertz) have differing characteristics and can be used interchangeably for solving specific problems in non-linear modeling.

Mathematics↗
PubMed2001

Renal proximal tubular cell growth and differentiation are differentially modulated by renotropic growth factors and tyrosine kinase inhibitors.

BACKGROUND: The renotropic growth factors (GFs), hepatocyte GF (HGF), epidermal GF (EGF), and insulin-like GF-I (IGF-I) accelerate renal regeneration in animal models after toxic or ischemic injury. These GFs initiate their biological effects on renal tubular cells by interaction with specific transmembrane receptor tyrosine kinases. MATERIALS AND METHODS: In the proximal tubular cell line PT-1, the biological effects of HGF, EGF, and IGF-I and the growth-inhibitory effects of different tyrosine kinase inhibitors (TKIs) were investigated. Receptor binding and tyrosine kinase phosphorylation were determined by ligand binding studies and Western blot analysis. RESULTS: HGF, EGF, and IGF-I bound with nanomolar affinity to their specific cell membrane receptor tyrosine kinases. In contrast to EGF or IGF-I, HGF induced a variety of cell morphological changes, including cell scattering, formation of tubular structures, and expression of long microvilli on the apical cell membrane. HGF was a 10-fold more potent and more effective growth promoter than EGF or IGF-I. Among the TKIs tested, the mitogenic effect of HGF could be more specifically inhibited by emodin and tyrphostin, that of EGF by methyl-2,5-dihydroxycinnamate, lavendustin A, and genistein, and that of IGF-I by geldanamycin. CONCLUSIONS: In contrast to EGF and IGF-I, HGF stimulated both growth and differentiation of renal proximal tubular cells, demonstrating the amazing biological potency of this renotropic growth factor. Selective TKIs may be a promising approach to modulate diseases with abnormalities in protein kinase signalling pathways such as renal cell carcinoma.

Animals↗
PubMed2000

A concept for pharmacokinetic-pharmacodynamic dosage adjustment in renal impairment: the case of aminoglycosides.

BACKGROUND: For patients with impaired renal function, dosage adjustment is necessary for many drugs. Adjustment with respect only to pharmacokinetic parameters may be insufficient. OBJECTIVE: To apply the theory of pharmacokinetics and pharmacodynamics to derive a mathematical model that links the concentration-time course and the clinical response by means of the pharmacokinetic-pharmacodynamic parameter 'area under the effect-time curve' (AUETC), and to use this analysis and clinical data for aminoglycosides to calculate dosage adjustments in renal impairment. METHODS: Model parameters were estimated for the antimicrobial and nephrotoxic effects of aminoglycosides on the basis of data from the literature. Effect parameters were calculated for various degrees of impaired renal function. RESULTS: Use of the model parameters gave a high correlation between the predicted and the observed (literature) values for antimicrobial efficacy and nephrotoxicity. When calculating dosage adjustments in renal impairment, it was possible to hold only one effect (antimicrobial or nephrotoxic) constant by dosage adjustment, whereas the other changed unfavourably. This was explained by differences between the pharmacodynamic parameters for each effect. For high antimicrobial efficacy, a target peak concentration of 9 mg/L (for gentamicin) should be obtained every 48 hours in advanced renal impairment. For low nephrotoxicity, the peak concentration should not exceed 3 mg/L. CONCLUSIONS: The parameter AUETC could be a useful pharmacokinetic-pharmacodynamic surrogate marker for dosage adjustment in renal impairment. Using the AUETC method, the beneficial effect can be balanced against the adverse effect.

Algorithms↗
PubMed1999

Individualized drug dosage in patients treated with continuous hemofiltration.

BACKGROUND: Subtherapeutic drug dosing may be even more dangerous than overdosage, especially for intensive care patients requiring hemofiltration. PROPOSAL: According to Dettli's fundamental equation, body clearance of any drug (Cl) is a linear function of creatinine clearance (Cl = Cl anur + a x C(Cr)), with [a = (Cl norm - Cl anur)/C(Cr), norm]. We propose to individualize drug dosage during high-flux hemofiltration by basing it on Dettli's equation and on total C(Cr) (C(Cr) tot = C(Cr) ren + C(Cr) filt). Using this approach, drug clearance will eventually be overestimated for drugs with substantial tubular secretion and for high-efficiency hemofiltration (C(Cr) tot > 30 ml/min). CONCLUSION: In patients undergoing hemofiltration, the total C(Cr) approach might be a practical alternative to standardized dosing schemes for deriving an individualized dosage from published pharmacokinetic data and functions.

Creatine↗
PubMed1998

Standardized structure and modular design of a pharmacokinetic database.

BACKGROUND: The accumulated knowledge on drugs can be used for an individual drug dosage adjustment if it is placed at our disposal in an informatically structured form. THEORY AND METHODS: We have started building up a pharmacokinetic database aimed at adjusting drug dosages, in exemplary form, to patients with renal impairment. Parameters needed for the three dosage adjustment rules (Dettli, Kunin, Holford) and the most general concept of pharmacokinetics constituted the theoretical basis. TWO PROCESSES PERTAIN TO ALL DRUGS: Distribution and elimination. Total drug clearance and at least two parameters representing distribution and elimination processes are closely interdependent in mathematical terms (clearance = volume of distribution*rate of elimination). This relation yields the unifying concept that serves as a prerequisite for a structured recording of 30 assigned pharmacokinetic and pharmacodynamic parameters within an informatic database. SOLUTIONS AND RESULTS: The information is retrieved and referenced from 2383 original publications by means of a standardized input module. The complete database at present contains 15,397 records for 1573 drugs. A programmed meta-analytic algorithm is used to calculate the statistical measures for the central value and variance--as available--from the pooled values of primary records. The statistically standardized parameters are extracted for 6601 pharmacokinetic parameters, and placed at the users disposal with the output module. PRACTICAL UTILITY: Following meta-analysis, published pharmacokinetics can be used as statistical estimates of population parameters. The statistical estimates with variances permit an individual drug dosage adjustment by applying the Bayesian approach or neural networks.

Algorithms↗
PubMed1998

Relationship between pharmacokinetic half-life and pharmacodynamic half-life in effect-time modeling.

A pharmacodynamic parameter relating time-dependent changes of the effect with time-dependent changes of concentrations has yet to be developed. In pharmacokinetics, half-lives (T1/2kin) are used to describe the relation between concentration (C) and time (t). In pharmacodynamics, often the sigmoid Emax model and the Hill equation are used (E = Emax CH/(EC50H + CH)) to describe the relation between effect (E) and concentration (C). To describe the correlation between effect (E) and time (t), a pharmacodynamic half-life (T1/2dyn) could be estimated if the use of the term half-life is not restricted only to log-linear first order processes. To bisect the drug effect a variable time (t1-2 = t2-t1) will be required for this nonlinear process. The bisection of the effect (E2 = 1/2 E1) is associated with a decrease in concentrations (C2 = C1 exp(-0.693 t1-2/T1/2kin)). A mathematical relationship can be derived between pharmacodynamic half-life (T1/2dyn = t1-2) and pharmacokinetic half-life (T1/2dyn = T1/2kin (ln (1 + ln(a)/ln(2))/H ) with (a = (EC50H + C1H)/(EC50H + C2H)). For concentrations in the range of the EC50 value with the Hill coefficient (H = 1), the pharmacodynamic half-life will be 1.6-2.0 times the kinetic half-life (T1/2dyn < or = 2.0 T1/2kin). For high concentrations (C1 > EC50), the dynamic half-life will grow much longer than the kinetic half-life, consequently the effect of a drug will not increase but it will last longer. The pharmacodynamic half-life turns out to be a specific estimate for the effect time relation, being a concentration-dependent function of the kinetic half-life.

Dose-Response Relationship, Drug↗
PubMed1998

Pharmacokinetic studies in volunteers with renal impairment.

According to Luzius Dettli, drug clearance is a linear function of renal function. The slope of this function can be predicted from the fraction of a drug that is eliminated by the renal route. Pharmacokinetics in patients with functional anuria can, however, considerably deviate from these predictions. All basic pharmacokinetic parameters depend differently and specifically on renal function: drug clearance and distribution volume depend on creatinine clearance, but elimination half-life and plasma-binding correlate better with serum creatinine. For drugs with saturable tubular secretion, it can be shown that drug clearance depends on creatinine clearance in accordance with a left-bent, convex function, but not in accordance with a right-bent, concave function. It might be reasonable to postulate that the pharmacokinetics of every new approved drug should be determined in individuals with renal impairment. For drugs with no severe risks of adverse effects, these studies can be performed in volunteers with renal impairment better than in patients.

Aged↗
PubMed1995

Aminoglycoside pharmacokinetics and -dynamics: a nonlinear approach.

A model which correctly describes the pharmacokinetic-pharmacodynamic relationship is necessary to perform a rational pharmacotherapy. This model could predict the effects under variable conditions. The prediction will provide a basis for adapting therapy to individuals. A nonlinear model should be most appropriate for describing drug effects. A new model, containing nonlinear pharmacokinetics and pharmacodynamics, is presented to describe effects of aminoglycosides on bacterial growth and accumulation in kidney tissue.

Amikacin↗