Epoetin theta: efficacy and safety of subcutaneous administration in anemic pre-dialysis patients in the maintenance phase in comparison to epoetin beta.

OBJECTIVE: To compare the efficacy and safety of epoetin theta and epoetin beta in anemic patients with chronic kidney disease (CKD) not yet receiving dialysis and previously on stable maintenance therapy with epoetin beta. METHODS: In this multicenter, randomized, controlled, double-blind, non-inferiority study, 288 patients were treated subcutaneously (s.c.) for 24 weeks with epoetin theta (n = 193) or epoetin beta (n = 95). The primary efficacy endpoint was change in hemoglobin (Hb) from a 2-week baseline period to end of treatment (12-week efficacy evaluation period [EEP], weeks 15-26). The non-inferiority limit was 1.0 g/dL (2-sided alpha = 0.05). Weekly doses of epoetin required to maintain Hb levels, dose changes, safety, tolerability, and immunogenicity were also evaluated. CLINICAL TRIAL REGISTRATION: EudraCT No. 2005-000142-37. RESULTS: Mean Hb values were comparable in both groups at baseline and during the 24-week treatment period. The estimated treatment difference between groups from baseline to EEP was 0.01 g/dL (95% confidence interval: -0.20, 0.22; p = 0.9207 (ANCOVA)), indicating that epoetin theta was non-inferior to epoetin beta. The weekly doses of epoetin theta or epoetin beta were nearly the same and the change from baseline to EEP in patients who switched to epoetin theta (36.6 to 30.0 IU/kg(BW)) was comparable to those continuing epoetin beta therapy (37.7 to 28.3 IU/kg(BW)). The profile and the frequency of adverse drug reactions (ADRs) were comparable in both groups (17.1% epoetin theta; 14.7% epoetin beta). The most common ADR was hypertension. No patient developed anti-erythropoietin antibodies. CONCLUSIONS: Epoetin theta (s.c.) has efficacy comparable with epoetin beta (s.c.) in pre-dialysis patients with renal anemia based on Hb changes from baseline to end of treatment (non-inferiority). The safety profile was also comparable. Patients could be switched from maintenance treatment with epoetin beta to epoetin theta without relevant dose changes.

Rearing conditions differentially affect the locomotor behavior of larval zebrafish, but not their response to valproate-induced developmental neurotoxicity.

Zebrafish (Danio rerio) are widely used in developmental research, but still not much is known about the role of the environment in their development. Zebrafish are a highly social organism; thus exposure to, or isolation from, social environments may have profound developmental effects. Details of rearing conditions are often sparse in the zebrafish literature. This study compared (1) the activity of larval zebrafish that were raised individually vs in groups, and (2) the effect of the developmental neurotoxicant valproate. We randomly assigned embryos to single- or group-reared social environments from 0 to 5days post fertilization (dpf), while treating them with or without valproate (final concentration 48µM) from 0 to 2dpf, resulting in a total of four groups (group control, group treated, single control, single treated). At 5dpf all embryos were transferred to singly-housed environments where they remained for locomotor activity testing (alternating periods of light and dark) conducted on day 6. Larvae that had been reared in groups had higher levels of activity in the dark period compared to larvae that had been raised individually. Valproate increased activity in both the singly-reared and group-reared larvae during periods of darkness but not light. Further analyses of dark activity indicated that rearing condition did not differentially affect larval responses to valproate. These results indicate that rearing conditions affected the locomotion of zebrafish larvae, but did not alter the effect of the developmental neurotoxicant valproate.

Large Salmonella Enteritidis outbreak with prolonged transmission attributed to an infected food handler, Texas, 2002.

In March 2002, an outbreak of Salmonella Enteritidis (SE) infections occurred at a convention centre in Dallas, Texas and continued for 6 weeks. We conducted epidemiological studies, obtained clinical and environmental cultures, and interviewed employees to identify risk factors for infection. From 17 March-25 April 2002, the implicated hotel kitchen catered 41 multi-day conferences attended by 9790 persons. We received 617 illness reports from residents of 46 states. Sauces or items served with sauces were implicated in three cohort studies. SE phage-type 8 was identified as the agent. Eleven food service employees, including one who prepared sauces and salsa, had stool cultures that yielded SE. Although the original source was not determined, prolonged transmission resulted in the largest food handler-associated outbreak reported to date, affecting persons from 46 US states. Transmission ended with implementation of policies to screen food handlers and exclude those whose stool cultures yielded salmonellas.

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.

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.

A SAS macro for sample size re-estimation.

The assessment of sample size in clinical trials comparing means requires a variance estimate of the main efficacy variable. If no reliable information about the variance of the key response is available at the beginning of a clinical trial, the use of data from the first 'few' patients entered in the trial ('internal pilot') may be appropriate to estimate the variance and thus to recalculate the required sample size. A SAS macro that implements the EM algorithm for carrying out and simulating such interim power evaluations without unblinding the treatment status is presented.

Blastic transformation of splenic marginal zone B-cell lymphoma.

To our knowledge, blastic transformation of splenic marginal zone lymphoma, a recently characterized low-grade lymphoproliferative disorder, has not been reported previously. In this regard, we report the unique case of a 70-year-old woman whose untreated splenic marginal zone lymphoma underwent blastic transformation 3 years after diagnosis. Her hematologic medical history started in 1988 as thrombocytopenia refractory to steroids associated with atypical lymphoid infiltrate in the bone marrow. She underwent splenectomy in 1989, which revealed splenic marginal zone lymphoma. One year later, the patient developed lymphadenopathy noted in the chest, axillary, abdominal, and retroperitoneal lymph nodes. Because she was asymptomatic, treatment was limited to a conservative supportive regimen. The nodal lymphoma cells had features associated with marginal zone lymphoma and expressed B-cell monotypic kappa light chain. She was readmitted for the last time 2 years later with findings of 16% blasts in the peripheral blood and massive infiltration of the bone marrow by large blastoid cells. The blasts showed dispersed chromatin and prominent nucleoli, and possessed a moderate amount of clear cytoplasm. The blasts, like the previous nodal and splenic lymphomas, had a CD20-, CD19-, IgM-positive phenotype, but lacked reactivity for CD5, CD10, and CD23. The patient displayed clinical remission after treatment with vincristine and prednisone, but died of aspiration pneumonia 1 month later. These observations suggest that, similar to the other low-grade lymphoproliferative disorders, an untreated splenic marginal zone lymphoma may undergo high-grade blastic transformation.

Evaluation of IGF system component levels and mitogenic activity of uremic serum on normal human osteoblasts.

To test the hypothesis that impairment in bone formation in renal osteodystrophy in adults with chronic renal failure (CRF) might be mediated in part by alterations in circulating levels of the insulin-like growth factor (IGF) system components, we compared serum levels of IGF-I, IGF-II, IGF-binding protein (IGFBP)-3, IGFBP-4 and IGFBP-5 in adults with CRF (CRF patients with parathyroid hormone (PTH) < 100 pg/ml, PTH > 300 pg/ml and end-stage renal failure (ESRF) patients) versus age-matched controls. To evaluate the biological significance of alterations in circulating level of IGF system components, we compared the mitogenic activity of the sera on proliferation of normal human osteoblasts in vitro by using [(3)H]thymidine incorporation. We found severalfold increased serum levels of IGFBP-3 (2-fold), IGFBP-4 (5-fold) and slightly increased IGF-II levels in ESRF patients as well as a 2.6-fold increase in free IGF-I in CRF patients with PTH < 100 pg/ml. The mitogenic activity was found to be increased in serum of kidney failure patients compared to controls. This was most pronounced in CRF patients with PTH < 100 pg/ml showing also a significant increase in free IGF-I and the lowest levels of the IGF-inhibitory IGFBP-4. Our data support the hypothesis that alterations in serum levels of stimulating (i.e. free IGF-I) and inhibitory IGF system components (i.e. IGFBP-4) may influence osteoblastic cell proliferation in renal osteodystrophy.

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.

Food liking and craving: A cross-cultural approach.

Spanish and American participants rated how much they liked three common sweets and three common beverages listed on a questionnaire. They also named the food or drink for which they had the strongest craving. Cross-cultural comparisons in liking were almost always consistent with cross-cultural comparisons in rates of exposure. In both cultures, among subjects whose cravings could be so classified more females (about 5/8) craved sweet foods than savories and more males (about 5/8) craved savories than sweets. Among sweet cravers, chocolate craving was much more frequent for American females (44.6%) than for American males (17.4%), but no such gender difference occurred for the Spaniards (28.6 and 22.2%). The results argue for a possible physiological basis for the gender differences in sweet/savory craving but against a physiological basis for chocolate craving.

Incidence of analgesic nephropathy in Berlin since 1983.

BACKGROUND: Phenacetin was removed from the German market in 1986 and was replaced mainly in analgesic compounds by acetaminophen. Our objective was to examine the effect of this measure on the incidence of analgesic nephropathy in light of the changes in other end-stage renal diseases. METHODS: We therefore compared the proportion of renal diseases in all patients starting dialysis treatment during three 18-month periods: 4/1982-9/1983 (n=57); 1/1991-6/1992 (n=81); and 10/1995-3/1997 (n=76). RESULTS: On the one hand, the proportion of end-stage analgesic nephropathy decreased significantly from 30% in 1981-1982 to 21% in 1991-1992 and 12% in 1995-1997 (P=0.01). On the other hand, type II diabetes increased significantly from 7% to 22% (P=0.01) and 29%, (P=0.001). Using the chi2 distribution test to analyze the frequencies of seven diseases at three different time intervals, however, showed that the changes in renal-disease proportions between 1982-1983, 1991-1992 and 1995-1997 were not significantly independent. There was a significant median age increase from 52 years (CI0.95 44-58) in 1982-1983 to 63 (CI0.95 55-67) in 1991-1992 and 63 (CI0.95 60-66) in 1995-1997 (P=0.003) for all patients starting dialysis but not for those with analgesic nephropathy [59 (55-71) vs 64 (53-67) and 61 (50-72); n.s.]. CONCLUSION: The decrease of end-stage analgesic nephropathy since 1983 may be partially due to the removal of phenacetin from the German market in 1986. However, considering the general increase in numbers of dialysis patients, their higher age and the increased incidence of type II diabetes, the decrease in analgesic nephropathy is not a statistically significant independent variable. Altered admittance policies for dialysis treatment have yielded a new pattern of renal-disease proportion which interferes with changes in the incidence of analgesic nephropathy.

The effect of color intensity and appropriateness on color-induced odor enhancement.

Coloring solutions has been shown to increase perceived odor intensity. In Experiment 1, subjects rated the odor intensity of red strawberry and green mint solutions that had four levels of color intensity. Ratings of strawberry odor peaked at the medium color intensity and ratings of mint odor increased monotonically with color intensity. Thus, color-induced odor enhancement can increase with increasing color intensity but need not. Experiment 2 found that the color intensities producing maximum odor enhancement in Experiment 1 are not always the ones perceived as most appropriate for the odorants. Using different odors, Experiment 3 found that color intensity has some influence on the strength of the color-induced odor enhancement and color appropriateness has little. The presence or absence of color in the solution seems to be the most important variable.

Synthesis of pharmacokinetic parameters of vancomycin via bootstrap methods.

OBJECTIVE: For the adjustment of individual vancomycin dosages, we estimate the important pharmacokinetic quantities half-life, clearance, and volume of distribution. MATERIAL: To obtain reliable information 293 observations from 244 patients were extracted from 23 published studies on vancomycin. Information about vancomycin's pharmacokinetics out of different sources represents an increase in sample size and, therefore, interpretive power. METHODS: Once the whole of the data had been stratified into a small number of homogeneous clusters based on cofactors, different (robust) estimators (mean, median, Winsorized, and trimmed mean) were calculated for the expected value of the pharmacokinetic parameters of vancomycin within the clusters. Measures of the statistical accuracy such as standard error, bias, mean square error, and confidence interval were estimated via bootstrap methods from large bootstrap sample sizes to compare the quality of the estimators. RESULTS: Due to the homogenization of the data all individual estimator functions yield very similar results and the empirical mean works fairly well as an estimate. The most frequently used estimator with the smallest estimated mean square error was the Winsorized mean.

Dependence of vancomycin clearance on renal function via regression and bootstrap methods.

BACKGROUND: Frequently, the estimation of vancomycin on the basis of renal function is too rough because the unknown parameters of a regression function between the vancomycin clearance (CL) and the creatinine clearance (ClCR) are based on small sample sizes. OBJECTIVE: In this study we aim to compare linear and nonlinear regression, spline interpolation and nonlinear kernel estimation for defining the relationship between measured Cl and ClCR. METHOD: We used data from published papers and appropriate numerical methods. The variability and accuracy of the estimated regression functions were determined from bootstrap methods and kernel density estimators. Tests to prove the usually assumed linearity of the regression were carried out and the influence of patient age and weight on Cl was determined. RESULTS: A linear relationship reported by several authors earlier has been determined as ClVAN = 0.763 ClCR + 2.715, (ml/min) (Cl = 0.011 ClCR + 0.055, (ml/min/ kg)). CONCLUSION: Nonparametric regression analysis shows that a nonlinear approximately parabolic function could fit the relationship between Cl and ClCR in the present case somewhat better than a linear function.

Risk of thromboembolic events in patients with atrial flutter.

Based on multiple studies, clear, guided anticoagulation therapy is recommended for patients with atrial fibrillation. The value of anticoagulation therapy in patients with atrial flutter, however, is less well established. Little is known about the incidence of thromboembolism in patients with atrial flutter. We evaluated the risk of thromboembolism in 191 consecutive unselected patients referred for treatment of atrial flutter. A history of embolic events was noted in 11 patients. Acute embolism (<48 hours) occurred in 4 patients (3 after direct current cardioversion, 1 after catheter ablation). During follow-up of 26+/-18 months, 9 patients experienced thromboembolic events. During the follow-up, the overall embolic event rate (including acute embolism and thromboembolic events during follow-up) was 7 % in this patient population. Risk indicators for an embolic event in an univariate analysis were organic heart disease (p = 0.037), depressed left ventricular function (p = 0.02), history of systemic hypertension (p = 0.004), and diabetes mellitus (p = 0.0038). Using multivariate analysis, a history of hypertension was the only independent predictor for elevated embolic risk in this patient population (odds ratio = 6.5; 95% confidence intervals 1.5 to 45). Thus, the thromboembolic risk is higher than previously recognized for patients with atrial flutter. Anticoagulation therapy may decrease this risk.

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.

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.

Dosage adjustment of antiinfective therapy in patients with renal impairment.

Schematic dosage adjustments for aminoglycosides, vancomycin, and ciprofloxacin were derived from published data on the prolongation of elimination half-lives in patients with renal impairment. Therapeutic drug monitoring was retrospectively evaluated with 84 severely ill patients, 29 of whom needed renal replacement therapy (35%). Mortality (n = 27) and antiinfective failures were high (n = 23). Toxicity was suspected in 5 patients, though it was demonstrated only in 1 case. As compared to the patients with normal renal function, patients with renal impairment exhibited peak levels that tended to be lower, although their trough levels tended to be higher; the aminoglycoside troughs even were significantly elevated in renal replacement patients (1.0 mg/l (0.6-1.4) versus 0.6 mg/l (0.3-0.8)). Seen in relation to toxicity, antiinfective failure was by far the greater problem even with dosage adjustments at high trough levels. Multivariate analysis showed antiinfective failure to be significantly correlated to 10 canonical variables (age, weight, leucocyte count, peak level, trough level, initial creatinine, increase in creatinine, fever, change of dosage, and renal replacement therapy). Among these variables, it were neither drug levels nor renal replacement, but only persistent fever and deteriorating renal function that independently contributed to antiinfective failure. For adjustment of antiinfective therapy, paradoxically we conclude that trough concentrations higher than normal must be allowed for to avoid underdosage in renal replacement patients.

Structured data entry for reliable acquisition of pharmacokinetic data.

A pharmacokinetic database was constructed that is as free of errors as possible. Pharmacokinetic parameters were derived from the literature using a text-processing system and a database system. A random data sample from each system was compared with the original literature. The estimated error frequencies using statistical methods differed significantly between the two systems. The estimated error frequency in the text-processing system was 7.2%, that in the database system 2.7%. Compared with the original values in the literature, the estimated probability of error for identical pharmacokinetic parameters recorded in both systems is 2.4% and is not significantly different from the error frequency in the database. Parallel data entry with a text-processing system and a database system is, therefore, not significantly better than structured data entry for reducing the error frequency.