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Wiesen sex

Zachariah Nathaniel Wiesen, 19, Spink St. He was indicted on a charge of unlawful sexual conduct with a minor.

Wiesen Sex

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Therapeutic sex is typically a process by which sexual contact and intimacy are used as therapeutic treatment for a variety of emotional or psychological issues. This type of practice can be fairly controversial, however, especially when used by a therapist with his or her client. Human sexuality is certainly an important element in mental health, though the way in which sex can be used to help someone who may be dealing with certain issues is debatable.

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Blood ; 14 : — Concentration-time data were fitted into an open 2-compartment model and total clearance, central compartment volume, intercompartment clearance, and volume of distribution at steady-state Vd ss were investigated. Total clearance was 9. Rituximab clearance was reduced 8. Body weight also affected Vd ss 0. A sex-dependent effect and the higher weight of males wiesen sex to their faster rituximab clearance, which might explain why elderly males benefit less from the addition of rituximab to CHOP than females.

This trial was registered on www. However, despite its widespread use in DLBCL, there are only scarce data on serum levels and pharmacokinetic patterns of rituximab in aggressive B-cell lymphoma.

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This practice carries the risk of suboptimal dosing and therefore may not exploit the whole therapeutic potential of rituximab. However, rituximab has a complex pharmacology that is thus far only partially understood. Based on the pharmacokinetic data obtained from this study, we performed simulations with various dosing intervals and dose-escalation protocols.

In brief, patients years of age with ly untreated and biopsy-confirmed DLBCL were eligible for the study. Patients with a diagnosis or history of indolent lymphoma or other malignancies, HIV infection, or marked impairment of organ or BM function were excluded. In the Pegfilgrastim trial, patients received a second randomization into pegfilgrastim on day 2 versus day 4.

Patients who were randomized to receive rituximab were asked to participate in the pharmacokinetic study. The study was conducted in accordance with the Declaration of Helsinki and the study protocol was approved by the ethical review committee of each participating center.


All participating patients ed an additional informed consent specific for the pharmacokinetic protocol. Ten minutes before and 10 minutes after each rituximab infusion, 10 mL of blood was drawn from each subject to obtain rituximab trough wiesen sex peak serum levels. Additional samples were taken 1 week and 1, 2, 3, 6, and 9 months after the last rituximab infusion, respectively. Whereas pre-dose samples were drawn from the indwelling venous catheter, postdose samples were drawn from a different catheter or, ideally, from a venous puncture at the contralateral side.

Rituximab serum levels were determined by Xendo Laboratories. Briefly, rituximab serum levels were measured by ELISA using microtiter high protein-affinity well plates coated with a polyclonal goat anti-rituximab Ab as described ly. Bound peroxidase was then visualized by a chromogenic reaction and rituximab was quantitated using absorbance spectrophotometry with a known standard curve of rituximab.

All study samples were analyzed in duplicate at a minimal dilution of fold. The mean value was then used for pharmacokinetic analysis.

The validated upper and lower limits of quantitation for fold—diluted samples were and If study samples did not meet this criterion, then they were considered as outliers and were excluded from the analysis. Based on this subroutine, the corresponding pharmacokinetic parameters Cl, central volume V 1intercompartmental clearance Qand Vd ss were calculated.

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Half-lives corresponding to the exponents for the constants of disposition were calculated as follows:. For prediction of plasma rituximab concentrations and pharmacokinetic parameters, a population approach was used.

In the first step of model building, a 2-compartmental model was developed as a basic structural model without covariates, but including an interindividual variability on pharmacokinetic parameters. An exponential error model was chosen for the interindividual variability of the kinetic parameters according to the following equation:. A proportional error model was used for the residual variability to describe the deviations between the model predictions and the plasma rituximab concentrations:. Fitting was performed with the first-order conditional estimates algorithm, not taking interactions between the parameters into first-order conditional expectation.

A decrease in the objective function of more than 3. Goodness-of-fit plots and improvement within the basic model.

Shown is an overview of the goodness-of-fit plots and the improvement of the basic model for rituximab after implementation of covariates WT and sex. The solid line indicates the line of identity.

Top graph shows the predicted Pred versus the observed concentrations DV. The bottom graph shows population model predictions versus wiesen sex residuals of the population model. Stability of the final pharmacokinetic model parameters was evaluated particularly with regard to a bootstrap analysis generating a total of successfully replicated dataset runs using the PLTTools software package, a graphical interface for the NONMEM system. Comparison of the alternative structural model and implementation of covariates to the final model were based on goodness-of-fit plots.

A visual predictive check served as an additional instrument for the evaluation of observed and predicted data. Pharmacokinetic data were obtained from 20 11 female and 9 male patients. There was no correlation between renal and hepatic function and rituximab serum levels within sexes and no differences in renal and hepatic function between the male and female patients included in this pharmacokinetic study Table 1.

None of these patients had a concomitant medication compromising hepatic or renal function. Blood samples were collected between January and June Patients received an absolute median dose of mg range, of rituximab per cycle.

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Trough rituximab serum levels increased over the entire 8 R-CHOP cycles, indicating a rituximab serum accumulation, and a plateau was not reached until the eighth and last application Figure wiesen sex and Table 2. After completion of therapy, serum levels decreased continuously, and 9 months after the last cycle, rituximab levels approximated baseline values but remained detectable in 9 of 10 evaluable patients. LBMc indicates lean body mass corrected.

To explore the effects of a dose-dense R-CHOP with a day interval of rituximab application on serum levels, a rituximab population-based pharmacokinetic simulation was performed using a 2-compartment model that allowed an adequate characterization of rituximab disposition in all patients.

Subsequently, the individual models were combined and a model for the mean pharmacokinetic parameters was adapted Table 3. Steady-state concentrations were not reached because of this relatively long elimination half-life Figure 2.

The coefficient of variation for residual variability was Body weight showed also an impact on volume of distribution 0. Sex and weight independently affected rituximab clearance and serum elimination half-life, respectively.

Conversely, the serum elimination half-life is 18 days and 30 days, respectively, in these 2 sample patients Table 4. Finally, the model for the standard-dose rituximab dose-dense day cycle was then varied by changing the cycle duration to 21 days R-CHOP The model showed a markedly slower increase of rituximab trough levels Figure 4. The model was then calculated for day intervals. The clinical impact of sex of the patients is shown in Table 5. This demonstrates that female patients, with their slower clearance and longer serum elimination half-life of rituximab, benefit considerably more from the addition of the CD20 Ab.

Weight also affected outcome Figure 5. Whereas rituximab is supposed to be degraded in the liver and other organs by a process of nonspecific catabolism, 5little is known about the mechanisms of rituximab metabolism and wiesen sex. Population-pharmacokinetic information about rituximab is available from only a few studies performed in different patient populations: in patients with rheumatoid arthritis, 17 in 8 patients with mostly indolent non-Hodgkin lymphoma, 14 and 10 patients with mostly DLBCL.

A comparison of our study with the pharmacokinetic of studies is shown in Table 6.

Comparison of pharmacokinetic parameters of rituximab referring obtained in studies with a population approach. Based on a 2-compartmental nonlinear, mixed-effects, population pharmacokinetic approach, a V c of 3. The pharmacokinetics of rituximab was appropriately described by a 2-compartmental model in our study, confirming ly published studies Table 6even though different subroutines for population analysis were used.

Evaluation of the final model was performed with a bootstrap analysis replicates. The wiesen sex population parameters obtained after bootstrap analysis were nearly identical to the parameter estimates generated after a single run of the original dataset because of the high stability of the developed model Table 3. In DLBCL, a rapid tumor control is critical to improving outcome because tumors becoming refractory have a poor prognosis, 18 particularly when pretreated with rituximab. In the present study, all patients with DLBCL received 8 dose-dense rituximab cycles and the median serum levels increased slowly and no plateau was reached over the entire 8 applications.

Interestingly, we found a rituximab half-life of 27 days in the whole study population, and in 9 of 10 evaluable patients, rituximab serum levels were detectable 9 months after the last infusion. In a study by Berinstein et al, the estimated half-life of rituximab was considerably shorter, but it increased from 3 days after the first cycle to 8. This difficult-to-explain prolonged half-life and long persistence of measurable rituximab serum levels were speculated to be because of the therapy-induced reduction of tumor mass and saturation of CDbinding sites, because serum rituximab levels were inversely correlated with both tumor bulk and the of circulating B cells at baseline.

Other studies have found similar. Our observation that rituximab serum levels are independent of tumor mass are in agreement with a study by Mangel wiesen sex al in mantle cell lymphoma in which the level of rituximab exposure was similar in patients with minimal disease states and patients with active disease.

The pharmacokinetics of an mAb depends on a variety of factors, such as the dose and frequency of administration, the metabolic turnover of the Ab, its distribution in the body, and its specific and unspecific clearance. In contrast, unspecific clearance, such as that caused by binding to Fc receptors, might depend on other factors such as the binding affinity of rituximab to distinct Fc receptor genotypes. It was concluded that the pharmacokinetic behavior of rituximab was not altered despite the treatment-induced tumor mass reduction. The determined rituximab half-life in that trial was 21 days.

Whereas age within the range of years, which was an inclusion criterion for the RICOVER and Pegfilgrastim trials did not influence pharmacokinetic parameters of rituximab in our study, it can only be speculated whether our can be generalized to other populations with DLBCL eg, young patients until data specifically obtained from these subpopulations is available. The most important finding of our study is that clearance is strongly and independently influenced by a patient's sex and, when rituximab dose is adjusted to body surface area, by weight.

Clearance was ificantly reduced in the female patients included in this study and was 1. These are similar to the findings of Ng et al using a population approach of rituximab in patients with rheumatoid arthritis. This discrepancy, however, can be explained by the fact that patients in our study received a rituximab dose calculated according to body surface area, whereas patients received a fixed total dose of mg of rituximab in the Ng et al study.

Clinically relevant sex wiesen sex in pharmacology have been described to date in only a few investigations. In one study, the pharmacokinetics of anti-D Ig kDwhich is comparable to rituximab with respect to chemical characteristics and molecular weight, was investigated for sex differences in healthy volunteers.

That rituximab pharmacokinetics might also have an impact on outcome when combined with chemotherapy regimens other than CHOP is suggested by a recent observation of patients with relapsed DLBCL, in whom rituximab maintenance treatment had a beneficial effect in younger years of age females, but not in wiesen sex.