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    Evidence for improved motor function by ceftriaxone despite striatal tyrosine hydroxylase loss following nigrostriatal lesion
    (2018-03-14) Meadows, Samantha; Cantu, Mark; Bishop, Chris; Salvatore, Michael; Kasanga, Ella
    Purpose: The beta-lactam antibiotic, ceftriaxone, attenuates tyrosine hydroxylase (TH) loss in striatum in rodent Parkinson’s disease (PD) models when given early after nigrostriatal lesion. This protection may be related to the well-known properties of ceftriaxone to increase expression of the glutamate transporter, GLT-1, which increases glutamate uptake. Ser19 TH phosphorylation, which is modulated by glutamate and Ca2+-influx, increases in proportion to TH loss following nigrostriatal lesion and may predispose TH to premature degradation via the ubiquitin-proteasome pathway. Here we evaluated if ceftriaxone could partially restore striatal TH loss, concomitant with a decrease in motor impairment, when administered 1 week after lesion induction. Methods: The ability of ceftriaxone to decrease motor impairment was evaluated after evidence of motor impairment by evaluation of forepaw adjustment steps (FAS) and open-field locomotor activity. Ceftriaxone (200 mg/kg, i.p.) was given intermittently on days 7-13, 21-27, and 35-38 post-lesion. Motor function 7 days after lesion induction was used as a baseline to evaluate if ceftriaxone could reduce motor impairment out to 40 days post-lesion. Results: There was a significant increase in FAS taken, with an overall 45% increase in mean FAS post-lesion compared to the day 7 baseline. Locomotor activity (ambulatory count and total distance) increased at the end of the study (38 days post-lesion) against the day 7 baseline following ceftriaxone. [greater than] 90% striatal TH protein loss was evident regardless of whether the rats received ceftriaxone or saline injection. However, in the substantia nigra, there was a significant increase in TH expression in the side contralateral to lesion in the ceftriaxone group. Conclusion: Taken together, these results suggest that ceftriaxone-mediated protection against locomotor decline, after the establishment of a nigrostriatal lesion, may be independent of any preservation or possible restoration of striatal TH.
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    Combination Therapy with Short-Contact Topical Calcipotriene and 5-FU For Actinic Keratosis
    (2018-03-14) Moore, Angela; Nguyen, Madalyn
    Background: Actinic keratoses (AKs) are precursor lesions to squamous cell carcinoma that arise from dysplasia of keratinocytes, which is enhanced by long-term ultraviolet radiation exposure. Treatment of actinic keratoses has traditionally involved cryotherapy, or various topical therapies such as topical 5-fluorouracil (5-FU) monotherapy, or combination therapy with cryotherapy. Because of irritation with use of topical 5-FU, short-contact therapy with 5-FU in combination with cryotherapy has been reported. Vitamin D derivatives have also been reported as systemic anti-cancer agents, though clinical data for usage is limited mainly due to hypercalcemia as an adverse effect and dose-limiting factor. Recent research has suggested that topical Vitamin D derivatives such as calcipotriene may be safe and efficacious agents for the treatment of AKs. Objective: The aim of this study was to evaluate efficacy and safety of short-contact topical treatment with calcipotriene and 5-FU with cryotherapy in the treatment of AKs. Combination short-contact calcipotriene and 5-FU with cryotherapy will be compared to short-contact 5-FU with cryotherapy and cryotherapy alone to determine differences in efficacy and safety between the treatment modalities. Methods: Subjects were identified as eligible for inclusion in this study based on a clinical diagnosis of actinic keratosis and treatment with cryotherapy, 5-FU, and/or topical calcipotriene between 2016 to 2018. The patients were divided into three treatment groups: 1) short-contact combination treatment with calcipotriene and 5-FU with cryotherapy, 2) short-contact 5-FU and cryotherapy, and 3) cryotherapy alone. Patients were assessed for baseline lesions in the face, scalp, upper extremities, chest, back, and lower extremities, and again at 1 month follow-up, 3 months follow-up, and 6 months follow-up. An analysis of covariance (ANCOVA) model with terms for treatment and baseline lesion count as covariate was used to compare post-treatment lesion count between treatment groups estimated at 95% confidence intervals (95% CI). Results: Data was collected on 50 patients in each subset. After adjusting for imbalances in baseline count, a statistically significant reduction in number of AK lesions occured after 6 months of treatment with short-contact combination treatment with calcipotriene and 5-FU with cryotherapy in comparison to short-contact 5-FU with cryotherapy and to cryotherapy. The mean total lesion count at month 6 in the short-contact combination treatment with calcipotriene and 5-FU with cryotherapy was significantly lower than in the other 2 subsets. Conclusions: Addition of topical calcipotriene to short-contact combination treatment of topical 5-FU with cryotherapy may result in improved long-term outcomes for patients with actinic keratoses. Larger series must be done to confirm increased efficacy and safety.
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    Population Pharmacokinetics of Pemetrexed in Adult Non-Small Cell Lung Cancer Patients in India
    (2018-03-14) Chaturvedula, Ayyappa; Srinivasan, Meenakshi
    Purpose: Pemetrexed (PEM) is indicated for the treatment of non-small cell lung cancer (NSCLC) in combination with cisplatin. The study aimed to characterize pharmacokinetics (PK) and effects of covariates on PK of PEM using a population pharmacokinetic (PPK) approach. Methods: PPK analysis was performed using plasma samples from 85 patients following 500 mg/m2 IV infusion. The model was developed using NONMEM® (v.7.3.0). Diagnostic plots were generated with packages XPOSE and ggplot2 in R (v.3.4.2). The structural model was a two compartment model parameterized with clearance (CL), central and peripheral volume of distribution (V1 & V2), and inter-compartmental clearance (Q). Exponential error model was assumed for inter-individual variability (IIV) in PK parameters. Residual variability (RV) was modeled as combined additive (ADD) and proportional (PROP) error model. The estimation method was the stochastic approximation expectation maximization (SAEM). Standard errors (SE) and objective function value were calculated using Monte Carlo importance sampling method. Full covariate model approach was utilized by specifying clinically meaningful covariates in the model. Power model was used to describe covariate relationships. Markov chain monte carlo Bayesian analysis (BAYES) was used to compute 95% credible intervals (CI) for the posterior distribution for covariate effects. This CI was used to reduce the full covariate model by eliminating the covariates whose CI included null hypothesis. Results:Total of 850 PEM levels were used for model development. The final model included weight allometrically scaled to V1, V2 and Q. The fixed effect parameter estimates were CL-3.13 L/h; V1–5.54 L; V2–7.01 L and Q–5.42 L/h. Covariates that retained significance following BAYES CI’s- CrCl on CL, Sex on CL and Albumin on V1 with estimates of 0.52, 1.22 and -1.46 respectively. IIV on CL, V1, V2 and Q were 52%, 51%, 122% and 88% respectively. Relative SE of estimates were in the range of 10 to 43 % and 18 to 128% for fixed and random effect parameters respectively. ADD (SD) was 0.54 µg/mL and PROP RV was 29%. Goodness-of-fit plots showed no major bias in the model. VPC showed agreement between distribution of model simulated and observed data. Conclusion: PPK model for PEM in Indian subjects was successfully developed using full covariate modeling approach. The covariate relationships identified could be used to individualize dosing based on patient characteristics.
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    Evaluation of the Sensitivity of Concluding Bioequivalence Using Stochastic Simulation and Estimation
    (2018-03-14) Chaturvedula, Ayyappa; Srinivasan, Meenakshi; Fairman, Kiara
    Purpose: Single dose (SD) bioequivalence (BE) studies can fail statistical criteria by maximum concentration (Cmax). Population pharmacokinetic (PoP PK) model based simulations are used in such instances to predict steady-state (SS) concentrations to evaluate BE criteria on simulated data. We evaluated the sensitivity of such PoP PK model based method to find true formulation differences in a simulation study. Methods: Stochastic simulation and estimation (SSE) method was applied. The structural model was a one compartment model with 1st order absorption. An exponential error (15% CV) for between subject variability and proportional error (15% CV) model for residual variability was assumed. PK studies (n=200) having 1000 virtual subjects dosed with test and reference formulations were simulated with NONMEM® software (v. 7.3.0) for SD and SS. The rate of absorption (Ka, hr-1) parameter varied between test and reference formulations to simulate passing and failing PK profiles for BE criteria. Different Ka combinations for test and reference formulations include 0.1/1, 0.2/1, and 0.5/1.5. Simulated PK profiles were analyzed using PKNCA (v. 0.8.4) package in R (v 1.0.143) software to conduct a non-compartmental analysis and iterated 200 times. The resulting Cmax and AUC were assessed using the Welch 2-sample t-test function to conclude BE. A 90% confidence interval of AUC and Cmax falling between 0.8-1.25 was set a priori as BE criteria. Lastly, the sensitivity of the PoP PK model based simulation method for concluding SD and SS based BE conclusion was calculated from 200 independent simulated studies. Results: Bioequivalent formulations of SS and SD that were designed by same absorption rate parameter met BE criteria set a priori for Cmax and AUC. Varying Ka parameters between test and reference formulations, with Ka combinations of 0.1/1 and 0.2/1, only failed BE criteria for Cmax on SD. The Ka parameter combination 0.5/1.5 did not result in failed Cmax on SD and is not considered as true failed criteria by design. Of the 200 simulated datasets in the fail BE criteria by design on SD, all of them passed the a priori BE criteria for Cmax for SS simulations. Conclusion: The PoP PK model based simulation method may not be sensitive to study BE of Cmax at SS after initial failure of two SD drug formulations. True differences in the formulation Ka cannot be detected in SS simulations. The method is still applicable for concluding the clinical relevance SS Cmax.