Browsing by Author "Wu, Lei"
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Item Clinical Pharmacokinetics of Intranasal Scopolamine for Space Motion Sickness(2014-12) Wu, Lei; Chow, Diana Shu-Lian; Putcha, Lakshmi; Tam, Vincent H.; Ghose, Romi; Liang, DongPurpose and Specific Aims: Space Motion Sickness (SMS) is a neurovestibular disturbance experienced by astronauts in microgravity environment, which causes acute symptoms and discomfort requiring treatment with medications during the early, mission critical time of space flight. Scopolamine (SCOP) is a historically known belladonna alkaloid used as an anticholinergic/antiemetic agent for a long time. It is a very common prescription medication for the prevention of nausea and vomiting associated with motion sickness. Earlier reports indicate that scopolamine is the most effective drug for suppressing nausea and vomiting caused by motion sickness. Bioavailability after oral administration of scopolamine is low and variable, and absorption from transdermal patch is slow and prolonged. Since the limitations of oral and other formulations of scopolamine, Pharmacotherapeutics Laboratory of Johnson Space Center developed a gel intranasal dosage form of scopolamine (INSCOP) and the bioavailability were evaluated under the Food and Drug Administration guidelines for phase I clinical trials with an Investigation New Drug (IND) application. Results showed that intranasal administration scopolamine achieves significantly higher and more reliable absolute bioavailability (83% vs 3.7%, p < 0.05). The proposed research focuses on the clinical pharmacokinetics of intranasal Scopolamine used for the treatment of space motion sickness. The data used in this study have been collected in two Phase II IND clinical trials in healthy human subjects with an overall goal of developing a new formulation of scopolamine which is a rapidly acting, efficacious and safe, , countermeasure for the treatment and prevention of space motion sickness in astronauts. The proposed specific aims are to; (1) establish PK of INSCOP with three escalating dose levels of 0.1, 0.2 and 0.4 mg; (2) estimate bioavailability of 0.2 and 0.4 mg doses of INSCOP during ambulation and simulated microgravity, Antiorthostatic Bed Rest, respectively; and (3) characterize the relationship between scopolamine concentrations in plasma, saliva and urine using co-modeling techniques. Methods: Aim 1: PK parameters were calculated by Winnonlin using data collected in a dose escalation pharmacokinetics (PK) study with twelve (6 male and 6 female) healthy subjects after administration of three escalating doses 0.1, 0.2, and 0.4 mgof the Investigational New Drug (IND) formulation of INSCOP administered in a completely randomized, double-blind cross-over study design. Aim 2: A Phase II, “Randomized, Double-Blind, and Bioavailability Study of Intranasal Scopolamine in a Simulated Microgravity Environment” were established with two dose level (0.2 and 0.4 mg) in 12 normal healthy subjects (6 male/ 6 female). Aim 3: Data from 24 subjects from the above two studies were used for PK modeling using Phoenix NLME Software. Concentrations of scopolamine in plasma, saliva and urine collected were determined using a modified LC-MS/MS method. PK parameters were derived by Phoenix WinNonlin. SAS program was used to perform statistical analysis. Results: Aim 1: Dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range (0.1mg-0.4mg). Plasma drug concentrations were significantly higher in females than in males after administration of 0.4 mg dose. Aim 2: The absorption and bioavailability of INSCOP were not changed during the microgravity environment which means that the microgravity condition does not change the pharmacokinetics of INSCOP in human. Aim 3: The relationship among scopolamine concentrations in plasma, saliva and urine was satisfactorily described by a validated compartmental PK model and for the first time it satisfactorily predicted PK of INSCOP in plasma, saliva and urine. Conclusion and Significance: Results of this study have a significant clinical implication in understanding the PK of intranasal scopolamine in astronauts as well as terrestrial populations receiving INSCOP for the treatment of motion sickness. Results presented here demonstrate that (1) absorption and bioavailability appear to be linear with respect to administered dose range (0.1-0.4 mg); (2) the impact of sex difference on pharmacokinetics of INSCOP was observed at high dose level of 0.4mg, indicating sex had significant influences on the clearance and volume distribution of scopolamine after IN administration; (3) Absorption and bioavailability are not significantly affected in the simulated microgravity condition; (4) PK model for scopolamine was developed which satisfactorily predicted the PK of INSCOP in plasma, saliva and urine. . Therefore, our findings support the clinical utility of INSCOP for the treatment of space motion sickness for astronauts.Item Performance Analysis of Blockchain and Smart Contracts(2017-12) Gao, Zhimin 1986-; Shi, Weidong; Chen, Guoning; Huang, Stephen; Wu, LeiBlockchain, or distributed ledger, provides a way to build various decentralized systems without relying on any single trusted party. It is especially attractive for smart contracts that different parties do not need to trust each other to have a contract, and the distributed ledger can guarantee correct execution of the contract. Several factors, such as low throughput and high latency, have already affected the performance of blockchain and smart contract system significantly. They also impede innovation and development of blockchain. For example, most existing distributed ledger and smart contract systems process smart contracts in a serial manner, i.e., all users have to run a contract before its result can be accepted by the system. Although this approach is easy to implement and manage, it is not scalable and greatly limits the system's capability of handling a large number of smart contracts. In order to address this problem, we propose a scalable smart contract execution scheme that can run multiple smart contracts in parallel to improve the throughput of the system. We also design a novel scheme to reduce the latency of blockchain creation by dividing the block mining period into two steps. Then, a mathematical model is introduced to discuss more about the scalability of blockchain and smart contracts. We utilize the concept of Nash equilibrium and game theory to prove that the system will scale up autonomously under some conditions. Finally, we discuss a hardware-based scheme to improve the performance of blockchain and smart contracts.Item Pharmacokinetic Modeling of Vincristine and Its Metabolite in Kenyan Pediatric Cancer Patients(2023-04-13) Cornett, Taylor; Dai, LuThe CYP3A5 enzyme more efficiently metabolizes VCR to its M1 metabolite than the CYP3A4 enzyme as reported by Renbarger. CYP3A5 expression varies among Kenyans (90%), African Americans (AA, 70%), and Caucasians (10-20%). In order to dose the patients rationally among the different ethnicities, the pre-requisite is to comprehensively understand the pharmacokinetic (PK) disposition of VCR and M1, as well as the conversion kinetics from VCR to M1. Seventy-seven Kenyan pediatric cancer patients with 9 types of cancers, Acute Lymphoblastic Leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, Wilm's Tumor, Retinoblastoma, Rhabdomyosarcoma, Hepatoma, Teratoma, and Neuroblastoma were recruited. Dried blood spot (DBS) samples of the Kenyan pediatric patients after an IV dose of VCR (0.9-2.2 mg/m2) were collected via finger stick at various time points depending on the feasibility. The PK co-models of VCR and M1 metabolite were developed, and PK parameters were derived for individual subjects. Using Phoenix NLME 8.0, model discrimination was performed by minimizing the Akaike Information Criteria (AIC) values and visual comparisons of the quality of fitness of the plots. The PK parameters were derived from the best fit Pk model. Large interpatient variability was observed. In conclusion, the feasibility study demonstrated that the current clinical protocol is suitable for the Phase 1 trial. In addition, the establishment of the PK co-models with Vincristine and M1 metabolite enables the derivation of conversion rate constant from VCR to M1 and elimination kinetics of VCR and M1 for individual subjects among the various types of tested cancers. ***This project was completed with contributions from Lorita Agu from Syntarat, Lei Wu from AbbVie Pharmaceuticals, and Jodi L. Skiles, Andrea R. Master, and Jamie L. Renbarger from the Indiana University School of Medicine.