Dissertation (Ph.D.)--University of Michigan.

<p> The ability of chitosan and tripolyphosphate to form an ionic crosslinked material and its effectiveness in sustained release formulations has been reported. However, key issues commonly observed with these formulations include inefficiencies and inaccuracies in the drug loading as well as an inability to achieve complete release of drug. Acetaminophen, as a model drug, was added to various chitosan-tripolyphosphate crosslinked powders to assess the sustained release characteristics when drug is added extragranularly as opposed to during the crosslinking process, which is the most common procedure for drug addition in prior literature. The influence of various process and formulation variables including chitosan concentration, chitosan:tripolyphosphate ratio, temperature, ionic strength, and pH was assessed. Design of experiments allowed the identification of factors and two factor interactions that have significant effects on particle size and size distribution, yield, zeta potential, true density, and drug release. Statistical model equations were successfully used to manufacture optimized chitosan-tripolyphosphate crosslinked powders with various properties for further evaluation. Analysis of the compressibility of the optimized powders revealed that the crosslinked powders had enhanced compression properties when compared to chitosan powder. Environmental scanning electron microscopy revealed a correlation between the rigidity and density of the powders and corresponding capabilities for enhanced sustained release. Analysis of the moisture sorption and desorption isotherms from dynamic vapor sorption analysis revealed various types and levels of water present and a correlation between the quantity of water internally absorbed during sorption and desorption and sustained release capability. Chitosan-tripolyphosphate crosslinked powder can be manufactured with optimized properties that allow desired sustained drug release profiles while simultaneously serving as the primary diluent for solid oral dosage forms.</p><p>

<p> The aims of this research was to evaluate the partial crystallinity of two BCS class II drugs (Ketoconazole and Chlorpropamide) when prepared as solid-dispersions with three viscosity grades of Ethyl -Cellulose (EC7, EC45, or EC100 cP). Two processes were explored for preparing the dispersions; namely, spray drying, and, co-precipitation induced by non-solvent addition. The partial crystallinity of the formulations was evaluated using Differential Scanning Calorimetry, with crystal enthalpy values of 103.4 J/G for Ketoconazole and 98.8 J/G for Chlorpropamide (from literature). Both formulation processes yielded free-flowing white powders with a size range of 3 to 49 &mu;m. Control formulations with no EC content showed crystal enthalpies ranging from 83-97%, suggesting practically no amorphous stabilization in the absence of Ethyl Cellulose. The co-precipitation process was ineffective in preparing amorphous formulations for Ketoconazole, as crystal enthalpies ranged from 82-100%. For Chlorpropamide, however, the efficiency of the co-precipitation process improved with the viscosity grade of the Ethyl Cellulose, with EC7, EC45, and EC100 showing % crystalline enthalpies of 98, 76, and 51% respectively. The progressive decrease in crystal enthalpies suggested a corresponding increase in the amorphous forms of these drugs. Spray-dried formulations prepared with EC7 showed practically no crystalline enthalpies for both Ketoconazole and Chlorpropamide, suggesting that these drugs were almost entirely trapped in their amorphous state, and would expect to show higher solubility upon dissolution. Overall, this research shows that spray-drying with low viscosity grade Ethyl Cellulose such as EC7 is an optimal approach for the preparation of amorphous solid-dispersions of BCS Class II drugs.</p><p>

<p> Application of learn-apply paradigm in drug development and clinical therapeutics increases efficiency and supports decision making. The current research highlights the role of pharmacometrics to inform trial design and propose individualized management of chemotherapy induced peripheral neuropathy (CIPN) in oncology. </p><p> The first project focuses on learning from early clinical trial of veliparib to inform future investigations. Population pharmacokinetics and exposure-response analyses were conducted to evaluate the contribution of intrinsic and extrinsic factors on veliparib PK, and assess the adequacy of veliparib dosing for the future trial. A 28% increase in AUC with mild renal impairment increases mucositis by only 7%, thus supporting the inclusion of patients with mild renal impairment in future trials without the need of dose adjustment. Exposure-response for efficacy (objective response rate and overall survival) and safety (mucositis) along with in vitro IC50 information supported 80 mg BID dose for veliparib. Multivariate exposure-response analysis provided supportive evidence to further evaluate veliparib in patients with myeloproliferative neoplasms and with 14 day treatment duration. </p><p> The second project proposes a novel strategy based on precision therapeutics for the management of CIPN in clinical setting. An indirect response model with linear drug effect was able to describe the longitudinal-CIPN data reasonably well for paclitaxel, nab-paclitaxel and ixabepilone. The model was utilized to identify an early time point of 3 months that predicted later time course of CIPN (concordance probability ~ 75%). Utilizing the dose-CIPN model, a novel strategy to use patients own early CIPN data to predict their future CIPN time course was proposed. 'CIPN management dosing card' and 'CIPN precision therapeutics tool' were developed to prospectively manage CIPN in patients who may be at risk of developing CIPN later in the therapy. For paclitaxel, nab-paclitaxel and ixabepilone, the proposed CIPN management dosing card resulted in 61%, 48% and 35% fewer patients with CIPN after 6 cycles as compared to administering cycle 3 doses for 4^th, 5^th and 6^th chemotherapy cycle. With CIPN precision therapeutics tool, oncologists can visualize the predicted CIPN time course and tailor the dosing to manage CIPN in an individual patient based on overall benefit/risk.</p>

Pyomyositis is a severe bacterial infection of skeletal muscle, commonly affecting children in tropical regions, predominantly caused by Staphylococcus aureus. To understand the contribution of bacterial genomic factors to pyomyositis, we conducted a genome-wide association study of S. aureus cultured from 101 children with pyomyositis and 417 children with asymptomatic nasal carriage attending the Angkor Hospital for Children, Cambodia. We found a strong relationship between bacterial genetic variation and pyomyositis, with estimated heritability 63.8% (95% CI 49.2-78.4%). The presence of the Panton-Valentine leucocidin (PVL) locus increased the odds of pyomyositis 130-fold (p=10- 17.9 ). The signal of association mapped both to the PVL-coding sequence and the sequence immediately upstream. Together these regions explained over 99.9% of heritability (95% CI 93.5-100%). Our results establish staphylococcal pyomyositis, like tetanus and diphtheria, as critically dependent on a single toxin and demonstrate the potential for association studies to identify specific bacterial genes promoting severe human disease.

Polymer based nanoparticle formulations have been shown to increase drug bioavailability and/or reduce drug adverse effects. Nonsteroidal anti-inflammatory drugs (e.g. celecoxib) reduce prostaglandin synthesis and cause side effects such as gastrointestinal and renal complications. The aim of this study was to formulate celecoxib entrapped poly lactide-co-glycolide based nanoparticles through a solvent evaporation process using didodecyldimethylammonium bromide or poly vinyl alcohol as stabilizer. Nanoparticles were characterized for zeta potential, particle size, entrapment efficiency, and morphology. Effects of stabilizer concentration (0.1, 0.25, 0.5, and 1% w/v), drug amount (5, 10, 15, and 20 mg), and emulsifier (lecithin) on nanoparticle characterization were examined for formula optimization. The use of 0.1, 0.25, and 0.5% w/v didodecyldimethylammonium bromide resulted in a more than 5-fold increase in zeta potential and a more than 1.5-fold increase in entrapment efficiency with a reduction in particle size over 35%, when compared to stabilizer free formulation. Nanoparticle formulations were also highly influenced by emulsifier and drug amount. Using 0.25% w/v didodecyldimethylammonium bromide NP formulations, peak zeta potential was achieved using 15 mg celecoxib with emulsifier (17.15±0.36 mV) and 20 mg celecoxib without emulsifier (25.00±0.18 mV). Peak NP size reduction and entrapment efficiency was achieved using 5 mg celecoxib formulations with (70.87±1.24 nm and 95.55±0.66%, respectively) and without (92.97 ±0.51 nm and 95.93±0.27%, respectively) emulsifier. In conclusion, formulations using 5 mg celecoxib with 0.25% w/v didodecyldimethylammonium bromide concentrations produced nanoparticles exhibiting enhanced size reduction and entrapment efficiency. Furthermore, emulsifier free formulations demonstrated improved zeta potential when compared to formulations containing emulsifier (p<0.01). Therefore, our results suggest the use of emulsifier free 5 mg celecoxib drug formulationscontaining 0.25% w/v didodecyldimethylammonium bromide for production of polymeric NPs that demonstrate enhanced zeta potential, small particle size, and high entrapment efficiency

Most antiepileptic drugs (AEDs) cause some degree of adverse drug reactions. Behavioral side effects (BSEs) associated with AEDs are often overlooked, but are a significant consideration. Agitation, aggression, psychosis, behavioral disorders, hyperactivity, and restlessness are some AED-related BSEs. Contributing causes may include pharmacologic activity, forced normalization, patient characteristics, individual susceptibility, and medication parameters such as dosage and drug interactions. The pharmacist must educate the patient and caregivers about possible BSEs in order to minimize the impact of behavioral changes and improve quality of life.

Non-steroidal anti-inflammatory drugs (NSAIDs) are used chronically to reduce pain and inflammation in patients with arthritic conditions, and also acutely as analgesics by many patients. Both therapeutic and adverse effects of NSAIDs are due to inhibition of cyclooxygenase (COX) enzyme. NSAIDs are classified as non-selective and COX-2-selective inhibitors (COXIBS) based on their extent of selectivity for COX inhibition. However, regardless of their COX selectivity, reports are still appearing on the GI side effect of NSAIDs particularly on the lower gastrointestinal (GI) tract and the harmful role of their controlled release formulations. In addition, previously unpublished data stored in the sponsor's files, question the GI sparing properties of rofecoxib, a COXIB that has been withdrawn due to cardiovascular (CV) side effects. Presently, the major side effects of NSAIDs are the GI complications, renal disturbances and CV events. There is a tendency to believe that all NSAIDs are associated with renal and CV side effects, a belief that is not supported by solid evidence. Indeed, lower but still therapeutics doses of some NSAIDs may be cardioprotective. In this review, we briefly discuss the GI toxicity of the NSAIDs and assess their renal and CV adverse effects in more detail.

Disability and health care-related costs continue to rise as a result of work-related low back injury. Our investigation examined treatment-independent variables that influenced return-to-work outcome in a sample of workers employed in Northeast Tennessee. METHODS: The review collected 11 variables from two different outpatient physical therapy clinics utilizing a balanced quota sampling design. The patients were enrolled if the documented complaint was low back pain and was an employment-related injury. The patients were grouped according to whether or not they returned to full-time pre-injury work. Twenty-five patients were enrolled in the positive outcome group, those who returned to full-time pre-injury work. Twenty-two patients who did not achieve this goal were enrolled in a separate group. RESULTS: Return-to-work for these patients was not dependent upon age, gender, insurer, number of physical therapy treatments attended, or previously reported low back injury. Those who returned to work had (1) a higher percentage of patients working full-time at their pre-injury position during the rehabilitation process (28% vs. 0%); (2) a higher compliance with the treatment schedule (97% vs. 93%); (3) a lower cancellation rate (0.5 vs. 2.4); (4) a shorter interval in days between reporting the injury and initiation of physical therapy rehabilitation (27 vs. 58); and (5) a lower percentage of previous surgeries resulting from low back injuries (12% vs. 36%), than those who did not. A relationship was also demonstrated between previous surgery and the interval prior to beginning treatments (P < or = 0.0001). However, no relationship was observed between previous surgery and compliance, or between the interval prior to beginning treatments and compliance. DISCUSSION: These results document two variables representing independent factors affecting return-to-work in this population. The first was previous injury influencing the current injury, as documented by both previous surgery and the interval between the current injury and beginning of treatments. The second was compliance with the treatment schedule for the current injury. The psychosocioeconomic aspects of these results are discussed.

Most antiepileptic drugs (AEDs) cause some degree of adverse drug reactions. Behavioral side effects (BSEs) associated with AEDs are often overlooked, but are a significant consideration. Agitation, aggression, psychosis, behavioral disorders, hyperactivity, and restlessness are some AED-related BSEs. Contributing causes may include pharmacologic activity, forced normalization, patient characteristics, individual susceptibility, and medication parameters such as dosage and drug interactions. The pharmacist must educate the patient and caregivers about possible BSEs in order to minimize the impact of behavioral changes and improve quality of life.