MPI Research Inc.

Mattawan, MI, United States

MPI Research Inc.

Mattawan, MI, United States
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Gauvin D.V.,MPI Research Inc | Yoder J.D.,MPI Research Inc | Tapp R.L.,MPI Research Inc | Baird T.J.,MPI Research Inc.
International Journal of Toxicology | Year: 2017

Life experiences, industrial/environmental exposures, and administration of Food and Drug Administration (FDA)-approved drugs may have unintended but detrimental effects on peripheral and central auditory pathways. Most relevant to the readership of this journal is the role that drug treatments approved by the FDA as safe and effective appear to interact with 3 independent modes of toxicity within the small compartment of the ear. What may seem to be trivial drug-induced toxicity has the potential to change important measures of quality of life and functional capacity of mid- to late-life patients. Drugs meant to treat can become the source of interference in the activities of daily living, and as a result, treatment compliance may be jeopardized. Ototoxicity has been defined as the tendency of certain therapeutic agents and other chemical substances to cause functional impairments and cellular degeneration of the tissues of the inner ear resulting in hearing loss. However, one of the largest contributors to hospitalizations is fall-related injuries in the elderly patients associated with disorders of vestibular function linked to progressive and drug-induced toxicities. Tinnitus affects 35 to 50 million adults representing approximately 25% of the US population, with 12 million seeking medical care and 2 to 3 million reporting symptoms that were severely debilitating. This review is intended to highlight these targets of neurotoxicity that threaten the usefulness of drug treatments deemed safe and effective prior to access by the general public. © The Author(s) 2016.

Gauvin D.V.,Neurobehavioral Research, Inc. | Zimmermann Z.J.,Neurobehavioral Research, Inc. | Zimmermann Z.J.,Western Michigan University | Baird T.J.,MPI Research Inc.
Journal of Pharmacological and Toxicological Methods | Year: 2017

All new molecular entities that enter the CNS and exert an activity in the brain must be assessed for abuse liability prior to a New Drug Application approval by the US Food and Drug Administration. One element of the screening process is the assessment of the reinforcing properties of the drug candidate using the regulatory-preferred species, the rat. We describe one method of data review from the standard rat IV SA study design that can be used to conclude the relative abuse liability of the new drug entity. While we do not claim the process as the only way to review or interpret the data, we believe the steps described highlight a process that the pharmaceutical development team can use as a starting point for a discussion during study protocol development. © 2017 Elsevier Inc.

Xie H.,Texas Southern University | Wang Z.J.,University of Texas Health Science Center at San Antonio | Wang Z.J.,MPI Research Inc. | Bao A.,University of Texas Health Science Center at San Antonio | And 2 more authors.
International Journal of Pharmaceutics | Year: 2010

Here we report the radiolabeling of gold nanoshells (NSs) for PET imaging in rat tumor model. A conjugation method was developed to attach NSs with the radionuclide, 64Cu. The resulting conjugates showed good labeling efficiency and stability in PBS and serum. The pharmacokinetics of 64Cu-NS and the controls (64Cu-DOTA and 64Cu-DOTA-PEG2K) were determined in nude rats with a head and neck squamous cell carcinoma xenograft by radioactive counting. Using PET/CT imaging, we monitored the in vivo distribution of 64Cu-NS and the controls in the tumor-bearing rats at various time points after their intravenous injection. PET images of the rats showed accumulation of 64Cu-NSs in the tumors and other organs with significant difference from the controls. The organ biodistribution of rats at 46h post-injection was analyzed by radioactive counting and compared between the 64Cu-NS and the controls. Different clearance kinetics was indicated. Neutron activation analysis (NAA) of gold concentration was performed to quantify the amount of NSs in major tissues of the dosed rats and the results showed similar distribution. Overall, PET images with 64Cu had good resolution and therefore can be further applied to guide photothermal treatment of cancer. © 2010.

Xie H.,Texas Southern University | Goins B.,University of Texas Health Science Center at San Antonio | Bao A.,University of Texas Health Science Center at San Antonio | Wang Z.J.,MPI Research Inc | Phillips W.T.,University of Texas Health Science Center at San Antonio
International Journal of Nanomedicine | Year: 2012

Background: Gold nanoshells are excellent agents for photothermal ablation cancer therapy and are currently under clinical trial for solid tumors. Previous studies showed that passive delivery of gold nanoshells through intravenous administration resulted in limited tumor accumulation, which represents a major challenge for this therapy. In this report, the impact of direct intratumoral administration on the pharmacokinetics and biodistribution of the nanoshells was systematically investigated. Methods: The gold nanoshells were labeled with the radionuclide, copper-64 (64). Intratumoral infusion of 64-nanoshells and two controls, ie, 64-DOTA (1,4,7,10-tetraazaciclododecane- 1,4,7,10-tetraacetic acid) and 64-DOTA-PEG (polyethylene glycol), as well as intravenous injection of 64-nanoshells were performed in nude rats, each with a head and neck squamous cell carcinoma xenograft. The pharmacokinetics was determined by radioactive counting of serial blood samples collected from the rats at different time points post-injection. Using positron emission tomography/computed tomography imaging, the in vivo distribution of 64-nanoshells and the controls was monitored at various time points after injection. Organ biodistribution in the rats at 46 hours was analyzed by radioactive counting and compared between the different groups. Results: The resulting pharmacokinetic curves indicated a similar trend between the intratumorally injected agents, but a significant difference with the intravenously injected 64-nanoshells. Positron emission tomography images and organ biodistribution results on rats after intratumoral administration showed higher retention of 64-nanoshells in tumors and less concentration in other healthy organs, with a significant difference from the controls. It was also found that, compared with intravenous injection, tumor concentrations of 64-nanoshells improved substantially and were stable at 44 hours post-injection. Conclusion: There was a higher intratumoral retention of 64-nanoshells and a lower concentration in other healthy tissues, suggesting that intratumoral administration is a potentially better approach for nanoshell-based photothermal therapy. © 2012 Xie et al, publisher and licensee Dove Medical Press Ltd.

Pugsley M.K.,Janssen Research and Development LLC. | Dalton J.A.,MPI Research Inc. | Authier S.,INC Research | Curtis M.J.,St Thomas Hospital
Journal of Pharmacological and Toxicological Methods | Year: 2014

What do you know about Safety Pharmacology? This is the question that was asked in 2000 with the inception of the Safety Pharmacology Society (SPS). There is now a widespread awareness of the role of safety pharmacology in drug discovery and increasing awareness among the wider community of methods and models used in the assessment of the core battery required set of safety studies. However, safety pharmacology does not stop with core battery studies. New methods are intensively sought in order to achieve a swifter and more reliable assessment of adverse effect liability. The dynamics of the discipline and method expansion are reflected in the content of this issue of the Journal of Pharmacological and Toxicological Methods (JPTM). We are into the second decade of publishing on safety pharmacology methods and models, reflected by the annual themed issue in JPTM, and on willingness of investigators to embrace new technologies and methodologies. This years' themed issue is derived from the annual Safety Pharmacology Society (SPS) meeting, held in Rotterdam, The Netherlands, in 2013. © 2014 Elsevier Inc.

Mahadevan B.,Abbott Laboratories | Thorsrud B.A.,MPI Research Inc. | Brorby G.P.,ToxStrategies Inc. | Ferguson H.E.,Abbott Laboratories
Food and Chemical Toxicology | Year: 2014

Octenyl succinic anhydride (OSA)-modified starch functions as both an emulsifier and emulsion stabilizer in foods, and is intended for use in infant formula, follow-on formula, and formulae for special medical purposes. These formulae predominantly include extensively hydrolyzed protein or free amino acids, rather than intact protein, which otherwise would provide emulsifying functionality. The study objectives were to evaluate (1) the safety of OSA-modified starch after three weeks of administration to neonatal farm piglets, beginning 2. days after birth and (2) the impact of OSA-modified starch on piglet growth. OSA-modified starch was added to formula at concentrations of 2, 4, and 20. g/L. The vehicle control, low-dose, and mid-dose diets were supplemented with Amioca™ Powder to balance the nutritional profiles of all formulations. There were no test article-related effects of any diet containing OSA-modified starch on piglet growth and development (clinical observations, body weight, feed consumption), or clinical pathology parameters (hematology, clinical chemistry, coagulation, urinalysis). In addition, there were no adverse effects at terminal necropsy (macro- and microscopic pathology evaluations). Therefore, dietary exposure to OSA-modified starch at concentrations up to 20. g/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth. © 2014 Elsevier Ltd.

Neaga A.,MPI Research Inc. | Lefor J.,MPI Research Inc. | Lich K.E.,MPI Research Inc. | Liparoto S.F.,MPI Research Inc. | Xiao Y.Q.,MPI Research Inc.
Journal of Immunological Methods | Year: 2013

Phagocytosis plays a pivotal and essential role in host immune defense, both as a focal constituent of the innate immune response and a bridging element linking innate and adaptive immunity. Phagocytosis has been demonstrated to be critical in development, tissue remodeling, wound healing and resolution of inflammation through clearance of foreign organisms, apoptotic cells and the production of anti-inflammatory mediators. During pre-clinical investigations, therapeutic drug candidates may alter host resistance to infectious agents by modulating the immune system. The assessment of phagocytic function can be a critical parameter of immunotoxicology for this adverse effect. Utilizing pH-sensitive pHrodo™ BioParticles®, a flow cytometric phagocytosis method was developed and validated in rodent and non-human primate (NHP) species under rigorous GLP compliant procedures. Using species-specific granulocyte markers as well as appropriate temperature and pharmacologic controls, we have developed an ex vivo assay to measure phagocytic function. The method has been optimized to utilize minimal sample volume of whole blood. The assay represents a rapid and reliable tool that can be implemented to evaluate the immunotoxic and immunomodulatory effects of therapeutic candidates. © 2011 Elsevier B.V.

This perspective article discusses key points to address in the establishment of sound partnerships between sponsors and bioanalytical CROs to assure the timeliness, quality and consistency of bioanalysis throughout biological therapeutic development. The performance of ligand-binding assays can be greatly impacted by low-grade reagents, lot-to-lot variability and lack of stability of the analyte in matrix, impacting both timelines and cost. Thorough characterization of the biologic of interest and its assay-enabling critical reagents will lend itself well to conservation of materials and continuity of assay performance. When unplanned events occur, such as performance declines or premature depletion of material, structured procedures are paramount to supplement the current loosely defined regulatory guidance on critical reagent characterization and method bridging. © 2015 Future Science Ltd.

Sazani P.,AVI Biopharma | Ness K.P.V.,AVI Biopharma | Weller D.L.,AVI Biopharma | Poage D.W.,MPI Research Inc | And 2 more authors.
International Journal of Toxicology | Year: 2011

AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) drug designed to restore dystrophin expression in a subset of patients with Duchenne muscular dystrophy (DMD). Previous reports demonstrated this clinical proof-of-principle in patients with DMD following intramuscular injection of AVI-4658. This preclinical study evaluated the toxicity and toxicokinetic profile of AVI-4658 when administered either intravenously (IV) or subcutaneously (SC) to cynomolgus monkeys once weekly over 12 weeks, at doses up to the maximum feasible dose of 320 mg/kg per injection. No drug-related effects were noted on survival, clinical observations, body weight, food consumption, opthalmoscopic or electrocardiographic evaluations, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic evaluations. Drug-related microscopic renal effects were dose-dependent, apparently reversible, and included basophilic granules (minimal), basophilic tubules (minimal to moderate), and tubular vacuolation (minimal to mild). These data establish the tolerability of AVI-4658 at doses up to and including the maximum feasible dose of 320 mg/kg by IV bolus or SC injection. © The Author(s) 2011.

Baird T.J.,MPI Research Inc. | Bailie M.,Integrated Nonclinical Development Solutions Inc. | Patrick D.J.,MPI Research Inc. | Moddrelle D.,Xenometrics LLC | And 3 more authors.
Journal of Pharmacological and Toxicological Methods | Year: 2013

Introduction: Understanding the appropriate application of telemetry and other technologies for nonclinical investigation of functional safety issues in the context of ongoing toxicology evaluations is a current industry challenge. One major issue is related to the potential impact of surgical implantation of a telemetry device on contemporarily established measures of drug toxicity, and potential for confounding pathological issues related to the systemic and local response of the experimental animal to the presence of a foreign body. This study was designed to evaluate the potential local and systemic impact of different implanted telemetry devices with varying requisite degrees of surgical complexity on general toxicology study endpoints. Methods: Sixteen male beagle dogs 1) no surgical instrumentation [n = 4], 2) Jacketed External Telemetry (JET) with femoral artery blood pressure implant (PA-C10 LA) [n = 4], or 3) fully implantable (DSI-D70-CCTP) devices [n = 8], were assigned to experimental groups and evaluated within the context of a standard repeat-dose toxicology design to determine the potential impact of these treatments on routine in-life and post-mortem toxicological endpoints. Results: Device implantation, regardless of the level of invasiveness/complexity was without effect on any in-life safety parameter, including clinical chemistry and hematology, assessed in the experimental design. Histopathological findings were limited to the expected, primarily minimal to mild localized effects characteristic of a foreign body reaction (fibrosis, inflammation) in the area immediately in contact with the body of the transmitter device and associated sites of ECG lead and pressure catheter interface with local tissues. Discussion: This study represents the first definitive evaluation of the influence of variably invasive telemetry device implantation on standardized, essential toxicology endpoints in the context of a simulated repeated dose experimental design. The data suggest that, when carefully evaluated, the local effects of implanted telemetry devices can be managed in the context of a standard Investigational New Drug (IND)-enabling toxicology study. This study provides support for the potential incorporation of unrestrained cardiovascular assessments via implanted or external telemetry into standard multi-dose toxicology studies. © 2013 Elsevier Inc.

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