We describe here an approach to boost detection sensitivity and expand dynamic range in the quantitation of large molecules while maintaining analytical specificity using summation of MRM (SMRM) transitions and LC separation technique.
Pharmacokinetics and Metabolism of 4R-Cembranoid
The purpose of this study was to examine the metabolism and pharmacokinetics of 4R as part of its preclinical development as a neuroprotective drug.
Formulation Approaches to Improving the Delivery of an Antiviral Drug with Activity against Seasonal Flu
The main objective of the present study was to develop formulations of noscapine hydrochloride hydrate with enhanced solubility and bioavailability using co-solvent- and cyclodextrin-based approaches. Different combinations of co-solvents, which were selected on the basis of high-throughput solubility screening, were subjected to in vitro intestinal drug permeability studies conducted with Ussing chambers. Vitamin E tocopherol polyethylene glycol succinate and propylene glycol based co-solvent formulations provided the maximum permeability coefficient for the drug. Inclusion complexes of the drug were prepared using hydroxypropyl-β-cyclodextrin and sulphobutylether cyclodextrins. Pharmacokinetic studies were carried out in male Sprague-Dawley rats for the selected formulations. The relative bioavailabilities of the drug with the co-solvent- and cyclodextrin-based formulations were found to be similar.
Nitrocobinamide, a New Cyanide Antidote That Can Be Administered by Intramuscular Injection
Here we show that adding sodium nitrite to cobinamide yields a stable derivative that rescues cyanide-poisoned mice and rabbits when given by intramuscular injection.
Cyanide Detoxification by Molybdenum Sulfur Complexes
Development of an Agonist of the TGF-Beta Signaling Pathway to Treat Alzheimer’s Disease
Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to progressive cognitive dysfunction. Current knowledge of the processes leading to AD is still limited, and no effective treatments are available. Because neurodegeneration is associated with injury and activation of innate immune responses in the brain, drugs that could mimic the beneficial aspects of this response are potential therapeutic candidates. The cytokine transforming growth factor (TGF)-?1 is an organizer of the brain’s response to injury and has been shown to have neuroprotective effects in models of brain injury and degeneration. Recombinant TGF-?1 has been used to treat various forms of brain injury in vivo but delivery is not suitable for human use. Studies from our lab have demonstrated that TGF-?1 can reduce the overall accumulation of A?, a key factor in AD pathogenesis, in mouse models for AD and in cell culture. Numerous studies have also demonstrated that TGF-?1 is a potent neurotrophic factor, although high-level chronic TGF-?1 production can also be detrimental. Recently, we reported that reduced TGF-?1 expression in vivo or in cultured neurons increases neurodegeneration. Additional studies show that reducing TGF-? signaling in neurons of a mouse model for AD increases A? accumulation and neurodegeneration and that TGF-? receptor expression is reduced in human AD brains. We have identified bioactive small molecule chemical compounds that can activate the TGF-? signaling pathway in hippocampal neurons of mice and that pass the blood-brain barrier. With reporter cell lines for the TGF-? signaling pathway we screened a diverse small molecule drug library and identified several compounds that are able to activate the reporter system in vitro and in TGF-? reporter mice in vivo. The compounds induce specific TGF-?-responsive genes in cell culture consistent with Smad dependent activation of the TGF-? pathway. These chemicals share common properties from which we propose here to derive a lead compound within 5 years. This project includes structure activity relationship analysis of identified active compounds, medicinal chemistry, toxicology and pharmacology in a subcontract with SRI International. Compounds will be tested in neuroprotection and neurotoxicity assays in cell culture and in TGF-? reporter mice in vivo. The two most promising compounds will then be tested in an in vivo model of neurodegeneration and in a mouse model for AD. Part of the in vivo analysis on neurodegeneration will be done in collaboration with researchers at UCSD. At the end of our studies we propose to have for the first time a novel neuroprotective and amyloid reducing investigational new drug based on the TGF-? signaling pathway for testing in patients with AD.
Evaluating the Toxicity of Novel Zn-DTPA Tablet Formulation in Dogs and Rats
The purpose of this research work is to evaluate toxicity of diethylenetriamine pentaacetic acid zinc trisodium salt (Zn-DTPA) tablets.
Pharmacokinetics and Toxicity of a Neuroprotective Cembranoid
Comparison of a New Cobinamide-Based Method to a Standard Laboratory Method for Measuring Cyanide in Human Blood
The authors developed and validated a method to quantify cyanide based on the high binding affinity of the vitamin B12 analog, cobinamide, for cyanide and a major spectral change observed for cyanide-bound cobinamide.