ABSTRACT
Intramuscular (IM) injection of nitrite (1-10 mg/kg) confers survival benefit and protects against lung injury after exposure to chlorine gas in preclinical models. Herein, we evaluated safety/toxicity parameters after single, and repeated (once daily for 7 days) IM injection of nitrite in male and female Sprague Dawley rats and Beagle dogs. The repeat dose studies were performed in compliance with the Federal Drug Administration's (FDA) Good Laboratory Practices Code of Federal Regulations (21 CFR Part 58). Parameters evaluated consisted of survival, clinical observations, body weights, clinical pathology, plasma drug levels, methemoglobin and macroscopic and microscopic pathology. In rats and dogs, single doses of ≥100 mg/kg and 60 mg/kg resulted in death and moribundity, while repeated administration of ≤30 or ≤ 10 mg/kg/day, respectively, was well tolerated. Therefore, the maximum tolerated dose following repeated administration in rats and dogs were determined to be 30 mg/kg/day and 10 mg/kg/day, respectively. Effects at doses below the maximum tolerated dose (MTD) were limited to emesis (in dogs only) and methemoglobinemia (in both species) with clinical signs (e.g. blue discoloration of lips) being dose-dependent, transient and reversible. These signs were not considered adverse, therefore the No Observed Adverse Effect Level (NOAEL) for both rats and dogs was 10 mg/kg/day in males (highest dose tested for dogs), and 3 mg/kg/day in females. Toxicokinetic assessment of plasma nitrite showed no difference between male and females, with Cmax occurring between 5 mins and 0.5 h (rats) or 0.25 h (dogs). In summary, IM nitrite was well tolerated in rats and dogs at doses previously shown to confer protection against chlorine gas toxicity.
Subject(s)
Antidotes/toxicity , Sodium Nitrite/toxicity , Toxicity Tests , Animals , Antidotes/administration & dosage , Dogs , Dose-Response Relationship, Drug , Female , Injections, Intramuscular , Male , Maximum Tolerated Dose , Methemoglobinemia/chemically induced , No-Observed-Adverse-Effect Level , Rats, Sprague-Dawley , Risk Assessment , Sex Factors , Sodium Nitrite/administration & dosage , Species Specificity , Toxicokinetics , Vomiting/chemically inducedABSTRACT
An oral gene-based avian influenza vaccine would allow rapid development and simplified distribution, but efficacy has previously been difficult to achieve by the oral route. This study assessed protection against avian influenza virus challenge using a chimeric adenovirus vector expressing hemagglutinin and a double-stranded RNA adjuvant. Immunized ferrets and mice were protected upon lethal challenge. Further, ferrets immunized by the peroral route induced cross-clade neutralizing antibodies, and the antibodies were selective against hemagglutinin, not the vector. Similarly, experiments in mice demonstrated selective immune responses against HA with peroral delivery and the ability to circumvent preexisting vector immunity.
Subject(s)
Adenoviridae/genetics , Adjuvants, Immunologic/administration & dosage , Drug Carriers , Genetic Vectors , Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/immunology , RNA, Double-Stranded/administration & dosage , Adjuvants, Immunologic/genetics , Administration, Oral , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Cross Reactions , Disease Models, Animal , Ferrets , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Influenza A Virus, H5N1 Subtype/genetics , Influenza Vaccines/administration & dosage , Influenza Vaccines/genetics , Male , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , RNA, Double-Stranded/genetics , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunologyABSTRACT
Parkinson's disease (PD) is characterized by the loss of dopamine-producing neurons in the nigrostriatal system. Numerous researchers in the past have attempted to track the progression of dopaminergic depletion in PD. We applied a quantitative non-invasive PET imaging technique to follow this degeneration process in an MPTP-induced mouse model of PD. The VMAT2 ligand (18)F-DTBZ (AV-133) was used as a radioactive tracer in our imaging experiments to monitor the changes of the dopaminergic system. Intraperitoneal administrations of MPTP (a neurotoxin) were delivered to mice at regular intervals to induce lesions consistent with PD. Our results indicate a significant decline in the levels of striatal dopamine and its metabolites (DOPAC and HVA) following MPTP treatment as determined by HPLC method. Images obtained by positron emission tomography revealed uptake of (18)F-DTBZ analog in the mouse striatum. However, reduction in radioligand binding was evident in the striatum of MPTP lesioned animals as compared with the control group. Immunohistochemical analysis further confirmed PET imaging results and indicated the progressive loss of dopaminergic neurons in treated animals compared with the control counterparts. In conclusion, our findings suggest that MPTP induced PD in mouse model is appropriate to follow the degeneration of dopaminergic system and that (18)F-DTBZ analog is a potentially sensitive radiotracer that can used to diagnose changes associated with PD by PET imaging modality.
