Pharmacokinetic analysis of nicotine and its metabolites (cotinine and trans-3'-hydroxycotinine) in male Sprague-Dawley rats following nose-only inhalation, oral gavage, and intravenous infusion of nicotine.

Nicotine is an alkaloid found in tobacco. Human exposure to nicotine primarily occurs through the use of tobacco products. To date, limited nicotine pharmacokinetic data in animals have been reported.

90-day nose-only inhalation toxicity study of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Sprague-Dawley rats.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the key tobacco-specific nitrosamines that plays an important role in human lung carcinogenesis. Repeated dose inhalation toxicity data on NNK, particularly relevant to cigarette smoking, however, is surprisingly limited. Hence, there is a lack of direct information available on the carcinogenic and potential non-carcinogenic effects of NNK via inhalational route exposure.

14-Day Nose-Only Inhalation Toxicity and Haber's Rule Study of NNK in Sprague-Dawley Rats.

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the key tobacco-specific nitrosamines that plays an important role in human lung carcinogenesis. However, repeated inhalation toxicity data on NNK, which is more directly relevant to cigarette smoking, are currently limited. In the present study, the subacute inhalation toxicity of NNK was evaluated in Sprague Dawley rats.

Toxicokinetic and Genotoxicity Study of NNK in Male Sprague Dawley Rats Following Nose-Only Inhalation Exposure, Intraperitoneal Injection, and Oral Gavage.

The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5 × 10-5, 5 × 10-3, 0.

Characterization and pathogenesis of aerosolized eastern equine encephalitis in the common marmoset (Callithrix jacchus).

Background: Licensed antiviral therapeutics and vaccines to protect against eastern equine encephalitis virus (EEEV) in humans currently do not exist. Animal models that faithfully recapitulate the clinical characteristics of human EEEV encephalitic disease, including fever, drowsiness, anorexia, and neurological signs such as seizures, are needed to satisfy requirements of the Food and Drug Administration (FDA) for clinical product licensing under the Animal Rule.

Methods: In an effort to meet this requirement, we estimated the median lethal dose and described the pathogenesis of aerosolized EEEV in the common marmoset (Callithrix jacchus).

Transient lipopolysaccharide-induced resistance to aerosolized Bacillus anthracis in New Zealand white rabbits.

Previous studies have demonstrated that prior infection by various bacterial pathogens induces nonspecific resistance to subsequent infection by other gram-negative and gram-positive bacterial pathogens. In the present study, we evaluated whether underlying inflammation enhanced host resistance to inhalational Bacillus anthracis infection in New Zealand White rabbits (SPF; Bordetella- and Pasteurella-free). Accordingly, rabbits were pretreated with either the inflammagen bacterial LPS (60,000 EU/kg), a component of the outer membrane of gram-negative bacteria, or saline (vehicle).

Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.

In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating glutathione (GSH) synthesis. In the present studies, the protective role of IL-4 in AILI was established definitively by showing that C57BL/6J mice made deficient in IL-4 genetically (IL-4(-/-)) or by depletion with an antibody, were more susceptible to AILI than mice not depleted of IL-4.

Aerosolized Bacillus anthracis infection in New Zealand white rabbits: natural history and intravenous levofloxacin treatment.

The natural history for inhalational Bacillus anthracis (Ames strain) exposure in New Zealand white rabbits was investigated to better identify potential, early biomarkers of anthrax. Twelve SPF Bordetella-free rabbits were exposed to 150 LD(50) aerosolized B. anthracis spores, and clinical signs, body temperature, complete blood count, bacteremia, and presence of protective antigen in the blood (that is, antigenemia) were examined.

Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury.

Recent studies in mice suggest that stress-activated c-Jun N-terminal protein kinase 2 (JNK2) plays a pathologic role in acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure (ALF). In contrast, we present evidence that JNK2 can have a protective role against AILI. When male C57BL/6J wild type (WT) and JNK2(-/-) mice were treated with 300mg APAP/kg, 90% of JNK2(-/-) mice died of ALF compared to 20% of WT mice within 48h.

Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease.

Recent evidence suggests that a deficiency in one or more hepatoprotective regulatory mechanisms may contribute to determining susceptibility in drug-induced liver disease. In the present study, we investigated the role of interleukin (IL)-13 in acetaminophen (APAP)-induced liver disease (AILD). Following APAP (200 mg/kg) administration to male C57BL/6 wild-type (WT) mice, hepatotoxicity developed up to 24 h post-APAP, with a concomitant increase in serum IL-13 concentration.

Recurrence of chromosome 10 Thiel-Behnke corneal dystrophy (CDB2) after excimer laser phototherapeutic keratectomy or penetrating keratoplasty.

Purpose: To evaluate the recurrence of Thiel-Behnke dystrophy (linked to the 10 q23-q24 locus) after phototherapeutic keratectomy or penetrating keratoplasty.

Methods: This is a retrospective study of 4 patients (8 eyes) who underwent phototherapeutic keratectomy and 1 patient (2 eyes) who underwent penetrating keratoplasty. Best corrected visual acuity was assessed, and biomicroscopic examinations for evidence of recurrent dystrophy were documented and photographed.

Prediction of corneal haze using an ablation depth/corneal thickness ratio after laser epithelial keratomileusis.

Purpose: To investigate the usefulness of ablation depth/corneal thickness (AD/CT) ratio to predict corneal haze after laser epithelial keratomileusis (LASEK) using a retrospective, comparative, interventional case series.

Methods: Fifty patients (90 eyes; mean age 40.9 years) with myopia, hyperopia, and/or astigmatism underwent bilateral or unilateral LASEK for correction of refractive error.

Update on laser subepithelial keratectomy (LASEK).

Purpose Of Review: This study reviews current concepts in laser subepithelial keratectomy (LASEK), variations in LASEK techniques, the role of pharmacology in LASEK, and optimizing outcomes in LASEK.

Recent Findings: Recent studies continue to support the use of LASEK over that of LASIK in the correction of refractive error. In addition, the advent of pharmacological/biologic intervention, improved algorithms, and wavefront technology have expanded the armamentarium available to ophthalmologists in the maximization of LASEK outcomes.

Exclusion of the human collagen type XVII (COL17A1) gene as the cause of Thiel-Behnke corneal dystrophy (CDB2) on chromosome 10q23-q25.

Purpose: Determination of the gene causing Thiel-Behnke Corneal Dystrophy (CDB2) would have important clinical implications. Previous studies in our laboratory have suggested that the COL17A1 gene may be the cause of Thiel-Behnke Corneal Dystrophy (CDB2) on Chromosome 10q23-q25.

Methods: We evaluated a five-generation family with CDB2 mapped to chromosome 10.

Cleavage of corneal basement membrane components by ethanol exposure in laser-assisted subepithelial keratectomy.

Purpose: To determine the anatomic cleavage plane after exposure to 20% ethanol for approximately 20 to 25 seconds to create an epithelial flap in laser-assisted subepithelial keratectomy (LASEK).

Setting: Ocular Surface Research & Education Foundation, Miami, Florida, and Hermann Eye Center Refractive Surgery Center, Houston, Texas, USA.

Methods: Immunofluorescence staining using monoclonal antibodies against laminin 5, collagen VII, and integrins beta(1) and beta(4) was performed to determine the anatomic location of the cleavage plane in an epithelial flap created by 20-second exposure to 20% ethanol in cadaver eyes and in epithelial flaps obtained from LASEK patients.

The coagulation system contributes to synergistic liver injury from exposure to monocrotaline and bacterial lipopolysaccharide.

Coexposure to a noninjurious dose of bacterial lipopolysaccharide (LPS; 7.4 x 106 EU/kg) and a nontoxic dose of the food-borne toxin monocrotaline (MCT; 100 mg/kg) leads to synergistic hepatotoxicity in Sprague-Dawley rats. Inflammatory factors, such as Kupffer cells (KCs), tumor necrosis factor-alpha (TNF)-alpha, and neutrophils (polymorphonuclear leukocytes; PMNs), are critical to the pathogenesis.

Endothelial cell injury and coagulation system activation during synergistic hepatotoxicity from monocrotaline and bacterial lipopolysaccharide coexposure.

A small, noninjurious dose of bacterial lipopolysaccharide (LPS; 7.4 x 106 EU/kg) administered 4 h after a small, nontoxic dose of monocrotaline (MCT; 100 mg/kg) produces synergistic hepatotoxicity in rats within 6 to 12 h after MCT exposure. The resulting centrilobular (CL) and midzonal (MZ) liver lesions are characterized by hepatic parenchymal cell (HPC) necrosis.

Role of neutrophils in the synergistic liver injury from monocrotaline and bacterial lipopolysaccharide exposure.

Synergistic liver injury develops in Sprague-Dawley rats from administration of a small, noninjurious dose (7.4 x 10(6) EU/kg) of bacterial lipopolysaccharide (LPS) given 4 h after a nontoxic dose (100 mg/kg) of the pyrrolizidine alkaloid, monocrotaline (MCT). Previous studies demonstrated that liver injury is mediated through inflammatory factors, such as Kupffer cells and tumor necrosis factor alpha (TNF-alpha), rather than through simple interaction between MCT and LPS.

The role of Kupffer cells and TNF-alpha in monocrotaline and bacterial lipopolysaccharide-induced liver injury.

Coexposure to small, noninjurious doses of the pyrrolizidine alkaloid phytotoxin monocrotaline (MCT) and bacterial lipopolysaccharide (LPS) results in synergistic hepatotoxicity. Both centrilobular and midzonal liver lesions occur and are similar to those seen from large, toxic doses of MCT and LPS, respectively. The nature of the lesions in vivo and results from studies in vitro suggest that injury is mediated indirectly rather than from a simple interaction of MCT and LPS with hepatic parenchymal cells.

The temporal relationship between bacterial lipopolysaccharide and monocrotaline exposures influences toxicity: shift in response from hepatotoxicity to nitric oxide-dependent lethality.

Liver injury from a variety of hepatotoxicants, including the food-borne phytotoxin monocrotaline (MCT), can be augmented by exposure to a noninjurious dose of the inflammagen bacterial lipopolysaccharide (LPS). In a previous study, a nontoxic dose of LPS given 4 h after MCT resulted in synergistic hepatotoxicity within 12-18 h. This study was designed to determine whether temporal differences in MCT and LPS exposure affect toxicity.