Review paper: Current strategies in the development of anti-obesity drugs and their safety concerns.

Obesity is a well-established risk factor for hypertension, hyperlipidemia, type II diabetes, coronary heart disease, stroke, obstructive sleep apnea, asthma, orthopedic disorders, and certain cancers. Despite this risk, the prevalence of obesity continues to increase worldwide, and there is a growing demand for safe and effective antiobesity drugs. Previous antiobesity drugs or anorexigens, particularly centrally acting agents, have poor safety records. Life-threatening safety issues led to the withdrawal of aminorex in 1968, fenfluramine and dexfenfluramine in 1997, and phenylpropanolamine in 2000. Many of the safety issues, such as valvulopathy with fenfluramine and pulmonary arterial hypertension with aminorex, were initially not predicted by routine preclinical toxicology studies. To date, there are no validated animal models or preclinical and/or toxicologic screens to accurately predict anorexigen-induced valvulopathy and pulmonary arterial hypertension in humans. This review covers the current state of antiobesity drugs and their safety concerns, and highlights new therapeutic targets and scientific advances toward the development of appropriate animal models by using novel techniques that will aid in understanding pathogenesis and pathophysiology of anorexigen-related safety issues.

Peroxisome proliferator-activated receptors in atherosclerosis and inflammation--an update.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor subfamily of transcription factors with pleiotropic effects on intra- and extracellular lipid metabolism, glucose homeostasis, cell proliferation, control of inflammation, and atherosclerosis. Three PPARs, namely alpha, delta, and gamma have been identified with distinct tissue distribution patterns and metabolic functions. PPAR-alpha is predominantly expressed in brown adipose tissue, liver, kidney, duodenum, heart, skeletal muscle, and vascular endothelial cells and is involved in the control of lipoprotein metabolism, fatty acid oxidation, and the cellular uptake of fatty acids. PPAR-gamma is highly expressed in brown and white adipose tissues and, to lesser extent, in large intestine, retina, and some parts of the immune system, and plays a critical role in adipocyte differentiation and fat deposition. PPAR-delta shows a widespread tissue distribution but its regulation and functions are not yet known. Considerable evidence indicates that PPARs (PPAR-alpha and PPAR-gamma) have beneficial effects in inflammatory diseases, including atherosclerosis, through regulation of cytokine production, adhesion molecule expression on the endothelial cells, fibrinolysis, and modulation of monocyte-derived macrophages. In this review, the general and specific roles of the PPAR isotypes and their implications in the control of vascular inflammation and atherosclerosis are discussed.

A subacute inhalation exposure evaluation of a scrubbing solution used in petroleum refineries.

The potential for subacute toxicity and neurotoxicity of a potassium carbonate-based scrubbing solution used in petroleum refineries was evaluated in Sprague-Dawley Crl:CD BR rats. Exposures were to aerosols of a "used" scrubbing solution by wholebody inhalation, 6 h/d, for 21 consecutive days at target concentrations of 0 (filtered air-control), 0.1, 0.2, or 0.4 mg/L (30 animals/sex/group). A functional observation battery (FOB) and locomotor activities tests were conducted and monitored. No apparent adverse effects were noted at any exposure level as determined by clinical observations, food consumption, hematology, serum chemistry, ophthalmologic observations, and gross pathology. Statistically significant increases in lung weights were noted at all treatment levels but returned to control values upon cessation of exposure except for the 0.4 mg/L female group. There were no significant changes in other organ weights. Histopathologic findings were restricted to the respiratory tract and characterized by minimal to moderate epithelial hyperplasia, epithelial necrosis, and cytoplasmic vacuolation at levels I and II of the nasal cavities. Lung bronchiolization and alveolar macrophage infiltration were also observed. The respiratory-tract findings were considered a local response to the high alkalinity of the test material as substantiated by the return to normal upon cessation of exposure. Exposure to scrubbing solution had no adverse effect on FOB endpoints and locomotor activity evaluations, brain weight and size, and neuropathologic examinations. In conclusion, inhalation exposure to a used scrubbing solution aerosol for 21 d did not result in any persistent systemic toxicity or neurotoxicity in either male or female rats.

A communicating intestinal duplication in a Sprague-Dawley rat.

Duplications of the gastrointestinal tract are exceedingly rare in laboratory animals. We report a case of a communicating intestinal duplication in a 17-wk-old Sprague-Dawley (SD) rat. The duplication was present in the mesenteric border of the ileum, and both proximal and distal ends were communicated with the lumen of ileum. Histologically, the duplicated portion had a thick muscle wall and a mucosa similar to that of the small intestine. This is the first reported case of intestinal duplication in an SD rat.

Cytochrome P450 induction in feral Cricetid rodents: a review of field and laboratory investigations.

The constitutive and inducible hepatic cytochromes P450 of various feral Cricetid rodents (family Cricetidae, comprising various New World rats and mice, hamsters, gerbils and voles), have been examined in a relatively limited number of field and laboratory investigations. These studies, reviewed herein, have employed substrates and immunochemical reagents that are diagnostic for individual P450 subfamilies of Rattus norvegicus (the common laboratory species derived from the Norway rat, a member of the family Muridae). The results have demonstrated that the feral rodents display hepatic responses to prototypic CYP1A inducers (3-methylcholanthrene, beta-naphthoflavone) similar to those displayed by R. norvegicus and Mus musculus (the common laboratory species derived from the house mouse, another member of the family Muridae). At least one study has demonstrated the induction, by ethanol, of a protein immunochemically similar to CYP2E1 in a Cricetid rodent. In Cricetid rodents, phenobarbital-type inducers cause the induction of a hepatic protein immunologically similar to that primarily induced (CYP2B) in R. norvegicus and M. musculus. The proteins induced in the Cricetid rodents, however, exhibit striking differences in substrate specificity, compared to the proteins induced in R. norvegicus. These results indicate that the previously described differences between the P450 induction responses exhibited by the commonly utilized laboratory species R. norvegicus and M. musculus (family Muridae) and the Syrian hamster and gerbil (family Cricetidae) are observed as a generality for members of the Cricetid family of rodents.

Cell adhesion molecules--update.

Cell adhesion molecules are glycoproteins expressed on the cell surface and play an important role in inflammatory as well as neoplastic diseases. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. The integrin family has eight subfamilies, designated as beta 1 through beta 8. The most widely studied subfamilies are beta 1 (CD29, very late activation [VLA] members), beta 2 (leukocyte integrins such as CD11a/CD18, CD11b/CD18, CD11c/CD18, and alpha d beta 2), beta 3 (CD61, cytoadhesions), and beta 7 (alpha 4 beta 7 and alpha E beta 7). The immunoglobulin superfamily includes leukocyte function antigen-2 (LFA-2 or CD2), leukocyte function antigen-3 (LFA-3 or CD58), intercellular adhesion molecules (ICAMs), vascular adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PE-CAM-1), and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). The selectin family includes E-selectin (CD62E), P-selectin (CD62P), and L-selectin (CD62L). Cadherins are major cell-cell adhesion molecules and include epithelial (E), placental (P), and neural (N) subclasses. The binding sites (ligands/receptors) are different for each of these cell adhesion molecules (e.g., ICAM binds to CD11/CD18; VCAM-1 binds to VLA-4). The specific cell adhesion molecules and their ligands that may be involved in pathologic conditions and potential therapeutic strategies by modulating the expression of these molecules will be discussed.

Cryptosporidiosis in a cotton rat (Sigmodon hispidus).

Cryptosporidiosis, previously unreported in cotton rats (Sigmodon hispidus), was observed in one of nine cotton rats from Pryor, Oklahoma (USA). Infection was confined to the large intestine. Microscopically, numerous cryptosporidians measuring 2 to 3 microns in diameter were intimately associated with the luminal surface of colonic and rectal mucosae. The affected lamina propria of the large intestine was diffusely infiltrated by eosinophils, lymphocytes and macrophages. Ultrastructurally, numerous trophozoites and a single schizont were observed. Microvilli were displaced by the presence of cryptosporidians at the attachment site.

Strongyloidiasis in cotton rats (Sigmodon hispidus) from central Oklahoma.

Thirty-one of 40 cotton rats (Sigmodon hispidus) collected from central Oklahoma were infected with Strongyloides sp. (78% prevalence). Larvae of Strongyloides sp. (rhabditiform or filariform) were not demonstrable in intestinal contents and scrapings. Female nematodes recovered from intestinal contents and scrapings had morphological similarities with Strongyloides sigmodontis. Cotton rats infected with Strongyloides sp. were indistinguishable clinically from non-infected hosts. Infected animals had no significant gross lesions, but the presence of Strongyloides sp. in the intestinal mucosa was associated with villus atrophy and mild to moderate infiltration of the lamina propria by lymphocytes, plasma cells and occasional eosinophils. Other organs or tissues examined were free from lesions induced by Strongyloides sp.

Cholangiocarcinoma in a blue-fronted Amazon parrot (Amazona estiva).

A case of cholangiocarcinoma in a 3-year-old blue-fronted Amazon parrot (Amazona estiva) is reported. Neoplastic tissue was limited to the liver, where it infiltrated and replaced much of the hepatic parenchyma. The only other reported cases of cholangiocarcinoma in an Amazon parrot (Amazona xanthops) also occurred in a bird in its fourth year of age.