Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis.

Recent case reports of acute pancreatitis in patients with type 2 diabetes (T2DM) treated with incretin-based therapies have triggered interest regarding the possibility of a mechanism-based association between pancreatitis and glucagon-like peptide-1 mimetics or dipeptidyl peptidase-4 (DPP-4) inhibitors. The objective of this review was to describe the controlled preclinical and clinical trial data regarding the incidence of pancreatitis with sitagliptin, the first DPP-4 inhibitor approved for use in patients with T2DM. Tissue samples from multiple animal species treated with sitagliptin for up to 2 years at plasma exposures substantially in excess of human exposure were evaluated to determine whether any potential gross or histomorphological changes suggestive of pancreatitis occurred. Sections were prepared by routine methods, stained with haematoxylin and eosin and examined microscopically. A pooled analysis of 19 controlled clinical trials, comprising 10,246 patients with T2DM treated for up to 2 years, was performed using patient-level data from each study for the evaluation of clinical and laboratory adverse events. Adverse events were encoded using the Medical Dictionary for Regulatory Activities (MedDRA) version 12.0 system. Incidences of adverse events were adjusted for patient exposure. Tissue samples from preclinical studies in multiple animal species did not reveal any evidence of treatment-related pancreatitis. The pooled analysis of controlled clinical trials revealed similar incidence rates of pancreatitis in patients treated with sitagliptin compared with those not treated with sitagliptin (0.08 events per 100 patient-years vs. 0.10 events per 100 patient-years, respectively). Preclinical and clinical trial data with sitagliptin to date do not indicate an increased risk of pancreatitis in patients with T2DM treated with sitagliptin.

Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models.

Farnesyl:protein transferase (FPTase) inhibitors (FTIs) were originally developed as potential anticancer agents targeting the ras oncogene and are currently in clinical trials. Whereas FTIs inhibit the farnesylation of Ha-Ras, they do not completely inhibit the prenylation of Ki-Ras, the allele most frequently mutated in human cancers. Whereas farnesylation of Ki-Ras is blocked by FTIs, Ki-Ras remains prenylated in FTI-treated cells because of its modification by the related prenyltransferase, geranylgeranyl:protein transferase type I (GGPTase-I). Hence, cells transformed with Ki-ras tend to be more resistant to FTIs than Ha-ras-transformed cells. To determine whether Ki-ras-transformed cells can be targeted by combining an FTI with a GGPTase-I inhibitor (GGTI), we evaluated potent, selective FTIs, GGTIs, and dual prenylation inhibitors (DPIs) that have both FTI and GGTI activity. We find that in human PSN-1 pancreatic tumor cells, which harbor oncogenic Ki-ras, and in other tumor lines having either wild-type or oncogenic Ki-ras, treatment with an FTI/GGTI combination or with a DPI blocks Ki-Ras prenylation and induces markedly higher levels of apoptosis relative to FTI or GGTI alone. We demonstrate that these compounds can inhibit their enzyme targets in mice by monitoring pancreatic and tumor tissues from treated animals for inhibition of prenylation of Ki-Ras, HDJ2, a substrate specific for FPTase, and Rap1A, a substrate specific for GGPTase-I. Continuous infusion (72 h) of varying doses of GGTI in conjunction with a high, fixed dose of FTI causes a dose-dependent inhibition of Ki-Ras prenylation. However, a 72-h infusion of a GGTI, at a dose sufficient to inhibit Ki-Ras prenylation in the presence of an FTI, causes death within 2 weeks of the infusion when administered either as monotherapy or in combination with an FTI. DPIs are also lethal after a 72-h infusion at doses that inhibit Ki-Ras prenylation. Because 24 h infusion of a high dose of DPI is tolerated and inhibits Ki-Ras prenylation, we compared the antitumor efficacy from a 24-h FTI infusion to that of a DPI in a nude mouse/PSN-1 tumor cell xenograft model and in Ki-ras transgenic mice with mammary tumors. The FTI and DPI were dosed at a level that provided comparable inhibition of FPTase. The FTI and the DPI displayed comparable efficacy, causing a decrease in growth rate of the PSN-1 xenograft tumors and tumor regression in the transgenic model, but neither treatment regimen induced a statistically significant increase in tumor cell apoptosis. Although FTI/GGTI combinations elicit a greater apoptotic response than either agent alone in vitro, the toxicity associated with GGTI treatment in vivo limits the duration of treatment and, thus, may limit the therapeutic benefit that might be gained by inhibiting oncogenic Ki-Ras through dual prenyltransferase inhibitor therapy.

Report of dysgerminoma in the ovaries of a snapping turtle (Chelydra serpentina) with discussion of ovarian neoplasms reported in reptilians and women.

A malnourished, captive, young adult (weight-11 kg, carapace length-25 cm), female snapping turtle (Chelydra serpentina) was presented for examination and treatment of malnutrition and multiple carapace necroses. Because treatment was unsuccessful, the animal was euthanatized and necropsied. The main necropsy observations showed the presence of a 9 cm greyish-white/yellow, soft, fleshy to fatlike mass involving the right ovary near the oviduct opening and multiple similar, pea-to-walnut sized masses involving both ovaries. Microscopic examination of formalin fixed, hematoxylin and eosin and silver stained tissue sections revealed the masses to be composed of primordial germ cells arranged in a pattern morphologically compatible with dysgerminoma as described in women and other mammals. Very rarely have ovarian neoplasms been reported in turtles or other reptiles. This is the first neoplasm described in the snapping turtle ovary and the first dysgerminoma reported in reptilians. A tabulation of previously documented ovarian neoplasia in reptiles and a comparison of this cancer to those occurring in women will be discussed.

Hepatocellular neoplasia in fish, rats and man: a selected comparative review.

Liver cancer is a common neoplasm of man that is especially frequent in parts of the world where hepatitis B virus is endemic and high aflatoxin ingestion is experienced. Hepatocellular carcinoma (HCC) has a very aggressive behavior, is quite resistant to radiotherapy and chemotherapy and is often inoperable, all of which lead to a five-year patient survival of less than 5 percent. Studies in lower animals (e.g. fish, rats) lend themselves to preplanned manipulations aimed at answering specific questions which are intended to elucidate the biology of HCC. Information derived from these studies can be applied to the human condition with the hope of earlier diagnosis, improved treatment and possibly prevention. This review touches on selected areas of similarity and dissimilarity in the histology, histochemistry, metastasis, etiology and molecular biology of HCC in fish, rats and man.

One-month inhalation toxicity study of tulobuterol hydrochloride in rats and dogs.

Tulobuterol hydrochloride (HCl) has beta 2-adrenergic agonist activity and is under development for use in the treatment of chronic obstructive lung disease. The purpose of this study was to determine the toxicity of inhaled tulobuterol HCl in rats and dogs. Rats were whole-body exposed to aerosol gravimetric concentrations of 0, 0.03, 0.22, or 1.1 mg/liter of tulobuterol HCl, 60 min/day for 28 days. Dogs were exposed (via insufflation) to estimated daily doses of 0, 0.2, 1.0, or 6.0 mg/kg for an equal period. Plasma levels of tulobuterol were determined following exposure on Days 1, 8, and 28 using a high-pressure liquid chromatographic method developed for this study. Results indicated that plasma tulobuterol levels were highly correlated with tulobuterol doses (p less than 0.001 for rats and dogs). No dose-related changes in body weight food consumption, hematological, or serum chemistry parameters were observed in either species. Anterior nasal cavity lesions were observed by light microscopy in rats exposed to 0.22 and 1.1 mg/liter tulobuterol HCl at an incidence of 14 and 93%, respectively. These lesions involved the nasal septum, turbinates, and/or the dorsolateral wall of the nasal cavity and consisted of suppurative rhinitis and necrosis. The corresponding mean plasma tulobuterol levels on Day 28 in mid- and high-dose rats were approximately 1000 and 15,000 ng/ml. Nasal lesions were not observed in rats allowed to recover for 2 weeks. No gross or microscopic lesions were detected in lungs or other tissues of either species.(ABSTRACT TRUNCATED AT 250 WORDS)

Amplification of the proto-oncogenes int-2, c-erb B-2 and c-myc in human breast cancer.

int-2 is a proto-oncogene that is partially homologous to angiogenesis-inducing fibroblast growth factor and is believed to play a role in mouse mammary carcinogenesis. Recent evidence has suggested that this proto-oncogene may also play a role in human breast cancer. In the present study, we used Southern hybridization analysis to examine DNA from 79 primary and 11 recurrent human breast cancers for evidence of activation of int-2 through either gene rearrangement or amplification. A similar analysis was performed for two other proto-oncogenes, c-erbB-2 and c-myc, also suspected of playing a role in the development of human breast cancer. Proto-oncogene status was correlated with estrogen (ER) and progesterone (PR) receptor status, patient age, and lymph node (LN) status at the time of surgery. Gene rearrangement was not a frequent occurrence with any of the proto-oncogenes. However, amplification of int-2 occurred at a significantly higher frequency in recurrent breast cancers than in primary cancers and in patients with primary cancers who were less than or equal to 50 years of age versus greater than 50 years of age at surgery. Although amplification of all three proto-oncogenes occurred at a greater frequency in primary tumors from patients with lymph node metastases than from those without lymph node metastases, a significant difference was noted only in the case of c-myc amplification. These findings confirm and extend earlier results of studies of int-2, c-erbB-2 and c-myc amplification in human breast cancers and point to a role for int-2 activation in certain cases of recurrent breast malignant neoplasia.

Role of zinc in the abatement of hepatocellular damage and mortality incidence in endotoxemic rats.

Intraperitoneal administration of zinc (ZnIP) as zinc chloride prior to or simultaneously with a lethal quantity of intraperitoneally administered Salmonella typhimurium endotoxin significantly protected rats against toxin-induced mortality and hepatocellular damage. Pretreatment with amounts of zinc chloride ranging from 0.4 to 2.0 mg/100 g of body weight resulted in 80 to 100% survival compared with 10% survival in untreated control rats at 24 h after endotoxin treatment. Zinc chloride treatment in excess of 2.0 mg/100 g of body weight appeared to be toxic and provided diminished protection. In contrast with the protection obtained with ZnIP, intravenously administered zinc did not provide protection. The effectiveness of ZnIP to enhance survival if it was given after endotoxin was greatly diminished as a function of time after endotoxin. The extent of hepatocellular damage was assessed at various times after endotoxin administration in ZnIP-treated and untreated rats by measurement of plasma ornithine carbamoyltransferase activity and histological examination of liver sections. Endotoxin absorption from the peritoneal cavity and hepatic uptake were studied by using 51Cr-labeled endotoxin. ZnIP pretreatment significantly reduced 51Cr-labeled endotoxin content of blood and liver when compared to untreated controls, and effectively prevented endotoxin-induced elevations in plasma ornithine carbamoyltransferase activity and hepatic tissue necrosis. These data indicate that protection afforded by ZnIP treatment results as a consequence of the ability of zinc to diminish absorption of the toxin from the peritoneal cavity and subsequent hepatic uptake.

Cerebral tuberculosis in a rhesus monkey.

Tuberculosis of the cerebrum was diagnosed in a young adult male rhesus monkey (Macaca mulatta). Tuberculous granulomas were also found in the lungs, bronchial lymph nodes, liver, and spleen. The affected monkey was the probable index case for 7 other Macaca mulatta with tuberculosis.