Safety of lotilaner flavoured chewable tablets (CredelioTM) after oral administration in cats.

BACKGROUND: Lotilaner is a new member of the isoxazoline class for treatment of flea and tick infestations in cats. This laboratory study with lotilaner vanilla-yeast flavoured chewable tablets (CredelioTM, Elanco) investigated the safety in healthy kittens starting at 8 weeks of age in a randomized, blinded, parallel-group design. Lotilaner tablets were given orally once a month over eight months at one, three and five times the upper level of the maximum recommended dose range (26 mg/kg). METHODS: The safety of lotilaner flavoured chewable tablets was assessed in healthy kittens when administered orally every 4 weeks for 8 months at the highest recommended dose rates, i.e. 1× (26 mg/kg) and at elevated dose rates, i.e. 3× (78 mg/kg) and 5× (130 mg/kg). Sixteen male and 16 female healthy 8-week-old kittens, with a mean body weight of 0.79 kg and 0.75 kg, respectively, were randomized to an untreated control group or lotilaner groups at dose rates of 26 mg/kg (1×), 78 mg/kg (3×), or 130 mg/kg (5×) every four weeks over eight months. The control group was sham-dosed. All animals were fed within 30 minutes prior to treatment. Safety assessment included general health observations, detailed clinical observations, complete physical/neurological examinations, including ophthalmological examinations, electrocardiographic (ECG) and clinical pathology evaluations (haematology, clinical chemistry and urinalysis), food and water consumption, body weight, pharmacokinetic blood collections, organ macroscopic and microscopic examinations. RESULTS: Systemic exposure to lotilaner was confirmed during the course of the study in all treated animals with the exception of the control group. No treatment-related effects were seen on daily clinical observations, food consumption (wet), ophthalmoscopic, physical/neurological and microscopic examinations. Statistically significant differences were recorded in some of the clinical pathology parameters, body weights, food consumption (dry), electrocardiograms, and organ weights, but none of the recorded observations was considered to be of clinical relevance. CONCLUSIONS: Lotilaner, when administered once monthly over eight months at the highest recommended dose and overdoses of three- and five-fold, to 8-week-old healthy kittens, is well tolerated.

Safety evaluation of lotilaner in dogs after oral administration as flavoured chewable tablets (Credelio™).

BACKGROUND: Lotilaner (Credelio™, Elanco) is a novel isoxazoline that provides rapid speed of flea and tick knockdown which is sustained for at least 1 month following oral administration to dogs. The safety of lotilaner flavoured chewable tablets was investigated in a randomized, blinded, parallel-group design study in healthy Beagle puppies starting at 8 weeks of age. Lotilaner was administered orally once a month over 8 months at one, three and five times the upper level of the recommended dose range (of 20 to 43 mg/kg). METHODS: The objective of this study was to determine the safety of lotilaner flavoured chewable tablets in healthy dogs when administered monthly over an extended time period at the highest recommended dose rate, i.e. 1× and at elevated dose rates, i.e. 3× and 5×. Sixteen male and 16 female healthy 8-week-old puppies, weighing ~1.5 to 3.0 kg, were randomized among four groups to be untreated controls or to receive lotilaner at dose rates of 43 mg/kg (1×), 129 mg/kg (3×), or 215 mg/kg (5×) on eight occasions - every 4 weeks over 8 months. The control group was sham-dosed. Study dogs were fed within 30 min prior to treatment. Assessment of safety was based on general health observations, detailed clinical observations, complete physical/neurological examinations, including ophthalmological examinations and clinical pathology evaluations (haematology, clinical chemistry and urinalysis), food and water consumption, body weight, pharmacokinetic blood collections, macroscopic and microscopic examinations. RESULTS: Blood concentrations of lotilaner confirmed systemic exposure of all study dogs with the exception of the control group. Lotilaner did not induce any treatment-related effects on body weight, food consumption, opthalmoscopic, physical/neurological and electrocardiographic examinations. For clinical pathology, no changes related to treatment were noted. There were no treatment-related changes in gross examinations. After microscopic examinations, minor findings recorded in kidneys were of no toxicological relevance. Changes in the reproductive tissues were attributed to the peri-pubertal age and growth of the animals. CONCLUSIONS: Lotilaner was well-tolerated in healthy puppies at 8 week of age when administered once monthly on eight occasion over 8 months at the highest recommended dose and at three and five-fold overdose.

Effects of cholecystokinin octapeptide on the exocrine pancreas in a new rat model of type 2 diabetes.

We investigated the effects of increasing concentrations of cholecystokinin octapeptide (CCK-8) on the exocrine pancreas of a new model of type 2 diabetic rats due to the partial protection exerted by nicotinamide against the beta-cytotoxic effect of streptozotocin. CCK-8, administered for 8 successive days, exerted a biphasic action on the growth of the pancreas in non-diabetic and type 2 diabetic rats; however, the latter were less sensitive to CCK-8. Similar results were obtained in vitro by measuring the uptake of 5-bromo-2'-deoxyuridine (BrdU) in cultured isolated acinar cells. This effect was completely blocked by 3S(-)(N'-2,3-dihydro-1-methyl-2-oxo5-phenyl-1H-1,4-benzo-diazepin-3-yl)-1H-indole-2-carboxamide (L 364,718; a CCK(1) receptor antagonist) but not by (3R)-3[N'-(3-methylphenyl)ureido]-1,3-dihydro-1-methyl-5-phenyl-2H1,4-benzo-diazepin-2-one (L 365,260; a CCK(2) receptor antagonist), suggesting a direct effect via CCK(1) receptors. Binding studies showed that these effects were mediated by a single class of low-affinity CCK(1) receptors in diabetic rats and two classes of CCK-8 binding sites (with high and low affinity) in non-diabetic rats. Thus, in our new type 2 diabetes model, the loss of sensitivity of the pancreas to CCK-8 could be attributed to the loss of CCK(1) receptors of high affinity.

Cholecystokinin octapeptide: a potential growth factor for pancreatic beta cells in diabetic rats.

CONTEXT: Diabetes is associated with the reduction of beta cell mass and activity. Cholecystokinin (CCK) is known to induce growth of the exocrine pancreas and to stimulate insulin secretion. OBJECTIVE: We investigated the possible role of CCK-octapeptide (CCK-8) in generating islet cell proliferation in type 1 and type 2 diabetic rats. METHODS: Streptozotocin-induced type 1 diabetic rats, streptozotocin/nicotinamide-induced type 2 diabetic rats and non-diabetic rats were subjected to CCK-8 (1, 2 and 4 microg/kg) or saline injections (for the control group), three times daily for 8 successive days. MAIN OUTCOME MEASURES: The islets of Langerhans were analyzed morphometrically; the beta-cell function was evaluated by an oral glucose tolerance test, and plasma basal glucose and insulin concentrations. RESULTS: In type 1 diabetic rats, CCK-8 induced an increase in beta cell surface associated with a marked increase in the mitotic index; this effect appeared at a concentration of 1 microg/kg CCK-8 and was the highest at a concentration of 4 microg/kg CCK-8. In addition, pancreatic- and plasma-insulin concentrations increased while fasting blood glucose concentrations were reduced when compared to saline-treated rats but the glycemic response to an oral glucose challenge did not significantly improve. In type 2 diabetic rats and in non-diabetic rats, CCK-8 treatment did not significantly affect either the structure or the functional state of beta-cells. CONCLUSIONS: CCK-8 could improve blood glucose concentrations in type 1 diabetic rats correlated with an increase in beta cell mass probably potentiated by the chronic hyperglycemic state.

Transcriptomics does not show adverse effects of beta-carotene in A/J mice exposed to smoke for 2 weeks.

Beta-carotene (betaC) supplementation in smokers was unexpectedly associated with increased incidence of lung cancer versus smoking alone. We performed a study in A/J mice to explore possible betaC/cigarette smoke (CS) interactions potentially influencing lung cancer risk in smokers. A/J mice received a diet containing 120 or 600 ppm betaC for six weeks, and exposed to mainstream CS (140 mg total suspended particulates/m(3)) during the last two weeks. Lung transcriptomics analysis revealed that CS induced drug metabolism, oxidative stress, extracellular matrix (ECM) degradation, inflammation markers, and apoptosis. betaC reduced CS-induced inflammation markers and ECM degradation. betaC modulated the CS effect on apoptosis without a clear pro- or anti-apoptotic trend. betaC alone induced only minor changes of gene expression. In conclusion, betaC/CS interactions caused gene regulations in lungs. CS was the main effector. The gene regulations overall did not indicate that betaC exacerbated CS effects. Dose-dependency of betaC effects was minor and not detectable by genome-wide data mining.

Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells.

High dose beta-carotene supplementation of smokers was associated with increased lung cancer risk in two intervention trials. It was proposed that generation of apocarotenals in smoke-exposed lungs impaired retinoic acid (RA) signaling, leading to squamous metaplasia and cell proliferation. To test this, we compared RA target gene regulation by retinoids, apocarotenals or beta-carotene by transcriptomics in BEAS-2B cells cultured to promote squamous differentiation. Retinoids, beta-carotene as well as apocarotenals induced known RA target genes. Retinoids upregulated involucrin, indicating that retinoids did not rescue BEAS-2B cells from squamous differentiation. Muc5AC, a marker for mucous differentiation, was transiently induced. beta-Carotene and apocarotenals less strongly induced involucrin and did not induce muc5AC. In summary, apocarotenals or beta-carotene upregulated RA target genes suggesting promotion, not inhibition, of RA signaling in BEAS-2B cells. Furthermore, apocarotenals and beta-carotene regulated gene expression independently of RA signaling. Squamous differentiation is not unequivocally linked to RA deficiency in BEAS-2B cells.

Effect of epiregulin on pancreatic beta cell growth and insulin secretion.

The aim of this study was to determine whether epiregulin, a novel member of EGF-related growth factor family, was able to affect proliferation and secretory function of rat insulinoma INS-1E and RINm5F cell lines. A 24 h treatment with epiregulin resulted in a stimulation of INS-1E and RINm5F cells proliferation; this effect was completely blocked in the presence of an anti-epiregulin antibody which did not affect basal DNA synthesis in the absence of added ligand. In acute experiments, epiregulin was able to potentiate insulin release in the presence of glucose or arginine, in the two cell lines. Finally, in the two cell lines expressing ErbB receptors, we demonstrated that only EGFR/ErbB1 was activated by epiregulin. Thus, epiregulin appears as a new growth and insulinotropic factor in pancreatic beta cell lines.