Levosimendan (LS), a Ca2ϩ sensitizer, is presently limited to i.v. administration. The dose-related pharmacodynamic effects of newly developed oral LS remain undetermined. We assessed the dose-response relationship of oral LS in nine normal and seven pacing-induced heart failure (HF), conscious, chronically instrumented mongrel dogs. Animals received a placebo capsule on day 1, and then LS was administered at single oral doses of 0.025 (day 2), 0.05 (day 4), and 0.1 (day 8) mg/kg. We serially measured plasma LS concentrations, hemodynamic, and left ventricular (LV) systolic and diastolic functional responses periodically until 12 h after oral LS. In both normal and HF, after three incremental dosages of oral LS, the peak plasma LS concentrations (34.6, 66.8, and 123.2 ng/ml in normal and 38.3, 71.5, and 137.4 ng/ml in HF) were achieved within 2 h in proportion to the dose, parallel to an increased LV contractility (normal, from 5.7 mm Hg/ml placebo to 8.2, 10.5, and 12.6 mm Hg/ml; HF, from 3.7 mm Hg/ml placebo to 5.7, 7.1, and 8.7 mm Hg/ml), and decreased time constant of LV relaxation () (normal, from 28.8 ms of placebo to 25.6, 24.7, and 23.5 mm Hg/ml; HF, from 44.7 ms of placebo to 38.9, 36.4, and 34.6 ms). Compared with placebo, total systemic vascular resistance and mean left atrial pressure were significantly reduced after LS. In HF, oral LS caused a dose-dependent increase of LV-arterial coupling and mechanical efficiency. Heart rate increased only after 0.1 mg/kg LS in normal dogs. In conclusion, oral LS produces vasodilatation and dose-dependent augmentation in LV contractility and relaxation both in normal and HF.

The effects of levosimendan on cerebrovascular lesions and mortality were investigated in models of primary and secondary stroke. We aimed to determine whether the effects of levosimendan are comparable to and/or cumulative with those of valsartan, and to investigate whether levosimendan-induced vasodilation has a role in its effects on stroke. In a primary stroke Dahl/Rapp rat model, mortality rates were 70% and 5% for vehicle and levosimendan, respectively. Both stroke incidence (85% vs. 10%, P<0.001) and stroke-associated behavioral deficits (7-point neuroscore: 4.59 vs. 5.96, P<0.001) were worse for vehicle compared to levosimendan. In a secondary stroke model in which levosimendan treatment was started after cerebrovascular incidences were already detected, mean survival times were 15 days with vehicle, 20 days with levosimendan (P=0.025, vs. vehicle), 22 days with valsartan (P=0.001, vs. vehicle), and 31 days with levosimendan plus valsartan (P<0.001, vs. vehicle). The respective survivals were 0%, 16%, 20% and 59%, and the respective incidences of severe lesions were 50%, 67%, 50% and 11%. In this rat model, levosimendan increased blood volume of the cerebral vessels, with significant effects in the microvessels of the cortex (∆R=3.5±0.15 vs. 2.7±0.17ml for vehicle; P=0.001) and hemisphere (∆R=3.2±0.23 vs. 2.6±0.14ml for vehicle; P=0.018). Overall, levosimendan significantly reduced stroke-induced mortality and morbidity, both alone and with valsartan, with apparent cumulative effects, an activity in which the vasodilatory effects of levosimendan have a role.

The study was designed to determine the pharmacokinetic profile and bioavailability of a novel pregabalin 50 mg/ml oral solution formulation (Bonqat ® , Orion Corporation Orion Pharma) in 6 healthy laboratory cats. The cats received pregabalin as single oral doses of 2.5, 5, and 7.5 mg/kg, dose 5 mg/kg on two consecutive days, and a single intravenous dose of 2.5 mg/kg. The washout period between each administration was four weeks. The cats were monitored for clinical signs and level of sedation, and blood samples were taken before pregabalin dosing and at pre-defined time points up to 168 h after dosing. Plasma concentrations of pregabalin were determined using a validated liquid chromatography-tandem mass spectrometry method. The mean maximum plasma concentration of 10.1 μg/ml was reached between 0.5 and 1 h after oral administration of the clinical dose 5 mg/kg. The mean half-life after oral administration of dose 5 mg/kg was 14.7 h and the mean systemic bioavailability was 94%.Pregabalin showed linear pharmacokinetics from 2.5 to 7.5 mg/kg. Exposures after a single dose and re-dosing of 5 mg/kg at 24 h were comparable. Pregabalin was well tolerated with mild sedation and mildly uncoordinated movements observed in few cats at dose 7.5 mg/kg. As a conclusion, study results show rapid absorption, linear pharmacokinetics, and high oral bioavailability of pregabalin without safety concerns after administration of oral solution in cats.

Background: Nausea and vomiting are common side effects of cancer therapies thereby seriously affecting the quality of life of patients. Therefore, the prevention or treatment of chemotherapy-induced nausea and vomiting has become an important part of the comprehensive treatment of cancer. Several 5-HT3 receptor antagonists have been developed in the treatment of nausea and vomiting using mainly the oral route of administration (which is not convenient due to vomiting) or the intravenous route. In this study we tested whether ocular administration of the 5-HT3 receptor antagonist palonosetron (eye drops) could prevent nausea and vomiting associated with intravenous cisplatin injection in dogs. Methods: Six adult male Beagle dogs (10-13 kg) were included in a randomized crossover study. This study was carried out in AAALAC facilities in strict accordance with the European and French animal welfare regulations for animal use in experimentation. Dogs were administered 18 mg/m2 cisplatin intravenously over a 20-min period, followed 45 min later by ocular administration (eye drops, 200µL/eye) of either placebo (2% povidone in saline) or palonosetron (30 or 120 µg/kg). The number of vomits and nausea associated behaviours, scored on a visual analogue scale (VAS), were recorded every 15 min for 7 h following cisplatin administration. Blood samples were collected to measure plasma levels of palonosetron. Results: The placebo treated group vomited an average number of 10.2±2.1 times (range 5-17) over the 7-h period following cisplatin infusion. Ocular administration of palonosetron at 30 μg/kg in cisplatin-treated dogs very strongly and significantly decreased vomiting episodes, with only 1 vomiting episode in 2 dogs overall (p&lt;0.0001). After ocular administration of palonosetron at 120 μg/kg, no vomiting episodes were observed in any dog throughout the observation period (p&lt;0.0001). With regards to the VAS, in the placebo-treated group the nausea-associated behaviour started between 2.5 and 2.75 h after the end of the cisplatin infusion and peaked between 3.75 and 4.25 h after the end of the cisplatin infusion. The area under the curve (AUC) of VAS was 7344 ± 1050 mm*min in the placebo-treated group. Ocular administration of palonosetron at 30 or 120 µg/kg in cisplatin-treated dogs decreased the VAS score strongly. The VAS AUCs were 320 ± 268 (p&lt;0.0001) and 0 ± 0 mm*m (p&lt;0.0001) in 30 µg/kg and 120 µg/kg palonosetron groups, respectively. Plasma palonosetron concentration reached 10.3 ± 3.9 ng/mL, 5 min after ocular administration of palonosetron at 30 µg/kg and 2.8 ± 0.5 ng/mL and 0.9 ± 0.2 ng/mL at 2 h and 6 h post dosing, respectively. Conclusions: This study demonstrates for the first time that palonosetron administered via ocular route produces a rapid clear-cut anti-emetic and anti-nausea effect in conscious dogs exposed to cisplatin. This finding points out the tremendous interest of this novel and convenient route of administration which could help improving the quality of life of patients. Citation Format: Sandra Nourry, Minja Hyttila-Hopponen, Pierre Montagne, Lasse Saloranta, Sari Pappinen, Jouko Levijoki, Christophe Drieu La Rochelle. Ocular drops of palonosetron reduce chemotherapy-induced acute nausea and vomiting in the dog [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 593.

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