Intravenous 15% isoflurane lipid nanoemulsion for general anesthesia in dogs.

OBJECTIVE: To investigate the efficacy of a new intravenous (IV) nanoemulsified isoflurane formulation for maintenance of general anesthesia in dogs. STUDY DESIGN: Prospective, crossover, experimental study. ANIMALS: Seven healthy, mature, mixed-breed dogs, three male and four female, weighing 11.5 ± 1.5 kg. METHODS: Anesthesia was induced with propofol for instrumentation. Measurements were obtained before administration of either inhaled isoflurane (Iso-I) or IV 15% isoflurane-loaded lipid nanoemulsion (Iso-nano). The minimum alveolar concentration (MAC) of isoflurane was determined using the 'up-and-down' technique. A tail clamp was applied every 15 minutes for a total time of 90 minutes and isoflurane administration was adjusted according to the response. Data were recorded at 30, 60 and 90 minutes for end-tidal isoflurane concentration (Fe´Iso), end-tidal carbon dioxide partial pressure (Pe'CO2), inspired isoflurane concentration (FIIso), arterial hemoglobin oxygen saturation (SaO2), peripheral hemoglobin oxygen saturation (SpO2), respiratory rate (fR), heart rate (HR), arterial blood pH, PaCO2, PaO2, base excess (BE), bicarbonate (HCO3-), systemic arterial pressure (sAP), and biochemical variables of blood urea nitrogen, alanine aminotransferase, creatine kinase and creatinine. RESULTS: No significant differences between treatments were detected for HR, fR, SaO2 or any biochemical variables (p > 0.05). In the Iso-nano treatment, sAP was significantly decreased throughout the study. Significant decreases in pH, Pe'CO2, BE and HCO3- were measured in the Iso-nano treatment. Isoflurane MAC was significantly lower in the Iso-nano than the Iso-I treatment. The dose of isoflurane (g hour-1) required to maintain general anesthesia did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of 15% isoflurane-loaded lipid nanoemulsion IV was effective in maintaining general anesthesia in dogs but did not reduce the amount of isoflurane necessary to maintain general anesthesia. Significant hypotension and nonrespiratory acidosis occurred with the injectable form.

Isoflurane-loaded nanoemulsion prepared by high-pressure homogenization: investigation of stability and dose reduction in general anesthesia.

Isoflurane is a halogenated ether which is used for general anesthesia. To stabilize a new formulation in order to evaluate the potential to reduce the dose required for general anesthesia, an isoflurane-loaded nanoemulsion was proposed. A high-pressure homogenization technique was used to develop drug-loaded nanoemulsions which presented droplet size of 150 +/- 0.78 nm with a narrow size distribution and low polydispersity index (0.08 +/- 0.01). The zeta potential was -18 +/- 2.4 mV and pH was 6.03 +/- 0.04. Rheological analysis showed Newtonian behavior for the formulations, whose physical stability was confirmed by multiple light scattering. It was verified that isoflurane volatilization did not occur in these formulations. The preclinical evaluation, carried out via the end-tidal isoflurane concentration, showed that the dose required for anesthetic maintenance significantly decreased when the nanostructured formulation was administered compared to inhaled isoflurane. There was no significant difference (p < 0.05) between experimental groups (inhaled isoflurane and intravenous isoflurane-loaded nanoemulsion) in terms of the cardiac rate, oxygen hemoglobin saturation, and arterial blood pressure, as well as the biomarkers of renal, hepatic and skeletal muscle system functionalities. Slight tachypnea, edema, and erythema were observed after isoflurane-loaded or unloaded-nanoemulsion. The stability and significant dose reduction observed for drug-loaded nanoemulsion render this formulation a promising option for intravenous delivery of isoflurane.

Toxicological effects of a mixture used in weight loss products: p-synephrine associated with ephedrine, salicin, and caffeine.

p-Synephrine is an adrenergic amine found in Citrus aurantium L. fruits and has been used for weight loss in dietary supplements. There are commercial products containing this substance associated to caffeine, salicin, and ephedrine. The aim of this study was to evaluate the acute toxicity of this mixture in mice of both sexes. The significative results observed after acute oral administration to male and female mice of 300, 350, and 400 mg/kg total of p-synephrine, ephedrine, salicin, plus caffeine in a 10:4:6:80 w/w ratio included a reduction in locomotor activity and ptosis in all treated groups for both sexes. Seizures were also observed in male (400 mg/kg) and female groups (350 and 400 mg/kg). Gasping and tearing were observed in males. Salivation (400 mg/kg), agitation (350 and 400 mg/kg), and piloerection (all treated groups) were significantly observed only in females. Deaths occurred in males at 350 and 400 mg/kg treated groups and the necropsy showed cardiopulmonary hemorrhage. A reduction in locomotor activity was confirmed through the spontaneous locomotor activity test, in which the number of crossings considerably decreased (P < .01) in all treated groups. The rotarod test showed a decrease in motor coordination at 400 mg/kg. Body temperature decreased significantly (P < .01) in all treated groups compared to controls. The results suggested clear signs of toxicity of p-synephrine, ephedrine, salicin, and caffeine association; this toxicity augments the attentiveness on commercial products containing this mixture, given the expressive number of adverse events related to its utilization.