There is a need for an effective and safe emetic agent that dog owners could easily administer to their dogs following veterinary advice in cases of potential poisoning. As a response to this need, a randomised, double-blind, multi-site, clinical field study was performed to assess the efficacy, safety and usability of ropinirole eye drops to induce vomiting in dogs. Ropinirole (target dose 3.75 mg/m2) was applied to eyes of 100 dogs, and 32 dogs received placebo. The drug was administered by the dog owner at a veterinary clinic under the supervision of a veterinarian and led to vomition in 95% of the ropinirole-treated dogs within 30 min. The median time to first vomit was 10 min (range: 3–37 min). None of the dogs receiving placebo vomited in this time period. All owners were able to administer the product and 96% of them assessed the administration to be very easy or easy, which was confirmed by the observing veterinarian. Some ocular signs were seen both with ropinirole and placebo, hyperaemia being the most common. All observed signs were transient and in most cases mild. Ropinirole eye drops provided an effective, safe and reliable means to induce emesis in dogs.
Nimodipine is a widely used medication for treating delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. When administrated orally or intravenously, systemic hypotension is an undesirable side effect. Intracranial subarachnoid delivery of nimodipine during aneurysm clipping may be more efficient way of preventing vasospasm and DCI due to higher concentration of nimodipine in cerebrospinal fluid (CSF). The risk of systemic hypotension may also be decreased with intracranial delivery. We used animal models to evaluate the feasibility of surgically implanting a silica-based nimodipine releasing implant into the subarachnoid space through a frontotemporal craniotomy. Concentrations of released nimodipine were measured from plasma samples and CSF samples. Implant degradation was followed using CT imaging. After completing the recovery period, full histological examination was performed on the brain and meninges. The in vitro characteristics of the implant were determined. Our results show that the biodegradable silica-based implant can be used for an intracranial drug delivery system and no major histopathological foreign body reactions were observed. CT imaging is a feasible method for determining the degradation of silica implants in vivo. The sustained release profiles of nimodipine in CSF were achieved. Compared to a traditional treatment, higher nimodipine CSF/plasma ratios can be obtained with the implant.
Nimodipine is an L-type calcium channel blocker and is used to treat vasospasm in patients with subarachnoid hemorrhage. Its putative mechanism of action is relaxation of smooth muscle cells in cerebral arteries. In addition, nimodipine may have pleiotropic effects against vasospasm. Systemic hypotension is an adverse effect when patients are treated with oral or intravenous nimodipine. Intracranial administration of nimodipine formulations may produce higher concentration of nimodipine in the cerebrospinal fluid (CSF) than is possible to achieve orally or intravenously, while resulting in lower incidence of systemic hypotension. The aim of this study was to provide information on plasma and CSF levels of nimodipine in beagle dogs as a comparative data for development of experimental intracranial treatment modalities. Plasma levels of nimodipine were measured after current 30 and 60 mg single oral dose of nimodipine (Nimotop(®) 30 mg tablets), a single intravenous bolus 0.72 mg/dog of nimodipine (Nimotop(®) 0.2 mg/ml infusion solution) and CSF levels after 60 mg single oral dose of nimodipine. CSF/Plasma concentration ratio of nimodipine after oral administration of 60 mg at 1 h was 0.013 ± 0.0005. The mean terminal elimination half-life of nimodipine after i.v. bolus dose 0.72 mg was 1.8 h and mean plasma clearance was 40.3 and 3.4 l/h/kg. Absolute bioavailability was 22 %. Maximum plasma concentration and area under the plasma concentration-time curve from time of administration until the last measurable plasma concentration increased in a dose-proportional manner comparing the exposure parameters at oral doses of 30 and 60 mg. Individual variation in the kinetic profile of nimodipine was measured.
Cancer treatments are frequently associated with nausea and vomiting despite greatly improved preventive medication. Administration of anti-nausea agents as eye drops might provide an easy and rapid access to the systemic circulation for prevention of nausea and vomiting and for the treatment of breakthrough nausea, but the ocular administration route has rarely been evaluated. Palonosetron is a second-generation 5-HT 3 receptor antagonist approved for prevention and treatment of chemotherapy-induced nausea and vomiting. We compared ocular administration of palonosetron to non-active vehicle eye drops and to intravenous palonosetron in the prevention of cisplatin-induced nausea and vomiting in beagle dogs. Palonosetron ocular drops at the dose of 30 µg/kg reduced cumulative nausea over time as measured with the area under the visual analog scale curve (VAS-AUC) by 98% compared with the vehicle, and reduced nausea-associated dog behavior by 95%. Vomiting was completely prevented with repeated palonosetron ocular dosing. Hydroxypropyl-βcyclodextrin (HP-β-CD) palonosetron formulation was well tolerated locally at the palonosetron concentration of 3 mg/mL. Absorption of palonosetron from eye drops was fast.Ten minutes after ocular administration, palonosetron plasma concentrations were similar compared to intravenous administration, and remained similar for six hours. We conclude that palonosetron is rapidly absorbed into the systemic circulation from eye drops. Ocularly administered palonosetron was well tolerated in the HP-β-CD formulation and was highly effective in the prevention of cisplatin-induced nausea and vomiting. Evaluation of the safety and efficacy of ocular administration of palonosetron is warranted in the prevention and treatment of chemotherapy-induced nausea and vomiting in clinical trials.
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