Pharmacokinetics of dexmedetomidine combined with methadone following oral-transmucosal and intramuscular administration in dogs

Oral-transmucosal (OTM) drug delivery refers to noninvasive and painless administration of medical preparations through any oral cavity membrane to achieve systemic effects (Sattar et al., 2014). Regarding sedative drugs, OTM administration is very attractive in veterinary medicine, especially for patients difficult to inject and restrain (Messenger et al., 2016). This study aims to compare the pharmacokinetics of dexmedetomidine after OTM and intramuscular (IM) administration combined with methadone. After obtaining Ethical Committee approval and owner’s written consent, eight dogs, were administered with dexmedetomidine (10 mg/kg) and methadone (0.4 mg/kg) by OTM and other 4 dogs by IM route. Blood samples were collected at prefixed times up to four hours. Dexmedetomidine was quantified by a validated HPLC-MS method. On dexmedetomidine concentrations, a pharmacokinetic analysis was carried out with a noncompartmental approach (Phoenix WinNonlin® 7.0, Pharsight, Cary, NC). Mean ± SD terminal half-lives of dexmedetomidine were 187.42 ± 109.66 and 94.78 ± 34.08 min after OTM and IM administration, respectively. Maximum serum (Cmax) concentrations were 0.83 ± 0.32 and 9.09 ± 2.46 ng/mL for OTM and IM administration, respectively. Time to maximum concentration (Tmax) were 44.38 ± 32.16 and 21.25±11.39 min by OTM and IM administration, respectively. Area under the curve from 0 to the last measured concentration (AUClast) were 103.75 ± 30.23 and 614.87 ± 77.15 min*ng/mL for OTM and IM administration, respectively. Cmax, Tmax and AUClast values by OTM route demonstrate a lower and delayed absorption of the drug compared to IM. To complete the study, the pharmacokinetic analysis of methadone is foreseen, so as a clinical trial to compare the clinical effects of the combination of dexmedetomidine and methadone by OTM and IM administration and to establish an effective dosage of oral-transumucosal route in dogs for this association

THE INFLUENCE OF ANESTHESIA IN THE CENTRAL NERVOUS SYSTEM STUDY

Central nervous system is a complex machine; it is constituted by more or less 172 billions of cells divided between neurons and glia. This incredible number of cells, particularly neurons, are constantly connected, working 24 hours a day, never stopping. Their activity is maintained even during particular conditions such as sleep, pathological unconsciousness (coma) or general anesthesia. For all these peculiarities, since ancient times, man has devoted much effort to the study of the most fascinating organ of living beings (mammals in particular). Nowadays, thanks to the advance in medical technology, many tools are available to \u201clook inside the brain\u201d. Magnetic resonance imaging and, particularly, functional magnetic resonance imaging (fMRI) is a modern biomedical imaging method, which allows a non-invasive assessment of brain function. The detection of brain activity is based on the coupling between neuronal activity, energy consumption, and blood flow. Functional connectivity (FC) of brain regions is modulated in various central nervous system diseases, during sleeping and general anesthesia. Anesthesia during MRI procedures is commonly used in preclinical setting and, sometimes, is required also in clinical setting (uncollaborative patients, children, drugs induced-coma etc). The study of the relationship between anesthetics and FC presents a double value: allows to distinguish the alterations induced by anesthesia on FC, avoiding possible confounding elements, and permits an in depth investigation of drugs behaviour. For all these reasons, the main topic of this PhD dissertation is the relationship between anesthesia and central nervous system. We started from theoretical studies in healthy subjects and we arrived to clinical setting, describing the possible application of anesthetics drugs as a treatment of neurologic diseases. The first study included aims to describe the way in which dexmedetomidine and isoflurane modulate FC in guinea pigs. We analysed the characteristic of cortical, subcortical and cortico- subcortical connectivity under both drugs with resting state fMRI. The second study presented partial results of a more complex work concerning FC in rats under 4 different anesthetics protocols. Because in FC studies blood flow represents a crucial element we dedicated a part of the work to the study of haemodynamic alterations through the administration 3 of contrast medium. Dynamic Suceptibility Contrast MRI analysis allows the study of cerebral blood flow and cerebral blood volume of different brain anatomic regions under dexmedetomidine, isoflurane, midazolam-dexmedetomidine and midazolam-isoflurane. Finally, we moved to clinical setting to describe the successful treatment of 3 dogs suffering from idiopathic epilepsy presented in emergency department in a state of super refractory status epilepticus. They were treated successfully with a continuous infusion of dexmedetomidine and ketamine. In conclusion, taken together this thesis gives a little contribute to better understand anesthetics behavior at brain level. We believe that it is important to make a \u201crational choice\u201d when we decide the anesthetic protocol for neuroimaging procedures (both in clinical and preclinical setting) and this \u201crational choice\u201d could be make only if we have a widespread literature that describe the highest number of anesthetic protocol and their interaction on central nervous system. Finally, thanks to the continuous improvement of our understanding of anesthetics mechanism of action, especially from a molecular and functional point of view, is it possible to use different anesthetics as a therapy for different neurologic conditions, particularly the one based on neurotransmitters imbalance

Ketamine-dexmedetomidine combination and controlled mild hypothermia for the treatment of long-lasting and super-refractory status epilepticus in 3 dogs suffering from idiopathic epilepsy

Objective - To describe the use of ketamine-dexmedetomidine combination for the treatment of status epilepticus in 3 dogs that did not respond to GABA-ergic medication. Case series summary \u2013 Three dogs with diagnosis of idiopathic epilepsy were presented to the emergency department in status epilepticus. Dogs were treated unsuccessfully with benzodiazepine as a first line therapy, followed by propofol intravenous anesthesia maintained for at least 12 hours. When general anesthesia was discontinued seizure recurred. All patients, then received a bolus of ketamine (1 mg/kg IV) over a period of 5 minutes followed by a bolus of dexmedetomidine (3\u3bcg/kg IV) over the same time. Both drugs were infused for 12 hours at a constant rate of 1 mg/kg/h for ketamine and at a variable rate of 3-7 \u3bcg/kg/h for dexmedetomidine. The dogs recovered uneventfully over the next 48 hours after treatment discontinuation with no evidence of seizure. No remarkable alteration in physiological parameters were observed during infusion. All dogs were discharged with negative neurological examination. New or unique information provided \u2013 This case series highlights the potential benefit of ketamine-dexmedetomidine infusion for the treatment of status epilepticus refractory to GABA-ergic therapy in dogs suffering from idiopathic epilepsy. After weaning from ketamine-dexmedetomidine infusion all dogs experienced a complete recovery. This case series introduces a novel, safe and effective approach to this dramatic condition

Angiostrongylus vasorum in a Red Panda (Ailurus fulgens): Clinical Diagnostic Trial and Treatment Protocol

Purpose: The literature refers that Angiostrongylus vasorum should always be considered in the differential diagnosis of respiratory diseases in captive red panda (Ailurus fulgens) from endemic areas, and the importance of undertaking a careful diagnostic process and timely medical treatment are crucial when the disease is suspected. The authors think that the description of this clinical case can help other colleagues in the deworming, clinical and anesthesiologic management of infected subjects. Methods: A red panda was referred to the Veterinary Teaching Hospital of the University of Milan in Lodi, due to a diagnosis of A. vasorum formulated in May 2015. The diagnosis was made after the detection of both first-stage larvae by Baermann technique and antigens by serological rapid in-clinic assay. In addition, haemochromocytometric and blood chemistry tests, echocardiography and a CT examination were carried out. Results: The subject was successfully treated by oral administration of milbemycin oxime and praziquantel (Milbemax, Novartis, Italy), respectively, at the weekly dose of 12.5 mg/subject and 125 mg/subject for three consecutive weeks, alternated with 20 days of suspension. Treatment continued with the same scheme until clinical examination carried out in Lodi in December 2018. Conclusion: The follow-up of the described clinical case demonstrates how appropriate management of the infection and the subsequent prophylaxis can correctly eliminate the parasite, thus avoiding the spread of the nematode and the onset of severe and lethal lung forms as described in the literature

Total intramuscular multimodal anesthesia in pond sliders (Trachemys scripta) undergoing endoscopic gonadectomy

Anesthetics\u2019 efficacy and pharmacological effects in reptiles are difficult information to retrieve due to specie-specific characteristics. Particularly, inhalant maintenance often results in unpredictable changes in anesthetic depth and prolonged recovery. The aim of the study was to assess a totally injectable protocol that could allow to avoid inhalant maintenance in Trachemys scripta undergoing elective endoscopic assisted gonadectomy. Seventeen clinically healthy turtles were induced with an intramuscular combination of dexmedetomidine (0.1 mg/kg), ketamine (3 mg/kg), midazolam (0.5 mg/kg) and alfaxalone (8.5 mg/kg). Mean induction time (IT), need for intra-operative inhalant anesthetic, heart rate (HR) and mean recovery time (RT) were recorded. Atipamezole (1 mg/kg) and flumazenil (0.05 mg/kg) were administered intramuscularly and intravenously at the end of the surgery to reverse dexmedetomidine and midazolam, respectively. Data were analyzed with descriptive statistics and, to further investigate potential differences between juvenile and adult specimens, student T test (p < 0.05) was applied. Mean IT was 17 \ub17 minutes. No reaction to skin incision was observed, and 2 out of 17 turtles required inhalant maintenance. Mean HR was 35 \ub1 5 bpm, with no significant alteration recorded during anesthesia. Mean RT was 10 \ub112 minutes. A significant difference between juveniles (8/17) and adults (9/17) was recorded (p = 0.0028), while no age-related differences in HR and RT were observed. This protocol in T. scripta appears to be safe and to provide a short induction and recovery time. Adequate depth of anesthesia could be maintained throughout elective procedure in 88% of subjects without inhalant anesthesia

Infestazione da Angiostrongylus vasorum nel panda rosso (Ailurus fulgens): review della letteratura e presentazione di un caso clinico = Angiostrongylus vasorum infestation in the red panda (Ailurus fulgens): review of the literature and presentation of a case report

L\u2019infestazione da Angiostrongylus vasorum nel panda rosso (Ailurus fulgens) determina una polmonite parassitaria ad andamento cronico potenzialmente letale. Gli Autori presentano una revisione della letteratura e un caso clinico. Un panda rosso \ue8 stato riferito all\u2019Ospedale Veterinario dell\u2019Universit\ue0 degli Studi di Milano a Lodi con una diagnosi di infestazione da A. vasorum che era stata formulata a maggio del 2015, non appena trasferito in un parco faunistico del Nord Italia. La diagnosi \ue8 stata emessa sulla base del riscontro di larve di prima et\ue0 (L1) nelle feci con tecnica di Baermann e della presenza dell\u2019antigene tramite tecnica di immunomigrazione eseguita presso un laboratorio di riferimento. Il soggetto \ue8 stato successivamente trattato con successo mediante somministrazione per via orale di milbemicina ossima e praziquantel rispettivamente alla dose settimanale di 12,5 mg/soggetto e 125 mg/soggetto per 3 settimane consecutive alternate a 20 giorni di sospensione. Il trattamento \ue8 continuato con lo stesso schema fino al controllo eseguito a Lodi a dicembre 2018. Grazie alla tecnica del rinforzo positivo e dell\u2019animal training, l\u2019animale ha assunto il farmaco regolarmente e direttamente dalle mani del Keeper nascosto in acini d\u2019uva, alimento molto gradito dai panda rossi. Non \ue8 stato riscontrato alcun effetto collaterale

Oral transmucosal cannabidiol oil formulation as part of a multimodal analgesic regimen: Effects on pain relief and quality of life improvement in dogs affected by spontaneous osteoarthritis

The aim of this study was to evaluate the efficacy of oral transmucosal (OTM) cannabidiol (CBD), in addition to a multimodal pharmacological treatment for chronic osteoarthritis-related pain in dogs. Twenty-one dogs were randomly divided into two groups: in group CBD (n = 9), OTM CBD (2 mg kg 121 every 12 h) was included in the therapeutic protocol (anti-inflammatory drug, gabapentin, amitriptyline), while in group C (n = 12), CBD was not administered. Dogs were evaluated by owners based on the Canine Brief Pain Inventory scoring system before treatment initiation (T0), and one (T1), two (T2), four (T3) and twelve (T4) weeks thereafter. Pain Severity Score was significantly lower in CBD than in C group at T1 (p = 0.0002), T2 (p = 0.0043) and T3 (p = 0.016). Pain Interference Score was significantly lower in CBD than in C group at T1 (p = 0.0002), T2 (p = 0.0007) and T4 (p = 0.004). Quality of Life Index was significantly higher in CBD group at T1 (p = 0.003). The addition of OTM CBD showed promising results. Further pharmacokinetics and long-term studies in larger populations are needed to encourage its inclusion into a multimodal pharmacological approach for canine osteoarthritis-related pain

Comparison of four peribulbar anaesthetic techniques: A preliminary study in equine cadavers

Objective To compare the peribulbar injectate distribution and probability of regional anaesthesia of four peribulbar anaesthetic techniques in equine cadavers. Study design Prospective experimental cadaver study. Animals A total of 12 isolated equine cadaver heads and 24 eyes. Methods The 24 orbits underwent one of four injection techniques (six orbits each) with a mixture (1:4) of contrast medium and saline (CM): 20 mL ventrolateral peribulbar injection (V-20), 20 mL dorsolateral peribulbar injection (D-20), combined ventrolateral and dorsolateral peribulbar injections 10 mL each (VD-20) or 20 mL each (VD-40). To evaluate and score CM distribution at the base of, within the extraocular muscle cone (EOMC), and around the optic nerve (before and after pressure application to the periorbital area), computed tomography was performed. To assess the probability of achieving locoregional anaesthesia, two criteria were applied and both scored as ‘likely’, ‘possible’ or ‘unlikely’. To compare CM distribution scores between injection techniques, Kruskal-Wallis analysis of variance was used. Mann-Whitney U test was used for post hoc comparisons between groups when needed. A p value < 0.05 was considered significant. Results The CM distribution within the EOMC and around the optic nerve circumference was detected as ‘possible’ only after pressure application in seven out of 24 orbits (V-20, 3; D-20, 1; VD-40, 3). It was never considered ‘likely’ either before or after pressure application. The CM distribution at the EOMC base was considered ‘likely’ to provide regional anaesthesia in 50% (V-20), 0% (D-20), 33% (VD-20), 100% (VD-40) and in 66% (V-20), 16% (D-20), 50% (VD-20), 100% (VD-40) before and after applying pressure, respectively. Conclusions and clinical relevance Complete regional anaesthesia seems more likely using the VD-40 technique, although the authors advise caution due to the risk of potential complications. Future studies are necessary to evaluate the efficacy of the technique in vivo

Clinical pharmacokinetics of a dexmedetomidine&#8211;methadone combination in dogs undergoing routine anaesthesia after buccal or intramuscular administration

This study aimed to define the pharmacokinetic profiles of dexmedetomidine and methadone administered simultaneously in dogs by either an oral transmucosal route or intramuscular route and to determine the bioavailability of the oral transmucosal administration relative to the intramuscular one of both drugs, so as the applicability of this administration route in dogs. Twelve client\u2010owned dogs, scheduled for diagnostic procedures, were treated with a combination of dexmedetomidine hydrochloride (10 \u3bcg/kg) and methadone hydrochloride (0.4 mg/kg) through an oral transmucosal route or intramuscularly. Oral transmucosal administration caused ptyalism in most subjects, and intramuscular administration caused transient peripheral vasoconstriction. The results showed reduced and delayed absorption of both dexmedetomidine and methadone when administered through an oral transmucosal route, with median (range) Cmax values of 0.82 (0.42\u20131.49) ng/ml and 13.22 (2.80\u201352.30) ng/ml, respectively. The relative bioavailability was low: 16.34% (dexmedetomidine) and 15.5% (methadone). Intramuscular administration resulted in a more efficient absorption profile, with AUC and Cmax values for both drugs approximately 10 times higher. Dexmedetomidine and methadone administered simultaneously by an oral transmucosal route using injectable formulations were not well absorbed through the oral mucosa. Nevertheless, additional studies on these drugs combination using alternative administration routes are recommended