Nicardipine constant rate infusion alleviates the cardiovascular effects of dexmedetomidine infusions without affecting the minimal alveolar concentration in sevoflurane-anesthetized dogs.

Two randomized crossover trials evaluated the effects of nicardipine constant rate infusion (CRI) on 1) the anesthetic potency of sevoflurane and 2) the ability to attenuate dexmedetomidine-induced cardiovascular depression in anesthetized dogs. First, six healthy Beagle dogs weighing 11.7 ± 0.9 kg were allocated to one of three treatments that administered a CRI of carrier (saline) or dexmedetomidine 0.5 or 3.0 µg/kg/h following a loading dose. The minimum alveolar concentration (MAC) of sevoflurane was determined utilizing electric stimuli before and after the loading dose of nicardipine (20 µg/kg intravenously for 10 min), followed by CRI at 40 µg/kg/h with 60 min of equilibration. Subsequently, cardiovascular and blood gas variables were evaluated in another trial under sevoflurane anesthesia at the individual 1.5 MAC. After baseline measurements, the dogs were assigned to two treatments (dexmedetomidine CRI at 0.5 or 3.0 µg/kg/h following a loading dose) with sevoflurane doses adjusted to 1.5 times of MAC equivalent, and the measurements were repeated every 15 min for 120 min. After 60 min, nicardipine CRI at 40 µg/kg/h with a loading dose was added to the dexmedetomidine CRI. Dexmedetomidine infusions significantly decreased the sevoflurane MAC but nicardipine did not significantly alter the MAC either with or without dexmedetomidine CRI in dogs. Dexmedetomidine dose-dependently decreased the cardiac index and increased the systemic vascular resistance index; these effects were fully counteracted by concomitant nicardipine CRI. Nicardipine CRI can be useful for controlling the cardiovascular depression elicited by dexmedetomidine in anesthetized dogs without affecting the anesthetic potency of sevoflurane.

Effects of plasma aldosterone concentration and treatment with eplerenone on the survival of cats with chronic kidney disease.

This study investigated the plasma aldosterone concentration (PAC) in cats with chronic kidney disease (CKD) and retrospectively evaluated the survival of cats with high PAC. Furthermore, this study prospectively examined eplerenone's effect on survival time in CKD cats with high PAC. The PAC was measured retrospectively in blood samples obtained from 156 client-owned cats that visited a veterinary hospital. The cats were designated into 2 groups: clinically healthy (n = 101) and those with CKD (n = 55). The PAC was measured by solid-phase radioimmunoassay; median (minimum-maximum) PAC in healthy cats was 97 pg/mL (range: 10 to 416 pg/mL) and the upper limit (95th percentile) was 243 pg/mL. In the CKD group, PAC [126 pg/mL (range: 10 to 981 pg/mL)] was higher (P < 0.01) than in the clinically healthy group. In cats with CKD, the survival time of those with high PAC (n = 16) (> 243 pg/mL) was shorter (P = 0.019) than that of those (n = 39) with normal PAC. Administering an aldosterone antagonist, eplerenone, at 2.5 to 5 mg/kg body weight prolonged survival (P = 0.005) in CKD cats with high PAC (n = 8). In conclusion, PAC could be a prognostic marker of CKD in cats and eplerenone may prolong survival in cats with CKD and a high PAC.

Effets de la concentration plasmatique d'aldostérone et du traitement à l'éplérénone sur la survie des chats atteints d'insuffisance rénale chronique. Cette étude a examiné la concentration plasmatique d'aldostérone (PAC) chez les chats atteints d'insuffisance rénale chronique (IRC) et a évalué rétrospectivement la survie des chats ayant une PAC élevée. De plus, cette étude a examiné de manière prospective l'effet de l'éplérénone sur le temps de survie chez les chats IRC avec une PAC élevée. La PAC a été mesurée rétrospectivement dans des échantillons de sang prélevés sur 156 chats appartenant à des clients ayant visité un hôpital vétérinaire. Les chats ont été répartis en 2 groupes : cliniquement sains (n = 101) et ceux atteints d'IRC (n = 55). La PAC a été mesurée par radio-immunodosage en phase solide; la PAC médiane (minimale-maximale) chez les chats sains était de 97 pg/mL (plage : 10 à 416 pg/mL) et la limite supérieure (95e centile) était de 243 pg/mL. Dans le groupe IRC, la PAC [126 pg/mL (plage : 10 à 981 pg/mL)] était plus élevée (P < 0,01) que dans le groupe cliniquement sain. Chez les chats atteints d'IRC, le temps de survie de ceux avec une PAC élevée (n = 16) (> 243 pg/mL) était plus court (P = 0,019) que celui de ceux (n = 39) avec une PAC normale. L'administration d'un antagoniste de l'aldostérone, l'éplérénone, à raison de 2,5 à 5 mg/kg de poids corporel a prolongé la survie (P = 0,005) chez les chats atteints d'IRC avec une PAC élevée (n = 8). En conclusion, la PAC pourrait être un marqueur pronostique de l'IRC chez le chat et l'éplérénone pourrait prolonger la survie des chats atteints d'IRC et d'une PAC élevée.(Traduit par Dr Serge Messier).

A randomized clinical trial on effects of alfaxalone combined with medetomidine and midazolam in preventing stress-related neurohormonal and metabolic responses of isoflurane-anesthetized cats undergoing surgery.

OBJECTIVE: To evaluate the effects of IM and IV administration of alfaxalone alone and in combination with medetomidine, midazolam, or both on key stress-related neurohormonal and metabolic changes in isoflurane-anesthetized cats undergoing ovariohysterectomy or castration. ANIMALS: 72 client-owned mixed-breed cats undergoing ovariohysterectomy or castration between October 4, 2018, and January 10, 2020. PROCEDURES: For each type of surgery, cats were assigned to 1 of 6 premedication protocols groups, with 6 cats/group: physiologic saline (0.9% NaCl) solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IV); physiologic saline solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IM); medetomidine (50 µg/kg, IM) and alfaxalone (5 mg/kg, IV); medetomidine (50 µg/kg, IM) and alfaxalone (5 mg/kg, IM); midazolam (0.5 mg/kg, IM), medetomidine (50 µg/kg, IM), and alfaxalone (5 mg/kg, IV); or midazolam (0.5 mg/kg, IM), medetomidine (50 µg/kg, IM), and alfaxalone (5 mg/kg, IM). Venous blood was taken before pretreatment, pre- and postoperatively during anesthesia with isoflurane and oxygen, and during early and complete recovery. RESULTS: Compared with baseline concentrations, plasma adrenaline and noradrenaline concentrations decreased during anesthesia in cats premedicated with alfaxalone alone and in combination with medetomidine. The combination of medetomidine, midazolam, and alfaxalone prevented an excessive increase in catecholamines during anesthesia and surgery in cats. Postoperative plasma cortisol concentration after ovariohysterectomy was lower for cats premedicated with the combination of medetomidine and alfaxalone or the combination of medetomidine, midazolam, and alfaxalone, compared with cats premedicated with alfaxalone alone. Cats treated with combinations that included medetomidine and midazolam had hyperglycemia during anesthesia. Cats treated with medetomidine or medetomidine and midazolam in combination with alfaxalone, compared with alfaxalone alone, had lower concentrations of nonesterified fatty acids during anesthesia. Behavioral recovery scores were lower (better) for cats that received medetomidine in addition to alfaxalone, compared with alfaxalone alone. CLINICAL RELEVANCE: Results indicated that pretreatments with medetomidine and alfaxalone or with medetomidine, midazolam, and alfaxalone were useful for preventing stress-related hormonal and metabolic responses, other than hyperglycemia, during isoflurane anesthesia and surgery in cats.

Reversal effects of atipamezole, flumazenil, and 4-aminopyridine on bradycardia and increases in blood pressures induced by medetomidine, midazolam, and ketamine in isoflurane-anesthetized cats.

OBJECTIVE: To investigate the effects of a fixed dose of atipamezole (AT), flumazenil (FL), and 4-aminopyridine (AP), both alone and in combination, on changes in arterial blood pressure and heart rate induced by medetomidine (ME), midazolam (MI), and ketamine (KE) under isoflurane anesthesia with controlled ventilation in healthy cats. DESIGN: Prospective experimental study. SETTING: University animal research facility. ANIMALS: Healthy adult mixed-breed cats were used for 8 investigation groups (6 cats per group), with ≥2 weeks between interventions. INTERVENTIONS: Cats were anesthetized with an end-tidal isoflurane concentration of 2% under controlled ventilation. A catheter was inserted into the right or left femoral artery for arterial pressure monitoring and blood gas sampling, and ECG electrodes were placed. Upon completed preparations, cats were administered a mixture of ME (0.05 mg/kg) and MI (0.5 mg/kg), followed 10 minutes later by intramuscular KE (10 mg/kg). Twenty minutes after KE injection, the cats received IV injection with either a physiological saline solution at 0.1 mL/kg (control), or 1 of 7 variations of experimental drugs, alone or in combination: AT (0.2 mg/kg), FL (0.1 mg/kg), AP (0.5 mg/kg), AT+FL, FL+AP, AT+AP, and AT+FL+AP. Arterial blood pressure and heart rate were continuously measured over 120 minutes after administration of potential antagonists. MEASUREMENTS AND MAIN RESULTS: ME+MI+KE induced an increase in blood pressure and bradycardia. Potential antagonists alone or in combination did not significantly alter the bradycardia. FL, AP alone, and FL+AP did not significantly alter the changes in blood pressures induced by ME+MI+KE. Meanwhile, administration of AT alone or in combination reversed the increase in blood pressure induced by ME+MI+KE but transiently caused excessive hypotension. CONCLUSION: These results revealed that AT alone or in combination is effective for antagonizing hypertension induced by ME+MI+KE; however, attention should be paid to temporary hypotension in cats anesthetized with isoflurane.

Effect of Pravastatin as an Adjunctive Therapeutic for Mitral Insufficiency with Hyperlipidemia in a Dog.

Pravastatin (PS) has been found to increase left ventricle (LV) expansion capacity and decrease LV constriction and left atrial pressure in healthy dogs. To date, there are no available reports on the effects of PS in dogs with hypercholesterolemia with chronic heart failure (CHF). This case report demonstrates a successful long-term treatment plan using PS in a dog suffering from mitral insufficiency with hyperlipidemia. A 12-year-old, castrated male Chihuahua dog had mitral insufficiency with hyperlipidemia. The dog presented with symptoms of chronic coughing. PS was orally administered (1 mg/kg, SID) in addition to general treatment for mitral insufficiency. The follow-up period was 375 days. PS administration decreased the heart rate (HR), vertebral heart size (VHS), and N-terminal probrain natriuretic peptide (NT-proBNP) concentration of the dog. In addition, PS administration also improved chronic cardiac failure induced by mitral insufficiency and hyperlipidemia. This report suggests that PS can be useful as an adjunctive therapeutic for dogs with hypercholesterolemia with mitral insufficiency.

Effects of pretreatment with medetomidine, midazolam, ketamine, and their combinations on stress-related hormonal and metabolic responses in isoflurane-anesthetized cats undergoing surgery.

OBJECTIVE: The purpose of this study was to compare the effects of pretreatment with medetomidine (Me), midazolam (Mi), and ketamine (Ke) on stress-related neurohormonal and metabolic responses in isoflurane-anesthetized cats undergoing ovariohysterectomy and castration. MATERIALS AND METHODS: We prospectively recruited 112 client-owned healthy mixed-breed cats. In both surgeries, we divided the cats into seven groups (eight cats per group): non-treatment (control), Me (50 µg/kg), Mi (0.5 mg/kg), Ke (5 mg/kg), Me + Mi, Me + Ke and Me + Mi + Ke administered intramuscularly. After pretreatments, we maintained anesthesia with isoflurane and oxygen. Venous blood was taken before pretreatment, pre- and post-operatively during anesthesia, and at early- and complete-recovery. RESULTS: Both plasma adrenaline and noradrenaline were reduced during anesthesia in all groups. Plasma cortisol increased during anesthesia and at early recovery in non-Me-treated groups, whereas it decreased in Me-treated groups in both surgeries. Plasma insulin and non-esterified fatty acid (NEFA) decreased, and glucose increased during anesthesia in all groups, but hyperglycemia and decrease in NEFA were greater in Me-treated groups. CONCLUSIONS: In isoflurane-anesthetized cats undergoing surgeries, premedication with Me alone and in combination is useful for reducing the perioperative stress-related increase in cortisol and catecholamines except for hyperglycemia.

Cardiovascular and renal effects of constant rate infusions of remifentanil, dexmedetomidine and their combination in dogs anesthetized with sevoflurane.

We evaluated changes in cardiovascular and renal functions as well as arginine vasopressin (AVP) secretion, with remifentanil and dexmedetomidine administration alone or in combination in sevoflurane-anesthetized dogs. Six healthy adult Beagle dogs received one of the following four treatments in a randomized crossover study: saline (C), remifentanil alone at successively increasing doses (R; 0.15, 0.60, and 2.40 µg/kg/min), dexmedetomidine alone (D; 0.5 µg/kg intravenously for initial 10 min followed by a constant rate infusion at 0.5 µg/kg/hr), and a combination of remifentanil and dexmedetomidine at the above-mentioned doses (RD). Sevoflurane doses were adjusted to 1.5 times of minimum alveolar concentration (MAC) equivalent according to MAC-sparing effects with remifentanil and dexmedetomidine as previously reported. Cardiovascular measurements, renal function data, and plasma AVP concentrations were determined before and every 60 min until 180 min after drug administration as per each treatment. In the R, D and RD, heart rate significantly decreased and mean arterial pressure significantly increased from baseline or with C. Cardiac index significantly decreased and systemic vascular resistance index increased with D and RD. Oxygen extraction ratio, renal blood flow, and glomerular filtration rate were not affected. The plasma AVP concentrations significantly decreased in D and RD, but increased in R. Only in D, the natriuresis was elicited. The combination of remifentanil and dexmedetomidine in sevoflurane-anesthetized dogs was acceptable in terms of the hemodynamics, oxygenation, and renal function. Remifentanil may interfere with dexmedetomidine-induced diuresis and inhibition of AVP secretion.

Effects of constant rate infusions of dexmedetomidine, remifentanil and their combination on minimum alveolar concentration of sevoflurane in dogs.

OBJECTIVE: To evaluate the effects of constant rate infusions (CRIs) of dexmedetomidine and remifentanil alone and their combination on minimum alveolar concentration (MAC) of sevoflurane in dogs. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: A total of six (three males, three females) healthy, adult neutered Beagle dogs weighing 12.6 ± 1.4 kg. METHODS: Anesthesia was induced with sevoflurane in oxygen until endotracheal intubation was possible and anesthesia maintained with sevoflurane using positive-pressure ventilation. Each dog was anesthetized five times and was administered each of the following treatments: saline (1 mL kg-1 hour-1) or dexmedetomidine at 0.1, 0.5, 1.0 or 5.0 µg kg-1 loading dose intravenously over 10 minutes followed by CRI at 0.1, 0.5, 1.0 or 5.0 µg kg-1 hour-1, respectively. Following 60 minutes of CRI, sevoflurane MAC was determined in duplicate using an electrical stimulus (50 V, 50 Hz, 10 ms). Then, CRI of successively increasing doses of remifentanil (0.15, 0.60 and 2.40 µg kg-1 minute-1) was added to each treatment. MAC was also determined after 30 minutes equilibration at each remifentanil dose. Isobolographic analysis determined interaction from the predicted doses required for a 50% MAC reduction (ED50) with remifentanil, dexmedetomidine and remifentanil combined with dexmedetomidine, with the exception of dexmedetomidine 5.0 µg kg-1 hour-1, obtained using log-linear regression analysis. RESULTS: The sevoflurane MAC decreased dose-dependently with increasing infusion rates of dexmedetomidine and remifentanil. Remifentanil ED50 values were lower when combined with dexmedetomidine than those obtained during saline-remifentanil. Synergistic interactions between dexmedetomidine and remifentanil for MAC reduction occurred with dexmedetomidine at 0.5 and 1.0 µg kg-1 hour-1. CONCLUSIONS AND CLINICAL RELEVANCE: Combined CRIs of dexmedetomidine and remifentanil synergistically resulted in sevoflurane MAC reduction. The combination of dexmedetomidine and remifentanil effectively reduced the requirement of sevoflurane during anesthesia in dogs.

Effects of Eplerenone on Blood Pressure and Echocardiographic and Serum Biochemical Variables in Five Healthy Dogs: A Pilot Study.

Eplerenone (EP), an aldosterone antagonist, is reported to produce renal and cardiac protective effects in noncanine species. However, there are no detailed reports available on cardiovascular effects of EP in dogs. This study aimed to determine effect of EP on echocardiographic parameters, blood pressures, and biochemical variables in healthy dogs. Five healthy Beagle dogs were randomly divided and repeatedly used in each of 3 dose groups, receiving 2.5, 5, or 10 mg/kg BW EP orally q24 h for 4 wks. Serum biochemical test, blood pressure, and Doppler echocardiography measurements were performed before EP administration and at 1, 2, and 4 weeks after EP administration. Treatment with EP reduced mean blood pressure in a dose-dependent manner and significantly (but in a dose-independent manner) decreased left atrium/aorta ratio, early diastolic transmitral flow, early diastolic transmitral flow/late diastolic transmitral flow, peak velocity of early diastolic transmitral flow/peak velocity of early diastolic mitral annular motion, left ventricle and right ventricle Tei indices, stroke volume, cardiac output, and mid systole myocardial velocity gradient 1 to 4 weeks after administration. Deceleration time of early diastolic transmitral flow significantly increased after EP administration. No significant changes were observed in serum biochemical variables. The results indicated that EP might reduce preload, thereby decreasing left atrial size. In addition, reduction of left ventricular stiffness may have theoretically taken place but this could not be tested using the present study design. It is suggested that EP administration within the dose range used in this study is safe for administration to healthy dogs. Further studies are needed to explore both safety and efficacy, as well as to seek a recommended dose range of EP treatment in client-owned dogs with heart disease.

Effects of imidazoline and nonimidazoline α-adrenoceptor agonists and antagonists, including xylazine, medetomidine, dexmedetomidine, yohimbine, and atipamezole, on aggregation of feline platelets.

OBJECTIVE: To examine the effects of imidazoline and nonimidazoline α-adrenergic agents on aggregation of feline platelets. SAMPLE: Blood samples from 12 healthy adult cats. PROCEDURES: In 7 experiments, the effects of 23 imidazoline and nonimidazoline α-adrenoceptor agonists or antagonists on aggregation and antiaggregation of feline platelets were determined via a turbidimetric method. Collagen and ADP were used to initiate aggregation. RESULTS: Platelet aggregation was not induced by α-adrenoceptor agonists alone. Adrenaline and noradrenaline induced a dose-dependent potentiation of ADP- or collagen-induced aggregation. Oxymetazoline and xylometazoline also induced a small potentiation of ADP-stimulated aggregation, but other α-adrenoceptor agonists did not induce potentiation. The α2-adrenoceptor antagonists and certain imidazoline α-adrenergic agents including phentolamine, yohimbine, atipamezole, clonidine, medetomidine, and dexmedetomidine inhibited adrenaline-potentiated aggregation induced by ADP or collagen in a dose-dependent manner. The imidazoline compound antazoline inhibited adrenaline-potentiated aggregation in a dose-dependent manner. Conversely, α1-adrenoceptor antagonists and nonimidazoline α-adrenergic agents including xylazine and prazosin were ineffective or less effective for inhibiting adrenaline-potentiated aggregation. Moxonidine also was ineffective for inhibiting adrenaline-potentiated aggregation induced by collagen. Medetomidine and xylazine did not reverse the inhibitory effect of atipamezole and yohimbine on adrenaline-potentiated aggregation. CONCLUSIONS AND CLINICAL RELEVANCE: Adrenaline-potentiated aggregation of feline platelets may be mediated by α2-adrenoceptors, whereas imidazoline agents may inhibit in vitro platelet aggregation via imidazoline receptors. Imidazoline α-adrenergic agents may have clinical use for conditions in which there is platelet reactivity to adrenaline. Xylazine, medetomidine, and dexmedetomidine may be used clinically in cats with minimal concerns for adverse effects on platelet function.

Effects of masitinib compared with tadalafil for the treatment of monocrotaline-induced pulmonary arterial hypertension in rats.

Targeting vascular remodeling in pulmonary arterial hypertension (PAH) remains a challenge given the lack of potent anti-remodeling abilities of the therapeutic drugs. Although sildenafil has been shown to ameliorate cardiopulmonary remodeling, that of tadalafil is questionable. Masitinib, a tyrosine kinase inhibitor appears safer and more potent than imatinib for treatment of malignancies, but its efficacy on PAH is unknown. Therefore, we investigated the anti-remodeling properties of masitinib (5, 15, 50 mg/kg) and tadalafil (5, 10 mg/kg) using a monocrotaline-induced rat model of PAH. The 14-day treatment with masitinib (15, 50 mg/kg) resulted in significantly decreased right ventricular (RV) systolic pressure (RVSP) and hypertrophy (RVH), and pulmonary vascular remodeling, whereas tadalafil showed weaker anti-remodeling properties. Besides, masitinib significantly blocked the mitogen-associated protein kinase (MAPK) pathway, and reduced phosphodiesterase (PDE)-5 mRNA expression in the lungs. By contrast, tadalafil did not significantly inhibit the MAPK pathway. Further, the 28-day treatment extension revealed that masitinib-treated rats (15 mg/kg) had significantly lower RVSP, and higher heart rate and serum cyclic guanosine monophosphate (cGMP) level, whereas those treated with tadalafil (10 mg/kg) showed insignificantly lower RVSP and higher cGMP level. Moreover, the RVH indices, heart rates, body weight gains, and survival rates of rats in both groups were comparable. Collectively, these results suggest that the treatment with a low-dose masitinib was non-inferior than tadalafil. A lower dose of masitinib may represent a novel approach to target both the cardiopulmonary remodeling and the dysregulated vasoconstriction in PAH.

Assessment of urinary pharmacokinetic and pharmacodynamic profiles of faropenem against extended-spectrum ß-lactamase-producing Escherichia coli with canine ex vivo modelling: a pilot study.

This study was carried out to investigate the urinary pharmacokinetics and pharmacodynamics of faropenem administered orally at 5 mg kg-1 in six healthy dogs to assess the efficacy of the drug for canine urinary tract infections (UTIs) with extended-spectrum ß-lactamase (ESBL)-producing bacteria. Six strains of ESBL-producing Escherichia coli (ESBL-EC) with the following faropenem minimum inhibitory concentrations (MICs) were used: 1 µg ml-1 (n=2), 2 µg ml-1 (n=2), 4 µg ml-1 (n=1) and 16 µg ml-1 (n=1). Urine samples were obtained every 4 h for the first 12 h after administration to measure urinary drug concentration and urinary bactericidal titres (UBTs). Both the urine concentration of faropenem and the UBTs for all tested strains peaked at 0-4 h after administration, and decreased markedly at 8-12 h. The mean urinary concentration of faropenem at 8-12 h (23±5.2 µg ml-1) exceeded the MIC of 1 µg ml-1 by fourfold, which is required to inhibit the growth of 90  % of ESBL-EC. These findings indicate that faropenem administered twice daily at a dose of 5 mg kg-1 is acceptable for the treatment of most dogs with ESBL-EC-related UTIs.

Effects of toceranib compared with sorafenib on monocrotaline-induced pulmonary arterial hypertension and cardiopulmonary remodeling in rats.

Sorafenib reverses pulmonary arterial hypertension (PAH) and cardiopulmonary remodeling (CPR), but the effects of toceranib are unknown. This study investigated anti-remodeling effects and determined optimal doses of toceranib and sorafenib on monocrotaline (MCT)-induced PAH and CPR in rats. MCT-treated rats were orally treated with a 14-day course of sorafenib (10, 30, or 100 mg/kg), toceranib (1, 3, or 10 mg/kg), or water. Both sorafenib and toceranib significantly reversed the right ventricular (RV) hypertrophy at 10 mg/kg, but only sorafenib significantly improved the RV systolic and mean pressures. Sorafenib significantly normalized the B-type natriuretic peptide mRNA level of the RV and increased the non-muscularized pulmonary artery percentage. However, these effects were only observed at the highest toceranib dose, and neither toceranib dose reduced the fully muscularized pulmonary artery percentage. Further, the inhibition on vascular endothelial growth factor (VEGF) signaling was stronger in sorafenib than in toceranib. Besides the stronger inhibition on mitogen-activated protein kinase signaling, the greater reversal ability of sorafenib may be also due to the simultaneous blockade on the C-X-C chemokine receptor type 4 and autophagy induction. Toceranib insignificantly reversed CPR, and a high-dose therapy did not improve the RV hemodynamic outcomes. Sorafenib significantly reversed CPR, and a low-dose sorafenib therapy may be a suitable therapeutic agent for PAH.

The effect of remifentanil on the minimum alveolar concentration (MAC) and MAC derivatives of sevoflurane in dogs.

Remifentanil is an ultra-short-acting µ-opioid receptor agonist. The purpose of this study was to determine the relationship of the minimum alveolar concentration (MAC) of sevoflurane and other MAC derivatives, including the MAC for blocking adrenergic responses (MAC-BAR) and the MAC at which tracheal extubation is occurred (MAC-extubation), with or without remifentanil infusion. Six healthy adult beagle dogs were randomly anesthetized three times for determining the MAC-BAR (SEVMAC-BAR), MAC (SEVMAC), and MAC- extubation (SEVMAC-extubation) of sevoflurane under infusion of saline and remifentanil at rates of 0.15, 0.30, 0.60, 1.20, and 2.40 µg/kg/min. The ratio of the SEVMAC-BAR and SEVMAC and that of the SEVMAC-extubation and SEVMAC were not significantly different at baseline and during treatment. The MAC-BAR95 and MAC95 decreased in a dose-dependent manner until reaching 1.20 µg/kg/min, and the MAC-extubation5 decreased in a dose-dependent manner until reaching 0.60 µg/kg/min. The percentage reduction of SEVMAC-BAR, SEVMAC, and SEVMAC-extubation increased in a dose-dependent manner during remifentanil infusion. The heart rate significantly decreased in the MAC-BAR and MAC groups, and the systolic and mean arterial pressures increased after remifentanil infusion compared with the baseline values. Remifentanil infusion caused reduction of the SEVMAC-BAR, SEVMAC, and SEVMAC-extubation in a dose-dependent manner, and ceiling effects were observed in the dogs. Higher doses of remifentanil and sevoflurane were necessary for blocking the sympathetic response to the supramaximal stimulus to prevent movement and extubation in dogs.

Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats.

High-dose imatinib reverses cardiopulmonary remodeling but adverse effects limit its clinical use. Efficacy of the multi-kinase inhibitor sunitinib remains questionable. We compared anti-remodeling effects of imatinib with sunitinib on monocrotaline-induced right ventricular (RV) hypertrophy and pulmonary arterial remodeling in rats, focusing on a lower dose. Fourteen days after monocrotaline injection, oral gavage of imatinib (5, 15, or 50mg/kg), sunitinib (0.3, 1, 3, or 10mg/kg), or water for 14days was started. RV hypertrophy and b-type natriuretic peptide mRNA levels were significantly and dose-dependently reduced, much greater in imatinib- than sunitinib-treated groups. Imatinib normalized muscularization of 20-50µm intra-acinar pulmonary arteries more significantly than sunitinib. At transcript levels, sunitinib significantly upregulated pulmonary nestin, and downregulated platelet-derived growth factor receptor beta (PDGFR-ß), fibroblast growth factor receptor 1, vascular endothelial growth factor receptor-2 and vascular endothelial growth factor (VEGF)-A, but not Raf-1 proto-oncogene serine/threonine kinase mRNAs. Sunitinib also suppressed VEGF-A, but not phosphorylated extra-cellular-signal-related kinase (ERK)-1/2 protein expression. The sole PDGFR-ß antagonism of imatinib resulted in significant Raf-1 mRNA and phosphorylated ERK-1/2 protein downregulation, suggesting that the equivocal reversal effect of sunitinib may be due to its VEGF signaling inhibition in the lung. Imatinib's greater dose-dependent reversal on cardiopulmonary remodeling may make a low dose suitable for PAH treatment.

In vitro efficacy of 16 antimicrobial drugs against a large collection of ß-lactamase-producing isolates of extraintestinal pathogenic Escherichia coli from dogs and cats.

PURPOSE: The aim of this study was to assess the in vitro efficacy of candidate antimicrobials against extended-spectrum ß-lactamase (ESBL)-producing isolates of extraintestinal pathogenic Escherichia coli (ExPEC) from companion animals. METHODOLOGY: A total of 90 ESBL-producing ExPEC isolates from dogs and cats were tested for susceptibility to 16 antimicrobials with the agar dilution method. We also identified the ESBLs and AmpC ß-lactamases of these isolates with PCR and DNA sequencing.Results/Key findings. All isolates were susceptible to meropenem, tebipenem and amikacin (AMK), and various proportions were susceptible to latamoxef (LMX, 97.8 %), fosfomycin (FOM, 97.8 %), faropenem (FPM, 96.7 %), nitrofurantoin (NFT, 96.7 %), flomoxef (FMX, 93.3 %), piperacillin/tazobactam (PTZ, 92.2 %), cefmetazole (CMZ, 91.1 %), chloramphenicol (80.0 %), trimethoprim/sulfamethoxazole (64.4 %), amoxicillin/clavulanic acid (63.3 %), ceftibuten (60.0 %), tetracycline (52.2 %) and enrofloxacin (10.0 %). A genetic analysis showed that 83 of the 90 (92.2 %) isolates were positive for CTX-M-type genes: CTX-M-14 (n=26), CTX-M-27 (n=20), CTX-M-55 (n=17), CTX-M-15 (n=12), CTX-M-2 (n=5), CTX-M-24 (n=2), CTX-M-104 (n=2) and CTX-M-3 (n=1). Eight isolates also expressed AmpC ß-lactamase phenotypes. CONCLUSION: This study demonstrates that the susceptibility rates to PTZ, CMZ, LMX, AMK, FOM, FPM, NFT and FMX were similar to those to carbapenems (>90 %), implying that these drugs are available alternatives to carbapenems for the treatment of companion animals infected with ExPEC-producing CTX-M-type ESBLs. Further in vivo studies of the effective use of these antimicrobials are required.

Assessment of urinary pharmacokinetics and pharmacodynamics of orbifloxacin in healthy dogs with ex vivo modelling.

PURPOSE: The aim of this study was to investigate the urinary pharmacokinetics (PK) of orbifloxacin (OBFX) administered at 5 mg kg-1 in six healthy dogs. A further aim was to use an ex vivo model to evaluate the urinary PK and pharmacodynamics (PD) of OBFX to determine its urinary bactericidal titre (UBT), which represents the maximal dilution of urine allowing bactericidal activity. METHODOLOGY: Fourteen urinary tract infection (UTI) pathogenic strains of five bacterial species (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis and Staphylococcuspseudintermedius) were used. Urine samples were obtained every 4 h for the first 24 h after OBFX administration, for measurement of urine drug concentration and UBT.Results/Key findings. The urine OBFX concentration peaked at 0-4, 4-8 or 4-8 h after administration, with a maximum concentration of 383±171 µg ml-1. Overall, the fluctuation in median UBT closely correlated with that of the mean urine OBFX concentration. In addition, the median areas under the UBT-time curves (AUBTs) were significantly inversely correlated with the MICs for OBFX in the tested strains (P<0.01). Notably, median UBTs and AUBTs were extremely low (0-0.5 and 2-5, respectively) in OBFX-resistant E. coli strains with MIC ≥8 µg ml-1. CONCLUSION: The fluctuation of UBTs closely correlated with that of urine concentration, and UBT values depended on the susceptibility of the bacterial strains to OBFX. We believe that ex vivo modelling to determine UBTs is useful to evaluate the urinary PK/PD of antimicrobials indicated for UTIs in dogs.

Effects in cats of atipamezole, flumazenil and 4-aminopyridine on stress-related neurohormonal and metabolic responses induced by medetomidine, midazolam and ketamine.

This study aimed to investigate the antagonistic effects of a fixed dose of atipamezole (ATI), flumazenil (FLU) and 4-aminopyridine (4AP), both alone and in various combinations, on key stress-related neurohormonal and metabolic changes induced by medetomidine (MED), midazolam (MID) and ketamine (KET) in healthy cats. Seven cats were used consistently in eight investigation groups. Cats were administered a mixture of 0.05 mg/kg MED and 0.5 mg/kg MID followed 10 mins later by 10 mg/kg KET intramuscularly. Twenty minutes after KET injection, the cats were intravenously injected with either a physiological saline solution at 0.1 ml/kg (control) or one of the seven variations of experimental drugs, alone or in combination: ATI, FLU, 4AP, ATI + FLU, FLU + 4AP, ATI + 4AP and ATI + FLU + 4AP. Blood samples were collected 10 times during the 24 h test period. Plasma glucose, insulin, cortisol, epinephrine, norepinephrine and non-esterified fatty acid levels were measured. The administration of MED + MID + KET resulted in hyperglycaemia and decreases in epinephrine, norepinephrine, cortisol and non-esterified fatty acid levels. FLU or 4AP alone or FLU + 4AP did not effectively antagonise the effects induced by MED + MID + KET but enhanced the hyperglycaemia. ATI alone was effective in antagonising these effects. Compared with non-ATI regimens, combinations with ATI were more effective in antagonising the effects induced by MED + MID + KET; however, ATI + FLU + 4AP caused large increases in cortisol, epinephrine and norepinephrine concentrations. ATI, both alone and in combination, is effective in antagonising the neurohormonal and metabolic effects of MED + MID + KET in cats. However, ATI + FLU + 4AP is not suitable because of large stress-related hormonal responses.

The efficacy of artemisinin, artemether, and lumefantrine against Babesia gibsoni in vitro.

Artemisinin has many derivatives, and it is effective against Plasmodium spp. However, only a limited number of reports have confirmed the efficacy of artemisinin derivatives against Babesia spp. In this study, whether artemisinin and artemether could inhibit the growth of Babesia gibsoni was evaluated in vitro. In addition, the interaction between artemether and lumefantrine was evaluated. These drugs inhibited the growth of B. gibsoni, but artemisinin and artemether showed lower sensitivity against atovaquone-resistant B. gibsoni than against wild-type B. gibsoni. The interaction between artemether and lumefantrine showed synergism against B. gibsoni. Although further study is needed, the combination of artemisinin derivatives could be useful for babesiosis.

Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats.

This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats. Five cats were repeatedly used in each of the 9 groups. One group was not medicated. Cats in the other groups received 2 mg/kg BW xylazine intramuscularly, and saline (as the control); 160 µg/kg BW prazosin; or 40, 160, or 480 µg/kg BW atipamezole or yohimbine intravenously 0.5 h later. Urine and blood samples were collected 10 times over 8 h. Urine volume, pH, and specific gravity; plasma arginine vasopressin (AVP) concentration; and creatinine, osmolality, and electrolyte values in both urine and plasma were measured. Both atipamezole and yohimbine antagonized xylazine-induced diuresis, but prazosin did not. The antidiuretic effect of atipamezole was more potent than that of yohimbine but not dose-dependent, in contrast to the effect of yohimbine at the tested doses. Both atipamezole and yohimbine reversed xylazine-induced decreases in both urine specific gravity and osmolality, and the increase in free water clearance. Glomerular filtration rate, osmolar clearance, and plasma electrolyte concentrations were not significantly altered. Antidiuresis of either atipamezole or yohimbine was not related to the area under the curve for AVP concentration, although the highest dose of both atipamezole and yohimbine increased plasma AVP concentration initially and temporarily, suggesting that this may in part influence antidiuretic effects of both agents. The diuretic effect of xylazine in cats may be mediated by α2-adrenoceptors but not α1-adrenoceptors. Atipamezole and yohimbine can be used as antagonistic agents against xylazine-induced diuresis in clinically normal cats.

La présente étude visait à examiner et comparer les effets antagonistes de l'atipamezole, la yohimbine et le prazosin sur la diurèse induite par la xylazine chez des chats cliniquement normaux. Cinq chats furent utilisés de manière répétée dans chacun des neuf groupes. Un groupe n'était pas médicamenté. Les chats dans les autres groupes reçurent de la xylazine par voie intramusculaire à un dosage de 2 mg/kg de poids corporel (PC), et de la saline (comme témoin); 160 µg/kg PC de prazosin; ou 40, 160, ou 480 µg/kg PC d'atipamezole ou de yohimbine par voie intraveineuse 0,5 h plus tard. Des échantillons d'urine et de sang furent prélevés 10 fois sur une période de 8 h. On mesura le volume, le pH, et la gravité spécifique de l'urine; la concentration plasmatique d'arginine vasopressine (AVP); les valeurs de créatinine, d'osmolalité, et d'électrolytes dans l'urine et le plasma ont également été mesurées. Autant l'atipamezole que la yohimbine ont antagonisé la diurèse induite par la xylazine, mais pas le prazosin. L'effet antidiurétique de l'atipamezole était plus puissant que celui de la yohimbine mais n'était pas dose-dépendant, contrairement à l'effet de la yohimbine aux doses testées. Autant l'atipamezole que la yohimbine ont renversé les diminutions induites par la xylazine de la gravité spécifique et l'osmolalité de l'urine, et l'augmentation de la clairance de l'eau libre. Le taux de filtration glomérulaire, la clairance osmolaire, et les concentrations d'électrolytes plasmatiques n'étaient pas affectés de manière significative. L'antidiurèse de l'atipamezole ou la yohimbine n'était pas liée à la surface sous la courbe de la concentration d'AVP, bien que les doses les plus élevées d'atipamezole et de yohimbine augmentèrent initialement et de manière temporaire la concentration d'AVP plasmatique, suggérant ainsi que ceci pourrait influencer partiellement les effets antidiurétiques de ces deux agents. L'effet diurétique de la xylazine chez les chats peut être médié par des adrénorécepteurs-α2 mais pas par des adrénorécepteurs-α1. L'atipamezole et la yohimbine peuvent être utilisés comme agents antagonistes contre la diurèse induite par la xylazine chez des chats cliniquement normaux.(Traduit par Docteur Serge Messier).