Effects of oral cisapride administration in chinchillas (Chinchilla lanigera) with experimentally induced fecal output reduction

BackgroundCisapride, a prokinetic drug, has been anecdotally recommended in chinchillas at a dose of 0.5 mg/kg PO q8-12h to treat gastrointestinal hypomotility. However, studies in other rodent species suggest that higher doses are necessary to be effective.MethodsIn two randomized, placebo-controlled, blinded, crossover studies, the effects of cisapride (10 mg/kg PO q12h for four doses), administered with or without concurrent syringe feeding of a critical care formula (25 mL/kg PO q12h for two doses) were evaluated in chinchillas following recovery from sedation induced by alfaxalone-butorphanol. Food intake and fecal output were quantified to assess the effects of cisapride on these parameters.ResultsOver the first 24 hours after recovery from sedation, animals that received cisapride and syringe feeding had the least reduction in fecal output (-27 ± 23%) compared to the control treatment (-48 ± 22%, P = 0.008) or to animals which received syringe feedings alone (-40 ± 23%, P = 0.12). Cisapride administered without concurrent syringe feedings had no effect on fecal output. No adverse effects were recorded following the administration of cisapride.Conclusions and clinical relevanceThe oral administration of cisapride at 10 mg/kg q12h in conjunction with syringe feeding resulted in a slight, but not clinically relevant, attenuation of fecal output reduction by ~13% compared to syringe feedings alone and by ~20% compared to no treatment. Without the concurrent administration of syringe feedings, cisapride had no effect on fecal output in chinchillas.     

Bioavailability and pharmacokinetics of metronidazole in fed and fasted horses

Britzi, M., Gross, M., Lavy, E., Soback, S., Steinman, A. Bioavailability and pharmacokinetics of metronidazole in fed and fasted horses. J. vet. Pharmacol. Therap. 33 , 511–514. Metronidazole (1‐[2‐hydroxyethyl]‐2‐methyl‐5‐nitroimidazole) is a bactericidal antimicrobial agent used for treatment of infectious diseases caused by anaerobic bacteria and protozoa. Pharmacokinetics of metronidazole following its administration to horses was previously described ( Sweeney et al., 1986 ; Baggot et al., 1988 ; Specht et al., 1992 ; Steinman et al., 2000 ). The bioavailability (F) was 85% (ranging from 57% to 105%) and the time to reach maximum serum concentration (t_max) was 1–2 h after oral dose at 25 mg/kg body weight ( Sweeney et al., 1986 ). Baggot et al. (1988) found that F was 74.5% (ranging from 58.4% to 91.5%) and t_max was 1.5 h after oral dose at 20 mg/kg body weight. Specht et al. (1992) reported that F was 97% (ranging from 79% to 111%) and t_max was 40 min after oral dose at 15 mg/kg body weight. In an earlier study by our group F was 74% and t_max was 65 min after oral dose at 20 mg/kg body weight ( Steinman et al., 2000 ). These individual variations in F might be partially explained by the effect of feed, among other factors, mainly on metronidazole absorption. Interactions between food and drugs may reduce or increase the drug effect. The majority of clinically relevant food–drug interactions are caused by food‐induced changes on the bioavailability of the drug ( Schmidt & Dalhoff, 2002 ). In dogs, absorption of metronidazole is enhanced when given with food, but delayed in humans ( Plumb, 1995 ). Although, metronidazole is used commonly to treat various clinical conditions in horses with relatively little adverse effects ( Sweeney et al., 1991 ), narrow margin of safety was suggested because histological evidence of peripheral neurotoxicity and hepatotoxicity were noted in horses treated with doses as low as 30 mg/kg body weight every 12 h orally for 30 days ( White et al., 1996 ). For drugs with a narrow therapeutic index, even small changes in dose–response effects can have significant consequences ( Schmidt & Dalhoff, 2002 ).     

Disposition of metronidazole in hens (Gallus gallus) and quails (Coturnix coturnix japonica): pharmacokinetics and whole-body autoradiography

Hens were given single intravenous or oral doses (30 mg/kg body weight) of metronidazole and the plasma concentrations of the drug were determined by high-performance liquid chromatography (HPLC) at intervals from 10 min to 24 h after drug administration. Pharmacokinetic variables were calculated by the Lagrange algorithm technique. The elimination half-life ( t _1/2β) after the intravenous injection was 4.2 ± 0.5 h, the volume of distribution ( V _d(ss)) 1.1±0.2 L/kg and the total body clearance ( Cl _B) 131.2 ± 20 mL/h.kg. Oral bioavailability of the metronidazole was 78 ± 16%. The plasma maximum concentration ( C _max) 31.9 ± 2.3 μg/mL was reached 2 h after the oral administration and the oral elimination half-life ( t ₁/2β) was 4.7 ± 0.2 h. The binding of metronidazole to proteins in hen plasma was very low (less than 3%). Whole body autoradiography of [³H] metronidazole in hens and quails showed an even distribution of labelled material in various tissues at short survival intervals (1-4 h) after oral or intravenous administration. A high labelling was seen in the contents of the small and large intestines. In the laying quails a labelling was also seen in the albumen and in a ring in the periphery of the yolk at long survival intervals. Our results show that a concentration twofold above the MIC is maintained in the plasma of hens for at least 12 h at an oral dose of 30 mg/kg metronidazole.     

Putative metronidazole neurotoxicosis in a cat

A presumptive case of metronidazole toxicity in a 3.4-kg adult cat is described. The cat had been treated for suspected inflammatory bowel disease with an anti-inflammatory dose of prednisone and metronidazole (73.5-147 mg/kg PO q24h) for approximately 40 days prior to presentation. Clinical signs were primarily related to the central nervous system, including acute tetraparesis, unresponsiveness, tremors, and vocalization. The patient was euthanatized after 12 days of supportive care. Necropsy revealed no significant macroscopic lesions. Histologic evaluation revealed multifocal, fairly well-demarcated foci of necrosis in the brainstem, extending from the diencephalon to the medulla oblongata. To our knowledge, this is the first report to document histologic lesions associated with metronidazole administration in a cat.     

ANTINOCICEPTIVE EFFICACY AND SAFETY OF SUBCUTANEOUS TRAMADOL IN CHINCHILLAS (CHINCHILLA LANIGERA)

Tramadol has been demonstrated to provide analgesia in rats and mice and has been increasingly used in other small companion mammals for treatment of moderate to severe pain. Currently no evidence is available that supports the use of tramadol as an effective analgesic in chinchillas. The purpose of this study was to evaluate the antinociceptive efficacy and safety of subcutaneously administered tramadol in chinchillas. Initial dose-escalation studies were performed to determine if dose-dependent adverse effects occur in chinchillas. At 60 mg/kg subcutaneously (SC), but not at lower doses, tramadol induced clinically significant dose-limiting adverse effects, consisting of whole body tremors and facial muscle fasciculation. Therefore, in a subsequent analgesimetry experiment, tramadol was evaluated at a single dose of 10, 20, and 40 mg/kg SC in a randomized, blinded, controlled, complete crossover design. Thermal antinociceptive efficacy was determined by measuring hindlimb withdrawal latencies following a thermal noxious stimulus (Hargreaves’ method) at 0, 1, 2, 4, and 8 hours after drug administration. Changes in daily food intake and fecal output following tramadol administration were measured. At 10 to 40 mg/kg SC no thermal antinociceptive effects could be demonstrated. A self-limiting and transient significant reduction in food intake and fecal output occurred in a dose-dependent manner when tramadol was administered at 20 and 40 mg/kg. Based on the results of this study tramadol cannot be recommended as an analgesic drug in chinchillas.     

The pharmacokinetics and in vitro cyclooxygenase selectivity of deracoxib in horses

Davis, J. L., Marshall, J. F., Papich, M. G., Blikslager, A. T., Campbell, N. B. The pharmacokinetics and in vitro cyclooxygenase selectivity of deracoxib in horses. J. vet. Pharmacol. Therap. 34 , 12–16. The purpose of this study was to determine the pharmacokinetics of deracoxib following oral administration to horses. In addition, in vitro equine whole blood cyclooxygenase (COX) selectivity assays were performed. Six healthy adult horses were administered deracoxib (2 mg/kg) orally. Plasma samples were collected prior to drug administration (time 0), and 10, 20, 40 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after administration for analysis with high pressure liquid chromatography using ultraviolet detection. Following PO administration, deracoxib had a long elimination half‐life (t_1/2k₁₀) of 12.49 ± 1.84 h. The average maximum plasma concentration (C_max) was 0.54 μg/mL, and was reached at 6.33 ± 3.44 h. Bioavailability was not determined because of the lack of an IV formulation. Results of in vitro COX selectivity assays showed that deracoxib was selective for COX‐2 with a COX‐1/COX‐2 ratio of 25.67 and 22.06 for the IC₅₀ and IC₈₀, respectively. Dosing simulations showed that concentrations above the IC₈₀ for COX‐2 would be maintained following 2 mg/kg PO q12h, and above the IC₅₀ following 2 mg/kg PO q24h. This study showed that deracoxib is absorbed in the horse after oral administration, and may offer a useful alternative for anti‐inflammatory treatment of various conditions in the horse.     

Effects of midazolam and lorazepam on food intake in budgerigars (Melopsittacus undulatus)

BackgroundMidazolam has been shown to increase food intake in budgerigars. However, its effect on appetite beyond one hour after administration is unknown. Lorazepam is a longer-acting benzodiazepine and may provide more sustained appetite-stimulating effects in birds, but currently, no information on its appetite or sedative effects in budgerigars is available.MethodsIn a randomized, placebo-controlled, blinded, complete crossover study, the effects of midazolam (1 mg/kg IM) or lorazepam (1 mg/kg IM) were compared to a control treatment (1 ml/kg sterile water IM) in healthy adult budgerigars (n = 22). Food intake was measured for one hour before and twelve hours after drug administration. Behavioral changes and adverse effects were monitored by video recording.ResultsCompared to the control treatment, food intake increased significantly following midazolam and lorazepam administration in the first hour after drug administration. The total amount of food ingested over time was significantly higher for the first five hours after midazolam or lorazepam administration compared to the control treatment. Sedation occurred for the first three hours after drug administration with both drugs. There was no clinical or statistical significance difference between lorazepam and midazolam regarding appetite stimulation or sedative effects in this study.Conclusions and clinical relevanceBoth midazolam and lorazepam are potent, short-acting appetite stimulants in budgerigars. To induce a sustained increase in food intake, the repeated administration of these drugs would be required. The use of lorazepam does not appear to provide any advantages compared to the more widely available and frequently used midazolam in budgerigars.     

Effects of oral administration of metronidazole on small intestinal bacteria and nutrients of cats

OBJECTIVE: To determine effects of oral administration of metronidazole on the number and species of duodenal bacteria and selective nutrients of cats. ANIMALS: 6 healthy domestic shorthair cats. PROCEDURE: Undiluted duodenal fluid was obtained for quantitative and qualitative bacterial culture to determine species and number of bacteria in healthy cats. Blood samples were assayed for taurine, total protein, albumin, cobalamin, and folate concentrations. Cats then were given metronidazole (20 mg/kg of body weight, PO, q 12 h) for 1 month, after which bacterial cultures and serum assays of nutrients were repeated. Nine months after cessation of antibiotic treatment, duodenal bacteria were re-evaluated and serum was assayed for total protein, albumin, cobalamin, and folate concentrations. RESULTS: Oral administration of metronidazole caused a significant decrease in aerobic and anaerobic bacterial counts in the duodenum of healthy cats, accompanied by emergence of Streptococcus spp and Corynebacterium spp. Serum concentrations of cobalamin and albumin increased when duodenal bacterial counts were decreased, although changes in folate or taurine concentrations were not detected. Measured variables did not differ, when comparing results obtained before and 9 months after cessation of metronidazole. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of metronidazole decreased the number of aerobic bacteria and altered indigenous flora in the small bowel of cats. Normal duodenal flora appeared to be stable, because species of bacteria were re-established by 9 months after cessation of metronidazole. Bacterial flora appeared to have an impact on nutrients, because albumin and cobalamin increased during antibiotic administration and returned to preadministration concentrations after cessation of the antimicrobial.     

Evaluation of antiplatelet effects of ticlopidine in cats

OBJECTIVE: To determine whether ticlopidine exerts an antiplatelet effect, estimate the pharmacodynamics of ticlopidine, and evaluate any acute adverse effects associated with administration of ticlopidine in cats. ANIMALS: 8 domestic purpose-bred sexually intact male cats. PROCEDURE: Ticlopidine was administered orally (50 mg, q 24 h; 100 mg, q 24 h; 200 mg, q 24 h; and 250 mg, q 12 h). Each treatment period consisted of 10 days of drug administration. Platelet aggregation studies with adenosine diphosphate (ADP) and collagen and evaluation of oral mucosal bleeding times (OMBTs) were performed on days 3, 7, and 10 during each drug administration. Serotonin was measured to evaluate secretion at baseline and on day 10 for cats that received the 250-mg dosage. RESULTS: A significant reduction in platelet aggregation was detected in response to ADP on days 7 and 10 at 100 mg, on day 3 at 200 mg, and on days 3, 7, and 10 at 250 mg. A significant increase in the OMBT and decrease in serotonin release on day 10 at 250 mg was also detected; however, the cats had anorexia and vomiting at the 250-mg dosage. CONCLUSIONS AND CLINICAL RELEVANCE: Although there was a consistent antiplatelet effect at the 250-mg dosage, there was dose-dependent anorexia and vomiting that we conclude precludes the clinical usefulness of this drug in cats.     

Pharmacokinetics,renal clearance and metabolism of ciprofloxacin following intravenous and oral administration to calves and pigs

Summary

The pharmacokinetics of ciprofloxacin, a quinoline derivative with marked bactericidal activity against gram‐negative bacteria, was studied in calves and pigs following intravenous and oral administration.

Ciprofloxacin was rapidly and well distributed in the body, exhibited a short elimination half‐life of 2.5 h in both species, and was rapidly absorbed after oral administration (T_max:2 to 3 h). The oral bioavailability in calves to was 53 ± 14% and for 1 pig 37.3%.

The renal clearance of the unbound ciprofloxacin for both species was of the same order, indicated a predominantly tubular secretion pattern, and accounted for about 46% of the total drug elimination. No complete drug mass balance could be demonstrated. Small amounts of two metabolites were detected in the urine of calves, but not in pig urine.     

Orally administered doxycycline accumulates in synovial fluid compared to plasma

Reasons for performing study: Tetracycline compounds have been used to slow the progression of osteoarthritis (OA) and rheumatoid arthritis but the concentration of doxycycline attained in synovial fluid following oral, low‐dose administration has yet to be determined. Objective: To determine the concentration of doxycycline in synovial fluid following oral, low‐dose administration. Methods: Six mature horses received doxycycline (5 mg/kg bwt q. 12 h for 5 doses). Venous blood and synovial fluid samples were collected at t = 0, 0.25, 0.5, 1, 12, 24, 48 and 72 h. Doxycycline concentrations were measured using reverse phase high pressure liquid chromatography with ultraviolet detection. Results: Doxycycline concentrations at all time points after t = 0 were above the lower limit of quantification for the assay. Plasma concentrations of doxycycline were above 0.21 µg/ml at t = 0.5 h. The mean ± s.d. peak concentration (C_max) of doxycycline in plasma was 0.37 ± 0.22 µg/ml and time to peak concentration was 0.54 ± 0.19 h. Synovial fluid concentrations of doxycycline were above 0.12 µg/ml 1 h after drug administration. The mean C_max of doxycycline in the synovial fluid was 0.27 ± 0.10 µg/ml. The penetration factor of doxycycline from plasma into synovial fluid, as determined by a ratio of the area‐under‐the‐curve for synovial fluid:plasma during the sampling period, was 4.6. Potential relevance: Orally administered doxycycline distributes easily into synovial fluid with a penetration factor of 4.6. Terminal half‐life of the drug in synovial fluid was longer than in the plasma, indicating possible accumulation in this compartment. Further in vivo studies are warranted to define a medication protocol prior to routine clinical use of doxycycline for the treatment of OA.     

Pharmacokinetics of metronidazole given to horses by intravenous and oral routes

Serum and peritoneal fluid concentrations of metronidazole were determined in 6 healthy adult horses given the drug (25 mg/kg) by IV or oral routes. The disposition of metronidazole in horses given the drug by the IV route conformed to a 2-compartment model with a distribution half-life of 0.16 hours, an elimination half-life of 2.9 hours, and a body clearance of 0.40 +/- 0.05 L/kg/hr. The oral absorption half-life was 0.40 hours, and the bioavailability, 85.0 +/- 18.6%. Peritoneal fluid concentrations were approximately equal to serum concentrations at all times, regardless of the route of administration. On the basis of reported minimal inhibitory concentrations for anaerobic bacteria, a dosage of 15 to 25 mg/kg given orally 4 times daily was recommended.     

Pharmacokinetics and pharmacodynamics of repeat dosing of gabapentin in adult horses

BackgroundThe repeated administration of high doses of gabapentin may provide better analgesia in horses than current clinical protocols.Hypothesis and ObjectivesAdministration of gabapentin at 40 and 120 mg/kg PO q 12 h for 14 days will not alter serum biochemistry findings or cause adverse effects. Our objectives were to evaluate the effect of gabapentin on serum biochemistry, physical examination, and plasma pharmacokinetics of gabapentin.AnimalsSix healthy adult mares.MethodsHorses received 40 and 120 mg/kg of gabapentin orally q 12 h for 14 days. Horses were examined and scored for ataxia and sedation daily. Serum biochemistry variables were analyzed before treatment and days 7 and 14 after gabapentin administration. Plasma disposition of gabapentin was evaluated after the first and last drug administration. Pharmacokinetic parameters were estimated using noncompartmental analysis.ResultsNo changes occurred in physiologic or biochemical variables. Median (range) maximal plasma gabapentin concentrations (μg/mL) after the last dose (day 15) were 7.6 (6.2‐11) and 22 (14‐33) for 40 mg/kg and 120 mg/kg doses respectively. Maximal concentration of gabapentin was reached within 1 hour after drug administration. Repeated administration of gabapentin resulted in a median (range) area under the curve (AUC_{0‐12 hours}) last/first dose ratio of 1.5 (1.00‐2.63) and 2.92 (1.4‐3.8) for the 40 and 120 mg/kg regimens, respectively.Conclusion and Clinical ImportanceOur results suggest that horses tolerate gabapentin up to 120 mg/kg PO q 12 h for 14 days. The analgesic effect of the dosage regimens evaluated in our study warrants further research.     

Safety and efficacy of oral mirtazapine in New Zealand White rabbits (Oryctolagus cuniculus)

BackgroundOne of the most common presenting complaints in rabbits is decreased food intake and/or fecal output. This can occur as a clinical consequence of pain, anesthesia and systemic or gastrointestinal disease. In conjunction with diagnosing and treating the underlying condition, veterinary care should aim to normalize food intake and fecal output. Mirtazapine is a tetracyclic antidepressant that has appetite stimulating effects in other species. However, studies in rabbits are currently lacking.MethodsNine six-month old, intact (4 male, 5 female) New Zealand White rabbits (Oryctolagus cuniculus) were used in a randomized, blinded, controlled, complete cross-over experiment. Each rabbit received a low-dose of mirtazapine (1 mg/kg), high-dose (3 mg/kg) and control treatment orally once a day for a total of 2 sequential days with a 5- day washout period between treatment groups. Fecal output, food intake and body weight were measured before, during and after treatment.ResultsFecal output was 25% higher (95% CI: 6.3%–46.9%, P= 0.01) on treatment days following high-dose mirtazapine treatment. Body weight was 1.5% higher (95% CI: 0. 5% to 2.6%, P= 0.006) for all groups on the 2 days following treatment compared to baseline. Body weight was reduced by 2.1% (95% CI: -3.6% to -0.6%, P= 0.011) the week following high-dose mirtazapine treatment. Mirtazapine did not have a statistically significant effect on food intake.Conclusions and clinical relevance:Oral administration of mirtazapine at 3 mg/kg once a day resulted in increased fecal output but not a concurrent increase in food intake. Overall, mirtazapine is well tolerated and may be a useful treatment to increase fecal output in rabbits. However, due to a mild reduction in weight following treatment, clinical monitoring is warranted.     

Evaluation of the inhibitory effects of telmisartan on drug-induced renin-angiotensin-aldosterone system activation in normal dogs

Introduction

This study examined whether the angiotensin II receptor blocker telmisartan had inhibitory effects on drug-induced renin-angiotensin-aldosterone system (RAAS) activation in normal dogs.

Influence of food intake on the absorption of lysine-acetylsalicylate in dogs

The influence of food intake on the absorption of a water-soluble aspirin, lysine-acetylsalicylate, was examined in six healthy adult mongrel dogs. Single-dose kinetics were determined following ingestion of 90 mg/kg of lysine-acetylsalicylate in dogs either fasted for 12 h or following a standard meal of either dry food or the same meal containing 20% of olive oil. Concurrent intake of food both reduced the serum salicylate concentration for 3 h after administration, and reduced the total amount of drug absorbed as reflected by the area under the plasma concentration/time curve(AUC). The effects were more pronounced following the fatty meal. Data from this investigation suggest that lysine-acetylsalicylate is therapeutically effective, without side effects when taken at the rate of 80 mg/kg at 12 h intervals, during or after feeding rather than before feeding.     

Effect of water deprivation on the disposition kinetics of enrofloxacin in camels

Concentrations of enrofloxacin equivalent activity were determined (by microbiological assay) in the serum of normal camels and camels at the end of a 14-day water-deprivation period following single intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administrations at 2.5 mg/kg. Also, normal camels were given an oral drench of the drug at 5 mg/kg. Pharmacokinetic variables were determined using compartmental and non-compartmental analytical methods. Camels lost on average 12.5% of body weight at the end of the water-deprivation period. The disposition kinetics of i.v. administered drug in normal and water-deprived camels were very similar. The t_1/2β was 3.0–3.5 h; MRT was 4.0–4.5 h; V_e was 0.3 L/kg; V₃₈ was 1.0 L/kg and Cl₈ was 4.0–4.6 mL/min/kg. The effect of water deprivation on the rate of drug absorption and elimination after i.m. administration was inconsistent, and there was also a large degree of variability in the normal animals that precluded statistical significance. After s.c. administration, the mean absorption half-life (t_1/2she in the water-deprived camels was significantly longer than in the normal camels. Systemic availability (F) was similar in both normal and water-deprived camels after i.m. dosing but was significantly greater (P < 0.05) in normal camels (0.92 compared with 0.65 in water-deprived camels) after s.c. treatment In normal camels, urinary recovery at 12 h after l.v. and s.c. dosing was 25% and 15%, respectively, and the extent of serum protein binding ranged between 1.7% at 1.8 μg/mL and 24% at 0.33 μg/mL. The drug was not detected in serum after oral administration. Serum and milk enrofloxacin equivalent activities were determined after i.v. (one camel) and i.m. (one camel) drug administration. Serum drug concentrations were consistently higher than in the milk. The AUC_milk/AUC_serust ratios were 0.27 and 0.39 after i.v. and i.m. drug administration, respectively. An i.m. or s.c. treatment regimen of 2.5 mg/kg q. 12 h is suggested for clinical and bacteriological efficacy trials with enrofloxacin in normally hydrated and dehydrated camels.     

The effects of concurrent administration of cytochrome P-450 inhibitors on the pharmacokinetics of oral methadone in healthy dogs

ObjectiveThe objective was to examine the effects of inhibiting cytochrome P450 (CYP) on the pharmacokinetics of oral methadone in dogs.Study designProspective non-randomized experimental trial.AnimalsSix healthy Greyhounds (three male and three female).MethodsThe study was divided into two phases. Oral methadone (mean = 2.1 mg kg^?1 PO) was administered as whole tablets in Phase 1. In Phase 2 oral methadone (2.1 mg kg^?1 PO) was administered concurrently with ketoconazole (13.0 mg kg^?1 PO q 24 hours), chloramphenicol (48.7 mg kg^?1 PO q 12 hours), fluoxetine (1.3 mg kg^?1 PO q 24 hours), and trimethoprim (6.5 mg kg^?1 PO q 24 hours). Blood was obtained for analysis of methadone plasma concentrations by liquid chromatography with mass spectrometry. The maximum plasma concentration (C_max), time to C_max (T_max), and the area under the curve from time 0 to the last measurable time point above the limit of quantification of the analytical assay (AUC_0–LAST) were compared statistically.ResultsThe C_max of methadone was significantly different (p = 0.016) for Phase 1 (5.5 ng mL^?1) and Phase 2 (171.9 ng mL^?1). The AUC_0–LAST was also significantly different (p = 0.004) for Phase 1 (13.1 hour ng mL^?1) and Phase 2 (3075.2 hour ng mL^?1).Conclusion and clinical relevanceConcurrent administration of CYP inhibitors with methadone significantly increased the area under the curve and plasma concentrations of methadone after oral administration to dogs. Further studies are needed assessing more clinically relevant combinations of methadone and CYP inhibitors.     

Diazepam as a treatment for metronidazole toxicosis in dogs: a retrospective study of 21 cases

The currently recommended treatment for metronidazole toxicosis is drug discontinuation and supportive therapy. Reported recovery times are 1-2 weeks. The records of 21 dogs with metronidazole toxicosis were retrospectively analyzed to determine whether diazepam improved recovery. The dosage and duration of metronidazole therapy and the response and recovery times of 13 dogs treated with diazepam were compared to those of 8 dogs receiving only supportive care. Response time was defined as the time to resolution of the debilitating clinical signs. Recovery time was the time to resolution of all residual clinical signs. The average dosage and duration of metronidazole administration for the diazepam-treated and untreated groups were 60.3 mg/kg/d for 44.9 days and 65.1 mg/kg/d for 37.25 days. The protocol for diazepam administration consisted of an initial i.v. bolus and then diazepam PO q8h for 3 days. The average dosage of both the i.v. and PO diazepam was 0.43 mg/kg. The average response time for the diazepam-treated dogs was 13.4 hours compared to 4.25 days for the untreated group. Recovery time also was markedly shorter for the diazepam-treated dogs (38.8 hours) compared to the untreated group (11 days). Results of this study showed that dogs with metronidazole toxicosis recover faster when treated with diazepam. Although the mechanism of metronidazole toxicosis or how diazepam exerts its favorable effect is not known, it is likely related to modulation of the gamma-aminobutyric acid (GABA) receptor within the cerebellar and vestibular systems.     

Pharmacokinetics of metronidazole in foals: influence of age within the neonatal period

Neonatal foals have unique pharmacokinetics, which may lead to accumulation of certain drugs when adult horse dosage regimens are used. Given its lipophilic nature and requirement for hepatic metabolism, metronidazole may be one of these drugs. The purpose of this study was to determine the pharmacokinetic profiles of metronidazole in twelve healthy foals at 1–2.5 days of age when administered as a single intravenous (IV) and intragastric (IG) dose of 15 mg/kg. Foals in the intravenous group were studied a second time at 10–12 days of age to evaluate the influence of age on pharmacokinetics within the neonatal period. Blood samples were collected at serial time points after metronidazole administration. Metronidazole concentration in plasma was measured using LC‐MS. Pharmacokinetic parameters were determined using noncompartmental analysis and compared between age groups. At 1–2.5 days of age, the mean peak plasma concentration after IV infusion was 18.79 ± 1.46 μg/mL, elimination half‐life was 11.8 ± 1.77 h, clearance was 0.84 ± 0.13 mL/min/kg and the volume of distribution (steady‐state) was 0.87 ± 0.07 L/kg. At 10–12 days of age, the mean peak plasma concentration after IV infusion was 18.17 ± 1.42 μg/mL, elimination half‐life was 9.07 ± 2.84 h, clearance was 1.14 ± 0.21 mL/min/kg and the volume of distribution (steady‐state) was 0.88 ± 0.06 L/kg. Oral approximated bioavailability was 100%. Cmax and T_max after oral dosing were 14.85 ± 0.54 μg/mL and 1.75 (1–4) h, respectively. The elimination half‐life was longer and clearance was reduced in neonatal foals at 1–2.5 days as compared to 10–12 days of age (P = 0.006, P = 0.001, respectively). This study warrants consideration for altered dosing recommendations in foals, especially a longer interval (12 h).