Bioavailability of levamisole after intramuscular and oral administration in sheep

AIMS: To determine the bioavailability of levamisole in sheep. METHODS: Levamisole was administered to three groups of six Merino sheep orally and intramuscularly at three dose levels of 5, 7.5 and 10 mg/kg. There was a washout period of 1 week between treatments. Blood samples were collected by jugular venepuncture and plasma was separated immediately by centrifugation and stored at 20 degrees C until analysed. The levamisole concentration in plasma was determined by high performance liquid chromatography with a U.V. detection method. Individual plasma levamisole concentration-time data were analysed using the compartmental method. RESULTS: The values obtained for k(a), C(max), t(max) and F show a moderate rate and extent of absorption after oral administration of levamisole while, after intramuscular administration, these values demonstrate a high rate and extent of absorption of levamisole. The intramuscular bioavailability was higher than the oral bioavailability (rate of absorption three-fold faster, extent of absorption 25-33% higher and C(max) two-fold higher). The Friedman test involving dose and route of administration showed that the route of administration affects k(a), C(max), t(max) and F; significant differences were found in these parameters. CLINICAL RELEVANCE: On the basis of these data, the recommended routes for the administration of levamisole in sheep are oral for gastro-intestinal nematodiasis and intramuscular for extragastric nematodiasis.     

Pharmacokinetics of a long-acting chloramphenicol formulation administered by intramuscular and subcutaneous routes in cattle

The pharmacokinetic properties of a long-acting formulation of chloramphenicol were determined in six yearling cattle after a single intravenous (i.v.) administration (40 mg/kg body weight) and after two sequential subcutaneous (s.c.) or intramuscular (i.m.) administrations (90 mg/kg/48 h). The two extravascular routes were studied during a crossover trial for a bioequivalence test. After i.v. administration, the plasma concentration-time graph was characteristic of a two-compartment open model. Mean values were a half-life of 4.1 h, a volume of distribution of 0.86 l/kg and a body clearance of 0.128 l/kg/h. Plasma concentrations of chloramphenicol following i.m. and s.c. administrations increased slowly to a broad peak at 10-15 micrograms/ml between 9 and 12 h. Bioavailability was 19.1% after i.m. injection and 12.4% after s.c. administration. The extent of absorption from the two routes did not differ significantly. The rate of absorption was significantly lower after s.c. application than it was after i.m. injection. The time necessary for the plasma concentration to exceed 5 micrograms/ml was the same for the two routes. Thus, i.m. and s.c. routes are bioequivalent.     

The plasma kinetics of sulbactam-ampicillin administered to calves by the intramuscular and subcutaneous routes

Sulbactam-ampicillin combines ampicillin, a broad spectrum beta-lactam antibiotic, with sulbactam, an irreversible beta-lactamase inhibitor. The sulbactam component prevents the degradation of ampicillin by several major classes of bacterial beta-lactamases and restores the activity of ampicillin against most strains of bacteria in which resistance is mediated by beta-lactamase production.A crossover study was conducted in Friesian calves of 98–119 kg bodyweight in which the plasma kinetics of sulbactam-ampicillin adminstered by the intramuscular and subcutaneous routes were defined, and the plasma kinetics of ampicillin derived from sulbactam-ampicillin and a commercially available formulation of ampicillin trihydrate were compared. Subsequent to both intramuscular and subcutaneous administration of sulbactam-ampicillin, peak plasma concentrations of sulbactam and ampicillin were recorded two hours post-injection. Higher peak plasma concentrations of both sulbactam and ampicillin were achieved by the subcutaneous route of administration and, for ampicillin, the difference between the two routes was statistically significant (p < 0·01). However, there was no significant difference in bioavailability (as measured by area under the curve) between the two routes of administration for either component. In addition, there were no significant differences between the peak plasma concentrations or areas under the curves for ampicillin derived from intramuscular administration of sulbactam-ampicillin, and ampicillin alone, indicating that combination with sulbactam does not alter the plasma kinetics of ampicillin.     

Pharmacokinetics of ceftriaxone administered by the intravenous, intramuscular or subcutaneous routes to dogs

The purpose of this study was to investigate the pharmacokinetics of ceftriaxone after single intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) doses in healthy dogs. Six mongrel dogs received ceftriaxone (50 mg/kg) by each route in a three-way crossover design. Blood samples were collected in predetermined times after drug administration. Results are reported as mean +/- standard deviation (SD). Total body clearance (Cl(t)) and apparent volume of distribution (V(z)) for the i.v. route were 3.61 +/- 0.78 and 0.217 +/- 0.03 mL/kg, respectively. Terminal half-life harmonic mean (t(1/2 lambda)) was 0.88; 1.17 and 01.73 h for the i.v., i.m and s.c. routes, respectively. Mean peak serum concentration (C(max)) was 115.10 +/- 16.96 and 69.28 +/- 14.55 microg/mL for the i.m and s.c. routes, respectively. Time to reach C(max) (t(max)) was 0.54 +/- 0.24 and 1.29 +/- 00.64 h for the i.m and s.c. routes, respectively. Mean absorption time (MAT) was 1.02 +/- 0.64 and 2.23 +/- 00.73 h for the i.m and s.c. routes, respectively. Bioavailability was 102 +/- 27 and 106 +/- 14% for the i.m and s.c. routes, respectively. Statistically significant differences were determined in C(max), t(max), MAT and t(1/2 lambda) of s.c. administered ceftriaxone when compared with the i.v and i.m. routes. These findings suggest that once or twice s.c. or i.m. daily administered ceftriaxone should be adequate to treat most susceptible infections in dogs.     

Liver disease in young rabbits infected by calicivirus through nasal and oral routes

Calicivirus infection causes rabbit haemorrhagic disease (RHD) that kills more than 90% of adult animals, whereas young rabbits are naturally resistant to this viral disease. It has been proposed that the different response of adult and young rabbits to calicivirus infection is due to absence of viral receptors in respiratory and digestive systems of young animals. We have searched for liver disease in 4-week-old rabbits inoculated with a calicivirus suspension by intranasal and oral routes. These young rabbits showed cell damage and mononuclear infiltration of the liver. The hepatic lesions were associated with mild to moderate increase in circulating transaminases. We conclude that the previously reported reduction of viral receptors in the epithelium of respiratory and digestive systems of young rabbits does not inhibit calicivirus from inducing liver disease in these hosts.     

Liver disease in young rabbits infected by calicivirus through nasal and oral routes

Calicivirus infection causes rabbit haemorrhagic disease (RHD) that kills more than 90% of adult animals, whereas young rabbits are naturally resistant to this viral disease. It has been proposed that the different response of adult and young rabbits to calicivirus infection is due to absence of viral receptors in respiratory and digestive systems of young animals. We have searched for liver disease in 4-week-old rabbits inoculated with a calicivirus suspension by intranasal and oral routes. These young rabbits showed cell damage and mononuclear infiltration of the liver. The hepatic lesions were associated with mild to moderate increase in circulating transaminases. We conclude that the previously reported reduction of viral receptors in the epithelium of respiratory and digestive systems of young rabbits does not inhibit calicivirus from inducing liver disease in these hosts.     

Influence of vehicle on kinetics of exogenous progesterone administered either by subcutaneous and intramuscular routes to sheep

This study aimed to determine the best vehicle and administration route for progesterone administration in sheep. In a first replicate, single intramuscular doses of 25mg progesterone were administered to ewes previously ovariectomized, either in propylene glycol (group IM-PG, n=6) or olive oil (group IM-OO, n=5). In a second replicate, the same solutions of progesterone were administered subcutaneously to the same ewes (groups SC-PG, n=6, and SC-OO, n=5). In the present study, the best pharmacokinetic results of a single dose of 25mg of progesterone were obtained, both using PG and OO as vehicles, by the subcutaneous route. Thus, progesterone remained in plasma for a longer time after subcutaneous administration in PG than in OO (t(1/2beta): 60.65+/-13.07 vs. 27.51+/-3.59 h; P<0.05); the mean residence time being higher in SC-PG than in SC-OO group (88.99+/-18.36 vs. 41.04+/-5.31h; P<0.05). However, both vehicles allowed maintained plasma levels 0.5 ng/ml for at least 30 h, so any of these treatments may be efficiently used for administration of exogenous progesterone.     

The pharmacokinetics of cytarabine in dogs when administered via subcutaneous and continuous intravenous infusion routes

This crossover study compared the pharmacokinetics of cytarabine in six healthy dogs following intravenous constant rate infusion (CRI) and subcutaneous (SC) administrations, as these are two routes of administration commonly employed in the treatment of meningoencephalitis of unknown etiology. Each dog received a SC cytarabine injection of 50 mg/m² or an 8 h CRI of 25 mg/m² per hour, with a 7‐day washout before receiving the alternative treatment. Blood samples were collected for 16 h after CRI initiation and for 8 h after SC injection. Plasma concentrations were measured by high‐pressure liquid chromatography (HPLC). Pharmacokinetic parameters were estimated using the best‐fit compartmental analysis for both CRI and SC routes. Terminal half‐life (T_½) of cytarabine was 1.35 ± 0.3 and 1.15 ± 0.13 h after SC administration and CRI, respectively. Mean peak concentration (C_max) was 2.88 and 2.80 μg/mL for SC and CRI administration, respectively. Volume of distribution was 0.66 ± 0.07 l/kg. The 8‐h CRI produced steady‐state plasma concentrations as determined by consecutive measurement that did not decline until the end of the infusion. The SC administration did not achieve steady‐state concentrations because cytarabine administered by this route was rapidly absorbed and eliminated quickly. The steady state achieved with the cytarabine CRI may produce a more prolonged exposure of cytarabine at cytotoxic levels in plasma compared to the concentrations after SC administration.     

Efficacy against Fasciola hepatica and the pharmacokinetics of triclabendazole administered by oral and topical routes

Objective   To determine the efficacy of triclabendazole (TCBZ) against 28-day-old, early immature liver fluke in cattle and its pharmacokinetics following administration by the oral or topical (pour-on) route.
Procedures   Cattle (n = 18) were infected with 500 TCBZ-susceptible liver fluke metacercariae and randomly allocated to three groups. At 28 days after infection, the groups were: (1) untreated controls; (2) treated with oral TCBZ at 12 mg/kg in combination with oxfendazole and selenium (TOS); (3) treated with pour-on TCBZ at 30 mg/kg in combination with abamectin (TA). Blood samples were taken immediately prior to treatment and serially after treatment to assess the plasma profile of TCBZ metabolites. Ten weeks after treatment all animals were slaughtered and total liver fluke counts, fluke egg counts and liver pathology were assessed.
Results   Both the TOS and TA treatments resulted in significant reductions of 28-day-old liver fluke, as assessed by fluke counts and fluke egg counts at slaughter, and the reductions following TOS treatment were significantly greater than those following TA treatment. The blood profile of TCBZ metabolites in TOS-treated animals showed a significantly greater area under the plasma concentration time curve and a higher maximum observed concentration than those treated with TA. There was significantly less liver pathology in TOS-treated animals than in the TA-treated animals.
Conclusion   TCBZ administered orally at 12 mg/kg resulted in greater efficacy against 28-day-old, early immature liver fluke than was achieved by topical administration at 30 mg/kg. Plasma metabolites of TCBZ were higher and liver pathology was less in TOS-treated animals than in TA-treated animals.     

Pharmacokinetics of levamisole in rabbits after intravenous administration

A compartmental and non-compartmental pharmacokinetic study was carried out on rabbits after intravenous (i.v.) administration of levamisole at the three dose rates: 12.5, 16.0 and 20.0 mg/kg body weight. Using compartmental analysis, the disposition of levamisole best fitted a two-compartmental open model with mean values of alpha = 0.1278, 0.1019 and 0.1282 min-1; beta = 0.0139, 0.0126 and 0.0124 min-1; A = 6.24, 5.27 and 10.58 micrograms/ml and B = 2.14, 3.83 and 5.08 micrograms/ml for each dose, respectively. The statistical moment theory was mainly used for non-compartmental analysis. Values for mean residence time (MRT) of 69.2, 71.7 and 73.1 min were obtained for each dose. The mean values for volume of distribution at steady state (Vd(ss)), determined by compartmental analysis, were 3879, 3279 and 2735 ml/kg for each dose, and values obtained using the statistical moment theory were 3760, 3015 and 2943 ml/kg; there were no statistically significant differences using Student's paired t-test. Identical conclusions were obtained using both methods when the parameters beta, AUC and Cl were compared.     

Efficacy of levamisole pour-on compared with levamisole subcutaneous injection against Dictyocaulus viviparus infection in calves.

The efficacy of levamisole pour-on against Dictyocaulus viviparus was compared to that of subcutaneous levamisole injection. Eighteen calves were raised individually and artifically infected with D. viviparus larvae. Faecal samples were collected 27 and 28 days later and larvae per gram (l.p.g.) determined. The animals were then divided into three comparable groups. Group 1 animals remained untreated as controls. Group 2 animals received levamisole 10% w/v subcutaneous injection at a dose of 5 mg kg-1 and Group 3 received levamisole pour-on 20% w/v at a rate of 10 mg kg-1 applied transdermally. Results of l.p.g. measurements from faecal samples taken 7 and 8 days post-treatment indicated a dramatic reduction in the worm burden of animals in both treatment groups. Necropsies at 14 days post-treatment revealed few adult worms in these groups, indicating a 99 and 98% kill rate for pouron and subcutaneous injection, respectively.     

Controlled test of anthelmintic activity of levamisole administered to calves via drinking water, subcutaneous injection, or alfalfa pellet premix.

A controlled test of the activity of 3 formulations of levamisole, at the dose level of approximately 8 mg/kg, against naturally occurring infections of gastrointestinal parasites and lungworms was made in 24 calves allotted to 4 groups of 6 calves each. Levamisole was administered to group I calves in the drinking water, to group II calves by subcutaneous injection, and to Group III calves by feeding alfalfa pellets mixed in corn silage; group IV calves were nontreated controls. Group I calves consumed the medicated water between 4 hours and 20 minutes and 9 hours and 40 minutes; group III calves consumed the medicated feed within 2 hours and 15 minutes. For calves of group I, II, and III, removals of 4th-stage Ostertagia sp were 64, 23, and 0%; of mature Ostertagia ostertagi, 90, 93, and 83%; and of mature Trichostrongylus axei, 92, 99, and 92%, respectively. For all 3 treated groups of calves, removal was 100% for 4th-stage Cooperia sp and for mature Trichostrongylus colubriformis, Cooperia oncophora, Cooperia punctata, and Oesophagostomum radiatum. Removals of Dictyocaulus vivipara were 90, 90, and 94% for calves of groups I, II, and III, respectively. There was no evidence of toxicosis. At necropsy, 2 calves in group II had small areas of edema at the sites of injection of levamisole.     

Bioavailability of gentamicin in dogs after intramuscular or subcutaneous injections

Healthy adult mixed-breed dogs, assigned to 2 groups of 6 dogs each, were given 3 mg of gentamicin sulfate/kg of body weight on 3 injection days 7 days apart. Group 1 was given gentamicin by rapid IV injection, by injection into the belly of the longissimus muscle at the first lumbar vertebrae (IM site 1), and by injection in the belly of the biceps femoris muscle (IM site 2). Group 2 was given gentamicin by rapid IV injection, by SC injection into the space over the cranial angle of the scapula on the midline (SC site 1), and by SC injection just caudal to the crest of the ilium (SC site 2). Pharmacokinetic values (mean +/- SD) from 12 dogs given gentamicin IV were 54.4 +/- 15.4 minutes for the effective half life, 2.29 +/- 0.48 ml/kg/min for clearance, and 172 +/- 25.4 ml/kg for volume of distribution at steady state. Bioavailability (93.92 to 96.65%) and peak plasma gentamicin concentration (9.43 to 10.89 micrograms/ml) were independent of injection site, but time to peak concentration when gentamicin was given at SC site 2 (43.33 minutes) was significantly (P less than 0.05) longer than that when gentamicin was given at IM site 1 (27.50 minutes). Absorption half-life was shorter after injections were given at both IM sites (8.9 and 9.8 minutes) than after injection was given at SC site 2 (18 minutes).     

The virulence and protective efficacy for chickens of pasteurella multocida administered by different routes

The relative virulence for chickens of five strains of Pasteurella multocida was evaluated. Twenty groups, each of ten chickens, were inoculated with a standard dose of 10(5) of each of five strains by the intramuscular (I.m.), intravenous (I.v.), intratracheal (I.tr.) or conjunctival (Co) routes. The highest mortality occurred in the groups dosed I.m. and I.v., followed by I.tr. inoculation. The relative virulence of each strain did not change when inoculated by the different routes. The most virulent strain, VP161, caused 100% mortality by all except the Co route. The least virulent strain, VP17, caused a single mortality by the I.v. route, but gave a high level of protection to birds inoculated by both the I.m. and I.v. routes, when challenged by intramuscular injection with (VP161). There was no protection against I.m. challenge in the birds inoculated by the I.tr. or Co routes. Serum antibody levels measured by ELISA correlated with the level of protection against virulent challenge for groups inoculated I.m. or I.v., but not I.tr. Western blots of pooled sera from each group did not show any specific antigen recognition that might explain the observed differences in protection. Inoculation with strain VP17, (both I.m. and I.tr.) also gave a high level of protection to birds challenged with strain VP161 by intratracheal instillation.     

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.     

Antibody responses to avian encephalomyelitis virus vaccines when administered by different routes

Antibody responses to a commercial avian encephalomyelitis virus (AEV) vaccine administered by different routes were measured by an enzyme-linked immunosorbent assay (ELISA). Responses to single doses of vaccine administered by the ocular route to 10% of a flock were comparable with those obtained when all birds received a single dose in the drinking water. However, ocular vaccination of 5% of the flock resulted in significantly lower responses than those obtained when 10% were vaccinated. Maternal antibody was shown by the ELISA to persist in chickens from vaccinated flocks for up to 21 days after hatching. Day-old chickens with serum absorbances of < 0.3 at 492 nm, as determined by the ELISA, were shown to be susceptible to intracerebral challenge with the neurotropic Van Roekel strain of AEV.