Irritation, bioavailability, and residue aspects of ten oxytetracycline formulations administered intramuscularly to pigs

After intramuscular administration to pigs (dosage 20-35 mg/kg) great differences were found among 10 injectable oxytetracycline (OTC) formulations with respect to irritation and persistence at the injection site and to the residue state of edible tissues. The OTC recovery percentages at the injection site 7-10 days after injection ranged from less than 0.001 to 0.15 per cent for three 10 per cent-formulations and from 0.12 to 20.5 per cent for seven 20 per cent-formulations. The OTC recovery percentage was obvious related to the extent of tissue irritation at the injection site, which was particularly evident for the 20 per cent-formulations. Serious doubt is expressed about advantages of so-called 'long-acting' formulations.     

Pharmacokinetics and bioavailability of ceftriaxone administered intravenously and intramuscularly to calves

Ceftriaxone was administered to Israeli-Friesian male calves by IV and IM routes. The antibiotic was administered IV (10 mg/kg) to 10 calves and IM to 23 calves; 8 were given the antibiotic at the rate of 10 mg/kg of body weight, 5 were given 20 mg/kg, and 10 were given 10 mg/kg, together with probenecid at 40 mg/kg. Serum concentration vs time profiles measured after IV and IM administration were analyzed by use of statistical moment theory. The following mean values +/- SD were found: elimination half-life (t1/2) was 83.8 +/- 8.6 minutes after IV administration and significantly longer 116.8 +/- 20.5 minutes (P less than 0.001) after IM administration at 10 mg/kg. The t1/2 was increased to 141.3 +/- 24.4 minutes by the coadministration of probenecid and to 145.0 +/- 48.2 minutes by doubling the IM dosage to 20 mg/kg. The total body clearance was 3.39 +/- 0.42 ml/min/kg and the renal clearance 2.37 +/- 0.74 ml/min/kg. The specific volume of distribution was 0.2990 +/- 0.0510 L/kg. The average mean residence time (MRT) was 94.0 +/- 12.3 minutes after IV administration and 137.6 +/- 19.9 minutes after IM administration of ceftriaxone at 10 mg/kg. The MRT was increased to 198 +/- 48.8 minutes by the coadministration of probenecid and to 191.0 +/- 59.4 minutes by doubling the IM dose. The former value was significantly different from the MRT after IM administration of the antibiotic at 10 mg/kg. Bioavailability of ceftriaxone after IM administration at 10 mg/kg and at 20 mg/kg was 78% and 83%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition kinetics of tylosin administered intravenously and intramuscularly to pigs

The distribution of tylosin was studied using a crossover design, in six pigs following i.v. and i.m. administration of 10 mgkg(-1) b.w. Plasma samples were analysed by HPLC and UV absorbance detection. After i.v. administration, t(1/2beta) was 271.3 min, V(d) 14.6 Lkg(-1), V(ss) 9.7 Lkg(-1) and CL 26.8 mLmin(-1)kg(-1). After i.m. administration, a C(max) of 1 microgmL(-1) was reached at 90 min. Mean absorption time was 1988.7 min and bioavailability was 95%.     

Pharmacokinetics of intravenously, intramuscularly and intra-adiposely administered carazolol in pigs

The beta-blocking agent carazolol is used for the prevention of stress syndromes in pigs. Little is known of the pharmacokinetics of this drug, and therefore of its residue status in meat. In this study carazolol pharmacokinetics were investigated in a randomized three-way cross-over design in five pigs. A dose of 0.025 mg/kg was given intravenously, intramuscularly and intra-adiposely (in the subcutaneous fat layer). Carazolol was rapidly distributed and had a short half-life of 1.2-4.2 h. The distribution volume was calculated to be 0.22-0.65 l/kg. After intramuscular or intra-adipose administration the absorption pattern was biphasic. A rapid initial phase was followed by a slow second phase. Absorption was found to be incomplete at 24 h after intramuscular and intra-adipose administration ranging from 24 to 59% and 25 to 66%, respectively. The biphasic behaviour could be explained by retention of the drug in the tissues after absorption of the solvent was complete. A few hours after intravenous administration only negligible amounts of the drug were circulating in the body; however, considerable amounts of drug might have remained at the intramuscular or intra-adipose injection site.     

Pharmacodynamics of oxytetracycline administered alone and in combination with carprofen in calves

The pharmacodynamics (PD) of oxytetracycline was investigated against a strain of Mannheimia haemolytica. In vitro measurements, comprising minimum inhibitory concentration (MIC), minimum bactericidal concentration and time-kill curves, were conducted in five matrices; Mueller Hinton Broth (MHB), cation-adjusted MHB (CAMHB) and calf serum, exudate and transudate. MICs were much higher in the biological fluids than in MHB and CAMHB. Ratios of MIC were, serum: CAMHB 19 : 1; exudate:CAMHB 16.1; transudate:CAMHB 14 : 1. Ex vivo data, generated in the tissue cage model of inflammation, demonstrated that oxytetracycline, administered to calves intramuscularly at a dose rate of 20 mg/kg, did not inhibit the growth of M haemolytica in serum, exudate and transudate, even at peak concentration. However, using in vitro susceptibility in CAMHB and in vivo-determined pharmacokinetic (PK) variables, average and minimum oxytetracycline concentrations relative to MIC (C(av)/MIC and C(min)/MIC) predicted achievement of efficacy for approximately 48 hours after dosing. Similar C(av)/MIC and C(min)/MIC data were obtained when oxytetracycline was administered in the presence of carprofen. PK-PD integration of data for oxytetracycline, based on MICs determined in the three biological fluids, suggests that it possesses, at most, limited direct killing activity against M haemolytica. These data raise questions concerning the mechanism(s) of action of oxytetracycline, when administered at clinically recommended dose rates.     

Disposition kinetics of tylosin administered intravenously and intramuscularly in desert sheep and Nubian goats

The pharmacokinetic behaviour of tylosin was compared in five Desert sheep and five Nubian goats. The animals were given a single dose of 20% tylosin (15 mg/kg), either intravenously (i.v.) or intramuscularly (i.m.). Following i.v. administration, the volumes of distribution and the elimination half-life times were similar in both species, whereas in goats a greater volume of the central compartment and faster clearance were observed. For the i.m. route, similar pharmacokinetics were observed in both species. The bioavailability (f) of the drug in goats (0.84 +/- 0.11) was not significantly higher than that in sheep (0.73 +/- 0.08). The present study has shown that, despite the significant differences in some of the drug pharmacokinetic parameters between sheep and goats for the i.v. route, identical intravenous and intramuscular dosage regimens of tylosin may be recommended for the two species.     

Comparison of pharmacokinetic variables for two injectable formulations of netobimin administered to calves

In a 4 x 4 crossover-design study, pharmacokinetic variables of 2 injectable formulations of netobimin (trisamine salt solution and zwitterion suspension) were compared after SC administration in calves at dosage of 12.5 mg/kg of body weight. Netobimin parent drug was rapidly absorbed, being detected between 0.25 and 12 hours after treatment, with maximal plasma drug concentration (Cmax) values of 2.20 +/- 1.03 micrograms/ml achieved at 0.75 +/- 0.19 hour (trisamine) and 1.37 +/- 0.59 micrograms/ml at 0.81 +/- 0.18 hour (zwitterion). Netobimin area under the plasma concentration-time curve (AUC) was 7.59 +/- 3.11 micrograms.h/ml (trisamine) and 6.98 +/- 1.60 micrograms.h/ml (zwitterion). Elimination half-life (t1/2 beta) was 2.59 +/- 0.63 hours (trisamine) and 3.57 +/- 1.45 hours (zwitterion). Albendazole was not detected at any time. Albendazole sulfoxide was detected from 4 hours up to 20 hours (trisamine) and from 6 hours up to 24 hours (zwitterion) after administration of the drug. The Cmax values were 0.48 +/- 0.16 micrograms/ml and 0.46 +/- 0.26 micrograms/ml for trisamine and zwitterion formulations, respectively, achieved at time to peak drug concentration (Tmax) values of 9.50 +/- 1.41 hours (trisamine) and 11.30 +/- 1.04 hours (zwitterion). Albendazole sulfoxide AUC was 3.86 +/- 1.04 micrograms.h/ml (trisamine) and 4.40 +/- 3.24 micrograms.h/ml (zwitterion); t1/2 beta was 3.05 +/- 0.75 hours (trisamine) and 3.90 +/- 1.44 hours (zwitterion). Albendazole sulfone was detected from 4 (trisamine) or 6 hours (zwitterion) to 24 hours after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of clindamycin HCl administered intravenously, intramuscularly and subcutaneously to dogs

A buffered aqueous solution of clindamycin Hcl (200 mg/mL) was injected intravenously (i.v.) intramuscularly (i.m.) and subcutaneously (s.c.) in a non-randomized, partial cross-over trial involving six male and six female dogs. Blood samples were collected at conventional, predetermined time periods and serum drug concentrations were determined by microbiological assay. Dogs were observed clinically for signs of pain, and activity of serum creatine phosphokinase (CPK) was monitored after i.m. dosing. The i.v. data from five of the dogs best fitted a two-compartment open-system pharmacokinetic model whereas a non-compartment model was most suitable for analysis of the data from the remaining seven dogs. The mean i.v. elimination half-life (t1/2 beta) and the mean residence time (MRT) were 124 and 143 min, respectively. The mean volume of distribution at steady state (Vss) was 0.86 L/kg. Little pain was recorded upon i.m. injection; mean peak serum drug concentration (Cmax) was 4.4 micrograms/mL, the elimination half-life (t1/2el) was 247 min and the calculated bioavailability (F) was 115% of the i.v. dose. Serum CPK activity was elevated to 25-fold the pretreatment level in samples collected 4, 8 and 12 h after i.m. injection. Pain was not recorded after s.c. drug administration; the mean Cmax of 20.8 micrograms/mL was significantly greater than the corresponding value for the i.m. route, and F was 310%. The s.c. route appears to be superior to the i.m. route in terms of local tolerance and serum drug level; a 10 mg/kg SID treatment regimen is suggested for treatment of canine infections due to clindamycin sensitive bacteria.     

Long-acting antibiotic formulations in the treatment of calf pneumonia: a comparative study of tilmicosin and oxytetracycline

The treatment of an outbreak of acute pneumonia in 50 four- to eight-month-old Friesian and Friesian cross calves is described. At the first visit (day 0) 16 calves received 20 mg/kg bodyweight of oxytetracycline dihydrate intramuscularly and 15 received 10 mg/kg of the macrolide tilmicosin subcutaneously. The remaining 19 in-contact animals were not considered ill enough to be included in the trial and received 20 mg/kg of oxytetracycline dihydrate. The rectal temperature, demeanour, respiratory rate and respiratory effort of each calf was assessed on days 1, 2, 3, 9, 14, 21 and 28, and calves which had not responded were given repeat injections of the same antibiotic. All the calves recovered from the outbreak and of the 19 calves treated strategically, three required a second injection. Among the calves with clinical pneumonia, fewer treatments (P less than 0.01) were required by those treated with tilmicosin. The rectal temperatures of both groups decreased (P less than 0.05) after the first injection, but on day 3 the decrease was greater (P less than 0.05) in the group treated with tilmicosin. Respiratory rates varied widely but respiratory effort was less (P less than 0.05) on day 2 in the calves treated with tilmicosin. When long-acting antibiotic injections are used to treat enzootic pneumonia it is suggested that a second visit should be made on day 3 to assess the animals' response to treatment.     

Electroanaesthesia or electroimmobilisation of calves, sheep and pigs by the Feenix Stockstill

Since the end of the last century many investigations with electroanaesthesia have been performed in animals and man. The interest in this method of anaesthesia has emerged because anaesthesia is achieved immediately after the onset of the current and the recovery is very rapid after cutting off of the current. Recently a battery operated apparatus became available (Feenix Stockstill) for application of electroanaesthesia and electroimmobilisation under field conditions, and an experiment was conducted with 10 calves, 10 sheep, and 9 pigs, which were equipped with EEG and ECG electrodes, to check the analgesic and other practical effects of the apparatus. The duration of current administration was 20 minutes. Three animals of each species were used as control animals. In all animals, during administration of the current, the breathing movements appeared to be somewhat impaired. The rectal body temperature, the plasma cortisol level, and the pulse rate were raised during the current administration. Moreover, the pulse rate was irregular. The corneal reflex remained positive in all animals, and the reaction to painful stimuli was positive in 15 out of 29 experimental animals. The rectal body temperature, pulse rate, and plasma cortisol level remained constant in the control animals. Before and after administration of the current the electroencephalogram recordings were similar, except in one calf and one sheep, both of which showed patterns suggesting a decreased consciousness. The electrocardiogram recordings showed pronounced changes in cardiac activity. In one pig the heart activity stopped some minutes after the onset of the current. Changes in the electroencephalogram and electrocardiogram were not observed in the control animals during their treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

The comparative susceptibility of five breeds of sheep to foot-rot

Five breeds of sheep, Romney Marsh, Dorset Horn, Border Leicester, Peppin Merinos and Saxon Merinos were examined for their susceptibility to foot-rot by exposure to natural transmission of infection on irrigated pasture or by the application of pure cultures of Bacteroides nodosus to each foot in a pen experiment. On pasture, the sheep encountered a moderate challenge and the British breeds were more resistant than Merinos to the development of severe foot-rot. Resistance was manifested by a rapid resolution of relatively benign lesions in the interdigital skin, rather than a reduction in the number of feet affected. However, under more severe challenges with foot-rot in pens, all breeds were equally susceptible. There was little difference between resistant and susceptible sheep in the kinetics and magnitude of their antibacterial immune responses indicating that resistance did not depend on pre-existing antibody or a more rapid induction of antibody production. In each experiment, humoral immune responses against B. nodosus were not greatly elevated until under-running lesions of the hoof developed.     

Electroanaesthesia or electroimmobilisation of calves,sheep and pigs by the Feenix Stockstill

Summary

Since the end of the last century many investigations with electroanaesthesia have been performed in animals and man. The interest in this method of anaesthesia has emerged because anaesthesia is achieved immediately after the onset of the current and the recovery is very rapid after cutting off of the current. Recently a battery operated apparatus became available (Feenix Stockstill^®) for application of electroanaesthesia and electroimmobilisation under field conditions, and an experiment was conducted with 10 calves, 10 sheep, and 9 pigs, which were equipped with EEG and ECG electrodes, to check the analgesic and other practical effects of the apparatus. The duration of current administration was 20 minutes. Three animals of each species were used as control animals.

In all animals, during administration of the current, the breathing movements appeared to be somewhat impaired. The rectal body temperature, the plasma cortisol level, and the pulse rate were raised during the current administration. Moreover, the pulse rate was irregular. The corneal reflex remained positive in all animals, and the reaction to painful stimuli was positive in 15 out of 29 experimental animals. The rectal body temperature, pulse rate, and plasma cortisol level remained constant in the control animals. Before and after administration of the current the electroencephalogram recordings were similar, except in one calf and one sheep, both of which showed patterns suggesting a decreased consciousness. The electrocardiogram recordings showed pronounced changes in cardiac activity. In one pig the heart activity stopped some minutes after the onset of the current. Changes in the electroencephalogram and electrocardiogram were not observed in the control animals during their treatment.

The results suggest that the apparatus did not cause electroanaesthesia or electrosleep but had mainly an electroimmobilising effect on the experimental animals. Because of the dubious effects on the animals’ welfare, the use of such an apparatus cannot be recommended.     

Comparison of the pharmacokinetics and local tolerance of three injectable oxytetracycline formulations in pigs

The pharmacokinetic properties and local tolerance of three oxytetracycline formulations, one conventional (Engemycine, 10%) and two long-acting (Oxyter LA, 20% and Terramycin LA, 20%) were compared in clinically healthy cross-bred pigs following intramuscular injection of single doses (20 mg/kg body weight) in the neck region. Non-compartmental methods were used to calculate the pharmacokinetic parameters. Assessment of local tolerance was based on serum creatine phosphokinase (CPK) concentration and a combination of echographical, macroscopic and histological examinations of the intramuscular injection site. Statistically significant differences (one-way analysis of variance, F-test) were obtained between the three formulations in peak plasma concentration, peak time and mean residence time. Area under the curve did not differ significantly between the formulations. Using the Students t-test for paired data, the two long-acting formulations differed significantly in peak plasma concentration and peak time. Both of the long-acting formulations differed significantly from the conventional formulation in the peak time and mean residence time. All three formulations produced an increase in serum CPK concentrations. The increase in CPK concentration was present from 6 to 24 h post treatment for Terramycin LA, from 6 to 72 h for Oxyter LA and from 6 to 96 h for Engemycine (the conventional formulation). Echographical examination of the injection site showed lesions of an inflammatory type up to 96 h after IM injection of the drug products, whereas from 7 days the lesions represented primarily scar formation. Histological examination of tissue from the injection site did not correlate with echographical scores. The results obtained in this study show that the long-acting formulations provide significantly longer mean residence times of oxytetracycline than the conventional formulation, and that local tolerance at the IM injection site was similar for all three formulations under the experimental conditions used in this study. It can be concluded that the longacting formulations provide the advantage of a longer dosage interval when administered to pigs by intramuscular injection in the neck region at a dose of 20 mg/kg body weight.     

The influence of disease on feed and water consumption and on pharmacokinetics of orally administered oxytetracycline in pigs

In the present study the feed and water consumption and pharmacokinetic parameters of orally administered oxytetracycline were compared in clinically healthy pigs and in the same pigs following a challenge with Actinobacillus (Haemophilus) pleuropneumoniae toxins. Endobronchial challenge with A. pleuropneumniae toxins was accompanied by anorexia, increased lassitude, labored breathing, fever, and increased white blood cell counts. Pleuropneumonia was evident in all pigs on autopsy. Following the challenge, both feed and water consumption were markedly reduced. In contrast to recommendations in the literature, it is concluded that drugs should not be administered to pneumonic pigs via water. In healthy pigs the oral bioavailability of oxytetracycline (50 mg/kg), given on an empty stomach, was 4.8% and the elimination half-life (t1/2 beta) was 5.92 h. After challenge, the pigs showed great variation in oxytetracycline plasma concentrations. In addition, the mean computed elimination rate constant (beta), t1/2 beta, the area under the plasma concentration-time curve (AUC), and clearance in pneumonic pigs differed significantly (P less than .05) from the values found in healthy pigs. The elimination half-life (t1/2 beta), AUC, and volume of distribution (Vd area) were increased. In diseased pigs the mean of maximum plasma concentrations (.87 micrograms/ml) was reached after 7 h, in contrast to 1.74 h (1.87 micrograms/ml) in the healthy pigs.     

Pharmacokinetic,residue and irritation aspects of chloramphenicol sodium succinate and a chloramphenicol base formulation following intramuscular administration to ruminants

Summary

The disposition of chloramphenicol (CAP) and of its glucuronide metabolite in plasma and milk was studied following a single intramuscular injection of a chloramphenicol base formulation (Amicole^®Forte; product A) and of chloramphenicol sodium succinate (product B) to dairy cows. The dose applied of both formulations was equivalent to 50 mg CAP base/kg body weight. The HPLC determined CAP concentrations were microbiologically active. Product A revealed 30% higher plasma CAP peak concentrations (13.0 vs 9.0 μg/ml) and 36% larger areas under the plasma concentration‐ time curves than product B, whereas their absorption and elimination half‐lives were of the same order of magnitude. In the onset phase (during 4 h p.i.) unhydrolysed CAP sodium succinate could be detected in plasma and the glucuronide fraction was 26% of the parent drug. After 25 h p.i. the glucuronide fraction equalled that of the parent drug.

The maximum CAP concentration in milk was for product B equal to, and for product A 80% of the CAP plasma concentration. In milk no chloramphenicol glucuronide metabolites could be detected. HPLC methods for detecting ultra‐trace CAP concentrations in edible tissues were developed by the employment of extraction with or without a clean‐up procedure.

Seven days after i.m. administration of product A and B to calves, the CAP residue concentrations in the kidney, liver, and muscle were less than 2 nanogram/g tissue. Traces of CAP residues could be still found at the injection site and in the urine.

Chloramphenicol sodium succinate (product B) caused extensive tissue irritation at the injection site, while in the case of product A the irritation was limited. It was concluded that product A (Amicol^®Forte) had more favourable pharmacokinetic characteristics than the sodium succinate formulation.