Levamisole pharmacokinetics and bioavailability in dogs.

Levamisole was given intravenously and orally (with and without food) to six dogs. All dogs reacted adversely to intravenous dosage and one died. For the remaining five, intravenous data fitted a one compartment model with first order elimination and a mean half-time of elimination of 1.8 hours. In fasting dogs drug absorption from the gut was rapid and the mean fraction absorbed (F) was 0.64. When levamisole was given with food, drug bioavailability was impaired, as absorption was slowed and possibly reduced (F = 0.49). The effect of ingesta on bioavailability of levamisole could affect treatment efficacy and side effects.

Comparative study of ampicillin and amoxycillin after intravenous, intramuscular and oral administration in homing pigeons (Columba livia).

Pharmacokinetics of ampicillin and amoxycillin after intravenous, intramuscular and oral administration was investigated in homing pigeons. The pharmacokinetic parameters in a cross-over study after intravenous administration of the sodium salts were comparable. The only significant difference was found for the distribution phase. The bioavailability after intramuscular injection of the sodium salts was especially low for ampicillin (26 per cent, as against 57 per cent for amoxycillin). The mean peak blood levels at 0.5 hours were 13.65 and 28.80 mg litre-1 for ampicillin and amoxycillin, respectively. After oral administration of trihydrate solutions (8 mg ml-1) the bioavailability was 20 and 35 per cent, respectively, and the mean peak blood levels were 8.46 and 16.98 mg litre-1, found at 1.04 and 1.26 hours. The recovery from the droppings, which include in birds the urine fraction as well, was unexpectedly low. Based on controls for recovery of added penicillin from the droppings and uric acid suspensions, indications were found that the pigeon enzymically inactivates penicillins. The in vitro activity of ampicillin against 266 strains of bacteria isolated from birds was determined. The minimum inhibitory concentration (MIC) for 65.4 per cent of the Escherichia coli was lower than 4 mg litre-1, for 91.1 per cent of the Salmonella species was lower than 2 mg litre-1 and for 100 per cent of the Yersinia pseudotuberculosis was lower than 0.25 mg litre-1. Based on these data and a literature study dosage regimens were calculated for MIC values of 0.5 and 2.5 mg litre-1.

Influence of gestation on the pharmacokinetics of four sulphonamides in goats.

The influence of gestation on the pharmacokinetics of four sulphonamides was studied in goats before, during and after pregnancy. Similar doses were given as intravenous boluses of 50 mg kg-1 each. Results were compared with those of non-pregnant goats to eliminate seasonal effects. With sulphadimidine elimination was mainly apparently first-order. In gestating goats the mean residence times decreased and mean plasma clearance rates increased with sulphadimidine during pregnancy, but this effect was continued after kidding at least until the end of May. The same happened with sulphadimethoxine, but sulphisomidine was not affected. In contrast to the other sulphonamides the mean residence time of sulphadoxine showed a maximum in February in gestating goats, while mean plasma clearance remained constant during and after pregnancy, at a lower level than in September. The mean plasma clearance of sulphadoxine decreased significantly from September to February in the non-pregnant control goats. In May five of six control goats and two of six goats which had kidded showed capacity-limited elimination against only two control goats in the foregoing experiments. With sulphadoxine one animal in the gestation group, but not the same one in each experiment, showed capacity-limited elimination against one, four and three in the control group in December, February and May, respectively. Distribution volumes increased significantly during and after pregnancy with sulphisomidine and sulphadimethoxine. A decrease in distribution volumes was seen in control goats with sulphadimidine, sulphisomidine and sulphadoxine, but was only significant for sulphadoxine. The pregnant uterus could not be recognised as an extra compartment, either in distribution volume nor in the pharmacokinetic model.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of three formulations of diphenylhydantoin in the dog.

The pharmacokinetics of the sodium salt of diphenylhydantoin was studied in three healthy dogs, using three formulations, a capsule, a tablet and a suspension. The results were essentially the same for all three formulations. The serum half life after intravenous injection ranged from 3.1 to 3.6 hours before and 1.3 to 1.6 hours after a two-week period of oral treatment. The bioavailability of the formulations varied from 43 to 54 per cent. Serum levels likely to be required for canine therapy could not be maintained with any of the formulations used in this experiment.

Pharmacokinetics of three sulphonamides in ruminant and preruminant kids.

The pharmacokinetic properties of three sulphonamides were determined in ruminant and preruminant kids after oral and intravenous administration. First, sulphisomidine (SIM, 50 mg kg-1) and sulphadoxine (SDX, 30 mg kg-1) were given to seven kids, 10 to 12 weeks old, while on a milk replacer diet and again at 15 to 18 weeks when fed roughage. Secondly, SIM (100 mg kg-1) and sulphadimidine (SDD, 100 mg kg-1) were given at six to nine, 12 to 15 and 18 to 21 weeks old to eight kids, of which four were fed milk replacer and four were with their mothers (with access to roughage) until 15 weeks, after which all were fed roughage only. SDX and SDD exhibited non-linear (or capacity limited) absorption after oral dosage, suggesting possible active absorption mechanisms, and both drugs also showed non-linear elimination. Intravenous curves for SDD and SIM indicated that recycling occurred. With SDX, ruminant kids showed poorer systemic availability after oral dosage, shorter t1/2(el) and higher B than did preruminants. For SDD, ruminant kids had lower Vd and higher B than preruminants. SIM's t1/2(el) tended to shorten and beta to increase in both groups throughout the experiment. Not all differences between ruminants and preruminants in sulphonamide pharmacokinetics could be explained by the accumulation of acidic forestomach contents and the change of urine pH from acid to alkaline in the maturing ruminant. Other potential contributing factors require investigation, including possible alterations in hepatic drug metabolism. Of the three drugs tested, SDX might be the most satisfactory for therapeutic use in preruminant animals, because it has good bioavailability after oral administration and long t1/2(el).

Chemotherapy and pharmacokinetics of some antimicrobial agents in healthy dwarf goats and those infected with Ehrlichia phagocytophila (tick-borne fever).

The therapeutic efficacy and pharmacokinetics of oxytetracycline (10 mg kg-1), ampicillin (20 mg kg-1) and a combination (TSS) of trimethoprim (20 mg kg-1), sulphadimidine (50 mg kg-1) and sulphamethylphenazole (50 mg kg-1) were investigated in normal dwarf goats and in those infected with Ehrlichia phagocytophila. Goats given oxytetracycline or TSS intravenously showed improvement, whereas ampicillin was ineffective. The infected goats had significantly prolonged elimination half-life values for sulphadimidine and oxytetracycline. The disposition kinetics of ampicillin and sulphamethylphenazole showed no marked differences between the healthy and infected animals. The tick-borne fever model used in the present study can be of value in testing the therapeutic efficacy and pharmacokinetics of chemotherapeutic agents in rickettsial infections.

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.

Effect of trenbolone and testosterone on the plasma elimination rates of sulfamethazine, trimethoprim, and antipyrine in female dwarf goats.

Plasma elimination rates of sulfamethazine (100 mg/kg of body weight, IV), trimethoprim (20 mg/kg, IV), and antipyrine (35 mg/kg, IV) were studied in adult female dwarf goats (n = 5) before and after implantation with trenbolone acetate (5 mg/kg). Pretreatment with trenbolone caused a significant decrease in the elimination rate of the drugs tested: for sulfamethazine, 5 times; for antipyrine, 3 times; and for trimethoprim, 2 times. After treatment with testosterone (1 mg/kg, SC, twice weekly for 2.5 weeks), female goats (n = 5) had a similar decrease in the elimination rate of sulfamethazine. Other induced effects included a change in social behavior, a lower voice, and the development of a typical billy goat-like odor. Plasma creatinine concentrations after androgen administration were significantly higher than those before androgen administration; changes were not observed in plasma urea values. Because of the differences observed, we believe that more attention should be paid to the effects of androgenic agents on drug kinetic properties, with particular reference to studies on clinical efficacy, side effects, and drug residues in food products.

Pharmacokinetic aspects of penicillins, aminoglycosides and chloramphenicol in birds compared to mammals. A review.

Based on a review of the literature, a comparison is made of the pharmacokinetics of penicillins, aminoglycosides, and chloramphenicol in birds and mammals. Penicillins in birds are likely to be more dependent for their elimination on biotransformation than in mammals. Amoxycillin had a relatively low availability (0.34) after p.o. administration. Higher doses (2 to 8 times) were needed to achieve the same peak levels in birds and mammals. Aminoglycosides, which for their elimination largely depend on renal excretion by glomerular filtration, show only minor differences in pharmacokinetics between birds and mammals. Chloramphenicol is mainly excreted after biotransformation and large differences in pharmacokinetic parameters are to be found, not only between birds and mammals, but also between avian species.

The influence of the injection site on the bioavailability of ampicillin and amoxycillin in beagles.

Influence of the injection site on bioavailability in dogs was investigated for injections with ampicillin anhydrate or amoxycillin trihydrate suspensions. Firstly, pharmacokinetic parameters were calculated after IV administration of the sodium salts. Then the dogs were injected in the neck (SC), in the lateral thorax region (SC), in the back (IM) and in the thigh (IM), respectively. The most obvious depot effect was seen after subcutaneous injection of ampicillin in the thorax region, though bioavailability seemed to be low. No differences were seen between the injection sites with amoxycillin. For ampicillin SC injection in the neck seems most favourable; for amoxycillin SC injection may be preferred because it is less burdening. Serum concentrations with amoxycillin were higher and persisted longer than with ampicillin. Further investigation is necessary to determine whether this also counts for tissues or focus of infection.

The effect of testosterone on the plasma disappearance rates of sulphadimidine and antipyrine in castrated dwarf goats.

Plasma disappearance of sulphadimidine and antipyrine was studied in adult castrated dwarf goats before and following pretreatment with testosterone. Comparison was made with entire males before and after castration. Testosterone pretreatment caused a significant increase in the apparent elimination half-life in castrates, whilst in entire males castration caused a significant decrease.

[Gentamicin: various pharmacotherapeutic aspects in comparison with other aminoglycosides]. / Gentamicine: enkele farmacotherapeutische aspecten met name in vergelijking met andere aminoglycosiden.

Gentamicin may be used in the treatment of infection with gram-negative bacteria including Pseudomonas spp and Proteus spp. Resistance will only appear in suboptimal or too prolonged courses of treatment and usually is due to 'multi-step mutation'. This resistance may be prevented, among others, by combined treatment with gentamicin and an antibiotic of the beta lactam group. When gentamicin is used correctly, it will have few toxic side-effects. Thus, 3 mg/kg of body weight three times daily will usually be indicated to ensure an optimum therapeutic effect. Parenteral administration of gentamicin would only appear to be useful in cases of bacteraemia and/or bacterial infection of the kidney and/or urinary excretory ducts; in the last-named case, the dose given at one time may be reduced by fifty per cent. Local treatment, the most recent method of which consists in administration by I(ntra-)T(racheal) route, apparently offers more prospects.

Bioavailability and pharmacokinetics of ampicillin and amoxycillin from tablets, capsules and long-acting preparations in the homing pigeon (Columba livia).

Three ampicillin and three amoxycillin formulations (tablets and capsules, administered orally, and oily suspensions, injected intramuscularly (i.m.) and subcutaneously (s.c.] were studied in twenty adult homing pigeons (Columba livia). Bioavailability, pharmacokinetics and recovery were determined for each product and administration route. A standard dose of 50 mg/pigeon or 100 mg/kg was used in each study. The mean availability calculated for each of these preparations was 7% for ampicillin anhydrate tablets, 22% for amoxycillin trihydrate tablets, 17% for ampicillin trihydrate capsules, 67% for amoxycillin trihydrate capsules, 46% for ampicillin oily suspension i.m., 67% for amoxycillin oily suspension i.m. and 43% for amoxycillin oily suspension s.c. The blood concentration-time curves for the tablets were very scattered, which was far less the case for the capsules. The maximum blood concentration (Cmax) for amoxycillin was twice as high as for ampicillin. The Cmax resulting from the oily suspensions administered i.m. were low (4.35 +/- 1.05 and 5.04 +/- 1.36 mg/l, for ampicillin and amoxycillin, respectively). The Tmax for ampicillin was 10 h and for amoxycillin it was 0.9 h after administration. Both curves showed biphasic absorption, the initial peak representing an absorption and a distribution phase and the second part reflecting the 'depot-nature' of the drug. After the s.c. administration of the amoxycillin oily suspension the same pattern was found, but the Cmax, which was found at 2.13 +/- 1.03 h after administration, was low (2.81 +/- 0.68 mg/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology and pharmacokinetics of flumequine after intravenous, intramuscular and oral administration in pigeons (Columba livia).

The in-vitro activity of flumequine against 157 strains of bacteria isolated from birds was determined. The minimum inhibitory concentration (MIC) of 96.3% of the Enterobacteriaceae, Proteus spp. and Yersinia pseudotuberculosis studied (n = 135) was less than or equal to 1 microgram/ml. Pharmacokinetics of flumequine in pigeons (Columba livia) was investigated after intravenous, intramuscular and oral administration. From the blood disappearance curves after i.v. bolus injection (10 mg/kg body weight) clearance rate, blood half-time and distribution volume were calculated. The recovery of unchanged flumequine from the droppings in 24 h was 37 +/- 10% of the administered dose. Flumequine was also given i.m. at two dose levels, 10 and 60 mg/kg body weight. The availability of flumequine as intact drug was 22 and 23%, respectively, in 24 h. Therapeutic blood levels were maintained for 4 and 10 h, respectively. After an oral dose of flumequine (60 mg/kg body weight) an availability of 6.7 +/- 2.5% and a peak blood concentration of 2.68 +/- 0.92 microgram/ml at 2 h after administration were found. The recovery of unchanged flumequine from the droppings in 24 h was 1.55 +/- 0.79% of the administered dose. With the exception of the i.m. dose of 10 mg/kg, all flumequine administrations made the pigeons vomit. It appears that blood concentrations below 3 micrograms/ml will not induce vomiting. On the basis of the present data, a dosage regimen for flumequine in pigeons of a priming dose of 30 mg/kg i.m., followed after 8 h by oral administration of 30 mg/kg, this dose being repeated every 8-12 h, would be expected to give blood concentrations between 1.44 and 2.88 micrograms/ml.

The effect of tick-borne fever on metabolism and renal clearance of sulfadimidine in goats.

The tick-borne fever (TBF) model was used to study the effect of fever on the metabolism of sulfadimidine in goats. During TBF the elimination half-lives were prolonged, and the renal clearance values of sulfadimidine and the majority of its metabolites were markedly diminished compared with those in the uninfected state. During TBF the steady-state levels of the hydroxy metabolites were markedly increased. TBF reduced the extent of hydroxymethylation of the pyrimidine side chain; TBF did not affect acetylation of sulfadimidine. In one goat a progressive accumulation of the metabolites was noticed.