The pharmacodynamic and nephrotoxic effects of cefamandole were investigated. Cefamandole at concentrations of 512 and 1024 micrograms/ml bath caused complete relaxation in isolated guinea pig ileum and rabbit duodenum, respectively. Concentrations of 2048 and 4096 micrograms cefamandole/ml bath caused marked stimulation in force and frequency of rat uterine muscle in all stages of sex cycle. Cefamandole in all tested concentrations did not induce any response on isolated guinea pig tracheal chain or isolated rabbit aortic strip. Cefamandole in concentrations of 256 to 1024 micrograms/ml bath as well as 256 and 512 micrograms/ml cannula produced marked inhibition on isolated guinea pig auricles and rabbit heart, respectively. The effect of graded increased concentrations on isolated frog gastrocnemius muscle, frog rectus abdominis muscle and rat phrenic nerve hemidiaphragm was recorded. Cefamandole in a dose of 53.2 mg/kg b. wt. in anaesthetized dogs caused very marked hypotensive effects and decrease in rate of respiration. Single intramuscular injection of cefamandole in a therapeutic (23.3 mg/kg b. wt.) and double therapeutic (46.6 mg/kg.b. wt.) doses in rabbits had no effect on electrocardiographic parameters among a period of 8 hours after injection. Effects of cefamandole on serum and urine concentrations of creatinine, urea, sodium, potassium, calcium, glucose and protein as well as clearance tests were investigated in rats.

Following a single intravenous injection of 10 mg netilmicin or 30 mg vancomycin/kg b.w. to normal chickens, the tested drugs obeyed a two or three compartments open model, with half-lives of distribution of 0.30 and 0.20 hours, respectively. The elimination half-lives following intravenous injection were 0.41 and 4.85 hours, respectively. Following a single intramuscular injection of 10 mg netilmicin or 30 mg vancomycin/kg b.w. to normal chickens, the serum drug concentrations peaked 2 hours post-injection with half-lives of absorption equal to 0.63 and 0.56 hours, respectively. The mean systemic bioavailability of netilmicin and vancomycin following a single intramuscular administration in normal chickens was 27.29 and 43.61%, respectively. These values indicated a limited and moderate absorption for netilmicin and vancomycin from intramuscular site, respectively. During repeated intramuscular administrations of both antibiotics for five consecutive days in normal chickens, the serum drug concentrations peaked two hours post each dose. The drugs concentrations during multiple dosage regimens were significantly increased in 2nd, 3rd, 4th and 5th days in comparison to the 1st day. Netilmicin and vancomycin persisted in liver and kidney for 96 and 120 hours, respectively, after the last intramuscular administration. The withdrawal time of netilmicin and vancomycin could be considered as five and six days, respectively. The in-vitro protein binding percents of netilmicin and vancomycin were 7.45 and 5.81%, respectively.

The pharmacokinetics of sulphaquinoxaline and amprolium hydrochloride were studied in Hubbard broiler chickens. Single doses of sulphaquinoxaline (100 mg/kg b. wt.), and amprolium hydrochloride (30 mg/kg b. wt.) were administered orally and intravenously to the same birds with 15 days interval between treatments. Sulphaquinoxaline and amprolium HCl were determined colorimetrically. Following i.v. administration, the concentration-time curve of sulphaquinoxaline and amprolium could be explained by a two compartments open model with a t1/2 alpha of 0.16 +/- 0.008 h; 0.17 +/- 0.09 h; t1/2 beta of 12.6 +/- 0.32 h, 4.89 +/- 0.3 h respectively. The total body clearance were 0.278 +/- 0.013 ml/kg/min; 0.562 +/- 0.015 ml/kg/min; volume of distribution at steady state were 0.44 +/- 0.009 L/kg, 0.34 +/- 0.005 L/kg and systemic bioavailability following oral administration were 72.65 +/- 3.38, 66.09 +/- 4.9 percent for sulphaquinoxaline and amprolium HCl respectively. Following oral administration of sulphaquinoxaline and amprolium (the same previous doses) the peak plasma concentrations (Cmax) were 107.8 +/- 1.49 micrograms/ml; 42.9 +/- 1.11 micrograms/ml and occurred at 5.56 +/- 0.1 h, 3.67 +/- 0.05 h respectively. Pharmacokinetic parameters after repeated oral daily administrations of sulphaquinoxaline and amprolium revealed that the Cmax was 184 +/- 1.02 micrograms/ml, and 55.19 +/- 0.35 micrograms/ml at 7.36 +/- 0.18 h and 5.17 +/- 0.15 h and the biological half lives were 1.67 +/- 0.057 h and 1.11 +/- 0.14 h respectively. Sulphaquinoxaline and its N4 acetyl metabolite disappeared from all body tissues at 120 hours, however amprolium persisted in most tissues for 72 hours after the last dose of repeated administrations.

The pharmacokinetics of cephradine was studied following single and repeated intramuscular injections in normal and Escherichia coli infected goats. Bioavailability of cephradine was determined in normal goats after a single intramuscular dose. The serum concentrations of cephradine following a single and repeated intramuscular administration of 10 mg/kg b.wt. twice daily for five consecutive days, peaked 2 hours after each intramuscular dose with a lower significant value recorded in E. coli infected goats than in normal goats. The absorption half-lives (t0.5(ab)) following a single intramuscular injection of cephradine was significantly higher in E. coli infected goats (1.18 h) than in normal goats (0.64 h). The elimination half-lives (t0.5(beta)) of cephradine were significantly higher in E. coli infected goats than in normal goats following the administration of fifth and ninth doses. The urine and milk concentrations of cephradine were significantly lower in E. coli infected goats than in normal goats. The mean systemic bioavailability of cephradine following a single intramuscular injection in normal goats was 73.9%.

Following a single oral dose of trimethoprim (10 mg/kg b. wt.) in normal fowls, the highest serum concentration achieved 4 hours post-administration with value of 0.64 microgram/ml. The absorption half-life time was 0.64 hours. The elimination half life was 4.73 hours. During repeated oral administration of 10 mg/kg b. wt., once daily for five consecutive days, trimethoprim peaked in serum, 4 h after each dose. Trimethoprim persisted in all fowl's tissues for 96 hours after stopping of drug administration. After oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) in normal fowls, a maximum serum concentration of trimethoprim was recorded at 2 hours with half-life of absorption (t0.5(ab)) valued 0.74 hour. The elimination half-life (t0.5 beta) was 4.37 hours. During repeated oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) once daily for five consecutive days in normal fowls, the highest plasma concentrations of trimethoprim occurred 2 hours post each dose. The daily maximum plasma concentrations during the repeated oral administration of both tested drugs were nearly constant.

Gentamicin concentrations in serum, urine and milk were assayed microbiologically after intramuscular and intrauterine administrations in normal and endometritic cows. Following intramuscular injections of 5 mg gentamicin/kg b. wt. 3 times daily for three consecutive days, the highest serum concentrations occurred 1 h post administration of each dose with absorption half-lives [t0.5(ab)] ranging from 0.23 to 0.30 h for normal cows and from 0.21 to 0.29 h for endometritic cows. The elimination half-lives [t0.5(beta)] ranged from 2.51 to 2.95 h (normal cows) and from 2.71 to 3.29 h (endometritic cows). Following intrauterine administration of 4 mg gentamicin/kg. b. wt. once daily for three consecutive days, the drug peaked in serum 2 h after each dose with [t0.5(ab)] ranging from 0.47 to 0.52 h (normal cows) and from 0.57 to 0.68 h (diseased cows), while the drug was eliminated faster in endometritic cows than in normal cows. The mean systemic bioavailability were (70%) and (30%) after intramuscular and intrauterine administration, respectively. To compare serum concentrations, gentamicin was assayed in urine and milk in high and low concentrations, respectively.

SUMMARY1. Monensin was given orally to female rats at two dose levels (1.75 and 3.50 mg/kg body weight) over the period of 9‐17 days of pregnancy where organogenesis of fetuses occur. The dams were killed on the nineteenth day of gestation and their fetuses were subjected to morphological, visceral and skeletal examination. The small dose of monensin increased the number of resorbed and dead fetuses and induced marked retardation in growth of viable fetuses, but visceral or skeletal defects in these fetuses were not seen. Large doses produced fetal resorption in all dams and no viable fetuses were delivered.2. Prolonged oral administration of monensin in male rats for 60 successive days at two dose levels, decreased the conception rate in non‐treated females (mated with treated males) to 33.3% and 0% for the small and large doses, respectively. Both doses markedly decreased the weights of testicles, epididymides and seminal vesicles. The small dose of monensin caused oligospermia, whereas the large dose induced azospermia. Both doses decreased the activity of spermatogenic epithelium and caused degeneration in germ cells after histopathological examination of the testicles.3. It is concluded that monensin given during pregnancy to female rats is fetotoxic and when administered chronically to male rats, causes damage to the reproductive organs. The delayed effects of this drug are especially prominent.

Evaluation of the pharmacokinetic properties of 4 antibiotics: penicillin-G (P), streptomycin (S), chloramphenicol (C) and oxytetracycline (O) was performed in groups of camels following a single i.m. injection of therapeutic doses, i.e. 6000 IU, 10, 4 and 3 mg/kg b.wt., respectively. The concentrations of these antibiotics in serum were determined by microbiological assay methods. The highest serum concentrations were reached after 0.42, 1.44, 4.02 and 0.94 hr for P, S, C, and O respectively with corresponding t 1/2 alpha values of 0.12, 0.28, 1.48 and 0.17 hr and t 1/2 beta values of 1.09, 8.28, 6.20 and 7.00 hr.

1. Three groups of four clinically healthy buffaloes were injected with sulphadiazine, or sulphadimidine, or sulphathiazole in a single dose of 100 mg/kg body weight. 2. Changes in the serum enzyme activities (SGOT, SGPT and alkaline phosphatase) observed with the tested sulphonamides were insignificant, except for increases in SGOT level 6 h after sulphathiazole injection, and in GOT/GPT ratio 30 min and 24 h after sulphadimidine injection. 3. The creatinine level was not affected in sulphonamide-injected animals. All blood samples collected 15 min to 24 h after sulphathiazole injection showed marked increase in glucose and urea levels. Concerning the other two sulphonamides, no significant change was observed in these parameters except for an increased glucose level 24 h after sulphadiazine injection.

Summary Following a single i. v. injection of sulphadiazine, sulphadimidine and sulphathiazole in buffaloes (100 mg./kg. b. wt.), it was found that: 1. Sulphathiazole was the most rapidly eliminated, with a half‐life value of 198 min, followed by sulphadiazine (230 min); sulphadimidine had the slowest rate (563 min). The volumes of distribution of the 3 sulphonamides were 579, 751 and 452 ml./kg. b. wt., respectively. 2. 24 h after injection no detectable amount of sulphadiazine, but a significant amount of sulphathiazole (10.10 μg./ml.) and sulphadimidine (40.54 μg./ml.), was found in plasma. The protein‐bindung tendency of the 3 sulphonamides, as calculated in vitro , showed that values for sulphadiazine and sulphathiazole were very similar (18.01 and 16.62 %, respectively), while that for sulphadimidine (4.31 %), was much lower. 3. Excretion of the 3 sulphonamides in saliva was higher than in milk, with the concentration of sulphadimidine in both higher than that of the other 2 compounds. Very high concentrations of the parent sulphonamides and their acetylated derivatives were found in urine. Zusammenfassung Pharmakokinetik einiger Sulfonamide bei Büffeln Die einmalige i. v. Injektion von Sulfadiazin, Sulfadimidin oder Sulfa‐ thiazol bei je 3 Büffeln (100 mg/kg KGW) führte zu folgenden Ergebnissen: Sulfathiazol wurde am schneüsten eliminiert (HWZ 198 min), gefolgt von Sulfadiazin (230 min) und Sulfadimidin (563 min). Die Verteilungsvolumen der 3 Sulfonamide betrugen 579, 751 und 452 ml/kg KGW. 2. 24 h nach der Injektion ließ sich im Plasma kein Sulfadiazin mehr nachweisen, dagegen noch beachtliche Konzentrationen von Sulfathiazol (10,1 μg/ml) und Sulfadimidin (40,5 μg/ml). Die in vitro Bestimmung der Proteinbindung ergab ähnliche Werte für Sulfadiazin (18 %) und Sulfathiazol (16,6 %), während der Anteil beim Sulfadimidin wesentlich niedriger lag (4,3 %). 3. Die Ausscheidung der 3 Sulfonamide war im Speichel größer als in der Milch. In beiden Sekreten war die Konzentration von Sulfadimidin größer als die der beiden anderen Verbindungen. Hohe Konzentrationen der Ausgangssubstanzen und ihrer acetylierten Metaboliten ließen sich im Urin nachweisen. Résumé Pharmacocinétique de quelques sulfonamides chez des buffles Les résultats suivants ont été obtenus après une injection intraveineuse de Sulfadiazine, de Sulfadimidine ou de Sulfathiazol chez des buffles (100 mg/kg de poids): 1. Le Sulfathiazol fut éliminé le plus rapidement (demi‐temps 198 min) suivi par la Sulfadiazine (230 min) et la Sulfadimidine (563 min). Le volume de répartition des 3 sulfonamides fut de 579, 751 et 452 ml/kg de poids. 2. Aucune Sulfadiazine ne fut mise en évidence dans le plasma 24 h après l'injection, mais par contre des concentrations marquées de Sulfathiazol (10,1 μg/ml) et de Sulfadimidine (40,5 μg/ml) ont été constatées. La détermination in vitro de la liaison protéique a donné des valeurs identiques pour la Sulfadiazine (18 %) et le Sulfathiazol (16,6 %), cette valeur étant nettement plus basse pour la Sulfadimidine (4,3 %). 3. L'excrétion des 3 sulfonamides fut plus grande dans la salive que dans le lait. La concentration de Sulfadimidine fut plus forte dans les deux excrétions. Des concentrations élevées des substances de sortie et de leurs métabolites acétiylés ont été mis en évidence dans l'urine. Resumen Fármacocinética de algunas sulfonamidas en búfalos La inyección iv. única de sulfadiazina, sulfadimidina o sulfatiazol en 3 búfalos cada vez (100 mg./kg. PC) conducía a los resultados siguientes: Sulfatiazol se eliminó más rápidamente (semitiempo de valor 198 min), seguida por sulfadiazina (230 min) y sulfadimidina (563 min). Los volúmenes de distribución de las 3 sulfonamidas eran del orden de 579, 751 y 542 ml./kg. PC. 24 horas después de la inyección no se pudo identificar en el plasma sanguíneo ninguna sulfadiazina, pero sí concentraciones considerables de sulfatiazol (10,1 μg./ml.) y sulfadimidina (40,5 μg./ml.). La valoración in vitro de la ligazón a la proteína ofreció valores semejantes para sulfadiazina (18 %) y sulfatiazol (16,6 %), mientras que el contingente en sulfadimidina era bastante menor (4,3 %). La eliminación de las 3 sulfonamidas era mayor en la saliva que con la leche. En las dos excreciones era mayor la concentración de sulfadimidina que las de las otras dos combinaciones. En la orina se hallaron concentraciones muy elevadas de las substancias madres y de sus metabolitos acetiladcs.

In 12 experiments on 6 mongrel dogs, furosemide was given both orally and i.v. in a dose of 20mg/kg. Following i.v. injection, the blood concentration curve followed an open one-compartment model. The elimination half-lives after both oral and i.v. routes were nearly similar, i.e. 1.42 +10.13 and 1.13 +0.06 hours respectively. The apparent volume of distribution corresponded well to the total body water (about 60%), i.e. 69.64 +5.61 and 52.06+4.82% b.wt. after oral and i.v. routes respectively. The body clearance of this drug after i.v. and oral administration showed close values, i.e. 5.27 +0.19 and 5.96 +0.14 mg/kg(-1) min(-1) respectively. The systemic bioavailablity of furosemide after oral administration amounted to 77.13 +5.24% with a maximum blood conc. (Cmax.) of 22.73 +2.03 microgram/ml, 30 min after administration.