A. Goudah

Synthesis and anti-inflammatory evaluation of some condensed [4-(3,4-dimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic acid hydrazide

Some new 1,3,4-triazolo-, 1,3,4-oxadiazolo-, 1,3,4-thiadiazol-, and pyrazolo-3,4-dimethylphenyl-1(2H)-oxo-phthalazine derivatives were synthesized and identified by IR, (1)H NMR, MS and elemental analysis. Most of the newly synthesized products were tested for their anti-inflammatory activities. Among them, compounds 11, 17b, 20, 21 and 22 are active compare to the activity of indomethacin.

Disposition Kinetics of Difloxacin in Rabbit after Intravenous and Intramuscular Injection of Dicural

This study investigated the pharmacokinetic behaviour of difloxacin following a single intravenous (i.v.) bolus and intramuscular (i.m.) administration of 5 mg/kg body weight (bw) to rabbits (n = 6). Plasma concentrations were determined in triplicate by agar plate diffusion usingE. coli (ATCC 25922) as the test organism. Difloxacin was assayed in plasma to determine its concentrations, kinetic behaviour and systemic availability. Plasma concentration–time data generated in the present study were analysed by non-compartmental methods based on statistical moment theory. Difloxacin was rapidly distributed to the tissues with a steady-state volume of distribution (Vdss) of 1.51 L/kg and the total body clearance (Cltot) was 0.59 L/kg/h. The elimination half-lives after i.v. and i.m. administration were 3.25 h and 3.82 h, respectively. After i.m. administration, difloxacin was rapidly absorbed, with mean peak plasma concentration (Cmax) of 3.85 μg/ml achieved at 1.61 h (Tmax) post administration. The extent of plasma protein binding of difloxacin in rabbits was 21.45% and the systemic bioavailability was 95.29%.

Pharmacokinetics and bioavailability of florfenicol following intravenous, intramuscular and oral administrations in rabbits.

This study examined the disposition kinetics and bioavailability of florfenicol after intravenous (i.v.), intramuscular (i.m.) and oral administration to rabbits at a dose of 30 mg/kg BW. Serial blood samples were collected through an indwelling catheter intermittently for 24 h for various routes. Plasma antibacterial concentrations were determined using a microbiological assay method withBacillus subtilis ATCC 6633 as a reference organism. Plasma concentration–time data generated in the present study were analysed by non-compartmental methods based on statistical moment theory. Following i.v. administration, the overall elimination half-life (t1/2β) was 1.54 h, mean residence time (MRT) was 1.69 h, mean volume of distribution at steady-state (Vdss) was 0.57 L/kg, and total body clearance (Cltot) was 0.34 L/kg/h. After i.m. and oral dosing, the terminal part of the curve should correspond to the absorption phase, instead of to the elimination phase, with terminal half-lives of 3.01 and 2.57 h, respectively. The mean absorption time (MAT) was 2.65 h for i.m. and 2.01 h for oral administration. Elimination rate constants differed with i.v., i.m. and oral administrations, suggesting a flip-flop situation. The observed mean peak plasma concentrations (Cmax obs) were 21.65 and 15.14 μg/ml achieved at a post-injection time (Tmax obs) of 0.5 h following i.m. and oral dosing, respectively. The absolute systemic availabilities were 88.25% and 50.79%, respectively, and the extent of plasma protein binding percent was 11.65%.

Synthesis, biological evaluation, and radioiodination of halogenated closo -carboranylthymidine analogues(1)

The synthesis and initial biological evaluation of 3-carboranylthymidine analogues (3CTAs) that are (radio)halogenated at the closo-carborane cluster are described. Radiohalogenated 3CTAs have the potential to be used in the radiotherapy and imaging of cancer because they may be selectively entrapped in tumor cells through monophosphorylation by human thymidine kinase 1 (hTK1). Two strategies for the synthesis of a (127)I-labeled form of a specific 3CTA, previously designated as N5, are described: (1) direct iodination of N5 with iodine monochloride and aluminum chloride to obtain N5-(127)I and (2) initial monoiodination of o-carborane to 9-iodo-o-carborane followed by its functionalization to N5-(127)I. The former strategy produced N5-(127)I in low yields along with di-, tri-, and tetraiodinated N5 as well as decomposition products, whereas the latter method produced only N5-(127)I in high yields. N5-(127)I was subjected to nucleophilic halogen- and isotope-exchange reactions using Na(79/81)Br and Na(125)I, respectively, in the presence of Herrmanns catalyst to obtain N5-(79/81)Br and N5-(125)I, respectively. Two intermediate products formed using the second strategy, 1-(tert-butyldimethylsilyl)-9-iodo-o-carborane and 1-(tert-butyldimethylsilyl)-12-iodo-o-carborane, were subjected to X-ray diffraction studies to confirm that substitution at a single carbon atom of 9-iodo-o-carborane resulted in the formation of two structural isomers. To the best of our knowledge, this is the first report of halogen- and isotope-exchange reactions of B-halocarboranes that have been conjugated to a complex biomolecule. Human TK1 phosphorylation rates of N5, N5-(127)I, and N5-(79/81)Br ranged from 38.0% to 29.6% relative to that of thymidine, the endogenous hTK1 substrate. The in vitro uptake of N5, N5-(127)I, and N5-(79/81)Br in L929 TK1(+) cells was 2.0, 1.8, and 1.4 times greater than that in L929 TK1(-) cells.

Some pharmacokinetic parameters of pefloxacin in lactating goats

The aim of this study was to elucidate some of the pharmacokinetic parameters of pefloxacin in lactating goats (n = 5) following intravenous (i.v.) or intramuscular (i.m.) injections of 10 mg/kg bw. Serially obtained serum, milk and urine samples were collected at precise time intervals, and the drug concentrations were assayed using a microbiological assay. A two-compartment open model best described the decrease of pefloxacin concentration in the serum after intravenous administration. The maximum serum concentration (Cp0) was 8.4±0.48 μg/ml; elimination half-life (t1/2β) was 1.6±0.3 h; total body clearance (Cltot) was 3.6±0.3 L/kg/h; steady-state volume of distribution (Vdss) was 5.14±0.21 L/kg; and the area under the curve (AUC) was 2.78±0.22 μg.ml/h. Pefloxacin was absorbed rapidly after i.m. injection with an absorption half-life (t1/2ab) of 0.32±0.02 h. The peak serum concentration (Cmax) of 0.86±0.08 μg/ml was attained at 0.75 h (Tmax). The absolute bioavailability after i.m. administration was 70.63±1.13% and the serum protein-bound fraction ranged from 7.2% to 14.3%, with an average value of 9.8±1.6%. Penetration of pefloxacin from the blood into the milk was rapid and extensive, and the pefloxacin concentration in milk exceeded that in serum from 1 h after administration. The drug was detected in milk and urine for 10 and 72 h, respectively; no samples were taken after 72 h.

Aspects of the Pharmacokinetics of Albendazole Sulphoxide in Sheep

The plasma disposition kinetics of albendazole sulphoxide (ABZSO), ((+)ABZSO and (–)ABZSO) and its sulphone metabolite (ABZSO2) were investigated in adult sheep. Six Corriedale sheep received albendazole sulphoxide by intravenous injection at 5 mg/kg live weight. Jugular blood samples were taken serially for 72 h and the plasma was analysed by high-performance liquid chromatography (HPLC) for albendazole (ABZ), ABZ sulphoxide (ABZSO) and albendazole sulphone (ABZSO2). Albendazole was not detected in the plasma at any time after the treatment, ABZSO and ABZSO2 being the main metabolites detected between 10 min and 48 h after treatment. A biexponential plasma concentration versus time curve was observed for both ABZSO and ABZSO2 following the intravenous treatment. The plasma AUC values for ABZSO and ABZSO2 were 52.0 and 10.8 (μg.h)/ml, respectively. The ABZSO2 metabolite was measurable in plasma between 10 min and 48 h after administration of ABZSO, reaching a peak concentration of 0.38 μg/ml at 7.7 h after treatment. Using a chiral phase-based HPLC method, a biexponential plasma concentration versus time curve was observed for both ABZSO enantiomers. The total body clearance was higher for the (–) than for the (+) enantiomer, the values being 270.6 and 147.75 (ml/h)/kg, respectively. The elimination half-life of the (–) enantiomer was shorter than that of the (+) enantiomer, the values being 4.31 and 8.33 h, respectively. The enantiomeric ratio (+)ABZSO/(–)ABZSO at t0 was close to unity. However, the ratio in the plasma increased with time.

Influence of Pasteurella multocida infection on the pharmacokinetic behavior of marbofloxacin after intravenous and intramuscular administrations in rabbits

The pharmacokinetic behavior of marbofloxacin was studied in healthy (n = 12) and Pasteurella multocida infected rabbits (n = 12) after single intravenous (i.v.) and intramuscular (i.m.) administrations. Six rabbits in each group (control and diseased) were given a single dose of 2 mg/kg body weight (bw) of marbofloxacin intravenously. The other six rabbits in each group were given the same dose of the drug intramuscularly. The concentration of marbofloxacin in plasma was determined using high-performance liquid chromatography. The plasma concentrations were higher in diseased rabbits than in healthy rabbits following both routes of injections. Following i.v. administration, the values of the elimination half-life (t(1/2beta)), and area under the curve were significantly higher, whereas total body clearance was significantly lower in diseased rabbits. After i.m. administration, the elimination half-life (t(1/2el)), mean residence time, and maximum plasma concentration (C(max)) were higher in diseased rabbits (5.33 h, 7.35 h and 2.24 microg/mL) than in healthy rabbits (4.33 h, 6.81 h and 1.81 microg/mL, respectively). Marbofloxacin was bound to the extent of 26 +/- 1.3% and 23 +/- 1.6% to plasma protein of healthy and diseased rabbits, respectively. The C(max)/MIC (minimum inhibitory concentration) and AUC/MIC ratios were significantly higher in diseased rabbits (28 and 189 h) than in healthy rabbits (23 and 157 h), indicating the favorable pharmacodynamic characteristics of the drug in diseased rabbits.

Pharmacokinetics and tissue residues of moxifloxacin in broiler chickens.

1. In this study the disposition kinetics and plasma availability of moxifloxacin in broiler chickens after single intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administrations of 5 mg/kg body weight were investigated. 2. Tissue residue profiles (liver, kidney, lung and muscle) and plasma were also studied after multiple intramuscular and oral administration of 5 mg/kg body weight, once daily for 5 consecutive days. 3. The concentrations of the drug in the plasma and tissues were measured using high-performance liquid chromatography (HPLC) with fluorescence detection on samples collected at frequent intervals after drug administration. 4. Following intravenous injection, plasma concentration–time curves were best described by a two-compartment open model. The decline in plasma drug concentration was bi-exponential with half-lives of (t 1/2α) 0·26 h and (t 1/2β) 2·27 h for distribution and elimination phases, respectively. 5. After intramuscular and oral administration of moxifloxacin at the same dose the peak plasma concentrations (C max) were 2·23 and 1·99 µg/ml and were obtained at 1·56 and 1·90 h (T max), respectively, and the elimination half-lives (T 1/2el) were 2·24 and 1·69 h, respectively. 6. The systemic bioavailabilities were 97·11 and 90·01%, respectively. In vitro protein binding percent was 37%. 7. The tissue levels following i.m. and p.o. administration were highest in liver and kidney, respectively, and decreased in the following order: plasma, lung and muscle. No moxifloxacin residues were detected in tissues and plasma after 120 h with both routes of administration, moxifloxacine was found in both the liver and kidney 144 h after i.m. and oral administration.

Disposition kinetics and tissue residues of danofloxacin in Muscovy ducks.

1. The disposition kinetics and plasma availability of danofloxacin in Muscovy ducks after single intravenous (i.v.), intramuscular (i.m.) and oral administrations of 5 mg/kg body weight were investigated. 2. Tissue residue profiles (liver, kidney and muscle) and plasma were also studied after multiple intramuscular and oral administration of 5 mg/kg once daily for 5 consecutive days. 3. The concentrations of the drug in the plasma and tissues were measured using high-performance liquid chromatography (HPLC) with fluorescence detection on samples collected at frequent intervals after drug administration. 4. Following intravenous injection, plasma concentration vs. time curves were best described by a two compartment open model. The decline in plasma drug concentration was bi-exponential with half-lives of (t 1/2α) 0·08 h and (t 1/2β) 3·91 h for distribution and elimination phases, respectively. 5. After intramuscular and oral administration of danofloxacin at the same dose the peak plasma concentrations (C max) were 0·89 and 0·81 µg/ml and attained at 1·17 and 1·21 h (T max), respectively, and the elimination half-lives (T 1/2el) were 2·91 and 2·39 h, respectively. The systemic bioavailabilities were 103·21 and 89·26%, following i.m. and oral admisistartion, respectively. In vitro protein binding percent of danofloxacin in Muscovy ducks plasma was 17%. 6. The tissue level following i.m. and oral administration were highest in liver and kidney, respectively, and decreased in the following order: plasma and muscle. No danofloxacin residues were detected in tissues and plasma after 96 h with either route of administration except in liver and kidney, after 120 h in case of oral administration.

Pharmacokinetics and milk distribution characteristics of orbifloxacin following intravenous and intramuscular injection in lactating ewes

The purpose of the current investigation is to elucidate the pharmacokinetic profiles of orbifloxacin (OBFX) in lactating ewes (n = 6) following intravenous (i.v.) and intramuscular (i.m.) administrations of 2.5 mg/kg W. In a crossover study, frequent blood, milk, and urine samples were drawn for up to 48 h after the end of administration, and were then assayed to determine their respective drug concentrations through microbiological assay using Klebsiella pneumoniae as the test micro-organism. Plasma pharmacokinetic parameters were derived from plasma concentration-time data using a compartmental and noncompartmental analysis, and validated a relatively rapid elimination from the blood compartment, with a slope of the terminal phase of 0.21 +/- 0.02 and 0.19 +/- 0.06 per hour and a half-life of 3.16 +/- 0.43 and 3.84 +/- 0.59 h, for i.v. and i.m. dosing, respectively. OBFX was widely distributed with a volume of distribution V((d(ss))) of 1.31 +/- 0.12 L/kg, as suggested by the low percentage of protein binding (22.5%). The systemic body clearance (Cl(B)) was 0.32 +/- 0.12 L/h x kg. Following i.m. administration, the maximum plasma concentration (C(max)) of 1.53 +/- 0.34 microg/mL was reached at t(max) 1.25 +/- 0.21 h. The drug was completely absorbed after i.m. administration, with a bioavailability of 114.63 +/- 11.39%. The kinetic milk AUC(milk)/AUC(plasma) ratio indicated a wide penetration of orbifloxacin from the bloodstream to the mammary gland. OBFX urine concentrations were higher than the concurrent plasma concentrations, and were detected up to 30 h postinjection by both routes. Taken together, these findings indicate that systemic administration of orbifloxacin could be efficacious against susceptible mammary and urinary pathogens in lactating ewes.