Sherifa Hasabelnaby

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.

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.

The disposition of marbofloxacin after single dose intravenous, intramuscular and oral administration to Muscovy ducks

Marbofloxacin is a fluoroquinolone antimicrobial agent developed exclusively for veterinary use. Marbofloxacin exhibits bactericidal activity against a broad spectrum of aerobic gram-negative and some gram-positive bacteria, and also against Mycoplasma spp. (Hannan et al., 1997). Fluoroquinolones exhibit bactericidal action by targeting the bacterial DNA topoisomerases II (gyrase) and IV, which is responsible for supercoiling of DNA around RNA core to provide a suitable spatial arrangement of DNA within the bacterial cell (Drlica & Zhao, 1997). Like other fluoroquinolones, marbofloxacin is an organic acid with good tissue penetration, high volume of distribution, low binding to plasma proteins and activity at very low concentrations. Marbofloxacin has similar or better antibacterial activity and shows a broad antibacterial spectrum compared with published data on the other fluoroquinolones (Spreng et al., 1995). Marbofloxacin differs in particular from other fluoroquinolones on account of its oxadiazine ring, which is supposed to give the molecule some pharmacokinetic advantages such as a long elimination half-life (t1⁄2b) and high bioavailability (Fitton, 1992). The pharmacokinetic properties of marbofloxacin have been reported in several animal species like broiler chickens (Anadon et al., 2002), ostriches (De Lucas et al., 2005) and turkey (Haritova et al., 2006). However, there have been no previous reports for marbofloxacin pharmacokinetics in Muscovy ducks. The Muscovy duck raised intensively in several parts of the world for meat production is not without attendant veterinary problems. Intorre et al., 1997 reported that pasteurellosis and respiratory colibacillosis are very common infectious diseases that are responsible for high rates of mortality and morbidity in many avian species, including ducks, with important economic implications for breeding. In view of the marked species variations in the kinetic data for antimicrobial drugs, this study was undertaken to determine the disposition kinetics of marbofloxacin in Muscovy ducks after a single intravenous, intramuscular and oral administration of 2.0 mg ⁄ kg body weight. Meanwhile, plasma protein binding and bioavailability of marbofloxacin were estimated. Additionally, an appropriate dosage regimen of marbofloxacin in Muscovy ducks was suggested using the surrogate markers of pharmacokinetic– pharmacodynamic integration. Marbofloxacin was used as 10% injectable aqueous solution purchased from Veterinary Pharmaceutical Laboratories, France (Marbocyl , Vetoquinol, Lure, France) (diluted to 0.5% in 5% dextrose solution for an accurate dosing) for i.v. and i.m. administration. The same sterile formulation was diluted with sterile distilled water to 1% and then used for oral administration. Marbofloxacin standard was provided by Vetoquinol (Lure, France), and ofloxacin (internal standard) was purchased from Sigma Chemical Company (St. Louis, MO, USA). We used thirty clinically healthy male Muscovy ducks that were 16week old, weighing 4.2 ± 0.36 kg and were obtained from a private farm, 2 week before the start of the study. During the acclimatization, they were fed antibacterial-free balanced commercial rations and drinking water was freely available. Also during the acclimatization period, the health status of Muscovy ducks was checked by daily observations without any clinical signs of disease being seen and did fecal examination to be free from intestinal parasites. The study was reviewed and approved by the Institutional Animal Care and Use Committee at Faculty of Veterinary Medicine. Thirty Muscovy ducks were individually weighed before drug administration, and individual doses were calculated precisely. The Muscovy ducks were allocated to three equal groups of 10 each. Marbofloxacin was administered at a dosage of 2 mg ⁄ kg of body weight, according to the manufacturer s instructions of other animal species. Birds in group one was given a single i.v. dose of marbofloxacin at a dose of 2 mg ⁄ kg into the left brachial vein. Birds in the other two groups were given the same dose of marbofloxacin by i.m. and oral routes through the left semimembranosus muscle, using a 23-gauge needle and into the crop by means of a feeding tube consisted of rubber catheter fit with a syringe, respectively. Half to one microliter venous whole blood samples were collected from the wing vein into 5mL heparinized vacutainers (Becton Dickinson vacutainer Systems, Rutherford, NJ, USA). The sampling times were 0 (blank sample), 0.16, 0.25, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 18, 24, 30 and 48 h after administration of marbofloxacin by i.v., i.m. and oral. All the blood samples were centrifuged at 3000 g for 15 min to separate the plasma. The plasma samples were frozen at )20 C until analyzed by high-performance liquid chromatography (HPLC). J. vet. Pharmacol. Therap. 34, 197–201. doi: 10.1111/j.1365-2885.2010.01225.x. SHORT COMMUNICATION

Pharmacokinetics, plasma protein binding and bioavailability of moxifloxacin in Muscovy ducks after different routes of administration.

In this study the disposition kinetics and plasma availability of moxifloxacin in Muscovy ducks after single intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administrations of 5 mg kg(-1) b.wt. were investigated. The concentrations of moxifloxacin in the plasma were measured using high-performance liquid chromatography (HPLC) with fluorescence detection on samples collected at frequent intervals after drug administration. Following intravenous injection, the decline in plasma drug concentration was bi-exponential with half-lives of (t(1/2)(alpha)) 0.22+/-0.10h and (t(1/2)(beta)) 2.49+/-0.26h for distribution and elimination phases, respectively. The volume of distribution at steady-state (V(dss)) was 1.02+/-0.14 l kg(-1) and the total body clearance (Cl(tot)) was 0.32+/-0.11 l kg(-1)h(-1), respectively. After intramuscular and oral administration of moxifloxacin at the same dose the peak plasma concentrations (C(max)) were 2.38+/-0.43 and 2.11+/-0.36 microg ml(-1) and were obtained at 1.47+/-0.26 and 1.83+/-0.16h (T(max)), respectively, the elimination half-lives (T(1/2el)) were 3.14+/-0.42 and 2.63+/-0.44h, respectively, and AUC(0-24) were 15.87+/-2.35 and 14.52+/-2.37 microg ml(-1)h(-1), respectively. The systemic bioavailabilities were 96.36+/-11.54% and 86.79+/-12.64%, respectively. In vitro plasma protein binding percent was 32%. We concluded that moxifloxacin might be clinically interesting alternative for the treatment of most sensitive bacterial infections in Muscovy ducks.

Cellular Influx, Efflux, and Anabolism of 3-Carboranyl Thymidine Analogs: Potential Boron Delivery Agents for Neutron Capture Therapy

3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH) is a first generation 3-carboranyl thymidine analog (3CTA) that has been intensively studied as a boron-10 (10B) delivery agent for neutron capture therapy (NCT). N5-2OH is an excellent substrate of thymidine kinase 1 and its favorable biodistribution profile in rodents led to successful preclinical NCT of rats bearing intracerebral RG2 glioma. The present study explored cellular influx and efflux mechanisms of N5-2OH, as well as its intracellular anabolism beyond the monophosphate level. N5-2OH entered cultured human CCRF-CEM cells via passive diffusion, whereas the multidrug resistance-associated protein 4 appeared to be a major mediator of N5-2OH monophosphate efflux. N5-2OH was effectively monophosphorylated in cultured murine L929 [thymidine kinase 1 (TK1+)] cells whereas formation of N5-2OH monophosphate was markedly lower in L929 (TK1–) cell variants. Further metabolism to the di- and triphosphate forms was not observed in any of the cell lines. Regardless of monophosphorylation, parental N5-2OH was the major intracellular component in both TK1+ and TK1– cells. Phosphate transfer experiments with enzyme preparations showed that N5-2OH monophosphate, as well as the monophosphate of a second 3-carboranyl thymidine analog [3-[5-(o-carboran-1-yl)pentan-1-yl]thymidine (N5)], were not substrates of thymidine monophosphate kinase. Surprisingly, N5-diphosphate was phosphorylated by nucleoside diphosphate kinase although N5-triphosphate apparently was not a substrate of DNA polymerase. Our results provide valuable information on the cellular metabolism and pharmacokinetic profile of 3-carboranyl thymidine analogs.

Pharmacokinetics and bioavailability of moxifloxacin in calves following different routes of administrations.

Background: Moxifloxacin is a new fourth-generation 8-methoxy fluoroquinolone developed primarily for the treatment of community-acquired pneumonia and upper respiratory tract infections. The aim of the study was to investigate the plasma pharmacokinetics characteristic of moxifloxacin in calves, after intravenous, intramuscular and subcutaneous administration of a single dose. Meanwhile, plasma protein binding and bioavailability of moxifloxacin were also estimated. Methods: Plasma concentrations of moxifloxacin were measured using a modified HPLC method, and the extent of plasma protein binding was determined in vitro using ultrafiltration. Results: Following intravenous administration, the half life of elimination, the volume of distribution at steady state and the area under the curve were 3.29 h, 0.94 l/kg and 24.72 µg·h/ml, respectively. After intramuscular and subcutaneous administration of moxifloxacin at the same dose, the peak plasma concentrations were 2.41 and 2.20 µg/ml and were obtained at 1.54 and 1.59 h, respectively. The systemic bioavailabilities were 87.19 and 75.94%, respectively. The in vitro plasma protein binding of moxifloxacin in plasma of calves was 27%. Conclusion: A high peak plasma concentration, area under the curve, rapid absorption and bioavailability following intramuscular and subcutaneous administration characterize the pharmacokinetics of moxifloxacin in calves.

Pyrrole and Fused Pyrrole Compounds with Bioactivity against Inflammatory Mediators

A new series of pyrrolopyridines and pyrrolopyridopyrimidines have been synthesized from aminocyanopyrroles. The synthesized compounds have been characterized by FTIR, 1H-NMR and mass spectroscopy. The final compounds have been screened for in vitro pro-inflammatory cytokine inhibitory and in vivo anti-inflammatory activity. The biological results revealed that among all tested compounds some fused pyrroles, namely the pyrrolopyridines 3i and 3l, show promising activity. A docking study of the active synthesized molecules confirmed the biological results and revealed a new binding pose in the COX-2 binding site.

Disposition kinetics of levofloxacin in sheep after intravenous and intramuscular administration.

The present study was planned to investigate the disposition kinetics of levofloxacin in plasma of female native Barky breed sheep after single intravenous (IV) and intramuscular (IM) administration of 4 mg/kg body weight. The concentrations of levofloxacin in the plasma were measured using high-performance liquid chromatography (HPLC) with a UV detector on samples collected at 0, 0.08, 0.16, 0.33, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, 24, 32, and 48 h after treatment. Following intravenous injection, the decline in plasma drug concentration was biexponential with half-lives of (t 1/2α) 0.33 ± 0.12 h and (t 1/2β) 3.29 ± 0.23 h for distribution and elimination phases, respectively. The volume of distribution at steady state V (d(ss)) was 0.86 ± 0.23 l/kg. After intramuscular administration of levofloxacin at the same dose, the peak plasma concentration (C max) was 3.1 ± 0.35 μg/mL and was obtained at 1.64 ± 0.29 h (T max), the elimination half-life (T 1/2el) was 3.58 ± 0.30 h, and AUC was 20.24 ± 1.31 μg.h/mL. The systemic bioavailability was 91.35 ± 6.81 %. In vitro plasma protein binding was 23.74%. When approved therapy fails, levofloxacin may be used in some countries for therapy of food animals, however, that is not true in the US.

Iodine Monochloride Facilitated Deglycosylation, Anomerization, and Isomerization of 3-Substituted Thymidine Analogues

The reaction of thymidine, 3-mono-, and 3,3′,5′-trialkylsubstitued thymidine analogues with iodine monochloride (ICl) was investigated. Treatment with ICl resulted in rapid deglycosylation, anomerization, and isomerization of thymidine and 3-substituted thymidine analogues under various reaction conditions leading to the formation of the nucleobases as the major products accompanied by minor formation of α-furanosidic-, α-pyranosidic-, and β-pyranosidic nucleosides. On the other hand, 3,3′,5′-trisubstitued thymidine analogues were only deglycosylated and anomerized. These results are similar to those observed for the acidic hydrolysis of the glycoside bond in nucleosides, but were presumably caused by the Lewis acid character of an iodine electrophile.

Plasma and Tissue Disposition of Moxifloxacin in Japanese Quail ( Coturnix japonica ).

Abstract Plasma disposition and depletion of moxifloxacin were investigated in Japanese quail (Coturnix japonica) after single intravenous, intramuscular, and oral administration of 5 mg/kg and after intramuscular and oral administration of 5 mg/kg q24h for 5 consecutive days, respectively. Drug concentrations in plasma and tissues were measured by high-performance liquid chromatography with fluorescence detection. After intravenous injection, plasma drug concentration–time curves were best described by a 2-compartment open model. The decline in plasma drug concentration was biexponential with half-lives of 0.3 hours and 2.18 hours for distribution and elimination phases, respectively. Steady-state volume of distribution and total body clearance after intravenous administration were estimated to be 1.12 L/kg and 0.41 L/h per kilogram, respectively. After intramuscular and oral administration of moxifloxacin at the same dose, the peak plasma concentrations were 2.14 and 1.94 μg/mL and were obtained at 1.4 and 1.87 hours, respectively, and the elimination half-lives were 2.56 and 1.97 hours, respectively. The systemic bioavailabilities were 92.48% and 87.94%, respectively. Tissue levels after intramuscular and oral administration were highest in liver and kidneys, respectively, and decreased in the following order: plasma, lungs, and muscle. Moxifloxacin concentrations after intramuscular and oral administration were below the detection limit of the assay in tissues and plasma after 120 hours.