Omar Shaheen

Changes in Glutathione, Glutathione Reductase and Glutathione-S-Transferase as a Function of Cell Concentration and Age

The activities of glutathione-S-transferase (GST) and glutathione reductase (GSR) in mouse lymphocytes as a function of cell concentration and age were determined. Lymphocytes from 2-, 9- and 24-month-old mice were isolated and the activity of GST was determined spectrophotometrically using 1-chloro-2,4-dinitrobenzene as the substrate. Lymphocyte concentrations of 0.44, 0.75 and 0.55 X 10(6) cells/ml were found to be optimal for assaying GST in 2-, 9- and 24-month-old mice, respectively. Determination of GSR activity was based on NADPH reduction of oxidized glutathione and cell concentrations of 0.29, 0.30 and 0.22 X 10(6) cells/ml were chosen for assaying the enzyme activity for the three age groups, respectively. Glutathione levels and GSR activity of mice lymphocytes were higher in 2- and 24-month-old mice as compared to 9-month-old animals. However, GST activity of mouse lymphocytes was low in 2- and 9-month-old mice and increased significantly in 24-month-old animals.

Comparison of pharmacokinetics and pharmacodynamics of a conventional and a new rapidly dissolving glibenclamide preparation

Abstract Glibenclamide is an oral hypoglycemie agent used in the treatment of non-insulin dependent diabetes. It is a weak acid and is poorly soluble in water. In this investigation, the pharmacokinetics and pharmacodynamics of a new rapidly dissolving formula (Oramide) containing only 3.5 mg of the drug was compared with a conventional 5 mg preparation (Daonil). The rate and extent of in vitro dissolution of Oramide was significantly higher than Daonil. Despite the higher amount of the drug in Daonil both preparations exhibited similar plasma glibenclamide concentration-time profiles. Furthermore, the release of insulin and the reduction of plasma glucose levels were not statistically different in both experimental groups. The faster dissolution rate of Oramide formulation has, therefore, rendered it bioequivalent to Daonil which contains a higher amount of active ingredient.

Effect of Ofloxacin on the Pharmacokinetics of a Single Intravenous Theophylline Dose

The effect of ofloxacin taken for 8 days (200 mg twice daily) on the pharmacokinetics of a single intravenous dose of theophylline (4.3 mg/kg over 15 min) was studied in a crossover procedure among seven healthy male volunteers. Theophylline concentrations were measured serially for 10 h by the immunofluorescence polarization technique. No significant effect of ofloxacin was found on theophylline clearance, half-life, or volume of distribution. It is therefore concluded that ofloxacin and theophylline can be safely administered together.

Effect of cimetidine on the pharmacokinetics of theophylline

1. The effect of the therapeutic doses of cimetidine (400 mg/twice daily) on theophylline metabolism in Jordanian volunteers was studied. 2. The administration of the above therapeutic cimetidine dose did not alter theophylline clearance and elimination half-life. 3. Cimetidine administration also failed to alter the elimination of theophylline metabolites in urine.

Effect of forskolin on cAMP accumulation and ketogenesis in isolated hepatocytes

The effect of forskolin on ketogenesis and cAMP accumulation was studied in hepatocytes from euthyroid and hypothyroid rats. Forskolin stimulated ketogenesis, cAMP production and potentiated glucagon-stimulated cAMP accumulation on both euthyroid and hypothyroid groups. The ketogenic effect of glucagon was inhibited by forskolin in both groups. Also, forskolin, glucagon and methylisobutylxanthine (MIX) combined did not significantly increase ketogenesis.

Structure based drug design of Pim-1 kinase followed by pharmacophore guided synthesis of quinolone-based inhibitors

Over expression of Human phosphatidyl inositol mannoside kinases isoform 1 (Pim-1 kinase) has been reported in several leukemia and solid tumors. Our continuous interest to reveal the secrecies of the mysterious Pim-1 kinase binding pocket has led us to employ a structure based drug design procedure based on receptor-ligand pharmacophore generation protocol implemented in Discovery Studio 4.5 (DS 4.5). Subsequently, we collected 104 crystal structures of Pim-1 kinase from the Protein Data Bank (PDB) and used them to generate pharmacophores based on the anticipated co-crystallized ligand-Pim 1 kinase receptor interactions. All selected pharmacophoric features were enumerated and only those that had corresponding valuable receptor-ligand interactions were retained. This was followed by modeling all pharmacophore combinations and scoring them according to their Receiver Operating Characteristic (ROC) curve analysis parameters as well as a DS.4.5 built-in Genetic Function Algorithm (GFA) validating model. Accordingly, 111 pharmacophores resulted with acceptable ROC performances; 1XWS_2_04, 2BIK_2_06, and 1XWS_2_06 (ROC AUC value of: 0.770, 0.743 and 0.741 respectively) were the best pharmacophores. These pharmacophores were employed to guide the synthesis of new series of 7-[(2-Carboxyethyl)amino]-1-substituted-6-fluoro-8-nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and their reduced 8-amino derivatives. The synthesized compounds were later evaluated for their Pim-1 kinase inhibitory potencies. Of which the most potent illustrated an IC50 value of 0.29µM against Pim-1 kinase.

Effects of glucagon on cAMP accumulation and ketogenesis in hepatocytes from euthyroid and hypothyroid rats

The resistance to the effects of glucagon was studied in isolated hepatocytes prepared from male rats treated with 6N‐propyl‐2‐thiouracil (PTU). Incorporation of [14C]oleate into ketone bodies in response to various concentrations of glucagon (10−5 to 10−10 M) was reduced in hepatocytes from hypothyroid rats compared with the euthyroid group. The reduced sensitivity to the effects of glucagon on ketogenesis after treatment with PTU was associated with a reduced ability of those hepatocytes to maintain cyclic adenosine‐3’,5’‐ monophosphate (cAMP) at levels required to stimulate ketogenesis. The concentration of cAMP in response to glucagon (10−5 to 10−10 M) was diminished in hepatocytes from hypothyroid rats, compared with those from euthyroid animals.

Data for: Ligand-Based Computer Aided Drug Design Reveals New Tropomycin Receptor Kinase A (TrkA) Inhibitors.

Targeting tropomycin kinase A (TrkA) by small molecule inhibitors is considered as a promising strategy for treating several human cancers. To achieve this goal, a ligand based QSAR model was applied using the Discovery studio 4.5 (DS 4.5). Hence, a total list of 161 TrkA inhibitors was investigated. The TrkA inhibitors were extensively explored to detect their optimal physicochemical properties and pharmacophoric binding modes, which were converted into numeric descriptors and allowed to compete within the context of the Genetic Function Algorithm (GFA) approximations to find the subset of terms that correlates best with the activity. The resulted successful QSAR equation had statistical criteria of (r2129=0.67, r2LOO=0.61 r2PRESS against 32 external test inhibitors=0.50). Afterwards, the most successful pharmacophore: HypoB-T5-3, was used to screen compounds within the National Cancer institute (NCI) database. Only 41 compounds were retrieved and 21 of them exhibited anti-TrkA activity. The most potent hit had an IC50 value of 2.4μM. Later, upon docking the active hits into the TrkA binding pocket, important interactions were revealed including hydrogen bonding with the amino acids Asp668 and Lys544 in addition to the cation-π interactions with the sidechain of Arg559.

Research advances in kinase enzymes and inhibitors for cardiovascular disease treatment

The targeting of protein kinases has great future potential for the design of new drugs against cardiovascular diseases (CVDs). Enormous efforts have been made toward achieving this aim. Unfortunately, kinase inhibitors designed to treat CVDs have suffered from numerous limitations such as poor selectivity, bad permeability and toxicity. So, where are we now in terms of discovering effective kinase targeting drugs to treat CVDs? Various drug design techniques have been approached for this purpose since the discovery of the inhibitory activity of Staurosporine against protein kinase C in 1986. This review aims to provide context for the status of several emerging classes of direct kinase modulators to treat CVDs and discuss challenges that are preventing scientists from finding new kinase drugs to treat heart disease.

Intersubject variability in plasma theophylline levels after oral and intravenous administration in Jordanian patients with chronic obstructive pulmonary disease.

Plasma theophylline concentrations were determined in 151 Jordanian patients with chronic obstructive pulmonary disease. Mean plasma levels after oral administration were below the therapeutic range and significantly lower than after intravenous administration. Plasma levels in patients with congestive heart failure (CHF) were higher than in patients with no CHF. Trough plasma theophylline concentrations after intravenous administration in patients less than 18 years of age were significantly lower than in those aged 18-60 years. The overall results are in agreement with observations made in other ethnic groups.