Iranian Journal of Pharmaceutical Research
Year:2009 | Volume:8 | Issue:3|Papers Count:13

Proteins are the main targets in drug discovery. Most large pharmaceutical companies now have a proteomics-oriented biotech or academic partner or have started their own proteomics division. Common applications of proteomics in the drug industry include target identification and validation, identification of efficacy and toxicity biomarkers from readily accessible biological fluids, and investigations into mechanisms of drug action or toxicity….

Domperidone is a widely used antiemetic, poorly water soluble drug, erratically absorbed in stomach and possess several dissolution-related problems thus it has poor bioavailability. Solubility of a drug plays a very important role in dissolution and hence absorption of drug which ultimately affects its bioavailability. Hence, by considering the facts related to drug, attempts have been made to formulate inclusion complexes using methylated b-cyclodextrin and also to study the effect of preparation method. Inclusion complexes were prepared using methylated b-cyclodextrin in 1:1 and 1:2 molar ratios. Kneading, ultrasonification and physical mixture method were used for preparation of inclusion complexes. All the inclusion complexes were characterized using FTIR, DSC and XRD. The solubility and dissolution results revealed that there was a considerable increase in solubility and dissolution of all inclusion complexes as compared to pure drug. It was highest in case of methylated b-cyclodextrin in 1:1 molar ratio using ultrasonification method (USM1). Stability study revealed that all complexes were stable for a period of three months.

The effect of 10 and 25 kGy g-irradiation on penicillin G plus procaine and sodium ampicillin has been assessed by different chemical and microbiological analytical methods. According to the chemical results obtained, the antibiotics showed a slight reduction in doses applied but the microbiological assays revealed that the activity of irradiated antibiotics did not reduce. Microbiological studies were carried out in order to determine the minimum absorbed dose required to achieve Sterility Assurance Level (SAL) of 10-6. Briefly, lower irradiation doses seem to be useful for decontamination purposes.

Determination of trace elements in food is of great importance, as some of them have nutritional significance, whilst others are toxic. Long-term exposure to low levels of toxic metals could be important, especially in relation to children.Differential Pulse Anodic Stripping Voltammetry (DPASV) is applied to simultaneous determination of lead, cadmium, copper and zinc in dry ash infant formula in nitric acid at 450±50°C.Determination of the elements was made in acetate buffer (pH 4.7) with a scan rate of 60 mVs-1 and a pulse height of 50 mV by Hanging Mercury Dropping Electrode (HMDE). The solution was stirred during pre-electrolysis at -1150 mV (vs. Ag/AgCl) for 90 s and the potential was scanned form -1150 mV to +100 mV(vs. Ag/AgCl). Precision of the method, expressed by relative standard deviation for lead, cadmium, copper and zinc, was calculated as 4.5%, 3.5%, 3.2% and 5.6%, respectively. Under these conditions, the limits of detection were 0.005, 0.005, 0.01 and 0.05 mg/kg for lead, cadmium, copper and zinc, respectively. Concentrations of lead, cadmium, copper and zinc in one of the infant formulas available in Iran were 0.384±0.222, 0.359±0.215, 4.436±0.811 and 37.426±8.951 mg/kg (mean±SD), respectively.In our study the concentrations of lead and copper were found significantly higher than those of standard and labelled values (P<0.001), respectively. Therefore, infant formula manufacturers, by virtue of the role of their products in the infants’ nutrition, have been acutely aware for sometime of the need to guard against any heterogeniety and contaminants.

Recently several 1,3,4-oxadiazole derivatives were identified as potentially active antimycobacterial agents. Various 5-aryl-2-thio-1,3,4-oxadiazoles have been reported having good antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). In this paper we report 3D QSAR studies for the 41 molecules of 1,3,4-oxadiazoles by using k-Nearest Neighbor Molecular Field Analysis (kNN-MFA) combined with various selection procedures. Using kNN-MFA approach 52 3D-QSAR models were generated; one of these models was selected on the basis of q2 and pred_r2 values. The selected model had shown good internal and external predictivity for the training set of 33 molecules and test set of 8 molecules with validation (q2) and cross validation (pred_r2) values of 0.5022 and 0.2898, respectively. This model can be used for preliminary screening of large diversified compound libraries. The model has shown that presence of sulphur is must for activity, however the larger bulky substituents reduce the activity. The presence of halogen and other non-halogen groups have also contributed to the activity.Hence the future schemes with smaller groups on sulphur and electronegative groups in the molecule would result in potentially active molecules.

Attempts to obtain experimental values for the kinetic parameters of phenanthridine oxidation by guinea pig or rabbit liver aldehyde oxidase using common spectrophotometric methods have not been successful due to a lower limit of detection. In the present study, a new spectrofluorimetric assay in combination with a multivariate calibration method for enzymatic kinetic study of aldehyde oxidase activity, using phenanthridine as the substrate, has been developed and validated. Phenanthridine and phenanthridinone binary mixtures were prepared in a dynamic linear range of 0.025-1 mM and the emission flourimetric spectra of the solutions recorded at the excitation and emission wavelengths of 236 and 320-450 nm, respectively. The optimized calibration model of partial least squares (PLS) method was applied for the simultaneous determination of the concentration of each chemical in the prediction set. The limits of detection for phenanthridine and phenanthridinone were found to be 2.13 ± 0.33 and 3.41 ± 0.34 nM (mean ±  SD, n = 5), respectively. This method was then used for kinetic study of phenanthridine oxidation using guinea pig and rat hepatic aldehyde oxidase. The results were compared with those obtained from a univariate spectroscopic method. Using this new spectrofluorimetric-multivariate calibration method, the Km value for the oxidation of phenanthridine with guinea pig and rat liver aldehyde oxidase were obtained as 0.83 ±  0.08 and 2.20 ±  0.40, mM (mean ±  SD, n = 3), respectively.

The methanolic extract of the aerial parts of Salvia leriaefolia (labiatae) afforded 5-hydroxy-4´, 6, 7-trimethoxy flavone (Salvigenin) and (5,4´-dihydroxy-7-methoxy flavone (Genkwanin). The structures of the isolated compounds were elucidated using 1 and 2 D-NMR, IR, UV and MS.

Intracerebroventricular (ICV) injection of streptozotocin (STZ) causes cognitive impairment in rats. The beneficial effect of Crocus sativus L. extract (CSE) was evaluated on ICV STZ-induced learning, memory, and cognitive impairment in male rats. For this purpose, rats were injected with ICV STZ bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats received CSE (60 mg/kg; i.p.) every other day, starting one day before surgery, for three weeks. The learning and memory performance was assessed using passive avoidance paradigm, and for spatial cognition evaluation, Y-maze task was used. It was found that CSE-treated STZ-injected rats show higher correct choices and lower errors in Y maze than vehicle-treated STZ-injected rats. In addition, CSE administration significantly attenuated learning and memory impairment in treated STZ-injected group in passive avoidance test. Therefore, these results demonstrate the effectiveness of CSE in preventing the cognitive deficits caused by ICV STZ in rats and its potential in the treatment of neurodegenerative diseases such as Alzheimer’s disease (AD).

Dihydropyridine calcium channel blockers consist one of the widely-used groups of drugs for the management of hypertension. In this study, antihypertensive effects of 5 newly synthesized derivatives of DHP was examined the in rat model of two-kidney, one-clip renal hypertension. The results showed that those compounds containing two nitroxy groups had less decreasing effect on MAP (Men Arterial Pressure) compared to those having one nitroxy group in 5 position. On the other hand, conformational analysis indicated that in two compounds with two chains (A and E), a great steric hindrance existed; therefore, steric hindrance is the most important factor for interaction of compounds with their receptors.

The current study dealt with the interaction of garlic homogenate (GH) with propranolol (PRO) in rat, and to determine whether this effect is associated with biochemical and histological changes.Albino rats were treated with GH at three different doses of 125 mg/kg (GH-125), 250 mg/kg (GH-250) and 500 mg/kg (GH-500) orally for 30 days and PRO was incorporated in the interactive groups during the last seven days of GH treatment. Blood was withdrawn under ether anesthesia from the retroorbital route and serum was separated. Heart tissue homogenate (HTH) of the excised heart was also prepared. Both serum and HTH were used for biochemical estimation. Histopathological studies were carried out subsequently for confirmation of biochemical findings. GH-125 and GH-250 were found to significantly augment the endogenous antioxidant synthesis whereas, GH-500 was found to significantly diminish the synthesis of superoxide dismutase (SOD) and catalase. Toxicity of GH-500 cannot be reversed by the addition of PRO in the therapy. However, incorporation of PRO in GH-125 or GH-250 treatment showed significant synergistic effect in terms of increasing antioxidant synthesis. Mild and moderate doses of GH were also shown to keep the integrity of myocardium intact, whereas GH-500 damages the myocardium. The findings of the present study indicate that it is safe to administer garlic in low to moderate doses in cardiac patients receiving propranolol. However, high doses of GH are found to be toxic to myocardium and hence care should be taken for proper selection of doses.

The present work describes a reverse phase HPLC method for the quantitation of drotaverine hydrochloride and mefenamic acid in human plasma. Organic solvent system used for liquid extraction composed of dichloromethane, and isopropyl alcohol in the ratio 80:20 (v/v). The compounds were separated on a Thermo BDS Hypersil C8 (25.0 cm×4.6 mm, 5 mm particle size) column in isocratic mode with a mixture of acetonitrile and ammonium acetate buffer (20 mM, pH 3.5 ± 0.05 adjusted with 85% phosphoric acid) in a ratio of 55: 45 (v/v), as the mobile phase, at a flow rate of 1.0 mL min-1. The effluent was monitored by UV detection at 230 nm. The method was validated for accuracy, precision, specificity, linearity, and sensitivity. The total chromatographic analysis time was approximately 10 min with diclofenac sodium (internal standard), drotaverine hydrochloride and mefenamic acid, eluting with retention times of 6.89, 8.21 and 9.67 min, respectively. Calibration plots were linear within the range of 32-960 ng mL-1 and 100-3000 ng mL-1 for drotaverine hydrochloride and mefenamic acid, respectively. The limit of detection values were 11 and 33 ng mL-1 and the limit of quantitation values were 32 and 100 ng mL-1 for drotaverine hydrochloride and mefenamic acid, respectively. Results from analysis of quality control samples at concentrations of 90, 450 and 750 ng mL-1 for drotaverine hydrochloride and 300, 1600 and 2400 ng mL-1 for mefenamic acid, were indicative of good repeatability and precision. Recovery from plasma was 98.68% for drotaverine hydrochloride and 94.51% for mefenamic acid.

The plant kingdom constitutes a source of new chemical compounds, which may be important due to their potential uses in medicine, or their other biological properties. In this study, the effects of Galbanic acid (GA), a sesquiterpene coumarin from roots of Ferula szowitsiana, were investigated as a modulator of antibiotic resistance in clinical isolates of Staphylococcus aureus. Isolates of S. aureus clinically resistant to methicillin, tetracycline and ciprofloxacin were isolated using disk diffusion method. The MICs of antibiotics were determined using broth macrotiter plate method against isolated bacteria. The inhibitory effects of GA alone and in combination with each antibiotic were investigated by macrotiter plate. None of the tested bacteria were affected by GA (up to 800  mg/mL). MICs of antibiotics against S. aureus (in mg/mL) were 10-80 for methicillin, 40->80 for tetracycline, andIO-20 for ciprofloxacin. The MICs of antibiotics in presence of 400 mg/mL GA were less than 1.25 mg/mL for S. aureus, which is usually much less than the MICs against sensitive isolates. This study provides interesting results suggesting a potentiating activity of GA on antibiotics against the resistant strains of S. aureus.

Anti-nociceptive activity of aerial parts of Phytolacca americana were investigated, using the hot plate method in mice. Results of the present study showed that the aqueous methanolic extract of aerial parts of P. americana produced a statistically significant increase in pain threshold after 30 min, in comparison with the control, at adose of 190 mg kg-1 (P<0.001). The activity was comparable to that of morphine (30 mg kg-1 i.p., p> 0.05). The anti-nociceptive activity of P. americana increased until the 60th min (P<0.05 compared to morphine). The results of this study support the extensive use of P. americana in Western Asia and America. The LD50 of extract following a 14 days acute toxicity study was calculated to be 208 mg kg-1 i.p.