DARU, Journal of Pharmaceutical Sciences
Volume:18 Issue: 2, Summer2010

Background and the purpose of the study: The success of any direct-tableting procedure is strongly affected by the quality of the crystals used in the process. Ibuprofen is a poorly compactible drug with a high tendency for capping. In order to use ibuprofen in direct compression formulations, physico-mechanical properties of ibuprofen should be improved considerably. The aim of the present investigation was to employ crystallization techniques in order to improve the physico-mechanical properties of ibuprofen for direct compression.The experimental methods involved the preparation of ibuprofen crystals by solvent change technique. Ibuprofen was dissolved in ethanol and crystallized out with water in the absence or presence of various hydrophilic additives (PEG 6000, 8000, Brij 98P and polyvinyl alcohol 22000, PVA 22000) with different concentrations. The physico-mechanical properties of the ibuprofen crystals were studied in terms of flow, density, tensile strength and dissolution behaviour. Morphology of ibuprofen crystals was studied by scanning electron microscopic (SEM). Solid state of the recrystallized particles was also investigated using differential scanning calorimeter (DSC) and FT-IR. Ibuprofen samples crystallized in the presence of PEG 6000 and 8000 and PVA showed remarkable increase in the tensile strengths of the directly compressed tablets, while some other additives, i.e. Brij 98P did not produce improved ibuprofen crystals. Ibuprofen powders made from particles obtained in the presence of PVA and Brij 98P showed similar dissolution profiles to the commercial ibuprofen particles. DSC and FT-IR results ruled out any significant interaction between ibuprofen and additives except for the samples crystallized in the presence of PEG 8000.The crystal habit of ibuprofen can be altered successfully by the crystallization technique which was developed in this study. The crystals developed in the presence of certain additives can be recommended for direct compression.

Background and the purpose of the study:Itraconazole is a poorly water soluble drug which results in its insufficient bioavailability. The purpose of the present study was to formulate Itraconazole in a nanosuspension to increase the aqueous solubility and to improve its formulation related parameters, dissolution and hence oral bioavailability.Itraconazole nanosuspension was prepared by pearl milling technique using zirconium oxide beads as a milling media, Poloxamer 407 as a stabilizer and glycerol as a wetting agent. Effects of various process parameters like, stirring time and the ratio of the beads were optimized by keeping drug:surfactant:milling media (1:3.0:50) as a constant initially and then optimized process parameters were used to optimize formulation parameters by 32 factorial designs. The optimized nanosuspension was lyophilized using mannitol (1:1 ratio) as a cryoprotectant. Nanosuspension was characterized by particle size and size distribution, drug content, scanning electron microscopy, differential scanning colorimetry and X-ray diffraction techniques. Optimized nanosuspension showed spherical shape with surface oriented surfactant molecules and a mean particle diameter of 294 nm. There was no significant change in crystalline nature after formulation and it was found to be chemically stable with high drug content.The in vitro dissolution profile of the optimized formulation compared to the pure drug and marketed formulation (Canditral Capsule) by using 0.1N Hydrochloric acid as release medium showed higher drug release.

Background and the purpose of the study:The potential of pectin as a bacterially degradable polysaccharide for colon drug delivery has been demonstrated. Due to the high solubility and swelling properties of pectin in aqueous media, it is frequently used in combination with water insoluble polymers for targeting drugs to the colon. The aim of this study was to evaluate free films containing pectin as a bacterially-degradable polysaccharide in combination with Eudragit RL (ERL) and/or RS (ERS) as a coating formulation for colonic drug delivery.Isolated free films comprising 20% pectin and 80% ERL or ERS and their combination in 1:1 ratio were prepared by casting method. Then, free films were evaluated by water vapor transmission (WVT), swelling and permeability experiments for theophylline and indomethacin in different media.Formulations containing ERL exhibited higher WVT, swelling and permeability compared with formulations containing ERS. The permeability of theophylline through free films composed of pectin and eudragit polymers in simulated colonic media was not significantly different from those obtained in other media. However indomethacin free films containing pectin and ERL showed higher permeation in simulated colonic fluid (SCF) compared to the other media.Major Formulation containing pectin and ERL may be suitable as a coating formulation for colon targeted delivery of drugs of low solubility such as indomethacin.

Background and the purpose of the study:To develop a simple, rapid and accurate HPLC method for the measurement of the venlafaxine and its main metabolites, O-desmethylvenlafaxine and O,N-didesmethylvenlafaxine in pharmacokinetic studies and therapeutic drug monitoring. Chromatographic separation was achieved with a ChromolithTM Performance RP-18e 100 mm×4.6 mm column equipped with a Fluorescence detectore (λex 200 nm/λem 300 nm) The mobile phase of methanol:water (35:65, v/v) adjusted to pH 2.5 by phosphoric acid was passed through the column in an isocratic mode at flow rate of 2 ml/min. The sample preparation involved a simple, one-step, extraction with ethyl acetate. The calibration curves were linear in the concentration range of 1-300 ng/ml for all analytes (r2 > 0.998). The lower limit of quantification was 1 ng/ml for all analytes. Within and between day precisions in the measurement of quality control (QC) of samples were in the range of 1.8-14.1% for all analytes.The developed procedure was used to assess the pharmacokinetics of venlafaxine and its main metabolites following oral administration of 75 mg venlafaxine to a healthy subject.

Background and the purpose of the study:It is believed that enteral nutrition (EN) support is the preferred route as compared to parenteral nutrition (PN). Critically ill patients on EN receive less than 60% of their metabolic requirements. To meet patients'' calorie goal addition of PN to EN was proposed. This study was conducted to determine whether supplemental PN have any difference with EN alone in regard to inflammatory indices.Twenty patients were randomized to either receive EN alone or EN+PN for 7 days. Pre albumin and inflammatory indices including interleukin IL-1, IL-6 and tumor necrosis factor-α (TNF-α) were measured on days of 0, 3,7. Also Sequential Organ Failure Assessment (SOFA) score and Therapeutic Intervention Scoring System-28 (TISS-28) score were calculated on days of 0, 3 and 7.Results and major IL-1, IL-6 and TNF-α did not show significant difference between two interventions. Pre-albumin was increased from baseline by 9% and 81% in EN and EN+PN groups respectively but it did not reach to statistical significance. SOFA score did not show significant difference. TISS score was higher in EN+PN group on days of 3 and 7.No difference was found between EN and EN+PN regimens in regard to inflammation, while severity of illness may not change with these regimens, nursing workload increases with implementation of supplemental PN.

Background and the purpose of the study:The aim of the present study was to examine factors that may influence the protein binding of morphine 6-glucuronide (M6G), the most active metabolite of morphine.An enzyme-linked immunoabsorbent assay technique was used to measure the M6G concentration in serum of 18 healthy adults, 18 neonatal and 7 children with cancer. Total and free M6G concentrations were measured following equilibrium dialysis for 3 hrs and at physiological pH at 37°C. The influence of vincristine, methotrexate, 6-mercaptopurine, morphine, human albumin, alpha-1-acid glycoprotein, palmitic acid, oleic acid and pH on M6G protein binding was examined.M6G was 66.87±0.73 percent free in human serum at physiological pH and temperature. The percentage free (unbound) was increased significantly by vincristine (4.33%) and methotrexate (9.68%), but 6- mercaptopurine and morphine had no significant effect on it. Free percentages of M6G was reduced by decreasing serum albumin concentration but was unaffected by the presence of alpa-1-acid glycoprotein (AAG) or changes in serum pH. Similar results were obtained in human serum albumin (HAS) solutions. Addition of palmitic acid and oleic acid reduced protein binding significantly by 6.3% and 7.4%, respectively.Major Although M6G in this study was not highly bounded, but because of its high analgesic potency, any change in its free concentration due to concurrent medication or disease caused significant changes in its effects. This dearth of evidence has been implicated in the reluctance of professionals to be cautious in prescribing them to children, particularly in the neonatal period.

Background and the purpose of the study: The quality of some of the human plasma derived drugs such as coagulation factor VIII and coagulation factor IX which can be used for the treatment of hemophilia A and B, depends on their activity which may be affected by filtration. In this study the quality of plasma with respect to coagulation factors FVII, FVIII, FIX, FV, FXI, Fibrinogen, antithrombin III, anti-plasmin and antitrypsin activities obtained after plasma filtration with CPD (citrate-phosphate-dextrose) using integral filter was evaluated. Sixty units of plasma were individually separated from whole blood by centrifugation and immediately filtered by integral filter system. Specific plasma filtration was carried out between 4 and 20 hrs after blood donation. Before filtration, 60 units of non filtered fresh plasmas were kept as control.Coagulation factors were determined by one-stage clotting assay in an automated system. Antithrombin III activity was determined by immunochrom assay in an automated system. Activity of anti-plasmin was determined by Berichrom α2 - antiplasmin and antitrypsin activity was assayed with human neutrophil elastase.The activity of coagulation factors FVIII, FIX, Fibrinogen, FV, and FXI, were not affected by filtration, in all experiments. Filtration only caused negligible change in FVII activity. Antithrombin III, anti-plasmin and antitrypsin activities were not influenced by filtration. Non-filtrated and filtrated plasma values were not significantly different (P> 0.05).Plasma filtration dose not result in a measurable impairment of coagulation factors and inhibitors. Although a little changes in FVII activity was observed after filtration, but these filtration-dependent changes apparently have no impact on the therapeutic quality of whole blood- filtered fresh plasma for transfusion.

Background and the purpose of the study: Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been a major problem worldwide in chemotherapy of infection disease. This study was designed to assess the enhancing effects of a new group of dihydropyridine-3,5-dicarboxamides, in combination with cloxacillin with distinctly different mechanisms of action against MRSAs.Dihydropyridine-3,5-dicarboxamides with 2-methylsulfonylimidazole at 4 position 6a-k were synthesized by the reaction of corresponding aldehyde 5 with different N-aryl acetoacetamides 3 in the presence of ammonium hydroxide. Agar disc diffusion method was used to determine the antibacterial and potentiating activity of different synthetic compounds in the presence and absence of cloxacillin to evaluate their activity as modulators of multidrug-resistant (MDR).Results and major The antibacterial effect of cloxacillin was enhanced by compounds 6g and 6h against cloxacillin-resistant strains (MRSA1 and MRSA2). The potentiation was found to be statistically significant (p<0.01). Compound 6g at concentration of 1000 μg/disc, caused a 329 percent potentiation of the activity of cloxacillin against MRSA1.

Background and the purpose of study: Galanthus transcaucasicus Fomin (Amaryllidaceae) is an endemic species to the Caucasia and Alborz mountains in Iran which locally named "Gol-e-Barfi". While there are many reports on pharmacological activities of Galanthus species'' alkaloids, there is no report on G. transcaucasicus and this article is the first phytochemical study on this species.Extracted alkaloids from G. transcaucasicus bulbs were isolated using different chromatographic methods and the structures of the components were determined by physical and spectroscopic data.Five isoquinoline type alkaloids namely galanthamine(8.04%), narwedine(6.90%), lycorine(19.48%), caranine(3.45%) and tazettine(5.75%) of total alkaloid extract were isolated from the bulbs of Galanthus transcaucasicus Fomin.Major Because of the presence of biologically active alkaloids especially galanthamine and the major alkaloid lycorine in Gol-e-Barfi, the plant may be used as a natural source for pharmaceutical purposes.

Background and the purpose of the study: Aging is the major risk factor for neurodegenerative diseases and oxidative stress is involved in the pathophysiology of them. Oxidative stress can induce neuronal damages and modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. In this study, the possible antioxidant and neuroprotective properties of the natural polyphenolic antioxidant compound, curcumin against homocysteine (Hcy) neurotoxicity was investigated.Curcumin (5, 15, 45 mg/kg) was injected intraperitonealy (i.p.) once daily for a period of 10 days beginning 5 days prior to Hcy (0.2 μmol/μl) intracerebroventricular (i.c.v) injection in rats. Biochemical and behavioral studies, including passive avoidance learning and locomotor activity tests were studied 24 hrs after the last curcumin or its vehicle injection. The cell density of hippocampus layers and apoptosis in rats'' hippocampi by immunohistochical methods were also studied.Results and major Results indicated that Hcy could induce lipid peroxidation and increase Malondialdehyde (MDA) and Super Oxide Anion (SOA) levels in rat''s brain.Additionally, Hcy impaired memory retention in passive avoidance learning test. However, curcumin decreased MDA and SOA levels significantly and improved learning and memory in rats. On the other hand Hcy could induce cell death and apoptosis in rats'' hippocampi which was inhibited by curcumin. These results suggest that Hcy may induce lipid peroxidation in rat''s brain. and polyphenol treatment (curcumin) improves learning and memory deficits by protecting the nervous system against Oxidative stress.

Background and the purpose of the study: Current anti-H. pylori therapies are based on the use of two antibiotics with a proton pump inhibitor and/or a bismuth component. Metronidazole is a key component of such combination therapies in Iran. The aim of this study was to determine the role of rdxA gene in resistant strains of H. pylori isolated from Shahrekord Hajar hospital to metronidazole. This study was a cross-sectional method, which was carried out on 263 patients who referred to endoscopy department of Hajar hospital, in 2007. Biopsy samples were cultured on selective Brucella agar containing 10% blood and incubated under microerophilic condition at 370C for 3 - 7 days. Suspected colonies were tested by Gram staining, urease, oxidase and catalase activities. Organisms were confirmed to be H. pylori on the basis of the presence of ureC(glmM) gene by PCR. Specific primers were used for detection of rdxA gene mutation. Eighty and four strains of H. pylori determined by PCR method. Of the isolated strains, 49 (58.33%) were resistant, 7 (8.33%) were semi-sensitive to metronidazole and 200bp deletion in rdxA gene was observed in 2 strains. Because of the high metronidazole resistance in patients under study it was necessary to replace it by other antibiotics in therapeutic regimens. On the basis of low frequency of resistance mutation in rdxA gene, sequence analysis for identification of other mechanisms is suggested.

Background and the purpose of the study: Etoposide is an antineoplastic agent used in multiple cancers. It is known that etoposide induce cell death via interaction with topoisomerase II; however, the etopoisde cellular response is poorly understood. Upon etoposide induced DNA damage, many stress signaling pathways including JNK are activated. In response to DNA damage, it has been shown that WWOX, a recently introduced tumor suppressor, can be activated. In this study the activation of WWOX and JNK and their interaction following etoposide treatment were evaluated.HEK293 cells treated with etoposide were lysed in a time course manner. The whole cell lysates were used to evaluate JNK and WWOX activation pattern using Phospho specific antibodies on western blots. The viability of cells treated with etoposide, JNK specific inhibitor and their combination was examined using MTT assay.Findings of this study indicate that WWOX and JNK are activated in a simultaneous way in response to DNA damage. Moreover, JNK inhibition enhances etoposide induced cytotoxicity in HEK293.Taken together, our results indicate that etoposide induces cytotoxicity and WWOX phosphorylation and the cytotoxicty is augmented by blocking JNK pathway.