Iranian Journal of Pharmaceutical Research
Volume:6 Issue: 1, Winter 2007

This review gives an overview of our recent findings and developments in research on brain mechanisms of morphine reward from studies using the place preference conditioning paradigm. Intracranial place conditioning methodology has become a valuable and firmly established and very widely used tool in behavioural pharmacology and drug reward mechanisms. Several studies have established that morphine induces a conditioned preference for the place in which it has been administered in rats. Transmitter systems that have been investigated with respect to their involvement in morphine reward mechanisms include dopamine, GABA, acetylcholine, adrenalin and nitric oxide, the motivational significance of which has been examined either directly, by using respective agonist or antagonist drugs. Although, considerable evidence suggested that the mesocorticolimbic DA system, which originates in the VTA and projects to the Nac, various limbic and cortical areas is a major neural substrate of the rewarding effects produced by morphine, but the role of other brain sites such as hippocampus and amygdala also exist. Overall, our intracranial place conditioning studies showed that there are a number of receptors, neuronal pathways and discrete central nervous system sites involved in the morphine reward mechanisms.

A study has been made of the compaction properties of two experimental starches, namely yam starch obtained from Dioscorea rotundata and rice starch obtained from Oryza sativa and the mechanical properties of their tablets, in comparison with those of official corn starch. The influences of the physical and geometric properties of the starch particles on the compression properties of the starches were determined. Further analysis of the compaction properties was done using density measurements, and the Heckel and Kawakita equations. The mean particle diameter and the shape factor of the starches were directly related to the loose initial density (Do) and rearrangement at low pressures (DA) characteristics of the starches, but inversely related to the rearrangement of the particles in the early stages of compression (DB). The packed initial relative density (DI) was also directly related to the particle diameter and shape factor. The three starches deform mainly by plastic flow. The values of the mean yield pressures, which are inversely related to the onset of plastic deformation in the starches were in the rank order rice>corn>yam. Another pressure term, inversely related to the amount of plastic deformation during compression, was in the rank order yam>corn>rice. The ranking of the values of both the tensile strength and brittle fracture index of tablets made from the starches was rice>corn>yam, indicating that rice starch tablets exhibited the highest bond strength and brittleness while yam starch exhibited the lowest values. The compaction properties of the experimental starches as characterized compared well with those of official corn starch. The results obtained showed that in tablet formulations, yam starch would be more useful in minimizing the problems of lamination and capping while rice starch would be more useful when high bond strength of the tablet is desired. Thus, yam and rice starches could be useful in formulations to produce tablets with desired mechanical properties for particular purposes.

The effects of crystallization of indomethacin as a poorly water-soluble drug in aqueous surfactant solutions (using the basket method), on the drug dissolution behavior was investigated.A significant enhancement of drug dissolution was observed for for the dissolution rates of crystals treated with hydrophilic surfactants, Tween 80 and sodium lauryl sulfate (SLS). However, asing Arlacel 60 as a hydrophobic surfactant incrystallization medium decreased the indomethacin dissolution rate. Differential scanning calorimetry (DSC) and Fourier Transform Infrared Spectroscopy (FT-IR) indicated the existence of both α and γ- polymorphs of indomethacin (with different percentages). The FT-IR results also showed that, only the α- form could be detected in indomethacin crystals without any surfactant. These results were also confirmed by X-ray powder diffraction and scanning electron microscopy (SEM). The nuclear magnetic resonance (NMR) studies demonstrate the presence of a small amount of Tween 80 and the absence of SLS in the treated crystals. In this study, we concluded that, the presence of small amounts of surfactant, adsorption of surfactant onto the crystal surface and the decrease in powder bulk density could be the possible mechanisms of alteration in the dissolution rate of crystals treated with Tween 80, Arlacel 60 and SLS respectivelyAntioxidant.

A multiple-unit oral floating system was prepared using the emulsification-solvent diffusion method to prolong the gastric emptying time of theophylline. For this purpose, theophylline, ethyl cellulose and dibutyl phthalate were dissolved in an ethanol/dichloromethane mixture, added to 0.1 M HCl containing NaCl (20%) or saturated theophylline and/or different concentrations of polysorbate 80 and polyvinyl alcohol. The mixture was stirred at different speeds for 3 h. The resulting microspheres were separated from the solution by filtration. Physical characteristics, including the shape and size distribution, floating capability, drug loading and drug release of the resulting theophylline microspheres were investigated. The prepared microspheres tended to float over the simulated gastric medium for over 12 h. Addition of NaCl (20%) to the aqueous phase increased the drug loading of microballoons. The mean geometric diameter of microspheres decreased, as the stirring speed rate or the polysorbate 80 concentration were increased. Microballoons prepared at higher stirring rates released their drug content faster. Also, it is concluded that particle size and floating capability of microballoons could be adjusted by altering the stirring rate during microencapsulation.

The effects of allopurinol, acyclovir and theophylline on the activity of adenosine deaminase (ADA) were studied in 50 mM sodium phosphate buffer pH 7.5 at 27°C, using a UV– Vis spectrophotometer. Adenosine deaminase is inhibited by these ligands, via different types of inhibition. Allopurinol, as a transition state analog of xanthine oxidase, and acyclovir competitively inhibit the catalytic activity of ADA. Inhibition constant values are 285 and 231 µM for allopurinol and acyclovir, respectively. Theophylline acts as a non-competitive inhibitor for ADA, which shows different affinity binding sites at various drug concentrations. There were two different types of inhibition constant, one of them due to a low concentration of the drug (Ki = 56 μM) and the other appearing at higher concentrations of theophylline (Ki = 201 μM). Thermodynamic parameters also show that ADA has two binding sites for theophylline. The comparison of inhibition constant for inosine (Ki=143 μM) and acyclovir (Ki = 231 μM) elucidates the critical role of the ribose ring within the inosine structure, relative to the open ring of acyclovir. Comparison of the inhibition constant of theobromine (Ki= 311 μM) with inosine (Ki= 143 μM) shows the critical binding role of N7 position within the purine ring. Interestingly, the N7 position in allopurinol is replaced by a CH2 group, which demonstrates the lower inhibiting potency of allopurinol (Ki = 285 μM) relative to inosine (Ki = 143 μM). In a structural sense, a comparison made between the structure of theophylline and theobromine besides a comparison between the inhibition constant of theophylline (Ki = 56 μM at low and 201 μM at higher concentrations) and caffeine (Ki = 342 μM) indicate that substitution of a bulky group in N1 and N7 positions of purine has a critical role in the binding affinity of the above- mentioned inhibitors to the enzyme.

It was thought previously that cardiac muscle gap junctions provide low-resistance connections between cells and permit the local-circuit current to flow. Some evidences show that myocardial cells may not require low-resistance connections for successful propagation of the action potential (AP). It seems that some other types of mechanisms must be involved in AP propagation. In this article, we study the different suggested mechanisms of AP propagation. We have calculated different conduction routes and hypothesized novel viewpoints on the mechanisms of conduction in myocyte. It seems that electric field and gap junctions are the main routes for propagation of action potential, but they are affected in different phases of action potential. Gap junction has a dynamic behavior in each cardiac cycle, managing different routes of propagation in the diverse moments. Gap junctions could be open in phases 0, 1, 3 and 4 and close in phase 2 (plateau) of action potential. Whenever gap junction is open, conduction can be fulfilled rapidly by current flow and whenever it is closed, the electrical field will be the main route of propagatio.This view on AP propagation may be useful for better exploitation of drugs or designing new remedies in arrhythmias and diseases that cause diminished cardiac contractility such as cardiac failure.

Pain control is a major concern in post-thoracotomy patients. The current prospective randomized double-blind study was designed to evaluate the analgesic effects of morphine and fentanyl given interpleurally after posterolateral thoracotomy. Thirty patients undergoing elective posterolateral thoracotomy in a teaching hospital in Tehran were divided into 3 groups with equal number of patients. Patients in group IPM, IPF1 and IPF2 received 0.1 mg/kg morphine sulfate, 5 µg/kg fentanyl and 2.5 µg/kg fentanyl in a total volume of 40 ml injected via an intrapleural catheter placed in the pleural space before the closure of chest. Subsequent doses of interpleural injections were administered at 4 and 8 h after operation. The intensity of pain was evaluated at rest and with coughing just before each interpleural injection and 30 min afterwards using a 10 point visual analogue scale (VAS). If patients needed additional analgesia, indomethacin suppository and intravenous morphine were given during the 20-h postoperative study period. In all of the 3 study groups VAS scores were significantly reduced 30 min after interpleural administration of the study solutions (p<0.05). However, inter-group comparisons revealed no significant differences for VSA scores, supplemental analgesic usage and systemic side effects. Briefly, interpleural morphine and fentanyl following thoracotomy produce equal analgesia without major side effects.

Antibacterial activity of the aerial extracts from Xanthium brasilicum prepared in methanol, diethyl ether, petroleum benzene and an equal mixture of the three solvents were studied against bacterial laboratory standards and clinical isolates using the disk diffusion method. The best antibacterial results were obtained when methanol or the solvent mixture was used. The crude extract with the highest antibacterial activity was fractionated by silica gel chromatography and the biologically active fractions were subjected to thin layer chromatography. All bands were separated and tested for antibacterial activity and the compounds of the active (TLC) bands were identified by 1HNMR spectroscopy. The results showed the presence of two substances, a xanthanolide and a flavonoid.

Helicobacter pylori is the causative agent of gastritis and peptic ulcer disease. Eradication of H. pylori is hard to achieve and often require multiple antibiotics regimens. These regimens are quite expensive and have substantial side effects. Licorice is a traditional drug which is frequently used for gastric discomforts in Iran. The susceptibility of H. pylori to the extract of licorice has been investigated in the present study. One hundred and eighty clinical H. pylori strains were isolated in this study. For comparison and control, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa were also included in this study. Agar dilution assay was used to test the susceptibility of the clinical isolates of H. pylori to the Glycyrrhiza extract at different concentration. The assay plates had 25, 50, 100, 150, 200, 300 and 400 mg/ml of licorice extract. Licorice extract inhibited the H. pylori strains with a MIC range of 50-400 mg/ml. The present results show that therapeutically administered concentrations of licorice extract could have growth-inhibiting effect on H. pylori in vitro. The above preliminary experiments indicated strongly that licorice extract has some anti-H. pylori property and H. pylori shows susceptibility to licorice extract in concentration ranges that are achievable in the stomach. The resistance of other bacterial species indicates the possibility of selective therapy without adverse effects on the normal bacterial flora.