Iranian Journal of Pharmaceutical Research
Year:2004 | Volume:3 | Issue:4|Papers Count:9

Pharmaceutical industry is currently undergoing a transient phase with new orientation. Loss of financial resources, presence of new therapeutic agents and increasing cost of research and development have called for a full-scale restructuring within the pharmaceutical industry to retain even the most basic competitiveness. The development of new technologies has been as one way out of the dilemma. Although at the end of the 20th century biotechnology was celebrated as the key technology and many scientists all around the world including Iranian scientists and pharmaceutical companies were optimistic about this basic science, today's technology is most certainly nanotechnology.

It has already been reported that muscle necrosis induced by various phenylenediamine derivatives are correlated with their autoxidation rate. Now in a more detailed investigation of the cytotoxic mechanism using a model system of isolated hepatocytes and ring-methylated structural isomer durenediamine (DD) we have shown that under aerobic conditions, phenylenediamine induced cytotoxicity and ROS formation were markedly increased by inactivating. DT-diaphorase but were prevented by a subtoxic concentration of the mitochondrial respiratory inhibitor cyanide. This suggests that the H2O2 generation could be attributed to a futile two electron redox cycle involving oxidation of phenylenediamine to the corresponding diimine by the mitochondrial electron transfer chain and re-reduction by the DT- diaphorase. The subcellular organelle oxidative stress effects leading to cytotoxicity has not yet been identified. Hepatocyte mitochondrial membrane potential was only slightly decreased by phenylenediamine before cytotoxicity ensued. However phenylenediamine induced lysosomal damage and hepatocyte protease activation. Endocytosis inhibitors, lysosomotropic agents or lysosomal protease inhibitors also prevented phenylenediamine induced cytotoxicity.Furthermore desferoxamine (a ferric chelator), antioxidants or ROS scavengers (catalase, mannitol, tempol or dimethylsulfoxide) prevented phenylenediamine cytotoxicity. It is concluded that H2O2 reacts with lysosomal Fe2+ to form "ROS" which causes lysosomal lipid peroxidation, membrane disruption; protease release and cell death.

Recently, it has been shown that a number of hydroxypyridinones such as 1,2-dimethy 1-3- hydroxypyridin-4-one (L1) are useful for the treatment of iron overload in place of desferrioxamine in thalassaemic patients. In this study, the intestinal absorption (I.A.) of L1 and one of its analogues namely 2-methy-3-hydroxypyridin-4-one (L2), which possesses a higher partition coefficient (Kpart) than L1, have been determined.The ligands L1 and L2, used in the present study, were synthesized from maltol and methylamine or ammonia, respectively in a three step reaction method. Identification and purity of compounds were achieved by spectroscopy and elemental analysis. The I.A. of drugs was determined using the Everted Gut Sac method at different concentrations and time intervals. The concentrations of samples were measured by a DVMs spectrophotometer (lmax=280 nm).The results showed that the rate and I.A. of L2 are not statistically different from those of L1. At a concentration of 60 mg/lit, and after 45 min, the absorption reached a maximum for both ligands. It is clear that for the prediction of I.A. of a new drug a simple measurement of Kpart is not sufficient and other factors such as the number of hydrogen bonds between drug molecules and the surrounding molecules should also be taken into account due to their possible interferences. It could be concluded that from the point of I.A, the drug L2 has no advantage over the L1.

The accurate prediction of protein stability is one of the most challenging goals in protein formulation and delivery. In this study, a gradient RP-HPLC method is described for the separation of human growth hormone (hGH) variants as deamidated and oxidized forms. The methodology employed a polymiric poly (styrene-co-divinylbenzene) column and a 1mL/min flow rate of a linear gradient of 0.1% v/v TFA/acetonitrile and TFA/Water (pH=2.0) mixture as the mobile phase. The overall run time of this method was 12 min and the average retention times were about 8.7 min for the native somatropin, 7.2 min for the deamidated form and 1.6 and 5.3 min for oxidized variants. The method was also validated in terms of selectivity, linearity, intra- and inter-day variations.In conclusion the method was found to have the potential for being applied as an initial and rapid evaluation method for assessing the quality and quantity of hGH during downstream processing, formulation and storage.

Substanye abuse is an important health, psychological and social problem in the world. Gabapentiri is a new antiepileptic drug. It is used in neurological and psychiatric disorders. Moreover the effects of gabapentin on increasing the analgesic effect of morphine and its inhibitory effects on dopamine release due to morphine in animal models have been proved. In the present study, the effect of gabapentin on withdrawal signs and symptoms in opium-addicted participants and on psychiatric disorders and electroencephalogram of these patients during the detoxification period has been investigated. Two groups of patients were selected randomly. The first group (n=36) received the current drugs based on their withdrawal symptoms and the second group (n=35) received an additional 900 mg gabapentin daily. All the patients were evaluated by electroencephalography and Symptom Check List-90-Revised on the first and last days of hospitalization and their demographic characteristics were gathered by using a general questionnaire. During the hospitalization period (10 days) all the patients were visited daily for withdrawal signs and symptoms. The analysis of data showed the excellent effect of gabapentin on all psychiatric symptoms and in decreasing signs and symptoms significantly. A gradual decrease of withdrawal signs and symptoms in the second group shows the efficacy of gabapentin. There was no significant difference between the two groups, regarding to the electroencephalogram indices. The results show that gabapentin improves the quality of therapeutic management in opium-addicts during the detoxification period.

T-2 toxin, a trichothecene mycotoxin, is considered to be one of the most toxic compounds that are produced byrilolds, particularly the Fusarium species. Fusarium species have been recognized as a great agricultural problem. They occur worldwide on a variety of plant hosts and cereal grains. The aim of this study was to investigate T-2 toxin-induced liver injury using in situ perfused rat liver. The in situ perfused rat liver (IPRL) was chosen because it permits studies of liver function in a system that resembles normal physiology. Elevation of aminotransferase activities have shown to be a good indicator of hepatocellular damage. In addition, glutathione levels have also shown to be an indicator of liver damage through lipid peroxidation. Male Sprague-Dawley rats (6-8 weeks) weighing 250-300 g were used in this study. They were randomly divided into 5 groups of 3-4 rats per cage. In group 1, liver was perfused by Krebs-Henseleit buffer alone (Control). Groups 2-5 received different concentration of T-2 toxin (4, 9, 21, 43 rmol/L) in Krebs-Henseleit buffer and biochemical changes in the liver were examined within 2 h. There was a significant increase in both ALT and AST activity in all dose levels compared with the control group (p<0.01 and p<0.05). T-2 toxin treatment enhanced lipid peroxidation in the liver, as indicated by the increased MDA content in liver homogenates. The MDA level was maximal 2 h after the T-2 toxin challenge (p<0.01 and p<0.05). The results also show that T-2 toxin causes an increase in lipid peroxidation while causing a decrease in glutathione (GSH) content in bile secretion (p<0.01). This result suggests that both lipid peroxidation and glutathione (GSH) depletion play a role in T-2 toxin liver induced damages.

The present study is a designed protocol for investigation of the analgesic effect of oral and intraperitoneal (i.p.) administration of alcoholic Datura stramonium (DS) seed extract as a rich source of alkaloid substances. Male NMRI rats were divided into control and treatment groups. the treatment rats received different doses of the DS seed extract, which was prepared from alcoholic smashed seeds. Then the animals from each group were subjected to pain scoring experiments such as hot plate and formalin tests. The results of the experiments i.e., antinociceptive effect of DS seeds extract in i.p (5, 10, 25,50, 100, 200 and 250mg/kg) and oral application methods (200, 400 and 800 mg/kg) were compared with other groups, morphine sulfate and naloxone as positive and negative control groups, respectively. We found the 30 and 100 mg/kg of the extract as intraperitoneal ED50 in the hot plate and formalin tests, respectively. However, the extract over than 100 mg/kg, i.p could potentially alleviate the pain in hot plate and both phases of formalin test. Besides, there was a marked antinociceptive effect for the extract (over than 400 mg/kg) in oral method in hot plate and both phases of formalin tests. In our following experiments the effective doses of morphine sulfate as positive control test were obtained over than 15mg/kg; i.p. and the acquired LD50 was close to 2300 mg/kg. In summary, comparing the analgesic effect of different doses of morphine sulfate with DS seed extract in i.p and oral conditions and considering to the extract LD50, we conclude that the DS seeds extract have a potent, absorbable, and nearly safe ingredient which can exert a potential analgesic effect in acute and chronic pain.

Hydroalcoholic extract of Pycnocycla spinosa is a relaxant of rat ileum and inhibits diarrhea in mice. As P. spinosa extract has spasmolytic activity on ileum, it could also affect other smooth muscles like bladder. Therefore, the aim of this study was to determine the effect of P. spinosa extract on rat bladder contraction.In an in vitro study, the effects of P. spinosa extract, nifedipine and propantheline were tested on isolated rat bladder contractions induced, by acetylcholine (ACh, 10 M) and KCl (80mM).P. spinosa extract, concentration-dependently, inhibited the bladder contractions induced by ACh with an IC50 of 265±28 mg/ml and KCl with an IC50 of 5l8±86 µg/ml. The muscarinic cholinoceptor antagonist, propantheline, inhibited the response of ACh without affecting KCl response. Nifedipine, on the other hand, abolished the KCI response, while partially inhibiting the ACh contraction in rat bladder. The antispasmodic effect of P. spinosa extract on bladder was observed at higher concentrations as compared to that of ileum. Therefore, it is unlikely that P. spinosa extract at anti-diarrheal doses affect the normal bladder emptying function.

Onion (Allium Cepa) contains high levels of flavonoids. Although there are many studies indicating the inhibitory effects of flavonoids on xanthine oxidase, there is no report on the effect of onion on this enzyme. Therefore, in the present study, the inhibitory effects of onion on xanthine oxidase are investigated.Fresh filtered juice of onion was prepared and its inhibitory effect on guinea pig liver and bovine milk xanthine oxidase activity was assayed spectrophotometrically using xanthine as substrate. In addition, the effects of hydromethanolic extract of the powdered onion and its major flavonoid, quercetin, were also studied. The juice caused more than 80% inhibition on both guinea pig and bovine milk xanthine oxidase. The extract also resulted in a marked inhibition on guihea pig liver (IC50=10 mg/ml) and bovine milk (IC50=13 mg/ml) xanthine oxidase activities. Quercetin exerted its inhibitory effect on bovine milk xanthine oxidase through a linear mixed-type (Ki=0.06±0.04 and KI=0.22±0.16 mM), whereas, the guinea pig enzyme was inhibited in a competitive manner (Ki=0.11±0.02 µM).In conclusion, consumytion of onion as a staple vegetable with a potent inhibitory effect on xanthine oxidase not only could be useful in some diseases such as gout, but also may result in some interactions with those drugs that are metabolized by xanthine oxidase.