Influence of ondansetron on the antitumor activity and lung toxicity of bleomycin

Bleomycin [BLM] is well known by its antitumor activity both in vitro and in vivo. However, pulmonary fibrosis has been considered the dose limiting toxicity of the drug. Moderate nausea and vomiting occur in virtually all patients taken BLM. Ondansetron [OND] is a highly selective 5-HT3 receptor antagonist with significant antiemetic activity. This study was conducted to investigate the effect of OND administration on the antitumor and lung toxicity of BLM. The antitumor activity was evaluated both in vitro and in vivo using Ehrlich ascites carcinoma [EAC] cells. Ondansetron did not alter the antitumor effect of BLM in vitro or in vivo. The lung toxicity of BLM was evidenced by decrease in the body weight, increase in the lung/body weight ratio, decrease in the response of pulmonary arterial rings to 5-HT and increase in the contractility of tracheal smooth muscles induced by ACh. The toxicity was also confirmed biochemically by marked increases in hydroxyproline and lipid peroxidation in rat lung and the decrease in GSH level. Pretreatment with ondansetron decreased lipid peroxidation and normalized GSH level and hence enhanced the percent survival of rats. The results of the present study indicate that OND did not modify the antitumor effect of BLM but ameliorated the increase in some biochemical markers associated with BLM-induced lung toxicity

Synthesis and investigation of novel shelf-stable, brain - specific chemical delivery system

A 1,4-dihydropyridine - pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs into the brain. Monoamine oxidase inhibitors [MAOIs] were used as a model example to be delivered into the brain. Chemical and biological oxidations of these compounds were investigated. The prepared 1,4-dihydropyridines were subjected to various chemical and biological oxidation to evaluate their ability to cross blood brain barrier [BBB], and to be oxidized biologically into their corresponding quaternary compounds. 1-[Ethoxy-carbonylmethyl]-3,5-bis[N-[2-fluoro-benzylideneamino] carbamoyl]-1,4-dihydropyridine [31] proved to cross BBB in adequate rate and converted by the oxidizing enzymes into the corresponding quaternary salt N-[ethoxycarbonylmethyl]-3,5-bis [N-[2-fluorobenzylideneamino] carbamoyl] pyridinium bromide [20]. Stability studies of the synthesized chemical delivery systems [CDSs] at various pH values and temperatures showed that the shelf life time of a solution containing compound 31 is 20.53 days at 5°C, which recommend a lower storage temperature for such solutions. The prepared CDSs proved to be fairly stable for powder form storage. The stability of the prepared compounds is attributed to the conjugation of the two carboxylic functions at C3 and C5 of the pyridine ring with their adjacent double bonds. These results are in consistency with the original rationale design

Effect of flouorides on the respiratory system of rats

The effects of sodium fluoride [NaF] on the isolated pulmonary arterial rings and the isolated tracheal strips of rats as well as the effect of long-term oral administration of NaF on the response pulmonary arterial rings and tracheal strips to biogenic amines were investigated. NaF concentrations of 3, 5 and 10 mM produced a concentration dependent contraction in isolated pulmonary arterial rings and in tracheal strips of rats. NaF-induced contractions were reduced after pretreatment with nifedipine or melatonin. Aminophylline produced significant decline in NaF-induced contraction of isolated pulmonary arterial rings. Phentolamine, atropine, chlorpheniramine, indomethacin, NDGA or L-NAME did not produce any alteration in the NaF-induced contractions. Chronic oral NaF administration produced significant decline in the response of the isolated pulmonary arterial ring and isolated tracheal strips to serotonin [5-HT] and acetylcholine [ACh], respectively. Histopathological examination of iso1ated trachea and lung of treated rats showed marked damage. In conclusion, the results of the present study suggest that calcium channel and/or release of free radicals may mediate the contractile effects of fluoride in isolated pulmonary arterial rings and in tracheal strips. Furthermore, chronic oral fluoride administration causes damage to tracheal and pulmonary tissues and thus, care should be taken to avoid ingestion of large amount of fluoride especially in children

Local anesthetic and antiarrhythmic activity of certain new 1,3,4-thiadiazole derivatives

A series of 2-[1-oxo-2-[substitutedamino] ethylamino and 2- or 3-[substitutedamino] propylamino] 5 trifluoromethy1-1,3,4-thiadiazoles [5a-f, 6a-f and 7a-f] was synthesized and evaluated for their local anesthetic and antiarrhythmic activity. Some of the tested compounds showed promising activity. The detailed synthesis, spectroscopic and biological data are reported