Nasal delivery of insulin using bioadhesive chitosan gels

Recently nasal delivery of insulin has gained considerable attention. Some limitations of this route include rapid mucociliary clearance of the drug from the site of deposition resulting in short time span available for absorption and low permeability of the nasal membrane for peptides. The objective of the present study was development of a chitosan bioadhesive gel for nasal delivery of insulin. A nasal perfusion test was used to study the toxicity of 4 absorption enhancers: saponin, sodium deoxycholate, ethylendiamine tetra-Acetic Acid (EDTA) and lecithin. The gels contained 4000 Iu/dl insulin, 2 or 4% of low and medium molecular weight of chitosan, and lecithin or EDTA. Drug release was studied by a membraneless diffusion method and bioadhesion by a modified tensiometry test. The optimized gel was administered nasally in diabetic rats. The serum insulin levels were analyzed by an insulin enzyme immunoassay kit and serum glucose by glucose oxidase method kits. Formulations containing 2% of low molecular weight of chitosan with EDTA had higher release percentage and dissolution efficiency (DE)_2.5%, lower T_50% (Time required to release 50% of the drug), mean dissolution time, and bioadhesion than gels containing 4% of medium molecular weight of chitosan with lecithin. Insulin was released by a zero-order kinetic from the gels. The gel of 2% medium molecular weight of chitosan with EDTA caused increase in insulin absorption and reduction the glucose level by as much as 46% of the intravenous route. Considering our in vitro and in vivo studies, the proposed gel formulation could be a useful preparation for controlled delivery of insulin through the nasal route.     

Effects of short-term and subchronic lead poisoning on nitric oxide metabolites and vascular responsiveness in rat

Chronic exposure to low levels of lead results in sustained hypertension in humans and experimental animals. The mechanism of lead-induced hypertension remains unclear. We investigated the short-term (4 and 8 weeks) and subchronic (12 weeks) effects of lead treatment on responsiveness of vascular adrenergic system and level of nitric oxide metabolites, that is, total nitrates and nitrites (NOx). Male Sprague-Dawley rats were treated with lead acetate (100 ppm in drinking water) for 12 weeks. Short-term lead administration resulted in marked elevation of blood pressure accompanied by significant reduction in serum NOx levels. In contrast, after subchronic lead administration the trend of decrease in NOx levels somehow reversed despite further increase in blood pressure. Both short-term and subchronic lead administration resulted in significant differences in vascular reactivity with respect to either vasoconstrictor (phenylephrine and clonidine) or vasodilator (isoproterenol) agents. We conclude that vascular adrenergic system and nitric oxide pathway change in short-term and subchronic phases of lead poisoning.     

Smoking behavior and its influencing factors in a national-representative sample of Iranian adolescents: CASPIAN study

OBJECTIVES: To determine the national prevalence of smoking among Iranian youths and its environmental influencing factors. METHODS: This study was performed in 2003-2004 among 11,966 school students, ages 11-18 years, selected by multi-stage random cluster sampling from 20 provinces in Iran. The participants filled out self-administered anonymous questionnaires. RESULTS: The prevalence of self-reported cigarette smoking was 14.3%, with a higher prevalence in boys than in girls (18.5% vs. 10.1%, respectively, P < 0.001), and in high school than in middle school students (17.4% vs. 10.6%, respectively, P < 0.001). Overall, 42.2% of smokers were daily smoker, and the rest were occasional smoker. The mean age of the first attempt to smoke was 13.2 +/- 2.5 years with no significant gender difference but was significantly lower in daily than in occasional smokers. The place of the first attempt to smoke was mostly in friend parties (41.6%) and traditional teahouses (23.2%) for boys and the family parties (37.1%) and the traditional teahouses (27.4%) for girls. The higher school level and having a tobacco user at home significantly increased the likelihood of smoking in adolescents, with the highest odds ratio (OR) found for having a smoker sister in girls (OR = 4.5, 95%CI, 2.5, 8.2), and having a smoker brother in boys (OR = 2.4, 95%CI, 2.03, 3.05). CONCLUSION: Smoking is becoming as a major public health threat among Iranian youths. Control measures should be considered not only for cigarette smoking, but also for the socially accepted habit of water pipe use that is revived in traditional teahouses.     

Antituberculosis agents x. synthesis and evaluation of<Emphasis Type="Italic">In Vitro</Emphasis> antituberculosis activity of 2-(5-nitro-2-furyl)- and 2-(1-methyl-5-nitro-1<Emphasis Type="Italic">H</Emphasis>-imidazol-2-yl)-1,3,4-thiadiazole derivatives

Two series of 2-(5-nitro-2-furyl)- and 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-propyl, allyl and propargyl)thio-1,3,4-thiadiazoles (6a-f) and 2-(5-nitro-2-furyl)- and 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-(nitrobenzyl)thio-1,3,4-thiadiazole derivatives (8a-f) have been synthesized and evaluated against Mycobacterium tuberculosis, as part of the TAACF TB screening program under direction of the US National Institute of Health, the NIAID division. Primary screening was conducted at a single concentration, 6.25 microg mL(-1), against M. tuberculosis H37Rv in BACTEC 12B medium, using the Microplate Alamar Blue Assay (MABA). The minimum inhibitory concentration (MIC) was determined for the compounds that demonstrated > or = 90% growth inhibition in the primary screening. A varying degree of antituberculosis activity (from 0-97% of growth inhibition) was observed with the alkylthio series (6a-f), and the nitroimidazole derivative with a propylthio group (6b) and the nitrofuran derivative with a propargylthio group (6e), were the most active compounds (MIC=3.13 and 1.56 microg mL(-1), respectively). Among the nitrobenzylthio derivatives (8a-f), all the ortho, meta and para nitrobenzyl isomers in the nitrofuran series exhibited good antituberculosis activity (MIC=3.13 microg mL(-1)), while the corresponding nitroimidazole analogues were completely inactive (Inhibition=0%).     

Genetic polymorphisms in three Iranian populations with different risks of esophageal cancer, an ecologic comparison

The age-standardized incidence of esophageal cancer (EC) varies from 3 to >100/100,000 per year in different provinces of Iran. This striking variation of incidence is associated with differences in ethnic backgrounds, raising the possibility that genetic factors are involved in the pathogenesis of EC. We compared the frequencies of polymorphisms in ten genes that have been hypothesized to have a role in risk of EC (CYP1A1, CYP2A6, CYP2E1, GSTM1, GSTP1, GSTT1, ADH2, ADH3, ALDH2, and O6-MGMT) among three Iranian ethnic groups with highly varying rates of EC. These three groups included high-risk Turkomans, medium-risk Turks, and low-risk Zoroastrian Persians. Compared to Zoroastrians, Turkomans had higher frequency of four alleles that are speculated to favor carcinogenesis (CYP1A1 m1, CYP1A1 m2, CYP2A6*9, and ADH2*1); these results are consistent with an influence of these allele variants on the population risk of EC. However, none of these four alleles had a high enough prevalence in Turkomans to explain the high rates of EC in this group. Three of these four alleles (CYP1A1 m1, CYP1A1 m2, CYP2A6*9) were less frequent among Turkomans than in some Asian populations with lower risks of EC. We conclude that it is unlikely that variations in these polymorphic genes are major contributors to the high incidence of EC among Turkomans in Iran.     

The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications

Multiple sclerosis (MS) has been recognised as a disease since the mid-19th century. The delineation of its CNS pathology, revealing the presence of inflammatory demyelination and relative sparing of axons, was originally interpreted as evidence of infection. Despite many studies, a primary infectious aetiology of MS has not been found. However, the occurrence of acute demyelinating disease following a variety of infections and vaccinations, leading to MS in about a third of cases, provides evidence for the existence of an auto-allergic pathogenesis for the disease. Improved understanding of the role of the blood-brain barrier in protecting the CNS, and the mechanisms by which cells gain entry into the brain and spinal cord has advanced the understanding of MS. Evidence of the central role of the adhesion molecule alpha4beta1-integrin (very late activation antigen-4 [VLA-4]) for lymphocytes in endothelial transmigration into the CNS specifically, has provided a major insight into the pathogenesis of human demyelinating disease and its experimental model, experimental autoimmune encephalomyelitis (EAE). This finding has led to a new window of therapeutic opportunity in MS. Monoclonal antibodies to VLA-4 abrogate the development of EAE in sensitised animals and may actually reverse its clinical and pathological findings in manifest disease. Natalizumab, one such monoclonal antibody, which is administered intravenously, has been found to be a promising agent in the treatment of MS. Although single doses produced no improvement in the speed or quality of recovery from acute exacerbations of MS in a phase II trial, long-term administration (in phase II and phase III trials) have produced significant benefits with results showing both a marked reduction in the risk of new magnetic resonance imaging lesions and a significant reduction in the risk of exacerbations within 2 months of the initiation of therapy. Phase III double-blinded controlled trials have provided additional evidence of safety and a favourable impact on exacerbation rates over the 1 year of administration. Unfortunately, the success of natalizumab has been curtailed by three cases of progressive multifocal leukoencephalopathy, which have prompted the manufacturer to voluntary withdraw the drug from the market. An independent review board is currently investigating the safety of the drug to determine whether it should return to the market. The demonstration that selective modulation (blocking) of the adhesion molecule VLA-4 by natalizumab in MS, resembling that observed in experimental disease, represents a major advance in rational therapy.     

Oxidative stress in acute human poisoning with organophosphorus insecticides; a case control study

Free radicals play an important role in toxicity of pesticides and environmental chemicals. Organophosphorus insecticides (OPIs) may induce oxidative stress leading to generation of free radicals and alteration in antioxidant system. To complete the previous surveys, this study was conducted to evaluate the existence of oxidative stress, balance between total antioxidant capacity and oxygen free radicals in patients with acute OPI exposure. In this case control study, a total of 22 acute OPI poisoning patients were included and blood samples were analyzed for lipid peroxidation, total antioxidant capacity, total thiol groups, and cholinesterase levels. The results showed significant lipid peroxidation accompanied with decreased levels of total antioxidant capacity, total thiols, and cholinesterase activity. A significant correlation existed between cholinesterase depression and reduced total antioxidant capacity. It is concluded that oxygen free radicals and their related interactions like lipid peroxidation are present in acute OPI poisoning. Use of antioxidants may be beneficial in treatment of OPIs acute poisoning which remains to be elucidated by further clinical trials.     

High prevalence of Demodex in eyelashes with cylindrical dandruff

PURPOSE: To determine the prevalence of Demodex in eyelashes with cylindrical dandruff (CD). METHODS: A modified sampling and counting method was applied to 55 clinical cases. Patients were divided in to group A (n = 20) with diffuse CD, group B (n = 12) with sporadic CD, and group C (n = 23) with clean lashes or greasy scales, of which the latter was divided into subgroup C1 (n = 15) without lid hygiene and subgroup C2 (n = 8) using daily lid hygiene for the past year. Each patient underwent a routine complete eye examination and modified counts of Demodex. RESULTS: Demodex was found in all group A and B patients (n = 32) with CD, which was significantly higher than the 22% of group C patients (n = 23) without CD (P < 0.001). The Demodex counts were 4.1 +/- 1.0 and 2.0 +/- 1.2 per epilated lash with retained CD, significantly higher than the 0.2 +/- 0.5 and 0.2 +/- 0.4 per lash without retained CD in groups A and B, respectively (each P < 0.001) and than the 0.01 +/- 0.09 and 0.12 +/- 0.41 per lash in subgroups C1 and C2, respectively (each P < 0.001). Demodex was still found in CD fragments left on the lid skin after epilation. Five Demodex brevis mites were found among the 422 Demodex specimens. CONCLUSIONS: The modified sampling and counting method showed that the prior controversy regarding Demodex has resulted from miscounting and confirmed that lashes with CD are pathognomonic for ocular Demodex infestation. Lid hygiene with shampoo reduces Demodex counts but does not eradicate the mites.