Showing papers by "Tehran University of Medical Sciences published in 2001"

Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam.

Abstract: Objective: Passionflower (Passiflora incarnata) is a folk remedy for anxiety. A double-blind randomized trial compared the efficacy of Passiflora incarnata extract with oxazepam in the treatment of generalized anxiety disorder. Methods: The study was performed on 36 out-patients diagnosed with GAD using DSM IV criteria. Patients were allocated in a random fashion: 18 to the Passiflora extract 45 drops/day plus placebo tablet group, and 18 to oxazepam 30 mg/day plus placebo drops for a 4-week trial. Results: Passiflora extract and oxazepam were effective in the treatment of generalized anxiety disorder. No significant difference was observed between the two protocols at the end of trial. Oxazepam showed a rapid onset of action. On the other hand, significantly more problems relating to impairment of job performance were encountered with subjects on oxazepam. Conclusion: The results suggest that Passiflora extract is an effective drug for the management of generalized anxiety disorder, and the low incidence of impairment of job performance with Passiflora extract compared to oxazepam is an advantage. A large-scale trial is justified.

Cyclosporin A is a promising alternative to corticosteroids in autoimmune hepatitis.

Abstract: Autoimmune hepatitis (AIH), a chronic T-cell-mediated liver injury, is treated with corticosteroids with or without Azathioprine. Corticosteroids are not universally effective and have serious side effects. Cyclosporin A was effective in refractory cases. To assess efficacy and safety of Cyclosporin A (Neoral) in induction of remission in AIH patients this study was performed. Nineteen consenting AIH patients (nine treatment-naive) were treated with cyclosporin A in an open label trial and followed for 26 weeks. Liver biopsy was done and hepatitis activity index (HAI) determined at the beginning and end of treatment. Four patients did not complete the study for various reasons. Mean AST and ALT levels decreased from 948.7 ± 103.5 and 454.8 ± 354 to 100.6 ± 111.8 and 78.5 ± 40.3 (P < 0.03, P < 0.001) respectively. HAI decreased from 15.2 ± 3.16 to 7.14 ± 4.01 (P < 0.005). Serum creatinine did not change significantly. In conclusion, low-dose cyclosporin A appears to be safe and effective even in treatment-naive autoimmune hepatitis patients. Randomized controlled trials are warranted.

Association of increased ferritin with premature coronary stenosis in men.

Abstract: Background: Body iron status has been implicated in atherosclerotic cardiovascular disease. The main hypothesis is that high iron status is associated with increased oxidation of LDL. We investigated the potential role of ferritin as an additional risk factor promoting atherosclerosis among a young population with coronary artery disease (CAD). Methods: Four hundred consecutive patients (218 males, 182 females) referred for diagnostic coronary angiography were examined, and risk factors for CAD, lipids, C-reactive protein (CRP), and ferritin concentrations were recorded for all participants. Results: Ferritin was higher in the male patients with CAD (121 μg/L; range, 56–258 μg/L) than in the men without significant CAD (73 μg/L; range, 32–138 μg/L; P <0.002). Multiple logistic regression analysis, after adjustment for the established coronary risk factors, showed ferritin as an independent discriminating risk factor for CAD ( P <0.01). Men in the highest quartile of ferritin had an odds ratio (OR) of 1.62 [95% confidence interval (95% CI), 1.12–2.42; P <0.01] compared with men in the lowest quartile of ferritin. The association between ferritin and CAD was more pronounced in male patients ≤50 years (OR = 2.65; 95% CI, 1.35–5.51; P <0.003). Ferritin was significantly higher in diabetic male patients in comparison with nondiabetic male patients [168 μg/L (range, 74–406 μg/L) vs 106 μg/L (range, 44–221 μg/L), respectively; P <0.002]. No association was observed between ferritin and CAD among the female patients. Conclusion: Our data suggest that increased ferritin might be an independent predictor of premature CAD in male Iranian patients.

Randomized controlled trial comparing botulinum toxin injection to pneumatic dilatation for the treatment of achalasia

Abstract: Background: Therapeutic options for achalasia include pharmacological therapy, surgical myotomy, pneumatic dilatation and intrasphincteric botulinum toxin injection. Aim: To compare botulinum toxin injection with pneumatic dilatation in a randomized trial. Patients/methods: Forty adults with newly diagnosed achalasia were randomized to receive botulinum toxin (n=20) or pneumatic dilatation (n=20). Symptom scores were evaluated at 1, 6 and 12 months. Clinical relapse was defined as a symptom score greater than 50% of baseline. Relapsers received a second botulinum toxin injection or pneumatic dilatation. Results: The cumulative 12-month remission rate was significantly higher after a single pneumatic dilatation (53%) compared to a single botulinum toxin injection (15%)(P < 0.01). The 12-month estimated adjusted hazard for relapse and need for retreatment for the botulinum toxin group was 2.69 times that of the pneumatic dilatation group (95% confidence interval; 1.18–6.14). When a second treatment was administered to the relapsers in each group, the cumulative remission rate 1 year after initial treatment was significantly higher in the pneumatic dilatation group (100%) compared to the botulinum toxin group (60%) (P < 0.01). There were no major complications in either group. Conclusions: Pneumatic dilatation is more efficacious than botulinum toxin in providing sustained symptomatic relief in patients with achalasia. The efficacy of a single pneumatic dilatation is similar to that of two botulinum toxin injections.

Clarithromycin vs. furazolidone in quadruple therapy regimens for the treatment of Helicobacter pylori in a population with a high metronidazole resistance rate.

Abstract: Background: The eradication of Helicobacter pylori plays a pivotal role in the treatment of peptic ulcer disease. Metronidazole resistance, common in Iran, is claimed to be a major reason for the failure of metronidazole-containing regimens. Both clarithromycin and furazolidone are potential alternatives for metronidazole. Aim: To assess and compare the effectiveness of clarithromycin- and furazolidone-based regimens in eradicating H. pylori in a population with a high metronidazole resistance rate. Methods: Patients with proven duodenal ulcer and H. pylori infection were randomly assigned to one of two groups. The patients received 2 weeks of omeprazole 20 mg b.d., amoxicillin 1000 mg b.d, bismuth subcitrate 240 mg b.d. and either clarithromycin 500 mg b.d. (the OABC group) or furazolidone 200 mg b.d. (the OABF group). Results: A total of 118 patients were randomized, 55 in the OABC group and 63 in the OABF group. The intention-to-treat eradication rate was 84% and 85% for the OABF and OABC groups, respectively. The per protocol eradication rates were 90% for both groups. Conclusions: OABC and OABF are both effective in eradicating H. pylori in areas where metronidazole resistance is a problem. OABF is a good alternative in the face of growing resistance to clarithromycin in developed countries, and is attractive for developing countries where clarithromycin is not readily available.

Urban injuries in Tehran: demography of trauma patients and evaluation of trauma care.

Abstract: Trauma now attracts more attention than ever before as a major cause of death and disability in developed and developing countries. To describe the characteristics and outcome of injuries in our environment, and to identify and discuss possible preventative and management protocols that may also be adopted in developing countries, we designed a prospective study on all trauma patients consecutively attending three emergency departments over a period of 1year in Tehran, Iran. Among the total of 58 013 patients studied, workers were the most vulnerable occupational group and deserve special preventative measures. The high frequency of traffic (especially pedestrian) accidents suggests that considerable progress is required in preventing these injuries. Our hospitalized patients were comparable with patients in the Major Trauma Outcome Study ( m =0.890), and the z (−15.485) and w (−2.447) statistics showed an unsatisfactory quality of care, which may partly be due to less usage of ambulances, the long time of transportation to hospital, frequent referrals between centres, and delayed and inadequate resuscitation by the emergency services. Based on our findings and the fact that the positive effect of trauma systems on outcome has been well documented, we suggest that an integrated trauma system be established in Tehran to improve the quality of trauma care.

In vitro characterization of human intact erythrocytes loaded by enalaprilat.

Abstract: In vitro characteristics of the human erythrocytes loaded by enalaprilat have been evaluated. Erythrocytes obtained from a healthy volunteer were loaded by enalaprilat using the hypotonic preswelling method, and the loading parameters, drug-release kinetics, hematological indices, particle size distribution, scanning electron microscopy view, osmotic and turbulence fragilities, and deformability of the resulting carrier cells were determined along with the sham encapsulated and unloaded cells. Carrier erythrocytes, having acceptable loading parameters, released their drug content according to zero-order kinetics. Mean corpuscular hemoglobin and mean corpuscular hemoglobin content values of the cells decreased, particle size dispersion increased, the cells transformed to cup-form, the erythrocytes became more fragile against osmotic pressure and turbulent flow, and, finally, the deformability of the cells decreased significantly upon drug loading.

Passionflower in the treatment of opiates withdrawal: a double-blind randomized controlled trial.

Abstract: Objective: Clonidine-based therapies have been utilized as the main protocol for opiate detoxification for several years. However, detoxification with clonidine has its limitations, including lack of efficacy for mental symptoms. Accumulating evidence shows the efficacy of Passiflora incarnata extract in the management of anxiety. In our continuing study of traditional medicines, which have neurotropic effects, this plant had an anxiolytic effect, which may be used as an adjuvant agent in the detoxification of opiates by clonidine. We present the results of a double-blind randomized controlled trial of clonidine plus passiflora extract vs. clonidine plus placebo in the outpatient detoxification of 65 opiates addicts. Methods: A total of 65 opiates addicts were assigned randomly to treatment with passiflora extract plus clonidine tablet or clonidine tablet plus placebo drop during a 14-day double-blind clinical trial. All patients met the DSM IV criteria for opioid dependence. The fixed daily dose was 60 drops of passiflora extract and a maximum daily dose of 0·8 mg of clonidine administered in three divided doses. The severity of the opiate withdrawal syndrome was measured on days 0, 1, 2, 3, 4, 7 and 14 using the Short Opiate Withdrawal Scale (SOWS). Conclusion: Both protocols were equally effective in treating the physical symptoms of withdrawal syndromes. However, the passiflora plus clonidine group showed a significant superiority over clonidine alone in the management of mental symptoms. These results suggested that passiflora extract may be an effective adjuvant agent in the management of opiate withdrawal. However, a larger study to confirm our results is warranted.

Unusual profile and high prevalence of p53 mutations in esophageal squamous cell carcinomas from northern Iran.

Abstract: Over 15,000 human tumor p53 mutations have been recorded in the scientific literature, including over 700 mutations in esophageal tumors. There are no data on p53 mutations in esophageal cancer patients from Iran yet; however, this country experiences one of the highest cancer mortality rates in the world for esophageal squamous cell carcinomas (ESCCs). The causes of this high cancer burden in Iran remain obscure and do not appear to be related to tobacco and alcohol consumption, the two major risk factors identified in Europe and North America. Because molecular analysis of tumors can provide clues to endogenous or environmental factors contributing to high cancer risk, we examined 74 Iranian ESCCs for the presence of mutations in exons 5-8 of the p53 gene by PCR and direct sequencing. Forty-eight of the 74 tumors (65%) had one or more p53 gene point mutations, including 5 patients with two or more mutations and one with a tandem mutation in codon 242. Surprisingly, over one-third of the 54 mutations we identified were transitions at CpG sites (20 of a total of 54 mutations, or 37%), a class of mutation that is significantly less common (16% of mutations) in the compilation of ESCC mutations from other countries (chi2 statistic, P < 0.0002), whereas transversions, which the literature shows to be common in ESCCs from non-Iranian patients, were infrequent in the tumors we examined here. Elevated levels of cyclooxygenase-2 and inducible nitric oxide synthase were observed in 74 and 91%, respectively, of tumors from Tehran as determined by immunohistochemistry, and high COX-2 expression correlated significantly with the presence of a p53 mutation in the tumor. Mediators of the inflammatory response in esophageal mucosa, perhaps in conjunction with specific dietary or cultural practices in Iran, may contribute importantly to the p53 mutation load in Iranian ESCC patients.

Seroepidemiological study of visceral leishmaniasis among humans and animal reservoirs in Bushehr province, Islamic Republic of Iran.

Abstract: Using direct agglutination tests a survey of visceral leishmaniasis was carried out among children and adults from 13 villages and from nomadic tribes in Bushehr province during 1998–99. Of the 1496 plasma samples the overall seropositive rate (titres ³ 1:3200) was 3.4%. Almost all cases (94.1%) were in children under 10 years old. Eighteen patients were diagnosed with kala azar; fever and splenomegaly were the predominant signs and symptoms. Parasitology and serology examinations of local animals identified dogs and jackals infected with Leishmania infantum. Suggestions for control of visceral leishmaniasis in this area are to eliminate stray dogs identify cases among humans and suspected leashed dogs and treat infected individuals. (authors)

Distinct pattern of TP53 mutations in squamous cell carcinoma of the esophagus in Iran.

Abstract: Extremely high rates of squamous cell carcinoma of the esophagus (SCCE) are observed in Iran, reflecting unknown, genetic and/or epidemiological risk factors. Among genetic alterations in SCCE, TP53 mutations are the most frequent, vary among populations, and may provide clues on etiological mechanisms. We have analysed mutations in TP53 (exons 5–8) in 98 SCCE from Iran by temporal temperature gel electrophoresis and direct sequencing. We found 58 mutations in 49 patients (50%), with a high prevalence of C to T transitions at CpG dinucleotides (29.3%). The TP53 mutation pattern in Iran was significantly different from that observed in SCCEs from high incidence areas of China and Western Europe (P=0.007). Moreover, the prevalence of mutations at A : T base pairs (transitions and transversions) was higher in men than in women (38.7% vs 11.1%, P=0.033). COX-2 overexpression was detected in 69% of the cases evaluated (24/35), without significant association with TP53 mutation. Accumulation of nitrotyrosine, a marker of protein damage by excess levels of nitric oxide, was observed in tumor cells in six of 16 cases analysed. These results are consistent with the hypothesis that several factors are involved in TP53 mutagenesis in Iran. These factors include a baseline of chronic inflammatory stress, which may have a multiplicative impact on the sensitivity of esophageal cells to exogenous factors of risk.

GABAA but not GABAB receptor stimulation induces antianxiety profile in rats

Abstract: The effect of GABA receptor agonists and antagonists on anxiety behavior in rats in the elevated-plus-maze has been investigated. The increase in two parameters of %open arm entries (%OAE) and %time spent in the open arms (%OAT) and decrease in the %time spent in closed arm (%CAT) was considered as antianxiety effects. Intracerebroventricular (i.c.v.) injection of different doses of the GABA(A) receptor agonist muscimol (0.25, 0.5, and 1 microg/rat) increased %OAE and %OAT and decreased %CAT in rats dose-dependently. The higher response was obtained with 1 microg/rat of the drug. Neither icv (0.05, 0.1, and 0.2 microg/rat) nor intraperitoneal (i.p.) (1, 2, and 4 mg/kg) injection of the GABA(B) receptor agonist baclofen altered %OAE, %OAT, and %CAT. However, the GABA(B) receptor antagonist CGP35348 (5, 10, and 30 microg/rat i.c.v.) increased %OAE and %OAT and decreased %CAT in the animals. The response induced by injection of muscimol (0.5 microg/rat i.c.v.) or administration of CGP35348 (10 microg/rat i.c.v.) was reduced by i.c.v. (1, 2, and 4 microg/rat) or i.p. (0.25, 0.5, and 0.75 mg/kg) injection of the GABA(A) receptor antagonist bicuculline, except the effect of CGP35348 on %CAT which was not significantly altered by i.p. administration of bicuculline. Ip but not i.c.v. administration of bicuculline by itself reduced both %OAE and %OAT but did not alter %CAT. None of the drugs altered the locomotor activity of the animals. The current findings support our hypothesis that the anxiolytic effects of GABA(B) antagonist are mediated by autoreceptor blockade-induced release of endogenous GABA, which in turn activates postsynaptic GABA(A) receptors.

Enumeration of hepatitis B surface antigen‐specific B lymphocytes in responder and non‐responder normal individuals vaccinated with recombinant hepatitis B surface antigen

Abstract: Determination of the frequency of specific B lymphocytes has important implications for investigation of the immune response to different antigens and pathogens. Unresponsiveness to some viruses and antigens, such as hepatitis B virus (HBV) and its surface antigen (HBsAg), has been attributed to lack or insufficient production of the specific B-cell repertoire. In this study, peripheral blood B lymphocytes of 45 adult normal individuals vaccinated with recombinant hepatitis B vaccine were transformed with Epstein-Barr virus (EBV) and cultured at different dilutions on human fetal fibroblasts as a feeder layer. The vaccinees were classified into good, poor and non-responder groups. Following 2 to 3 weeks of incubation, culture supernatants were collected from wells containing transformed and proliferating B lymphocytes. The supernatants were subsequently screened for the presence of total immunoglobulin and antibody to HBsAg (anti-HBs) by enzyme-linked immunosorbent assay (ELISA). Accordingly, positive and negative wells were enumerated in each plate and the frequency of B lymphocytes producing anti-HBs antibody was estimated based on the Poisson statistical analysis. The total number of CD19+ B lymphocytes were counted in the peripheral blood of all subjects by flow cytometry. Our results demonstrated a similar precursor frequency of specific B lymphocytes in all subject groups before vaccine administration (< 2 x 10(-5)). Following vaccination, however, a significant increase in the number of specific B lymphocytes was observed in good-responder (1.5 x 10(-4)) and to a lesser extent poor-responder (3.5 x 10(-5)) individuals, but not in non-responders. These findings suggest a defect in either the primary B-cell repertoire or helper T-cell function in non-responder individuals.

The 5-HT hypothesis of schizophrenia.

Abstract: Schizophrenia is a serious psychiatric illness that is responsible for a substantial proportion of mental illness worldwide. Symptoms include hallucination, delusions, thought disorder and negative symptoms, including poverty of thought and emotion, and social withdrawal. Early theories of schizophrenia implicated disturbed serotonin (5-HT) neurotransmission, but these were largely overshadowed by the dopamine theory of schizophrenia, which became established after the introduction of chlorpromazine. However, the importance of 5-HT in CNS function is once again being recognized. The ability of antipsychotic drugs to diminish positive symptoms has been correlated with their ability to block dopamine D(2) receptors, although negative symptoms are not as effectively treated by typical neuroleptics. There is increasing interest in the correlation between negative symptoms of schizophrenia and 5-HT(2) receptors. The rationale for these studies is the hypothesis that abnormal neurotransmission at 5-HT(2) receptors may be involved in the pathophysiology of schizophrenia. This review highlights recent pharmacological and clinical advances in the understanding of the potential use of serotonin 5-HT(2) receptor antagonists in the treatment of schizophrenia.

Radioprotective Effects of 2-Iminothiazolidine Derivatives against Lethal Doses of Gamma Radiation in Mice

Abstract: Although thiol-containing compounds have long been known to possess radioprotective properties, their therapeutics utility is limited by their side effects at radioprotective doses. In this study, a series of 2-iminothiazolidine derivatives were prepared and their toxicity and radioprotective effects in NMRI mice were determined using the LD50/30 end point. The LD50 values, as determined by a Probit analysis, were between 11 and 14 mg/kg. For studying radioprotective effects, one-sixth of the toxic LD50 values were used, namely 2 and 2.2 mg/kg. To evaluate the radioprotective capabilities, mice were exposed to lethal doses of cobalt-60 γ-radiation alone or in the presence of compounds. The percentage survival of mice at 30 days for these compounds compared to control mice were 10 to 30 when injected 15 and 30 minutes before γ-irradiation. They were significant compared to the control group (P 0.05).

Interleukin-13 in Iranian patients with visceral leishmaniasis: relationship to other Th2 and Th1 cytokines.

Abstract: The role of interleukin (IL)-13, a Th2 cytokine sharing many of the features of IL-4, has not previously been examined in patients with visceral leishmaniasis (VL). We examined sera from Iranian patients with VL caused by Leishmania infantum. Serum IL-13 was detected in 50% (22/44) of patients with active primary disease. In comparison, IL-10 was detected in 79.5% (35/44), interferon gamma (IFN gamma) in 38.5% (17/44), and IL-4 in only 5% (2/44) of these patients. With few exceptions all 3 cytokines were undetectable after clinical recovery following antimony therapy. Five of 7 patients (71%) who failed antimony therapy and had relapsing disease had similar levels of IL-10 to patients with active primary disease. However, with only 1 exception, IL-13, IFN gamma and IL-4 were not detected in such patients. These data suggest that relapsing disease may result from defective cellular immunity, unrelated to immunosuppression mediated by IL-10.

Antituberculosis agents II. Evaluation of in vitro antituberculosis activity and cytotoxicity of some 2-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole derivatives.

Abstract: Using the radiometric BACTEC 460-TB methodology, the minimum inhibitory concentration (MIC) of a series of 2-(1-methyl-5-nitro-2-imidazolyl-1,3,4-thiadiazole-5-alkylsulfides, alkylsulfoxides and alkylsulfones which had been reported previously as antifungal agents, were determined. Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line. The results indicate that compounds bearing a primary alkylthio substitution displayed good antituberculosis activity (MIC = 3.13-6.25 microg/ml). Oxidation to sulfone abolished the antituberculosis activity in methyl and propyl derivatives while the ethylsulfonyl analogue was active (MIC = 1.56 microg/ml). The cytotoxic effects indicate that 2-(1-methyl-5-nitro-2-imidazolyl)-5-methylthio-1,3,4-thiadiazole was the least toxic compound (IC50 > 10 microg/ml). Generally, all compounds showed a low selectivity index.

Cytokine Gene Expression in Healing and Non‐Healing Cases of Cutaneous Leishmaniasis in Response to In vitro Stimulation with Recombinant gp63 Using Semi‐Quantitative RT–PCR

Abstract: Objectives of this study were to test the cytokine gene expression in peripheral blood mononuclear cells (PBMCs) from cases with nonhealing and healing cutaneous leishmaniasis (CL) in response to in vitro stimulation of recombinant gp63 (rgp63) and soluble Leishmania antigen (SLA). Healing and nonhealing cases are, respectively, defined as recovered from disease and refractory to various treatments. To evaluate the type of immunological response, mRNA transcription level for interleukin (IL)-4, IL-10, IL-12 and interferon (IFN)-γ were determined using semiquantitative reverse transcription–polymerase chain reaction (RT–PCR) technique in PBMCs of these volunteers. The results clearly demonstrated a high level of IL-4 expression in nonhealing cases of CL and a low expression level of transcripts for IFN-γ and IL-12. In contrast, a high level of IFN-γ and IL-12 expression and a low level of IL-4 and IL-10 expression were detected in the healing cases. These findings not only support the balance of Th1/Th2 cytokines in the inducing predominant profile in healing and nonhealing cases, but it may also show the potential of rgp63 as a proper immunogen which might induce protective responses.

Enhanced Susceptibility to Oxidation and Diminished Vitamin E Content of LDL from Patients with Stable Coronary Artery Disease

Abstract: Background: Convincing evidence points to oxidative modification of LDL as an important trigger in a complex chain of events leading to atherosclerosis. We investigated the occurrence of enhanced susceptibility of LDL to oxidation and decreased vitamin E concentration in LDL as additional risk factors promoting atherosclerosis among patients with established coronary artery disease (CAD). Methods: We examined 132 patients with angiographically confirmed CAD and compared them with 111 healthy control individuals. We measured conjugated diene production to assess susceptibility of LDL to copper-mediated oxidation. Vitamin E content of LDL was measured by HPLC. Results: The mean lag time of LDL oxidation and LDL α-tocopherol/LDL-cholesterol ratio were lower in the patients with CAD (55 ± 14 min and 2.4 ± 1.0 mmol/mmol) than in the controls (63 ± 13 min and 2.9 ± 1.1 mmol/mmol; P <0.0001 and <0.001, respectively). Multiple stepwise regression analysis demonstrated the lag time (odds ratio, 1.96; 95% confidence interval, 1.34–2.87; P <0.0001) and concentration of vitamin E in LDL (odds ratio, 1.65; 95% confidence interval, 1.16–2.33; P <0.005) as independent determinants of CAD. Significant inverse Spearman rank correlations were found between lag time ( r = −0.285; P <0.001) or concentration of vitamin E in LDL ( r = −0.197; P <0.002) and severity of CAD. Lag times were not significantly correlated with serum C-reactive protein or ferritin. Conclusions: Our data suggest that a short LDL oxidation lag time and a low concentration of vitamin E in LDL might be independent coronary risk factors for stable CAD in Iranian people.

Second-line Helicobacter pylori eradication with a furazolidone-based regimen in patients who have failed a metronidazole-based regimen.

Abstract: Background/Aim: In developing countries the standard quadruple therapy containing metronidazole results in suboptimal eradication rates of Helicobacter pylori (

The role of the interaction between endogenous opioids and nitric oxide in the pathophysiology of ethanol-induced gastric damage in cholestatic rats.

Abstract: Interaction between endogenous opioids and nitric oxide (NO) has been shown in different biological models and pharmacological evidence suggest that opioids can induce NO release in endothelium as well as in neural cells. Cholestasis is associated with NO overproduction. The reason for increased NO synthesis is not clearly known but it can potentiate development of gastric mucosal damage in cholestatic subjects. Based on increased plasma levels of endogenous opioids and existence of NO overproduction in cholestasis, the present experiments were performed to investigate the role of interaction between endogenous opioids and NO in generation of ethanol-induced gastric damage in cholestatic rats. Cholestasis was induced by surgical ligation of bile duct and sham-operated rats served as controls. The animals received either 20 mg/kg of naltrexone or saline for 6 days and then were fasted and received L-arginine (200 mg/kg), NG-nitro-L-arginine methylester (L-NAME; 2, 5 and 10 mg/kg) or saline. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than in sham-operated animals (115 +/- 12 mm2 vs. 72 +/- 11 mm2, P < 0.05). L-NAME significantly enhanced the development of gastric mucosal lesions in sham-operated rats. But in cholestatic animals, L-NAME decreased and L-arginine enhanced the severity of gastric damage. Pretreatment of animals with naltrexone decreased severity of gastric mucosal damage in cholestatic rats. Concurrent administration of naltrexone with L-arginine was protective against ethanol-induced gastric damage in both normal and cholestatic groups. Administration of naltrexone with L-NAME had the same effect in cholestatic and control rats and increased severity of gastric damage. Plasma levels of NO2- + NO3- were significantly higher in cholestatic rats than control animals (72 +/- 6 microM vs. 39 +/- 3 microM, P < 0.05). Pretreatment of animals with naltrexone significantly reduced plasma levels of NO2- + NO3- in cholestatic animals, but not in control rats (33 +/- 6 microM vs. 32 +/- 4 microM). The protective effect of L-NAME against gastric damage in cholestatic rats can be explained by inhibition of NO overproduction and it seems that interaction between opioids and NO may have an important role in generation of NO overproduction and gastric complications in cholestatic rats.