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Introduction: An interaction between oxidative stress, neuroinflammation, and nitric oxide (NO) has been suggested to have a role neurotoxicity. The aim of current research was to investigate the effect of aminoguanidine (AG) as an inducible NO synthase (iNOS) inhibitor, on brain-derived neurotrophic factor (BDNF), oxidative stress, and interleukin-6 (IL-6) concentrations in the brain tissues of neonates born from the rats exposed to titanium dioxide nanoparticles (TiO2 NPs) during gestation. Methods: The pregnant rats were grouped into three and received: (1) saline, (2) TiO2 (200 mg/kg, gavage), and (3) TiO2-AG [200 mg/kg intraperitoneal (IP)]. The treatment was started since the second gestation day up to the delivery time. The neonates born from the rats were deeply anesthetized, sacrificed, and the brains were collected for biochemical evaluations. Results: The neonates born from the rats exposed to TiO 2 showed a lower BDNF ( p  < .001) but a higher IL-6 ( p  < .01) concentrations in their hippocampal tissue. TiO 2 exposure also increased malondialdehyde (MDA) ( p  < .001) and NO metabolites ( p  < .001), while diminished thiol ( p  < .001), superoxide (SOD) ( p  < .001), and catalase (CAT) ( p  < .001) in all hippocampal, cortical, and cerebellar tissues. Administration of AG improved BDNF ( p  < .01) but attenuated IL-6 ( p  < .01) concentrations in the hippocampal tissue. AG also decreased MDA ( p  < .001) and NO metabolites ( p  < .01- p  < .001), while increased thiol ( p  < .01- p  < .001), SOD ( p  < .001), and CAT ( p  < .05- p  < .001) in all cerebellar, hippocampal, cortical, and tissues. Conclusion: The results of the current research revealed that iNOS inhibitor AG, ameliorated oxidative stress, IL-6 concentration, and improved BDNF in the brain tissues of neonates born from TiO 2 NPs exposed rats.

Aim: The present study was designed to investigate the effect of mercurius solubilis (merc sol) on scopolamine induced memory deficits and motor coordination in mice., Materials and Methods: Three different formulations of merc sol (30X, 200M, 1M) were screened for their in vitro antioxidant potential through DPPH (2, 2-diphenyl-1-picrylhydrazyl) and nitric oxide scavenging activity using response surface methodology. Memory impairment was induced by the administration of scopolamine (1mg/kg i.p.) for 3 days to mice and assessment of memory acquisition and retention was done using Morris water maze test, passive avoidance test, elevated plus maze test, light and dark box test, motor coordination was evaluated using rotarod test and inclined plan test. The involvement of ion channels and nitric oxide pathway in the observed effect of merc sol was elucidated by administration of veratrine (0.125 μg/kg, i.p.), A23187 (20 μg/kg, i.p.), L- arginine (40 mg/kg, i.p.), aminoguanidine (50 mg/kg, i.p.) 30 min prior to merc sol. Acute toxicity studies were performed in accordance with the OECD (Organisation for Economic Co-operation and Development) guidelines., Results: In vitro studies have revealed merc sol 30 X to have maximum free radical and nitric oxide scavenging activity. Administration of merc sol 30 X to mice significantly reduced scopolamine induced memory deficits and motor incoordination in all the performance tasks. The calcium ionophore, A23187 significantly altered the effect of merc sol in mice. No major signs of toxicity were observed., Conclusion: Merc sol has antiamnesic effect in scopolamine induced deficits and motor coordination in mice.

Primary Objective: We aim to study the effects of chronic aminoguanidine (AG) administration on learning and memory impairment after TBI and explore the potential mechanism involved in this process., Research Design: Male C57BL/6J mice were divided into 6 groups: Control, TBI + Veh, TBI+ AG (50, 100, 200 and 400 mg/kg, i.p.)., Methods and Procedures: Then, we measured cyclicadenosine 3', 5'-monophosphate (cAMP) content, phosphorylated form of cAMP-response element binding protein (p-CREB) level, iNOS, brain-derived neurotrophic factor (BDNF) and postsynaptic density-93/95 (PSD-93/95) expression in hippocampus. The learning and memory abilities were assessed using Morris water maze and step-down test., Main Outcomes and Results: The results demonstrate that TBI induced down-regulation of BDNF, loss of PSD-93/95, learning and memory deficits with down-regulation of cAMP content and p-CREB/CREB ratio. Administration of AG (200 and 400 mg/kg) reversed TBI induced down-regulation of BDNF and PSD-93/95, up-regulated the cAMP content and p-CREB/CREB ratio, which resulted in improvement of learning and memory ability., Conclusions: We suspect that AG (200 and 400 mg/kg) might reverse TBI-induced selective loss of postsynaptic proteins and learning and memory deficits with the activation of cAMP/CREB/BDNF signalling pathway.

Introduction: Peramivir (BCX-1812, RWJ-270201) is a highly selective inhibitor of influenza A and B neuraminidase that has recently been approved in the USA by the FDA to treat acute, uncomplicated influenza in adults., Areas Covered: This review examines the discovery and development of peramavir as well as its role in the treatment of influenza. Peramivir is currently the only FDA-approved anti-influenza agent that can be given as an intravenous injection, granting it a unique role in therapy with the potential to improve adherence and outcomes in patients who are unable to tolerate oral agents. In vitro, animal, human and safety data are presented as well as information regarding special populations, resistance and drug approval., Expert Opinion: Clinical trial data support the use of peramivir to relieve influenza symptoms in acute, uncomplicated influenza, with improvements over placebo similar to those of other approved anti-influenza treatments. The ability to give a one-time injectable dose offers improved adherence over currently available oral regimens. While not approved for hospitalized patients, available data suggest that multiple dose peramivir may also have a role in treatment of severally ill, hospitalized patients. Supportive data for the use of peramivir in special patient populations such as pediatrics and those especially at-risk to develop severe influenza symptoms are promising; however, they require further study.

Continuous renal replacement therapy (CRRT) has emerged as the preferred dialysis modality for critically ill patients with acute kidney injury. The objectives of this retrospective study were to assess the effect of nafamostat on circuit patency of CRRT and the safety regarding bleeding complications in patients at high risk of bleeding. We conducted a retrospective study of 243 CRRT patients at high risk of bleeding. We started CRRT without anticoagulation, and nafamostat was used if hemofilter lifespan was less than 12 h. The average hemofilter lifespan was measured before and after drug infusion to evaluate the efficacy of nafamostat. The frequency and number of red blood cell (RBC) transfusions were measured to assess the safety of nafamostat. Of the 243 patients, 62 (25.5%) received nafamostat. In nafamostat group, the hemofilter lifespan was lengthened from 10.2 (7.5-13.0) h to 19.8 (12.6-26.6) h after drug infusion (p < 0.001). The hemofilter lifespan was 27.5 (17.5-38.2) h in anticoagulation-free group. The frequency of RBC transfusion during CRRT did not differ between the nafamostat group and the anticoagulation-free group (71% vs. 70%, p = NS). The median number of RBC units transfused per CRRT day was also not different between the two groups [0.7 (0.5-1.0) units/day vs. 0.7 (0.4-1.1) units/day; p = NS]. The use of nafamostat in patients at high risk of bleeding who require CRRT effectively lengthened the filter survival time without an increase in RBC transfusion. However, 74.5% of patients at high risk of bleeding maintained an acceptable CRRT hemofilter lifespan without circuit anticoagulation.

The sphingolipid metabolic pathway controls the balance of bioactive lipids including apoptotic ceramide and proliferative sphingosine 1-phosphate and, therefore, represents a potential source of new therapeutic targets for numerous diseases. Targets, such as sphingosine kinases (SphK), have been extensively studied, and numerous strategies have been used to develop inhibitors against these enzymes. The WO2010078247 patent application shows the development of some novel sphingo-guanidines, including their water soluble salts, as inhibitors of SphK, and for use in treating and/or preventing diseases and disorders related to undesirable ceramidase, ceramidase-related or SphK activity, including cancer and other proliferative diseases. The synthesis of two agents D-erythro-2-N-(1'-carboxamidino)sphingosine hydrochloride (LCL146) and L-erythro-2-N-(1'-carboxamidino)sphingosine hydrochloride (LCL351) is described and they have been shown to inhibit SphK activity, be cytotoxic to cancer cells and decrease the migration rate of human prostate (DU145) cells.

Human infections with avian influenza A (H5N1) are relatively rare but are associated with high mortality. As of July 5, 2010 there had been 500 cases and 296 fatalities. The influenza virus readily undergoes mutation and reassortment, and there are concerns that an H5N1 variant could be responsible for a future pandemic. The influenza neuraminidase inhibitors zanamivir and oseltamivir are approved for the treatment and prophylaxis of influenza. Oseltamivir is being used to treat H5N1 infections and the case has been made for a role for zanamivir; however, there are no case reports for the latter. Zanamivir is a potent inhibitor of H5N1, attains high lung concentrations immediately on administration, distributes into plasma at antiviral concentrations, has a low propensity for generating resistant virus, and retains activity against H275Y oseltamivir-resistant virus. There have been several reports of oseltamivir-resistant H5N1 arising during treatment with oseltamivir, and zanamivir retains effectiveness (in vitro or in vivo) against these isolates. Compassionate use of intravenous zanamivir for the treatment of seriously ill patients, including those with H275Y H1N1 infections, has also shown promising results. It is concluded that there is a role for zanamivir in treating H5N1 infections either as the approved, inhaled formulation in patients capable of using the Diskhaler, or as the intravenous formulation if compassionate use is warranted. The relatively small number of patients with these infections remains an obstacle to completion of clinical trials. Evidence is therefore likely to be based on carefully documented case reports, ideally in patients treated early in the course of the infection.

Kasabach-Merritt syndrome is a life-threatening congenital disorder characterized by an enlarging hemangioma, thrombocytopenia, and consumption coagulopathy. We report the case of a one-month male infant who presented with a large cutaneous tumor in his right axilla with ecchymosis, thrombocytopenia, and chronic consumption coagulopathy. Three-dimensional computed tomography was useful for accurate diagnosis of the cutaneous tumor and for determining the precise vascular constitution of the hemangioma, suggesting the efficacy of this method for diagnosing Kasabach-Merritt syndrome. Although administration of a corticosteroid was not effective, additional administration of vincristine resulted in the reversal of thrombocytopenia and coagulopathy with reduction of the hemangioma.

Acute renal failure secondary to ischemia/reperfusion (I/R) injury is associated with significant mortality and morbidity. Aminoguanidine (AG), an inducible nitric oxide synthase inhibitor with antioxidant properties, has been reported beneficial in renal I/R injury. The aim of the present study was to investigate the effect of AG on renal I/R injury and compare the effectiveness of different AG treatment modalities. Sprague-Dawley rats were randomly assigned to one of four groups. The control group (n = 6) received sham operation. The I/R group (n = 6), AG-I group (n = 8), and AG-II group (n = 8) received bilateral renal ischemia for 45 min followed by 24 hours of reperfusion. The AG-I group received AG (50 mg/kg) intraperitoneally four hours and 10 minutes before the induction of ischemia. The AG-II group received AG (50 mg/kg) intraperitoneally four hours and 10 minutes after the initiation of reperfusion. Serum urea and creatinine levels increased significantly in the I/R and AG-I groups compared to the control group. Kidney samples from rats in the I/R and AG-I groups revealed severe tubular damage at histopathological examination. Posttreatment with AG significantly reduced serum urea and creatinine levels and improved histopathological lesions compared with the I/R group. Although pretreatment with AG failed to protect kidneys against I/R injury in this experimental model, posttreatment with AG attenuated renal dysfunction and histopathological changes after I/R injury.

Objective: Mast cell tryptase has been proposed to be involved in the pathogenesis of human inflammatory bowel disease (IBD). Recently, it was reported that a low dose of nafamostat mesilate (NM), a serine protease inhibitor that is widely used to treat disseminated intravascular coagulation (DIC) and acute pancreatitis, can selectively inhibit human tryptase activity. The aim of this study was to investigate the anti-inflammatory effects of NM on experimental colitis in rats., Material and Methods: Colitis was induced in male Wistar rats using an enema of trinitrobenzene sulfonic acid (TNBS) dissolved in 50% ethanol. NM or 5-aminosalicylic acid (5-ASA), foundation therapy for mild-to-moderate IBD, was administered via the anus once a day on each of the 6 days after administration of TNBS. Colonic inflammation was assessed 1 week after TNBS administration., Results: Intracolonic administration of TNBS resulted in the infiltration of numerous tryptase-positive cells in the colonic mucosa. The colonic mucosal injury induced by TNBS was significantly decreased by treatment with NM or 5-ASA. The increases in thiobarbituric acid-reactive substances (TBA-RS), myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractants-1 (CINC-1) in the colonic mucosa were inhibited in the NM group and the 5-ASA group, without significant differences between them., Conclusions: These results indicate that a low dose of NM can inhibit the colonic mucosal inflammation induced by TNBS in rats, which suggests that anti-tryptase therapy using low doses of NM has excellent potential to become a new therapeutic strategy for IBD.

Purpose: This study determined the role of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in the resistance response of BALB/c mice to P. aeruginosa-induced keratitis., Methods: RT-PCR, nitrite detection, iNOS inhibition, ELISA, and immunohistochemistry were used., Results: Early after infection, iNOS mRNA expression and nitrite levels in cornea were elevated compared to levels in the uninfected cornea. Treatment with aminoguanidine sulfate (AG), an inhibitor of iNOS, resulted in extensive corneal destruction, reduced nitrite levels, and reduced nitrotyrosine staining. Infected mice also had increased bacterial burden and elevated levels of MIP-1alpha, IL-1beta, and MIP-2 in the cornea. Dual-labeling immunohistochemistry established the macrophage as the major source of iNOS in the infected cornea., Conclusions: These data provide evidence that iNOS is constitutively expressed in the BALB/c cornea; that iNOS-derived NO is required for bacterial killing/stasis; and that the macrophage is the major cell source of NO.

Purpose: Inflammation, in general, causes the release of a variety of inflammatory mediators that in turn induce cyclooxygenase (COX) 2, nitric oxide synthase (iNOS) and 5-lipoxygense (LP) synthesis, producing large amounts of inflammatory prostaglandins (PG), nitric oxide (NO), and leukotriene (LT) B4. Therefore, inhibition of these enzymes may abrogate intraocular inflammation in experimental autoimmune anterior uveitis (EAAU)., Methods: Lewis rats were immunized with melanin-associated antigen (MAA) isolated from bovine iris and ciliary body. These animals were divided into three groups. The first group of rats received subcutaneous injection of COX 2 inhibitor CS 236 at different time points. The second and third groups of animals received subcutaneous aminoguanidine (AG), an iNOS inhibitor, and nordihydroguaiaretic acid (NDGA), a 5-LP inhibitor, respectively. Control animals received vehicle. Rat eyes were examined daily by slit-lamp biomicroscopy from Day 7 to 30 post injection for uveitis. Animals were also sacrificed at various time points for histologic analysis., Results: Control animals developed severe EAAU in both eyes. The disease started in these animals on Day 12 post immunization and lasted for ten days. Interestingly, CS 236, a potent COX 2 inhibitor, completely abrogated EAAU when the animals were treated daily from the Day 0 to 14 or Day 0 to 20 after MAA injection. Furthermore, daily CS 236 treatment after the onset of EAAU (Day 14-20) significantly reduced the severity (both clinical and histologic) of EAAU and shortened the duration of disease. iNOS inhibitor (AG) and 5-LP inhibitor (NDGA) partially attenuated EAAU., Conclusions: Our results show that EAAU was partially attenuated by AG and NDGA. Interestingly, CS 236, a potent COX 2 inhibitor, completely inhibited EAAU in male Lewis rats most likely by inhibiting the initial phase and onset of the disease.

Graft versus host disease (GVHD) remains the major obstacle to successful allogeneic bone marrow transplantation. Cyclosporin with methotrexate is the most common prophylactic regimen. Tacrolimus is associated with less GVHD and is gaining ground especially in unrelated donor transplants where current regimens are unsatisfactory. Mycophenolate mofetil (MMF) and rapamycin have not yet shown benefit in acute GVHD prophylaxis. In vivo T-cell depletion with Campath 1H or thymoglobulin used during transplant conditioning are increasingly used in place of ex vivo T-cell depletion, where results remain disappointing. Steroids remain first choice for therapy of GVHD but anti-CD25 antibodies, daclizumab or basiliximab are gaining popularity as second-line therapy ahead of ATG. Chronic GVHD is increasing with greater use of peripheral blood stem cell grafts and older patients. The combination of tacrolimus and MMF is promising for patients with extensive disease. Tolerance induction using CTLA-4-Ig, anti-CD40L, tresperimus and/or rapamycin may revolutionise GVHD therapy. However, due to the desirability of tumour intolerance, tolerance is likely to be developed in organ transplantation before bone marrow transplantation for traditional indications. Bone marrow transplants performed to induce organ tolerance may see increasing use of these agents. TNF blockade using infliximab or etanercept (Enbrel) is promising but the role of these agents is not yet defined.

Purpose: The role of nitric oxide in the development of selenite-induced cataracts in rats was examined using nitric oxide synthase (NOS) inhibitors., Methods: Subcutaneous injection of sodium selenite was used to induce cataracts in rats, with or without pretreatment with NOS inhibitors. The anterior eye segment analysis system (EAS-1000, Nidek) was used to measure lens opacity. The glutathione content of the lenses was determined by an HPLC method and the Ca2+ content by atomic absorption spectrometry. Nitrite, a stable metabolite of nitric oxide, was determined fluorometrically. NADPH-diaphorase activity staining and Western blot analysis were used to determine NOS levels., Results: Administration of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited lens opacification in selenite-treated rats. NG-nitro-d-arginine methyl ester, an inactive enantiomer of l-NAME, had no effect. Aminoguanidine, another NOS inhibitor, also inhibited the development of cataracts in a dose-dependent manner. On the other hand, L-arginine, a substrate of NOS, accelerated the development of cataracts. Although the opacification of the lenses was apparent approximately 3 days after selenite injection, the nitrite level was increased within one day. In addition, NOS was induced in the eye within one day of selenite injection., Conclusions: The present study demonstrated that NOS inhibitors prevented the development of cataracts in selenite-treated rats. The results also suggest that nitric oxide had an important role in the development of selenite-induced cataracts.

To elucidate whether an inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine (AMG), affects the expression of iNOS in the spinal cords of rats with experimental autoimmune encephalomyelitis (EAE), we induced EAE in Lewis rats, and treated EAE rats with AMG. AMG (200mg/kg administered intraperitoneally from day 0 to day 7 post-immunization) significantly reduced the clinical severity of EAE paralysis. AMG, however did not prevent the occurrence of EAE. Western blot analysis showed that iNOS expression was significantly reduced in the spinal cords of rats with EAE treated with AMG compared with rats treated with the vehicle. This finding supports the conclusion that the production of nitric oxide by iNOS plays an important role in the induction of EAE. The corollary is that the amelioration of EAE paralysis by the treatment with AMG is associated with the suppression of iNOS expression in the target organ i.e. the spinal cord.

The aim of this study was to investigate the dose-dependent effect of pretreatment with the selective sodium-hydrogen exchange NHE-subtype 1 inhibitor cariporide on myocardial infarct mass in a rabbit model of coronary ligation and reperfusion. Furthermore, in a second part of the study, we tested the effect of cariporide in the rabbits when given prior to reperfusion. Rabbits (n=49) were randomized in 7 groups: saline vehicle, cariporide: 0.01, 0.03, 0.1 and 0.3 mg/kg, and subjected to a 30 min occlusion of a branch of the left coronary artery followed by 2 h reperfusion. Cariporide was given as a bolus intravenously 10 min before occlusion or 5 min before reperfusion. After reperfusion, myocardial infarct mass was determined by triphenyl tetrazolium chloride staining and expressed as a percent of area at risk. Cariporide given intravenously 10 min before occlusion in doses of 0.01, 0.03, 0.1, 0.3 mg/kg, led to a dose-dependent reduction in infarct mass from 58+/-6% in controls to 48+/-4% (-17%, NS), 36+/-5% (-38%, p<0.05), 26+/-6% (-55%, p<0.05), 11+/-4% (-81%, p<0.05) respectively, whereas area at risk did not differ in between the groups. The effect of the lowest dose of 0.01 mg/kg did not reach significance. Plasma levels at different doses of cariporide were correlated to the respective infarct mass. After coronary occlusion left ventricular end-diastolic pressure (LVEDP) significantly increased throughout occlusion and reperfusion. Cariporide in the doses of 0.3, 0.1 and 0.03 mg/kg normalized LVEDP when measured after 2 h reperfusion. In controls hemodynamic parameters such as mean arterial blood pressure (MAP), heart rate (HR), left ventricular pressure (LVP) and LV dP/dt(max) were not significantly changed by ischemia/reperfusion with the exception of MAP, LVP and LV dP/dt(max) which were significantly decreased after 120 min reperfusion. Cariporide at doses of 0.1, 0.03 and 0.01 mg/kg did not significantly influence these parameters, whereas the highest dose of 0.3 mg/kg prevented the decrease of MAP and LVP. Cariporide (0.3 mg/kg i.v.) administered 5 min before reperfusion significantly reduced infarct mass by 31%. Under these conditions the increase of LVEDP after coronary occlusion was not influenced by cariporide. As in the pretreatment experiments, the decrease of MAP and LVP was prevented when measured 2 h after reperfusion. The results show that pretreatment with the NHE-subtype 1 inhibitor cariporide is cardioprotective by reducing infarct mass in rabbits in a dose-dependent manner. While the cardioprotective effect of pretreatment could be demonstrated over a broad range of doses, the efficacy of the compound when given only on reperfusion was significant but more limited.

To investigate the effects of synthetic trypsin inhibitors on pancreatic cancer, camostat (FOY-305) was administered orally to hamsters with experimental pancreatic cancer induced by diisopropanol nitrosamine (DIPN). The effect of free radicals on carcinogenesis was examined by measuring the tissue levels of the scavengers superoxide dismutase (SOD) and glutathione peroxidase (GSX-Px), and pancreatic tissues were examined histologically. Cancers developed in all hamsters that survived 24 weeks in the DIPN group and the FOY group, but 80% of the cancers in the DIPN group were tubular adenocarcinomas, and 91% of those in the FOY group papillary adenocarcinomas. The SOD activity in the DIPN group was significantly lower in the cancerous area and the borderline region than in the non-cancerous region and normal tissue. SOD activity in the cancerous and borderline regions was higher in the FOY groups than in the DIPN group. GSH-Px levels in the borderline and non-cancerous regions were significantly higher in the FOY group than in the DIPN group. These results suggest that the synthetic protease inhibitor slows the progress of pancreatic cancer by its free radical scavenging activity.

In order to understand the mechanism of acute renal failure frequently observed in severe acute pancreatitis, renal microcirculation and renal hemodynamics were investigated during experimental acute pancreatitis in dogs induced by autologous bile and trypsin mixture into the pancreatic duct. Renal tissue blood flow (hydrogen gas clearance method), renal arterial blood flow, and cardiac output (transonic blood flow meter) were each measured for 5 h after induction of pancreatitis. The effect on renal hemodynamics of a new synthesized protease inhibitor--E-3123; 4-(2-succinimidoethylthio)phenyl-4-quanidinobenzoate methane sulfonate--intravenously infused at the rate of 3 mg/kg/h was also investigated. The mean blood pressure and pulse pressure decreased after induction of pancreatitis. Renal microcirculation and renal artery blood flow decreased during the experiment. However, in dogs with treated by E-3123, renal microcirculation was preserved during the first hour of the experiment and decreased gradually afterward, but it was significantly higher than that of the dogs without E-3123 during 3-5 h. The mean blood pressure and pulse pressure were preserved nearly at preoperative levels during the experimental period. We concluded that renal microcirculation decreased concomitantly with a deterioration of acute pancreatitis, and that the new pancreatic protease inhibitor E-3123 may have some beneficial effect to improve renal hemodynamics in the early period of acute pancreatitis.

To evaluate the effects of acute pancreatitis on hepatic function and hepatic cellular and subcellular organellar fragility, we studied 1) the hepatic secretion of lysosomal enzymes (beta-glucuronidase, beta-galactosidase, and N-acetyl-beta-glucosaminidase) into bile in the isolated perfused rat liver model; 2) the aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and lysosomal enzyme levels in the effluent in an isolated liver model; 3) hepatic lysosomal fragility in an in vitro incubation study; and 4) protective effects of a new low molecular weight synthetic protease inhibitor, ONO 3307, against hepatic injury in doses of 2 and 5 mg/kg.h in acute pancreatitis induced by a supramaximal dose of cerulein in rats. Decreased hepatic secretion of lysosomal enzymes into bile and accelerated hepatic lysosomal fragility were observed in acute pancreatitis induced by cerulein. ONO 3307 showed a significant protective effect against this hepatic injury in acute pancreatitis, the dose of 5 mg/kg.h showing a more potent effect than the dose of 2 mg/kg.h. These results suggest that the impaired hepatic function, including depressed hepatic secretion of lysosomal enzymes, seems to be closely related to accelerated hepatic fragility and that some unknown protease, which is present in pancreatitis and is susceptible to inhibition by ONO 3307, plays a crucial pathologic role in the development of this liver injury during acute pancreatitis.

The effects of 3 months' maintenance treatments with cimetidine, 400 mg at bedtime, or with carbenoxolone, 150 mg/daily, in patients whose duodenal ulcers healed after an initial course with cimetidine were compared. Carbenoxolone promoted a significant enhancement of cimetidine-altered mucus secretion, whereas in the cimetidine group no mucus recovery was found. Within 6 months from healing time 48.1% of the patients in the cimetidine group relapsed, compared with 21.4% in the carbenoxolone group. The difference is statistically significant (p < 0.05). Our results suggest that carbenoxolone maintenance is more effective than cimetidine in preventing recurrence of ulcers, being also a cheaper and shorter maintenance treatment.

Twenty-one patients with endoscopically confirmed recurrent ulceration after proximal gastric vagotomy entered an open trial of treatment with cimetidine, 1.0 g/day. Twenty patients completed 6 weeks' treatment, and repeat endoscopy showed ulcer healing in 18 of 20 patients. One patient's ulcer was found to be healed on X-ray examination, and the other patient had a healed ulcer after an additional 2 weeks' treatment. Eighteen of the patients with healed ulcer entered a maintenance trial of cimetidine, 400 mg at night. During the 1-year follow-up period the occurrence of symptoms led to re-endoscopy in 11 patients. Re-ulceration was confirmed in six patients (33%), and mean time to ulcer recurrence was 18.2 weeks. Ulcer recurrence was treated with an increased dose of cimetidine and antacids. All the ulcers then healed again, and the patients remained well on a maintenance dose of cimetidine, 800 mg/day. None of the patients had to be operated on during the trial. Two patients developed gynaecomastia during maintenance treatment with 400 mg cimetidine a day. No serious untoward signs or symptoms occurred that necessitated withdrawal from the trial. It seems as if recurrent ulcers after proximal gastric vagotomy respond to cimetidine treatment approximately as do peptic ulcers in unoperated patients.

A double-blind trial was carried out in 30 patients with peptic ulcers to assess the effects of treatment with a gastrin-receptor antagonist, proglumide, compared with a histamine H2-blocker, cimetidine. Patients received either 1200 mg proglumide or 1200 mg cimetidine per day for 28 days. The results showed that both drugs significantly reduced clinical symptoms and gastric secretion. In patients treated with cimetidine there was a significant increase in blood gastrin levels and marked hypertrophy and hyperplasia of the antral mucosa was observed in almost all patients. No such changes were found in the patients treated with proglumide.

Nineteen patients entered a double-blind randomized trial of the prophylactic effect of cimetidine in gastric ulcer disease. The diagnosis of gastric ulcer had been established endoscopically prior to the trial, but at the time of entry the patients were symptom-free and their ulcers had healed. The patients received either cimetidine, 400 mg twice daily or inactive tablets. Ten cimetidine-treated patients completed 12 months' treatment without suffering a recurrence of symptoms, whereas 5 of 9 placebo-treated patients suffered a symptomatic relapse after 7 to 18 weeks (P less than 0.025). In 4 of the 5 patients an ulcer was found at gastroscopy. It is concluded that maintenance treatment with cimetidine helps to prevent symptomatic relapses in gastric ulcer patients.

The healing-rate of duodenal ulcer after short-term treatment with carbenoxolone was not significantly different from that after treatment with cimetidine. There seems to be no evidence of a significant difference in the tendency of duodenal ulceration to relapse following successful short-term therapy with either treatment. In the case of cimetidine treatment the rate of 58% relapse within 12 months after withdrawal of the drug corresponds well to the data of other authors (3, 19) and does not exceed the relapse rate during placebo medication. The post-treatment relapse study was markedly hampered by a low compliance of patients to cooperate in the long-term follow-up. The drop-out rate was greater in patients previously treated with carbenoxolone than in those of the cimetidine group.

Urinary albumin and beta 2-microglobulin excretion and creatinine clearance were measured during 8 weeks' conventional cimetidine treatment in 13 ulcer patients without signs of renal disease. No changes were found in albumin or in beta 2-microglobulin excretion, indicating no changes in glomerular permeability and tubular reabsorption of proteins in the kidney. Creatinine clearance fell about 28 ml/min (26%) during cimetidine treatment but normalized after termination of medication. Concomitantly, serum creatinine increased by 22% during treatment and fell again after termination of treatment. The mechanism behind the changes in renal handling of creatinine during cimetidine was not clarified in the present study. It is concluded that the conventional 8 weeks' cimetidine treatment seems safe from the renal point of view, at least in patients without signs of renal disease.

The effect of pirenzepine and cimetidine on healing, symptoms and relapse rate of duodenal ulcer was studied in a placebo-controlled double-blind trial. Cimetidine (1 g daily) was superior at the beginning of therapy to a low dose of pirenzepine (75 mg daily) and placebo with regard to symptoms. No significant differences in ulcer healing were found between the 3 groups of treatment. The relapse rate after treatment with pirenzepine was lower than after treatment with cimetidine.

The effect of prostaglandin E2 (PGE2), cimetidine, and atropine on ethanol-induced gastric mucosal damage was studied in anaesthetised rats. Intravenous infusion of PGE2 (120 micrograms/kg X h) protected the gastric mucosa against lesions produced by irrigation of the stomach with 30% (v/v) ethanol in 100 mM HCl plus 50 mM NaCl. PGE2 had no effect on back-diffusion of H+ ions, whereas outflow of Na+ and K+ ions decreased. The increases in pepsinogen secretion and gastric mucosal blood flow during mucosal damage were not affected by PGE2. Cimetidine (25 mg/kg intravenously) failed to prevent mucosal haemorrhages induced by ethanol. Cimetidine caused a slight decrease in outflow of Na+ ions but otherwise had no effect on the variables measured. Atropine sulphate (1 mg/kg X h intravenously) similarly did not protect the gastric mucosa against ethanol-induced lesions, nor did it change ion fluxes, fluid output, or pepsinogen secretion during mucosal damage. Gastric mucosal blood flow, however, was lower in the atropine-treated rats than in the control rats. The results indicate that PGE2, but not cimetidine or atropine, protects the gastric mucosa against ethanol-induced damage in anaesthetised rats, but that this effect is not due to prevention of back-diffusion of H+ ions or to increased mucosal blood flow.

The plasma concentration of cimetidine was measured in 40 patients with duodenal ulcer after an oral dose of 200 mg cimetidine. The peak plasma concentration was on average 1.33 mg x 1(-1) (S.D. = 0.53) and the area under the plasma concentration curve (AUC) between 60 and 120 min after cimetidine was 1.13 mg x h x 1(-1) (S.D. = 0.48). The percentage inhibition (I%) of maximal acid output (MAO) to pentagastrin during this 60-min period was 49% (S.D. = 19) with a very low, but statistically significant, correlation with the AUC, r = 0.35 (p less than 0.05), thus demonstrating a very great individual variation in sensitivity to cimetidine. In 37 of the patients the time from start of treatment with cimetidine, 1.0 g/day, to disappearance of ulcer symptoms could be assessed, and it was found that neither the individual sensitivity to cimetidine, I%/AUC, nor the gastric secretory capacity, MAO, correlated significantly with the clinical effectiveness of the cimetidine treatment, although 8 patients with a low sensitivity to cimetidine and a high MAO improved more slowly (28 days) than the other 29 patients (13 days) (p less than 0.1).

Gastric acid and pepsin output in response to 0.10 and 6.0 microgram . kg-1h-1 of pentagastrin was studied in ten duodenal ulcer patients before and after cessation of 6 weeks of cimetidine treatment, 1 g/day. Acid output in response to the low dose of pentagastrin was on average 63% of the response to the high dose before and on average 65% after treatment. The corresponding values for pepsin output were on average 88% both before and after treatment. Thus, the parietal and chief cell sensitivity stayed unchanged after cimetidine treatment. Mean maximal acid output decreased insignificantly, from 39.4 mmol/h before 34.9 mmol/h after cimetidine treatment. The results suggest an unchanged gastric acid and pepsin secretion capacity after short-term treatment with cimetidine for duodenal ulcer.

Colloidal bismuth subcitrate (CBS, DE-NOL) and cimetidine have been compared in a double-blind randomized trial in the management of 75 patients with duodenal ulcer. The drugs had similar potency with respect to ulcer healing. At one month the healing rates were 66% for CBS and 59% for cimetidine. At two months the rates were 89% and 85% respectively. When the drugs were withdrawn patients who had received CBS had significantly lower relapse rates than those who had received cimetidine. Relapse rates for CBS and cimetidine were 13% and 70% at six months and 39% and 85% at one year respectively.

Cimetidine promotes the healing of duodenal ulcer, but prolonged use (perhaps in low dosage) seems to be necessary in many cases to prevent relapse. H2 receptors are widely distributed in body tissue, but important effects of blockade of the extragastric receptors have not been detected. Nor has serious toxicity been noted. Cimetidine probably will become a familiar, much-used, and valuable drug.

Fifty-eight patients with endoscopically verified duodenal ulcers were treated with cimetidine, 1 g/day, for 6--10 weeks. The ulcers healed in 52 out of the 54 patients completing the treatment (96.3%). Forty-seven of the patients with healed ulcer were randomly allocated to 1 year of maintenance treatment, 23 patients with cimetidine, 400 mg at night, and 24 patients with placebo tablets. In the cimetidine-treated group 2 out of the 20 patients (10%) completing the trial had recurrence of ulceration, whereas 16 out of the 23 patients (70%) completing the placebo treatment had ulcer recurrence (p less than 0.001). The drug was well tolerated and, except for a marked increase in serum transaminases in three patients, no serious side effects were seen.

In a randomized, controlled multicenter-study 126 patients with endoscopically proven duodenal ulcer were treated with 100 mg Pirenzepine daily and 128 patients with 1000 mg Cimetidine daily. Endoscopic evaluation was done by an independent endoscopist after four weeks. At this time 64.3% of the Pirenzepine-treated patients and 73.4% of the patients on Cimetidine had the ulcer healed. The chi-square value of 2.48 indicates that the difference was not statistically significant, that Pirenzepine is equally or at least not essentially less effective than Cimetidine in the treatment of duodenal ulcer. Pain relief was good in both groups with a trend in favour of Cimetidine. Side effects were seldom, mild and reversible.

Using a method described earlier, an investigation of the gastro-oesophageal region was made on duodenal ulcer patients before and during cimetidine treatment. During cimetidine treatment there was a small increase in the gastro-oesophageal sphincter pressure (p less than 0.05), although the pressure still was lower than in normal individuals (p less than 0.05). The acid perfusion test and the acid-clearing test were unchanged. The intensity of the acid gastro-oesophageal reflux at pH less than or equal to 4 was reduced p less than 0.05) but still greater than in normal individuals (p less than 0.05). A tendency to an increase of the intragastric pH postprandially (0.05 less than p less than 0.01) was found during treatment, whereas the intragastric pH fasting 12 h after the intake of the last tablet was unchanged. There was no change in the number of amplitudes registered at the proximal and distal pressure catheters (p greater than 0.1), whereas the reversed peristaltic activity still was increased compared with normal individuals (p less than 0.00u). Before treatment a reflux episode at pH less than or equal to 3 needed longer time and greater peristaltic activity to be cleared than was the case during treatment. Nineteen of 20 patients improved their symptoms during treatment. Cimetidine increased the gastro-oesophageal sphincter pressure in duodenal ulcer patients, which may be due to either the reduced intragastric acid secretion or to a direct influence on the gastro-oesophageal region. The reduction in the acid gastro-oesophageal reflux is partly due to an increased gastro-oesophageal sphincter pressure and partly due to a reduced output of acid reflux material. Low pH and the volume of the reflux material in the distal part of the oesophagus are important in regulating the peristaltic activity in duodenal ulcer patients.

Quantitative ultrastructural analyses of the parietal cells have been performed on eleven patients with chronic duodenal ulcer, before and after 8 weeks' treatment with a histamine H2-receptor antagonist (cimetidine, 1 g/day). The treatment caused a significant decrease of the secretory surface density; this result seems to differ from those of ultrastructural reports on parietal cells when acid secretion is inhibited by vagotomy. Furthermore, it was demonstrated that the profile of the tubulo-vesicles of parietal cells could be seen in three phases, tentatively suggesting that this system is able to take up material from the surrounding cytoplasm by encircling it.

In a 47-year-old male with Ménétrier's disease (protein-losing gastropathy) the histamine-H2-receptor antagonist Cimetidine stops the protein loss and improves the clinical condition. Gastric perfusion studies on net and bidirectional ionic fluxes, protein secretion rates, and permeability, with simultaneous recording of the transmural electrical potential difference indicate that Cimetidine decreases a paracellular protein secretion by 'tightening' the tight junctions of the gastric epithelium.

Twenty-one consecutive patients with endoscopically proven recurrent ulcer were treated continuously with cimetidine, 1 g daily for 8 weeks. After 4 weeks' treatment 18 (86%) of the patients were free of symptoms, and the ulcers had healed in 17 (81%). At the 8th-week examination symptoms had disappeared, and ulcers were healed in 19 patients (91%). Within 6 weeks after withdrawal of cimetidine six patients (28%) presented recurrence of ulcers and symptoms. This study demonstrates that recurrent ulcer patients respond to cimetidine with regard to healing of ulcers and disappearance of symptoms, as do unoperated duodenal ulcer patients. Because operation for recurrent ulcer carries an increased mortality, we suggest that cimetidine should be attempted in the treatment.

Zaltidine is a new H2-receptor antagonist. This study compares the safety and efficacy of zaltidine with those of placebo in the short-term treatment of duodenal ulcer. One hundred and thirty-five patients were randomly allocated to 4 weeks' treatment with either 150 mg zaltidine once daily or placebo. Fifty-nine were treated for a full 4 weeks with zaltidine before the trial was stopped. Healing rates after 4 weeks of zaltidine and placebo were 86% and 19%, respectively (p less than 0.001). Five patients in the zaltidine group had increased serum aminotransferase levels at the final (4-week) visit. The values normalized when treatment was stopped. Liver biopsy specimens provide strong evidence of drug-induced injury. Hepatic damage was associated with plasma levels of zaltidine in the upper half of the observed range. Zaltidine appears to be an effective treatment of duodenal ulcer. However, the incidence of hepatic damage (8%) seems higher than with commonly used H2-receptor antagonists.

The therapeutic efficacy of ranitidine, pirenzepine, cimetidine and placebo in the 28 day treatment of duodenal ulcer was evaluated through an open randomized study performed in 120 patients. At the end of treatment, ranitidine, pirenzepine and cimetidine demonstrated a significantly higher efficacy on ulcer healing as well as on symptom relief in comparison with placebo (P less than 0.05). Data regarding cimetidine and ranitidine failed to reveal significant differences: pirenzepine, on the contrary, when compared with both the H2 blockers employed showed a slower effect on symptom disappearance. As far as functional data are concerned, placebo administration did not induce any variation of secretory or gastrinemic behaviour: on the contrary, after the end of ranitidine and cimetidine treatment a significant decrease of BAO and of MAO were found, failing to reveal any serum gastrin variation. After pirenzepine therapy no differences in the acid secretory behaviour were seen, while a significant increase of fasting gastrinemia was observed.

Ninetyfive patients with endoscopically verified duodenal ulcer were randomly allocated in a double blind manner to 3 different treatments. Thirtyfive patients were treated with trimipramine 25 mg nocte, 32 patients with cimetidine 400 mg nocte and 26 patients with cimetidine 200 mg 3 times a day and 400 mg nocte (standard dose). In addition all patients got intensive antacid treatment with LinkR, 20 ml 1 and 3 hours after meals. Two patients were excluded from the trial. After 6 weeks of treatment re-endoscopy revealed healed ulcer in 35 patients (86%) in the trimipramine group, in 32 patients (85%) in the group treated with low dose of cimetidine and in 26 patients (100%) in the group treated with standard dose of cimetidine. The differences in healing rate were not significant. The time until complete relief of pain was significantly longer in the trimipramine group than in the cimetidine groups. The drugs were well tolerated but constipation was reported by 31% of the patients.