A simple light-driven transmembrane proton pump.

Light-induced lipophilic porphyrin/aqueous acceptor charge separation across a single lipid-water interface can pump protons across the lipid bilayer when the hydrophobic weak acids, carbonylcyanide m-chlorophenylhydrazone and its p-trifluoromethoxyphenyl analogue, are present. These compounds act as proton carriers across lipid bilayers. In their symmetric presence across the bilayer, the positive currents and voltages produced by the photogeneration of porphyrin cations are replaced by larger negative currents and voltages. The maximum negative current and voltage occur at the pH of maximum dark conductance. The reversed larger current and voltage show a positive ionic charge transport in the same direction as the electron transfer. This transport can form an ion concentration gradient. The movement of protons is verified by an unusual D2O isotope effect that increases the negative ionic current by 2- to 3-fold. These effects suggest that an interfacial pK shift of the weak acid caused by the local electric field of photoformed porphyrin cations/acceptor anions functions as the driving force. The estimated pumping efficiency is 10-30%. Time-resolved results show that proton pumping across the bilayer occurs on the millisecond time scale, similar to that of biological pumps. This light-driven proteinless pump offers a simple model for a prebiological energy transducer.

The photoreceptor sensory rhodopsin I as a two-photon-driven proton pump.

Proton translocation experiments with intact cells of Halobacterium salinarium overproducing sensory rhodopsin I (SRI) revealed transport activity of SRI in a two-photon process. The vectoriality of proton translocation depends on pH, being outwardly directed above, and inwardly directed below, pH 5.7. Activation of the transport cycle requires excitation of the initial dark state of SRI, SRI590, to form the intermediate SRI380. Action spectra identify the photocycle intermediates SRI380 and SRI520 as the two photochemically reactive species in the outwardly directed transport process. As shown by flash photolysis experiments, SRI520 undergoes a so-far unknown photochemical reaction to SRI380 with a half-time of <200 micros. Mutation of SRI residue Asp-76, the residue which is equivalent to the proton acceptor Asp-85 in bacteriorhodopsin, to asparagine leads to inactivation of proton translocation. This demonstrates that the underlying mechanisms of proton transport in both retinal proteins share similar features. However, SRI is to our knowledge the first case where photochemical reactions between two thermally unstable photoproducts of a retinal protein constitute a catalytic ion transport cycle.

Drugs and the gastrointestinal tract

16.1. Agents to control acidity 16.1.1 Antacids 16.1.2 Proton pump inhibitors and antibiotics for Helicobacter pylori 16.1.3 Histamine H2 receptor antagonists 16.1.4 Misoprostol 16.1.5 Sucralfate 16.2. Prokinetics and emetics 16.2.1 Introduction to prokinetics 16.2.2 Prokinetic agents 16.2.3 Emesis with cytotoxic drugs and drugs for 16.2.4 Motion sickness and drugs for 16.2.5 Drugs for post-operative emesis 16.3. Agents used for diarrhea, constipation, irritable bowel syndrome 16.3.1 Treatment for diarrhea 16.3.2 Treatment for constipation 16.3.3 Treatment for opioid-induced constipation 16.4. Drugs for inflammatory bowel disease 16.4.1 Mesalazine 16.4.2 Glucocorticoids 16.4.3 Infliximab

A comparison of the application of STOPP/START to patients' drug lists with and without clinical information

Background A European screening tool (STOPP/START) has been formulated to identify the prescribing of potentially inappropriate medicines (PIMs) and potential prescribing omissions (PPOs). Pharmacists working in community pharmacies could use STOPP/START as a guide to conducting medication use reviews; however, community pharmacists do not routinely have access to patients' clinical records. Objective To compare the PIM and PPO detection rates from application of the STOPP/START criteria to patients' medication details alone with the detection rates from application of STOPP/START to information on patients' medications combined with clinical information. Setting Community Pharmacy. Method Three pharmacists applied STOPP/START to 250 patient medication lists, containing information regarding dose, frequency and duration of treatment. The PIMs and PPOs identified by each pharmacist were compared with those identified by consensus agreement of two other pharmacists, who applied STOPP/START criteria using patients' full clinical records. Main outcome measure The main outcome measures were: (1) PIM and PPO detection rates among pharmacists with access to patients' clinical information compared to PIM and PPO detection rates among pharmacists using patients' medication information only, and (2) the levels of agreement (calculated using Cohen's kappa statistic (k)) for the three most commonly identified PIMs and PPOs. Results Pharmacists with access to patients' clinical records identified significantly fewer PIMs than pharmacists without (p = 0.002). The three most commonly identified PIMs were benzodiazepines, proton pump inhibitors and duplicate drug classes, with kappa (k) statistic agreement ranges of 0.87-0.97, 0.60-0.68 and 0.39-0.85 respectively. PPOs were identified more often (p 

Effectiveness of a Multifaceted Intervention for Potentially Inappropriate Prescribing in Older Patients in Primary Care: A Cluster-Randomized Controlled Trial (OPTI-SCRIPT Study)

PURPOSE Potentially inappropriate prescribing (PIP) is common in older people and can result in increased morbidity, adverse drug events, and hospitalizations. The OPTI-SCRIPT study (Optimizing Prescribing for Older People in Primary Care, a cluster-randomized controlled trial) tested the effectiveness of a multifaceted intervention for reducing PIP in primary care.

METHODS We conducted a cluster-randomized controlled trial among 21 general practitioner practices and 196 patients with PIP. Intervention participants received a complex, multifaceted intervention incorporating academic detailing; review of medicines with web-based pharmaceutical treatment algorithms that provide recommended alternative-treatment options; and tailored patient information leaflets. Control practices delivered usual care and received simple, patient-level PIP feedback. Primary outcomes were the proportion of patients with PIP and the mean number of potentially inappropriate prescriptions. We performed intention-to-treat analysis using random-effects regression.

RESULTS All 21 practices and 190 patients were followed. At intervention completion, patients in the intervention group had significantly lower odds of having PIP than patients in the control group (adjusted odds ratio = 0.32; 95% CI, 0.15–0.70; P = .02). The mean number of PIP drugs in the intervention group was 0.70, compared with 1.18 in the control group (P = .02). The intervention group was almost one-third less likely than the control group to have PIP drugs at intervention completion, but this difference was not significant (incidence rate ratio = 0.71; 95% CI, 0.50–1.02; P = .49). The intervention was effective in reducing proton pump inhibitor prescribing (adjusted odds ratio = 0.30; 95% CI, 0.14–0.68; P = .04).

CONCLUSIONS The OPTI-SCRIPT intervention incorporating academic detailing with a pharmacist, and a review of medicines with web-based pharmaceutical treatment algorithms, was effective in reducing PIP, particularly in modifying prescribing of proton pump inhibitors, the most commonly occurring PIP drugs nationally.

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.

OBJECTIVE: To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," published in 2004. DESIGN: Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding. METHODS: We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation (1) indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost) or clearly do not. Weak recommendations (2) indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations. RESULTS: Key recommendations, listed by category, include early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7-10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure > or = 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for postoperative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7-9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B), targeting a blood glucose < 150 mg/dL after initial stabilization (2C); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D). Recommendations specific to pediatric severe sepsis include greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); and a recommendation against the use of recombinant activated protein C in children (1B). CONCLUSIONS: There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.

Factores asociados a la infección para Clostridium difficile en un hospital universitario de Bogotá

Introducción La infección por Clostridium difficile, es una de las causas más frecuentes de diarrea nosocomial con una alta morbimortalidad, con un aumento exponencial en su incidencia, en Estados Unidos se duplicó, de 261 casos x 100.000 en 1993 pasó a 546 x 100.000 en 2003 2, y en Canadá se encontraron datos similares con un aumento de 4.5 veces, en 1991 de 35.6 casos x 100.000 a 156.3 casos por 100.000 en 2004 3 . Se han descrito varios factores asociados Materiales y Métodos Se trata de un estudio descriptivo de tipo serie de casos en el que se evaluaron pacientes con diagnóstico de infección por C. Difficile y los factores asociados en un Hospital Universitario entre febrero de 2010 hasta septiembre de 2011 Resultados Se recolectaron 31 pacientes la edad promedio fue de 58 años con un rango entre 18 y 93 años, de los cuales 19 (61%) fueron mujeres y 12 (39%) hombres. El factor asociado a la infección por C. Difficile más frecuentemente encontrado fue el uso de inhibidores de bomba de protones con 54.84% (n=17) .No se encontraron pacientes VIH positivos o con diagnóstico de enfermedad inflamatoria intestinal. Ningún paciente presentó complicaciones asociadas a la infección ni mortalidad alguna. Conclusión El factor asociado que más se presentó fue el uso de antimicrobianos en los quince dias previos al inicio del cuadro en el 74% de los pacientes lo que coincide con lo presentado en la literatura mundial.

Preliminary Study of the Gastric Acidity in Thoroughbred Horses at Rest after Enteral Administration of Esomeprazole Magnesium (Nexium)

The regulation of gastric secretion is of crucial importance to the equilibrium of the gastroenteric system. Despite the large number of factors involved in the causes of peptic illnesses, pH = 4 is considered the threshold between physiologic and deleterious effects of stomach acid secretion. With the aim of maintaining pH greater than 4, proton-pump inhibitors, such as esomeprazole magnesium (NEXIUM), have shown excellent results in the control of acid secretion. Aimed at examining the action of this drug in the control of pH levels of gastric secretion in thoroughbreds, a single dose of 40 or 80 mg of esomeprazole magnesium was administered daily, and pH was determined serially for 5 consecutive days. The results obtained corroborated the efficacy of esomeprazole magnesium in the control of gastric pH at both doses tested, with 100% of the mean pH being greater than 5. Moreover, no statistical difference was noted between the two doses tested.

Brazilian consensus on gastroesophageal reflux disease: Proposals for assessment, classification, and management

The Brazilian Consensus on Gastroesophageal Reflux Disease considers gastroesophageal reflux disease to be a chronic disorder related to the retrograde flow of gastroduodenal contents into the esophagus and/or adjacent organs, resulting in a variable spectrum of symptoms, with or without tissue damage. Considering the limitations of classifications currently in use, a new classification is proposed that combines three criteria - clinical, endoscopic, and pH-metric - providing a comprehensive and more complete characterization of the disease. The diagnosis begins with the presence of heartburn, acid regurgitation, and alarm manifestations (dysphagia, odynophagia, weight loss, GI bleeding, nausea and/or vomiting, and family history of cancer). Also, atypical esophageal, pulmonary, otorhinolaryngological, and oral symptoms may occur. Endoscopy is the first approach, particularly in patients over 40 yr of age and in those with alarm symptoms. Other exams are considered in particular cases, such as contrast radiological examination, scyntigraphy, manometry, and prolonged pH measurement. The clinical treatment encompasses behavioral modifications in lifestyle and pharmacological measures. Proton pump inhibitors in manufacturers' recommended doses are indicated, with doubling of the dose in more severe cases of esophagitis. The minimum time of administration is 6 wk. Patients who do not respond to medical treatment, including those with atypical manifestations, should be considered for surgical treatment. Of the complications of gastroesophageal reflux disease, Barrett's esophagus presents a potential development of adenocarcinoma; biopsies should be performed, independent of Barrett's esophagus extent or location. In this regard the designation short Barrett's is not important in terms of management and prognosis. © 2002 by Am. Coll. of Gastroenterology.

Úlcera de cameron como causa incomum de anemia por deficiência de ferro

Cameron ulcers are chronic linear lesions willing on the mucosal folds, the level of diaphragmatic impression, in patients with hiatal hernia. Its clinical relevance is due to the potential risk of gastrointestinal complications, such as acute or chronic bleeding and anemia. Usually, the diagnosis is incidental by upper gastrointestinal endoscopy. Proton pump inhibitors are essential for the conduct of cases and the administration of iron when the anemia is associated. Already, the benefit of surgery is in refractory cases. We present a case of this entity of a 50-year-old patient in postmenopausal who developed anemia due to iron deficiency and normal initial endoscopy.

Avaliação do efeito protetor e cicatrizante do extrato hidroalcóolico de folhas de Solanum paniculatum L. frente á úlceras pépticas

Pós-graduação em Biologia Geral e Aplicada - IBB

Avaliação dos mecanismos de ação envolvidos na atividade antiulcerogênica de Serjania marginata frente á doença ulcerosa péptica experimental

Pós-graduação em Ciências Biológicas (Farmacologia) - IBB

Challenges to the treatment and new perspectives for the eradication of helicobacter pylori

Helicobacter pylori (H. pylori) is one of the leading causes of gastric diseases such as chronic gastritis, peptic ulcer, and gastric adenocarcinoma. The current treatment of H. pylori infection with antibiotics and proton pump inhibitors has several limitations, including poor adherence and intrinsic patient-related factors, drug resistance, and the absence of adequate treatments. This review summarizes the current therapeutic approaches to eradicating H. pylori, the difficulties associated with its treatment, and several new perspectives aimed at improving existing treatment strategies.

Efeitos da administração em longo prazo do omeprazol sobre a densidade mineral óssea e as propriedades mecânicas do osso

Objectives: Epidemiological studies have shown a relationship between long-term use of proton pump inhibitors and bone metabolism. However, this relationship has not yet become established. The aim of the present study was to analyze the mechanical properties and bone mineral density (BMD) of rats that were subjected to long-term omeprazole use. Methods: Fifty wistar rats weighing between 200 and 240 g were divided equally into five groups: OMP300 (omeprazole intake at a dose of 300 moL/kg/day); OMP200 (200 moL/ kg/day); OMP40 (40 moL/kg/day); OMP10 (10 moL/kg/day); and Cont (control group; intake of dilution vehicle). The solutions were administered for 90 consecutive days. After the rats had been sacrificed, their BMD, the mechanical properties of the dissected femurs and their serum Ca++ levels were analyzed. Results: The BMD of the OMP300 group was lower than that of the controls (p = 0.006). There was no difference in comparing the OMP200, OMP40 and OMP10 groups with the controls. The maximum strength and rigidity of the femur did not differ in the experimental groups in comparison with the controls. The OMP300 group had a statistically lower serum Ca++ concentration than that of the controls (p = 0.049), but the other groups did not show any difference in relation to the controls. Conclusion: Daily intake of 300moL/kg/day of omeprazole decreased the BMD of the femur, but without changes to the rigidity and strength of the femur in adult rats. © 2

Association of a probiotic to a Helicobacter pylori eradication regimen does not increase efficacy or decreases the adverse effects of the treatment: a prospective, randomized, double-blind, placebo-controlled study

Abstract Background The treatment for the eradication of Helicobacter pylori (H. pylori) is complex; full effectiveness is rarely achieved and it has many adverse effects. In developing countries, increased resistance to antibiotics and its cost make eradication more difficult. Probiotics can reduce adverse effects and improve the infection treatment efficacy. If the first-line therapy fails a second-line treatment using tetracycline, furazolidone and proton-pump inhibitors has been effective and low cost in Brazil; however it implies in a lot of adverse effects. The aim of this study was to minimize the adverse effects and increase the eradication rate applying the association of a probiotic compound to second-line therapy regimen. Methods Patients with peptic ulcer or functional dyspepsia infected by H. pylori were randomized to treatment with the furazolidone, tetracycline and lansoprazole regimen, twice a day for 7 days. In a double-blind study, patients received placebo or a probiotic compound (Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium bifidum and Streptococcus faecium) in capsules, twice a day for 30 days. A symptom questionnaire was administered in day zero, after completion of antibiotic therapy, after the probiotic use and eight weeks after the end of the treatment. Upper digestive endoscopy, histological assessment, rapid urease test and breath test were performed before and eight weeks after eradication treatment. Results One hundred and seven patients were enrolled: 21 men with active probiotic and 19 with placebo plus 34 women with active probiotic and 33 with placebo comprising a total of 55 patients with active probiotic and 52 with placebo. Fifty-one patients had peptic ulcer and 56 were diagnosed as functional dyspepsia. The per-protocol eradication rate with active probiotic was 89.8% and with placebo, 85.1% (p = 0.49); per intention to treat, 81.8% and 79.6%, respectively (p = 0.53). The rate of adverse effects at 7 days with the active probiotic was 59.3% and 71.2% with placebo (p = 0.20). At 30 days, it was 44.9% and 60.4%, respectively (p = 0.08). Conclusions The use of this probiotic compound compared to placebo in the proposed regimen in Brazilian patients with peptic ulcer or functional dyspepsia showed no significant difference in efficacy or adverse effects. Trial registration Current Controlled Trials ISRCTN04714018