Arjunolic acid reverses fluoxetine-induced alterations in testicular steroidogenic enzymes and membrane bound ionic pump imbalance through suppression of oxido-inflammatory stress and apoptosis.

OBJECTIVE: The impact of the anti-depressant therapy on gonadal function has been recognized and discussed over the years. However, data to supplement our understanding of the impact of arjunolic acid (AA) therapies in protecting against FXT-induced gonadal dysfunction is lacking clear scientific evidence. Hence, this study aimed to investigate the possible effect of AA on fluoxetine-induced altered testicular function in rats. METHODS: After 14 days acclimatization, Thirty-six (36) adult male rats were randomly divided into 6 groups (n=6). Rats in groups 1 received normal saline (10mL/kg); groups 2 & 3 were given AA (1.0mg/kg body weight) and AA (2.0mg/kg body weight), respectively; whereas, rats in group 4 were given FXT (10mg/kg/p.o/day), and groups 5 & 6 were given a combination of FXT (10mg/kg) + AA (1.0mg/kg body weight); and FXT (10mg/kg) + AA (2.0mg/kg body weight), respectively. RESULTS: The results shows that FXT significantly altered testicular steroidogenic enzymes (3ß-HSD and 17ß-HSD) and proton pump ATPase (Na+/K+ ATPase, Ca2+ ATPase and H+ ATPase) activities, as well as testicular architecture when compared with controls. More so, FXT caused oxido-inflammation and apoptosis, as evidence by increases in MDA, MPO, TNF-α, IL-1ß, Caspase 3 and p53. However, AA at a different dose significantly ameliorated the destructive impacts of FXT on steroidogenic enzymes, proton pump ATPase as well as increased Bcl-2, SOD, CAT, GSH and improved testicular architecture in rats. CONCLUSIONS: AA reverses fluoxetine-induced alterations in testicular steroidogenic enzymes and membrane-bound ionic pump through suppression of oxido-inflammatory stress and apoptosis.

Analyzing the use of proton pump inhibitors in elite athletes: understanding the impact on cardiovascular health and performance

Objective: To assess the impact of proton pump inhibitors (PPIs) on cardiovascular health and performance in elite athletes. This study aims to understand the utilization patterns, potential cardiovascular implications, and performance outcomes associated with PPI use in this specific population. Methods: A comprehensive review of PPI use among elite athletes was conducted, including a detailed analysis of medication type, dosage, frequency, and duration. The study involved a retrospective examination of medical and training records of athletes whoused PPIs in 2021. The analysis focused on evaluating the correlation between PPI use and cardiovascular health markers, as well as performance metrics in these athletes. Results: The study found a significant prevalence of PPI use among elite athletes, primarily for managing exercise-induced gastrointestinal symptoms. Key findings include: (1) a notable variation in the type and dosage of PPIs used; (2) a correlation between long-term PPI use and certain cardiovascular health markers; (3) athletes on PPIshad varied performance outcomes, with some showing decreased endurance. Conclusion: The study highlights the need for a more nuanced understanding of PPI use in elite athletes, emphasizing the importance of personalized medical guidance. While PPIs can bebeneficial for managing specific gastrointestinal issues in athletes, their impact on cardiovascular health and athletic s requires careful consideration and monitoring. This research underscores the necessity for developing tailored medication strategiesfor elite athletes to optimize health and performance outcomes (AU)

Targeting ATP12A, a Nongastric Proton Pump α Subunit, for Idiopathic Pulmonary Fibrosis Treatment.

Idiopathic pulmonary fibrosis (IPF) is a pathological condition of unknown etiology that results from injury to the lung and an ensuing fibrotic response that leads to the thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear, and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to cystic fibrosis lung disease. The ATP12A gene encodes the α-subunit of the nongastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in patients with cystic fibrosis. It is hypothesized that the ATP12A protein may play a role in the pathogenesis of IPF. The authors' studies demonstrate that ATP12A protein is overexpressed in distal small airways from the lungs of patients with IPF compared with normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened bleomycin induced experimental pulmonary fibrosis. This was prevented by a potassium competitive proton pump blocker, vonoprazan. These data support the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has potential as a novel therapeutic strategy in IPF treatment.

Consideraciones prácticas en el manejo de los inhibidores de la bomba de protones / Practical considerations in the management of proton-pump inhibitors

Los inhibidores de la bomba de protones (IBP) son uno de los principios activos más prescritos en España. En las últimas décadas se ha observado un sobreuso de estos fármacos tanto a nivel extrahospitalario como hospitalario que ha producido un aumento importante en el gasto sanitario y un incremento en el riesgo de posibles efectos adversos. Es importante que los profesionales sanitarios se ajusten a las indicaciones admitidas y a las dosis correctas para el empleo de estos medicamentos. Existen en el mercado diferentes tipos de IBP: omeprazol, pantoprazol, lansoprazol, rabeprazol y esomeprazol. El omeprazol es el más antiguo y utilizado, siendo también el más barato. Si bien en la mayoría de las indicaciones terapéuticas en las que se emplean estos medicamentos no se describen diferencias entre los distintos IBP en la curación de las enfermedades, el esomeprazol, IBP de última generación, ha demostrado mayor eficacia en la erradicación del H. pylori y en la curación de la esofagitis grave respecto al resto de IBP. En los últimos años el uso de los fármacos genéricos se ha extendido; este tipo de medicamentos presentan la misma biodisponibilidad que los medicamentos originales. En el caso de los IBP, los pocos estudios comparativos disponibles en la literatura entre los fármacos originales y los genéricos no han demostrado diferencias significativas en la eficacia clínica (AU)

Proton-pump inhibitors (PPIs) are one of the most active ingredients prescribed in Spain. In recent decades there has been an overuse of these drugs in both outpatient clinics and hospitals that has lead to a significant increase in healthcare spending and to an increase in the risk of possible side effects. It is important for health professionals to know the accepted indications and the correct doses for the use of these drugs. On the market there are different types of PPI: omeprazole, pantoprazole, lansoprazole, rabeprazole and esomeprazole. Omeprazole is the oldest and most used PPI, being also the cheapest. Although there are no important differences between PPIs in curing diseases, esomeprazole, a new-generation PPI, has proved to be more effective in eradicating H. pylori and in healing severe esophagitis compared to other PPIs. In recent years the use of generic drugs has spread; these drugs have the same bioavailability than the original drugs. In the case of PPIs, the few comparative studies available in the literature between original and generic drugs have shown no significant differences in clinical efficacy (AU)

Mecanismo de acción y farmacocinética de rilpivirina / Mechanism of action and pharmacokinetics of rilpivirine

Rilpivirina es un potente inhibidor no nucleósido de la transcriptasa inversa que ha mostrado gran eficacia en el tratamiento de la infección por el virus de la inmunodeficiencia humana 1 (VIH-1) en pacientes naïve. Rilpivirina es un fármaco activo, tanto frente a cepas salvajes de VIH-1 como frente a una extensa variedad de cepas virales resistentes a los inhibidores no nucleósidos de la transcriptasa inversa de primera generación. Posee un perfil farmacocinético muy favorable, aunque al ser su absorción dependiente del pH gástrico debe ser administrada con comida para asegurar su correcta absorción. Su metabolismo está mediado a través del citocromo P450 (CYP) 3A, por lo que deben considerarse las potenciales interacciones cuando se administre conjuntamente con inductores o inhibidores de esta vía enzimática. Aunque a dosis más altas puede comportarse como inductor enzimático, no es esperable que rilpivirina a la dosis de 25mg al día pueda alterar las concentraciones de otros fármacos metabolizados por esta vía. Su prolongada vida media permite su administración por vía oral 1 vez al día

Rilpivirine is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) with high efficacy in the treatment of HIV infection in treatment-naïve patients. This drug is active against both wild-type HIV-1 and a wide variety of first-generation NNRTI. Rilpivirine has a highly favorable pharmacokinetics profile, but, because its absorption depends on gastric pH, it should be administered with food to ensure correct absorption. Rilpivirine is metabolized by cytochrome P450 (CYP) 3A and consequently potential interactions should be considered when it is administered with P450 (CYP) 3A inducers or inhibitors. Although higher doses can behave as enzyme inducers, at a dose of 25mg/day, rilpivirine is unlikely to alter the concentrations of other drugs metabolized through this pathway. Because of its prolonged half-life, rilpivirine can be administered orally once daily

Microbial light-activatable proton pumps as neuronal inhibitors to functionally dissect neuronal networks in C. elegans.

Essentially any behavior in simple and complex animals depends on neuronal network function. Currently, the best-defined system to study neuronal circuits is the nematode Caenorhabditis elegans, as the connectivity of its 302 neurons is exactly known. Individual neurons can be activated by photostimulation of Channelrhodopsin-2 (ChR2) using blue light, allowing to directly probe the importance of a particular neuron for the respective behavioral output of the network under study. In analogy, other excitable cells can be inhibited by expressing Halorhodopsin from Natronomonas pharaonis (NpHR) and subsequent illumination with yellow light. However, inhibiting C. elegans neurons using NpHR is difficult. Recently, proton pumps from various sources were established as valuable alternative hyperpolarizers. Here we show that archaerhodopsin-3 (Arch) from Halorubrum sodomense and a proton pump from the fungus Leptosphaeria maculans (Mac) can be utilized to effectively inhibit excitable cells in C. elegans. Arch is the most powerful hyperpolarizer when illuminated with yellow or green light while the action spectrum of Mac is more blue-shifted, as analyzed by light-evoked behaviors and electrophysiology. This allows these tools to be combined in various ways with ChR2 to analyze different subsets of neurons within a circuit. We exemplify this by means of the polymodal aversive sensory ASH neurons, and the downstream command interneurons to which ASH neurons signal to trigger a reversal followed by a directional turn. Photostimulating ASH and subsequently inhibiting command interneurons using two-color illumination of different body segments, allows investigating temporal aspects of signaling downstream of ASH.

Estudio del uso de omeprazol en una farmacia comunitaria de la costa de Girona / Study of the Use of Omeprazole in a Community Pharmacy on the Coast of Girona

Antecedentes: En España se vendieron, durante el año 2007,50 millones de fármacos del grupo de los inhibidores de la bomba de protones (IBP), un 26% más que en el año 2006 según los datos de la empresa IMS Health España. Los IBP son fármacos de consumo elevado y en crecimiento progresivo en el Sistema Nacional de Salud. La elevada prevalencia de la dispepsia, su cronicidad y la potencia farmacológica del omeprazol justificarían, en principio, tan elevado consumo. Sin embargo, su utilización en la prevención gastrointestinal es muchas veces inadecuada, tanto por exceso cuando no están indicados, como por defecto en pacientes que deberían tomarlos. Método: Estudio observacional, descriptivo y transversal, realizado durante un periodo de 52 días (de mayo a junio de 2008). Se incluyó a los pacientes mayores de 18 años, que acudieron a la oficina de farmacia solicitando omeprazol, con o sin receta, y que aceptaron participar en el estudio. Los datos se procesaron mediante el programa SPSS V.15. Se estableció la significación estadística a partir de un valor de p <0,05, mediante las pruebas de la t de Student y la chi al cuadrado de Pearson. Resultados: Se incluyó un total de 82 pacientes, situándose la media de edad (± desviación estándar) en 60,8 ± 14,1 años (rango: 25-87), con diferencias significativas por sexos (p=0,048; intervalo de confianza [IC] del 95%: -12,24 a -0,04). El nivel cultural fue alto. La patología más prevalerte resultó ser la dispepsia funcional en un 36% de las solicitudes, la hernia de hiato en el 20,7% y la úlcera gastroduodenal en el 4,9% de la muestra. La demanda de omeprazol por tratamiento representó el 8% de las solicitudes, por prevención el 26% y por mantenimiento el 57%. Un 28% de la muestra no cumplía con los criterios de uso del omeprazol y un 8,5% se automedicaba. El 70,7% de los usuarios de omeprazol lo utilizaba de forma continua, y la duración media del tratamiento era de 4,65 ± 4,4 años (rango: 1-15). En el momento de la adquisición, el 86,6% de los pacientes no presentaba ningún síntoma, y el 91,5% de la muestra creía que el medicamento controlaba su problema de salud (AU)

Background: throughout the year 2007 in Spain, 50 million medicines of the group of proton pump inhibitors were sold, which according to data from the IMS1 is 26% more than in the year 2006. The consumption of these proton pump inhibitors (PPIs)in the Spanish National Health System is high, and is growing steadily. In principle, the high prevalence of dyspepsia, its chronic nature and the pharmacological potency of Omeprazole justify the above mentioned high consumption. However, in many cases its use for gastrointestinal prevention is inappropriate, due both toan excess in cases in which they are not recommended, as well as a lack in patients who should be taking them. Method: cross-sectional, descriptive, observational study, conducted over a period of 52 days (May-June 2008). The study included patients over the age of 18 years who went to the community pharmacy and requested Omeprazole with or without a prescription, and who agreed to participate in the study. The data was processed using SPSS V.15, establishing statistical significance at p<0.05, using Student's t and Pearson's chi-squaretests. Results: a total of 82 patients were included, with an average age of 60.8 years (SD: 14-1) (range of 25 to 87 years), with significant differences by gender (p= 0.048; CI: -12.24 to -0.04). The cultural level was high. The most prevalent pathology turned out to be Functional Dyspepsia, accounting for 36% of the requests; hiatal hernias accounted for 20.7% and gastroduodenal ulcers for 4.9% of the sample. The requests for Omeprazole as a treatment accounted for 8% of the requests, as preventionfor 26% and as maintenance for 57%. Of the total sample, 28% did not meet the criteria for use of Omeprazole3 and 8.5% was self-medicating. Of the Omeprazole users, 70.7% used it in a continuous manner, with an average treatment duration of 4.65 years (SD: 4.4) (range of 1 to 15 years). In 86.6% of the cases the patients did not show any symptoms at the time of acquisition, and 91.5% of the sample believed that the drug controlled their health problem (AU)

Treatment of gastroesophageal reflux disease.

OBJECTIVES: To review the literature on the treatment of gastroesophageal reflux disease (GERD) with emphasis on pharmacological aspects. To identify particularities of pharmacological treatment of esophageal and extraesophageal manifestations of the disease. SOURCES: Electronic search of the PubMed/MEDLINE and Cochrane Collaboration databases. Controlled and randomized studies published since 2000 and reviews representing consensus positions and directives published within the last 10 years were identified. SUMMARY OF THE FINDINGS: The drugs currently available for the treatment of GERD do not act in the primary mechanism of the disease, i.e. transitory relaxation of the lower esophageal sphincter. Pharmacological treatment of GERD with symptoms or with esophageal injury is based on the suppression of acid secretion, particularly with proton pump inhibitors. When the hyperreactivity of the lower airways coexists with esophageal GERD symptoms, suppression of acid secretions should be of benefit in managing the respiratory disease in the presence of a causal relationship; however, this is not usual. When esophageal symptoms are not present, esophageal 24-hour pH study should be carried out prior to starting pharmacological treatment for GERD. Improvement of respiratory symptoms may be delayed with relation to esophageal symptoms. It is common for GERD to recur and pharmacological treatment should be repeated or continued indefinitely, depending on clinical presentation of the disease. CONCLUSIONS: The strategies that have been proposed for the pharmacological treatment of GERD in children are primarily based on studies of case series or on studies with adults. There have been very few controlled and randomized studies in children. Undertaking a greater number of these studies might reinforce existing aspects or establish new aspects of management.

Treatment of gastroesophageal reflux disease

OBJETIVO: Rever a literatura sobre tratamento da doença do refluxo gastroesofágico (DRGE) com ênfase nos aspectos farmacológicos. Identificar particularidades do tratamento farmacológico nas manifestações esofágicas e extra-esofágicas da doença. FONTES DE DADOS: Busca eletrônica na base de dados PubMed/MEDLINE e Cochrane Collaboration. Procurou-se identificar estudos controlados e randomizados publicados a partir de 2000, bem como revisões que representassem consensos e diretrizes publicados nos últimos 10 anos. SíNTESE DOS DADOS: Nenhuma das drogas atualmente usadas no tratamento da DRGE altera comprovadamente o mecanismo principal da doença, ou seja, os relaxamentos transitórios do esfíncter esofágico inferior. O tratamento farmacológico da DRGE com sintomas ou com lesões esofágicas é baseado na inibição da secreção ácida, em particular pelos inibidores da bomba de prótons (IBP). Nas situações em que a hiper-reatividade das vias aéreas inferiores coexiste com sintomas esofágicos da DRGE, a inibição da secreção ácida deve trazer benefícios na condução da doença respiratória se houver uma relação causal; contudo, essa situação não é comum. Quando não coexistem sintomas esofágicos, a pHmetria esofágica de 24 h deve ser realizada previamente ao tratamento farmacológico da DRGE. A melhora dos sintomas respiratórios pode ser tardia em relação aos sintomas esofágicos. A DRGE freqüentemente recorre, e o tratamento farmacológico deve ser repetido ou mantido indefinidamente, conforme a apresentação clínica da doença. CONCLUSÃO: As condutas propostas para o tratamento farmacológico da DRGE na criança são oriundas principalmente de estudos de séries de casos ou de estudos em adultos. Existem poucos estudos controlados e randomizados em crianças. A realização de um número maior desses estudos poderá reafirmar ou introduzir novos aspectos nas condutas propostas.

OBJECTIVE: To review the literature on the treatment of gastroesophageal reflux disease (GERD) with emphasis on pharmacological aspects. To identify particularities of pharmacological treatment of esophageal and extraesophageal manifestations of the disease. SOURCES: Electronic search of the PubMed/MEDLINE and Cochrane Collaboration databases. Controlled and randomized studies published since 2000 and reviews representing consensus positions and directives published within the last 10 years were identified. SUMMARY OF THE FINDINGS: The drugs currently available for the treatment of GERD do not act in the primary mechanism of the disease, i.e., transitory relaxation of the lower esophageal sphincter. Pharmacological treatment of GERD with symptoms or with esophageal injury is based on the suppression of acid secretion, particularly with proton pump inhibitors. When the hyperreactivity of the lower airways coexists with esophageal GERD symptoms, suppression of acid secretions should be of benefit in managing the respiratory disease in the presence of a causal relationship; however, this is not usual. When esophageal symptoms are not present, esophageal 24-hour pH study should be carried out prior to starting pharmacological treatment for GERD. Improvement of respiratory symptoms may be delayed with relation to esophageal symptoms. It is common for GERD to recur and pharmacological treatment should be repeated or continued indefinitely, depending on clinical presentation of the disease. CONCLUSIONS: The strategies that have been proposed for the pharmacological treatment of GERD in children are primarily based on studies of case series or on studies with adults. There have been very few controlled and randomized studies in children. Undertaking a greater number of these studies might reinforce existing aspects or establish new aspects of management.

Comparative study of salivary pH and volume in adults with chronic laryngopharyngitis by gastroesophageal reflux disease before and after treatment.

INTRODUCTION: Gastroesophageal Reflux Disease (GERD) is the most prevalent digestive disease of the modern society and has been associated with abnormalities in the larynx and pharynx (LPR). Nonetheless, little is known about the mechanisms involved in this atypical form of the disease. Contradictory clinical data suggest a defense deficit at this segment. Saliva with its organic and inorganic components is responsible for the homeostasis of the oral mucosa and the digestive tract. Salivary pH and volume abnormalities have been linked to laryngopharyngeal symptoms of GERD and LPR. In a recent study we demonstrated significant salivary pH reduction in patients with LPR. Another study found correlation between reduced salivary pH and volume directly related to esophageal pH-metry results. AIM: To evaluate salivary pH and volume before and after clinical treatment of LPR. MATERIAL AND METHOD: Twenty-three adults with LPR had total fasting saliva tested before and after a 12-week course of oral proton pump inhibitor. RESULTS: A statistically significant difference was found in salivary pH before and after treatment with increase of pH values after control of the disease (p<0.001). Salivary volumes of treated patients were also significantly higher than in pre-treated patients (p=0.009). DISCUSSION: These findings suggest that salivary pH and volume are influenced by the presence of gastroesophageal contents and that salivary pH monitoring can potentially become a cost-effective method for diagnosing and controlling LPR.

Bile acids and Barrett's oesophagus: a sine qua non or coincidence?

BACKGROUND: Barrett's oesophagus (BO), a premalignant condition associated with the development of oesophageal adenocarcinoma (OAC), is thought to be a consequence of chronic duodeno-gastro-oesophageal reflux. Of the refluxates, bile acids, either alone or in combination with acid, are probably the most important. METHODS: Analysis of the literature on the role played by bile acids in inducing BO and/or progression to OAC. RESULTS: Combined pH and Bilitec 2000 (as a measure of bile reflux) monitoring and oesophageal aspiration studies in humans suggest a combined role for bile acids, particularly taurine conjugated bile acids, in causing oesophageal mucosal injury. Evidence from animal models has demonstrated that duodenal juice alone is also able to induce BO and/or OAC. Likewise, ex vivo studies with biopsies from BO patients show that increased proliferation and cyclo-oxygenase-2 expression are present after a pulsed exposure to acid or conjugated bile acids, but not if acid and bile acids are combined. Proton-pump inhibitors (PPIs) have been shown to decrease the biliary component of the refluxate. There is some evidence that PPIs are able to reduce neoplastic progression in BO. On the other hand, chronic PPIs can also stimulate bacterial overgrowth, which can result in increased production of secondary bile acids, particularly deoxycholic acid, in the stomach. Deoxycholic acid has been demonstrated to have a tumour-promoting capacity. CONCLUSIONS: It is unknown what factors of the refluxate (acid and/or bile) induce BO and/or promote carcinogenesis, but there is evidence that secondary bile acids play a role. A better understanding of the molecular steps involved in the induction of BO, and the role of bile acids herein, may identify targets at which preventive therapies can be directed.

Estudo comparativo do pH e do volume salivar em indivíduos com laringofaringite crônica por doença do refluxo gastroesofágica antes e após o tratamento / Comparative study of salivary pH and volume in adults with chronic laryngopharyngitis by gastroesophageal reflux disease before and after treatment

INTRODUÇÃO: A Doença do Refluxo Gastroesofágico (DRGE) é a doença digestiva mais prevalente da atualidade e, recentemente, tem sido implicada em uma gama de alterações do seguimento laringofaríngeo (RLF). No entanto, pouco se sabe dos mecanismos fisiopatológicos destas manifestações supraesofágicas da DRGE. Os achados clínicos contraditórios e recentes pesquisas sugerem haver deficiências na capacidade de defesa deste seguimento. Uma das principais responsáveis pela homeostase da mucosa oral e do trato digestivo é a saliva com seu conteúdo orgânico e inorgânico. Tanto alterações do pH quanto do volume salivar já foram correlacionados com os sintomas e sinais sugestivos da DRGE e RLF. Estudo recente de nossa autoria demonstra diminuição estatisticamente significante do pH salivar de indivíduos com RLF quando comparado a controles sem a doença. Outro estudo constatou correlação entre a redução do volume X pH da saliva em indivíduos com DRGE, estando esta redução diretamente relacionada aos níveis de pH esofágico constatados durante pH-metria esofágica de 24 horas. OBJETIVOS: Avaliar como se comportam o pH e volume da saliva em um mesmo indivíduo com DRGE e RLF antes e após o tratamento clínico. MATERIAL E MÉTODO: Vinte e três pacientes com RLF tiveram o pH e volume da saliva total testados antes e após receberem tratamento com droga bloqueadora de bomba de prótons durante 12 semanas. RESULTADOS: Houve uma diferença estatisticamente significante (p<0,001) entre o pH da saliva antes e após o tratamento, estando este maior após o controle clínico da doença. O volume de saliva no paciente tratado foi significativamente maior do que no paciente pré-tratamento (p=0.009). DISCUSSÃO: Os achados sugerem que o pH salivar é influenciado pela presença de refluxo gastroduodenal à região laringofaríngea. Caso estudos futuros com populações maiores realmente comprovem esta correlação, poderemos cogitar a possibilidade de usar a mensuração do pH salivar, que é feita de forma rápida e não invasiva, como um meio de diagnosticar e avaliar o comportamento e controle do Refluxo Laringofaríngeo.

INTRODUCTION: Gastroesophageal Reflux Disease (GERD) is the most prevalent digestive disease of the modern society and has been associated with abnormalities in the larynx and pharynx (LPR). Nonetheless, little is known about the mechanisms involved in this atypical form of the disease. Contradictory clinical data suggest a defense deficit at this segment. Saliva with its organic and inorganic components is responsible for the homeostasis of the oral mucosa and the digestive tract. Salivary pH and volume abnormalities have been linked to laryngopharyngeal symptoms of GERD and LPR. In a recent study we demonstrated significant salivary pH reduction in patients with LPR. Another study found correlation between reduced salivary pH and volume directly related to esophageal pH-metry results. AIM: To evaluate salivary pH and volume before and after clinical treatment of LPR. MATERIAL AND METHOD: Twenty-three adults with LPR had total fasting saliva tested before and after a 12-week course of oral proton pump inhibitor. RESULTS: A statistically significant difference was found in salivary pH before and after treatment with increase of pH values after control of the disease (p<0.001). Salivary volumes of treated patients were also significantly higher than in pre-treated patients (p=0.009). DISCUSSION: These findings suggest that salivary pH and volume are influenced by the presence of gastroesophageal contents and that salivary pH monitoring can potentially become a cost-effective method for diagnosing and controlling LPR.

Immune suppressor factor confers stromal cell line with enhanced supporting activity for hematopoietic stem cells.

Immune suppressor factor (ISF) is a subunit of the vacuolar ATPase proton pump. We earlier identified a short form of ISF (ShIF) as a stroma-derived factor that supports cytokine-independent growth of mutant Ba/F3 cells. Here, we report that ISF/ShIF supports self-renewal and expansion of primary hematopoietic stem cells (HSCs). Co-culture of murine bone marrow cells with a stromal cell line overexpressing ISF or ShIF (MS10/ISF or MS10/ShIF) not only enhanced their colony-forming activity and the numbers of long-term culture initiating cells, but also maintained the competitive repopulating activity of HSC. This stem cell supporting activity depended on the proton-transfer function of ISF/ShIF. Gene expression analysis of ISF/ShIF-transfected cell lines revealed down-regulation of secreted frizzled-related protein-1 and tissue inhibitor of metalloproteinase-3, and the restoration of their expressions in MS10/ISF cells partially reversed its enhanced LTC-IC supporting activity to a normal level. These results suggest that ISF/ShIF confers stromal cells with enhanced supporting activities for HSCs by modulating Wnt-activity and the extracellular matrix.

Acute interstitial nephritis due to pantoprazole.

OBJECTIVE: To describe what is believed, as of November 4, 2003, to be the first case published in the literature of acute interstitial nephritis (AIN) due to pantoprazole. CASE SUMMARY: A 77-year-old white woman presented to the hospital with elevated serum creatinine, oliguria for the past 24 hours, arthralgia, fatigue, fever, and bilateral flank pain. The patient had initiated treatment with oral pantoprazole 40 mg/d for gastroesophageal reflux 2 months prior to admission. After 5 weeks of therapy, she stopped taking pantoprazole due to general malaise. Upon admission, all home medications, including pantoprazole, were reinitiated based on the patient's medication list. Serum creatinine increased to 6.1 mg/dL on day 4 of admission from a baseline of 1.0 mg/dL. Pantoprazole therapy was promptly discontinued, and prednisone 40 mg/d was initiated. Urinalysis revealed eosinophils, and a subsequent renal biopsy confirmed a diagnosis of AIN. The serum creatinine level gradually declined over 2 weeks, and the patient was discharged home with a serum creatinine level of 1.6 mg/dL. The Naranjo probability scale suggests a highly probable relationship between AIN and pantoprazole therapy in this patient. DISCUSSION: Drug hypersensitivity reactions are the most common cause of AIN. There have been several reported cases of omeprazole-induced AIN. Although there are very few prospective data on the efficacy of treatment of drug-induced AIN, corticosteroids may have a role in recovery of renal function. Prednisone doses of 1 mg/kg/d have been suggested. CONCLUSIONS: Physicians should be aware that drug-induced AIN can be associated with proton-pump inhibitors. Early detection of this rare adverse reaction may prevent acute renal insufficiency.

Patterns of proton pump inhibitor use in clinical practice.

BACKGROUND: Little is known about differences between gastroenterologists and primary care physicians in their patterns of prescribing proton pump inhibitors. SUBJECTS AND METHODS: A survey of practicing primary care physicians from the American Board of Medical Specialties and practicing gastroenterologists from the American Gastroenterological Association was conducted by facsimile. The survey instrument consisted of 13 questions about pharmacokinetics and administration of proton pump inhibitors. RESULTS: The overall response rate was 15% (491 of 3273), and 80% (395 of 491) of respondents were nontrainee gastroenterologists or primary care physicians. Approximately 90% (n = 355) of eligible respondents correctly identified proton pump inhibitors as inhibitors of H+,K+-adenosinetriphosphatase. Proton pump inhibitors were prescribed by 80% (n = 314) of each group for reflux esophagitis. They were prescribed by 67% (122 of 182) of gastroenterologists and 27% (58 of 213) of primary care physicians to prevent ulcers induced by nonsteroidal anti-inflammatory drugs (P <0.001). And they were prescribed by 40% (n = 73) of gastroenterologists and 16% (n = 34) of primary care physicians for uncomplicated heartburn (P <0.001). Proton pump inhibitors were prescribed before a meal by 95% (n = 173) of gastroenterologists and 33% (n = 70) of primary care physicians (P <0.001). Nearly 99% (n = 391) of respondents agreed that proton pump inhibitors were safe, but only 15% (n = 59) thought they should be available without prescription. CONCLUSION: Our survey suggests that the use of proton pump inhibitors differs between gastroenterologists and primary care physicians. Furthermore, although most physicians believe that proton pump inhibitors are safe, few believe that they should be available without a prescription.

Pharmacological and pharmacodynamic essentials of H(2)-receptor antagonists and proton pump inhibitors for the practising physician.

The suppression of gastric acid secretion with anti-secretory agents has been the mainstay of medical treatment for patients with acid-related disorders. Although the majority of Helicobacter pylori -related peptic ulcers can be healed with antibiotics, ulcer healing and symptom control can be significantly improved when antibiotics are given with anti-secretory agents, especially with a proton pump inhibitor. There is a dynamic relationship between the suppression of intragastric acidity and the healing of peptic ulcer and erosive oesophagitis and control of acid-related symptoms. The suppression of gastric acid secretion achieved with H(2)-receptor antagonists has, however, proved to be suboptimal for effectively controlling acid-related disorders, especially for healing erosive oesophagitis and for the relief of reflux symptoms. H(2)-receptor antagonists are also not effective in inhibiting meal-stimulated acid secretion, which is required for managing patients with erosive oesophagitis. Furthermore, the rapid development of tolerance to H(2)-receptor antagonists and the rebound acid hypersecretion after the withdrawal of an H(2)-receptor antagonist further limit their clinical use. Although low-dose H(2)-receptor antagonists are currently available as over-the-counter medications for self-controlling acid-related symptoms, their pharmacology and pharmacodynamics have not been well studied, especially in the self-medicating population. Proton pump inhibitors have been proved to be very effective for suppressing intragastric acidity to all known stimuli, although variations exist in the rapidity of onset of action and the potency of acid inhibition after oral administration at the approved therapeutic doses, which may have important clinical implications for the treatment of gastro-oesophageal reflux disease and perhaps for eradicating H. pylori infection when a proton pump inhibitor is given with antibiotics. Once-daily dosing in the morning is more effective than dosing in the evening for all proton pump inhibitors with respect to the suppression of intragastric acidity and daytime gastric acid secretion in particular, which may result from a better bio-availability being achieved with the morning dose. When higher doses are needed, these drugs must be given twice daily to achieve the optimal suppression of 24 hour intragastric acidity. Preliminary results have shown that esomeprazole, the optical isomer of omeprazole, given at 40 mg, is significantly more effective than omeprazole 40 mg, lansoprazole 30 mg or pantoprazole 40 mg for suppressing gastric acid secretion. However, more studies in different patient populations are needed to compare esomeprazole with the existing proton pump inhibitors with regard to their efficacy, cost-effectiveness and long-term safety for the management of acid-related disorders.

Review article: the clinical influence of Helicobacter pylori in effective acid suppression-implications for the treatment of gastro-oesophageal reflux disease.

The relationship between gastro-oesophageal reflux disease (GERD) and Helicobacter pylori is unclear. Recent data indicate that H. pylori probably exerts a protective effect against GERD. In recent years, the interaction between H. pylori, proton pump inhibitors and GERD has been widely studied. Currently available proton pump inhibitors produce significantly higher intragastric pH in H. pylori-positive patients than in those who are H. pylori negative, and this phenomenon may be clinically relevant. The mechanisms responsible for this difference in efficacy are not fully understood, although there are two major theories. Ammonia, produced by H. pylori, is able to neutralize gastric acid, and thus apparently increase the effect of acid suppressive agents (the 'ammonia theory'). The other theory is that decrease in acid output is due to the development of corpus gastritis during treatment with a proton pump inhibitor (the 'gastritis theory'). Treatment strategies to overcome this lowered sensitivity to acid suppression are to increase the frequency/dose of a proton pump inhibitor or to add an H2-receptor antagonist in the evening-but both have pharmaco-economic implications. An agent that could provide adequate pH control regardless of H. pylori status would be highly beneficial in the treatment of GERD, and may also lower treatment costs.

Effect of proton pump inhibitor alone or in combination with clarithromycin on mycobacterial growth in human alveolar macrophages.

The effect of omeprazole, a clinically used proton pump inhibitor, alone or in combination with clarithromycin was evaluated against Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium tuberculosis, using a human alveolar macrophage model of infection. Omeprazole exhibited no significant effect on the growth of the two M. avium complex strains or on the mycobactericidal activity of clarithromycin against them. In contrast, omeprazole significantly promoted the growth of Mycobacterium tuberculosis and the anti-mycobacterial activity of clarithromycin against it in human alveolar macrophages. It was speculated that intracellular acidic milieu around M. tuberculosis might be one reason for the lower activity of clarithromycin in the treatment of human tuberculosis.