Acid Pump Inhibitor Research Articles

Autoimmune hepatitis – an increasingly common cause of hypertransaminasaemia among children. Case report and literature review

Autoimmune hepatitis is a chronic inflammatory process of unknown ethology, characterised by high levels of transaminases and IgG antibodies, the presence of tissue autoantibodies, and a typical histological picture. In the population of children, the paediatric form of autoimmune hepatitis and autoimmune sclerosing cholangitis are collectively classified as juvenile autoimmune liver disease. The condition often coexists with other autoimmune disorders. This paper aims to present the clinical profile of a paediatric patient with full-blown autoimmune hepatitis and describe the available therapies. The patient, a 13-year-old boy, was referred to a specialised hospital because of increasing hypertransaminasaemia. The patient was hospitalised for the first time at a district hospital for abdominal pain, and during his stay, elevated transaminases were found with a tendency to increase in follow-up tests. The picture suggested an inflammatory process of the liver and biliary tract. Upper gastrointestinal endoscopy revealed lesions consistent with chronic gastritis and portal gastropathy. Treatment included thiazolidinedioic acid, vitamin K, ursodeoxycholic acid, rifaximin, ciprofloxacin, and proton pump inhibitors. Therapy is aimed at maintaining immunosuppression and inhibiting the inflammatory response that leads to cirrhosis, and most commonly uses steroids alongside proton pump inhibitors for added protection or, alternatively, mycophenolate mofetil, cyclosporine A, tacrolimus, and biologic therapy. Ursodeoxycholic acid also exhibits immunomodulatory properties and makes it possible to reduce steroid doses and thus decrease the likelihood of adverse effects of therapy.

Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Exploratory analysis of the SPARTAN trial

BackgroundWe performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Patients and methodsSPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant. ResultsWe did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15–0.28) versus without concomitant statins (aHR: 0.31 [0.24–0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS. ConclusionsIn this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS.

Modeled Hepatic/Plasma Exposures of Omeprazole Prescribed Alone in Cytochrome P450 2C19 Poor Metabolizers Are Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database.

Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available. The maximum plasma concentration of omeprazole was pharmacokinetically modeled after a single oral 40-mg dose in P450 2C19-defective poor metabolizers and was 2.4-fold higher than that in extensive metabolizers. The modeled area under the hepatic concentration curves of omeprazole in P450 2C19 poor metabolizers after virtual daily 40-mg doses for 7 d was 5.2-fold higher than that in the extensive metabolizers. Omeprazole-induced P450 2C19 (approx. 2-fold), resulting in increased hepatic intrinsic clearance in repeated doses, was considered after the second day. Virtual plasma/hepatic exposure estimated using pharmacokinetic modeling in subjects with P450 2C19 poor metabolizers indicated that these exposure levels virtually estimated could be one of causal factors for unexpected hepatic disorders induced by prescribed omeprazole, such as those resulting from drug interactions with repeatedly co-administered medicines.

Infections associated with clozapine: a pharmacovigilance study using VigiBase®.

Introduction: Clozapine is primarily reserved for treatment-resistant schizophrenia due to safety concerns associated with its use. Infections have been reported with clozapine, which may lead to elevated serum levels of the drug. However, the existing literature on this topic is limited. Therefore, we conducted a study using VigiBase® to investigate the potential over-reporting of infections associated with clozapine, to explore the presence of dose-dependency, and to investigate the underlying mechanism. Methods: Disproportionality analyses were performed using VigiBase to assess the association between clozapine and all types of infections, the association between clozapine-associated infections and neutropenia, the association between clozapine-associated infections and agranulocytosis, the dose-effect relationship between clozapine and infections, and the interaction between clozapine and the main strong CYP450 inhibitors using reports carried out until 11 April 2023. Results: A statistically significant signal of infections was observed with clozapine, as indicated by an information component of 0.43 [95% CI: (0.41-0.45)]. The most commonly reported infections were respiratory and gastrointestinal in nature. Neutropenia showed weaker association with clozapine-associated reports of infections compared to other clozapine-associated reports [X2 (1, N = 204,073) = 454; p < 0.005], while agranulocytosis demonstrated a stronger association with clozapine-associated reports of infections [X2 (1, N = 204,073) = 56; p < 0.005]. No evidence of dose-dependency was observed. Among the 17 tested CYP inhibitors, significant drug-drug interactions were found with clarithromycin, metronidazole, valproic acid, lansoprazole, omeprazole, amiodarone, and esomeprazole. Discussion: Our study revealed a significant safety signal between clozapine use and infections, predominantly respiratory and gastrointestinal infections. The co-administration of clozapine with valproic acid or proton pump inhibitors may potentially contribute to an increased risk of infection. Further vigilance is warranted in clinical practice, and consideration of therapeutic drug monitoring of clozapine in cases involving concomitant use of these drugs or in the presence of infections may be beneficial.

Drug-Drug Interactions Between Mycophenolic Acid and Proton Pump Inhibitors: A Systematic Review and Meta-Analysis.

The objective of the present study was to determine the impact of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA). PubMed, Embase, Web of Sciences, and Scopus were systematically searched to identify relevant studies reporting pharmacokinetic parameters [including trough concentration (C0), maximum concentration (Cmax), time to maximum concentration (Tmax), the dose-adjusted area under the concentration-time curve from time 0-12 hours (AUC0-12 h/D), and half-life (t1/2)], and pharmacodynamic outcomes of MPA (eg, acute graft rejection and adverse drug reactions), with and without PPI administration. Pooled effect estimates were calculated using a random-effects model. Twelve studies involving 473 participants were eligible for inclusion, 11 of which were included in the meta-analysis. PPI exposure was significantly associated with lower C0 [mean difference (MD) = -0.62 mg/L; P = 0.003] lower Cmax (MD = -4.71 mg/L; P = 0.01), and longer Tmax (MD = 0.30 hours; P = 0.0001) of MPA. However, no significant association was observed between PPI exposure and AUC0-12 h/D, t1/2, or any pharmacodynamic outcomes. Based on subgroup analysis, it can be suggested that a significant association between PPI exposure and altered MPA pharmacokinetics was mainly associated with mycophenolate mofetil but not enteric-coated mycophenolate sodium. Coadministration of PPIs and mycophenolate mofetil significantly altered the pharmacokinetics of MPA, particularly by decreasing MPA absorption. However, PPI-MPA interactions did not impact pharmacodynamic outcomes of MPA.

Impact of Concomitant Cardiovascular Medication on Survival of Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib or Pazopanib in the First Line.

Patients with metastatic renal cell carcinoma (mRCC) are often elderly and have various comorbidities, including cardiovascular diseases. Although these patients have extensive co-exposure to targeted therapy and cardiovascular drugs, the impact of this co-exposure on outcomes for patients with mRCC remains unclear. Our objective was to evaluate the association between the use of cardiovascular medication and survival of patients with mRCC. The study included 343 consecutive patients with mRCC treated with sunitinib or pazopanib in the first line. Clinical data obtained from the Renal Cell Carcinoma Information System (RENIS) clinical registry and hospital information systems were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were compared according to the use of common medications, including antihypertensives (i.e., β-blockers [BBs], angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics), acetylsalicylic acid (aspirin), statins, and proton pump inhibitors. The univariate Cox analysis evaluating the impact of the assessed comedications on patient survival revealed that only BBs were significantly associated with PFS (hazard ratio [HR] 0.533, p < 0.001) and OS (HR 0.641, p = 0.006). The median PFS and OS for users of BBs was 18.39 and 37.60 months versus 8.16 and 20.4 months for patients not using BBs (p < 0.001 and p < 0.001, respectively). The Cox multivariate analysis showed that the use of BBs was a significant factor for both PFS (HR 0.428, p = 0.001) and OS (HR 0.518, p = 0.001). The results of this retrospective study suggest that the use of BBs is associated with favorable outcomes for patients with mRCC treated with sunitinib or pazopanib in the first line.

Efficient incorporation and protection of lansoprazole in cyclodextrin metal-organic frameworks.

Lansoprazole (LPZ) is an acid pump inhibitor, which readily degrades upon acidic or basic conditions and under heating. We investigated here LPZ stability upon incorporation in particles made of cyclodextrin metal-organic frameworks (CD-MOFs). LPZ loaded CD-MOFs were successfully synthesized, reaching high LPZ payloads of 23.2±2.1wt%, which correspond to a molar ratio of 1:1 between LPZ and γ-CD. The homogeneity of LPZ loaded CD-MOFs in terms of component distribution was confirmed by elemental mapping by STEM-EDX. Both CTAB, the surfactant used in the CD-MOFs synthesis, and LPZ compete for their inclusion in the CD cavities. CTAB allowed obtaining regular cubic particles of around 5µm with 15wt% residual CTAB amounts. When LPZ was incorporated, the residual CTAB amount was less than 0.1wt%, suggesting a higher affinity of LPZ for the CDs than CTAB. These findings were confirmed by molecular simulations. Vibrational circular dichroism studies confirmed the LPZ incorporation inside the CDs. Solid-state NMR showed that LPZ was located in the CDs and that it remained intact even after three years storage. Remarkably, the CD-MOFs matrix protected the drug upon thermal decomposition. This study highlights the interest of CD-MOFs for the incorporation and protection of LPZ.

Inadequação da ingestão alimentar em idosos: interação fármaco-nutriente

Aims: to evaluate the inadequacy of food consumption and the estimated nutrient depletion caused by the use of drugs in the elderly.Methods: a cross-sectional population study, attended by 427 elderly. Food consumption was obtained from the 24-hour Food Recall Survey and the Research Dietetic History. The use of drugs was assessed by a pharmacotherapeutic questionnaire.Results: 85.8% of elderly use medications, the most prevalent inhibitors angiotensin converting enzyme inhibitor (29.2%), acetylsalicylic acid (28.7%), hydrochlorothiazide (24.4%), hydroxymethyl-glutaryl coenzyme A reductase enzyme inhibitor (17.0%), calcium carbonate (12.6%) and proton pump inhibitors (8.2%). Acetylsalicylic acid, hydrochlorothiazide and proton pump inhibitors are the drugs that possibly deplete the greatest number of nutrients. Users of hydroxymethyl-glutaryl coenzyme A reductase enzyme inhibitor, 97% could had inadequate for vitamin E; of potassium-sparing diuretics, 90.0% of inadequacy for magnesium; digoxin, 83.3% of inadequate for magnesium and 58.3% for calcium and potassium.Conclusions: the drugs most commonly used by elderly are responsible for the depletion of numerous micronutrients, often associated with a high prevalence of inadequate consumption, which may cause possible nutritional deficiencies.

Formulation Development and Evaluation of Lansoprazole Mucoadhesive Microsphere

Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but rather suppress gastric acid secretion by specific inhibition of the (H+,K+)-ATPase enzyme system at the secretary surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The aim of the present study was to develop lansoprazole loaded thiolated chitosan microspheres were prepared by emulsifying method using liquid paraffin light and heavy in ratio of 50:50 as a dispersing medium and glutaraldehyde used as a cross-linking agent. The prepared microspheres were evaluated for mean particle size and particle size distribution, drug content, mucoadhesion measurement and in-vitro drug release. FT-IR spectroscopic analysis was performed to ascertain drug polymer interaction. The release profiles showed first order release behavior up to 12 hours where the highest drug release was 88.89 % of the lansoprazole loaded in the thiolated chitosan microspheres, indicating a strong crosslinking between chitosan and glutaraldehyde. From the results of the present investigation it may be concluded that drug loaded chitosan microspheres can be prepared by a simple technique which avoids the use of complex apparatus and special precautions. Keywords: Lansoprazole, Thiolated chitosan, Microspheres, Glutaraldehyde, Mucoadhesion measurement

686 - Risk of Both upper and Lower Gastrointestinal Bleeding Associated with Low-Dose Acetylsalicylic Acid and Proton Pump Inhibitors Among Nearly 400,000 Individuals in Routine General Practice in the United Kingdom

686 - Risk of Both upper and Lower Gastrointestinal Bleeding Associated with Low-Dose Acetylsalicylic Acid and Proton Pump Inhibitors Among Nearly 400,000 Individuals in Routine General Practice in the United Kingdom

Patterns of Antiplatelet Therapy in Patients Who Have Experienced an Acute Coronary Event: A Descriptive Study in UK Primary Care.

Antiplatelet (AP) therapy is well established for the secondary prevention of acute coronary events. However, patients may discontinue treatment, often owing to gastrointestinal (GI) complications, leaving them at elevated risk of recurrent cardiovascular events. This descriptive retrospective study assessed trends in prescription of AP agents and coprescription of gastroprotective therapy, after an acute coronary event. Discontinuation of AP therapy within 2 years of an event and factors predicting discontinuation were investigated. The study was conducted in a UK primary care setting from 2000 to 2008; a total of 27, 351 patients aged 50 to 84 years were included in the analysis. Main outcome measures were exposures to low-dose acetylsalicylic acid (ASA), clopidogrel, and proton pump inhibitors (PPIs). At 90 days after an acute coronary event, 85.9% of patients had been prescribed some form of AP therapy and 33.6% of patients who were issued at least 1 ASA prescription in this period were also issued a PPI prescription. The use of dual antiplatelet therapy (DAT) 90 days after an event increased from 2% in 2000 to over 50% in 2008. An estimated 15.1% of patients on ASA monotherapy and 37.5% on DAT discontinued treatment within 1 year. A bleeding event during follow-up, including upper GI bleeding or hemorrhagic stroke, was the strongest predictor of discontinuation. Although most patients were prescribed AP therapy in the 90 days following an acute coronary event, a substantial proportion discontinued DAT or ASA monotherapy within 1 year. It is essential that physicians consider strategies to reduce the risk of discontinuation of AP therapy.

W1004 Time Trends in the Prescription of Low-Dose Acetylsalicylic Acid, Clopidogrel and Proton Pump Inhibitors in UK Primary Care

W1004 Time Trends in the Prescription of Low-Dose Acetylsalicylic Acid, Clopidogrel and Proton Pump Inhibitors in UK Primary Care

Electrochemical Redox Behavior of Omeprazole Using a Glassy Carbon Electrode

AbstractThe electrochemical redox behavior of omeprazole (OMZ), a gastric acid pump inhibitor, was investigated at a glassy carbon electrode using cyclic, differential pulse and square‐wave voltammetry over a wide pH range. The pH‐dependent oxidation occurs in two irreversible consecutive charge transfer reactions. Adsorption of the nonelectroactive product was also observed. The first oxidation involves removal of one electron, followed by deprotonation and leads to the formation of a hydroxylated species. The second oxidation process is related to the hydroxyl and amino groups in the benzimidazole moiety. The reduction is irreversible, also pH‐dependent, and occurs in a single step at the sulfoxide group in a diffusion‐controlled mechanism. The diffusion coefficient of omeprazole was calculated to be DOMZ=2.31×10−6 cm2 s−1.

Risikofaktorer for blødende magesår

Many drugs increase the risk for gastroduodenal ulcer bleeding. The aim of this study was to investigate Helicobacter pylori infection and drug use in patients who had gastroduodenal ulcer bleeding in 2002 or 2007, and possible differences between the periods. Patients with gastroduodenal ulcer bleeding were prospectively included in the periods 1.1 - 31.12. 2002 and 1.1 - 31.12. 2007. Information was recorded about Helicobacter pylori infection and intake of NSAIDs (non steroidal anti-inflammatory drugs), acetylsalicylic acid, warfarin, clopidogrel, low-molecular heparine, SSRIs (selective serotonin reuptake inhibitors), corticosteroids, paracetamol and proton pump inhibitors. Inhabitants in Oslo age >or= 60 years in 2007, were used as a control for drug use. 78.2 % of patients in 2002 and 90.7 % of those in 2007 used at least one of the drugs (p = 0.01). In 2002, 25.7 % of patients used non-selective NSAIDs and in 2007 46.1 % used such drugs (p = 0.001). In 2002, 36.7 % of patients used more than one of the studied drugs, versus 50.9 % in 2007 (p = 0.02). Compared to controls, the patients used more NSAIDs, acetylsalicylic acid, clopidogrel, low- molecular heparine, SSRIs and corticosteroids. Helicobacter pylori infection was diagnosed in 51.0 % of patients in 2002, versus 41.1 % in 2007 (p = 0.11). Most patients with gastroduodenal ulcer bleeding use drugs that have a known risk of adverse effects such as ulcer and/or gastrointestinal bleeding.

Hernia de hiato y lesiones por enfermedad por reflujo gastroesofágico diagnosticadas por cápsula endoscópica

We report the case of a 73-year-old woman with a personal history of unilateral nephrectomy secondary to lithiasis, hypertension, and hypercholesterolemia, currently treated with simvastatin (20 mg/day), acetylsalicylic acid (100 mg/day) and proton pump inhibitors (20 mg/day), who presented with iron deficiency anemia (hemoglobin: 9.8 mg/dL, MCV: 83.1 fL, iron: 29 μg/dL). Our patient reported no gastroesophageal symptoms, bowel disorders, or pathological findings in her stools. The only symptom was mild asthenia. Physical exploration was normal. An esophago-gastro-duodenoscopy was performed with no endoscopic findings. Biopsies from the antrum showed mild superficial gastritis, and no anomalies were detected in the duodenum. Amild melanosis coli, 2 small polyps that were coagulated, and diverticula in the sigmoid colon were found during colonoscopy. Finally, in order to complete the study, a capsule endoscopy was performed and, surprisingly, a hiatal hernia was visualized (Fig. 1) with associated grade I-IV peptic esophagitis (Fig. 2), with no other potential bleeding lesions in the small bowel. The patient received treatment with anti-reflux measurements and proton pump inhibitors. Three months later, laboratory tests were normal. The incidence of lesions (theoretically accessible to conventional upper endoscopy) during capsule endoscopy is still unknown and poorly investigated. However, the existence of cases similar to the one reported herein shows that they are not rare, as can be seen in the literature (1-4). This means that, in spite of not being a priority for this exploration, pictures taken along the esophagus, stomach, and colon must be carefully checked by the endoscopist.

The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett’s esophagus

Bile acids may play a role in the pathogenesis of Barrett's esophagus (BE). Bile composition can be influenced by oral administration of ursodeoxycholic acid (UDCA). We prospectively investigated the effect of proton pump inhibitors (PPI) supplemented with UDCA in vivo in patients with BE. Patients with no or low-grade dysplasia who were clinically asymptomatic on PPI were eligible for the study. In order to exclude the effects of acid reflux, all patients were initially treated with 40 mg esomeprazole (ESO) twice daily for 6 months and continued on this dose till the end of the study (t = 12 months). During a period of 6 months (t = 6 month - t = 12 month) patients were treated with oral UDCA (600 mg twice daily). Patients underwent endoscopy at t = 0 months, t = 6 months and t = 12 months with multiple biopsies of the distal and proximal BE segment, normal squamous and gastric cardia. In addition, pH was measured at t = 0 months and t = 6 months using a BRAVO wireless pH capsule. Bile was sampled at the beginning of the UDCA treatment and 6 months later (t = 6 month and t = 12 month). All biopsies were reviewed for the extent of metaplasia, dysplasia, and acute and chronic inflammation. In addition, proliferation (Ki67), differentiation (villin, cytokeratins 7 and 20) and inflammation (COX-2) were investigated by immunohistochemistry (IHC). Nine patients (mean age 60 years, median BE length 7 cm) were included, of whom six had no dysplasia and three had low-grade dysplasia. pH measurements revealed a normal acid exposure in most patients at t = 0 and t = 6 months. In addition, bile composition analysis demonstrated the efficacy of UDCA. Combining the results of both phases of the study, no significant changes were seen in any of the histological or IHC parameters. Differentiation and proliferation parameters showed no significant changes. In this study, in BE patients who were clinically asymptomatic on PPI, increasing the PPI dose to the maximum for 6 months followed by the addition of UDCA for 6 months did not result in significant histological or IHC changes in their BE.

GASTRIC ANGIODYSPLASIA IN A CHILD WITH BERNARD-SOULIER SYNDROME: Efficacy of Octreotide in Long-Term Management

Gastrointestinal angiodysplasia in association with Bernard-Soulier syndrome has been previously described in adults. The authors report on a 14-year-old boy presenting with massive upper gastrointestinal bleeding due to a large gastric angiodysplasia, in whom medical history and laboratory investigations were consistent with Bernard-Soulier syndrome. The vascular lesion was so widespread that surgical or endoscopic therapy was not considered. Therefore, treatment with octreotide, a somatostatin analog, was commenced, following a short course of tranexamic acid and proton pump inhibitor. During the 16-month follow-up with octreotide therapy, no occult or gross bleeding occurred. This case illustrates the utility of using octreotide for the long-term treatment of children with bleeding disorders and angiodysplasia.

Does the change of omeprazole to pantoprazole affect clozapine plasma concentrations?

Many chronic psychiatric inpatients suffer from schizophrenia and gastric disorders. Some of them are therefore treated with a combination of clozapine and an acid pump inhibitor. The atypical antipsychotic clozapine is metabolized by CYP1A2, CYP3A4 and CYP2D6. The acid pump inhibitor omeprazole can inhibit the activity of CYP2C19 and induce the activity of CYP2C8‐9, CYP3A4 and CYP1A2. The acid pump inhibitor pantoprazole is largely devoid of these activities. The possibility of pharmacokinetic drug drug interactions with psychotropic drugs lead in Spring 2000 to the replacement of omeprazole by pantoprazole in the drug formulary of Delta Psychiatric Hospital. In this hospital the plasma concentrations of clozapine and its primary metabolite are measured at regular intervals on a routine basis. This offers the opportunity to investigate the possible consequences of the change of acid pump inhibitor.The aim was to retrospectively assess the possible effect of the change of omeprazole to pantoprazole on the plasma concentrations of clozapine.The medication records of all long‐stay psychiatric in‐patients were checked and those patients were selected who used omeprazole and clozapine on April 4, 2000 and who were changed to pantoprazole for the rest of the year. The medical records of these patients were searched for data on clozapine plasma concentrations before and at least 6 weeks after the change, necessary changes of the clozapine dosage due to a changed clinical condition, and possibly reported adverse events. The data were controlled for co‐medication that influences the activity of CYP isoforms and for smoking habits.Out of 430 long‐stay patients 49 used omeprazole and 15 also used clozapine. Of these, 13 were finally evaluable. The 13 patients used 423±153.6 mg clozapine per day (mean±s.d.). Before the change, the clozapine concentrations measured 382±190.6 µg l−1. After the change, these concentrations measured 382±158.9 µg l−1. In five patients an increase in plasma concentrations was observed. Three of them were non‐smokers. A significant correlation (Pearson Rank, −0.615, P=0.025) was found between the second clozapine concentration and the amount of tobacco smoked per day. There existed no reports of changes in the medical condition, particularly the occurrence of relevant adverse events, that could be attributed to a change in clozapine plasma concentrations.No relevant changes were observed retrospectively in the plasma concentrations and clinical effects of clozapine due to the alteration of omeprazole to pantoprazole in this small patient population. However, there appears to exist a relationship between the smoking habits and the sensitivity to this change. This might be due to the CYP inducing activity of tobacco smoke, which may be more important than the CYP inducing activity of omeprazole.

Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man

H 335/25, a 4-amino quinoline, belongs to a new class of reversible gastric acid pump inhibitors. A potential advantage of such drugs over the irreversible proton pump inhibitors (PPIs) is better control over the effect–time profile. Dose escalation studies were performed to characterize the effect on acid secretion in dogs ( n=24) and healthy male subjects ( n=12). The effect–time profile was delayed compared to the concentration–time profile. A model-based approach, using non-linear mixed effects modelling, was applied to quantify and elucidate the mechanism for the delayed effect. Three different models were investigated: (1) a slow equilibration preceding the formation of drug–enzyme complex, modelled by an effect-compartment, (2) a slow equilibration between free drug, free enzyme and drug–enzyme complex, described by a kinetic binding model, and (3) a delay between enzyme inhibition and the measured response, described by an indirect response model. Model 2 was shown to be superior to models 1 and 3, for both dog and human data. The dissociation rate constant, k off, was estimated to be 0.85 and 0.88 h and the calculated equilibration constant, K d, was 160 and 250 nM in dog and man, respectively. Simulations of the predicted time-course of the effect beyond the 4–5-h observation period was similar for the three models.

Treatment of Helicobacter pylori

Over the 14 years since Helicobacter pylori came to the attention of the medical community, we have reached the position that the organism is generally believed to be a serious pathogen. It causes a chronic infection with complications that include gastric and duodenal ulcer, gastric mucosa-associated lymphoid tissue lymphoma and gastric cancer. It is therefore an important cause of morbidity and mortality. We still do not have a perfect treatment for the infection, but enormous strides have been made since its discovery and acceptable treatments are now available. The best of these are the acid pump inhibitor- and ranitidine bismuth citrate-based triple therapies that provide 85-95% eradication in most studies. Better treatments and vaccination programmes may become available now that the Helicobacter genome has been decoded, raising the possibility of 'designer' antibiotics and vaccines. In the meantime, the current key questions are: How can our current therapies be improved? Who should be treated? What, if any, are the potential risks of widespread H. pylori eradication? And how is the organism transmitted? Without doubt, many of these questions will be addressed in the succeeding years. The papers presented in these proceedings represent an up-to-date analysis (much of it based on new data) by recognized experts. The views expressed are often provocative, but are backed by scientific data.