Curriculum for Vestibular Medicine (VestMed) proposed by the Bárány Society.

This document presents the initiative of the Bárány Society to improve diagnosis and care of patients presenting with vestibular symptoms worldwide.The Vestibular Medicine (VestMed) concept embraces a wide approach to the potential causes of vestibular symptoms, acknowledging that vertigo, dizziness, and unsteadiness are non-specific symptoms that may arise from a broad spectrum of disorders, spanning from the inner ear to the brainstem, cerebellum and supratentorial cerebral networks, to many disorders beyond these structures.The Bárány Society Vestibular Medicine Curriculum (BS-VestMed-Cur) is based on the concept that VestMed is practiced by different physician specialties and non-physician allied health professionals. Each profession has its characteristic disciplinary role and profile, but all work in overlapping areas. Each discipline requires good awareness of the variety of disorders that can present with vestibular symptoms, their underlying mechanisms and etiologies, diagnostic criteria and treatment options. Similarly, all disciplines require an understanding of their own limitations, the contribution to patient care from other professionals and when to involve other members of the VestMed community. Therefore, the BS-VestMed-Cur is the same for all health professionals involved, the overlaps and differences of the various relevant professions being defined by different levels of detail and depth of knowledge and skills.The BS-VestMed-Cur defines a Basic and an Expert Level Curriculum. The Basic Level Curriculum covers the VestMed topics in less detail and depth, yet still conveys the concept of the wide net approach. It is designed for health professionals as an introduction to, and first step toward, VestMed expertise. The Expert Level Curriculum defines a Focused and Broad Expert. It covers the VestMed spectrum in high detail and requires a high level of understanding. In the Basic and Expert Level Curricula, the range of topics is the same and runs from anatomy, physiology and physics of the vestibular system, to vestibular symptoms, history taking, bedside examination, ancillary testing, the various vestibular disorders, their treatment and professional attitudes. Additionally, research topics relevant to clinical practice are included in the Expert Level Curriculum. For Focused Expert proficiency, the Basic Level Curriculum is required to ensure a broad overview and additionally requires an expansion of knowledge and skills in one or a few specific topics related to the focused expertise, e.g. inner ear surgery. Broad Expert proficiency targets professionals who deal with all sorts of patients presenting with vestibular symptoms (e.g. otorhinolaryngologists, neurologists, audiovestibular physicians, physical therapists), requiring a high level of VestMed expertise across the whole spectrum. For the Broad Expert, the Expert Level Curriculum is required in which the minimum attainment targets for all the topics go beyond the Basic Level Curriculum. The minimum requirements regarding knowledge and skills vary between Broad Experts, since they are tuned to the activity profile and underlying specialty of the expert. The BS-VestMed-Cur aims to provide a basis for current and future teaching and training programs for physicians and non-physicians. The Basic Level Curriculum could also serve as a resource for inspiration for teaching VestMed to students, postgraduate generalists such as primary care physicians and undergraduate health professionals, or anybody wishing to enter VestMed. VestMed is considered a set of competences related to an area of practice of established physician specialties and non-physician health professions rather than a separate clinical specialty. This curriculum does not aim to define a new single clinical specialty. The BS-VestMed-Cur should also integrate with, facilitate and encourage translational research in the vestibular field.

Single-nuclei transcriptomes from human adrenal gland reveal distinct cellular identities of low and high-risk neuroblastoma tumors.

Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. Here we study single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compare tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles a subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations reveal different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome.

Quantifying the frequency and volume of urine deposition by grazing sheep using tri-axial accelerometers.

Urine patches deposited in pasture by grazing animals are sites of reactive nitrogen (N) loss to the environment due to high concentrations of N exceeding pasture uptake requirements. In order to upscale N losses from the urine patch, several urination parameters are required, including where, when and how often urination events occur as well as the volume and chemical composition. There are limited data available in this respect, especially for sheep. Here, we seek to address this knowledge gap by using non-invasive sensor-based technology (accelerometers) on ewes grazing in situ, using a Boolean algorithm to detect urination events in the accelerometer signal. We conducted an initial study with penned Welsh Mountain ewes (n = 5), with accelerometers attached to the hind, to derive urine flow rate and to determine whether urine volume could be estimated from ewe squat time. Then accelerometers attached to the hind of Welsh Mountain ewes (n = 30 at each site) were used to investigate the frequency of sheep urination events (n = 35 946) whilst grazing two extensively managed upland pastures (semi-improved and unimproved) across two seasons (spring and autumn) at each site (35-40 days each). Sheep urinated at a frequency of 10.2 ± 0.2 and 8.1 ± 0.3 times per day in the spring and autumn, respectively, while grazing the semi-improved pasture. Urination frequency was greater (19.0 ± 0.4 and 15.3 ± 0.3 times per day in the spring and autumn, respectively) in the unimproved pasture. Ewe squat duration could be reliably used to predict the volume of urine deposited per event and was thus used to estimate mean daily urine production volumes. Sheep urinated at a rate of 16.6 mL/s and, across the entire dataset, sheep squatted for an average of 9.62 ± 0.03 s per squatting event, producing an estimated average individual urine event volume of 159 ± 1 mL (n = 35 946 events), ranging between 17 and 745 mL (for squat durations of 1 to 45 s). The estimated mean daily urine volume was 2.15 ± 0.04 L (n = 2 669 days) across the entire dataset. The data will be useful for modelling studies estimating N losses (e.g. ammonia (NH3) volatilisation, nitrous oxide (N2O) emission via nitrification and denitrification and nitrate (NO3-) leaching) from urine patches.

Terapia con presión positiva para enfermedad de Ménière / Positive pressure therapy for Ménière's disease

INTRODUCCIÓN La enfermedad de Ménière es una anomalía del oído interno caracterizada por episodios de vértigo espontáneo, hipoacusia fluctuante y tinnitus. La terapia con presión positiva ha sido utilizada para reducir la intensidad y la frecuencia de las crisis, pero existe controversia respecto a su eficacia. MÉTODOS Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES Identificamos cinco revisiones sistemáticas que en conjunto incluyeron 22 estudios primarios, de los cuales cinco corresponden a ensayos aleatorizados. Concluimos que la terapia de presión positiva probablemente empeora levemente la audición y no reduce la intensidad del vértigo. Además, no es posible establecer con claridad si la terapia de presión positiva mejora la funcionalidad o si disminuye la frecuencia de los ataques de vértigo, porque la certeza de la evidencia existente ha sido evaluada como muy baja.

INTRODUCTION Ménière's disease is a disorder of the inner ear characterized by episodes of spontaneous vertigo, fluctuating hearing loss and tinnitus. Positive pressure therapy has been used to reduce the intensity and frequency of episodes, but it is not clear whether it is actually effective. METHODS We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS We identified five systematic reviews including 22 studies overall, of which five were randomized trials. We concluded positive pressure therapy probably leads to slightly worse hearing and makes little or no difference in the intensity of vertigo. In addition, we are uncertain whether positive pressure therapy improves functionality or decreases vertigo attacks as the certainty of the evidence has been assessed as very low.

p53 protein aggregation promotes platinum resistance in ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC), the most lethal gynecological cancer, often leads to chemoresistant diseases. The p53 protein is a key transcriptional factor regulating cellular homeostasis. A majority of HGSOCs have inactive p53 because of genetic mutations. However, genetic mutation is not the only cause of p53 inactivation. The aggregation of p53 protein has been discovered in different types of cancers and may be responsible for impairing the normal transcriptional activation and pro-apoptotic functions of p53. We demonstrated that in a unique population of HGSOC cancer cells with cancer stem cell properties, p53 protein aggregation is associated with p53 inactivation and platinum resistance. When these cancer stem cells differentiated into their chemosensitive progeny, they lost tumor-initiating capacity and p53 aggregates. In addition to the association of p53 aggregation and chemoresistance in HGSOC cells, we further demonstrated that the overexpression of a p53-positive regulator, p14ARF, inhibited MDM2-mediated p53 degradation and led to the imbalance of p53 turnover that promoted the formation of p53 aggregates. With in vitro and in vivo models, we demonstrated that the inhibition of p14ARF could suppress p53 aggregation and sensitize cancer cells to platinum treatment. Moreover, by two-dimensional gel electrophoresis and mass spectrometry we discovered that the aggregated p53 may function uniquely by interacting with proteins that are critical for cancer cell survival and tumor progression. Our findings help us understand the poor chemoresponse of a subset of HGSOC patients and suggest p53 aggregation as a new marker for chemoresistance. Our findings also suggest that inhibiting p53 aggregation can reactivate p53 pro-apoptotic function. Therefore, p53 aggregation is a potential therapeutic target for reversing chemoresistance. This is paramount for improving ovarian cancer patients' responses to chemotherapy, and thus increasing their survival rate.

Intoxications of the new psychoactive substance 5-(2-aminopropyl)indole (5-IT): a case series from the Swedish STRIDA project.

CONTEXT: 5-(2-aminopropyl)indole (5-IT) is a new psychoactive substance (NPS; "legal high" or "research chemical") structurally related to indoleamines and substituted phenethylamines and implicated in several fatalities. We describe the clinical characteristics and results of laboratory investigations of 14 analytically confirmed nonfatal cases of 5-IT intoxication within the Swedish STRIDA project. STUDY DESIGN: Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden in 2012. PATIENTS AND METHODS: Blood and/or urine samples were collected from intoxicated patients presenting to emergency departments and intensive care units over the country. Analysis of NPS was performed using an LC-MS/MS multi-component method. Clinical data were collected when caregivers consulted the Poisons Information Centre and also retrieved from medical records. The severity of poisoning was graded retrospectively using the Poisoning Severity Score (PSS). RESULTS: Eleven male and three female patients (age: 21-53 years, median: 27) tested positive for 5-IT in 2012, all cases appearing in April-July. The 5-IT concentration in serum ranged between 0.015 and 0.59 µg/mL (median: 0.22; n = 8) and in urine between 0.005 and 24.7 µg/mL (median: 5.95; n = 12). Five intoxications were indicated to be caused by 5-IT alone, whereas additional psychoactive substances were detected in the other nine cases. Six (43%) of fourteen cases were graded as severe (PSS 3), five (36%) as moderate (PSS 2), and three (21%) as minor (PSS 1) poisonings. In the severe cases, agitation, hallucinations, dilated pupils without light reaction, tachycardia, hypertension, hyperthermia, myoclonus, muscle rigidity, arrhythmias, seizures, rhabdomyolysis, and/or renal failure were noted. CONCLUSIONS: The results demonstrated that severe clinical toxicity was commonly present in patients with analytically confirmed 5-IT exposure. The clinical features are consistent with a sympathomimetic toxidrome, and some patients also displayed symptoms associated with serotonin toxicity.

Population structure and residency of whale sharks Rhincodon typus at Utila, Bay Islands, Honduras.

There were 479 reported whale shark Rhincodon typus encounters between 1999 and 2011 at the island of Utila, which forms part of the Meso-American Barrier Reef System (MBRS) in the western Caribbean Sea. The majority of R. typus were found to feed on small bait fish associated with various tuna species. Ninety-five individual R. typus, ranging from 2 to 11 m total length (LT ), were identified through their unique spot patterns. A significant male bias (65%) was present. There was no significant difference between the mean ± s.d. LT of female (6·66 ± 1·65 m) and male (6·25 ± 1·60 m) R. typus. Most R. typus were transient to Utila, with 78% sighted only within a single calendar year, although some individuals were sighted in up to 5 years. Mean residency time was modelled to be 11·76 days using maximum likelihood methods.

Constitutive proteasomal degradation of TWIST-1 in epithelial-ovarian cancer stem cells impacts differentiation and metastatic potential.

Epithelial-mesenchymal transition (EMT) is a critical process for embryogenesis but is abnormally activated during cancer metastasis and recurrence. This process enables epithelial cancer cells to acquire mobility and traits associated with stemness. It is unknown whether epithelial stem cells or epithelial cancer stem cells are able to undergo EMT, and what molecular mechanism regulates this process in these specific cell types. We found that epithelial-ovarian cancer stem cells (EOC stem cells) are the source of metastatic progenitor cells through a differentiation process involving EMT and mesenchymal-epithelial transition (MET). We demonstrate both in vivo and in vitro the differentiation of EOC stem cells into mesenchymal spheroid-forming cells (MSFCs) and their capacity to initiate an active carcinomatosis. Furthermore, we demonstrate that human EOC stem cells injected intraperitoneally in mice are able to form ovarian tumors, suggesting that the EOC stem cells have the ability to 'home' to the ovaries and establish tumors. Most interestingly, we found that TWIST-1 is constitutively degraded in EOC stem cells, and that the acquisition of TWIST-1 requires additional signals that will trigger the differentiation process. These findings are relevant for understanding the differentiation and metastasis process in EOC stem cells.

TWISTing stemness, inflammation and proliferation of epithelial ovarian cancer cells through MIR199A2/214.

Cancer stem cells are responsible for sustaining the tumor and giving rise to proliferating and progressively differentiating cells. However, the molecular mechanisms regulating the process of cancer stem cell (CSC) differentiation is not clearly understood. Recently, we reported the isolation of the epithelial ovarian cancer (EOC) stem cells (type I/CD44+). In this study, we show that type I/CD44+ cells are characterized by low levels of both miR-199a and miR-214, whereas mature EOC cells (type II/CD44-) have higher levels of miR-199a and miR-214. Moreover, these two micro RNAs (miRNAs) are regulated as a cluster on pri-miR-199a2 within the human Dnm3os gene (GenBank FJ623959). This study identify Twist1 as a regulator of this unique miRNA cluster responsible for the regulation of the IKKbeta/NF-kappaB and PTEN/AKT pathways and its association of ovarian CSC differentiation. Our data suggest that Twist1 may be an important regulator of 'stemness' in EOC cells. The regulation of MIR199A2/214 expression may be used as a potential therapeutic approach in EOC patients.

Up to 21-day banked red blood cells collected by apheresis and stored for 14 days after automated wash at different times of storage.

BACKGROUND AND OBJECTIVES: A closed-system technology (ACP-215, Haemonetics, Braintree, MA) enables automated washing and extended storage of frozen red blood cells (RBC). This technology was applied to wash banked RBC for removal of undesirable protein and metabolites before transfusion. We studied protein and metabolite depletion as well as RBC metabolism and viability up to 14 days postwash with regard to various pre-storage times. MATERIALS AND METHODS: Thirty RBC units were collected by means of apheresis and subdivided into three arms based on prewash storage time period (6 days/group 1, 14 days/group 2, 21 days/group 3). Wash efficacy (protein depletion, IgA), RBC metabolism (pH, lactate, potassium, haemolysis) and cell viability (ATP) were analysed immediately and 14 days after washing. RESULTS: Total protein and IgA postwash were lowered by automated wash in all groups and uniformly met EC guidelines. Potassium (mmol/l) was below 1.2 mmol/l postwash and significantly below prewash values in all groups, even after 14 days of storage (prewash vs. postwash; P < 0.05). RBCs washed after 14 and 21 days, respectively, showed significantly lower pH values and lower ATP content than RBCs washed after only 6 days of storage. Haemolysis rate remained significantly below 0.8%, the maximum level recommended by the EC guidelines, immediately and 14 days after washing in all units. CONCLUSION: Our data confirm that RBC units banked up to 21 days can be effectively protein- and potassium-depleted with the ACP-215 independent from prewash storage time. With respect to high ATP levels and pH, postwash storage of 2 weeks should be limited to units not older than 7 days before wash. This new washing technology ensures better standardization in washed RBC and provides blood centres with a logistical alternative to 24-h washed RBC products.

Treatment of phobic postural vertigo. A controlled study of cognitive-behavioral therapy and self-controlled desensitization.

In balance clinic practice, phobic postural vertigo is a term used to define a population with dizziness and avoidance behavior often as a consequence of a vestibular disorder. It has been described as the most common form of dizziness in middle aged patients in dizziness units. Anxiety disorders are common among patients with vestibular disorders. Cognitive-behavioral therapy is an effective treatment for anxiety disorders, and vestibular rehabilitation exercises are effective for vestibular disorders. This study compared the effect of additional cognitive-behavioral therapy for a population with phobic postural vertigo with the effect of self-administered vestibular rehabilitation exercises. 39 patients were recruited from a population referred for otoneurological investigation. Treatment effects were evaluated with the Dizziness Handicap Inventory, Vertigo Symptom Scale, Vertigo Handicap Questionnaire, and Hospital Anxiety and Depression Scale. All patients had a self treatment intervention based on education about the condition and recommendation of self exposure by vestibular rehabilitation exercises. Every second patient included was offered additional cognitive behavioral therapy. Fifteen patients with self treatment and 16 patients with cognitive- behavioral treatment completed the study. There was significantly larger effect in the group who received cognitive behavioral therapy than in the self treatment group in Vertigo Handicap Questionnaire and the Hospital Anxiety and Depression scale and its subscales. Cognitive-behavioral therapy has an additional effect as treatment for a population with phobic postural vertigo. A multidisciplinary approach including medical treatment, cognitive-behavioral therapy and physiotherapy is suggested.

Tubular repair of the median or ulnar nerve in the human forearm: a 5-year follow-up.

The long-term outcome from silicone tube nerve repair was compared with the outcome from routine microsurgical repair in a clinical randomized prospective study, comprising 30 patients with median or ulnar nerve injuries in the distal forearm. Postoperatively, the patients underwent neurophysiological and clinical assessments of sensory and motor function regularly over a 5-year period. After 5 years there was no significant difference in outcome between the two techniques except that cold intolerance was significantly less severe with the tubular technique. In the total group there was ongoing improvement of functional sensibility throughout the 5 years after repair. It is concluded that tubular repair of the median and ulnar nerves is at least as good as routine microsurgical repair, and results in less cold intolerance.

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.

Arthritis induced in rats with nonimmunogenic adjuvants as models for rheumatoid arthritis.

Rat models are useful for studies of the pathogenesis of rheumatoid arthritis (RA) since rats are extraordinarily sensitive to induction of arthritis with adjuvants. Injection of not only the classical complete Freund's adjuvant but also mineral oil without mycobacteria and pure adjuvants such as pristane and squalene, induce severe arthritis in many rat strains. Models like pristane-induced arthritis in rats are optimal models for RA since they fulfill the RA criteria including a chronic relapsing disease course. Arthritogenic adjuvants like pristane, avridine, squalene and mineral oil are not immunogenic since they do not contain major histocompatibility complex (MHC) binding peptides. Nevertheless, the diseases are MHC-associated and dependent on the activation of alphabetaTCR (T-cell receptor)-expressing T cells. However, it has not been possible to link the immune response to joint antigens or other endogenous components although immunization with various cartilage proteins induce arthritis but with different pathogeneses. To unravel the mechanisms behind adjuvant-induced arthritis, a disease-oriented genetic approach is optimal. Several loci that control onset of arthritis, severity and chronicity of the disease have been identified in genetic crosses and most of these have been confirmed in congenic strains. In addition, many of these loci are found in other autoimmune models in the rat as well as associated with arthritis in mice and humans.

Regulation of repulsion versus adhesion by different splice forms of an Eph receptor.

Eph tyrosine kinase receptors and their membrane-bound ephrin ligands mediate cell interactions and participate in several developmental processes. Ligand binding to an Eph receptor results in tyrosine phosphorylation of the kinase domain, and repulsion of axonal growth cones and migrating cells. Here we report that a subpopulation of ephrin-A5 null mice display neural tube defects resembling anencephaly in man. This is caused by the failure of the neural folds to fuse in the dorsal midline, suggesting that ephrin-A5, in addition to its involvement in cell repulsion, can participate in cell adhesion. During neurulation, ephrin-A5 is co-expressed with its cognate receptor EphA7 in cells at the edges of the dorsal neural folds. Three different EphA7 splice variants, a full-length form and two truncated versions lacking kinase domains, are expressed in the neural folds. Co-expression of an endogenously expressed truncated form of EphA7 suppresses tyrosine phosphorylation of the full-length EphA7 receptor and shifts the cellular response from repulsion to adhesion in vitro. We conclude that alternative usage of different splice forms of a tyrosine kinase receptor can mediate cellular adhesion or repulsion during embryonic development.

Esomeprazole provides improved acid control vs. omeprazole In patients with symptoms of gastro-oesophageal reflux disease.

BACKGROUND: Esomeprazole (Nexium) is a new proton pump inhibitor for the treatment of acid-related diseases. METHODS: In this double-blind crossover study, 38 patients with gastro-oesophageal reflux disease (GERD) symptoms were randomized to esomeprazole 40 and 20 mg and omeprazole 20 mg once daily for 5 days. On day 5 of each dosing period, 24-h intragastric pH and pharmacokinetic variables were measured. RESULTS: Thirty-six patients aged 29-58 (mean 45) years completed the study. Esomeprazole 40 and 20 mg maintained intragastric pH > 4 for (mean) 16.8 and 12.7 h, respectively, vs. 10.5 h for omeprazole 20 mg (P < 0.001 and P < 0. 01). Twenty-four-hour median intragastric pH was significantly higher with esomeprazole 40 mg (4.9) and 20 mg (4.1) than with omeprazole 20 mg (3.6) (P < 0.001 and P < 0.01). Area under the plasma concentration-time curve (AUC) was 80% higher for esomeprazole 20 mg vs. omeprazole, while that for esomeprazole 40 mg was more than five times higher (each P < 0.0001). Interpatient variability in intragastric pH and AUC was less with esomeprazole than with omeprazole. Esomeprazole was well tolerated and there were no safety concerns. CONCLUSIONS: Esomeprazole provides more effective acid control than omeprazole, with reduced interpatient variability, thereby offering the potential for improved efficacy in acid-related diseases.

Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole.

AIMS: To study the pharmacokinetics of three proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole, as well as any potential influence on CYP1A2 activity (measured by means of rate of caffeine metabolism) of these compounds at single dose and repeated dose administration. METHODS: Fourteen healthy males, classified as 12 extensive metabolizers (EMs) and two poor metabolizers (PMs) according to the urinary S/R mephenytoin ratio, completed this open, randomized, three-way cross-over study. In each of the three 7-day treatment periods either omeprazole (20 mg), lansoprazole (30 mg) or pantoprazole (40 mg) in therapeutically recommended doses was administered once daily, and the pharmacokinetics of the proton pump inhibitors as well as the rate of caffeine metabolism was measured on days 1 and 7. RESULTS: In the EMs there was an increase in AUC from day 1 to day 7 for omeprazole. In the PMs the AUC of both omeprazole and lansoprazole was unchanged during repeated dosing, while for pantoprazole there was a tendency to a slight decrease. The AUC at steady state was for all three proton pump inhibitors 5 fold higher in PMs compared with EMs, indicating that the same proportion of the dose, irrespective of compound, is metabolized by CYP2C19. No induction of CYP1A2 was evident for any of the compounds in either EMs or PMs. CONCLUSIONS: The approximately 5 fold difference in AUC between EMs and PMs indicates that approximately 80% of the dose for all three proton pump inhibitors is metabolized by the polymorphically expressed CYP2C19. None of the three proton pump inhibitors, administered in therapeutically recommended doses, is an inducer of CYP1A2--neither in PMs nor in EMs.