Occupational risk of COVID-19 in foreign-born employees in Denmark.

BACKGROUND: Foreign-born workers in high-income countries experience higher rates of COVID-19 but the causes are only partially known. AIMS: To examine if the occupational risk of COVID-19 in foreign-born workers deviates from the risk in native-born employees in Denmark. METHODS: Within a registry-based cohort of all residents employed in Denmark (n = 2 451 542), we identified four-digit DISCO-08 occupations associated with an increased incidence of COVID-19-related hospital admission during 2020-21 (at-risk occupations). The sex-specific prevalence of at-risk employment in foreign born was compared with the prevalence in native born. Moreover, we examined if the country of birth modified the risk of a positive SARS-CoV-2 polymerase chain reaction (PCR) test and COVID-19-related hospital admission in at-risk occupations. RESULTS: Workers born in low-income countries and male workers from Eastern Europe more often worked in at-risk occupations (relative risks between 1.16 [95% confidence interval {CI} 1.14-1.17] and 1.87 [95% CI 1.82-1.90]). Being foreign-born modified the adjusted risk of PCR test positivity (test for interaction P < 0.0001), primarily because of higher risk in at-risk occupations among men born in Eastern European countries (incidence rate ratio [IRR] 2.39 [95% CI 2.09-2.72] versus IRR 1.19 [95% CI 1.14-1.23] in native-born men). For COVID-19-related hospital admission, no overall interaction was seen, and in women, country of birth did not consistently modify the occupational risk. CONCLUSIONS: Workplace viral transmission may contribute to an excess risk of COVID-19 in male workers born in Eastern Europe, but most foreign-born employees in at-risk occupations seem not to be at higher occupational risk than native born.

Prenatal exposure to airborne polychlorinated biphenyl congeners and male reproductive health.

STUDY QUESTION: Is fetal exposure to lower-chlorinated polychlorinated biphenyls (LC-PCBs) in indoor air of private homes built with PCB-containing materials associated with semen characteristics and testicular volume in adult men? SUMMARY ANSWER: We observed only marginal and inconsistent associations between maternal exposure to PCBs in indoor air and semen quality, testicular size and reproductive hormones in the adult offspring. WHAT IS KNOWN ALREADY: Recent studies have shown LC-PCBs to exhibit endocrine-disrupting properties and increase the risk of cryptorchidism. Although exposure to LC-PCBs in indoor air is relatively common, the long-term impact of prenatal exposure on male reproductive health has not yet been investigated. STUDY DESIGN, SIZE, DURATION: In this cohort study, participants were men (18+ years) whose mothers carried them while living in one of two residential areas where indoor air had been contaminated by LC-PCB evaporating from building materials in subsets of the apartments. Men were considered prenatally exposed if their mother had lived in a PCB-contaminated apartment and unexposed if their mother had lived in an uncontaminated apartment for a minimum of 1 year during the 3.6 years before conception or during the first trimester. Mothers of prenatally unexposed men could not have lived in a contaminated apartment at any point. Recruitment lasted from 2017 to 2019. In total, 73 exposed and 111 unexposed men gave a blood and semen sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Percentage differences in semen volume, sperm concentration, total sperm count, morphologically normal spermatozoa, progressively motile spermatozoa and DNA fragmentation index (DFI) between prenatally exposed and unexposed men were estimated using negative binomial regression. Associations with total and calculated free testosterone (CFT), LH and FSH were modeled using the linear regression. Odds of small testicular volume was estimated with logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the results of this study were conflicting. No differences in semen volume, sperm concentration, testosterone and CFT were observed between the groups, but there were slight indications of lower total sperm count, increased FSH and risk of small testicles, alongside lower sperm DFI and a higher proportion of normal spermatozoa in men exposed to LCB-PCBs from indoor air during fetal life. There is no apparent biologically plausible explanation for the apparently improved measures of DNA fragmentation and morphology, and these findings may have occurred purely by chance. LIMITATIONS, REASONS FOR CAUTION: Owing to the indirect measure of exposure, lack of adjustment for paternal factors, the potential for self-selection due to known exposure status and fertility issues, inability to take time spent away from the residence, limited statistical power and lack of comparable literature, independent replication of the study in larger cohorts is warranted. WIDER IMPLICATIONS OF THE FINDINGS: While our findings may appear reassuring for the large number of people residing and/or working in buildings with indoor air contaminated with LC-PCBs, further efforts to understand the full range of health consequences of fetal LC-PCB exposure are needed. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Independent Research Fund Denmark (ref no. 6110-00085B), Bispebjerg Hospital, Landsbyggefonden, Realdania (ref. no. PRJ-2017-00176), Grundejernes Investeringsfond (ref. no. 18-58) and Helsefonden (ref. no. 16-B-01-22 and 21-B-0412). K.S.H. was supported by FFIKA, Focused Research Effort on Chemicals in the Working Environment, from the Danish Government. The authors declare that they have no financial, personal or professional competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

F376A/M388A-solulin, a new promising antifibrinolytic for severe haemophilia A.

INTRODUCTION: Haemophilia is a major bleeding disorder due to a deficiency of procoagulant factor VIII (type A) or IX (type B). The treatment is substitutive and based on infusion of factor concentrates. Main limitations of this therapy are cost, short factor half-life and the development of inhibitors (up to 30% of severe HA patients). An important aggravating factor of haemophilia is due to a premature fibrinolysis, directing attention to the therapeutic potential of suitable antifibrinolytics. Thrombomodulin (TM) is a key player of the coagulation cascade by activating protein C (an inhibitor of thrombin generation, thus antagonizing coagulation) and of the fibrinolytic cascade by activating thrombin activatable fibrinolysis inhibitor TAFI (thus reducing fibrinolysis). Solulin is a soluble form of TM that shows both capabilities. AIM: Here, we developed a new generation of solulin variants (F376A-, M388A- and F376A/M388A-solulin) with a decreased ability to activate protein C and a conserved capacity to activate TAFI. METHODS: We produced and characterized solulin variants in vitro. In addition, F376A/M388A-solulin was tested ex vivo, using blood samples of haemophilic A patients, with thromboelastography. RESULTS: The solulin variants (F376A, M388A and the double-mutant F376A/M388A) lost their abilities to activate protein C but are still capable to activate TAFI. Thrombelastography showed increased clot firmness and stability, that, as opposed to wild-type solulin, was maintained even at high concentrations of F376A/M388A-solulin (100 nm). CONCLUSION: In sum, these results open new opportunities for the development of specific medication for haemophilic patients.

[Psychiatric comorbidities with tobacco-related disorders]. / Psychiatrische Komorbiditäten bei tabakbedingten Störungen.

The coincidence of tobacco smoking and psychiatric disorders is of great epidemiological and therapeutic importance. Tobacco smoking by people with mental disorders leads to disproportionately high somatic health risks, an adverse clinical course, poorer clinical outcomes and reduced quality of life (QoL). The etiological causes of the high comorbidity between smoking and mental disorders are still unclear: currently, tobacco smoking is discussed as being either the consequence or contributory cause of psychological disorders or both disorders share common antecedents and interactions. Psychiatric patients are motivated to quit and smoking cessation is not generally less effective with smokers with mental disorders than with mentally healthy individuals. Specific smoking cessation programs in the inpatient and outpatient settings are time-consuming and complex but effective. Within the framework of the current S3 guidelines the international evidence has been updated and transformed into treatment guidelines following an elaborate consensus process. Basically the same interventional measures should be used as with mentally healthy individuals; however, smokers with a psychological comorbidity often need more intensive adjuvant psychotherapeutic interventions and often need pharmaceutical support, (bupropion, varenicline and nicotine replacement therapy). Due to the overall unsatisfactory findings the treatment guidelines are partially based on clinical consensus decisions. In this field, a considerable need for research has been determined.

[Psychotherapy and pharmacotherapy for harmful tobacco use and tobacco dependency]. / Psycho- und Pharmakotherapie bei schädlichem Tabakgebrauch und -abhängigkeit.

Tobacco consumption is one of the major preventable health risk factors. In Germany approximately 110,000 people prematurely die from tobacco-related diseases and approximately 50% of regular smokers are considered to be tobacco dependent. Nevertheless, motivation to quit smoking is low and the long-term abstinence rates after attempts to stop smoking without professional support are far below 10%. As part of the S3 treatment guidelines 78 recommendations for motivation and early interventions for smokers unwilling to quit as well as psychotherapeutic and pharmacological support for smokers willing to quit were formulated after an systematic search of the current literature. More than 50 professional associations adopted the recommendations and background information in a complex certification process. In this article the scientific evidence base regarding the psychotherapeutic and pharmacological treatment options as well as recommendations and further information about indications and treatment implementation are presented. By following these guidelines for treatment of heavy smokers who are willing to quit combined with individual and group therapies on the basis of behavioral treatment strategies and pharmacological support, long-term success rates of almost 30% can be achieved.

[Caffeine in analgesics--myth or medicine?]. / Koffein in Schmerzmitteln Mär oder Medizin?

Caffeine as an analgesic adiuvant has been discussed for many years. In a recent Cochrane review based on 19 studies with a total of 7238 patients, caffeine enhanced the efficacy of paracetamol, ibuprofen or aspirin with a number needed to treat (NNT) of about 16, comparable to the effect of doubling the dose of the primary analgesic, reported by other authors. Analgesia by caffeine is best explained by antagonism at adenosine receptors. Recent studies confirmed a favourable tolerability profile of caffeine when consumed in "normal" quantities (e.g. 300 mg or about 3 cups of coffee per day), including possible cardiovascular risks, effects on bone density, and exposure in pregnancy. Beneficial effects are known,e.g.,in Parkinson's disease and liver cirrhosis and fibrosis. Caffeine remains an analgesic adiuvant with a favourable risk-benefit balance.

[Acetaminophen and the liver: damage at therapeutic dose levels?]. / Paracetamol und die Leber. Schäden bei zugelassenen Dosen?

The possibility of liver intoxication at therapeutic doses of paracetamol (maximal dailydose of 4 x 1 g) is supported by retrospective, but not by controlled prospective studies. Intended orsuicidal overdosages are frequently misjudged in retrospektive reports. Malnutrition, ethanol consumption, and drugs inducing hepatic metabolism are no established riskfactors at therapeutic dose levels. Dose adaptation in existing liver disease is recommended for longer-term use.Transient increases in transaminase values (> 3 x upper limits of normal) after regulardoses of paracetamol are not proof of hepatic damage unless associated with corresponding symptoms or laboratory changes indicative of compromised hepatic function (total bilirubin, INR). There is insufficient evidence of liver injury by paracetamol at regular dose levels.

[Pathological Internet use--epidemiology, diagnostics, co-occurring disorders and treatment]. / Pathologischer Internetgebrauch--Epidemiologie, Diagnostik, komorbide Störungen und Behandlungsansätze.

In 2009, we can look back on a history of 40 years of internet use. While most consumers make use of the internet in a controlled fashion, a progressive loss of the ability to control the frequency and duration of internet activities emerges in some users. As a consequence, the excessive time devoted to internet use and the behavioural narrowing can lead to dramatic psychosocial outcomes. This phenomenon is referred to as "pathological internet use" (PIU). On behalf of the German ministry of health a systematic review of the literature since 1996 has been carried out. The main results will be presented in this review. Prevalence data on pathological internet use are limited by methodological difficulties concerning the diagnosis and the heterogeneity of diagnostical instruments. International prevalence rates range from 1.5 % to 8.2 %. Annual studies on representative samples of the German population describe their internet use and patterns of use, but information on the prevalence of PIU is missing. Diagnostical instruments are needed that show sufficient reliability and validity and allow international comparisons. Research on the Dutch "Compulsive Internet Use Scale" may close this gap. Cross-sectional studies on samples of patients report high comorbidity of PIU with psychiatric disorders, e. g. affective disorder and attention deficit hyperactivity disorder (ADHD). If PIU and these co-occurring disorders could be explained by shared risk factors or better as secondary disorders is largely unknown. The treatment currently is based on therapeutical interventions and strategies successful in the treatment of substance use disorders. Due to the lack of methodological sufficient research it is currently impossible to recommend any evidence-based treatment of PIU.

[MR sialography: evaluation of an ultra-fast sequence in consideration of a parallel acquisition technique and different functional conditions in patients with salivary gland diseases]. / MR-Sialographie: Prospektive Evaluation ultraschneller Sequenzen mit paralleler Bildgebung und oraler Stimulation bei Patienten.

PURPOSE: To evaluate an ultra-fast sequence for MR sialography requiring no post-processing and to compare the acquisition technique regarding the effect of oral stimulation with a parallel acquisition technique in patients with salivary gland diseases. MATERIALS AND METHODS: 128 patients with salivary gland disease were prospectively examined using a 1.5-T superconducting system with a 30 mT/m maximum gradient capability and a maximum slew rate of 125 mT/m/sec. A single-shot turbo-spin-echo sequence (ss-TSE) with an acquisition time of 2.8 sec was used in transverse and oblique sagittal orientation. All images were obtained with and without a parallel imaging technique. The evaluation of the ductal system of the parotid and submandibular gland was performed using a visual scale of 1-5 for each side. The images were assessed by two independent experienced radiologists. An ANOVA with post-hoc comparisons and an overall two tailed significance level of p = 0.05 was used for the statistical evaluation. An intraclass correlation was computed to evaluate interobserver variability and a correlation of > 0.8 was determined, thereby indicating a high correlation. RESULTS: Depending on the diagnosed diseases and the absence of abruption of the ducts, all parts of excretory ducts were able to be visualized in all patients using the developed technique with an overall rating for all ducts of 2.70 (SD +/- 0.89). A high correlation was achieved between the two observers with an intraclass correlation of 0.73. Oral application of a sialogogum improved the visibility of excretory ducts significantly (p < 0.001). In contrast, the use of a parallel imaging technique led to a significant decrease in image quality (p = 0,011). CONCLUSION: The applied ss-TSE for MR sialography allows fast and sufficient visualization of the excretory ducts of the main salivary glands in patients, and no elaborate post-processing is required. Use of an oral sialogogum is suggested to improve the results of MR sialography.

Thrombomodulin-dependent protein C activation is required for mitochondrial function and myelination in the central nervous system.

Essentials The role of protein C (PC) activation in experimental autoimmune encephalitis (EAE) is unknown. PC activation is required for mitochondrial function in the central nervous system. Impaired PC activation aggravates EAE, which can be compensated for by soluble thrombomodulin. Protection of myelin by activated PC or solulin is partially independent of immune-modulation. SUMMARY: Background Studies with human samples and in rodents established a function of coagulation proteases in neuro-inflammatory demyelinating diseases (e.g. in multiple sclerosis [MS] and experimental autoimmune encephalitis [EAE]). Surprisingly, approaches to increase activated protein C (aPC) plasma levels as well as antibody-mediated inhibition of PC/aPC ameliorated EAE in mice. Hence, the role of aPC generation in demyelinating diseases and potential mechanisms involved remain controversial. Furthermore, it is not known whether loss of aPC has pathological consequences at baseline (e.g. in the absence of disease). Objective To explore the role of thrombomodulin (TM)-dependent aPC generation at baseline and in immunological and non-immunological demyelinating disease models. Methods Myelination and reactive oxygen species (ROS) generation were evaluated in mice with genetically reduced TM-mediated protein C activation (TMPro/Pro ) and in wild-type (WT) mice under control conditions or following induction of EAE. Non-immunological demyelination was analyzed in the cuprizone-diet model. Results Impaired TM-dependent aPC generation already disturbs myelination and mitochondrial function at baseline. This basal phenotype is linked with increased mitochondrial ROS and aggravates EAE. Reducing mitochondrial ROS (p66Shc deficiency), restoring aPC plasma levels or injecting soluble TM (solulin) ameliorates EAE in TMPro/Pro mice. Soluble TM additionally conveyed protection in WT-EAE mice. Furthermore, soluble TM dampened demyelination in the cuprizone-diet model, demonstrating that its myelin-protective effect is partially independent of an immune-driven process. Conclusion These results uncover a novel physiological function of TM-dependent aPC generation within the CNS. Loss of TM-dependent aPC generation causes a neurological defect in healthy mice and aggravates EAE, which can be therapeutically corrected.

Cyclic AMP-induced chloride permeability in the apical membrane of Necturus gallbladder epithelium.

The effects of theophylline, 8-Br-cAMP, and cAMP on necturus gallbladder epithelium were investigated using microelectrode techniques. Each of these substances depolarized the cell membranes by approximately 15 mV and decreased the apparent ratio of apical to basolateral membrane resistances to a value not significantly different from zero. Examination of the ionic selectivity of the apical membrane by ion substitutions in the mucosal bathing medium revealed a large increase in Cl permeability with no apparent changes in K and Na permeabilities. Intracellular Cl activity ((a)CL(i)) was measured using Cl- sensitive liquid ion-exchanger microelectrodes. Under control conditions, (a)Cl(i) was approximately 20 mM, 2.5 times higher than the value expected for equilibrium distribution ((a)Cl(i/eq). After addition of 8-Br-cAMP, (a)Cl(i) decreased within less than 60 s to approximately 13 mM, a value not significantly different from ((a)Cl(i/eq)). Virtually identical results were obtained with theophylline. Under control conditions, luminal Cl removal caused (a)Cl(i) to fall at an initial rate of 1.8 mM/min, whereas in tissues exposed to 8-Br- cAMP or theophylline a rate of 11.6 mM/min was observed. The apical membrane Cl transference number was estimated from the change of (a)Cl(i) upon exposure to 8-Br-cAMP as well as from the changes in apical membrane potential during variation of the luminal Cl concentration. The results, 0.91 and 0.88, respectively, are indicative of a high Cl permeability of the apical membrane during cAMP. This effect may explain, at least in part, the complete inhibition of fluid absorption produced by theophylline in this tissue. Moreover, enhancement of apical membrane Cl permeability may account for a variety of cAMP effects in epithelial tissues.

Cyclic AMP inhibits Na+/H+ exchange at the apical membrane of Necturus gallbladder epithelium.

The effects of elevating intracellular cAMP levels on Na+ transport across the apical membrane of Necturus gallbladder epithelium were studied by intracellular and extracellular microelectrode techniques. Intracellular cAMP was raised by serosal addition of the phosphodiesterase inhibitor theophylline (3 mM) or mucosal addition of either 8-Br-cAMP (1 mM) or the adenylate cyclase activator forskolin (10 microM). During elevation of intracellular cAMP, intracellular Na+ activity (alpha Nai) and intracellular pH (pHi) decreased significantly. In addition, acidification of the mucosal solution, which contained either 100 or 10 mM Na+, was inhibited by approximately 50%. The inhibition was independent of the presence of Cl- in the bathing media. The rates of change of alpha Nai upon rapid alterations of mucosal [Na+] from 100 to 10 mM and from 10 to 100 mM were both decreased, and the rate of pHi recovery upon acid loading was also reduced by elevated cAMP levels. Inhibition was approximately 50% for all of these processes. These results indicate that cAMP inhibits apical membrane Na+/H+ exchange. The results of measurements of pHi recovery at 10 and 100 mM mucosal [Na+] and a kinetic analysis of recovery as a function of pHi suggest that the main or sole mechanism of the inhibitory effect of cAMP is a reduction in the maximal rate of acid extrusion. In conjunction with the increase in apical membrane electrodiffusional Cl- permeability, produced by cAMP, which causes a decrease in net Cl- entry (Petersen, K.-U., and L. Reuss, 1983, J. Gen. Physiol., 81:705), inhibition of Na+/H+ exchange contributes to the reduction of fluid absorption elicited by this agent. Similar mechanisms may account for the effects of cAMP in other epithelia with similar transport properties. It is also possible that inhibition of Na+/H+ exchange by cAMP plays a role in the regulation of pHi in other cell types.

Mental disorders in current and former heavy ecstasy (MDMA) users.

BACKGROUND: Ecstasy use has often been found to be associated with psychopathology, yet this research has so far been based largely on subjective symptom ratings. AIMS: To investigate whether ecstasy users suffered from long-term psychopathological consequences. MEASUREMENTS: We compared the prevalence of Diagnostic and Statistical Manual version IV (DSM-IV) mental disorders in 30 current and 29 former ecstasy users, 29 polydrug and 30 drug-naive controls. Groups were approximately matched by age, gender and level of education. The current ecstasy users reported a life-time dose of an average of 821 and the former ecstasy users of 768 ecstasy tablets. FINDINGS: Ecstasy users did not significantly differ from controls in the prevalence of mental disorders, except those related to substance use. Substance-induced affective, anxiety and cognitive disorders occurred more frequently among ecstasy users than polydrug controls. The life-time prevalence of ecstasy dependence amounted to 73% in the ecstasy user groups. More than half of the former ecstasy users and nearly half of the current ecstasy users met the criteria of substance-induced cognitive disorders at the time of testing. Logistic regression analyses showed the estimated life-time doses of ecstasy to be predictive of cognitive disorders, both current and life-time. CONCLUSIONS: The motivation for ecstasy use is not likely to be self-medication of pre-existing depressive or anxiety disorders as these did not occur more frequently in the ecstasy users than in control groups or in the general population. Cognitive disorders still present after over 5 months of ecstasy abstinence may well be functional consequences of serotonergic neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA).

[MR-sialography: optimisation and evaluation of an ultra-fast sequence in parallel acquisition technique and different functional conditions of salivary glands]. / MR-Sialographie: Optimierung und Bewertung ultraschneller Sequenzen mit paralleler Bildgebung und oraler Stimulation.

PURPOSE: To optimise a fast sequence for MR-sialography and to compare a parallel and non-parallel acquisition technique. Additionally, the effect of oral stimulation regarding the image quality was evaluated. MATERIAL AND METHODS: All examinations were performed by using a 1.5-T superconducting system. After developing a sufficient sequence for MR-sialography, a single-shot turbo-spin-echo sequence (ss-TSE) with an acquisition time of 2.8 sec was used in transverse and oblique sagittal orientation in 27 healthy volunteers. All images were performed with and without parallel imaging technique. The assessment of the ductal system of the submandibular and parotid gland was performed using a 1 to 5 visual scale for each side separately. Images were evaluated by four independent experienced radiologists. For statistical evaluation, an ANOVA with post-hoc comparisons was used with an overall two-tailed significance level of P =.05. For evaluation of interobserver variability, an intraclass correlation was computed and correlation >.08 was determined to indicate a high correlation. RESULTS: All parts of salivary excretal ducts could be visualised in all volunteers, with an overall rating for all ducts of 2.26 (SD +/- 1.09). Between the four observers a high correlation could be obtained with an intraclass correlation of 0.9475. A significant influence regarding the slice angulations could not be obtained (p = 0.74). In all healthy volunteers the visibility of excretory ducts improved significantly after oral application of a Sialogogum (p < 0.001; eta (2) = 0.049). The use of a parallel imaging technique did not lead to an improvement of visualisation, showing a significant loss of image quality compared to an acquisition technique without parallel imaging (p < 0.001; eta (2) = 0.013). CONCLUSION: The optimised ss-TSE MR-sialography seems to be a fast and sufficient technique for visualisation of excretory ducts of the main salivary glands, with no elaborate post-processing needed. To improve results of MR-sialography, it is reasonable to use an oral Sialogogum.

Review article: omeprazole and the cytochrome P450 system.

Enzymes of the cytochrome P450 superfamily play a key role in xenobiotic metabolism. Their properties and significance are discussed with particular reference to interactions with the H+,K(+)-ATPase blocker, omeprazole. Such interactions include both inhibitory (subfamily 2C) and inducing effects (subfamily 1A). Delayed metabolic elimination of diazepam, warfarin, carbamazepin and phenytoin is probably due to omeprazole competition for the concerned isoform of subfamily 2C; however, these effects are modest to negligible in magnitude and, for phenytoin, not consistently reproducible. Also, induction of subfamily 1A is only minor as assessed from the resultant changes in N-3-demethylation of caffeine, a reaction specific to this subfamily. Concerns about a possible activation of procarcinogens that might arise from subfamily 1A induction appear ill-founded given the fact that cruciferous vegetables such as broccoli and Brussels sprouts are potent inducers, but rather seem to lower the incidence of certain types of cancer. Likewise, the idea that the toxicity of acetaminophen might increase upon subfamily 1A induction appears far-fetched, mainly because much stronger inducers of subfamily 1A (cigarette smoke and charcoaled beef) are unable to alter acetaminophen metabolism.

A summary of Food and Drug Administration-reported adverse events and drug interactions occurring during therapy with omeprazole, lansoprazole and pantoprazole.

BACKGROUND: Pantoprazole is claimed to have a lower potential for drug interaction than other proton pump inhibitors. AIM: To estimate the frequency of adverse events and drug interactions reported to the Food and Drug Administration in patients receiving omeprazole, lansoprazole or pantoprazole. METHODS: The study involved a search of the Food and Drug Administration's database for adverse events and drug interactions with omeprazole, lansoprazole or pantoprazole as primary or secondary suspect drug. An estimate of the amount of drug dispensed during the adverse event collection period (from US drug launch) was obtained from the International Medical Statistics health database. RESULTS: Of the suspected drug interactions recorded, vitamin K antagonist interactions, although rare, were the most common. The frequency of vitamin K antagonist interactions was 0.09 per million packages for omeprazole and 0.11 per million packages for lansoprazole and pantoprazole. Interactions with benzodiazepines or phenytoin were even rarer, being reported in less than 10 patients on each proton pump inhibitor. CONCLUSION: The frequency of reported drug interactions was low for omeprazole, lansoprazole and pantoprazole and vitamin K antagonist interactions were by far the most common. These potentially important drug interactions, although rare, were no less frequent on pantoprazole than on omeprazole or lansoprazole, suggesting a class effect.

Naloxone-insensitive transport effects of loperamide in guinea-pig gallbladder epithelium.

The effects of the antidiarrheal drug, loperamide, on HCO3 and Na transport across guinea-pig gallbladder epithelium were investigated using Ussing-chamber methods. Under basal conditions, mucosal loperamide (10(-4) mol/l) moderately lowered both the absorptive (JHCO3ms) and the secretory HCO3 flux (JHCO3sm) (pH-stat method), most likely by changing paracellular HCO3 flow. Exposure to serosal prostaglandin E1 (10(-6) mol/l) abolished Na absorption and turned HCO3 secretion electrogenic. The associated short-circuit current (Isc) was inhibited by loperamide in a concentration-dependent manner; mucosal addition (threshold at 3 x 10(-6) mol/l) of the drug was more effective. Inhibition of Isc was related to a decrease in JHCO3sm, but exceeded the drop in JHCO3net. The effects on JHCO3sm and Isc were mimicked by [Met5]enkephalin. Naloxone (10(-6) mol/l) was unable to influence the effects of loperamide and [Met5]enkephalin on Isc. There were no pro-absorptive effects of loperamide on unidirectional Na fluxes. We conclude that antisecretory properties of loperamide are solely due to inhibition of electrogenic HCO3 secretion, an effect unrelated to opiate receptor binding.