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1. The potential interaction between selective beta 1-adrenoceptor blockers and sulphonylureas or biguanides was studied by comparing the beta 1-adrenoceptor antagonist betaxolol with placebo in 12 normal subjects taking glibenclamide or metformin in a single-blind crossover group study. 2. After a 4 day run-in period on no treatment, six subjects took glibenclamide 2.5 mg twice daily, and six subjects took metformin 850 mg twice daily from day 5 to day 19. All subjects took betaxolol 20 mg daily from day 10 to day 13, and placebo from day 5 to day 10 and from day 13 to day 19. 3. Plasma glucose and insulin concentrations were measured fasting and 60 min after a standard breakfast for 3 successive days during each study treatment; plasma potassium, sodium and betaxolol concentrations were also measured. 4. Fasting glucose, insulin and potassium concentrations did not differ significantly between betaxolol and placebo treatment periods in either glibenclamide- or metformin-treated groups. Post-prandial glucose and insulin concentrations were lower and higher, respectively, relative to fasting concentrations but there was no significant difference between any of the treatment periods. Glibenclamide produced significant increases in insulin concentrations compared with drug-free periods (P less than 0.01). Plasma potassium and sodium concentrations were not affected by any of the treatments. 5. Plasma betaxolol concentrations were adequate for beta 1-adrenoceptor blockade. 6. This study suggests that selective beta 1-adrenoceptor blockade with betaxolol does not change fasting or post-prandial glucose-insulin relationships during simultaneous treatment with either the sulphonylurea glibenclamide or the biguanide metformin. [ABSTRACT FROM AUTHOR]

1. The cardiovascular and anticholinergic effects of femoxetine and amitriptyline were compared with those of placebo in a double-blind cross-over trial in 12 healthy men. The daily doses administered were therapeutic: 600 mg femoxetine and 150 mg amitriptyline. Duration of treatment with each drug was 13 days. 2. The statistically significant effects on systolic time intervals and ECG comprised a larger decrease of QS2 index during femoxetine than during amitriptyline, and an increase of PEP/LVET ratio and QRS duration by amitriptyline. These results suggest that femoxetine and, to a lesser extent, amitriptyline increase contractility compared with placebo, and amitriptyline, but not femoxetine, causes delay in intracardiac conduction. 3. The effects of amitriptyline on the systolic time intervals are difficult to interpret because of the changes in heart rate and intracardiac electrical conduction caused by the drug. These problems of interpretation are discussed. 4. No significant changes in blood pressure were observed. The heart rate during both femoxetine and amitriptyline periods was significantly faster than during the placebo period, amitriptyline causing a significantly greater increase. 5. Salivary secretion was decreased more by amitriptyline (26%) than by femoxetine (8%), the latter being not significantly different from placebo. Femoxetine tended to increase pupil diameter and amitriptyline to increase accommodation near point, but no visual disturbances were reported on any treatment. Symptoms such as dry mouth, constipation and sedation were significantly less frequently reported during femoxetine than during amitriptyline treatment. [ABSTRACT FROM AUTHOR]

1. Alfuzosin is a post-synaptic alpha-adrenoceptor antagonist with antihypertensive and peripheral vasodilator properties. 2. We measured the effect of alfuzosin, 5 mg, on sympathetically-mediated venoconstriction by changes in the venous reflex response (VRR) in a randomised, double-blind, placebo-controlled, crossover study in a group of 10 healthy volunteers. 3. There was a significant inhibition of the VRR after alfuzosin compared with placebo (P less than 0.001) which was present 1 h after the dose and still evident at 6 h. 4. Supine blood pressure was significantly lower (P less than 0.01) and supine heart rate was significantly higher (P less than 0.001) after alfuzosin compared with placebo. 5. Inhibition of the VRR by alfuzosin was observed to precede the development of reflex tachycardia. [ABSTRACT FROM AUTHOR]

1. We have examined the problem of how systolic time intervals (STI) should be corrected for heart rate in clinical pharmacological studies. 2. 'Individual' linear regression equations describing the relationship between STI and heart rate were derived for each of 43 healthy young adults (30 men and 13 women) by measuring STI at different heart rates produced by incremental doses of intravenous atropine. 'Population' equations for each sex were obtained by taking the mean of the 'individual' regression coefficients. 3. In order to assess which method more effectively reduced variability of the STI, 'individual' regression coefficients were derived for eight men who had previously participated in a placebo-controlled study which had used STI to test the cardiovascular effects of calcium antagonists alone and in combination with propranolol. 4. Within-subject variability in rate- corrected STI was similar after application of 'individual' and 'population' regression equations. Between-subject variability tended to be less after the use of 'population' equations. 5. 'Population' regression equations were more effective than 'individual' regression equations in allowing detection of differences between treatments, as judged by F values from ANOVA. 6. In clinical pharmacological studies including measurements of STI in healthy young subjects, 'individual' regression equations appear to have no advantage over 'population' equations derived in a group of subjects of similar age and sex. [ABSTRACT FROM AUTHOR]

Plasma concentrations and haemodynamic effects at rest and during exercise have been measured in six healthy volunteers after single oral dosing with two Oros drug delivery systems containing 190 mg metoprolol fumarate but with initial release rates of 14 and 19 mg/h, respectively. Sub-maximal exercise heart rates were attenuated by both Oros systems throughout most of the 30 h study period but no significant differences were detected between the 14/190 and 19/190 forms. Resting pulse rates and blood pressure were similarly affected by the Oros preparations. Approximately the same amount of drug reached the circulation from the Oros systems, but the 19/190 form produced higher peak concentrations at earlier times after dosing. At 24 h higher plasma concentrations were observed for the 14/190 preparation, reflecting its longer duration of drug release. There was no apparent advantage of one form over the other as regards haemodynamic response. The reduced peak plasma concentration with 14/190 Oros may, however, be an advantage in terms of tolerability. [ABSTRACT FROM AUTHOR]

Oxprenolol was administered in single doses by mouth to healthy volunteers either in a polymer-matrix slow-release formulation (Slow Trasicor) or in osmotic drug-delivery systems (oxprenolol Oros). Plasma oxprenolol concentrations and heart rates after exercise were measured. Plasma concentrations of the drug were maximal at 3 h but negligible at 24 h after administration of Slow Trasicor. Following ingestion of the Oros systems measurable concentrations were maintained throughout 24 h. Significant reduction of exercise-induced tachycardia persisted for 24 h after administration of oxprenolol Oros. With Slow Trasicor heart rate responses had returned to baseline values by this time. The osmotic drug-delivery systems appear to sustain significant beta- adrenoceptor blockade for 24 h after a single oral dose. [ABSTRACT FROM AUTHOR]

A new osmotic drug delivery system (Oros) has been evaluated in multiple-dose studies in young healthy volunteers as a sustained- release vehicle for once-daily administration of oxprenolol. Two Oros systems were examined in two separate studies, one containing 170 mg oxprenolol succinate with an initial zero-order release rate of 10 mg/h, and the other containing 260 mg oxprenolol succinate with an initial release rate of 16 mg/h. These were compared respectively with conventional oxprenolol hydrochloride (Trasicor) 80 mg twice daily and polymer-matrix oxprenolol hydrochloride (Slow Trasicor) 160 mg once daily. Variations in mean plasma levels and beta-adrenoceptor blockade (measured by inhibition of exercise tachycardia) were considerably reduced on the 10/170 Oros once-daily compared with the Trasicor 80 mg twice-daily regimen. With both formulations there was no significant change in mean plasma concentrations or areas under the curve after 8 days' treatment, and similar pre-dose plasma concentrations were obtained. There was significant inhibition of exercise tachycardia throughout 24 h after the 10/170 Oros on the eighth day. The 16/260 Oros system gave smoother pharmacokinetic and pharmacodynamic profiles, and on repeated dosing a higher mean pre-dose plasma oxprenolol concentration than Slow Trasicor. Drug availability was similar for the two dose forms, suggesting an acceptable level of absorption of oxprenolol from most of the gastrointestinal tract. On the eighth day exercise heart rate was significantly reduced throughout 24 h with 16/260 oxprenolol Oros, but only between 1 and 15 h with Slow Trasicor. [ABSTRACT FROM AUTHOR]

The influence of the site of drug delivery on the systemic availability of metoprolol has been evaluated by measuring plasma drug concentrations in six healthy volunteers after administration of a continuous 13.5 h intragastric infusion and a 14/190 Oros controlled- release dosage form, on two separate occasions. The same total amount of drug was administered at the same rate on both occasions but the Oros system moved through the gut whereas the site of the infusion was constant. The differences between treatments were confined largely to the period 6-15 h after dosing when lower plasma concentrations were obtained after administration of the Oros system. The levels after 20 h were higher for Oros, however, reflecting its longer duration of drug release. The amount of drug reaching the circulation was 19.8% less for the Oros preparation compared with intragastric infusion but this was not due to incomplete release since the residual amounts of drug in three systems recovered from faeces corresponded to less than 12% of the administered dose. Analysis of the plasma profiles by the Wagner- Nelson method indicated a reasonable agreement between in vitro release and in vivo absorption. The appearance of drug in plasma was delayed for both treatments, and for Oros the apparent absorption rate slowed 6 h after dosing. Plasma profiles after 14/190 metoprolol Oros were consistent with prolonged in vivo delivery and absorption from the gut. The absorption process, however, was associated with some reduction both in the rate, after 6 h, and in the total amount reaching the circulation. [ABSTRACT FROM AUTHOR]

The pharmacodynamic effects of single doses of trazodone (100 mg), amitriptyline (50 mg) or placebo either alone or with ethanol (0.5 ml/kg) were investigated in six healthy volunteers in a double-blind crossover study. Plasma concentrations of the drugs and ethanol were also measured. Pharmacodynamic tests were critical flicker fusion frequency threshold (CFF), choice reaction time (CRT), manual dexterity, a digit span test and visual analogue scales. Blood ethanol concentrations were not influenced by the co-administration of either antidepressant. tmax for trazodone was prolonged by ethanol but the other pharmacokinetic parameters for trazodone and amitriptyline were not influenced by ethanol. Trazodone and amitriptyline caused the expected profound depressant effects on CFF, CRT, manual dexterity and on the rating scales for drowsiness, 'clear-headedness', aggression and disinhibition. Ethanol alone impaired manual dexterity, increased drowsiness, reduced 'clear headedness' and also tended to reduce feelings of aggression. In combination with either trazodone or amitriptyline, ethanol caused little additional effect except in the case of manual dexterity which was further impaired. This result may reflect the profound effects of the antidepressants alone and does not suggest that it is safe for patients receiving antidepressant medication to take ethanolic drinks. [ABSTRACT FROM AUTHOR]

Treatment of angina pectoris with beta-adrenoceptor antagonists and verapamil in combination is effective and increasingly common. The study reported here was designed to show whether the pharmacokinetics of verapamil are influenced by concurrent treatment with three different beta-adrenoceptor blockers, and whether there is any pharmacodynamic interaction between these drugs. Twelve healthy volunteers (eight men, four women) aged 21-25 years and weighing 48-82 kg consented to participate in the study. They received verapamil 50 mg three times daily for four 1-week periods, each separated by a 1 week 'washout' period. During three of the four treatment periods, the subjects took either atenolol 100 mg once daily, metoprolol 100 mg twice daily or propranolol 80 mg twice daily; in the remaining period they took verapamil alone. The concentration/time curve and plasma elimination half-life of verapamil and norverapamil, its major metabolite, were not influenced by 1 weeks co-administration atenolol, metoprolol or propranolol. As expected, co-administration of each of the beta-adrenoceptor blockers significantly reduced exercise heart rate when compared with verapamil alone. [ABSTRACT FROM AUTHOR]

1 The acute cardiovascular response to nicardipine was investigated using non invasive techniques in normal subjects. 2 In six subjects, i.v. nicardipine in an increasing dose (0.5-20 mg) was compared with saline, under double-blind conditions. A dose related increase in heart rate and fall in blood pressure were found. Pre-ejection period (PEP) and PEP/left ventricular ejection time (LVET) ratio of the systolic time intervals were shortened in a clearly dose related manner. Total electromechanical systole index (QS2 I) was decreased and LVET index prolonged. 3 In four subjects increasing oral doses (10-40 mg) of nicardipine, administered in a randomized double-blind placebo control design, demonstrated the same pattern, marked changes being found with the 40 mg dose. 4 Comparison with nifedipine in a double-blind-placebo controlled balanced trial in six subjects confirmed that 40 mg nicardipine and 20 mg nifedipine exhibited similar effects. Maximum response was reached between 0.5 and 1.5 h, and changes in some cardiovascular variables were still evident at 3 h. [ABSTRACT FROM AUTHOR]

1 The pharmacological effects and plasma levels of diacetolol, the major human metabolite of acebutolol, were measured in a double-blind, balanced study in which five healthy men received single oral doses of diacetolol 100, 200, 400 and 800 mg, or placebo, at weekly intervals. 2 Resting and exercise heart rate (HR), forced expiratory volume in 1 second (FEV1), resting and exercise peak expiratory flow rate (PEFR), and plasma concentrations of diacetolol were determined at 0, 2, 4, 6, 8 and 24 h after each treatment. 3 Diacetolol caused a slight dose- related reduction in resting HR and a substantial dose-related reduction in exercise HR. AT the same time it was found that diacetolol had no significant effects on FEV1 and resting and exercise PEFR. 4 Mean highest observed plasma concentrations (ng/ml) of diacetolol were 177 at a mean of 4.4 h after the 100 mg dose, 243 at 4.0 h after the 200 mg dose, 807 at 5.2 h after the 400 mg dose, and 1,306 at 4.4 h after the 800 mg dose. 5 Using the mean data, there was a strong correlation (r = 0.90) between % reduction in exercise HR and the logarithm of the plasma concentration of diacetolol. 6 Diacetolol exhibits marked cardiac beta-adrenoceptor blocking activity in man which is still evident 24 h after the administration of the higher doses of the drug. No adverse effects on pulmonary function could be detected. [ABSTRACT FROM AUTHOR]

1 The effects of beta-adrenoceptor antagonists given intravenously in single doses were examined in a double-blind, placebo controlled study performed in six healthy volunteers. Heart rate and peak expiratory flow rate (PEFR) were measured at rest and during standardised exercise. 2 Atenolol 0.2 mg/kg, betaxolol 0.15 mg/kg, practolol 1 mg/kg and propranolol 0.2 mg/kg all reduced heart rate to a similar extent during exercise at 2 and 4 h after administration; betaxolol 0.6 mg/kg had a significantly greater effect than the other treatments at all times. Only betaxolol 0.15 and 0.6 mg/kg significantly inhibited exercise tachycardia at 24 h. 3 None of the treatments studied had any effect on PEFR at rest or during exercise. 4 A second study was performed to determine whether this lack of effect of propranolol on exercise PEFR could have been due to the warm and humid conditions prevailing during the experiment. Eight healthy men underwent a standardised exercise test under alternately 'warm and humid' and 'cool and dry' conditions before and after propranolol 0.2 mg/kg or saline placebo intravenously. 5 Propranolol treatment did not influence resting or exercise PEFR in either environment, but did reduce FEV1 immediately after exercise under the cool and dry conditions but not under the warm and humid conditions. 6 Comparison of the effects of beta-adrenoceptor antagonists on exercise heart rate and PEFR is not a reliable or sensitive method of measuring the cardioselectivity of these drugs. 7 Environmental temperature and humidity should ideally be controlled when the action of any drug on airflow resistance is being studied. [ABSTRACT FROM AUTHOR]

1 In normal subjects, intravenous betaxolol given in doses which inhibited the tachycardia of exercise failed to affect the peak expiratory flow rate. 2 From 2 to 48 h after administration of 150 micrograms/kg in four normal subjects, there was no significant difference between the blood levels, whether given orally or intravenously. 3 At all times, heart rate and blood pressure, at rest and during exercise, were reduced equally after administration by both routes, but the area under the curve of exercise heart rate against time was significantly smaller (P < 0.05) after intravenous drug. 4 The absolute bioavailability of betaxolol was 89 +/- 5%. [ABSTRACT FROM AUTHOR]

1 The pharmacokinetics of disopyramide were studied after the oral administration of a 300 mg dose to 11 patients with stable chronic renal impairment (creatinine clearance 2-53 ml min-1). 2 Absorption half-life and volume of distribution were similar to those seen in normal subjects. 3 Mean plasma elimination half-life in these patients was 12.7 h, which is substantially greater than that reported for normal subjects. Elimination half-life tended to increase as creatinine clearance fell, and renal clearance of disopyramide correlated significantly (r=0.814; P < 0.001) with creatinine clearance. 4 From these results, we have calculated that patients with renal impairment should be started on a dose of disopyramide 1.5 mg kg-1 thrice daily and the regimen subsequently altered according to plasma concentrations of the drug. However, further studies are needed to define the handling of the metabolites of disopyramide. [ABSTRACT FROM AUTHOR]

Metastasizing cells express the intermediate filament protein vimentin, which is used to diagnose invasive tumors in the clinic. However, the role of vimentin in cell motility, and if the assembly of non-filamentous variants of vimentin into filaments regulates cell migration remains unclear. We observed that the vimentin-targeting drug ALD-R491 increased the stability of vimentin filaments, by reducing filament assembly and/or disassembly. ALD-R491-treatment also resulted in more bundled and disorganized filaments and an increased pool of non-filamentous vimentin. This was accompanied by a reduction in size of cell-matrix adhesions and increased cellular contractile forces. Moreover, during cell migration, cells showed erratic formation of lamellipodia at the cell periphery, loss of coordinated cell movement, reduced cell migration speed, directionality and an elongated cell shape with long thin extensions at the rear that often detached. Taken together, these results indicate that the stability of vimentin filaments and the soluble pool of vimentin regulate the speed and directionality of cell migration and the capacity of cells to migrate in a mechanically cohesive manner. These observations suggest that the stability of vimentin filaments governs the adhesive, physical and migratory properties of cells, and expands our understanding of vimentin functions in health and disease, including cancer metastasis., Competing Interests: Authors DS and RC were employed by Aluda Pharmaceuticals, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Warrington, López-Guajardo, Al Hennawi, Cook, Griffith, Symmes, Zhang, Qu, Xu, Chen and Gad.)

Planar polarity describes the coordinated polarization of cells within a tissue plane, and in animals can be determined by the "core" or Fat-Dachsous pathways. Current models for planar polarity establishment involve two components: tissue-level "global" cues that determine the overall axis of polarity and cell-level feedback-mediated cellular polarity amplification. Here, we investigate the contributions of global cues versus cellular feedback amplification in the core and Fat-Dachsous pathways during Drosophila pupal wing development. We present evidence that these pathways generate planar polarity via distinct mechanisms. Core pathway function is consistent with strong feedback capable of self-organizing cell polarity, which can then be aligned with the tissue axis via weak or transient global cues. Conversely, generation of cell polarity by the Ft-Ds pathway depends on strong global cues in the form of graded patterns of gene expression, which can then be amplified by weak feedback mechanisms., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Here, we present a detailed protocol for fluorescence recovery after photobleaching (FRAP) to measure the dynamics of junctional populations of proteins in living tissue. Specifically, we describe how to perform FRAP in Drosophila pupal wings on fluorescently tagged core planar polarity proteins, which exhibit relatively slow junctional turnover. We provide a step-by-step practical guide to performing FRAP, and list a series of controls and optimizations to do before conducting a FRAP experiment. Finally, we describe how to present the FRAP data for publication., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction Transvenous pacemaker insertion is a critical life-saving procedure that is infrequently performed. Traditional mannequin-based training paradigms are resource intensive and sometimes inadequate due to time constraints. Rapid Cycle Deliberate Practice (RCDP) is an effective teaching modality for highly scripted procedures. We propose using a simulation-based technique of RCDP in virtual reality (VR) to teach this procedure. Methods Sixteen emergency medicine residents were recruited. A pre-survey was administered at the start of the session, followed by a baseline task trainer checklist-based assessment. This checklist was created based on expert consensus. Participants then underwent the RCDP VR intervention with a subsequent repeat checklist-based assessment as well as a post-survey.  Results Post-test scores were found to be significantly higher than pre-test scores after residents completed VR deliberate practice simulation (19.5±3.5 vs 24.1±2.0; p<0.001). Subanalysis did not reveal any significant difference based on post-graduate year, previous performance of procedure on a live patient, or previous VR experience. The experience increased participant feelings of preparedness and comfort in performing the procedure (2-disagree vs 4-agree) based on a 5-point Likert scale.  Conclusions Virtual reality using RCDP to teach transvenous pacemaker insertion demonstrated an improvement in task trainer performance. Further investigation into whether this translates into better patient outcomes or can be generalized to other procedures needs to be considered., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Peng et al.)

Relebactam is a novel class A and C β-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg) and multiple-dose (50 to 625 mg every 6 h [q6h] for 7 to 14 days) escalation study with men and (ii) a single-dose (125 mg) study with women and elderly individuals. Following single- or multiple-dose intravenous administration over 30 min, plasma relebactam concentrations declined biexponentially, with a terminal half-life ( t 1/2 ) ranging from 1.35 to 1.85 h independently of the dose. Exposures increased in a dose-proportional manner across the dose range. No clinically significant differences in pharmacokinetics between men and women, or between adult and elderly participants, were observed. Urine pharmacokinetics demonstrated that urinary excretion is the major route of relebactam elimination. No drug-drug interaction between relebactam and imipenem-cilastatin was observed, and the observed t 1/2 values for relebactam, imipenem, and cilastatin were comparable, thus supporting coadministration. Relebactam administered alone or in combination with imipenem-cilastatin was well tolerated across the dose ranges studied. No serious adverse events or deaths were reported. The pharmacokinetic profile and favorable safety results supported q6h dosing of relebactam with imipenem-cilastatin in clinical treatment trials., (Copyright © 2018 Rhee et al.)

The core planar polarity pathway coordinates epithelial cell polarity during animal development, and loss of its activity gives rise to a range of defects, from aberrant morphogenetic cell movements to failure to correctly orient structures, such as hairs and cilia. The core pathway functions via a mechanism involving segregation of its protein components to opposite cells ends, where they form asymmetric intracellular complexes that couple cell-cell polarity. This segregation is a self-organizing process driven by feedback interactions between the core proteins themselves. Despite intense efforts, the molecular pathways underlying feedback have proven difficult to elucidate using conventional genetic approaches. Here we investigate core protein function during planar polarization of the Drosophila wing by combining quantitative measurements of protein dynamics with loss-of-function genetics, mosaic analysis, and temporal control of gene expression. Focusing on the key core protein Frizzled, we show that its stable junctional localization is promoted by the core proteins Strabismus, Dishevelled, Prickle, and Diego. In particular, we show that the stabilizing function of Prickle on Frizzled requires Prickle activity in neighboring cells. Conversely, Prickle in the same cell has a destabilizing effect on Frizzled. This destabilizing activity is dependent on the presence of Dishevelled and blocked in the absence of Dynamin and Rab5 activity, suggesting an endocytic mechanism. Overall, our approach reveals for the first time essential in vivo stabilizing and destabilizing interactions of the core proteins required for self-organization of planar polarity., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: FP-01.1 is a novel synthetic influenza A vaccine consisting of six fluorocarbon-modified 35-mer peptides that encapsulate multiple CD4+ and CD8+ T-cell epitopes and is designed to induce an immune response across a broad population., Methods: FP-01.1 was evaluated for safety and immunogenicity in a randomised, double-blind, placebo-controlled, dose-escalation, phase I clinical study in healthy adult volunteers (n=49). IFNγ ELISpot assays and multicolour flow cytometry were used to characterise the immune response., Results: FP-01.1 was safe and well tolerated at all doses tested with a similar adverse event profile in actively vaccinated subjects compared with controls. Maximum immunogenicity was in the 150 μg/peptide dose group where a robust response (243 spots/million PBMC) was demonstrated in 75% subjects compared with 0% in placebo controls. All six peptides were immunogenic. FP-01.1 induced dual CD4+ and CD8+ T cell responses and vaccine-specific T cells cross-recognise divergent influenza strains., Conclusions: This first-in-human study showed that FP-01.1 has an acceptable safety and tolerability profile and generated robust anti-viral T cell responses in a high proportion of subjects tested. The results support the further clinical testing of FP-01.1 prior to clinical, proof-of-concept, live viral challenge studies., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection., Methods: Four healthy men each received two single, 100 μg microdoses of ¹⁴C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of ¹⁴C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 μg microdose of ¹⁴C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS., Results: After IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8-12 h after IV dosing, ¹⁴C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, ¹⁴C was still mostly associated with AR-709 at 12 h after dosing., Conclusions: The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.

Morphogenesis is dependent on the orchestration of multiple developmental processes to generate mature functional organs. However, the signalling pathways that coordinate morphogenesis and the mechanisms that translate these signals into tissue shape changes are not well understood. Here, we demonstrate that changes in intercellular adhesion mediated by the transmembrane protein Fasciclin III (FasIII) represent a key mediator of morphogenesis. Using the embryonic Drosophila hindgut as an in vivo model for organogenesis, we show that the tightening of hindgut curvature that normally occurs between embryonic stage 12 and 15 to generate the characteristic shepherd's crook shape is dependent on localised JAK/STAT pathway activation. This localised pathway activity drives the expression of FasIII leading to its subcellular lateralisation at a stage before formation of septate junctions. Additionally, we show that JAK/STAT- and FasIII-dependent morphogenesis also regulates folds within the third instar wing imaginal disc. We show that FasIII forms homophilic intercellular interactions that promote intercellular adhesion in vivo and in cultured cells. To explore these findings, we have developed a mathematical model of the developing hindgut, based on the differential interfacial tension hypothesis (DITH) linking intercellular adhesion and localised surface tension. Our model suggests that increased intercellular adhesion provided by FasIII can be sufficient to drive the tightening of tube curvature observed. Taken together, these results identify a conserved molecular mechanism that directly links JAK/STAT pathway signalling to intercellular adhesion and that sculpts both tubular and planar epithelial shape.

Introduction: Emergency medicine residents use simulation training for many reasons, such as gaining experience with critically ill patients and becoming familiar with disease processes. Residents frequently criticize simulation training using current high-fidelity mannequins due to the poor quality of physical exam findings present, such as auscultatory findings, as it may lead them down an alternate diagnostic or therapeutic pathway. Recently wireless remote programmed stethoscopes (simulation stethoscopes) have been developed that allow wireless transmission of any sound to a stethoscope receiver, which improves the fidelity of a physical examination and the simulation case., Methods: Following institutional review committee approval, 14 PGY1-3 emergency medicine residents were assessed during 2 simulation-based cases using pre-defined scoring anchors on multiple actions, such as communication skills and treatment decisions (Appendix 1). Each case involved a patient presenting with dyspnea requiring management based off physical examination findings. One case was a patient with exacerbation of heart failure, while the other was a patient with a tension pneumothorax. Each resident was randomized into a case associated with the simulation stethoscope. Following the cases residents were asked to fill out an evaluation questionnaire., Results: Residents perceived the most realistic physical exam findings on those associated with the case using the simulation stethoscope (13/14, 93%). Residents also preferred the simulation stethoscope as an adjunct to the case (13/14, 93%), and they rated the simulation stethoscope case to have significantly more realistic auscultatory findings (4.4/5 vs. 3.0/5 difference of means 1.4, p=0.0007). Average scores of residents were significantly better in the simulation stethoscope-associated case (2.5/3 vs. 2.3/3 difference of means 0.2, p=0.04). There was no considerable difference in the total time taken per case., Conclusion: A simulation stethoscope may be a useful adjunct to current emergency medicine simulation-based training. Residents both preferred the use of the simulation stethoscope and perceived physical exam findings to be more realistic, leading to improved fidelity. Potential sources of bias include the small population, narrow scoring range, and the lack of blinding. Further research, focusing on use for resident assessment and clinical significance with a larger population and blinding of graders, is needed.

Polarised tissue elongation during morphogenesis involves cells within epithelial sheets or tubes making and breaking intercellular contacts in an oriented manner. Growing evidence suggests that cell adhesion can be modulated by endocytic trafficking of E-cadherin (E-cad), but how this process can be polarised within individual cells is poorly understood. The Frizzled (Fz)-dependent core planar polarity pathway is a major regulator of polarised cell rearrangements in processes such as gastrulation, and has also been implicated in regulation of cell adhesion through trafficking of E-cad; however, it is not known how these functions are integrated. We report a novel role for the core planar polarity pathway in promoting cell intercalation during tracheal tube morphogenesis in Drosophila embryogenesis, and present evidence that this is due to regulation of turnover and levels of junctional E-cad by the guanine exchange factor RhoGEF2. Furthermore, we show that core pathway activity leads to planar-polarised recruitment of RhoGEF2 and E-cad turnover in the epidermis of both the embryonic germband and the pupal wing. We thus reveal a general mechanism by which the core planar polarity pathway can promote polarised cell rearrangements.

Aims: To assess the steady-state pharmacokinetic and QT(c) effects of domperidone and ketoconazole, given alone and together., Methods: A randomized, placebo-controlled, double-blind, crossover study was carried out. Healthy subjects (14 men, 10 women; age 18-39 years; mean weight 73.5kg, range 53.8-98.8kg; 23 Europid, 1 Afro-Caribbean) received orally, for 7 days each, placebo, domperidone 10mg, four doses daily, at 4h intervals, ketoconazole 200mg 12-hourly and domperidone and ketoconazole together. The washout period was 15 days. Pharmacokinetics and serial 12-lead ECGs were assessed on day 7, and serial ECGs on day -1 and at follow-up. Two subjects withdrew before the third treatment period, so data were available for 22-24 subjects. RESULTS Ketoconazole tripled domperidone concentrations at steady-state. Domperidone, ketoconazole and their combination significantly increased QT(c) F in men. Overall adjusted mean differences from placebo were 4.20 (95% CI 0.77, 7.63), 9.24 (95% CI 5.85, 12.63) and 15.90 (95% CI 12.47, 19.33) ms, respectively. In women, QT(c) F was not significantly different from placebo on either domperidone or ketoconazole alone, or in combination. However, QT(c) was positively correlated with plasma drug concentrations, in both men and women. ΔQT(c) F increased by about 2ms per 10ngml(-1) rise in domperidone concentration, and per 1µgml(-1) rise in ketoconazole concentration., Conclusions: Ketoconazole tripled the plasma concentrations of domperidone. Domperidone and ketoconazole increased QT(c) F in men, whether given together or separately. The effect of domperidone alone was below the level of clinical importance. The negative result in women is unexplained., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

The core planar polarity proteins localize asymmetrically to the adherens junctions of epithelial cells, where they have been hypothesized to assemble into intercellular complexes. Here, we show that the core proteins are preferentially distributed to discrete membrane subdomains ("puncta"), where they form asymmetric contacts between neighboring cells. Using an antibody internalization assay and fluorescence recovery after photobleaching in prepupal and pupal wings, we have investigated the turnover of two key core proteins, Flamingo and Frizzled, and find that the localization of both within puncta is highly stable. Furthermore, the transmembrane core proteins, Flamingo, Frizzled, and Strabismus, are necessary for stable localization of core proteins to junctions, whereas the cytoplasmic core proteins are required for their concentration into puncta. Thus, we define the distinct roles of specific core proteins in the formation of asymmetric contacts between cells, which is a key event in the generation of coordinated cellular asymmetry., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The core planar polarity proteins play important roles in coordinating cell polarity, in part by adopting asymmetric subcellular localisations that are likely to serve as cues for cell polarisation by as yet uncharacterised pathways. Here we describe the role of Multiple Wing Hairs (Mwh), a novel formin homology 3 (FH3)-domain protein, which acts downstream of the core polarity proteins to restrict the production of actin-rich prehairs to distal cell edges in the Drosophila pupal wing. Mwh appears to function as a repressor of actin filament formation and, in its absence, ectopic actin bundles are seen across the entire apical surface of cells. We show that the proximally localised core polarity protein Strabismus acts via the downstream effector proteins Inturned, Fuzzy and Fritz to stabilise Mwh in apico-proximal cellular regions. In addition, the distally localised core polarity protein Frizzled positively promotes prehair initiation, suggesting that both proximal and distal cellular cues act together to ensure accurate prehair placement.

Favourable genetic endowment has been proposed as part of the explanation for the success of East African endurance athletes, but no evidence has yet been presented. The Y chromosome haplogroup distribution of elite Ethiopian athletes (n=62) was compared with that of the general Ethiopian population (n=95) and a control group from Arsi (a region producing a disproportionate number of athletes; n=85). Athletes belonged to three groups: marathon runners (M; n=23), 5-km to 10-km runners (5-10K; n=21) and other track and field athletes (TF; n=18). DNA was extracted from buccal swabs and haplogroups were assigned after the typing of binary markers in multiplexed minisequencing reactions. Frequency differences between groups were assessed by using contingency exact tests and showed that Y chromosome haplogroups are not distributed amongst elite Ethiopian endurance runners in the same proportions as in the general population, with statistically significant (P<0.05) differences being found in four of the individual haplogroups. The geographical origins and languages of the athletes and controls suggest that these differences are less likely to be a reflection of population structure and that Y chromosome haplogroups may play a significant role in determining Ethiopian endurance running success.

Objective: To derive normal ranges of serum testosterone and luteinizing hormone (LH) concentrations in healthy men, and thus evaluate whether testosterone replacement therapy is prescribed inappropriately., Subjects and Method: The study comprised 266 healthy male volunteers (aged 18-75 years) who were defined as healthy by strict eligibility criteria. Subjects had a body mass index (BMI) of 18.6-32.2 kg/m2, smoked 0-10 cigarettes/day, and had an alcohol intake 0-40 units/week (one unit = 8 g ethanol). We measured serum testosterone and LH concentrations in the morning (08.00-09.00 hours) and evening (20.00-21.00 hours)., Results: Morning normal ranges of testosterone for men aged < or = 40 years were 10.07-38.76 nmol/L (2.90-11.18 microg/L), and for men age > or = 40 years, 7.41-24.13 (2.14-6.96); the respective evening normal ranges were 6.69-31.51 (1.93-9.09) and 6.46-21.93 (1.86-6.33). Both morning and evening serum testosterone declined significantly with increasing age and BMI. LH was significantly higher in the morning than in the evening, but did not vary between the age groups or with BMI. The calculated normal ranges of LH were 0.9-7.0 IU/L (morning) and 0.7-6.8 IU/L (evening)., Conclusions: The lower limit of normal for serum testosterone was 3-4 nmol/L (0.86-1.15 microg/L) lower than that of published ranges. The results have important implications for the diagnosis of hypogonadism and use of testosterone replacement therapy.

Objectives: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF 101, an A3 adenosine receptor (A3AR) agonist, in healthy men., Methods: One single and 1 repeated dose, parallel-group, ascending dose, double-blind and placebo-controlled study in normal volunteers. In the single dose study, n = 15 subjects received 1, 5 or 10 mg oral CF101; in each group 1 subject received placebo, the remainder active CF101. In the repeat-dose study, n = 28 subjects received repeated 12-hourly oral doses of CF 101 (2, 3, 4 or 5 mg) for 7 days, in each group 2 subjects received placebo, the remainder active CF101. TEST MATERIALS: Single-dose study: CF101 in 30% Cremophor RH40. Multiple-dose sudy: CF101 in 0.5% methylcellulose suspension. Both studies: the corresponding vehicles were used as placebos. Galenicals were prepared remotely from the clinical study site to ensure double-blind nature of the study. RESULTS TOLERABILITY: Single doses up to 5 mg CF101 were safe and well-tolerated. However, the single dose of 10 mg CF101 was associated with flushing, tachycardia, nausea and vomiting, which were viewed as dose-limiting in normal volunteers. Single doses of CF101 (as well as the first of the multiple doses) were associated with increases in heart rate (8 - 24 beats/min after 5 mg and 18 - 55 beats/min after 10 mg). Multiple doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. However, the 5 mg multiple-dose group reported headache, drowsiness, hot flushes and dizziness on standing; this declined with dosing duration and was not dose-limiting in this study. Adverse events were commonest near t(max). RESULTS PHARMACOKINETICS: For oral CF101, the t(max) was always 1 - 2 h post-dose and t 1/2 about 9 h, in both the single- and multiple-dose studies. For a single 5 mg dose (mean +/- SD) C(max) = 81.6 +/- 23.6 ng/ml in the single dose study, and 63.6 +/- 22.0 ng/ml after the first of the multiple doses; AUC if was 904.0 +/- 221.9 ng.h/ml and 596.1 +/- 196.6 ng.h/ml for the 2 studies, respectively. After 7 days of multiple dosing there was little change, and AUC(0-24h) = 601.0 +/- 163.6 ng.h/ml. These pharmacokinetic parameters were linearly proportional to dose in the other treatment groups. RESULTS PHARMACODYNAMICS: Increases in heart rate were related to plasma concentration and evident only in the upper range of concentrations observed. There were no changes on ECG monitoring beyond sinus tachycardia, and, in particular, no evidence of PR prolongation in any subject (n = 43). In comparison with single doses, this response was almost absent after 7 days of dosing. Leucocytosis (increases up to about 1.5 x 10(9)/l after 5 and 10 mg) was similarly transient and reversible after multiple dosing., Conclusions: Single oral doses up to 5 mg CF101 and repeated doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. Multiple-dose CF101 pharmacokinetics were unchanged and predictable from single-dose estimates, and were linearly proportional to dose. Increases in heart rate and neutrophil count were reversible during multiple dosing and were not dose-limiting in the repeat dose study. CF101 warrants further study for its efficacy in treating human disease.

Aims: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men., Methods: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses., Materials: A6 for subcutaneous injection in phosphate buffer, pH 5.6-6.0. Phosphate-buffered saline was used as placebo., Results: All dose regimens of A6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454-10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300 mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was 94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger production of anti-A6 IgG antibodies within 14 days of the first dose., Conclusion: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. A6 did not trigger an early immunogenic response.

We used a randomised, double-blind, crossover design to evaluate the pharmacokinetics, safety and tolerability of three doses of buccal adhesive testosterone tablets (BATT). Twenty-four healthy men, whose endogenous testosterone was suppressed to

Background: Interleukin-12 (IL-12) is a macrophage-derived cytokine that modulates T lymphocyte responses and has the capacity to suppress allergic and eosinophilic inflammation., Methods: We carried out a double-blind, randomised, parallel group clinical study, in which patients with mild allergic asthma were given subcutaneous recombinant human IL-12 at increasing weekly injections of 0.1, 0.25, 0.5 microg/kg (n=19), or placebo (n=20). We compared responses to inhaled allergen challenge 24 h before the first injection and 24 h after the final injection. Airways hyper-responsiveness and concentrations of peripheral blood eosinophils and sputum eosinophils were also assessed., Findings: IL-12 caused a significant decrease from baseline in the main peripheral blood eosinophil count 24 h after the fourth injection compared with placebo (p=0.0001). Sputum eosinophils were also significantly decreased 24 h after allergen challenge when treated with IL-12 compared with placebo (p=0.024). IL-12 caused a non-significant trend towards improvement in airway hyper-responsiveness to histamine, but had no significant effect on the late asthmatic reaction after inhaled allergen challenge. After administration of IL-12, four of 19 patients withdrew prematurely; two with cardiac arrhythmias, one with abnormal liver function, and a single patient with severe flu-like symptoms., Interpretation: We have shown that IL-12 lowers numbers of blood and sputum eosinophils, but without any significant effects on airway hyper-responsiveness or the late asthmatic reaction. This questions the role of eosinophils in mediating these reactions, and has important implications for development of new anti-inflammatory treatments.

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.

Positron emission tomography (PET) and 11C-raclopride were used to assess the time course of binding to central dopamine D2 receptors by the novel neuroleptic ziprasidone. In a third party blind study, six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose. One additional subject was assigned to placebo predose and was scanned at 4 h post-dose. Binding potential (BP) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers. Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP, indicative of extensive D2 receptor binding by ziprasidone. With increasing time between dosing and PET scanning there was a curvilinear increase in BP, so that all studies performed at or after 18 h post-dose gave BPs in the normal range (mean +/- 2 SD). Elevated prolactin levels returned to within the normal range by 18 h post-dose. PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time.

A double-blind, randomized, three-way complete crossover study was carried out to compare pharmacodynamic effects and tolerability during a 24-h intravenous infusion of ITF 296, isosorbide dinitrate (ISDN), and placebo, in the supine position and during 70 degrees head-up tilt. Ten healthy men aged 21-34 years participated in the study to obtain complete data in nine. Dosing started at 1 microgram/kg/min and was titrated up during the first 30 min of infusion, to produce a 10% reduction in diastolic blood pressure (DBP). At least 6 days elapsed between consecutive treatments. Heart rate (HR) and blood pressure were measured at least half hourly throughout the infusion period and up to 2 h afterwards. Systolic time intervals were measured before and at 0.5, 1, 2, 3, and 24 h of infusion in the fasting state. Tilt tests (70 degrees head-up for 2 min) were performed at 1, 6, 12, and 24 h of infusion. From 60 min before tilt, during tilt, and up to 15 min after end of tilt, ECG was monitored and BP, HR, and b/a ratio were recorded by means of fingertip plethysmography. Plasma-renin activity and concentrations of epinephrine and norepinephrine were measured preinfusion, and before and after tilt tests. Subjects were questioned frequently about adverse events. General tolerability of ISDN in the nine subjects who completed the study was poor, with eight suffering from headache and four from symptoms suggesting postural hypotension during tilt tests. Tolerability of ITF 296 was better, with 5 of 10 subjects reporting headache and 2 of 10 symptoms of postural hypotension during the first tilt only. Both active treatments successfully reduced DBP by at least 10% in all subjects at similar dose levels (final infusion rates 2.8 and 2.3 micrograms/kg/min for ITF 296 and ISDN, respectively). Systolic blood pressure (SBP) was reduced by about 6-7 mm Hg by both treatments. HR was increased by about 5 beats/min by ISDN but not by ITF 296. Those changes in BP and HR persisted throughout the 24-h infusion and reversed when it was discontinued. Fingertip plethysmography showed a profound reduction of b/a ratio, which persisted throughout the 24-h infusion. ISDN had consistently greater effects than ITF 296, suggesting that ISDN has the greater effects on small arterial vessels. Both active treatments reduced QS2 index throughout the 24-h period. Both treatments also reduced left-ventricular ejection time (LVET) index up to 3 h of infusion, with ISDN having the greater effects on LVET index and ITF 296 being intermediate between ISDN and placebo. ISDN prolonged pre-ejection period (PEP) at 1 h, had no effect at 2 h, and shortened PEP at 3 and 24 h. ITF 296 decreased PEP consistently during the 24-h infusion. Plasma-renin activity, epinephrine, and norepinephrine were increased by ISDN substantially more than by ITF 296. These results show that both ITF 296 and ISDN had comparable effects on diastolic blood pressure at similar dose-levels. ISDN increased HR, whereas ITF 296 did not. b/a Ratio was reduced more by ISDN, suggesting a greater activity on small arterial vessels. Arterial effects were maintained throughout the 24-h infusion. ISDN had a greater effect on venous return than ITF 296. ITF 296 seemed to show more balanced effects on preload and afterload than ISDN. ISDN caused significantly greater neurohumoral counter-regulation than ITF 296. Hemodynamic response to tilt was attenuated, as judged by the fact that hypotension occurred only during the early hours of the infusion, but the variability in the response of BP to tilt does not allow any firm conclusions to be drawn about possible development of tolerance. Tolerability of ISDN was poor and that of ITF 296 was better.

Helicobacter pylori and nonsteroidal antiinflammatory drugs independently cause gastroduodenal mucosal injury but the relationship between them remains unclear. We have performed a double-blind, parallel-group, placebo-controlled prospective study in 77 healthy volunteers aged 19-35 years who were randomly allocated to indomethacin (N = 15), one of three oxicams (piroxicam, chlortenoxicam, or CHF 1194; N = 36), or placebo (N = 26). Esophagogastroduodenoscopy was performed before and after four weeks of treatment and the mucosal appearances graded. Colonization with H. pylori was established at each endoscopy and gastrointestinal symptoms were assessed by daily diary card. Seven subjects (9%) were positive for H. pylori before treatment (one placebo, one indomethacin, and five an oxicam); their H. pylori status remained unchanged. Two of 70 H. pylori-negative subjects became H. pylori-positive (2.9%), both of whom had received placebo. The endoscopic score deteriorated in 1/6 drug-treated H. pylori-positive subjects and in 0/1 taking placebo. Of the H. pylori-negative subjects whose endoscopic score deteriorated, three (13%) were taking placebo, four (28.6%) indomethacin, and eight (25.8%) an oxicam. Upper gastrointestinal symptoms were reported in eight (30.8%) of the subjects taking placebo (one subject negative for H. pylori became positive), eight (53.3%) indomethacin (one H. pylori-positive), and 10 (27.8%) an oxicam (one H. pylori-positive). There were no statistically significant differences between the H. pylori-negative and H. pylori-positive groups whether on drug or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)