Cognitive deficits in patients with peripheral vestibular dysfunction.

BACKGROUND AND PURPOSE: Previous studies demonstrated cognitive deficits in patients with peripheral vestibulopathy (PVP) with dysfunction of spatial navigation and orientation, but also documented cognitive decline in nonspatial abilities. This study evaluates cognitive deficits in patients with unilateral vestibulopathy (UVP) as well as bilateral vestibulopathy (BVP) in multiple cognitive domains using common screening tests to reliably detect these deficits in clinical practice. METHODS: This prospective study compared patients with UVP and BVP to age- and sex-matched healthy controls (HC). Tests included the Alzheimer's Disease Assessment Scale (ADAS), Mini-Mental Status Examination (MMSE), Trail Making Test Part A and B, Clock Drawing Task, Executive Interview-25 (EXIT25), Dementia Detection (DemTect), and the Judgment of Line Orientation (JLO). The Montgomery-Åsberg Depression Rating Scale was used to control for depression. Videonystagmography objectively reconfirmed PVP. The Vertigo Symptoms Scale and the Dizziness Handicap Inventory were used to assess for symptom severity and restrictions of activities of daily living. RESULTS: Eighty-one patients (65 UVP, 16 BVP) were compared to 55 HC. Patients showed impairment in ADAS, MMSE, DemTect, EXIT25, and JLO. No differences between UVP and BVP were detected. The relative risk (RR) estimates of developing cognitive deficits following PVP were increased. The RR for the ADAS was higher in BVP (RR = 4.91, 95% confidence interval [CI] = 1.87-12.9, p = 0.001) than in UVP (RR = 3.75, 95% CI = 1.65-8.51, p = 0.002), but was similar for the MMSE and DemTect between groups. CONCLUSIONS: Patients with PVP showed deficits in multiple cognitive domains including nonspatial cognitive abilities. Vestibulopathy could be a risk factor for the development of cognitive impairment.

The impact of a standardized Enhanced Recovery After Surgery (ERAS) protocol in patients undergoing minimally invasive heart valve surgery.

BACKGROUND: An enhanced recovery after surgery (ERAS) protocol is a multimodal and multi-professional strategy aiming to accelerate postoperative convalescence. Pre-, intra- and postoperative measures might furthermore reduce postoperative complications and hospital length of stay (LOS) in a cost-effective way. We hypothesized that our unique ERAS protocol leads to shorter stays on the intensive care unit (ICU) and a quicker discharge without compromising patient safety. METHODS: This retrospective single center cohort study compares data of n = 101 patients undergoing minimally invasive heart valve surgery receiving a comprehensive ERAS protocol and n = 111 patients receiving routine care. Hierarchically ordered primary endpoints are postoperative hospital length of stay (LOS), postoperative complications and ICU LOS. RESULTS: Patients risk profiles and disease characteristics were comparably similar. Age was relevantly different between the groups (56 (17) vs. 57.5 (13) years, p = 0.015) and therefore adjusted. Postoperative LOS was significantly lower in ERAS group (6 (2) days vs. 7 (1) days, p<0.01). No significant differences, neither in intra- or postoperative complications, nor in the number of readmissions (15.8% vs. 9.9%, p = 0.196) were shown. In hospital LOS (7 (3) days vs. 8 (4) days, p<0.01) and ICU LOS (18.5 (6) hours vs. 26.5 (29) hours, p<0.01) a considerable difference was shown. CONCLUSION: The ERAS protocol for minimally invasive heart valve surgery is safe and feasible in an elective setting and leads to a quicker hospital discharge without compromising patient safety. However, further investigation in a randomized setting is needed.

The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid ß Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer's Disease.

Soluble amyloid ß (Aß) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer's disease (AD). That makes soluble Aß oligomers a promising drug target. In addition to eliminating these toxic species from the patients' brain with antibody-based drugs, a new class of drugs is emerging, namely Aß aggregation inhibitors or modulators, which aim to stop the formation of toxic Aß oligomers at the source. Here, pharmacological data of the novel Aß aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aß1-42 monomers (KD = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aß oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aß1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aß oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aß1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.

Assessment of OMT-28, a synthetic analog of omega-3 epoxyeicosanoids, in patients with persistent atrial fibrillation: Rationale and design of the PROMISE-AF phase II study.

We designed a placebo controlled, double-blind, randomized, dose-finding phase II study on OMT-28 in the maintenance of sinus rhythm after electrical cardioversion (DCC) in patients with persistent atrial fibrillation (PROMISE-AF). OMT-28 is a first-in-class, synthetic analog of 17,18-epoxyeicosatetetraenoic acid, a bioactive lipid mediator generated by cytochrome P450 enzymes from the omega-3 fatty acid eicosapentaenoic acid. OMT-28 improves Ca2+-handling and mitochondrial function in cardiomyocytes and reduces pro-inflammatory signaling. This unique mode of action may provide a novel approach to target key mechanism contributing to AF pathophysiology. In a recent phase I study, OMT-28 was safe and well tolerated and showed favorable pharmacokinetics. The PROMISE-AF study (NCT03906799) is designed to assess the efficacy (primary objective), safety, and population pharmacokinetics (secondary objectives) of three different doses of OMT-28, administered once daily, versus placebo until the end of the follow-up period. Recruitment started in March 2019 and the study will include a total of 120 patients. The primary efficacy endpoint is the AF burden (% time with any AF), evaluated over a 13-week treatment period after DCC. AF burden is calculated based on continuous ECG monitoring using an insertable cardiac monitor (ICM). The primary efficacy analysis will be conducted on the modified intention-to-treat (mITT) population, whereas the safety analysis will be done on the safety population. Although ICMs have been used in other interventional studies to assess arrhythmia, PROMISE-AF will be the first study to assess antiarrhythmic efficacy and safety of a novel rhythm-stabilizing drug after DCC by using ICMs.

[Evaluation of Quality Indicators of Evidence-Based Guidelines Using ADT/GEKID Base Dataset and its Organ-Specific Modules]. / Berechenbarkeit der Qualitätsindikatoren der onkologischen S3-Leitlinien mit dem ADT-/GEKID-Basisdatensatz und seiner Zusatzmodule.

AIM: According to the Cancer Screening and Registers Act (KFRG, §65c SGB V), clinical cancer registration in Germany has to be based on the consistent set of variables developed by the "Association of German Tumor Centers" (ADT) and "Association of Population-based Cancer Registries in Germany" (GEKID) to improve oncological care. Quality indicators in evidence-based guidelines are measures to assess the quality of treatment and outcome in clinical care. The aim of this study was to find out the extent to which it is possible to determine these quality indicators using the ADT/GEKID's set of variables and the organ-specific modules. METHODS: After screening all available evidence-based guidelines for inclusion and exclusion criteria to calculate quality indicators, we evaluated for each indicator whether it can be computed using a single variable or a combination of variables of the ADT/GEKID's base variables set and the organ-specific modules. RESULTS: A total of 151 quality indicators were defined in 17 available evidence-based guidelines. Of these, 82 (54%) quality indicators could be determined with the variables of the base dataset. The highest proportion of calculable quality indicators was 100% for pancreatic cancer, which, however, was the only entity where all indicators were calculable. The least proportion of quality indicators was calculable for cancer of the oral cavity (10%). CONCLUSIONS: This analysis shows considerable differences in the possibility to evaluate the quality indicators defined in S3-guidelines for different tumor entities based on the variables documented in the clinical cancer registries throughout Germany. The ADT/GEKID core variables set should be extended with additional modules, for instance, for colorectal cancer, to allow a complete documentation of all criteria needed for the determination of clinical quality indicators as suggested in the pertinent evidence-based guidelines.

Status and perspective of lab-on-a-chip systems for common diseases: a systematic review from 2003 to 2013.

BACKGROUND: Lab-on-a-chip systems (LOCs) are a useful aid for the individualization of therapeutic algorithms at the point-of-care. MATERIALS & METHODS: We performed a systematic literature review on LOCs for diseases with a global impact for healthcare. RESULTS: A total of 1007 articles matched the previously specified search criteria, thereof 65 studies could be included in this review. A total of 55 different LOCs were evaluated, most for diagnosis or monitoring of cancer (n = 24). For other diseases we found considerably less analyzed LOCs. The analytical performance of the LOCs was usually very good, 37 (67%) LOCs had a sensitivity higher than 90%. CONCLUSION: Although LOC systems performance has been positively evaluated in the great majority of studies, the testing was mostly limited to the research laboratory setting rather than real-world scenarios.

Diagnostic lab-on-a-chip systems at the doctor's office: a survey amongst German physicians in routine medical care.

AIM & METHOD: We conducted a physician's survey to ask the potential 'users' about needs and options for lab-on-a-chip systems (LOCs) in their office to provide information about the feasibility of the implementation of LOCs into the healthcare system. RESULTS: From a random sample of 300 questionnaires, 61 were returned. The willingness to use LOCs is very high (91.9%) and only 6.5% mentioned that they would continue to use conventional tests strictly in the future. Reliability is seen as the most important prerequisite for a successful implementation (85%). CONCLUSION: Generally, physicians are very open-minded and positive regarding the implementation of LOCs in routine care.

Opportunities and risks of diagnostic lab-on-a-chip systems in healthcare from a health system stakeholder's perspective.

AIM: The aim of personalized medicine is to respond to the needs of individuals with appropriate treatment. Lab-on-a-chip systems (LOCs) can help to individualize therapeutic algorithms at the point of care. Herein, we discuss the perspectives, demands and concerns associated with LOCs. METHODS: Interviews with 30 experts in the field of personalized medicine were conducted, addressing the requirements, potentials and risks of LOCs. The interviews were transcribed and evaluated by means of qualitative content analysis. RESULTS: The majority of experts emphasize a considerable potential for the lab-on-a-chip industry with the largest potential in the context of point-of-care diagnostics. The direct-to-costumer use is regarded as risky, in particular with respect to the reliability of the results. CONCLUSION: In addition to a major potential of the implementation of LOCs, their impact on delivery of healthcare have to be considered, and early communication between physicians and LOC developers and manufacturers have to be ensured.

Validation of the THI-12 questionnaire for international use in assessing tinnitus: a multi-centre, prospective, observational study.

OBJECTIVE: To investigate and confirm the reliability and validity of the tinnitus handicap inventory 12 (THI-12) in various countries and languages. DESIGN: Prospective, observational study conducted in seven countries, using linguistically harmonized versions of the THI-12 in six languages. These were evaluated for test-retest reliability, internal consistency reliability, known-groups validity, and construct validity. Basic psychometric properties of supporting instruments were compared. Questionnaires were completed by the subjects at baseline and again after 12-30 days. STUDY SAMPLE: Adults with a clinical diagnosis of subjective tinnitus. RESULTS: An exploratory factor analysis of the THI-12 items for the U.S. study population at baseline revealed a single common factor of high eigenvalue. Confirmatory factor analysis supported this in the separate countries. Test-retest reliability was moderate to high, and the conclusions were supported by a known-groups analysis; correlations with other scales expected to support construct validity were moderate. CONCLUSIONS: The THI-12 total score showed acceptable psychometric properties for all countries tested. The relationships between the THI-12 and the one-month and one-week versions of the TRS and TSS were similar and convergent. The THI-12 is thus a promising diagnostic tool for assessing treatment effects in multi-cultural and multi-lingual trials on tinnitus therapy.

Assessment of tinnitus-related impairments and disabilities using the German THI-12: sensitivity and stability of the scale over time.

OBJECTIVE: To evaluate the reliability, dimensionality, predictive validity, construct validity, and sensitivity to change of the THI-12 total and sub-scales as diagnostic aids to describe and quantify tinnitus-evoked reactions and evaluate treatment efficacy. DESIGN: Explorative analysis of the German tinnitus handicap inventory (THI-12) to assess potential sensitivity to tinnitus therapy in placebo-controlled randomized studies. Correlation analysis, including Cronbach's coefficient α and explorative common factor analysis (EFA), was conducted within and between assessments to demonstrate the construct validity, dimensionality, and factorial structure of the THI-12. STUDY SAMPLE: N = 618 patients suffering from subjective tinnitus who were to be screened to participate in a randomized, placebo-controlled, 16-week, longitudinal study. RESULTS: The THI-12 can reliably diagnose tinnitus-related impairments and disabilities and assess changes over time. The test-retest coefficient for neighboured visits was r > 0.69, the internal consistency of the THI-12 total score was α ≤ 0.79 and α ≤ 0.89 at subsequent visits. Predictability of THI-12 total score and overall variance increased with successive measurements. The three-factorial structure allowed for evaluation of factors that affect aspects of patients' health-related quality of life. CONCLUSIONS: The THI-12, with its three-factorial structure, is a simple, reliable, and valid instrument for the diagnosis and assessment of tinnitus and associated impairment over time.

A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of neramexane in patients with moderate to severe subjective tinnitus.

BACKGROUND: Neramexane is a new substance that exhibits antagonistic properties at α9α10 cholinergic nicotinic receptors and N-methyl-D-aspartate receptors, suggesting potential efficacy in the treatment of tinnitus. METHODS: A total of 431 outpatients with moderate to severe subjective tinnitus (onset 3-18 months before screening) were assigned randomly to receive either placebo or neramexane mesylate (25 mg/day, 50 mg/day and 75 mg/day) for 16 weeks, with assessment at 4-week intervals. The primary (intention-to-treat) efficacy analysis was based on the change from baseline in Week 16 in the total score of the adapted German short version of the validated Tinnitus Handicap Inventory questionnaire (THI-12). RESULTS: Compared with placebo, the largest improvement was achieved in the 50 mg/d neramexane group, followed by the 75 mg/d neramexane group. This treatment difference did not reach statistical significance at the pre-defined endpoint in Week 16 (p = 0.098 for 50 mg/d; p = 0.289 for 75 mg/d neramexane), but consistent numerical superiority of both neramexane groups compared with placebo was observed. Four weeks after the end of treatment, THI-12 scores in the 50 mg/d group were significantly better than those of the controls. Secondary efficacy variables supported this trend, with p values of < 0.05 for the 50 mg/d neramexane group associated with the functional-communicational subscores of the THI-12 and the assessments of tinnitus annoyance and tinnitus impact on life as measured on an 11-point Likert-like scale. No relevant changes were observed for puretone threshold, for tinnitus pitch and loudness match, or for minimum masking levels. The 25 mg/d neramexane group did not differ from placebo. Neramexane was generally well tolerated and had no relevant influence on laboratory values, electrocardiography and vital signs. Dizziness was the most common adverse event and showed a clear dose-dependence. CONCLUSIONS: This study demonstrated the safety and tolerability of neramexane treatment in patients with moderate to severe tinnitus. The primary efficacy variable showed a trend towards improvement of tinnitus suffering in the medium- and high-dose neramexane groups. This finding is in line with consistent beneficial effects observed in secondary assessment variables. These results allow appropriate dose selection for further studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00405886.

A validated grading scale for forehead lines.

BACKGROUND: As with other facial wrinkles, the gradual loss and disorganization of collagen fibers and elastin, connective tissues that provide underlying support for skin, cause horizontal forehead rhytides in large part. OBJECTIVES: To develop the Forehead Lines Grading Scale for objective quantification of horizontal forehead rhytides at rest and with expression and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: The Forehead Lines Grading Scale is a 5-point photonumeric rating scale that was developed to objectively quantify resting (static) and hyperkinetic (dynamic) forehead lines. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: The agreement between the experts was highly significant. Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. CONCLUSION: The 5-point photonumeric scale generated spans the severity of forehead lines for which patients commonly seek correction. The scale is well stratified for consistent rating.

A validated brow positioning grading scale.

BACKGROUND: One of the first areas to show facial aging is the periorbital region, where brow malposition contributes to the overall appearance of aging. Movement and positioning of the brows are also sex specific. Men may desire a low brow, whereas women may prefer high, arched brows. OBJECTIVES: To develop the Brow Positioning Grading Scale for objective quantification of eyebrow position and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: A 5-point photonumeric rating scale was developed to objectively quantify positioning of eyebrows at rest. Nine experts rated photographs of 35 subjects twice with regard to positioning of the eyebrow in comparison with morphed images. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. The test-retest correlation coefficients were acceptable for each expert. CONCLUSION: The 5-point photonumeric scale generated spans the positioning of the eyebrow for which patients commonly seek correction. The scale is well stratified for consistent rating.

A validated lip fullness grading scale.

OBJECTIVES: To develop the Lip Fullness Grading Scale for objective quantification of lip volume for a reliable assessment and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: A 5-point photonumeric rating scale was developed to objectively quantify fullness of upper and lower lip separately. Nine experts rated photographs of 35 subjects, twice, separately for upper and lower lip. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: Agreement between the experts was high. Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. CONCLUSION: The 5-point photonumeric scale generated spans the fullness of the upper and lower lip for which patients commonly seek correction. This scale is well stratified, with low intra- and interrater variability.

A validated grading scale for marionette lines.

BACKGROUND: Melomental folds, or marionette lines, are one of the consequences of facial aging. The curvilinear wrinkles formed because of facial movements and the aging process extend downward from the oral commissures. OBJECTIVES: To develop the Marionette Lines Grading Scale for objective quantification of the severity of melomental folds and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: A 5-point photonumeric rating scale was developed to objectively quantify the severity of melomental folds. Nine experts rated photographs of 35 subjects, twice, with regard to marionette lines in comparison with morphed images. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: The agreement between the experts was high. Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. CONCLUSION: The 5-point photonumeric scale generated spans the severity of marionette lines for which patients commonly seek correction. The scale is well stratified for consistent rating.

A validated hand grading scale.

BACKGROUND: Following the popularity of facial cosmetic procedures to reverse the signs of aging, cosmetic procedures that rejuvenate the hand are being sought. Irregular surface pigmentation, prominence of superficial veins and tendons, thinning of the dermis, and loss of subcutaneous fat typically characterize aging of the hand. OBJECTIVES: To develop the Hand Grading Scale for objective quantification of the severity of hand aging and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: The Hand Grading Scale is a 5-point photonumeric rating scale that was developed to objectively quantify the severity of aging of the hand. Nine experts rated photographs of 35 subjects, twice, with regard to the aspect "hand aging" in comparison with morphed images. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: The agreement between the experts was considerably high. Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. CONCLUSION: The 5-point photonumeric scale generated spans the severity of hand aging for which patients most commonly seek correction. The scale is well stratified for consistent rating.

A validated grading scale for crow's feet.

OBJECTIVE: To develop the Crow's Feet Grading Scale for objective quantification of the severity of lateral canthal lines and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: A 5-point photonumeric rating scale was developed to objectively quantify the severity of lateral canthal lines at rest and at maximum contracture of the orbicularis oculi. Nine experts rated photographs of 35 subjects, twice, with regard to the aspect crow's feet in comparison with morphed images. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: The agreement between the experts was significantly high. Furthermore, the test-retest correlation coefficients were high for each expert after an overnight interval, demonstrating low inter- and intraevaluator variability. CONCLUSION: The 5-point photonumeric scale generated spans the severity of the type of crow's feet for which patients most commonly seek correction. The scale is well stratified for consistent rating.

Direct and rapid inhibition of factor Xa by otamixaban: a pharmacokinetic and pharmacodynamic investigation in patients with coronary artery disease.

BACKGROUND: New anticoagulants that combine effective anticoagulation with low bleeding rates are still sought after. We investigated the safety, pharmacokinetics, and pharmacodynamics of otamixaban, a direct factor Xa inhibitor, in patients with stable coronary artery disease. METHODS: This was a randomized, placebo-controlled, double-blind, multicenter study in 119 patients with stable coronary artery disease taking maintenance doses of their comedication. Of these patients, 50% had mild renal impairment (creatinine clearance >45 mL/min but <80 mL/min). Patients were randomized in a 4:1 ratio to receive either otamixaban or placebo as a 1-minute bolus followed by a 24-hour continuous infusion. Anti-factor Xa activity, clotting times (activated partial thromboplastin time, dilute prothrombin time, Russell's viper venom test), and international normalized ratio were measured. RESULTS: All patients completed the study according to the protocol. No major or minor bleeding occurred according to Thrombosis in Myocardial Infarction criteria. Anti-factor Xa activity and anticoagulant effect were measurable early after the start of the infusion and remained during the infusion. Upon cessation, these effects declined rapidly and returned to baseline within 6 hours after the end of infusion. Anti-factor Xa activity coincided with the otamixaban plasma concentrations. The fold changes from baseline at the end of infusion with regard to the clotting times ranged from 1.7 to 4.4 (1.15 for placebo), 1.29 to 3.15 (0.98 for placebo), and 1.19 to 2.11 (0.94 for placebo) for Russell's viper venom test, dilute prothrombin time, and activated partial thromboplastin time, respectively, and ranged from 0.94 to 1.70 (0.94 for placebo) for the international normalized ratio. CONCLUSION: In patients with stable coronary artery disease taking maintenance doses of their usual concomitant medication, otamixaban exerts a rapid onset of anticoagulation and anti-factor Xa activity. Our data provide evidence that further studies are warranted to investigate the safety and efficacy of otamixaban in the target population.

Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid.

The pharmacokinetics, pharmacodynamics and safety of the direct factor Xa inhibitor, otamixaban, with and without concomitant acetylsalicylic acid (ASA) were investigated in healthy volunteers. The study was a double-blind, placebo-controlled 3-way crossover study. Sixty-eight male volunteers in total were randomised to otamixaban, ASA, or otamixaban with ASA. ASA (300 mg once a day) was started 2 days before and continued on the day of the otamixaban 6-hour IV infusion (0.3 and 0.5 mg/kg). Pharmacokinetic and pharmacodynamic parameters (coagulation markers, platelet function tests and skin bleeding time) were determined. Drug interaction was assessed by the ratios of geometric means and 90% confidence intervals (90% CI)of the parameter estimates. Pharmacokinetic parameters of otamixaban remained unchanged with ASA. Ratios of geometric means (90% CI) were for Ceoi 96.54 (91.21-102.19) and 95.04 (90.10-100.24) and for AUC 98.0 (93.92-102.25) and 95.90 (92.61-99.31), for 0.3 and 0.5 mg/kg, respectively. No drug interaction was observed between otamixaban and ASA on the coagulation and platelet function parameters. Neither otamixaban nor ASA had an effect on skin bleeding time; their co-administration led to a slight prolongation of skin bleeding time above the normal range without any clinically relevant bleeding. This study demonstrated that the desired effects of otamixaban and ASA, namely anticoagulation and platelet inhibition, respectively, are maintained during co-administration of both drugs.