New Generation of sGC Stimulators: Discovery of Imidazo[1,2-a]pyridine Carboxamide BAY 1165747 (BAY-747), a Long-Acting Soluble Guanylate Cyclase Stimulator for the Treatment of Resistant Hypertension.

Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.

First randomized evaluation of safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, an antibody targeting coagulation factor XI and factor XIa, in healthy men.

BACKGROUND: Bleeding is a clinically significant issue with all current anticoagulants. Safer antithrombotic strategies are required. OBJECTIVES: To investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, a humanized, factor XI (FXI)-directed monoclonal antibody, after single intravenous (i.v.) or subcutaneous (s.c.) doses in healthy volunteers. PATIENTS/METHODS: In a first-in-human, phase I study, 70 volunteers were randomly assigned (4:1) to receive single-dose BAY 1831865 (3.5, 7, 17, 35, 75, or 150 mg i.v. or 150 mg s.c.) or placebo. Adverse events, pharmacodynamics, and pharmacokinetics were evaluated. RESULTS: In this study, no hemorrhage, or hypersensitivity or infusion-/injection-related reactions were reported. Drug-related adverse events occurred in 3 (5.4%) of 56 volunteers; all were mild and self-limited. Dose-dependent prolongation of activated partial thromboplastin time (aPTT) and inhibition of FXI clotting activity was observed with BAY 1831865 i.v. (geometric mean maximum ratio-to-baseline: aPTT, range, 1.09-3.11 vs. 1.05 with placebo; FXI, range, 0.70-0.04 vs. 0.91 with placebo). Onset of effect was rapid after i.v. administration, with duration of effect (up to 55 days) determined by dose. BAY 1831865 s.c. had similar pharmacodynamic effects but a slower onset of action. Terminal half-life increased continuously with increasing i.v. dose (range, 28-208 h), leading to strong and continuous increases in systemic exposure to BAY 1831865. Absolute bioavailability of BAY 1831865 s.c. was 47.2% (95% confidence interval, 30.2-73.7). CONCLUSIONS: BAY 1831865 i.v. or s.c. was well tolerated, with no evidence of bleeding in healthy volunteers. BAY 1831865 exhibited pronounced, sustained dose-dependent prolongation of aPTT and duration of FXI inhibition.

First evaluation of the safety, pharmacokinetics, and pharmacodynamics of BAY 2433334, a small molecule targeting coagulation factor XIa.

BACKGROUND: Coagulation factor XI (FXI) contributes to the development of thrombosis but appears to play a minor role in hemostasis and is, therefore, an attractive anticoagulant drug target. OBJECTIVES: To evaluate the safety, pharmacokinetic, and pharmacodynamic properties of BAY 2433334, an orally administered small molecule targeting activated FXI (FXIa), in healthy men. PATIENTS/METHODS: This phase 1 study was conducted in two parts. In part 1, 70 volunteers were randomized 4:1 to receive a single oral dose of BAY 2433334 (5-150 mg as oral solution or immediate-release tablets) or placebo. In part 2, 16 volunteers received a single oral dose of five BAY 2433334 5-mg tablets with or without a high-calorie breakfast in a randomized crossover study design. Adverse events, pharmacokinetic parameters, and pharmacodynamic parameters were assessed up to 72 h after drug administration. Volunteers were followed up after 7 to 14 days. RESULTS: BAY 2433334 demonstrated favorable safety and tolerability with a dose-dependent increase in exposure and a terminal half-life of 14.2 to 17.4 h. A high-calorie breakfast reduced mean maximum plasma concentration and exposure by 31% and 12.4%, respectively. AY 2433334 was associated with a dose-dependent inhibition of FXIa activity and an increase in activated partial thromboplastin time. Bleeding times in volunteers who had received BAY 2433334 were similar to those in volunteers who had received placebo. CONCLUSIONS: These data indicate that BAY 2433334 is a promising development candidate for once-daily oral anticoagulation; it is being evaluated in phase 2 dose-finding studies in patients at risk of thrombosis.

Safety, pharmacodynamic, and pharmacokinetic characterization of vericiguat: results from six phase I studies in healthy subjects.

PURPOSE: To characterize the safety, pharmacodynamics, and pharmacokinetics (PK) of vericiguat in healthy males. METHODS: Six phase I studies were conducted in European, Chinese, and Japanese males. Subjects received oral vericiguat as a single dose (0.5-15.0 mg solution [for first-in-human study] or 1.25-10.0 mg immediate release [IR tablets]) or multiple doses (1.25-10.0 mg IR tablets once daily [QD] or 5.0 mg IR tablets twice daily for 7 consecutive days). Bioavailability and food effects on vericiguat PK (IR tablets) were also studied in European subjects. RESULTS: Overall, 255 of 265 randomized subjects completed their respective studies. There were no deaths or serious adverse events. Vericiguat was generally well tolerated at doses ≤ 10.0 mg. In the first-in-human study, the most frequent drug-related adverse events were headache and postural dizziness (experienced by five subjects each [7.2%]). Three of four subjects who received vericiguat 15.0 mg (oral solution, fasted) experienced orthostatic reactions. Vericiguat (≤ 10.0 mg, IR tablets) was rapidly absorbed (median time to reach maximum plasma concentration ≤ 2.5 h [fasted]) with a mean half-life of about 22.0 h (range 17.9-27.0 h for single and multiple doses). No evidence for deviation from dose proportionality or unexpected accumulation was observed. Administration of vericiguat 5.0 mg IR tablets with food increased bioavailability by 19% (estimated ratio 119% [90% confidence interval]: 108; 131]), reduced PK variability, and prolonged vericiguat absorption relative to the fasted state. CONCLUSION: In general, vericiguat was well tolerated. These results supported further clinical evaluation of vericiguat QD in patients with heart failure. REGISTRY NUMBERS: EudraCT: 2011-001627-21; EudraCT: 2012-000953-30.

Metabolism and Pharmacokinetic Drug-Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies.

BACKGROUND: Vericiguat is a stimulator of soluble guanylate cyclase currently under investigation as a first-in-class therapy for worsening chronic heart failure (NCT02861534). Patients with heart failure often require polypharmacy because of comorbidities. Hence, understanding the clearance mechanisms, elimination, and potential for pharmacokinetic drug-drug interactions of vericiguat is important for dose recommendations in this patient population. METHODS: Biotransformation and perpetrator properties of vericiguat were characterized in vitro using human hepatocytes, liver microsomes, and recombinant enzymes. This was complemented by a human mass balance study and ten drug-drug interaction studies in healthy volunteers wherein vericiguat was co-administered orally with omeprazole, magnesium/aluminum hydroxide, ketoconazole, rifampicin, mefenamic acid, midazolam, warfarin, digoxin, sacubitril/valsartan, aspirin, or sildenafil. RESULTS: In the human mass balance study, mean total radioactivity recovered was 98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, respectively). The main metabolic pathway of vericiguat is glucuronidation via uridine diphosphate-glucuronosyltransferase 1A9 and 1A1. In vitro studies revealed a low risk of vericiguat acting as a perpetrator by inhibiting cytochrome P450s, uridine diphosphate-glucuronosyltransferase isoforms, or major transport proteins, or by inducing cytochrome P450s. These observations were supported by phase I drug-drug interaction studies. Phase I studies that assessed the propensity of vericiguat as a victim drug showed changes in the range that did not warrant recommendations for dose adjustment in phase III. CONCLUSIONS: A low pharmacokinetic interaction potential of vericiguat was estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable for a patient population with multiple comorbidities requiring polypharmacy.

Investigation of bioequivalence, safety, and tolerability of a fixed-dose combination of nifedipine GITS and candesartan compared with the corresponding loose-dose combination under fed conditions
.

OBJECTIVE: To investigate the bioequivalence, safety, and tolerability of single-dose nifedipine gastrointestinal therapeutic system (GITS) and candesartan as a fixed-dose combination (FDC) relative to the loose combination in healthy males under fed conditions. MATERIALS AND METHODS: A total of 48 subjects received nifedipine GITS 60 mg and candesartan 32 mg as an FDC or loose combination in an open-label, 2-way crossover, 2-treatment sequence design, with a washout of at least 5 days between treatments. Study medications were administered following an overnight fast of at least 10 hours, and 30 minutes after ingestion of a high-fat test meal. Plasma samples were collected at intervals over a 48-hour period post-dosing. Safety and tolerability parameters were documented throughout the study. RESULTS: For nifedipine, 90% confidence intervals (CIs) for the ratios of FDC/loose combination were within acceptance limits of bioequivalence (i.e., 80 - 125%) for both AUC0-tlast (91.36%; 111.5%) and Cmax (87.93%; 100.5%). For candesartan, 90% CIs for the ratios of FDC/loose combination were within acceptance limits for AUC0-tlast (112.8%; 124.4%), but not for Cmax (120.5%; 137.8%). There were no serious adverse events (AEs) or AEs leading to treatment discontinuation and no clinically relevant changes in vital signs or laboratory parameters. CONCLUSION: A single dose of the FDC-containing nifedipine GITS 60 mg and candesartan 32 mg, when compared to the corresponding loose combination under fed conditions, met the criterion for bioequivalence based on AUC0-tlast, while the slightly higher Cmax for candesartan is not considered clinically relevant. The FDC displayed safety and tolerability profiles similar to the loose combination.

BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics.

BACKGROUND: Coagulation factor XI (FXI) contributes to the development of thrombosis but appears to play only a minor role in hemostasis and is therefore an attractive anticoagulant drug target. OBJECTIVES: To evaluate the safety, pharmacodynamic, and pharmacokinetic properties of BAY 1213790, a fully human immunoglobulin (Ig) G1 antibody targeting activated coagulation FXI (FXIa), in healthy men. METHODS: In this phase 1, single-blind, parallel-group, placebo-controlled, dose-escalation study, 83 healthy Caucasian men were randomized 4:1 to receive a single 60-minute intravenous infusion of BAY 1213790 (0.015-10 mg/kg) or placebo. Adverse events, pharmacodynamic parameters (including activated partial thromboplastin time [aPTT]) and pharmacokinetic parameters were determined. Volunteers were followed up for 150 days. RESULTS: BAY 1213790 demonstrated favorable safety and tolerability; there were no observed cases of bleeding or clinically relevant antidrug antibody formation. One volunteer (1.2%) experienced an infusion reaction. Following intravenous administration of BAY 1213790, dose-dependent increases in aPTT (maximal mean increase relative to baseline: 1.85 [conventional method] and 2.17 [kaolin-triggered method]) and rotational thromboelastometry whole blood clotting time were observed, as well as dose-dependent reductions in FXI activity. Bleeding times did not increase following administration of BAY 1213790 and were similar for all dose cohorts, including placebo. Measurable and dose-dependent increases in systemic exposure were detected for all doses of BAY 1213790 of 0.06 mg/kg or higher. CONCLUSIONS: Based on these safety, pharmacodynamic, and pharmacokinetic results, further evaluation of BAY 1213790 in patients with, or at risk of, thrombosis is warranted.

Pharmacokinetic interaction of riociguat with ketoconazole, clarithromycin, and midazolam.

Riociguat is a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension that is principally metabolized via the cytochrome P450 (CYP) pathway. Three studies in healthy males investigated potential pharmacokinetic interactions between riociguat and CYP inhibitors (ketoconazole, clarithromycin, and midazolam). In two studies, subjects were pretreated with either once-daily ketoconazole 400 mg or twice-daily clarithromycin 500 mg for 4 days before cotreatment with either riociguat 0.5 mg ± ketoconazole 400 mg or riociguat 1.0 mg ± clarithromycin 500 mg. In the third study, subjects received riociguat 2.5 mg 3 times daily (tid) for 3 days, followed by cotreatment with riociguat 2.5 mg tid ± midazolam 7.5 mg. Pharmacokinetic parameters, the effect of smoking on riociguat pharmacokinetics, safety, and tolerability were assessed. Pre- and cotreatment with ketoconazole and clarithromycin led to increased riociguat exposure. Pre- and cotreatment with riociguat had no significant effect on midazolam plasma concentrations. In all studies, the bioavailability of riociguat was reduced in smokers because its clearance to the metabolite M1 increased. Riociguat ± ketoconazole, clarithromycin, or midazolam was generally well tolerated. The most common treatment-emergent adverse events (TEAEs) across all studies were headache and dyspepsia. One serious TEAE was reported in the midazolam study. Owing to the potential for hypotension, concomitant use of riociguat with multipathway inhibitors, such as ketoconazole, should be approached with caution. Coadministration of riociguat with strong CYP3A4 inhibitors, for example, clarithromycin, does not require additional dose adjustment. No significant drug-drug interaction was revealed between riociguat and midazolam.

Investigation of bioequivalence of a new fixed-dose combination of nifedipine and candesartan with the corresponding loose combination as well as the drug-drug interaction potential between both drugs under fasting conditions.

OBJECTIVE: To determine the bioequivalence of a nifedipine and candesartan fixed-dose combination (FDC) with the corresponding loose combination, and to investigate the pharmacokinetic drug-drug interaction potential between both drugs. METHODS: 49 healthy, white, male subjects received: 60 mg nifedipine and 32 mg candesartan FDC, the loose combination of 60 mg nifedipine GITS and 32 mg candesartan, 60 mg nifedipine GITS alone, or 32 mg candesartan alone in a randomized, non-blinded, 4-period, 4-way crossover design with each dosing following overnight fasting. Treatment periods were separated by washout periods of ≥ 5 days. Plasma samples were collected for 48 hours after dosing and assayed using a validated LC-MS/MS method. RESULTS: Bioequivalence between the FDC and the loose combination as well as the impact of combined treatment with both drugs on candesartan pharmacokinetics was evaluated in 47 subjects, while the corresponding impact of treatment with both drugs on nifedipine pharmacokinetics was assessed in 46 patients. For AUC(0-tlast) and Cmax the 90% confidence intervals (CIs) for the ratios of the FDC vs. the corresponding loose combination were within the acceptance range for bioequivalence of 80 - 125%. When comparing AUC(0-tlast) and Cmax of nifedipine and candesartan after dosing with the loose combination vs. each drug alone, the 90% CIs remained within the range of 80 - 125% indicating the absence of a clinically relevant pharmacokinetic drug-drug interaction. Nifedipine and candesartan as well as the combinations were well tolerated. CONCLUSIONS: The FDC containing 60 mg nifedipine and 32 mg candesartan was bioequivalent to the corresponding loose combination following single oral doses under fasting conditions. No clinically relevant pharmacokinetic drug-drug interaction between nifedipine and candesartan was observed.

Acromioclavicular dislocation Rockwood III-V: results of early versus delayed surgical treatment.

INTRODUCTION: The management of acute acromioclavicular joint (ACJ-) injuries especially of type III is still controversial. METHODS: In this retrospective study the results of early ACJ reconstructions immediately after trauma (group early repair, ER) were compared with the results of delayed reconstructions in patients who first got conservative treatment and failed after some time (group delayed repair, DR). Overall, 49 patients were analysed clinically and radiographically with a mean follow-up of 53 months (range 20-92). In group ER twenty-nine patients were treated with a modified Phemister technique according to Mayr including a PDS coracoclavicular sling and temporary K- wire fixation. In group DR twenty patients were treated with a modified Weaver-Dunn-procedure with additionally transposition of the coracoacromial ligament and AC-joint resection. RESULTS: A comparison of the overall results revealed a statistically significant better outcome in the early repair group, regarding the Constant Score, the degree of acromioclavicularjoint-reduction, numbers of complications and patient;s satisfaction. CONCLUSION: Our results point out that early reconstruction of ACJ-injuries in type III-V avoids the inferior clinical results of delayed reconstructions using a modified Weaver-Dunn-procedure.

Lacosamide.

Lacosamide is a new chemical entity being investigated as an adjunctive treatment for epilepsy, as well as monotherapy for diabetic neuropathic pain. Lacosamide appears to have a dual mode of action: selective enhancement of sodium channel inactivation and modulation of collapsin response mediator protein-2. Rapidly and completely absorbed after oral administration, lacosamide has an elimination half-life of approximately 13 hours and a low potential for drug interactions. Additionally, lacosamide exhibits linear, dose-proportional pharmacokinetics with low intra- and interpatient variability. Randomized controlled trials of adjunctive lacosamide (200, 400, and 600 mg/day) have demonstrated statistically significant reduction in median seizure frequency compared with placebo. In addition, 50% responder rates for lacosamide (400 and 600 mg/day) were statistically superior to placebo. The most frequently reported adverse events (> or =10% of lacosamide-treated patients) included dizziness, headache, and nausea. A double-blind, double-dummy randomized trial of intravenous lacosamide (30- and 60-minute infusion) as replacement for oral lacosamide showed that the safety and tolerability profiles were comparable for intravenous and oral lacosamide. The efficacy and safety results from completed clinical trials, as well as the favorable pharmacokinetic profile, suggest that lacosamide may represent a significant advance in antiepileptic drug therapy.

Rotator cuff tears associated with os acromiale.

INTRODUCTION: Os acromiale is a rare anatomical condition; its incidence in cadaver studies has been found to be approximately 8%. In this retrospective study we investigated the incidence and types of os acromiale in patients with rotator cuff tears. METHODS: We assessed operation notes and axillary radiographs for the presence and the type of os acromiale in 1000 consecutive patients with open rotator cuff repairs. RESULTS: 62 patients (6.2%) showed an os acromiale in the axillary radiographs. In 6 of these the os acromiale was not described in the operation notes. 57 os meso-acromiale and 5 os pre-acromiale were found. The average number of tendons involved in the cuff tear was the same (1.4) in patients with and without os acromiale. The average age of patients with os acromiale was 55 years, and 56 years in patients without os acromiale. INTERPRETATION: Os acromiale is a co-condition in patients with rotator cuff tear. The prevalence of os acromiale in patients with rotator cuff tear is similar to that in a standard population with unknown integrity status of the rotator cuff. Thus, it seems debatable whether an os acromiale is a pathological condition leading to rotator cuff tears.

Dynamic ultrasonography of rotator cuff muscles.

PURPOSE: To confirm the neuromuscular integrity of the rotator cuff and to investigate the effect of different contraction patterns on shoulder function, we sonographically analyzed dynamic contraction patterns of this muscle group. METHODS: Fifty supra- and 50 infraspinatus muscle contraction patterns of patients with different shoulder pathologies examined with a 7.5-MHz transducer were recorded and saved as video files. Both data sets were analyzed by 3 independent observers who then assigned a grade to each contraction pattern: normal, slightly disturbed, severely disturbed, or no contraction. Intra- and inter-observer variations were calculated. In 43 patients with isolated supraspinatus tears, the clinical relation to shoulder function as measured with the Constant score was evaluated. RESULTS: In the 100 cases tested, the intraclass correlations for the 3 observers were 0.82, 0.88, and 0.88. The inter-observer reliability was 0.74. No pair of first and second readings for either the supraspinatus or infraspinatus muscle differed by more than 1 grade. In patients with a supraspinatus tear, the contraction type of the supraspinatus correlated significantly with the Constant score (p=0.02). CONCLUSIONS: When dynamic ultrasonography is used to assess the contraction patterns of the supra- and infraspinatus muscles, good intra- and inter-observer reliability is attained. Because a better contraction type correlates significantly with better shoulder function, this new diagnostic criterion may improve decision-making in the treatment of shoulder diseases.

Tumor necrosis factor-alpha-dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability.

The pleiotropic cytokine tumor necrosis factor-alpha (TNF-alpha) and thrombin lead to increased endothelial permeability in sepsis. Numerous studies demonstrated the significance of intracellular cyclic nucleotides for the maintenance of endothelial barrier function. Actions of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are terminated by distinct cyclic nucleotide phosphodiesterases (PDEs). We hypothesized that TNF-alpha could regulate PDE activity in endothelial cells, thereby impairing endothelial barrier function. In cultured human umbilical vein endothelial cells (HUVECs), we found a dramatic increase of PDE2 activity following TNF-alpha stimulation, while PDE3 and PDE4 activities remained unchanged. Significant PDE activities other than PDE2, PDE3, and PDE4 were not detected. TNF-alpha increased PDE2 expression in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Endothelial barrier function was investigated in HUVECs and in isolated mice lungs. Selective PDE2 up-regulation sensitized HUVECs toward the permeability-increasing agent thrombin. In isolated mice lungs, we demonstrated that PDE2 inhibition was effective in preventing thrombin-induced lung edema, as shown with a reduction in both lung wet-to-dry ratio and albumin flux from the vascular to bronchoalveolar compartment. Our findings suggest that TNF-alpha-mediated up-regulation of PDE2 may destabilize endothelial barrier function in sepsis. Inhibition of PDE2 is therefore of potential therapeutic interest in sepsis and acute respiratory distress syndrome (ARDS).

Ultrasonography for intraoperative control of the amount of bone resection in arthroscopic acromioclavicular joint resection.

Remaining superior osteophytes or osseous spurs after arthroscopic lateral clavicle resection can cause persistent pain and could lead to revision surgery. A new method of intraoperative ultrasonographic imaging of the result of the operation during arthroscopic lateral clavicle resection is presented. In 10 patients with acromioclavicular arthritis, standardized arthroscopic lateral clavicle resection was performed. Intraoperatively, the space between the clavicle and the acromion was measured before and after arthroscopic acromioclavicular resection using a Sonosite 180 plus (SonoSite, Bothell, WA) with a 10-MHz broadband linear array in a sterile bag. The width of the joint space between the clavicle and the acromion was between 0.38 and 0.56 cm before operation and 0.92 cm and 1.28 cm after operation (nine cases). In one case, the anticipated minimum resection of 0.5 cm was not achieved at the sonographic measurement and further resection was required. Real-time ultrasonography allows exact measurement of the amount of resected bone during arthroscopic lateral clavicle resection. This could avoid revision surgery resulting from persisting disability caused by insufficient or extensive bone resection.