The 5-hydroxytryptamine type-4 receptor agonist felcisetrag (TAK-954) is being investigated for improving gastrointestinal motility in postoperative gastrointestinal dysfunction. Polypharmacy often occurs in this setting, and as in vitro data indicate, felcisetrag is primarily metabolized by cytochrome P450 (CYP) 3A4, its CYP3A4-mediated drug-drug interaction potential requires consideration. This phase 1, fixed-sequence, open-label, crossover trial (ClinicalTrials.gov identifier NCT03173170) investigated the effect of itraconazole, a potent CYP3A4 inhibitor, on felcisetrag pharmacokinetics in healthy adults. Over 2 study periods (period 1, 6 days; period 2, 9 days), participants received a single felcisetrag 0.2-mg intravenous dose (day 1, period 1; and day 4, period 2), and once-daily oral itraconazole 200-mg doses (days 1-8, period 2). For felcisetrag alone, felcisetrag total systemic exposure was lower than with itraconazole coadministration. The geometric mean ratio for area under the plasma concentration-time curve from time 0 to infinity of felcisetrag plus itraconazole: felcisetrag alone was 1.49 (90% confidence interval, 1.39-1.60). Peak exposure was similar between regimens (geometric mean ratio, 1.06; 90% confidence interval, 0.96-1.18), and both treatments were well tolerated. These data suggest limited CYP3A4-mediated drug-drug interaction inhibition for felcisetrag.

Trazpiroben (TAK-906) is a peripherally selective dopamine D2 /D3 receptor antagonist being developed to treat chronic gastroparesis. This phase I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, parallel-group study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy Japanese men. Findings were compared with those from a prior US trial in healthy individuals. Overall, 24 participants were enrolled into 3 cohorts (each n = 8). Per cohort, 6 participants received trazpiroben (cohort 1, 50 mg; 2, 100 mg; 3, 10 mg) once on day 1 and twice daily on days 3 through 7, and two received placebo. Trazpiroben was well tolerated, with no clinically meaningful adverse events observed. Following single- and multiple-dose administration, trazpiroben was rapidly absorbed and eliminated (mean elimination half-life, 1.89-6.45 hours; median time to maximum serum concentration [steady state], 1.00-1.25 hours). Serum prolactin increased with trazpiroben treatment (mean maximum serum concentration 93.32 ng/mL [10 mg] vs. 10.83 ng/mL [placebo]), illustrating receptor target engagement. Results reflected those from healthy US participants, indicating a lack of differences between these ethnic populations in trazpiroben disposition and safety profile. Trazpiroben may represent a promising therapy for chronic gastroparesis across different populations, with further evaluation ongoing in a phase IIb study (NCT03544229).

Gastroparesis is a chronic neuromuscular disorder of the upper gastrointestinal tract in which episodic exacerbation can lead to frequent hospitalizations and severe disability. Dopamine D 2 /D 3 receptor antagonists have been used to treat patients with gastroparesis with some efficacy; however, their chronic use is limited owing to associated central nervous system (CNS) or cardiovascular safety concerns. Trazpiroben (TAK‐906) is a dopamine D 2 /D 3 receptor antagonist under development for the long‐term treatment of gastroparesis. Preclinical studies in rat and dog have shown trazpiroben to have minimal brain penetration and low affinity for the human ether‐à‐go‐go‐related gene (hERG) potassium channel (IC 50 , 15.6 µM), thereby reducing the risk of the CNS and cardiovascular adverse effects seen with other dopamine D 2 /D 3 receptor antagonists. This phase 1 trial evaluated the safety, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy participants. Trazpiroben was rapidly absorbed and eliminated (T max , ∼1.1 hours; t 1/2 , 4–11 hours) after administration of single (5–300 mg) and multiple (50 or 100 mg) doses. Receptor target engagement was confirmed for all doses, as indicated by an increase in serum prolactin levels compared with placebo (mean prolactin C max , 134.3 ng/mL after administration of trazpiroben 10 mg vs 16.1 ng/mL with placebo). Therapeutically relevant single and multiple doses of trazpiroben were well tolerated in healthy participants, and no clinically meaningful cardiovascular adverse effects were observed across the whole dose range. These data support the further development of trazpiroben for the treatment of gastroparesis.

Purpose: Treatment options for gastroparesis, such as metoclopramide and domperidone, are limited because of safety concerns, which may be exacerbated in the presence of inhibitors of drug metabolism. This study evaluated the effect of itraconazole on the pharmacokinetics, safety, and tolerability of trazpiroben (previously TAK-906), a novel, peripherally selective D-2/D-3 dopamine receptor antagonist. Methods: This was a phase 1, two-period, crossover trial in healthy participants (NCT03161405). On day 1, period 1 (days 1-3), participants received a single oral dose of trazpiroben 25 mg. During period 2 (days 4-9), participants received oral itraconazole 200 mg once daily (days 1-5) and one oral dose of trazpiroben 25 mg post itraconazole on day 4. Trazpiroben pharmacokinetics were assessed. Safety assessments included triplicate electrocardiograms. Results: Twelve healthy males (24-45 years old) were studied. Co-administration of itraconazole increased trazpiroben area under the concentration-time curve from time 0 to infinity by 1.28-fold (90% confidence interval: 1.10, 1.49) and maximum plasma concentration (C-max) by 1.98-fold (1.64, 2.39) versus trazpiroben alone. Placebo-corrected, change from baseline in corrected QT interval at the observed geometric mean C-max for trazpiroben alone (9.53 ng/mL) and with itraconazole (18.00 ng/mL) was estimated at 1.31 ms (-0.39, 3.01) and 1.54 ms (-0.15, 3.24), respectively. There were no clinically relevant abnormalities in any safety parameters. Conclusion: These results indicate that TAK-906 is relatively insensitive to inhibition of cytochrome P450 3A4, and cardiovascular safety concerns associated with domperidone are unlikely to be elicited by trazpiroben under similar conditions.

Gastroparesis is a chronic neuromuscular disorder of the upper gastrointestinal tract in which episodic exacerbation can lead to frequent hospitalizations and severe disability. Dopamine D 2 /D 3 receptor antagonists have been used to treat patients with gastroparesis with some efficacy; however, their chronic use is limited owing to associated central nervous system (CNS) or cardiovascular safety concerns. Trazpiroben (TAK-906) is a dopamine D 2 /D 3 receptor antagonist under development for the long-term treatment of gastroparesis. Preclinical studies in rat and dog have shown trazpiroben to have minimal brain penetration and low affinity for the human ether-à-go-go-related gene (hERG) potassium channel (IC 50 ,  15.6 µM), thereby reducing the risk of the CNS and cardiovascular adverse effects seen with other dopamine D 2 /D 3 receptor antagonists. This phase 1 trial evaluated the safety, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy participants. Trazpiroben was rapidly absorbed and eliminated (T max , ∼1.1 hours; t 1/2 , 4–11 hours) after administration of single (5–300 mg) and multiple (50 or 100 mg) doses. Receptor target engagement was confirmed for all doses, as indicated by an increase in serum prolactin levels compared with placebo (mean prolactin C max , 134.3 ng/mL after administration of trazpiroben 10 mg vs 16.1 ng/mL with placebo). Therapeutically relevant single and multiple doses of trazpiroben were well tolerated in healthy participants, and no clinically meaningful cardiovascular adverse effects were observed across the whole dose range. These data support the further development of trazpiroben for the treatment of gastroparesis.

IntroductionTAK‐906 (previously designated as ATC‐1906M, [3‐((1‐cyclohexyl‐4‐oxo‐8‐(4‐oxo‐4‐phenylbutyl)‐1,3,8‐triazaspiro[4.5]decan‐3‐yl)methyl)benzoic acid. maleate]) is in development for the symptomatic treatment of gastroparesis. TAK‐906 is designed to retain the dopamine receptor antagonist profile and minimal central nervous system (CNS) penetration of domperidone whilst avoiding the cardiac effects. This study aimed to evaluate the pharmacokinetics, pharmacodynamics and safety of single and multiple ascending doses of TAK‐906 in healthy adults.MethodsThis Phase 1, randomized, double‐blind, placebo‐controlled, 2‐phase study was conducted in 72 healthy male and female subjects. In the single‐ascending dose (SAD) phase, TAK‐906 or placebo was administered orally, in the fasted state, to cohorts of 8 subjects each at doses of 5, 10, 25, 50, 100, 200, or 300 mg. Subjects in the 25‐mg cohort received a second 25‐mg dose in the fed state. In the multiple‐ascending dose (MAD) phase, TAK‐906 was administered orally to successive cohorts of 8 subjects each at 50 or 100 mg twice daily (BID) for 4 days with a single dose on Day 5.Results and ConclusionsPharmacokineticsTAK‐906 was rapidly absorbed (median plasma TAK‐906 Tmax ~1.1 hours across all cohorts) and rapidly eliminated (mean plasma TAK‐906 t1/2 ~4.0 hours [SAD cohorts], and 11.0 and 6.2 hours at the 50‐ and 100‐mg BID doses, respectively, on Day 5 [MAD cohorts]). Elimination was monophasic over the first 12 hours after dosing. With single oral doses, TAK‐906 exposure increased proportional to dose (mean Cmax ~2 ng/mL [5‐mg dose] and ~190 ng/mL [300‐mg dose]); CL/F, Vz/F, and t1/2 were not dose dependent. Accumulation was minor with BID dosing for 5 days (<40% for Cmax; <30% for AUC0–12). Food significantly reduced exposure to TAK‐906 25 mg.PharmacodynamicsSerum prolactin concentration, a biomarker for D2 antagonism, increased substantially following administration of single doses of TAK‐906 compared to placebo; the increase was rapid (median Tmax ~0.7 to 1.1 hours) and short‐lived (mean t1/2 10.82 hours). Serum prolactin concentration did not increase in proportion to dose; the prolactin response was maximal at the single 10‐mg dose level (mean TAK‐906 Cmax ~6 ng/mL), with little accumulation with BID dosing for 5 days.Cardiac SafetySingle doses of TAK‐906 between 5 and 300 mg, resulting in plasma concentrations of up to 170 ng/mL, did not have a clinically meaningful effect on placebo‐corrected change from baseline corrected QT interval using Frederica’s method (QTcF).SafetyMonitoring of adverse events, vital signs, clinical laboratory evaluations, CNS and general physical examinations indicated that oral administration of single or multiple doses of TAK‐906 was well tolerated in healthy male and female subjects.Support or Funding InformationThis study was sponsored by Altos Therapeutics, LLC. Formatting and editing support were provided by Oxford PharmaGenesis, Oxford, UK and funded by Takeda Pharmaceutical Company Ltd

We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT4 receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defecation frequency in slow transit constipation while avoiding the onset of diarrhea. Model sensitivity analysis predicted that changes in HAPC frequency and liquid secretion have the greatest impact on colonic motility. However, exclusively increasing the liquid secretion can lead to diarrhea. In contrast, increasing HAPC frequency alone can enhance bowel frequency without leading to diarrhea. The quantitative systems pharmacology approach used here demonstrates how mechanistic modeling of disease pathophysiology expands our understanding of biology and supports judicious hypothesis generation for therapeutic intervention.

Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into 1 of 6 treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol (20 mg), valsartan (320 mg), and nebivolol-valsartan combination (20/320 mg). Outcomes included AUC0-τ,ss, Cmax,ss, Tmax,ss, changes in BP, pulse rate, plasma angiotensin II, plasma renin activity, 24-hour urinary aldosterone, and adverse events. Steady-state pharmacokinetic interactions were observed but deemed not clinically significant. Systolic and diastolic BP reduction was significantly greater with nebivolol-valsartan combination than with either monotherapy. The mean pulse rate associated with nebivolol and nebivolol-valsartan treatments was consistently lower than that associated with valsartan monotherapy. A sharp increase in mean day 7 plasma renin activity and plasma angiotensin II that occurred in valsartan-treated participants was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at day 7 was substantially decreased after combined treatment, as compared with either monotherapy. All treatments were safe and well tolerated. In conclusion, nebivolol and valsartan coadministration led to greater reductions in BP compared with either monotherapy; nebivolol and valsartan lower BP through complementary mechanisms.

After demonstration of the antihypertensive efficacy of the combination of the beta-blocker nebivolol and the angiotensin receptor blocker valsartan in an 8-week, randomized, placebo-controlled trial (N = 4161), we now report the effects of this treatment on the renin-angiotensin-aldosterone system in a substudy (n = 805). Plasma renin activity increased with valsartan (54%-73%) and decreased with nebivolol (51%-65%) and the combination treatment (17%-39%). Plasma aldosterone decreased with individual treatments (valsartan, 11%-22%; nebivolol, 20%-26%), with the largest reduction (35%) observed with maximum combination dose (20 mg nebivolol/320 mg valsartan). Baseline ln(plasma renin activity) correlated with the 8-week reductions in 24-hour systolic and diastolic BP following treatments with the combination (all doses combined, P = .003 and P < .001) and nebivolol (both, P < .001), but not with valsartan. Baseline ln(aldosterone) correlated with 24-hour systolic and diastolic BP reductions following combination treatment only (P < .001 and P = .005). The implications of the renin-angiotensin-aldosterone system effects of this beta blocker-angiotensin receptor blocker combination should be explored further. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of American Society of Hypertension.

La disfagia orofaríngea es muy frecuente en enfermedades neurológicas, siendo un síntoma grave, con complicaciones nutricionales y respiratorias que pueden causar la muerte del paciente.Determinar la prevalencia de disfagia orofaríngea en las unidades de rehabilitación neurológica de la Fundación Instituto San José (FISJ); conocer el estado funcional y las enfermedades que influyen en la posible aparición de la disfagia orofaríngea de dichos pacientes.Estudio descriptivo transversal teniendo como población accesible los pacientes ingresados desde el 1 de enero hasta el 30 de septiembre del año 2012, en la Unidad de Trastornos Neurológicos Moderados (UTNM) y en la Unidad de Trastornos Neurológicos Severos (UTNS) de la FISJ.En el periodo de estudio ingresaron 109 pacientes en la UTNM y 31 pacientes en la UTNS. Tenemos una prevalencia de 31,2% en la UTNM y una prevalencia muy alta, 64,5% en la UTNS. En la UTNM se diagnosticaron 14 casos nuevos de disfagia orofaríngea y en la UTNS se diagnosticaron 6 casos nuevos. Los pacientes con disfagia orofaríngea han ingresado con diagnóstico principal de ictus (63%) y un 18,5% con hemorragias/hematomas cerebrales. Asimismo, verificamos que el 85,2% de los pacientes diagnosticados de disfagia presentan un nivel de dependencia total, 11,1% con dependencia severa y 3,7% una dependencia moderada.La prevalencia de disfagia en nuestras unidades de trastornos neurológicos es muy elevada, en especial en pacientes con enfermedad cerebro vascular y con nivel de dependencia total/severa.Oropharyngeal dysphagia is very common in neurological diseases. It is a serious symptom with nutritional and respiratory complications that may lead to the death.To determine the prevalence of oropharyngeal dysphagia in Neurological Rehabilitation Units of the Fundación Instituto San José (FISJ), Madrid, as well as to determine the functional status and diseases that may lead to the possible occurrence of oropharyngeal dysphagia in these patients.A descriptive cross-sectional study was conducted on all patients admitted from 1 January to 30 September 2012, in the Moderate Neurological Disorders (UTNM) and Severe Neurological Disorders Units (UTNS) of the FISJ.A total of 109 patients were admitted to the UTNM and 31 patients to the UTNS during the study period. There was a 31.2% prevalence of oropharyngeal dysphagia in the UTNM, with a very high prevalence of 64.5% in UTNS. A total of 14 new cases were diagnosed In the UTNM, and 6 new cases in the UTNS. Patients with oropharyngeal dysphagia have been admitted with a primary diagnosis of stroke (63%) and 18.5% with cerebral hemorrhage/hematoma. It was also determined that of the 85.2% of patients diagnosed with dysphagia, 11.1% presented levels of total dependence, whilst 3.7% presented severe/moderate dependence.The prevalence of dysphagia in Neurological Disorders Units in Madrid is very high, especially in patients with cerebrovascular disease and total/severe dependency level.

Screenings recovered from the inlet works of wastewater treatment plants were digested without pre-treatment or dilution using a lab-scale, leach-bed reactor. Variations in recirculation ratio of the leachate of 4 and 8 l/lreactor/day and pH values of 5 and 6 were evaluated in order to determine the optimal operating conditions for maximum total volatile fatty acids (VFA) production. By increasing the recirculation ratio of the leachate from 4 to 8 l/lreactor/day it was possible to increase VFA production (11%) and soluble COD (17%) and thus generate up to 264 g VFA/kg-dry screenings. These VFA were predominantly acetic acid with some propionic and butyric acid. The optimum pH for VFA production was 6.0, when the methanogenic phase was inhibited. Below pH 5.0, acid-producing fermentation was inhibited and some alcohols were produced. Ammonia release during the hydrolysis of screenings provided adequate alkalinity; consequently, a digestion process without pH adjustment could be recommended. The leach-bed reactor was able to achieve rapid rates of screenings degradation with the production of valuable end-products that will reduce the carbon footprint associated with current screenings disposal techniques.

Background: Combining different classes of antihypertensive drugs is more effective for achieving blood pressure (BP) control than increasing the dose of monotherapies. An aim of this study was to investigate pharmacodynamic (PD) interactions between nebivolol, a β1 selective, vasodilatory beta blocker and valsartan, an angiotensin II type 1 receptor blocker. Methods: This was a single-center, randomized, open-label, multiple-dose, three-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into one of six treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol 20 mg, valsartan 320 mg, or nebivolol 20 mg plus valsartan 320 mg. Outcomes included changes in BP, heart rate (HR), plasma angiotensin II, plasma renin activity (PRA), and 24-hour urinary aldosterone. Results: The drop in least square mean values of systolic and diastolic BP was significantly greater following the concomitant administration of nebivolol and valsartan than either monotherapy alone. The mean HR after treatment with nebivolol alone, as well as after the combined treatment, was consistently lower than valsartan monotherapy. A sharp increase in mean Day 7 PRA and plasma angiotensin II occurred in subjects receiving valsartan alone and this was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at Day 7 was substantially decreased after combined treatment, as compared to either monotherapy treatment. All treatments were safe and well tolerated. Conclusion: Nebivolol and valsartan co-administration led to greater reductions in BP compared to either monotherapy. Nebivolol attenuated valsartan-induced increases in angiotensin II levels and PRA and reduced urinary aldosterone levels. Hence, these mechanisms for BP lowering are complementary and provide a rationale for further investigation of this combination in patients with essential hypertension.