Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human.

BACKGROUND: Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology. METHODS: Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans. RESULTS: In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300 mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10mg). CONCLUSIONS: We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.

Tirasemtiv amplifies skeletal muscle response to nerve activation in humans.

INTRODUCTION: In this study we tested the hypothesis that tirasemtiv, a selective fast skeletal muscle troponin activator that sensitizes the sarcomere to calcium, could amplify the response of muscle to neuromuscular input in humans. METHODS: Healthy men received tirasemtiv and placebo in a randomized, double-blind, 4-period, crossover design. The deep fibular nerve was stimulated transcutaneously to activate the tibialis anterior muscle and produce dorsiflexion of the foot. The force-frequency relationship of tibialis anterior dorsiflexion was assessed after dosing. RESULTS: Tirasemtiv increased force produced by the tibialis anterior in a dose-, concentration-, and frequency-dependent manner with the largest increases [up to 24.5% (SE 3.1), P < 0.0001] produced at subtetanic nerve stimulation frequencies (10 Hz). CONCLUSIONS: The data confirm that tirasemtiv amplifies the response of skeletal muscle to nerve input in humans. This outcome provides support for further studies of tirasemtiv as a potential therapy in conditions marked by diminished neuromuscular input.

Safety, Pharmacokinetics, and Pharmacodynamics of Trazpiroben (TAK-906), a Novel Selective D2 /D3 Receptor Antagonist: A Phase 1 Randomized, Placebo-Controlled Single- and Multiple-Dose Escalation Study in Healthy Participants.

Gastroparesis is a chronic neuromuscular disorder of the upper gastrointestinal tract in which episodic exacerbation can lead to frequent hospitalizations and severe disability. Dopamine D2 /D3 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 D2 /D3 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 (IC50 ,  15.6 µM), thereby reducing the risk of the CNS and cardiovascular adverse effects seen with other dopamine D2 /D3 receptor antagonists. This phase 1 trial evaluated the safety, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy participants. Trazpiroben was rapidly absorbed and eliminated (Tmax , ∼1.1 hours; t1/2 , 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 Cmax , 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.

Inhaled loxapine and intramuscular lorazepam in healthy volunteers: a randomized placebo-controlled drug-drug interaction study.

Pharmacodynamic effects and safety of single-dose inhaled loxapine administered via the Staccato(®) system and intramuscular (IM) lorazepam in combination versus each agent alone were compared in a randomized, double-blind, crossover study in healthy volunteers. Subjects received: inhaled loxapine 10 mg + IM lorazepam 1 mg; inhaled loxapine 10 mg + IM placebo; IM lorazepam 1 mg + Staccato placebo in random order, each separated by a 3-day washout. Primary endpoints were maximum effect (minimum value) and area under the curve (AUC) from baseline to 2 h post treatment for respirations/min and pulse oximetry. Least-squares means (90% confidence interval [CI]) for concomitant treatment versus each agent alone were derived and equivalence (no difference) confirmed if the 90% CI was within 0.8-1.25. Blood pressure (BP), heart rate (HR), sedation (100-mm visual analog scale), and adverse events (AEs) were recorded. All 18 subjects (mean age, 20.4 years; 61% male) completed the study. There was no difference between inhaled loxapine + IM lorazepam and either agent alone on respiration or pulse oximetery during the 12-h postdose period, confirmed by 90% CIs for AUC and C min ratios. BP and HR were no different for inhaled loxapine + IM lorazepam and each agent alone over a 12-h postdose period. Although the central nervous system sedative effects were observed for each treatment in healthy volunteers, the effect was greater following concomitant lorazepam 1 mg IM + inhaled loxapine 10 mg administration. There were no deaths, serious AEs, premature discontinuations due to AEs, or treatment-related AEs.

Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects.

Accumulating evidence indicates that selective antagonism of kappa opioid receptors may provide therapeutic benefit in the treatment of major depressive disorder, anxiety disorders, and substance use disorders. LY2456302 is a high-affinity, selective kappa opioid antagonist that demonstrates >30-fold functional selectivity over mu and delta opioid receptors. The safety, tolerability, and pharmacokinetics (PK) of LY2456302 were investigated following single oral doses (2-60 mg), multiple oral doses (2, 10, and 35 mg), and when co-administered with ethanol. Plasma concentrations of LY2456302 were measured by liquid chromatography-tandem mass spectrometry method. Safety analyses were conducted on all enrolled subjects. LY2456302 doses were well-tolerated with no clinically significant findings. No safety concerns were seen on co-administration with ethanol. No evidence for an interaction between LY2456302 and ethanol on cognitive-motor performance was detected. LY2456302 displayed rapid oral absorption and a terminal half-life of approximately 30-40 hours. Plasma exposure of LY2456302 increased proportionally with increasing doses and reached steady state after 6-8 days of once-daily dosing. Steady-state PK of LY2456302 were not affected by coadministration of a single dose of ethanol. No clinically important changes in maximum concentration (Cmax ) or AUC of ethanol (in the presence of LY2456302) were observed.

Multiple-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy overweight and obese subjects: a randomized double-blind study.

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium-dependent glucose cotransporter-2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose-proportional pharmacokinetic characteristics. Mean half-life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose reabsorption, resulting in a dose-related glucosuria, and a transient increase in urinary electrolyte and fluid loss; plasma glucose, insulin, and electrolyte levels were unchanged. Sergliflozin etabonate produced a rapid, dose-related reduction in body weight (mean changes of -0.09, -1.55, and -1.74 kg from baseline to day 15 with placebo, sergliflozin etabonate 500 mg, and sergliflozin etabonate 1000 mg, respectively), apparently through increased urinary calorie loss rather than through osmotic diuresis. Sergliflozin etabonate 500 or 1000 mg tid was generally well tolerated; no clinically significant adverse events were identified. Renal function (creatinine clearance) was not affected by sergliflozin etabonate, although urinary microalbumin, N-acetyl-beta-D-glucosaminidase, and beta(2)-microglobulin levels tended to increase.

Parecoxib sodium demonstrates gastrointestinal safety comparable to placebo in healthy subjects.

BACKGROUND: The gastrointestinal safety of the novel injectable cyclooxygenase-2 selective inhibitor, parecoxib sodium, was compared with the nonselective nonsteroidal anti-inflammatory drug, ketorolac, and placebo in healthy subjects. STUDY: In a multicenter, randomized, double-blind, placebo-controlled design, 123 adults with endoscopically-confirmed normal upper gastrointestinal mucosae received parecoxib sodium 40 mg twice daily (7 days); placebo (2 days) followed by ketorolac 30 mg 4 times daily (5 days); or placebo (7 days) (each group n = 41). Posttreatment endoscopy scores were analyzed at 3 levels of severity: ulcers (scores of 7), > or =11 erosions/ulcers (scores of 5-7), and any erosions/ulcers (scores of 3-7). RESULTS: No subjects treated with parecoxib sodium or placebo developed gastroduodenal ulcers or > or =11 erosions/ulcers. Parecoxib sodium was comparable to placebo with respect to the combined incidence of erosions/ulcers (12% vs. 7%, P = 0.419). In contrast, in the ketorolac group, 11 (28%) subjects developed ulcers, 19 (48%) subjects developed > or =11 gastroduodenal erosions/ulcers, and the rate of combined ulcers/erosions was 85% (P < 0.001 vs. placebo and parecoxib sodium). CONCLUSIONS: Parecoxib sodium 40 mg twice daily for 7 days has a gastrointestinal safety profile superior to ketorolac 30 mg 4 times daily for 5 days, and comparable to placebo.

Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects.

OBJECTIVE: The aim of this study was to compare the upper GI mucosal effects of i.v. parecoxib sodium with i.v. ketorolac tromethamine and placebo in healthy elderly subjects. METHODS: This was a two-center, double-blind, randomized, placebo-controlled study. Healthy subjects aged 65-75 yr who were shown at baseline endoscopy to have no gastric or duodenal lesions received either parecoxib sodium 40 mg b.i.d. for 7 days, ketorolac 15 mg q.i.d. for 5 days, or placebo for 7 days. Endoscopy was repeated at the end of dosing. Measures of upper GI effects were: 1) ulceration, 2) incidence of an ulcer and/or any erosions, and 3) incidence of an ulcer and/or > or = 11 erosions in the stomach, duodenum, or both. RESULTS: No gastric or duodenal ulcers occurred in any subjects receiving parecoxib sodium (n = 29) or placebo (n = 32). In contrast, seven (23%) of the 31 ketorolac subjects had at least one ulcer; five (16%) had gastric ulcers, and two (6%) had duodenal ulcers (p < 0.05 vs parecoxib sodium and placebo for gastroduodenal ulcers and for gastric ulcers). A total of 28 (90%) ketorolac subjects had an ulcer or at least one erosion in the stomach, compared with incidences of four (14%) and two (6%) for parecoxib sodium and placebo, respectively. Incidences of duodenal ulcers/erosions were 45% (n = 14) for ketorolac, 10% (n = 3) for parecoxib sodium, and none for placebo. The differences between ketorolac and both other treatment groups were statistically significant for both stomach and duodenum. No parecoxib sodium or placebo subjects had an ulcer or > or = 11 erosions in the stomach, compared with eight (26%) ketorolac subjects (p < 0.05 vs both parecoxib sodium and placebo). No subject in any group had > or = 11 duodenal erosions. CONCLUSIONS: These results indicate that multiple dose administration of parecoxib sodium is safe and well tolerated in healthy elderly subjects, with a decreased risk of gastroduodenal mucosal injury compared with ketorolac.

Patient satisfaction with alosetron for the treatment of women with diarrhea-predominant irritable bowel syndrome.

OBJECTIVE: The efficacy and tolerability of alosetron in women with diarrhea-predominant irritable bowel syndrome (IBS) have been established in double-blind, placebo-controlled trials. However, the degree to which alosetron fulfills the needs of those suffering from IBS has not been thoroughly examined from the patient's perspective. This randomized, double-blind, placebo-controlled study conducted in women with diarrhea-predominant IBS evaluated patients' overall satisfaction with treatment as well as their satisfaction with respect to several specific medication attributes. METHODS: Patients randomized to receive either alosetron 1 mg b.id. (n = 532) or placebo (n = 269) were administered a questionnaire on which they rated on 7-point Likert scales their prestudy IBS treatment (at the screening visit) or study medication (on wk 12 or final study visit) with respect to overall satisfaction and 11 specific medication attributes. RESULTS: Whereas approximately 10% of patients were satisfied or very satisfied overall with prestudy IBS medication, 69% of patients were satisfied or very satisfied overall with alosetron and 46% with placebo (p < 0.001) at the end of 12 wk of therapy. The majority of alosetron-treated patients (61-87%) were satisfied or very satisfied with each of 11 specific medication attributes (p < 0.001 vs placebo for each attribute). Favorable satisfaction ratings for alosetron were assigned to the five medication attributes that patients considered to be most important, including relief of urgency (68% alosetron vs 41% placebo), speed of relief (71% vs 40%), time to return to normal activities (75% vs 49%), relief of abdominal pain (62% vs 44%), and prevention of return of urgency (68% vs 42%). CONCLUSIONS: Women with diarrhea-predominant IBS are satisfied with alosetron 1 mg b.i.d. treatment overall and also with respect to specific attributes of IBS medication they consider most important.