Safety and Efficacy of Perioperative Intravenous Meloxicam for Moderate-to-Severe Pain Management in Total Knee Arthroplasty: A Randomized Clinical Trial.

OBJECTIVE: To evaluate the effect of perioperative meloxicam IV 30 mg on opioid consumption in primary total knee arthroplasty (TKA). DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial. SUBJECTS: In total, 181 adults undergoing elective primary TKA. METHODS: Subjects received meloxicam 30 mg or placebo via an IV bolus every 24 hours, the first dose administered prior to surgery as part of a multimodal pain management protocol. The primary efficacy parameter was total opioid use from end of surgery through 24 hours. RESULTS: Meloxicam IV was associated with less opioid use versus placebo during the 24 hours after surgery (18.9 ± 1.32 vs 27.7 ± 1.37 mg IV morphine equivalent dose; P < 0.001) and was superior to placebo on secondary endpoints, including summed pain intensity (first dose to 24 hours postdosing, first dose to first assisted ambulation, and first dose to discharge) and opioid use (48-72 hrs., 0-48 hrs., 0-72 hrs., hour 0 to end of treatment, and the first 24 hours after discharge). Adverse events (AEs) were reported for 69.9% and 92.0% of the meloxicam IV and placebo groups, respectively; the most common AEs were nausea (40% vs. 59%), vomiting (16% vs 22%), hypotension (14% vs 15%), pruritus (15% vs 11%), and constipation (11% vs 13%). CONCLUSIONS: Perioperative meloxicam IV 30 mg as part of a multimodal analgesic regimen for elective primary TKA reduced opioid consumption in the 24-hour period after surgery versus placebo and was associated with a lower incidence of AEs typically associated with opioid use.

Analgesic Efficacy and Safety of Intravenous Meloxicam in Subjects With Moderate-to-Severe Pain After Open Abdominal Hysterectomy: A Phase 2 Randomized Clinical Trial.

BACKGROUND: An intravenous (IV) formulation of meloxicam was developed for moderate-to-severe pain management. This study evaluated the safety and efficacy of meloxicam IV after open abdominal hysterectomy. Meloxicam IV is an investigational product not yet approved by the US Food and Drug Administration. METHODS: Women (N = 486) with moderate-to-severe pain after open abdominal hysterectomy were enrolled in this multicenter, randomized, double-blind, placebo- and active-controlled trial. Subjects were randomized to receive a single dose of meloxicam IV (5-60 mg), placebo, or morphine (0.15 mg/kg) in ≤6 hours after morphine dosing on postoperative day 1 and were evaluated for 24 hours. Rescue morphine (≈0.15 mg/kg IV) was available if needed for pain not relieved by the study medication. In an open-label extension (N = 295), meloxicam IV was administered once daily for the remaining hospital stay (or per the investigator's discretion). The coprimary efficacy end points were the summed pain intensity difference (SPID24) and total pain relief (TOTPAR24) from hour 0 to 24 hours after dosing. Effect size, the standardized difference between means reported in standard deviation (SD) units, was calculated to indicate the magnitude of the difference in the mean analgesic effect measured for different intervention groups. RESULTS: Subjects who received morphine or meloxicam IV had a median time to first perceptible pain relief within 6-8 minutes. Morphine and meloxicam IV 5-60 mg produced statistically significant differences than placebo in SPID24 and TOTPAR24. SPID24 (standard error [SE]) for meloxicam IV 5-60 mg ranged from -56276.8 (3926.46) to -33517.1 (3930.1; P < .001); SPID24 (SE) for morphine and placebo were -29615.8 (3869.2; P < .001) and 4555.9 (3807.1), respectively. SPID24 effect sizes (95% confidence intervals) for the 60, 30, 15, 7.5, and 5 mg meloxicam IV doses and morphine were 1.93 (1.61-2.25), 2.00 (1.65-2.35), 1.70 (1.35-2.05), 1.28 (0.95-1.60), 1.25 (0.90-1.61), and 1.12 (0.77-1.45) SDs, respectively. TOTPAR24 (SE) for meloxicam IV 5-60 mg ranged from 3104.5 (155.28) to 4130.4 (191.17; P < .001); TOTPAR24 (SE) for morphine and placebo were 2723.3 (188.4; P < .001) and 1100.6 (185.4), respectively. TOTPAR24 effect sizes (95% confidence interval) for the 60, 30, 15, 7.5, and 5 mg meloxicam IV doses and morphine were 2.03 (1.70-2.35), 2.05 (1.70-2.40), 1.78 (1.43-2.13), 1.35 (1.03-1.67), 1.37 (1.01-1.72), and 1.10 (0.75-1.45) SDs, respectively. The mean total opioid consumed (SD) during the double-blind phase was 4.6 (8.17), 5.3 (8.85), 5.9 (7.85), 8.5 (9.67), 9.3 (9.47), 9.6 (8.12), and 16.0 (10.15) mg for patients in the 60, 30, 15, 7.5, and 5 mg meloxicam IV, morphine, and placebo groups, respectively. Generally, meloxicam IV was well tolerated, evidenced by the incidence of adverse events compared to placebo and lack of deaths and treatment-related serious adverse events. CONCLUSIONS: A meloxicam IV dose of 5-60 mg was generally well tolerated and appeared to reduce opioid consumption in subjects with moderate-to-severe pain after open abdominal hysterectomy. Once-daily administration of meloxicam IV produced analgesic effect within 6-8 minutes postdose that was maintained over a 24-hour dosing interval.

Safety and efficacy of epelsiban in the treatment of men with premature ejaculation: a randomized, double-blind, placebo-controlled, fixed-dose study.

AIM: To assess the efficacy and safety of the selective oxytocin receptor antagonist epelsiban in the treatment of premature ejaculation (PE). METHODS: Double-blind, randomized, parallel-group, placebo-controlled, stopwatch-monitored, phase 2, multicenter study (GSK557296; NCT01021553) conducted in men (N=77) 18-55 years of age, with PE defined as per International Society for Sexual Medicine consensus definition. Patients provided informed consent prior to a 4-week un-medicated run-in to determine baseline intravaginal ejaculatory latency times (IELT) recorded in an electronic diary. Patients needed to make a minimum of four intercourse attempts and have a mean IELT<65 seconds to be considered for randomization. Men with moderate-to-severe erectile dysfunction were excluded from the study. Eligible patients were randomized to placebo, epelsiban 50 mg, or 150 mg, taken 1 hour before sexual activity. Active treatment IELT times were recorded in an electronic diary, along with subjective measures of intercourse satisfaction, over an 8-week treatment period. The Modified Index of Premature Ejaculation and International Index of Erectile Function were completed at study visits. MAIN OUTCOME MEASURES: Stopwatch timed IELT recordings and a modified version of the patient-reported outcome questionnaire the IPE were used in this study to determine the effect of epelsiban when taken orally prior to intercourse in subjects diagnosed with PE. RESULTS: The baseline (mean) IELT for patients pretreatment was (0.52, 0.63, and 0.59 minutes) for placebo, epelsiban 50 mg and 150 mg, respectively. On-treatment, average geometric least squares means of the median IELT values (mean) were slightly higher in the 50 mg and 150 mg groups (0.72 and 0.69 minutes), respectively, vs. the placebo group (0.62 minutes). Headache was the most common adverse event, and rates were similar across all groups. CONCLUSIONS: Epelsiban 50 mg and 150 mg were well tolerated, but did not result in a clinically or statistically significant change in IELT in men with PE, compared with placebo.

Meloxicam for intravenous use: review of its clinical efficacy and safety for management of postoperative pain.

Meloxicam for intravenous use (meloxicam iv.) is a nanocrystal formulation with improved dissolution properties and shortened time to peak plasma concentrations versus oral meloxicam. In Phase III and IIIb trials, 30 mg once daily relieved pain following pre- or postoperative administration in orthopedic, abdominal and colorectal surgeries. Meloxicam iv. was associated with reduced opioid consumption, the clinical benefit of which remains unclear. The drug may be administered alone or in combination with other non-nonsteroidal anti-inflammatory drugs. In Phase III trials, it demonstrated adverse event profile similar to placebo, with nausea, constipation, vomiting and headache occurring most frequently. Meloxicam iv. does not appear to adversely affect platelet function or wound-healing parameters. No new safety signals were detected in the Phase IIIb studies.

Economic Impact of Preoperative Meloxicam IV Administration in Total Knee Arthroplasty: A Randomized Trial Sub-Study.

We evaluated the economic impact associated with preoperative meloxicam IV 30 mg vs placebo administration among adult total knee arthroplasty (TKA) recipients enrolled in Phase IIIB NCT03434275 trial. Data on total hospital costs and length of stay (LOS) obtained from the trial were compared between meloxicam IV 30 mg and placebo groups. Patients in the meloxicam IV 30 mg vs placebo group (n = 93 vs 88) incurred an adjusted $2,266 (95% CI: -$1,035, $5,116; p = 0.1689) lower total hospital costs and an adjusted 8.6% (95% confidence interval [CI]: -2.0%, 18.1%; p = 0.1082) shorter LOS. While statistically non-significant, based on 95% CIs, the results from this sub-study may suggest a favorable impact associated with meloxicam IV 30 mg on hospital costs and LOS.

Preoperative intravenous meloxicam for moderate-to-severe pain in the immediate post-operative period: a Phase IIIb randomized clinical trial in 55 patients undergoing primary open or laparoscopic colorectal surgery with bowel resection and/or anastomosis.

Aim: Evaluate safety/efficacy of intravenous meloxicam in a colorectal enhanced recovery after surgery protocol. Methods: Adults undergoing primary open or laparoscopic colorectal surgery with bowel resection and/or anastomosis received meloxicam IV 30 mg (n = 27) or placebo (n = 28) once daily beginning 30 min before surgery. Results: Adverse events: meloxicam IV, 85%; placebo, 93%. Adverse events commonly associated with opioids: 41 versus 61% - including nausea (33 vs 50%), vomiting (19 vs 18%) and ileus (4 vs 18%). Wound healing satisfaction scores (physician-rated), clinical laboratory findings and vital signs were similar in both groups. No anastomotic leaks were reported. Opioid consumption, postoperative pain intensity, length of stay and times to first bowel sound, first flatus and first bowel movement were significantly lower with meloxicam IV versus placebo. Most subjects (>92%) were satisfied with postoperative pain medication. Conclusion: Meloxicam IV was generally well tolerated and associated with decreased opioid consumption, lower resource utilization and functional benefits. Clinical Trial Registration: NCT03323385 (ClinicalTrials.gov).

Safety, Tolerability, and Effect on Opioid Use of Meloxicam IV Following Orthopedic Surgery.

OBJECTIVE: A Phase 3 randomized multicenter, double-blind, placebo-controlled trial (NCT02720692) compared once-daily intravenous (IV) meloxicam 30 mg to placebo, when added to the standard of care pain management regimens, in adults with moderate-to-severe pain following major elective surgery and concluded that meloxicam IV had a safety profile similar to placebo and reduced opioid consumption. METHODS: In this post hoc subgroup analysis of orthopedic surgery subjects, 379 subjects received meloxicam IV 30 mg or IV-administered placebo every 24 hrs for ≤7 doses. Safety was assessed via AEs, laboratory tests, vital signs, and ECG, with an emphasis on specific AEs, including injection site reactions, bleeding, cardiovascular, hepatic, renal, thrombotic, and wound healing events. Daily opioid consumption was assessed during treatment. RESULTS: Among meloxicam IV-treated subjects, 64.7% experienced ≥1 AE versus 68.8% of placebo-treated subjects. Investigators assessed most AEs to be mild or moderate in intensity and unrelated to treatment. Total opioid consumption (36.8 mg versus 50.3 mg IV morphine equivalent dose; P=0.0081) and opioid consumption during time points 0‒24, 24‒48, 0‒48, and 0‒72 hrs were statistically significantly lower in the meloxicam IV group. CONCLUSION: Meloxicam IV demonstrated no significant differences in the number and frequency of AEs versus placebo in subjects following orthopedic surgery. Opioid consumption was reduced in the meloxicam IV group versus placebo. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02720692).

Intravenous meloxicam for the treatment of moderate to severe acute pain: a pooled analysis of safety and opioid-reducing effects.

BACKGROUND AND OBJECTIVES: To describe the safety and tolerability of intravenous meloxicam compared with placebo across all phase II/III clinical trials. METHODS: Safety data and opioid use from subjects with moderate to severe postoperative pain who received ≥1 dose of intravenous meloxicam (5-60 mg) or placebo in 1 of 7 studies (4 phase II; 3 phase III) were pooled. Data from intravenous meloxicam 5 mg, 7.5 mg and 15 mg groups were combined (low-dose subset). RESULTS: A total of 1426 adults (86.6% white; mean age: 45.8 years) received ≥1 dose of meloxicam IV; 517 (77.6% white; mean age: 46.7 years) received placebo. The incidence of treatment-emergent adverse events (TEAEs) in intravenous meloxicam and placebo-treated subjects was 47% and 57%, respectively. The most commonly reported TEAEs across treatment groups (intravenous meloxicam 5-15 mg, 30 mg, 60 mg and placebo, respectively) were nausea (4.3%, 20.8%, 5.8% and 25.3%), headache (1.5%, 5.6%, 1.6% and 10.4%), vomiting (2.8%, 4.6%, 1.6% and 7.4%) and dizziness (0%, 3.5%, 1.1% and 4.8%). TEAE incidence was generally similar in subjects aged >65 years with impaired renal function and the general population. Similar rates of cardiovascular events were reported between treatment groups. One death was reported (placebo group; unrelated to study drug). There were 35 serious adverse events (SAEs); intravenous meloxicam 15 mg (n=5), intravenous meloxicam 30 mg (n=15) and placebo (n=15). The SAEs in meloxicam-treated subjects were determined to be unrelated to study medication. Six subjects withdrew due to TEAEs, including three treated with intravenous meloxicam (rash, localized edema and postprocedural pulmonary embolism). In trials where opioid use was monitored, meloxicam reduced postoperative rescue opioid use. CONCLUSIONS: Intravenous meloxicam was generally well tolerated in subjects with moderate to severe postoperative pain. TRIAL REGISTRATION NUMBERS: NCT01436032, NCT00945763, NCT01084161, NCT02540265, NCT02678286, NCT02675907 and NCT02720692.

A Phase 3, Randomized, Placebo-Controlled Evaluation of the Safety of Intravenous Meloxicam Following Major Surgery.

An intravenous (IV) formulation of meloxicam is being studied for moderate to severe pain management. This phase 3, randomized, multicenter, double-blind, placebo-controlled trial evaluated the safety of once-daily meloxicam IV 30 mg in subjects following major elective surgery. Eligible subjects were randomized (3:1) to receive meloxicam IV 30 mg or placebo administered once daily. Safety was evaluated via adverse events, clinical laboratory tests, vital signs, wound healing, and opioid consumption. The incidence of adverse events was similar between meloxicam IV- and placebo-treated subjects (63.0% versus 65.0%). Investigators assessed most adverse events as mild or moderate in intensity and unrelated to treatment. Adverse events of interest (injection-site reactions, bleeding, cardiovascular, hepatic, renal, thrombotic, and wound-healing events) were similar between groups. Over the treatment period, meloxicam IV was associated with a 23.6% (P = .0531) reduction in total opioid use (9.2 mg morphine equivalent) compared to placebo-treated subjects. The results suggest that meloxicam IV had a safety profile similar to that of placebo with respect to numbers and frequencies of adverse events and reduced opioid consumption in subjects with moderate to severe postoperative pain following major elective surgery.

Evaluation of the safety and efficacy of an intravenous nanocrystal formulation of meloxicam in the management of moderate-to-severe pain after bunionectomy.

OBJECTIVE: This randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of an intravenous (IV) nanocrystal formulation of meloxicam in subjects with moderate-to-severe pain following a standardized unilateral bunionectomy. METHODS: Fifty-nine subjects aged 18-72 years were randomized to receive doses of either 30 mg (n=20) or 60 mg (n=20) meloxicam IV or placebo (n=19), administered once daily as bolus IV injections over 15-30 seconds (two or three doses). Safety, the primary objective, was assessed by physical examination, clinical laboratory tests, and the incidence of adverse events (AEs). Efficacy was evaluated by examining summed pain intensity differences over the first 48 hours (SPID48) using analysis of covariance models. Use of opioid rescue analgesic agents was evaluated. RESULTS: Generally, AEs were mild-to-moderate in intensity, and their incidence was similar across the three treatment groups. No serious AEs were reported; there were no withdrawals due to AEs, including injection-related AEs. The estimated effect size for SPID48 versus placebo was 1.15 and 1.01 for meloxicam IV doses 30 mg and 60 mg, respectively (P≤0.01). Both doses produced significantly greater pain reductions versus placebo (P≤0.05) at all evaluated times/ intervals during the 48-hour period. The proportions of subjects with ≥30% and ≥50% overall reduction in pain from baseline after 6 and 24 hours were significantly higher with meloxicam IV 30 mg doses versus placebo, but not with meloxicam IV 60 mg doses. The time to first use of rescue medication was significantly longer versus placebo with meloxicam IV 60 mg (P<0.05), but not with meloxicam IV 30 mg doses. CONCLUSION: Meloxicam IV was generally safe and well tolerated in subjects with moderate-to-severe post-bunionectomy pain. Once-daily administration of meloxicam IV 30 mg and 60 mg exhibited rapid onset of analgesia (as early as 15 minutes) with maintenance of analgesic effect for two consecutive 24-hour periods.

A Randomized Double-Blind Controlled Trial of Intravenous Meloxicam in the Treatment of Pain Following Dental Impaction Surgery.

This randomized, controlled phase 2 study was conducted to evaluate the analgesic efficacy, safety, and tolerability of single intravenous (IV) doses of 15 mg, 30 mg, and 60 mg meloxicam compared with oral ibuprofen 400 mg and placebo after dental impaction surgery. The primary efficacy end point was the sum of time-weighted pain intensity differences for 0-24 hours postdose. Among 230 evaluable subjects, meloxicam IV 60 mg produced the greatest reduction in pain, followed by the 30-mg and 15-mg doses. Statistically significant differences in summed pain intensity differences over 24 hours were demonstrated for each active-treatment group vs placebo (favoring active treatment) and for meloxicam IV 30 mg and 60 mg vs ibuprofen 400 mg (favoring meloxicam IV). Moreover, there was a statistically significant dose response for meloxicam IV 15 mg to 60 mg. The onset of action for meloxicam IV was rapid and sustained; significant differences in pain intensity differences were detected as early as 10 minutes postdose and lasted through the 24-hour postdose period. Subjects in the meloxicam IV groups were more likely than placebo recipients to achieve perceptible and meaningful pain relief and were less likely to use rescue medication. Patient-reported global evaluation showed that meloxicam IV 60 mg had the highest rating. There were no deaths, serious adverse events, or discontinuations due to adverse events. The incidence of subjects with ≥1 treatment-emergent adverse event was greatest in the placebo group, followed by the groups that received ibuprofen, meloxicam IV 15 mg, 30 mg, and 60 mg. Nausea was the most commonly reported treatment-emergent adverse event. CLINICAL TRIAL REGISTRATION NUMBER: NCT00945763.

Efficacy and Safety of Intravenous Meloxicam in Patients With Moderate-to-Severe Pain Following Bunionectomy: A Randomized, Double-Blind, Placebo-controlled Trial.

OBJECTIVE: To evaluate the analgesic efficacy and safety of a novel intravenous (IV) formulation of meloxicam (30 mg) in patients with moderate-to-severe pain following a standardized, unilateral bunionectomy with first metatarsal osteotomy and internal fixation. MATERIALS AND METHODS: Patients who met the criteria for moderate-to-severe postoperative pain were randomized to receive bolus injections of meloxicam IV 30 mg (n=100) or placebo (n=101) administered once daily. The primary efficacy endpoint was the Summed Pain Intensity Difference over 48 hours (SPID48). Secondary efficacy endpoints included sum of time-weighted pain intensity differences (SPID) values at other timepoints/intervals, time to first use of rescue analgesia, and number of rescue doses taken. Safety assessments included the incidence of adverse events (AEs), physical examinations, laboratory tests, 12-lead electrocardiography, and wound healing. RESULTS: Patients randomized to meloxicam IV 30 mg exhibited a statistically significant difference in SPID48 versus the placebo group (P=0.0034). Statistically significant differences favoring meloxicam IV over placebo were also observed for secondary efficacy endpoints, including SPID at other times/intervals (SPID6: P=0.0153; SPID12: P=0.0053; SPID24: P=0.0084; and SPID24-48: P=0.0050) and first use of rescue medication (P=0.0076). Safety findings indicated that meloxicam IV 30 mg was generally well tolerated; no serious AEs or bleeding events were observed. Most AEs were assessed by the investigator to be mild in intensity, and no patients discontinued due to AEs. There were no meaningful differences between the study groups in vital signs, electrocardiographic findings, or laboratory assessments. In most cases, investigators found that wound healing followed a normal course and mean wound-healing satisfaction scores were similar for meloxicam IV 30 mg and placebo. DISCUSSION: Meloxicam IV doses of 30 mg provided effective pain relief when administered once daily by bolus injection to patients with moderate-to-severe pain following bunionectomy, and had an acceptable safety profile.

Efficacy and Safety of Intravenous Meloxicam in Subjects with Moderate-to-severe Pain Following Abdominoplasty.

BACKGROUND: A nanocrystal intravenous (IV) formulation of meloxicam is being studied with the aim of providing postoperative analgesia. METHODS: This randomized, multicenter, double-blind, placebo-controlled trial evaluated meloxicam IV 30 mg or placebo (≤ 3 doses) in 219 subjects undergoing abdominoplasty. The primary endpoint was the summed pain intensity difference over 24 hours postdose (SPID24). RESULTS: Meloxicam IV-treated subjects had a statistically significant reduction in the least squares mean of SPID24 compared with placebo-treated subjects (-4,262.1 versus -3,535.7; P = 0.0145). Meloxicam IV was associated with statistically significant differences over placebo on several other secondary endpoints, including other SPID intervals (ie, SPID12, SPID48, and SPID24-48), achievement of perceptible pain relief, the proportion of subjects with a ≥ 30% improvement in the first 24 hours, and Patient Global Assessment of pain at hour 48. Meloxicam IV was also associated with a reduction in the number of subjects receiving opioid rescue medication during hours 24-48 and the total number of doses of opioid rescue analgesia. Meloxicam IV was generally well tolerated, with the numbers and frequencies of adverse events similar to that of the placebo group. There was no evidence of an increased risk of adverse events commonly associated with nonsteroidal anti-inflammatory drugs including bleeding, thrombotic, cardiovascular, renal, hepatic, cardiovascular, injection site, and wound healing events. CONCLUSION: Meloxicam IV provided sustained pain relief and generally was well tolerated in subjects with moderate-to-severe pain following abdominoplasty.

Sildenafil improves cardiac output and exercise performance during acute hypoxia, but not normoxia.

Sildenafil causes pulmonary vasodilation, thus potentially reducing impairments of hypoxia-induced pulmonary hypertension on exercise performance at altitude. The purpose of this study was to determine the effects of sildenafil during normoxic and hypoxic exercise. We hypothesized that 1) sildenafil would have no significant effects on normoxic exercise, and 2) sildenafil would improve cardiac output, arterial oxygen saturation (SaO2), and performance during hypoxic exercise. Ten trained men performed one practice and three experimental trials at sea level (SL) and simulated high altitude (HA) of 3,874 m. Each cycling test consisted of a set-work-rate portion (55% work capacity: 1 h SL, 30 min HA) followed immediately by a time trial (10 km SL, 6 km HA). Double-blinded capsules (placebo, 50, or 100 mg) were taken 1 h before exercise in a randomly counterbalanced order. For HA, subjects also began breathing hypoxic gas (12.8% oxygen) 1 h before exercise. At SL, sildenafil had no effects on any cardiovascular or performance measures. At HA, sildenafil increased stroke volume (measured by impedance cardiography), cardiac output, and SaO2 during set-work-rate exercise. Sildenafil lowered 6-km time-trial time by 15% (P<0.05). SaO2 was also higher during the time trial (P<0.05) in response to sildenafil, despite higher work rates. Post hoc analyses revealed two subject groups, sildenafil responders and nonresponders, who improved time-trial performance by 39% (P<0.05) and 1.0%, respectively. No dose-response effects were observed. During cycling exercise in acute hypoxia, sildenafil can greatly improve cardiovascular function, SaO2, and performance for certain individuals.

Assessing Colonic Exposure, Safety, and Clinical Activity of SRT2104, a Novel Oral SIRT1 Activator, in Patients with Mild to Moderate Ulcerative Colitis.

BACKGROUND: Sirtuins are a class of proteins with important physiologic roles in metabolism and inflammation. Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, activation is an unexplored therapeutic approach for the treatment of ulcerative colitis (UC). METHODS: Patients with mild to moderately active UC were blindly randomized to 50 mg or 500 mg daily of SRT2104, a selective activator of SIRT1, for 8 weeks. Colonic exposure and safety were assessed, as well as blinded endoscopic scoring and disease activity by Mayo score, Simple Clinical Colitis Activity Index and fecal calprotectin. RESULTS: Across both SRT2104 groups, only 3 of 26 evaluable subjects achieved remission on blinded endoscopic assessment. Clinical remission (Mayo score ≤2, no subscore >1) was achieved in 4 patients (2 of 13 evaluable patients in each dose group). Fecal calprotectin levels declined with treatment in both groups, but after 56 days of treatment subjects were still found to have levels approximately 4-fold elevated above normal. One subject experienced an SAE requiring study withdrawal and another was withdrawn for a severe UC flare; 19 subjects (61%) across both treatment groups experienced at least 1 treatment emergent adverse event. Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104, and colonic exposure was 140 to 160 times higher than plasma exposures. CONCLUSIONS: SRT2104 did not demonstrate significant clinical activity in mild to moderately active UC. This suggests that further evaluation of SRT2104 as a therapeutic strategy for the treatment of UC is not warranted.

A single- and multiple-dose study to investigate the pharmacokinetics of epelsiban and its metabolite, GSK2395448, in healthy female volunteers.

An open-label single- and repeat-dose study was conducted to investigate the pharmacokinetics, safety, and tolerability of ascending doses of epelsiban in healthy female volunteers (n = 48). The pharmacokinetics of the epelsiban metabolite, GSK2395448, were also assessed. Epelsiban was readily absorbed and parent and metabolite readily appeared in plasma. The parent drug's median tmax was approximately 0.5 hours, and the metabolite's median tmax ranged from 0.5 to 1.0 hours post-parent dosing. Both epelsiban and GSK2395448 had rapid elimination half-lives, ranging between 2.66 and 4.85 hours. The metabolite:parent ratios for exposure (AUC and Cmax ) ranged from approximately 70% to greater than 100%, and therefore, GSK2395448 is considered a major metabolite of epelsiban. Mean epelsiban and GSK2395448 AUC values increased in a dose-proportional manner following both single-dose administration from 10 to 200 mg and repeat administration from 10 to 150 mg following twice daily or 4-times-daily dosing. Single-dose epelsiban pharmacokinetics in women was similar to single-dose pharmacokinetics previously observed in men. Epelsiban was generally well tolerated, and no events of clinical concern were observed in volunteers dosed in this study. The safety findings were consistent with the previous study in men, with headache the most commonly reported adverse effect.

Female sexual arousal: a behavioral analysis.

OBJECTIVE: This study was designed to assess female sexual arousal by using a combination of physiologic measures and self-reported level of arousal. DESIGN: Twenty subjects viewed a 23-minute sequence of randomly ordered relaxation and erotic tapes, both with and without auditory stimulus. The physiologic parameters of vaginal blood flow, galvanic skin resistance, respiration, pulse, and blood pressure, as well as self-reported level of arousal, were simultaneously recorded and correlated with video segments. SETTING: An academic teaching hospital. PATIENT(S): The 20 subjects (mean age +/- SD: 24.9 +/- 3.0 years) included Caucasian (10), Hispanic (2), Asian-American (4), and African-American (4) women. All women were screened for normal sexual function with the Female Sexual Function Index (FSFI) and with the Beck Anxiety Inventory and Beck Depression Inventory. INTERVENTION(S): Randomly ordered sequences of erotic and relaxation tapes with and without sound. MAIN OUTCOME MEASURE(S): Physiologic and behavioral data, as well as subjective arousal rating, were acquired. The resulting set of multichannel data was correlated with erotic segments and analyzed for sound vs. no sound and time to maximal physiologic arousal. RESULT(S): Four independent variables were found to have beta values that were significantly different from 0: respiration (mean = -0.239, SD = 0.177, range = -0.55-0.09, t = -6.04), VPP (mean = 0.158, SD = 0.37, range = -0.48-0.80, t = 1.91), rVPP (mean = 0.161, SD = 0.35, range = -0.537-0.686, t = 2.075), and erotic marker (mean = 0.582, SD = 0.191, range = 0.16-0.85, t = 13.6). Neither heart rate nor galvanic skin resistance beta values approached significance. Respiration period was correlated negatively with arousal rating, indicating that subjects breathed faster when aroused. Auditory stimuli during erotic segments did not increase subjective arousal, and for both subjective arousal rating as well as VPP measurement, maximal response occurred within 2 minutes. CONCLUSION(S): Simultaneous measurement of vaginal blood flow, respiration, pulse, and a variable accounting for the onset and offset of erotic video segments accounts for approximately 50% of the variance in predicting subjective female arousal. Regardless of the presence or absence of audio input, 2 minutes was the average minimum time required to reach maximal arousal in young, sexually functional women.

Use and outcomes of intracytoplasmic sperm injection for non-male factor infertility.

OBJECTIVE: To determine whether intracytoplasmic sperm injection (ICSI) is associated with improved outcomes for non-male factor infertility. DESIGN: We examined the patient characteristics associated with treatment choice-ICSI and conventional in vitro fertilization (IVF)-among patients without a diagnosis of male factor infertility and compared outcomes between the two groups, adjusting for patient characteristics using multivariate regression models. SETTING: Academic fertility center. PATIENT(S): We evaluated 696 consecutive assisted reproductive technology (ART) cycles performed for couples with normal semen analysis at the Stanford Reproductive Endocrinology and Infertility Center between 2002 and 2003. We compared patient characteristics, cycle details, and outcomes for ICSI and IVF. MAIN OUTCOME MEASURE(S): Fertilization, pregnancy, and live birth rates. RESULT(S): Patient characteristics were similar between the two groups, except the proportion of patients with unexplained infertility (IVF 15.1% vs. ICSI 23.5%), previous fertility (IVF 62.6% vs. ICSI 45.5%), and previous ART cycle (IVF 41.2% vs. ICSI 67.7%). More oocytes were fertilized per cycle for the IVF group (6.6 oocytes versus 5.1 oocytes). Fertilization failure, pregnancy, and live birth rates did not differ between IVF and ICSI. Using logistic regressions, having had previous ART was found to be positively associated with ICSI. Treatment choice of ICSI was not associated with fertilization, pregnancy, or live birth rates. CONCLUSION(S): No clear evidence of improved outcomes with ICSI was demonstrated for non-male factor infertility.

Assessment of patient concern and adequacy of informed consent regarding infertility resulting from prostate cancer treatment.

OBJECTIVES: To address in a questionnaire-based study the frequency at which fertility is a concern for men when they consider their prostate cancer treatment options. A secondary aim was to assess the rate at which men were informed of the fertility implications of prostate cancer treatment by their physician before their selection of a treatment option. METHODS: Two questionnaires were used. One questionnaire was distributed to men with localized prostate cancer who had undergone treatment within the past year. These questions addressed whether continence, erectile function, and fertility were discussed with them by their physician during the prostate cancer treatment selection process. The second questionnaire was distributed to men with newly diagnosed prostate cancer and queried their level of concern about the effects of prostate cancer treatment on sexual function, urinary function, and fertility. RESULTS: All patients receiving the first questionnaire stated that they were informed of the incontinence and impotence side effects of prostate cancer treatments, but only 8.7% stated that they were informed of the effect that prostate cancer treatments would have on their future fertility. Of the patients completing the second questionnaire, 53.7% responded that incontinence was the side effect of prostate cancer treatment that caused them the most concern, 42.6% stated that erectile dysfunction was the most concerning, and 3.7% listed fertility as the major concern. CONCLUSIONS: Urologists should consider approaching the topic of infertility when discussing the pros and cons of various prostate cancer therapies with their younger patients.