A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy.

BACKGROUND & AIMS: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis. METHODS: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. RESULTS: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. CONCLUSION: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone. LAY SUMMARY: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2016-003651-30.

Exploring anorectal manometry as a method to study the effect of locally administered ropivacaine in patients with ulcerative colitis.

The symptoms of distal ulcerative colitis have been related to changes in rectal sensitivity and capacity due to inflammation, altered gastrointestinal motility, and sensory perception. With the use of anorectal manometry, the function was measured in seven patients with active distal proctitis during local treatment with ropivacaine. Seven healthy subjects were studied in the same way for comparison with normal conditions. The anal resting pressure and squeezing pressure were similar in all groups. Significantly lower rectal distention volumes were required for rectal sensation, critical volume, and to induce rectal contractility in patients with active disease compared to controls. Rectal compliance was significantly reduced in patients with active and quiescent disease. The increased rectal sensitivity and contractility in patients with active colitis appear to be related to active mucosal inflammation and ulceration. The frequency and urgency of defecation and the fecal incontinence may be due to a hypersensitive, hyperactive, and poorly compliant rectum. The findings in our study indicate that the inflammatory damage to the rectal wall with poor compliance is unaffected by local anaesthetics such as ropivacaine. The symptomatic relief and reduction in clinical symptoms following treatment are not reflected in the anorectal manometric findings.

Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient-initiated clinical trial.

BACKGROUND: Prior pilot studies support the use of antiviral medications with topical corticosteroids for herpes simplex labialis (HSL). ME-609 (Xerese, Xerclear) is a combination of 5% acyclovir and 1% hydrocortisone developed for the topical treatment of HSL. OBJECTIVES: The primary study end point was the prevention of ulcerative HSL lesions. METHODS: In all, 2437 patients with a history of HSL were randomized to self-initiate treatment with ME-609, 5% acyclovir in ME-609 vehicle, or ME-609 vehicle (placebo) at the earliest sign of a cold sore recurrence. Cream was applied 5 times/d for 5 days. A total of 1443 patients experienced a recurrence and initiated treatment with ME-609 (n = 601), acyclovir (n = 610), or placebo (n = 232). RESULTS: Of patients receiving ME-609, 42% did not develop an ulcerative lesion compared with 35% of patients receiving acyclovir in ME-609 vehicle (P = .014) and 26% of patients receiving placebo (P < .0001). In patients with ulcerative lesions, healing times were reduced in the ME-609 and acyclovir groups compared with placebo (P < .01 for both). The cumulative lesion area for all lesions was reduced 50% in patients receiving ME-609 compared with the placebo group (P < .0001). There were no differences among groups in the number of patients with positive herpes simplex virus cultures. The side-effect profile was similar among treatments. LIMITATIONS: The study did not contain a group treated with a topical corticosteroid alone. CONCLUSIONS: ME-609 prevented progression of cold sores to ulcerative lesions and significantly reduced the cumulative lesion area compared with acyclovir and placebo. ME-609 treatment offers additional therapeutic benefit compared with therapy with topical acyclovir alone.

Rectal ropivacaine is absorbed proportionally to the dose, with low intraindividual variability.

AIMS: This study investigated the absorption characteristics and the tolerability of rectally administered ropivacaine, a local anaesthetic, intended as a new local therapy for ulcerative colitis. METHODS: Thirty-two healthy volunteers participated in a randomized, placebo-controlled study. In study phase 1 (n = 16, double-blind, crossover) single rectal doses of ropivacaine corresponding to 50, 100 and 200 mg base were given as 20-ml gel enemas. Eight of these subjects also received an i.v. infusion corresponding to 20 mg (2H3)ropivacaine base given with the last rectal dose. In study phase 2 (n = 16, single-blind, crossover) the same rectal doses were given but formulated in 20, 40 and 80 ml gel, respectively. Peripheral venous plasma samples and urine were collected over 12 h after dosing and analysed for ropivacaine base by gas chromatography and (2H3)ropivacaine by gas chromatography-mass spectrometry. Ropivacaine and metabolites were analysed in urine by reversed phase liquid chromatography. RESULTS: AUC was proportional to the dose with a point estimate [95% confidence interval (CI)] for the increase, after doubling the dose, of 1.91 (1.66-2.20) and 1.95 (1.78-2.13) in study phases 1 and 2, respectively. The increase in Cmax was also proportional to the dose with corresponding results of 1.76 (1.52-2.04) and 1.84 (1.70-1.99). The volume of the rectal formulation had no influence on either the extent or the time course of absorption. The mean (s.d.) absolute bioavailability (%F) was 56 (18)%. AUC and Cmax showed a two- to three-fold lower intra- than interindividual variability. Zero-order kinetics dominated the first 4 h of the absorption phase. Thereafter first-order kinetics were observed. The terminal half-lives were similar between the rectal doses and were longer than that after the i.v. administration, indicating an absorption-dependent half-life. The main urinary metabolite was 3-hydroxyropivacaine corresponding to about 23% of the dose. The subjects had no difficulties in retaining the doses and rectal administration of ropivacaine was well tolerated, both locally and systemically. CONCLUSIONS: Plasma drug concentrations were proportional to the dose after rectally administered doses corresponding to 50-200 mg ropivacaine base in a gel formulation. The drug was well-tolerated. Mean bioavailability was about 60% and not influenced by variations in the enema volume. Initial absorption seemed to follow zero-order kinetics and then first-order kinetics after about 4 h. Cmax and AUC showed considerably less intra- compared with inter-individual variability, resulting in more consistent plasma concentrations within subjects.

Hypercarbic and hypoxic ventilatory responses after intrathecal administration of bupivacaine and sameridine.

Sameridine is a new compound with both local anesthetic and opioid properties (partial micro -opioid receptor agonist). It was intended for intrathecal administration to provide anesthesia for surgery and extended postoperative analgesia. In this double-blinded pharmacodynamic study with a two-parallel-group design, we investigated, during a 24-h period, the effects of intrathecal sameridine and bupivacaine on ventilation at rest and at ventilatory challenges during hypercarbia and hypoxia. Twenty-four healthy volunteers received either 25 mg of sameridine or 15 mg of bupivacaine intrathecally. Ventilation was measured by pneumotachography and in-line capnography. Sedation was rated by a visual analog scale. Segmental spread and development of motor and sensory block were similar in both groups. There was a decrease in tidal volume 2.5 to 6 h after injection in the bupivacaine group. This was seen only at 4 h in the sameridine group. There were no other major ventilatory differences between sameridine and bupivacaine during resting ventilation. Hypercarbic (tidal volume, mean inspiratory flow) and hypoxic (mean inspiratory flow) ventilatory responses were slightly decreased in the sameridine group, but not in the bupivacaine group. We conclude that intrathecal administration of sameridine or bupivacaine in healthy volunteers produces similar, minor effects on ventilatory responses over a 24-h observation period.