Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia and Chorea Associated with Huntington Disease.

Introduction: Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia (TD) and chorea associated with Huntington disease (HD). To enhance detection of safety signals across individual trials, integrated safety analyses of deutetrabenazine in TD and HD chorea were conducted.

Methods: For TD, safety data were integrated from two 12-week pivotal studies (ARM-TD and AIM-TD) and through week 15 of the open-label extension (OLE) study (RIM-TD).

Safety and Efficacy of Long-Term Deutetrabenazine Use in Children and Adolescents with Tics Associated with Tourette Syndrome: An Open-Label Extension Study.

Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics.

Objective: To assess the safety and efficacy of deutetrabenazine (Teva Neuroscience, Inc, Parsippany, NJ), a vesicular monoamine transporter 2 inhibitor, in children and adolescents with TS.

Methods: Alternatives for Reducing Tics in TS (ARTISTS) open-label extension (OLE) (NCT03567291) was a 54-week, global, phase 3, open-label extension study of deutetrabenazine (6-48 mg daily) conducted May 28, 2018 to April 3, 2020 with a 2-week randomized withdrawal period.

Safety and Efficacy of Flexible-Dose Deutetrabenazine in Children and Adolescents With Tourette Syndrome: A Randomized Clinical Trial.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics; treatments for tics are associated with safety concerns. Deutetrabenazine is a selective vesicular monoamine transporter 2 inhibitor approved for the treatment of chorea associated with Huntington disease and tardive dyskinesia in adults.

Objective: To examine whether deutetrabenazine is effective and safe for the treatment of Tourette syndrome in children and adolescents.

The effect of potent CYP2D6 inhibition on the pharmacokinetics and safety of deutetrabenazine in healthy volunteers.

Purpose: Deutetrabenazine is a deuterated form of tetrabenazine with a confirmed lower rate of CYP2D6 metabolism of the active metabolites, α- and β-HTBZ. In this study, we assessed the effect of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics and safety of deutetrabenazine and its metabolites.

Methods: In this open-label sequential drug-drug-interaction study, 24 healthy adults who were CYP2D6 extensive or intermediate metabolizers received a single deutetrabenazine 22.

ATH434 Reduces α-Synuclein-Related Neurodegeneration in a Murine Model of Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by aggregated α-synuclein (α-syn) in oligodendrocytes and accompanied by striatonigral and olivopontocerebellar degeneration and motor symptoms. Key features of MSA are replicated in the PLP-α-syn transgenic mouse, including progressive striatonigral degeneration and motor deterioration. There are currently no approved treatments for MSA.

Pharmacokinetics of Deutetrabenazine and Tetrabenazine: Dose Proportionality and Food Effect.

Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). One study was an open-label 2-part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.

The identification of nuclear αvβ3 integrin in ovarian cancer: non-paradigmal localization with cancer promoting actions.

Nuclear translocation of transmembrane proteins was reported in high-grade serous ovarian cancer (HGSOC), a highly aggressive gynecological malignancy. Although the membrane receptor αvβ3 integrin is amply expressed in HGSOC and involved in disease progression, its nuclear localization was never demonstrated. Nuclear αvβ3 was explored in HGSOC cells (OVCAR3, KURAMOCHI, and JHOS4), nuclear localization signal (NLS) modified β3 OVCAR3, Chinese hamster ovaries (CHO-K1) and human embryonic kidney (HEK293) before/after transfections with β3/β1 integrins.

Pharmacokinetic and Metabolic Profile of Deutetrabenazine (TEV-50717) Compared With Tetrabenazine in Healthy Volunteers.

Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in Huntington's disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (β-HTBZ), metabolite profile, safety, and tolerability.

Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

Objective: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD).

Method: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106).

Safety of Converting From Tetrabenazine to Deutetrabenazine for the Treatment of Chorea.

Importance: Tetrabenazine is efficacious for chorea control; however, tolerability concerns exist. Deutetrabenazine, a novel molecule that reduces chorea, was well tolerated in a double-blind, placebo-controlled study.

Objectives: To evaluate the safety and explore the efficacy of conversion from tetrabenazine to deutetrabenazine in patients with chorea associated with Huntington disease (HD).

Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial.

Background: Tardive dyskinesia results from exposure to dopamine receptor antagonists, such as typical and atypical antipsychotics. If clinically appropriate, clinicians often manage this disorder by lowering the dose of, or discontinuing, the causative drug. There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses.

Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study.

Objective: To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD).

Methods: One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment.

Indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease.

Background: Vesicular monoamine transporter 2 (VMAT2) inhibitors can improve hyperkinetic movements, and are effective treatment options for chorea of Huntington disease (HD). Tetrabenazine was assessed for treating chorea in the TETRA-HD trial, and while efficacious, there are tolerability concerns possibly due to its pharmacokinetic properties. Deutetrabenazine is a novel VMAT2 inhibitor that contains deuterium, which extends active metabolite half-lives and minimizes drug concentration fluctuations.

Deutetrabenazine in Tics Associated with Tourette Syndrome.

Background: Deutetrabenazine, an inhibitor of vesicular monoamine transporter type 2 (VMAT2) depletes presynaptic dopamine and is useful in the treatment of hyperkinetic movement disorders. This study explored the safety, tolerability, and preliminary efficacy of deutetrabenazine in adolescents with moderate-to-severe tics associated with Tourette syndrome (TS).

Methods: In this open-label study of 12-18-year-old patients with TS-related tics, deutetrabenazine was titrated up to 36 mg/day over 6 weeks to adequately suppress tics without bothersome adverse effects (AEs), followed by maintenance at optimal dose for 2 weeks.

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.

Objective: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.

Design, Setting, And Participants: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.

Wearable Sensors in Huntington Disease: A Pilot Study.

Background: The Unified Huntington's Disease Rating Scale (UHDRS) is the principal means of assessing motor impairment in Huntington disease but is subjective and generally limited to in-clinic assessments.

Objective: To evaluate the feasibility and ability of wearable sensors to measure motor impairment in individuals with Huntington disease in the clinic and at home.

Methods: Participants with Huntington disease and controls were asked to wear five accelerometer-based sensors attached to the chest and each limb for standardized, in-clinic assessments and for one day at home.

Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.

Study Design: Randomized, double-blind, placebo-controlled, two-period crossover.

Objectives: To evaluate the efficacy and safety of arbaclofen placarbil (AP) in patients with spasticity secondary to spinal cord injury (SCI).

Setting: United States and Canada.

Arbaclofen placarbil in GERD: a randomized, double-blind, placebo-controlled study.

Objectives: It has been shown that arbaclofen placarbil (AP) inhibits reflux in gastroesophageal reflux disease (GERD) following single oral dosing. This study evaluated the efficacy and safety of AP over 4 weeks in subjects with symptomatic GERD.

Methods: One hundred fifty-six subjects with heartburn and/or regurgitation ≥3 days/week and either no history of taking proton pump inhibitors (PPIs naive, n=58) or at least partial symptom response to PPI therapy (PPI responsive, n=98) were enrolled in this randomized, double-blind, placebo-controlled trial.

Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month, double-blind, randomized, dose-ranging study.

Objective: To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA).

Methods: This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.

Short-course therapy with amoxycillin-clarithromycin triple therapy for 10 days (ACT-10) eradicates Helicobacter pylori and heals duodenal ulcer. ACT-10 Study Group.

Background: Whilst the role of Helicobacter pylori eradication in managing duodenal ulcers has been established, consensus regarding the ideal regimen has not been achieved.

Methods: Patients with H. pylori-positive active duodenal ulcer were randomly assigned to receive triple therapy with amoxycillin 1000 mg b.

PCR-RFLP typing of ureC from Helicobacter pylori isolated in Argentina from gastric biopsies before and after treatment with clarithromycin.

A clinical trial was conducted in Argentina to determine the efficacy of clarithromycin plus lansoprazole for the treatment of Helicobacter pylori in duodenal ulcers and non-ulcer dyspepsia. PCR-RFLP was conducted on an 820-bp amplified product of the ureC gene of H. pylori to determine the genetic heterogeneity of 83 pretreatment and 21 post-treatment isolates.

Human and guinea pig immune responses to Legionella pneumophila protein antigens OmpS and Hsp60.

We studied the immune responses of guinea pigs and humans to two Legionella pneumophila antigens. Guinea pigs surviving a lethal intraperitoneal challenge dose of virulent L. pneumophila exhibited strong cutaneous delayed-type hypersensitivity (DTH) reactions to purified OmpS (28-kDa major outer membrane protein) and Hsp60 (heat shock protein or common antigen), while weak DTH reactions were noted for extracellular protease (major secretory protein [MSP] [ProA]) and no reaction was observed with an ovalbumin (OA) control.

Azithromycin pharmacokinetics and intracellular concentrations in Legionella pneumophila-infected and uninfected guinea pigs and their alveolar macrophages.

Azithromycin pharmacokinetics in Legionella pneumophila-infected and uninfected guinea pigs were assessed by measuring the drug concentration in whole lungs or the drug content in bronchoalveolar lavage (BAL) fluid in separate experiments. Azithromycin concentrations were measured by using a bioassay. The mean azithromycin content in the BAL fluid of infected guinea pigs was higher than that in controls at 10 h (0.