Efficacy and Safety of DaxibotulinumtoxinA for Injection in Cervical Dystonia: ASPEN-1 Phase 3 Randomized Controlled Trial.

Background And Objectives: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD).

Methods: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection.

A technology evaluation of the atypical use of a CPP-containing peptide in the formulation and performance of a clinical botulinum toxin product.

Introduction: Cell-penetrating peptides (CPPs), are small peptides that facilitate cytosolic access and, thus, transport of therapeutic macromolecules to intracellular sites when conjugated to cargo proteins. As with all new delivery platforms, clinical development of CPP-containing therapeutics has faced considerable challenges.

Areas Covered: RTP004 is a novel, 35-amino acid, bi-CPP-containing excipient that binds noncovalently with its cargo (botulinum toxin type A) rather than conjugated as a fusion protein.

Treatment of Upper Facial Lines With DaxibotulinumtoxinA for Injection: Results From an Open-Label Phase 2 Study.

Background: Simultaneous treatment of moderate-to-severe upper facial lines is reflective of real-world clinical practice.

Objective: To evaluate the efficacy and safety of daxibotulinumtoxinA-lanm for injection (DAXI) for simultaneous treatment of glabellar, forehead, and lateral canthal (LC) lines.

Methods: In this open-label, single-arm Phase 2 study, patients (48 enrolled, 94% completed, follow-up 24-36 weeks) received DAXI 40U (glabellar), 32U (forehead), and 48U (LC) lines.

A Large, Open-Label, Phase 3 Safety Study of DaxibotulinumtoxinA for Injection in Glabellar Lines: A Focus on Safety From the SAKURA 3 Study.

Background: SAKURA 3 was a Phase 3, open-label, repeat-dose safety study of DaxibotulinumtoxinA for Injection (DAXI); a component of the largest Phase 3 clinical development program of an aesthetic neuromodulator in glabellar lines.

Objective: To evaluate the use of DAXI (40U) up to 3 treatments for moderate or severe glabellar lines.

Methods: Eligible subjects rolled over from the placebo-controlled trials (n = 477) or were de novo (n = 2,214) and received 1 to 3 treatments over a maximum of 84 weeks.

Safety and Efficacy of EB-001, a Novel Type E Botulinum Toxin, in Subjects with Glabellar Frown Lines: Results of a Phase 2, Randomized, Placebo-Controlled, Ascending-Dose Study.

Background: Botulinum neurotoxins, which are widely used commercially for therapeutic and cosmetic applications, have historically belonged to serotypes A and B. Serotype E has a distinct profile with a faster onset and shorter duration of effect. EB-001 is a proprietary formulation of serotype E in development for aesthetic (cosmetic) and therapeutic uses.

The Potential Role of Botulinum Toxin in Improving Superficial Cutaneous Scarring: A Review.

Botulinum toxins have been utilized in a number of cosmetic and therapeutic applications. One of the more novel uses of botulinum toxin involves its use to mitigate the effects of superficial cutaneous scarring. This is accomplished by decreasing the dynamic tension of a wound by denervating the underlying muscle.

Phase 3 Study of OnabotulinumtoxinA Distributed Between Frontalis, Glabellar Complex, and Lateral Canthal Areas for Treatment of Upper Facial Lines.

Background: Although commonly practiced, simultaneous onabotulinumtoxinA injections to multiple facial areas have not been investigated in prospective studies.

Objective: Evaluate safety and efficacy of onabotulinumtoxinA for treatment of forehead lines (FHL) distributed between the frontalis (20 U) and glabellar complex (20 U), with or without simultaneous lateral canthal areas (crow's feet lines [CFL], 24 U) treatment.

Methods: Subjects with moderate to severe FHL were randomized (2:2:1) to onabotulinumtoxinA 40 U, onabotulinumtoxinA 64 U, or placebo.

Forehead Line Treatment With OnabotulinumtoxinA in Subjects With Forehead and Glabellar Facial Rhytids: A Phase 3 Study.

Background: Effacement of horizontal forehead lines (FHL) with onabotulinumtoxinA has not been investigated in prospective Phase 3 studies.

Objective: To evaluate safety and efficacy of onabotulinumtoxinA treatment of FHL together with glabellar lines (GL).

Materials And Methods: A 12-month, Phase 3 study randomized subjects with moderate-to-severe FHL and GL to onabotulinumtoxinA 40 U or placebo, distributed between the frontalis (20 U) and glabellar complex (20 U).

Remofovir mesylate: a prodrug of PMEA with improved liver-targeting and safety in rats and monkeys.

Adefovir dipivoxil (Hepsera), a first-line therapy for chronic hepatitis B, is an esterase-activated prodrug of PMEA. Dose-limiting nephrotoxicity necessitates suboptimal dosing at 10 mg/day. Remofovir mesylate (MB06866Q) (Hepavir B) is a CYP3A4-activated prodrug of PMEA based on the HepDirect technology that targets PMEA to the liver.

Viramidine demonstrates better safety than ribavirin in monkeys but not rats.

The safety of viramidine was evaluated and compared with ribavirin in one-month and six-month studies in rats and one-month and nine-month studies in monkeys. Viramidine administration produced hemolytic anemia, characterized by decreases in hemoglobin (Hgb) concentrations, which was accompanied by erythroid hyperplasia of the bone marrow or increase in reticulocyte counts. In the 1-month study in rats, viramidine or ribavirin dosing at 120 mg/kg/day reduced Hgb concentrations (12-16% and 13-20% compared to controls, respectively) and caused slight erythroid hyperplasia in the bone marrow.

Viramidine, a prodrug of ribavirin, shows better liver-targeting properties and safety profiles than ribavirin in animals.

Ribavirin, part of the current first line combination therapy for the treatment of chronic hepatitis C, may cause haemolytic anaemia and poses a significant challenge to the clinical management of the disease. Viramidine, a prodrug of ribavirin, is currently under development. In-vitro partition demonstrated that viramidine had less association with RBCs than ribavirin in rat, monkey and man, and thus has less liability for haemolytic anaemia than ribavirin.

Pulmonary clearance of manganese phosphate, manganese sulfate, and manganese tetraoxide by CD rats following intratracheal instillation.

Manganese (Mn) is ubiquitous in ambient air due to both industrial and crustal sources. It is also a component of the octane-enhancing fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The combustion of MMT by the automobile engine results in the formation of Mn particulates including phosphate, sulfate, and oxide forms.

Neurotoxicity of manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral exposure.

The purpose of this study was to evaluate the relative sensitivity of neonatal and adult CD rats to manganese-induced neurotoxicity. Identical oral manganese chloride (MnCl(2)) doses (0, 25, or 50 mg kg(-1) body wt. day(-1)) were given to neonatal rats throughout lactation (i.

Pharmacokinetics of inhaled manganese phosphate in male Sprague-Dawley rats following subacute (14-day) exposure.

Methylcyclopentadienyl manganese tricarbonyl (MMT) is used as a gasoline octane enhancer. Manganese phosphate is the primary respirable (PM(2.5)) MMT-combustion product emitted from the automobile tailpipe.

Methylmercury-induced inhibition of regulatory volume decrease in astrocytes: characterization of osmoregulator efflux and its reversal by amiloride.

Swelling of neonatal rat primary astrocyte cultures by hypotonic media leads to regulatory volume decrease (RVD) and the resumption of resting cell volume. RVD is associated with activation of conductive K+ and Cl- channels, allowing for the escape of KCl, as well as the release of osmoregulators, such as taurine and myoinositol. As we have previously shown [D.

Methylmercury-induced astrocytic swelling is associated with activation of the Na+/H+ antiporter, and is fully reversed by amiloride.

Astrocytes are a known 'sink' for brain methylmercury (MeHg) deposition. Yet, the significance of the preferential accumulation of MeHg within these cells is imprecisely defined. To determine whether MeHg in isotonic buffer has the potential to interfere with homeostatic functions, we measured its effect on astrocytic volume using an electrical impedance method [E.

Metallothionein induction protects swollen rat primary astrocyte cultures from methylmercury-induced inhibition of regulatory volume decrease.

Metallothionein (MT) proteins have been postulated to play a role in the detoxification of heavy metals. Since methylmercury (MeHg) preferentially accumulates in astrocytes, and MT-1 and MT-2 are astrocyte-specific MT isoforms, we investigated the ability of MTs to attenuate MeHg-induced cytotoxicity. The toxic effects of MeHg on astrocytes were investigated in a model of regulatory volume decrease (RVD) in which the cells are swollen by exposure to a hypotonic buffer.

Inhibition of regulatory volume decrease in swollen rat primary astrocyte cultures by methylmercury is due to increased amiloride-sensitive Na+ uptake.

Primary astrocyte cultures from neonatal rats were swollen by exposure to hypotonic buffer with and without 10 microM methylmercury (MeHg). We investigated the effects of MeHg on K+ (using 86Rb), taurine, D-aspartate (a non metabolizable analogue of glutamate) and Na+ fluxes during regulatory volume decrease (RVD), with an electrical impedance method for determination of cell volume, coupled with on-line measurements of efflux of radioactive ions and amino acids. Addition of 10 microM MeHg completely inhibited RVD in swollen astrocytes, increased the uptake of 22Na+, increased 86Rb release, and decreased 3H-taurine release.

Regulatory volume decrease in primary astrocyte cultures: relevance to methylmercury neurotoxicity.

Because of the multiple and varied roles of astrocytes in brain homeostasis, primary cultures of astrocytes from neonatal rat brains have proven to be an excellent model for the study of in vitro cell functions and control mechanisms. In addition, their ability to preferentially sequester a number of heavy metals, such as methylmercury, has lead to intense research on their potential to modulate heavy metal-induced dysfunction. In the present review we briefly discuss the mechanisms associated with astrocytic swelling, an early and prominent event in brain injury, followed by a description on cellular mechanisms associated with regulatory volume decrease (RVD) processes, and specifically those likely to represent sensitive sites for MeHg-induced cytotoxicity.

Metallothionein induction in neonatal rat primary astrocyte cultures protects against methylmercury cytotoxicity.

Metallothionein (MT) protein and mRNA levels were monitored following exposure of rat neonatal primary astrocyte cultures to methylmercury (MeHg). MT-I and MT-II mRNAs were probed on northern blots with an [alpha-32P]dCTP-labeled synthetic cDNA probe specific for rat MT mRNA. MT-I and MT-II mRNAs were detected in untreated cells, suggesting constitutive MT expression in these cells.

Cadmium chloride (CdCl2)-induced metallothionein (MT) expression in neonatal rat primary astrocyte cultures.

Metallothionein (MT) protein and mRNA levels were studied following exposure of rat neonatal primary astrocyte cultures to cadmium chloride (CdCl2). MT mRNA was probed on Northern blots with a 32P labeled synthetic cDNA probe specific for rat MT mRNA. The probe hybridizes to a single mRNA with a size appropriate for MT, approximately 550 bases.

Astrocytes as potential modulators of mercuric chloride neurotoxicity.

1. MC has been shown to inhibit the uptake of L-glutamate and increase D-aspartate release from preloaded astrocytes in a dose-dependent fashion. 2.

Potassium and taurine release are highly correlated with regulatory volume decrease in neonatal primary rat astrocyte cultures.

Neonatal rat primary astrocyte cultures were swollen by exposure to hypotonic buffer. Using an electrical impedance method for determination of cell volume coupled with on-line measurements of efflux of radioactive ions or amino acids, we have investigated the role of K+ (using 86Rb), taurine, and D-aspartate (an analogue of glutamate) in regulatory volume decrease (RVD). Addition of 1 mM quinine, 10 microM nimodipine, 100 microM BAPTA-AM, 10 microM trifluoperazine, or a calcium-free buffer significantly (p < 0.

The role of sulfhydryl groups in D-aspartate and rubidium release from neonatal rat primary astrocyte cultures.

We have recently demonstrated that both methylmercury (MeHg) and mercuric chloride (MC) induce D-aspartate release from neonatal rat primary astrocyte cultures maintained in isotonic conditions. In the present study, we compare several other sulfhydryl-(-SH) selective alkylating reagents [methyl methanethiosulfonate (MMTS), N-ethylmaleimide (NEM), and iodoacetamide (IA)] in isotonic, as well as hypotonic conditions to discern the functional importance of -SH groups in [3H]D-aspartate and 86rubidium (86Rb) release from astrocytes. Treatment of astrocytes (5 min) in isotonic buffer with the hydrophobic reagent NEM (10 microM) caused a marked increase in 86Rb release but had no effect on [3H]D-aspartate release.