Safety Challenges of Using High Dose Baclofen for Alcohol Use Disorder: A Focused Review

Since the early 2000s, the gamma-aminobutyric acid type B (GABA-B) receptor agonist baclofen has been extensively used for treating alcohol use disorder (AUD). In some countries, like France, Australia, or Germany, baclofen has been used at patient-tailored dose regimens, which can reach 300 mgpd or even more in some patients. The GABA-B-related pharmacology of baclofen expose patients to a specific profile of neuropsychiatric adverse drug reactions (ADRs), primarily some frequent sedative symptoms whose risk of occurrence and severity are both related to the absolute baclofen dosing and the kinetics of dose variations. Other frequent neuropsychiatric ADRs can occur, i.e., tinnitus, insomnia, or dizziness. More rarely, other serious ADRs have been reported, like seizures, manic symptoms, or sleep apnea. However, real-life AUD patients are also exposed to other sedative drugs, like alcohol of course, but also benzodiazepines, other drugs of abuse, or other sedative medications. Consequently, the occurrence of neuropsychiatric safety issues in these patients is essentially the result of a complex multifactorial exposure, in which baclofen causality is rarely obvious by itself. As a result, the decision of initiating baclofen, as well as the daily dose management should be patient-tailored, according the medical history but also the immediate clinical situation of the patient. The overall safety profile of baclofen, as well as the clinical context in which baclofen is used, have many similarities with the use of opiate substitution medications for opiate use disorder. This empirical statement has many implications on how baclofen should be managed and dosing should be adjusted. Moreover, this constant patient-tailored adjustment can be difficult to adapt in the design of clinical trials, which may explain inconsistent findings in baclofen-related literature on AUD

Pharmacokinetic Studies of Baclofen Are Not Sufficient to Establish an Optimized Dosage for Management of Alcohol Disorder

Several clinical randomized trials have evaluated the interest of baclofen in patients with alcohol use disorder. Depending on the study design and the inclusion criteria, the results vary from enthusiastic to pessimistic. However, all researchers and practitioners agree that they observe a wide variability in the therapeutic responses. If some patients exhibit a clinical response at low doses, ~40 mg daily, others require doses higher than 300 mg. Before multiplying new other clinical trials, it is required to better understand the reason of this variability. Several mechanisms may be responsible for providing different effects with an identical daily dose. Especially, each pharmacokinetic step, absorption, distribution, metabolism, and elimination may lead to a different exposure after an identical dose. Absorption may imply a saturation process limiting the bioavailability (F) of baclofen in some patients. In such a situation, food, or drug-drug interaction can change the absorption rate of the drug modifying the maximum concentration (Cmax) and area under the curve (AUC). Distribution and brain penetration across the blood-brain barrier may depend of a specific transporter. These transporters are subject to genetic polymorphism and drug-drug interaction. Finally, elimination may be increased by a specific secretion pathway. This review describes all available pharmacokinetic data on these different pharmacokinetics steps aiming to identify the source of variability of baclofen in patients with alcohol use disorder

How to Manage Self-Poisoning With Baclofen in Alcohol Use Disorder? Current Updates

Specialists in addiction medicine continue to debate whether baclofen is still indicated to treat alcohol use disorders in view of conflicting results as to its efficacy. This review summarizes current knowledge on self-poisoning with baclofen focusing of alcohol-use disorder in order to provide an overview of the reliable scientific knowledge on management of such an intoxication. Moreover, as alcohol-dependent patients experience many psychiatric co-morbidities, the risk in suicide attempt using baclofen seems real. Numerous studies have suggested that patients given daily-doses of baclofen higher than 80 mg/day are more likely to attempt suicides than others. Following an ingestion of a large amount of baclofen, central nervous system depression is usually observed. Seizures require the patient to be admitted in intensive care unit and should be treated like other toxicological seizures. Cardiac complications include prolonged QTc interval, degree heart block, premature atrial contractions, and supraventricular tachycardia, hypotension and bradycardia. In cases of intoxication, the elimination half-life of baclofen may last between 12 and 36 h post-overdose and renal failure is known to delay its clearance. Rarely measured in clinical practice, the toxic level of baclofen blood level ranges from 1.1 to 3.5 mg/l, and coma or fatal intoxication are observed from 6 to 9.6 mg/l. Baclofen withdrawal has been observed but making the diagnosis of withdrawal in case of suspected self-poisoning is difficult as baclofen intoxication and baclofen withdrawal share many clinical signs. Admission to hospital to manage of suicide attempt with baclofen is mandatory and should not be limited to baclofen alone. It needs to include other aspects of the overall care of patients with alcohol disorders (psychological and psychosocial interventions, management of comorbid mental conditions and physical complications)

Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder

Baclofen a gamma amino-butyric acid type B (GABA-B) receptor agonist, which has raised some interest for the treatment of alcohol use disorder (AUD), occasionally at dose up to 300 mg/d. We conducted the first full-profile pharmacokinetic study on baclofen in AUD subjects, up to the oral daily dose of 300 mg. Sixty subjects treated for AUD with marketed baclofen were enrolled in a prospective phase-1 study. Participants were divided into four dose groups (1: <60 mg/d; 2: 60–120 mg/d; 3: >120 mg/d-180 mg/d; and 4: >180 mg/d), and they underwent a full-profile pharmacokinetic analysis of baclofen, using a nonlinear mixed effects modeling. The influence of different clinical and biological covariates was assessed in an upward modeling. Fifty-seven participants completed the study (522 observed concentrations collected). Racemic baclofen showed a linear pharmacokinetic profile, corresponding to a one-compartment model, with no influencing clinical or biological factor. The pharmacokinetic parameters of baclofen were (bootstrap 95% confidence intervals): absorption constant (Ka) 1.64 1/h (1.34–2), clearance (Cl/F) 11.6 L/h (10.8–12.3) and volume of distribution (Vd/F) 72.8 L (66.5–80.4) leading to a half-life of 4.4 h. The interindividual variability (IIV) was 44% (19–65), 21% (16–27), and 22% (11–36) for Ka, Cl/F, and Vd/F, respectively. The residual variability was 24% (21–26). No serious adverse event was reported.Registration: EudraCT #2013-003412-4

A model to predict image formation in the three-dimensional field ion microscope

This article presents a numerical model dedicated to the simulation of field ion microscopy (FIM). FIM was the first technique to image individual atoms on the surface of a material. By a careful control of the field evaporation of the atoms from the surface, the bulk of the material exposed, and, through a digitally processing a sequence of micrographs, a three-dimensional reconstruction can be achieved. 3DFIM is particularly suited to the direct observation of crystalline defects such as vacancies, interstitials, vacancy clusters, dislocations, and any combinations of theses defects that underpin the physical properties of materials. This makes 3DFIM extremely valuable for many material science and engineering applications, and further developing this technique is becoming crucial. The proposed model enables the simulation of imaging artefacts that are induced by non-regular field evaporation and by the impact of the perturbation of the electric field distribution of the distorted distribution of atoms close to defects. The model combines the meshless algorithm for field evaporation proposed by Rolland et al. (Robin-Rolland Model, or RRM) with fundamental aspects of the field ionization process of the gas image involved in FIM

Setting sub-organellar sights: accurate targeting of multi-transmembrane-domain proteins to specific chloroplast membranes

Engineering novel chloroplast functions requires an understanding of how to accurately target proteins to specific chloroplast sub-compartments. This is particularly difficult in the case of membrane proteins where localization can be confounded by multiple membrane types. In an elegant study, Singhal and Fernandez (2017) have now provided greater insight into this challenge by dissecting out the signals that control differential targeting of two related proteins to specific chloroplast membranes. Further development of this information should inform attempts to direct engineered proteins to specific sub-organellar membranes, bringing about desired phenotypic changes

A new shape memory porous material made up of a single entangled NiTi wire

Avec leur architecture légère et leurs propriétés mécaniques potentiellement exceptionnelles, les matériaux poreux en alliages à mémoire de forme NiTi se positionnent comme des solutions intéressantes pour un large spectre d'applications, e.g. prothèses biomédicales, systèmes absorbeurs de chocs... Aujourd'hui, la plupart de ces matériaux sont produits par frittage de poudres (naturel ou SPS). Cependant, leurs propriétés mécaniques sont bien loin d’être aussi bonnes qu'attendues (peu ou pas de superélasticité ou d’effet mémoire) : ceci est en grande partie dû aux grandes difficultés pour induire des microstructures appropriées lors du frittage. Pour contourner ces problèmes, nous proposons un procédé de fabrication alternatif et original, basé sur l'auto-enchevêtrement d'un fil de NiTi, sans frittage. D’une part, les mésostructures des pelotes ainsi produites, caractérisées par microtomographie RX, sont relativement homogènes ; elles peuvent être architecturées à façon en adaptant les conditions de mise en forme. D’autre part, les propriétés thermomécaniques des pelotes peuvent être pilotées simplement par des traitements thermiques. Ces deux atouts procurent à ces matériaux de grandes possibilités. Par exemples, le comportement superélastique des pelotes en compression simple est excellent et étonnant : il combine (i) très grandes déformations recouvrables en décharge (30 à 40%), (ii) niveaux de contraintes raisonnables (5 à 10 MPa), peu dépendants de la température (0.05MPa/K) et (iii) variations de volume importantes avec des séquences complexes de consolidation et de dilatance. Le comportement ferroélastique est quant à lui très proche de celui des milieux fibreux élastoplastiques, avec un écrouissage notable en charge et une forte déformation rémanente en décharge (de l’ordre de 20%). Enfin, un simple chauffage à charge nulle permet de recouvrir totalement cette déformation par effet mémoire de forme

Poisson's function of single-wire entangled materials : below 0 in traction and above ½ in compression

The mechanics of fibrous materials is both complex and intriguing. Here, we explore one class of such materials, made of the disordered entanglement of a single long fiber. This architected material is of both fundamental and technological interests. From a theoretical point of view, this system can be seen as a disordered material, akin to glasses, but with very long (possibly infinite) ranged correlations transmitted along the single fiber. From an applied point of view, this material is a potential replacement for sintered materials, because with comparable porosities, entangled structures are highly ductile while sintered powders are often intrinsically brittle. We study the mechanics of single-wire materials using a combination of experiments and simulations. Experimentally, we produce cylindrical samples by entangling a single fiber made either of NiTi, polyamide or copper. Spatial homogeneity and stress relaxation are achieved by series of thermomechanical treatments that allow to first transform the wire into a coil and then entangle the coil. The samples are subjected to cycles of compressions followed by unloading, tracking the local deformations in the samples with optical cameras and x-ray microtomography. Numerically, we employed Kirchhoff's elastic rod theory to simulate the same mechanical cycles on both numerical substitutes of the experimental samples (i.e. cylindrical samples of geometry and density comparable to the experiments) and idealized samples with a cubic and periodic geometry. We will discuss our main observations on the mechanical properties of the single-wire systems. First, stress-strain curves show a prolonged regime of non-linear elasticity and a marked hysteresis between compression loading and unloading. Also, by tracking the sample shape variations, we observe surprising non-monotonous variations of the sample volume, both in the experiments and in the simulations. At the local level, we use image analysis to follow the evolution of the local orientation of the fiber and of the number and orientation of the contacts, the latter two quantities also showing non-monotonous behaviors.  In particular, we show that this material exhibits at finite strains an unexpected variation of its Poisson's function, beyond the usual bounds: Poisson's function is above ½ in compression and below zero in tension. This material is thus reversibly compress dilatant in compression and auxetic in tension. This means that the structure expands laterally in both traction and compression and so rapidly in compression that its volume increases. This unusual variation of Poisson's function arises from the interplay between the elongation of the coiled segments that constitute the entanglement and fiber rearrangements due to steric effects.  This work illustrates that a property (Poisson's function not limited to 0 or ½), rare in bulk materials, can be readily obtained in "simple" architected materials and opens the way to developing architectures with very large, negative but also positive, Poisson's functions

Generality of shear thickening in suspensions

Suspensions are of wide interest and form the basis for many smart fluids. For most suspensions, the viscosity decreases with increasing shear rate, i.e. they shear thin. Few are reported to do the opposite, i.e. shear thicken, despite the longstanding expectation that shear thickening is a generic type of suspension behavior. Here we resolve this apparent contradiction. We demonstrate that shear thickening can be masked by a yield stress and can be recovered when the yield stress is decreased below a threshold. We show the generality of this argument and quantify the threshold in rheology experiments where we control yield stresses arising from a variety of sources, such as attractions from particle surface interactions, induced dipoles from applied electric and magnetic fields, as well as confinement of hard particles at high packing fractions. These findings open up possibilities for the design of smart suspensions that combine shear thickening with electro- or magnetorheological response.Comment: 11 pages, 9 figures, accepted for publication in Nature Material

The Case for a Muon Collider Higgs Factory

We propose the construction of a compact Muon Collider Higgs Factory. Such a machine can produce up to \sim 14,000 at 8\times 10^{31} cm^-2 sec^-1 clean Higgs events per year, enabling the most precise possible measurement of the mass, width and Higgs-Yukawa coupling constants.Comment: Supporting letter for the document: "Muon Collider Higgs Factory for Smowmass 2013", A White Paper submitted to the 2013 U.S. Community Summer Study of the Division of Particles and Fields of the American Physical Society, Y. Alexahin, et. al, FERMILAB-CONF-13-245-T (July, 2013