Pharmacokinetic and Pharmacologic Characterization of the Dihydrotetrabenazine Isomers of Deutetrabenazine and Valbenazine.

Valbenazine and deutetrabenazine are vesicular monoamine transporter 2 (VMAT2) inhibitors approved for tardive dyskinesia. The clinical activity of valbenazine is primarily attributed to its only dihydrotetrabenazine (HTBZ) metabolite, [+]-α-HTBZ. Deutetrabenazine is a deuterated form of tetrabenazine and is metabolized to four deuterated HTBZ metabolites: [+]-α-deuHTBZ, [+]-ß-deuHTBZ, [-]-α-deuHTBZ, and [-]-ß-deuHTBZ. An open-label, crossover study characterized the pharmacokinetic profiles of the individual deuHBTZ metabolites, which have not been previously reported. VMAT2 inhibition and off-target interactions of the deuHTBZ metabolites were evaluated using radioligand binding. The only valbenazine HTBZ metabolite, [+]-α-HTBZ, was a potent VMAT2 inhibitor, with negligible affinity for off-target dopamine, serotonin, and adrenergic receptors. Following deutetrabenazine administration, [-]-α-deuHTBZ represented 66% of circulating deuHTBZ metabolites and was a relatively weak VMAT2 inhibitor with appreciable affinity for dopamine (D2S , D3 ) and serotonin (5-HT1A , 5-HT2B , 5-HT7 ) receptors. [+]-ß-deuHTBZ was the most abundant deuHTBZ metabolite that potently inhibited VMAT2, but it represented only 29% of total circulating deuHTBZ metabolites. The mean half-life of [+]-α-HTBZ (22.2 hours) was ∼3× longer than that of [+]-ß-deuHTBZ (7.7 hours). These findings are similar to studies with tetrabenazine, in that deutetrabenazine is metabolized to four deuHTBZ stereoisomers, the most abundant of which has negligible interaction with VMAT2 in vitro and appreciable affinity for several off-target receptors. In contrast, valbenazine's single HTBZ metabolite is a potent VMAT2 inhibitor in vitro with no discernible off-target activity. Determination of the effects of intrinsic/extrinsic variables on deutetrabenazine's safety/efficacy profile should incorporate assessment of the effects on all deuHTBZ metabolites.

High Percentage of Complications and Re-Operations Following Dynamic Locking Plate Fixation with the Targon® FN for Intracapsular Proximal Femoral Fractures: An Analysis of Risk Factors.

The ideal surgical treatment of femoral neck fractures remains controversial. When treating these fractures with internal fixation, many fixation constructs exist. The primary aim of this study was to evaluate the incidence and specific risk factors associated with complication and re-operation following fixation of intracapsular proximal femoral fractures using the Targon-FN system (B.Braun Melsungen AG). A secondary aim was to identify if lateral prominence of the implant relative to the lateral border of the vastus ridge was a specific risk factor for elective plate removal. Methodically, a retrospective case series was conducted of all consecutive adult patients treated at a single level 1 trauma center in Switzerland for an intracapsular proximal femoral fracture with the Targon-FN. Demographic data were collected. Patients with a follow-up of less than three months were excluded. Complications as well as plate position were recorded. Statistical analysis to identify specific risk factors for re-operation and complications was performed. In result, a total of 72 cases with intracapsular femoral neck fractures were treated with the Targon-FN locking plate system between 2010 and 2017. Thirty-four patients (47.2%) experienced one or more complications. The most common complication was mechanical irritation of the iliotibial band (ITB) (23.6%, n = 17). Complications included intraarticular screw perforation (6.9%, n = 5), avascular necrosis (5.6%, n = 4), non-union (5.6%, n = 4) among others. In total, 46 re-operations were required. Younger age, fracture displacement and time to postoperative weight bearing were identified as risk factors for re-operation. In conclusion, intracapsular femoral neck fractures treated with the Targon-FN system resulted in a high rate of post-operative complication and re-operation. Statistical analysis revealed patient age, fracture displacement, time to postoperative full weight bearing were risk factors for re-operation. The main limitation is the limited number of cases and a short follow-up of less than 12 months in a subgroup of our patients.

Efficacy of Vesicular Monoamine Transporter 2 Inhibition and Synergy with Antipsychotics in Animal Models of Schizophrenia.

Antipsychotic medications function by blocking postsynaptic dopaminergic signaling in the central nervous system. Dopamine transmission can also be modulated presynaptically by inhibitors of vesicular monoamine transporter 2 (VMAT2), which inhibit loading of dopamine into presynaptic vesicles. Here we investigated the combination of these mechanisms in animal models of schizophrenia and weight gain (a primary side effect of antipsychotics). When dosed alone, the highly selective VMAT2 inhibitor RRR-dihydrotetrabenazine (RRR-DHTBZ, also known as [+]-α-HTBZ) elicited efficacy comparable to conventional antipsychotics in prepulse inhibition and conditioned avoidance models without eliciting weight gain. In combination experiments, synergy was observed: subthreshold doses of RRR-DHTBZ and risperidone or olanzapine produced robust efficacy, and in dose response experiments, RRR-DHTBZ increased the antipsychotic potency in the efficacy models but did not affect weight gain. The combinations did not affect plasma compound concentrations. The synergy is consistent with VMAT2 inhibition blocking the counterproductive presynaptic stimulation of dopamine by antipsychotics. These results suggest a therapeutic strategy of adding a VMAT2 inhibitor to lower the antipsychotic dose and reduce the side effect burden of the antipsychotic while maintaining and potentially enhancing its therapeutic effects. SIGNIFICANCE STATEMENT: Antipsychotics are often necessary and life-changing medications that reduce psychotic symptoms; however, these benefits come with a high side effect burden. This study shows that combining these postsynaptic dopaminergic modulators with a presynaptic dopamine modulator (vesicular monoamine transporter 2 [VMAT2] inhibitor) potentiates efficacy synergistically in animal models of schizophrenia without potentiating weight gain. Our data suggest that adding a VMAT2 inhibitor may be a viable therapeutic strategy for reducing antipsychotic side effects by lowering antipsychotic dose while maintaining therapeutic efficacy.

Electrospinning for building 3D structured photoactive biohybrid electrodes.

We describe the development of biohybrid electrodes constructed via combination of electrospun (e-spun) 3D indium tin oxide (ITO) with the trimeric supercomplex photosystem I and the small electrochemically active protein cytochrome c (cyt c). The developed 3D surface of ITO has been created by electrospinning of a mixture of polyelthylene oxide (PEO) and ITO nanoparticles onto ITO glass slides followed by a subsequent elimination of PEO by sintering the composite. Whereas the photosystem I alone shows only small photocurrents at these 3D electrodes, the co-immobilization of cyt c to the e-spun 3D ITO results in well-defined photoelectrochemical signals. The scaling of thickness of the 3D ITO layers by controlling the time (10 min and 60 min) of electrospinning results in enhancement of the photocurrent. Several performance parameters of the electrode have been analyzed for different illumination intensities.

Advanced In Vitro Modeling to Study the Paradox of Mechanically Induced Cardiac Fibrosis.

In heart failure, cardiac fibrosis is the result of an adverse remodeling process. Collagen is continuously synthesized in the myocardium in an ongoing attempt of the heart to repair itself. The resulting collagen depositions act counterproductively, causing diastolic dysfunction and disturbing electrical conduction. Efforts to treat cardiac fibrosis specifically have not been successful and the molecular etiology is only partially understood. The differentiation of quiescent cardiac fibroblasts to extracellular matrix-depositing myofibroblasts is a hallmark of cardiac fibrosis and a key aspect of the adverse remodeling process. This conversion is induced by a complex interplay of biochemical signals and mechanical stimuli. Tissue-engineered 3D models to study cardiac fibroblast behavior in vitro indicate that cyclic strain can activate a myofibroblast phenotype. This raises the question how fibroblast quiescence is maintained in the healthy myocardium, despite continuous stimulation of ultimately profibrotic mechanotransductive pathways. In this review, we will discuss the convergence of biochemical and mechanical differentiation signals of myofibroblasts, and hypothesize how these affect this paradoxical quiescence. Impact statement Mechanotransduction pathways of cardiac fibroblasts seem to ultimately be profibrotic in nature, but in healthy human myocardium, cardiac fibroblasts remain quiescent, despite continuous mechanical stimulation. We propose three hypotheses that could explain this paradoxical state of affairs. Furthermore, we provide suggestions for future research, which should lead to a better understanding of fibroblast quiescence and activation, and ultimately to new strategies for the prevention and treatment of cardiac fibrosis and heart failure.

Effects of NBI-98782, a selective vesicular monoamine transporter 2 (VMAT2) inhibitor, on neurotransmitter efflux and phencyclidine-induced locomotor activity: Relevance to tardive dyskinesia and antipsychotic action.

Valbenazine, a vesicular monoamine transporter 2 (VMAT2, SLC18A2) inhibitor, is a newly approved treatment for tardive dyskinesia. VMAT2 is present in the membrane of secretory vesicles and transports dopamine (DA), norepinephrine (NE), serotonin (5-HT), histamine, glutamate (Glu), and GABA into vesicles for presynaptic release. We utilized microdialysis in awake, freely moving mice to determine the effect of NBI-98782, the active metabolite of valbenazine, alone, or in combination with several antipsychotic drugs (APDs), to influence neurotransmitter efflux in the medial prefrontal cortex (mPFC), dorsal striatum (dSTR), hippocampus and nucleus accumbens (NAC); we also compared it with tetrabenazine, the prototypical VMAT2 inhibitor. Acute NBI-98782 and tetrabenazine decreased mPFC, dSTR, hippocampus, and NAC DA, 5-HT, and NE efflux, while increasing that of DOPAC, HVA, and 5-HIAA. Sub-chronic NBI-98782 (7 days) decreased baseline DA and 5-HT efflux in both mPFC and dSTR. NBI-98782 elicited similar effects on neurotransmitter efflux in sub-chronic NBI-98782-treated mice but also enhanced ACh and GABA; the decrease in DA efflux in mPFC and dSTR was not significant in the sc-treated animals. NBI-98782 suppressed clozapine-, olanzapine- and risperidone-induced DA efflux in both mPFC and dSTR, and ACh efflux in mPFC. NBI-98782 suppressed the haloperidol-induced DA efflux in dSTR, with minimal effect on GABA efflux. NBI-98782 attenuated PCP-induced DA, 5-HT, NE and Glu efflux, and AMPH-induced DA and NE efflux, in both mPFC and dSTR, as well as PCP- and AMPH-induced hyperlocomotion, suggesting possible beneficial antipsychotic effects.

Swiss chocolate and free beverages to increase the motivation for scientific work amongst residents: a prospective interventional study in a non-academic teaching hospital in Switzerland.

BACKGROUND: The success of a clinical trial depends on its recruitment of eligible patients; therefore, the recruitment period requires special attention. We hypothesized that with a new approach focused on continuous information and gratification, resident motivation to participate in scientific work will increase and recruitment rates will improve. METHODS: Our new recruitment approach was applied to the recruitment phase of two prospective randomized trials (registered at the German Clinical Trials Register). Randomization of these trials was performed first using blinded envelopes; later a soft drink machine was used as the delivery tool of randomization as a lighthearted motivation to join scientific work and to reward the resident with free soft drinks for each recruitment. Residents were informed about the trial via a lecture and by mail. To increase interest everyone received Swiss chocolate. With a multiple choice survey we investigated the success of our actions at 6 and 12 months. Recruitment rates of the trials were evaluated and associated with the motivational approaches. RESULTS: Our residents rated their awareness of the trials with median 9 (IQR 7;9) during the first and 8 (IQR 5;9) during the second survey and their interest in scientific work with median 7 (IQR 4;8) and 6 (IQR 5;8). The percentage of residents feeling highly motivated improved from 58% to 70%. The recruitment rates stayed stably high over time with 73% and 72% in trial 1 and 90% and 85% in trial 2; 24% of residents stated their motivation could be increased by gratifications. CONCLUSIONS: After implementation of our new recruitment approach we found positively motivated residents and high recruitment rates in the corresponding trials. We propose this procedure may help to ensure the successful initiation of clinical trials. Larger studies testing this approach are warranted.

The importance of target binding kinetics for measuring target binding affinity in drug discovery: a case study from a CRF1 receptor antagonist program.

In drug discovery, it is essential to accurately measure drug-target binding affinity. Here, we revisit the fact that target binding kinetics impact the measurement of affinity, using a case study: development of corticotropin-releasing factor antagonists. Slow dissociation of the drug-target complex results in affinity assays being far from equilibrium, which results in erroneous estimates of affinity. This scenario can impair prediction of human dosing, assessment of target selectivity, identification of high-affinity ligands and determination of SAR. We describe strategies to detect lack of equilibration in affinity assays and methods to correctly measure affinity of slowly dissociating compounds. These considerations will facilitate drug discovery by ensuring reliable measurement of drug-target binding affinity.

Comparison of fracture healing and long-term patient-reported functional outcome between dorsal and volar plating for AO C3-type distal radius fractures.

PURPOSE: This study aimed to evaluate the differences in long-term functional outcome and radiographic fracture healing between volar and dorsally approached comminuted intra-articular distal radius fractures (DRF) (AO C3-type). METHODS: A retrospective, age-matched, case-control study with a 1:2 allocation ratio was conducted in 84 patients C3-type DRFs patients who underwent either dorsal locking plating (DLP) group (n = 28) or volar locking plating (VLP) group (n = 56). Standardized wrist radiographs (posterior-anterior and 15° lateral) were assessed immediately postoperative and at final follow. To evaluate for loss of reduction standard radiographic measurements were performed. Fracture healing was assessed radiologically. Patient-reported outcomes were assessed with the patient-related wrist evaluation and the EQ-5D-3L for health-related quality of life. Patient satisfaction was assessed with the use of a numeric analog scale ranging from 0 (not satisfied) to 100 (very satisfied). RESULTS: All fractures united within 3 months postoperatively. Average age was 59 ± 12 years. Fifty-five patients (66%) participated in the follow-up survey at an average of 76.6 ± 23.8 months. DLP group showed a significant change in sagittal tilt compared with VLP group (3.4 ± 3.0° vs - 0.4 ± 4.1°, p < 0.001). No significant difference in other radiographic and long-term functional outcome was found between both groups (p > 0.05). CONCLUSION: Dorsal locking plating fixation in C3-type DRFs resulted in a minimal, but statistically significant, volar collapse of sagittal tilt compared with volar locking plating fixation. However, this difference in volar collapse did not significantly influence the long-term clinical outcome.

Intraoperative evaluation of acetabular cup position during anterior approach total hip arthroplasty: are we accurately interpreting?

INTRODUCTION: Intraoperative radiographic evaluation during total hip arthroplasty (THA) has shown to improve the accuracy of acetabular component placement, however, differences in interpretation based on radiographic technique has not been established. This study aims to determine if differences exist in the interpretation of acetabular component abduction and anteversion between different radiographic projections. METHODS: 55 consecutive direct anterior THAs in 49 patients were prospectively enrolled. Target anteversion and abduction was defined by the Lewinnek zone. Fluoroscopy was used to direct acetabular component placement intraoperatively. After final cup implantation, fluoroscopic posterior-anterior hip and pelvis images were obtained for analysis. After completion of the procedure, an anterior-posterior plain pelvis radiograph was obtained in the operating room. Acetabulum component abduction and anteversion were postoperatively determined using specialised software on each of the 3 image acquisition methods. RESULTS: Average acetabular cup abduction for intraoperative fluoroscopic posterior-anterior hip (FH), intraoperative fluoroscopic posterior-anterior pelvis (FP), and postoperative, standard, anteroposterior pelvis radiographs (PP) was 40.95° ± 2.87°, 38.87° ± 3.82° and 41.73° ± 2.96° respectively. The fluoroscopic hip and fluoroscopic pelvis tended to underestimate acetabular cup abduction compared to the postoperative pelvis (p < 0.001). Average acetabular cup anteversion for FH, FP, and PP was 19.89° ± 4.87°, 24.38° ± 5.31° and 13.36° ± 3.52° respectively. Both the fluoroscopic hip and fluoroscopic pelvis overestimated anteversion compared to the AP pelvis, with a 6.38° greater mean value measurement for FH (p < 0.001), and an 11° greater mean value measurement for FP (p < 0.001). CONCLUSIONS: Fluoroscopic technique and differences between radiographic projections may result in discrepancies in component position interpretation. Our results support the use of the fluoroscopic posterior-anterior hip as the choice fluoroscopic imaging technique.

Interprosthetic femoral fractures: management challenges.

Interprosthetic femur fractures are a rare but serious complication following total hip and knee arthroplasty. Classification systems have focused not only on diagnosis but also on treatment algorithm. Critical to the evaluation of patients with these fractures are an assessment of fracture location, bone quality, and the presence of stemmed implants. The gold standard for fracture fixation is locked plating with bicortical and unicortical screws, supplemented with wires or cables as needed. For patients with compromised bone stock or insufficient bony area for fixation, allograft augmentation with struts or interprosthetic sleeves may be used. For fractures with severe bone loss, conversion to a megaprosthesis or total femur replacement may be warranted.

Developing a Prognostic Information System for Personalized Care in Real Time.

CONTEXT: Electronic medical records hold promise to transform clinical practice. However, technological and other barriers may preclude using them to guide care in real time. We used the Virtual Data Warehouse (VDW) to develop a tool that enables physicians to generate real-time, personalized prognostic information about survival after cancer. CASE DESCRIPTION: Patients with cancer often ask their oncologists, "Have you ever seen a patient like me?" To help oncologists answer this question, we developed a prototype Prognostic Information System (PRISM), a web-based tool that gathers data about the index patient from Kaiser Permanente's clinical information systems, selects a historical cohort of similar patients, and displays the survival curve of the similar patients relative to key points in their treatment course. FINDINGS AND MAJOR THEMES: The prototype was developed by a multidisciplinary team with expertise in oncology, research, and technology. We have completed two rounds of user testing and refinement. Successful development rested on: (1) executive support and a clinical champion; (2) collaboration among experts from multiple disciplines; (3) starting with simple cases rather than ambitious ones; (4) extensive research experience with the Virtual Data Warehouse, related databases, and an existing query tool; and (5) following agile software development principles, especially iterative user testing. CONCLUSION: Clinical data stored in health care systems' electronic medical records can be used to personalize clinical care in real time. Development of prognostic information systems can be accelerated by collaborations among researchers, technology specialists, and clinicians and by use of existing technology like the Virtual Data Warehouse.

VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine).

The dopaminergic system plays a key role in the central nervous system, regulating executive function, arousal, reward, and motor control. Dysregulation of this critical monoaminergic system has been associated with diseases of the central nervous system including schizophrenia, Parkinson's disease, and disorders such as attention deficit hyperactivity disorders and addiction. Drugs that modify the dopaminergic system by modulating the activity of dopamine have been successful in demonstrating clinical efficacy by providing treatments for these diseases. Specifically, antipsychotics, both typical and atypical, while acting on a number of monoaminergic systems in the brain, primarily target the dopamine system via inhibition of postsynaptic dopamine receptors. The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Despite acting on opposing sides of the synapse, both antipsychotics and VMAT2 inhibitors act to decrease the activity of central dopaminergic systems. Tardive dyskinesia is a disorder characterized by involuntary repetitive movements and thought to be a result of a hyperdopaminergic state precipitated by the use of antipsychotics. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2 through an active metabolite, has been developed for the treatment of tardive dyskinesia and is the first drug approved for the treatment of this disorder. This chapter describes the process leading to the discovery of valbenazine, its pharmacological characteristics, along with preclinical and clinical evidence of its efficacy.

Non-Conventional Thermodynamics and Models of Gradient Elasticity.

We consider material bodies exhibiting a response function for free energy, which depends on both the strain and its gradient. Toupin-Mindlin's gradient elasticity is characterized by Cauchy stress tensors, which are given by space-like Euler-Lagrange derivative of the free energy with respect to the strain. The present paper aims at developing a first version of gradient elasticity of non-Toupin-Mindlin's type, i.e., a theory employing Cauchy stress tensors, which are not necessarily expressed as Euler-Lagrange derivatives. This is accomplished in the framework of non-conventional thermodynamics. A one-dimensional boundary value problem is solved in detail in order to illustrate the differences of the present theory with Toupin-Mindlin's gradient elasticity theory.

Quantitative Effect of Pelvic Position on Radiographic Assessment of Acetabular Component Position.

BACKGROUND: Intraoperative fluoroscopy aims to improve component position in total hip arthroplasty. Measurement bias related to image quality, however, has not been quantified. We aim to quantify measurement bias in the interpretation of acetabular component position as a function of pelvis and fluoroscopic beam position in a simulated supine total hip arthroplasty model. METHODS: Posterior-anterior pelvis and hip images were obtained using a previously described pelvic model with known acetabular component position. Pelvic position was varied in 5° increments of pelvis rotation (iliac-obturator) and tilt (inlet-outlet), and in 1 cm increments from beam center in cranial-caudal and medial-lateral planes. Multiple regression analyses were conducted to evaluate the relationship between the resulting bias in interpretation of component position relative to pelvis position. RESULTS: Anteversion and abduction measurement bias increased exponentially with increasing deviation in rotation and tilt. Greater bias occurred for anteversion than for abduction. Hip centered images were less affected by pelvis malposition than pelvis centered images. Deviations of beam center within 5 cm in the coronal plane did not introduce measurement bias greater than 5°. An arbitrarily defined acceptable bias of ±5° for both abduction and anteversion was used to identify a range of optimum pelvic positioning each for hip and pelvis centered imaging. CONCLUSION: Accurate measurement of acetabular component abduction and anteversion, especially anteversion, is sensitive to proper pelvic position relative to the chosen radiographic plane. An acceptable measurement bias of ±5° is achieved when the pelvis is oriented within a newly identified range of optimum pelvic positioning.

Functional aspects of salivary nitric oxide synthase of Rhodnius prolixus (Hemiptera, Reduviidae) and nitric oxide trafficking at the vector-host interface.

Rhodnius prolixus expresses nitric oxide synthase (NOS) in the cytosol of the salivary gland (SG) cells. The NO produced is stored in the SG lumen bound to NO-carrier haemeproteins called nitrophorins (NPs). NPs bind tightly to NO in the acidic SG lumen, but release NO when the pH becomes high, e.g., at the host skin (pH~7.4). NO elicits potent and transient relaxation of vascular smooth muscle. Here, we investigated the role of salivary NO in the R. prolixus feeding behaviour and the salivary vasodilator activity of the host microcirculation. NOS knockdown in R. prolixus changed the SG colour, decreased the number of NO-loaded NPs and caused impairment of feeding performance. When salivary gland extracts (SGEs) were obtained from NOS- and NPs-knockdown insects and prepared in pH 5.0 solution and injected (i.v.) into mice via the tail vein, no vasodilation was observed, whereas SGEs from control insects caused long-term venodilation in the mouse skin. SGs disrupted directly in PBS (pH 7.4) containing BSA produced long-term vasodilation compared to the controls without BSA due to the possible formation of nitroso-albumin, suggesting that host serum albumin extends the NO half-life when NO is injected into the host skin by triatomine during their blood-feeding.

Differences in Dihydrotetrabenazine Isomer Concentrations Following Administration of Tetrabenazine and Valbenazine.

BACKGROUND: Tetrabenazine (TBZ) activity is thought to result from four isomeric dihydrotetrabenazine (HTBZ) metabolites ([+]-α-HTBZ, [-]-α-HTBZ, [+]-ß-HTBZ, [-]-ß-HTBZ). Each isomer has a unique profile of vesicular monoamine transporter 2 (VMAT2) inhibition and off-target binding. Previously published data only report total isomer (α) and (ß) concentrations. We developed a method to quantify the individual HTBZ isomers in samples from patients with Huntington's disease receiving TBZ. For comparison, concentrations of [+]-α-HTBZ, the single active metabolite shared by valbenazine (VBZ) and TBZ, were determined in samples from patients with tardive dyskinesia receiving VBZ. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of the four individual HTBZ isomers. Concentrations were determined in serum from patients with Huntington's disease administered TBZ and plasma from patients with tardive dyskinesia administered VBZ once daily. RESULTS: In patients administered TBZ, [-]-α-HTBZ and [+]-ß-HTBZ were the most abundant HTBZ isomers while [-]-ß-HTBZ and [+]-α-HTBZ were present as minor metabolites. Only [+]-α-HTBZ was observed in patients administered VBZ. CONCLUSIONS: Based on relative abundance and potency, [+]-ß-HTBZ appears to be the primary contributor to VMAT2 inhibition by TBZ, a finding in contrast with the generally held assertion that [+]-α-HTBZ is the major contributor. [-]-α-HTBZ, the other abundant TBZ metabolite, has much lower VMAT2 inhibitory potency than [+]-ß-HTBZ, but increased affinity for other CNS targets, which may contribute to off-target effects of TBZ. In contrast, pharmacological activity for VBZ is derived primarily from [+]-α-HTBZ. Individual HTBZ isomer concentrations provide a more clinically relevant endpoint for assessing on- and off-target effects of TBZ than total isomer concentrations.

Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites.

The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2, is approved for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)-α-dihydrotetrabenazine (R,R,R-HTBZ) and a mono-oxy metabolite, NBI-136110. Radioligand-binding studies were conducted to assess and compare valbenazine, tetrabenazine, and their respective metabolites in their abilities to selectively and potently inhibit [3H]-HTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates. A broad panel screen was conducted to evaluate possible off-target interactions of valbenazine, R,R,R-HTBZ, and NBI-136110 at >80 receptor, transporter, and ion channel sites. Radioligand binding showed R,R,R-HTBZ to be a potent VMAT2 inhibitor in homogenates of rat striatum (Ki = 1.0-2.8 nM), rat forebrain (Ki = 4.2 nM), and human platelets (Ki = 2.6-3.3 nM). Valbenazine (Ki = 110-190 nM) and NBI-136110 (Ki = 160-220 nM) also exhibited inhibitory effects on VMAT2, but with lower potency than R,R,R-HTBZ. Neither valbenazine, R,R,R-HTBZ, nor NBI-136110 had significant off-target interactions at serotonin (5-HT1A, 5-HT2A, 5-HT2B) or dopamine (D1 or D2) receptor sites. In vivo studies measuring ptosis and prolactin secretion in the rat confirmed the specific and dose-dependent interactions of tetrabenazine and R,R,R-HTBZ with VMAT2. Evaluations of potency and selectivity of tetrabenazine and its pharmacologically active metabolites were also performed. Overall, the pharmacologic characteristics of valbenazine appear consistent with the favorable efficacy and tolerability findings of recent clinical studies [KINECT 2 (NCT01733121), KINECT 3 (NCT02274558)].

Non-peptide CRF-Receptor Antagonists: Allosterism, Kinetics and Translation to Efficacy in Human Disease.

G-Protein coupled receptors (GPCRs) have been, and remain a key target of drug discovery programs for human disease. While many drugs have been developed that interact with these proteins in the simple classic manner - that is - physically blocking the cognate ligand from simply binding to its target receptor, drug discovery approaches have elucidated alternative more complex methods by which small molecules can interact with these receptors and block their function. This is most evident in the Class B GPCRs where the cognate ligands are relatively large peptides with multiple points of contact on the GPCR spanning both hydrophilic and hydrophobic domains on the same protein to elicit function. It has therefore been difficult to precisely determine not only the mechanism by which a small molecule can inhibit the function of a large peptide but also the nature of that mechanism that drives the differences in efficacy. This review will examine in detail the nature of small molecule inhibition of corticotropin-releasing factor receptors and illustrate the role that allosteric binding and kinetics play in the functional inhibition of this Class B GPCR.

The Impact of Metabolic Syndrome on 30-Day Complications Following Total Joint Arthroplasty.

BACKGROUND: The arthroplasty population increasingly presents with comorbid conditions linked to elevated risk of postsurgical complications. Current quality improvement initiatives require providers to more accurately assess and manage risk presurgically. In this investigation, we assess the effect of metabolic syndrome (MetS), as well as the effect of body mass index (BMI) within MetS, on the risk of complication following hip and knee arthroplasty. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database for total hip or knee arthroplasty cases. Thirty-day rates of Centers for Medicare and Medicaid Services (CMS)-reportable complications, wound complications, and readmissions were compared between patients with and without a diagnosis of MetS using multivariate logistic regression. Arthroplasty cases with a diagnosis of MetS were further stratified according to World Health Organization BMI class, and the role of BMI within the context of MetS was assessed. RESULTS: Of the 107,117 included patients, 11,030 (10.3%) had MetS. MetS was significantly associated with CMS complications (odds ratio [OR] = 1.415; 95% confidence interval [CI], 1.306-1.533; P < .001), wound complications (OR = 1.749; 95% CI, 1.482-2.064; P < .001), and readmission (OR = 1.451; 95% CI, 1.314-1.602; P < .001). When MetS was assessed by individual BMI class, the MetS + BMI >40 group was associated with significantly higher risk of CMS complications, wound complications, and readmission compared to the lower MetS BMI groups. CONCLUSION: MetS is an independent risk factor for CMS-reportable complications, wound complications, and readmission following total joint arthroplasty. The risk attributable to MetS exists irrespective of obesity class and increases as BMI increases.