The Endogenous Analgesia Signature in the Resting Brain of Healthy Adults and Migraineurs

Altered pain modulation and resting state functional connectivity (rsFC) were found to be related to migraine pathology and clinical manifestation. We examined how pain modulation psychophysical measures are related to resting-state networks and rsFC between bottom-up and top-down pain modulation areas. Thirty-two episodic migraineurs and 23 age-matched healthy individuals underwent temporal summation of pain (TSOP) and conditioned pain modulation (CPM) tests, followed by a resting-state imaging scan. No differences in temporal summation of pain and CPM were found between groups. However, in healthy individuals, more efficient CPM was correlated with 1) stronger rsFCs of the posterior cingulate cortex, with the ventromedial prefrontal cortex and with the pregenual anterior cingulate cortex; 2) weaker rsFC of the anterior insula with the angular gyrus. Conversely, in migraineurs, the association between CPM and rsFC was altered. Our results suggest that the functional connectivity within the default mode network (DMN) components and the functional coupling between the DMN and pain inhibitory brain areas is linked with pain inhibition efficiency. In migraineurs, this interplay is changed, yet enables normal pain inhibition. Our findings shed light on potential functional adaptation of the DMN and its role in pain inhibition in health and migraine.PerspectiveThis article establishes evidence for the relationship between the resting-state brain and individual responses in psychophysical pain modulation tests, in both migraine and healthy individuals. The results emphasize the significant role of the default mode network in maintaining pain inhibition efficiency in health and in the presence of chronic pain.     

Pharmacokinetics and Safety of an Antirhinoviral Agent, Ruprintrivir, in Healthy Volunteers

A single-dose study and a multiple-dose study of the safety and pharmacokinetics of ruprintrivir, a new selective irreversible inhibitor of human rhinovirus 3C protease, were conducted with healthy adult volunteers. Both studies were double-blind, randomized, placebo-controlled, parallel-group investigations of ruprintrivir administered intranasally at two dose levels. The parent drug and its acid metabolite, AG7185, were measured in plasma samples and nasal washings, and the safety of the treatments was monitored. Intranasal ruprintrivir, administered as single doses of 4 and 8 mg or every 3 h, six times per day, for 7 days was safe and well tolerated. Adverse events were mild, short-lived, and confined to the upper respiratory tract (i.e., nose and throat, taste and smell perceptions). Adverse events were similar after placebo and after single or multiple doses of active drug. Systemic exposure to ruprintrivir was rarely detectable with the highest measured concentration of < or =0.52 ng/ml; the assay had a lower limit of quantification of 0.2 ng/ml. Systemic exposure to the metabolite was also low, with a highest measured concentration of 3.25 ng/ml. Concentrations of AG7185 observed during multiple dosing were higher than those observed after the first dose but were no more than predicted from the single-dose study. Substantial amounts of ruprintrivir were observed intranasally for at least 9 h after multiple doses of ruprintrivir.     

Kinematics of Pointing Movements Made in a Virtual Versus a Physical 3-Dimensional Environment in Healthy and Stroke Subjects

Knaut LA, Subramanian SK, McFadyen BJ, Bourbonnais D, Levin MF. Kinematics of pointing movements made in a virtual versus a physical 3-dimensional environment in healthy and stroke subjects.

Objective

To compare kinematics of 3-dimensional pointing movements performed in a virtual environment (VE) displayed through a head-mounted display with those made in a physical environment.

Design

Observational study of movement in poststroke and healthy subjects.

Setting

Motion analysis laboratory.

Participants

Adults (n=15; 4 women; 59±15.4y) with chronic poststroke hemiparesis were recruited. Participants had moderate upper-limb impairment with Chedoke-McMaster Arm Scores ranging from 3 to 6 out of 7. Twelve healthy subjects (6 women; 53.3±17.1y) were recruited from the community.

Interventions

Not applicable.

Main Outcome Measures

Arm and trunk kinematics were recorded in similar virtual and physical environments with an Optotrak System (6 markers; 100Hz; 5s). Subjects pointed as quickly and as accurately as possible to 6 targets (12 trials/target in a randomized sequence) placed in arm workspace areas requiring different arm movement patterns and levels of difficulty. Movements were analyzed in terms of performance outcome measures (endpoint precision, trajectory, peak velocity) and arm and trunk movement patterns (elbow and shoulder ranges of motion, elbow/shoulder coordination, trunk displacement, rotation).

Results

For healthy subjects, precision and trajectory straightness were higher in VE when pointing to contralateral targets, and movements were slower for all targets in VE. Stroke participants made less accurate and more curved movements in VE and used less trunk displacement. Elbow/shoulder coordination differed when pointing to the lower ipsilateral target. There were no group-by-environment interactions.

Conclusions

Movements in both environments were sufficiently similar to consider VE a valid environment for clinical interventions and motor control studies.     

Virtual Reality and Computer-Enhanced Training Applied to Wheeled Mobility: An Overview of Work in Pittsburgh

Some aspects of assistive technology can be enhanced by the application of virtual reality. Although virtual simulation offers a range of new possibilities, learning to navigate in a virtual environment is not equivalent to learning to navigate in the real world. Therefore, virtual reality simulation is advocated as a useful preparation for assessment and training within the physical environment. We are engaged in several efforts to develop virtual environments and devices for mobility skills assessment and training, exercise training, and environment assessment. Virtual reality offers wheelchair users a training tool in different risk-free environments without any indoor (e.g., walls, furniture, and stairs) and outdoor (e.g., curb cuts, uneven terrain, and street traffic) physical constraints. Virtual reality technology will probably become more common in the field of assistive technology, especially given the rapid expansion of gaming technology and the continued exponential growth of computing power.     

Comparative Pharmacokinetics of a Controlled-release Pregabalin Tablet (GLA5PR GLARS-NF1) and an Immediate-release Pregabalin Capsule in Healthy Male Volunteers

Purpose

Pregabalin is a widely used drug for the management of neuropathic pain. This study compared the pharmacokinetics of the GLA5PR GLARS-NF1 tablet, a 150-mg controlled-release formulation of pregabalin taken once daily, with those of a 75-mg immediate-release (IR) capsule formulation of pregabalin taken twice daily with a 12-h interval between doses.

Effect of the Hepatitis C Virus Protease Inhibitor Faldaprevir on the Pharmacokinetics of an Oral Contraceptive Containing Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor. Faldaprevir is known to inhibit P-glycoprotein, CYP3A4, and UDP-glucuronosyltransferase 1A1. This study evaluated the effect of steady-state 240 mg faldaprevir on the pharmacokinetics (PK) of an oral contraceptive containing ethinylestradiol (EE) and levonorgestrel (LNG) in healthy premenopausal women. In period 1, subjects received EE/LNG once daily (QD) for 14 days. Blood samples were taken on days 1, 11, and 12, with intensive PK blood sampling for EE and LNG on day 13. In period 2, subjects received EE-LNG QD and 240 mg faldaprevir QD on days 14 to 21 (240 mg faldaprevir twice daily on day 14). Blood samples were taken on days 14, 19, and 20, with PK profiling samples obtained for EE and LNG on day 21. A total of 15/16 subjects completed the study. Overall, EE and LNG exposure (assessed by the area under the curve) was approximately 1.4-fold higher when EE and LNG were coadministered with faldaprevir than when administered alone. Median t_1/2 (terminal half-life in plasma at steady state) values were prolonged for both EE (2.4 h longer) and LNG (4.7 h longer) when EE and LNG were coadministered with faldaprevir. The mean oral clearance and apparent volume of distribution of both EE and LNG were lower (∼30%) when EE and LNG were coadministered with faldaprevir. Coadministration of faldaprevir and an oral contraceptive resulted in a moderate increase in exposure to both EE and LNG. However, this increase was not considered clinically meaningful, and no dose adjustment of oral contraceptives was deemed necessary. (This study has been registered at ClinicalTrials.gov under registration number {"type":"clinical-trial","attrs":{"text":"NCT01570244","term_id":"NCT01570244"}}NCT01570244.)     

Diverse Physiological Roles of Calcitonin Gene-Related Peptide in Migraine Pathology: Modulation of Neuronal-Glial-Immune Cells to Promote Peripheral and Central Sensitization

The neuropeptide calcitonin gene-related peptide (CGRP) is implicated in the underlying pathology of migraine by promoting the development of a sensitized state of primary and secondary nociceptive neurons. The ability of CGRP to initiate and maintain peripheral and central sensitization is mediated by modulation of neuronal, glial, and immune cells in the trigeminal nociceptive signaling pathway. There is accumulating evidence to support a key role of CGRP in promoting cross excitation within the trigeminal ganglion that may help to explain the high co-morbidity of migraine with rhinosinusitis and temporomandibular joint disorder. In addition, there is emerging evidence that CGRP facilitates and sustains a hyperresponsive neuronal state in migraineurs mediated by reported risk factors such as stress and anxiety. In this review, the significant role of CGRP as a modulator of the trigeminal system will be discussed to provide a better understanding of the underlying pathology associated with the migraine phenotype.     

The Effects of Designing an Educational Animation Movie in Virtual Reality on Preoperative Fear and Postoperative Pain in Pediatric Patients: A Randomized Controlled Trial

PurposeThe purpose of the study was to investigate the effects of watching an educational animated movie on fear and pain in children aged 6 to 12 years old.DesignA randomized controlled trial.MethodsIn this study, the CONSORT checklist was used as a guide. The sample of participants (n = 132) was allocated to the Educational Animation Group (n = 44), Documentary Group (n = 44), and Control Group (n = 44) using block randomization. During the data collection, an information form, the Children's Fear Scale and Wong-Baker Faces Pain Rating Scale were used.FindingsPreoperative fear and postoperative pain scores were significantly lower in the Educational Animation group than in the other groups.ConclusionsThe educational animated movie was found to be an effective method in reducing preoperative fear and postoperative pain. Educational animated movies, which were effective in reducing the fear and pain of the child in the preparatory operations, increased the educational effectiveness and cooperation of the child.     

A Phase I Study to Assess the Effect of Speed of Injection on Pain,Tolerability, and Pharmacokinetics After High-volume Subcutaneous Administration of Gantenerumab in Healthy Volunteers

PurposeGantenerumab, a fully human anti–amyloid-β IgG1 monoclonal antibody that binds to aggregated forms of amyloid-β, is being investigated as a potential disease-modifying treatment for early (prodromal to mild) Alzheimer disease (AD). Our study compared the pain associated with 5- and 15-s subcutaneous injections of gantenerumab and evaluated the tolerability and pharmacokinetic properties of subcutaneous gantenerumab.MethodsThis randomized, open-label, single-active-dose, placebo-controlled crossover study was conducted in 50 healthy volunteers aged 40–80 years with no history of clinically significant disorders, drug or alcohol abuse, familial history of early-onset AD, or prior gantenerumab exposure. Eligible participants were randomized to a sequence of one 300-mg SC gantenerumab injection into the abdomen and 2 SC placebo injections (1 into the abdomen and 1 into the thigh) during 5 or 15 s. All injections were administered at least 90 min apart. Participants were assessed for local pain by visual analog scale (VAS) and verbal rating scale; safety profiles were assessed by recording adverse events (AEs), and plasma pharmacokinetic properties were also evaluated.FindingsImmediately after the subcutaneous gantenerumab injection, the pain VAS score was numerically higher without reaching statistical significance in the 5-s versus 15-s injection group (VAS least-squares mean difference, 7.492 mm; 95% CI, −4.439–19.423 mm). In both injection speed groups, the mean pain VAS score was comparable after subcutaneous gantenerumab and placebo injections into the abdomen. Pain was reported after needle insertion and immediately after dosing, subsiding within 5 min after the dose. The pain VAS score was numerically higher after SC placebo injection into the thigh versus abdomen (5-s injection group: mean [SD] VAS score, 26.68 [27.83] vs 19.20 [25.60] mm; 15-s injection group: mean [SD] VAS score, 14.16 [20.62] vs 9.48 [12.04] mm). No serious AEs were reported; no participants withdrew because of an AE. All AEs were of mild intensity, were transient, and had resolved without sequelae at follow-up. The most common AEs were injection site reactions; redness was the most frequently observed skin reactivity event after subcutaneous gantenerumab administration (5-s injection group: 36%; 15-s injection group: 32%). After subcutaneous administration, gantenerumab reached a peak plasma concentration at a median time of 119 h (approximately 5 days); plasma concentrations declined in a monoexponential manner. Comparable pharmacokinetic profiles were observed between the injection speed groups.ImplicationsSubcutaneous gantenerumab injections at speeds of 5 and 15 s were well tolerated in healthy volunteers and could enable at-home administration by patients with AD or their caregivers. ClinicalTrials.gov identifier: NCT02882009.     

A Randomized Phase I Study to Evaluate the Safety,Tolerability, and Pharmacokinetics of Recombinant Erwinia Asparaginase (JZP‐458) in Healthy Adult Volunteers

L‐asparaginase has been an important component of acute lymphoblastic leukemia (ALL) therapy for over 40 years, and is standard therapy during ALL induction and consolidation treatment. L‐asparaginases are immunogenic and can induce hypersensitivity reactions; inability to receive asparaginase has been associated with poor patient outcomes. There are L‐asparaginases of varied bacterial origins, with the most commonly used being Escherichia coli (E. coli); therefore, to ensure that patients who develop hypersensitivity to E. coli‐derived asparaginases receive an adequate therapeutic course, alternative preparations are warranted. JZP‐458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme with no immunologic cross‐reactivity to E. coli‐derived asparaginases. To evaluate the safety, tolerability, and pharmacokinetics (PK) of a single dose of JZP‐458, a randomized, single‐center, open‐label, phase I study was conducted with JZP‐458 given via i.m. injection or i.v. infusion to healthy adult volunteers. At the highest doses tested for each route of administration (i.e., 25 mg/m² i.m. and 37.5 mg/m² i.v.), JZP‐458 achieved serum asparaginase activity (SAA) levels ≥ 0.1 IU/mL at 72 hours postdose for 100% of volunteers. Bioavailability for i.m. JZP‐458 was estimated at 36.8% based on SAA data. All dose levels were well‐tolerated, with no unanticipated adverse events (AEs), no serious AEs, and no grade 3 or higher AEs. Based on PK and safety data, the recommended JZP‐458 starting dose for the pivotal phase II/III study in adult and pediatric patients is 25 mg/m² i.m. and 37.5 mg/m² i.v. on a Monday/Wednesday/Friday dosing schedule.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Inability to receive asparaginase secondary to hypersensitivity has been associated with poor patient outcomes, thus alternative asparaginase preparations are needed.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This study evaluated safety, tolerability, and pharmacokinetics of a single dose of i.m. or i.v. JZP‐458, a recombinant Erwinia asparaginase with no immunologic cross‐reactivity to Escherichia coli (E. coli)‐derived asparaginases in healthy adult volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ At the highest doses tested (i.e., 25 mg/m² for i.m. and 37.5 mg/m² for i.v.), JZP‐458 achieved serum asparaginase activity levels ≥ 0.1 IU/mL at 72 hours postdose in each route for 100% of the healthy volunteers with complete asparagine depletion and no unanticipated adverse events (AEs), serious AEs, or grade ≥ 3 AEs. The recommended pivotal phase II/III JZP‐458 starting dose for patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who develop hypersensitivity to E. coli‐derived asparaginases is 25 mg/m² i.m. and 37.5 mg/m² i.v. on a Monday/Wednesday/Friday dosing schedule.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ JZP‐458 may become a treatment alternative for patients with ALL/LBL who develop hypersensitivity to E. coli‐derived asparaginases.

Acute lymphoblastic leukemia (ALL) is the most common cancer among children and the most frequent cause of death from cancer before 20 years of age. In the past several decades, a substantial improvement in the survival of patients with ALL was achieved as a result of multi‐agent chemotherapeutic regimens. ¹ L‐asparaginase has been an important component of ALL therapy for over 40 years, and is standard therapy during ALL induction and consolidation in all pediatric regimens and most adult protocols. ² , ³ L‐asparaginase hydrolyzes the amino acid asparagine to aspartic acid and ammonia. Leukemic blast cells express only limited amounts of asparagine synthetase and are dependent on the availability of extracellular asparagine for growth. These cells may be selectively killed when L‐asparaginase depletes the circulating endogenous asparagine pool. ² , ³ The dependence of leukemic cells on exogenous asparagine supplies the rationale for asparaginase treatment.The pharmacodynamic (PD) goal of asparaginase therapy is asparagine depletion. Asparagine levels are difficult to measure accurately when asparaginase is present in blood because the enzyme can continue to break down asparagine ex vivo if the sample is not immediately processed and stored on ice. Therefore, monitoring of serum asparaginase levels is more reliable than measurement of asparagine itself. In clinical practice, serum asparaginase activity (SAA) levels serve as a surrogate marker for asparagine depletion. Although the level of asparaginase activity required for complete asparagine depletion still remains under debate, nadir SAA levels ≥ 0.1 IU/mL have been used in various studies and treatment protocols and are the accepted threshold for demonstrating adequate asparagine depletion. ⁴ , ⁵ Due to the short half‐life, the administration schedule of some L‐asparaginases is an important variable requiring dosing every 48–72 hours, a schedule that in clinical practice translates to a dosing schedule of Monday/Wednesday/Friday for 2 weeks, for a total of 6 doses. Clinical practice guidelines also recommend checking SAA levels after dosing to make any necessary adjustments to maintain nadir SAA levels ≥ 0.1 IU/mL. If the 48‐ or 72‐hour postdose level is below the lower limit of quantification (LLOQ), this may indicate a need for higher or more frequent dosing. The route of administration of L‐asparaginases is also an important component; in clinical practice, both the i.m. and i.v. routes are used routinely, depending on the treating oncologist’s preference and/or institutional guidelines. ⁴ L‐asparaginases are immunogenic and can induce hypersensitivity reactions with high titers of neutralizing antibodies that may limit their therapeutic effect. ³ , ⁶ Previous studies reported hypersensitivity reactions in up to 30% of patients treated with asparaginases, leading to early discontinuation of asparaginase treatment in some of those patients. ⁷ , ⁸ , ⁹ Unfortunately, the inability to receive asparaginase due to hypersensitivity reactions is associated with poor patient outcomes. ¹⁰ , ¹¹ High‐risk and slow early responding standard‐risk patients with ALL who do not complete their prescribed asparaginase course have a significantly inferior event‐free survival (EFS) compared with patients who complete their prescribed course. ¹⁰ , ¹¹ Additionally, some patients may develop antibodies to asparaginases that neutralize the asparaginase without leading to clinical hypersensitivity; this is known as silent inactivation. ³ Alternative asparaginase preparations are needed to ensure that patients who develop hypersensitivity to Escherichia coli (E. coli)‐derived asparaginases are able to complete their full treatment course. Asparaginase Erwinia chrysanthemi (ERW; crisantaspase) is an effective treatment option for patients with ALL who have developed hypersensitivity to E. coli‐derived asparaginase. ³ , ¹² However, since 2016, there has been a worldwide shortage of ERW due to ongoing manufacturing issues, which have resulted in disruptions in the ability to make the product available on a consistent basis. ¹³ Both JZP‐458 and ERW are forms of Erwinia asparaginase or crisantaspase. JZP‐458 is a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform. The primary amino acid sequence of JZP‐458 is the same as Erwinia asparaginase, and the activity is comparable based on a broad range of in vitro measurements (Jazz Pharmaceuticals data on file). Therefore, similar to Erwinia asparaginase, JZP‐458 is also expected to have no immunologic cross‐reactivity to E. coli‐derived asparaginases. ¹⁴ JZP‐458 is being developed as a component of a multi‐agent chemotherapeutic regimen to treat patients with ALL or lymphoblastic lymphoma (LBL) who develop hypersensitivity to E. coli‐derived asparaginases.JZP‐458 was evaluated in a randomized, single‐center, open‐label phase I study. The study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of a single dose of JZP‐458 in healthy adult volunteers following either an i.m. injection or a 2‐hour i.v. infusion. Data from this study will facilitate the selection of an appropriate starting dose and dosing regimen of JZP‐458 for use in a pivotal phase II/III study in adult and pediatric patients with ALL or LBL who develop hypersensitivity to E. coli‐derived asparaginases.     

Virtual reality and computer-enhanced training applied to wheeled mobility: an overview of work in Pittsburgh

Some aspects of assistive technology can be enhanced by the application of virtual reality. Although virtual simulation offers a range of new possibilities, learning to navigate in a virtual environment is not equivalent to learning to navigate in the real world. Therefore, virtual reality simulation is advocated as a useful preparation for assessment and training within the physical environment. We are engaged in several efforts to develop virtual environments and devices for mobility skills assessment and training, exercise training, and environment assessment. Virtual reality offers wheelchair users a training tool in different risk-free environments without any indoor (e.g., walls, furniture, and stairs) and outdoor (e.g., curb cuts, uneven terrain, and street traffic) physical constraints. Virtual reality technology will probably become more common in the field of assistive technology, especially given the rapid expansion of gaming technology and the continued exponential growth of computing power.     

Changes in the Cell Surface Hydrophobicity of Oral Candida albicans from Smokers,Diabetics, Asthmatics,and Healthy Individuals following Limited Exposure to Chlorhexidine Gluconate

Objective

The objective of this study was to determine the cell surface hydrophobicity of 40 oral Candida albicans isolates obtained from smokers, diabetics, asthmatics using steroid inhalers, and healthy individuals, following brief exposure to subtherapeutic concentrations of chlorhexidine gluconate.

Materials and Methods

Forty C. albicans oral isolates (10 isolates each from smokers, diabetics, asthmatics using steroid inhalers, and healthy individuals) were exposed to 3 subtherapeutic concentrations of chlorhexidine gluconate (0.00125, 0.0025, and 0.005%) for 30 min. Thereafter, the antiseptic was removed and the cell surface hydrophobicity was measured by a biphasic aqueous-hydrocarbon assay.

Results

Compared to the unexposed controls, the cell surface hydrophobicity of C. albicans isolates was suppressed by 5.40% (p > 0.05), 21.17% (p < 0.05), and 44.67% (p < 0.05) following exposure to 0.00125, 0.0025, and 0.005% chlorhexidine gluconate, respectively.

Conclusions

A brief period of transient exposure to subtherapeutic concentrations of chlorhexidine gluconate may modulate the cell surface hydrophobicity of C. albicans isolates and thereby may reduce candidal pathogenicity.Key Words: Candida albicans, Cell surface hydrophobicity, Chlorhexidine gluconate     

Early maturation and liver necrosis in the fingerling stage of Oreochromis mossambicus due to BPA can cause an ecological imbalance

We investigated the effect of Bisphenol-A (BPA) on the fingerlings of Oreochromis mossambicus collected from industrial waste. Fluorescence quenching assay using Rhodamine-B and mass detection assay using ESI-MS revealed that BPA was predominantly present in plastic industry effluent, where the fingerlings'' ovaries exhibited early maturation. The histopathology of those fingerlings revealed a similar result. Both quantitative and qualitative data obtained by ELISA and FPLC showed elevated levels of vitellogenin in the fingerling stages after prolonged exposure to BPA present in the contaminated water. Our qRT-PCR data showed a subsequent increased expression of vitellogenin in those fingerlings obtained from contaminated effluent. FACS analysis suggested that BPA generated a significant amount of ROS in the livers of those fingerlings, leading to necrosis in hepatocytes.

We investigated the effect of Bisphenol-A (BPA) on the fingerlings of Oreochromis mossambicus collected from industrial waste.