Pascal J.D. Grolaux

Department of Osteopathy, Kinesis Health Associates, 2d floor, 155 Ochterloney Street, Dartmouth, B2Y1C9, Nova Scotia, Canada

Background: Generalized anxiety disorder (GAD), chronic pain (CP) and irritable bowel syndrome (IBS) are debilitating inflammatory disorders that are frequently seen in primary care facilities but not sufficiently addressed by classical medical treatments. Transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic tool for a wide range of conditions that showed already encouraging clinical results. However, the effects of tVNS, on GAD, IBS and CP, were not yet explored in the context of an investigation conducted in a private healthcare center.

Objective: In an uncontrolled, open label, small investigation scale study, we investigated the feasibility, safety and the effects of tVNS for patients suffering from GAD, CP and IBS in a multidisciplinary healthcare center.

Methods: The effects of tVNS on GAD, CP and IBS in 10 participants (anxiety, 40%; chronic pain, 30%; IBS, 30%) were investigated during a 4-week period and a 2-month follow-up. GAD, CP and IBS were assessed using the Generalized Anxiety Disorder GAD-7, the Brief Pain Inventory Short Form questionnaire and the Irritable Bowel Syndrome Severity Scoring System. Transcutaneous vagus nerve stimulation was performed using a transcutaneous electrical nerve stimulation device and ear clip electrodes plugged in the concha area of the ear. All participants, received a bi-weekly 30-minute stimulation for 4 weeks. The tVNS parameters, (GAD: 20Hz-80µs), (CP: 5Hz-200 µs), (IBS: 3Hz-250µs), were set for each group to target different physiological effects meditated by the vagus nerve.

Results: The anxiety and the IBS group showed a non-statistically significant improvement but an improved clinical status (mean score from “severe” to “moderate”) both at the end of the stimulation period (4 weeks) and at 2-month follow-up. The CP group didn’t show any significant clinical improvement (mean score from “moderate” to “moderate”). Furthermore, tVNS was demonstrated to be likely safe and was well tolerated.

Conclusions: Due to low sample size, this study failed to demonstrate significant clinical effects of tVNS on GAD, IBS and CP. However, trend analysis may carefully suggest tVNS to be a noteworthy clinical alternative to be used in private healthcare center in the treatment of chronic inflammation disorders like GAD and IBS. Acute tVNS was well-tolerated and is likely safe. Powerful, double-blind controlled studies are needed to support the use of tVNS on these disorders.

Clinical Trial Registration: http:/www.clinicaltrials.gov. Unique identifier: NCT03440255.

Abbreviations: α7nAChR, alpha7 nicotinic acetylcholine receptor; ABVN, auricular branch of the vagus nerve; CAN, central autonomic network; CAP, cholinergic anti-inflammatory pathway; CP, chronic pain; DMVN, dorsal motor nucleus of the vagus; GABA, γ-aminobutyric acid; GAD, general anxiety disorder; HR, heart rate; HPA, hypothalamic pituitary adrenal; HRV, heart rate variability; IBS, irritable bowel syndrome; IL, Interleukin; fMRI, functional magnetic resonance imagery; NF-κB, nuclear factor kappa B; NTS, nucleus tractus solitarius; pNN50, percentage of successive R-R intervals that differ by more than 50ms from the preceding one; PW, pulse width; RMSSD, root mean square of successive R-R interval differences; RR, respiratory rate; RSA, respiratory sinus arrhythmia; SD1, standard deviation of the distance of each point from the y = x axis in a Poincaré plot; TENS, transcutaneous electrical nerve stimulation; TNF, tumor necrosis factor; VN, vagus nerve; nVNS, non-invasive vagus nerve stimulation; tVNS, transcutaneous vagus nerve stimulation.

DOI: 10.29245/2572.942X/2019/5.1251 View / Download Pdf

Lisa M. James1,2,3,4, Apostolos P. Georgopoulos1,2,3,4,5*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

4Center for Cognitive Sciences, University of Minnesota, Minneapolis, MN 55455, USA

5Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Human Leukocyte Antigen (HLA) Class II DRB1*13 alleles have recently been found to protect against age-related brain deterioration, even in the presence of apolipoprotein E4 (apoE4),1,2 suggesting a possible protection against dementia. Here we evaluated the association between the population frequency of common DRB1*13 alleles and the prevalence of dementia in Continental Western Europe. Prevalence of dementia in Continental Western Europe was derived from published reports on dementia frequency from the Global Burden of Disease Study 2016 and population totals obtained from the Population Reference Bureau. DRB1*13:01 and DRB1*13:02 allele frequencies were obtained from a publicly available database (allelefrequency.net) and apolipoprotein E was obtained from published reports on the world distribution of apoE4. The prevalence of dementia in 14 Continental Western European (CWE) countries, where life expectancy is practically identical, significantly decreases exponentially with increasing frequency of DRB1*13:02 (R2 = 0.452, P = 0.008), even when adjusted for the prevalence of apolipoprotein E4 allele, a known risk factor for Alzheimer’s disease. This finding documents the protective effect of DRB1*13:02 on dementia prevalence in CWE. Since the function of HLA class II genes is to aid in the elimination of pathogens by enabling the production of antibodies against their antigens in specific immunity, the protective effect of DRB1*13:02 points to the presence of persistent harmful antigens as causal factors in development of dementia, antigens specific to DRB1*13:02 that could not be eliminated in its absence.

DOI: 10.29245/2572.942X/2019/5.1253 View / Download Pdf

Uwe Ernsberger

Institute for Clinical Neuroanatomy, Johann-Wolfgang-Goethe University, Frankfurt/Main, Germany

The molecular characterization of postganglionic sympathetic neurons by RNA sequencing has allowed the full assessment of gene expression in individual cells and classification of neurons into subpopulations defined by their gene expression profile and developmental history. The identification of growth factor receptor subunits specifically expressed by select neuron subpopulations enabled the demonstration of GDNF family ligands and the respective receptor subunits as instrumental in the innervation of certain targets. These are first critical steps in the attempt to characterize the molecular processes leading to the establishment and maintenance of target-specific sympathetic efferent pathways.

DOI: 10.29245/2572.942X/2019/4.1252 View / Download Pdf

Jerrod Brown1,2,3*, Diane Harr1

1Concordia University, St. Paul, MN, USA

2Pathways Counseling Center, Inc., St. Paul, MN, USA

3American Institute for the Advancement of Forensic Studies, St. Paul, MN, USA

Traumatic brain injuries (TBI) are a major community health problem in the United States. Traumatic brain injury can result in disruption to normal brain functions and is caused by a bump, blow, or external damage to the head. Ranging from mild to severe in nature, TBIs can result in physical, cognitive, emotional, social, personality, adaptive, and behavioral changes in an individual. These devastating symptoms contribute to individuals with TBIs having the potential for a host of short and long-term issues. Traumatic brain injury can result in cognitive impairments, including disinhibition and risky decision-making behaviors, thus increasing the risk of substance abuse. Because many people do not have visible or physical signs, TBI can be difficult to screen, assess, and diagnose. Despite these difficulties, mental health and substance use disorder professionals can make a positive difference for clients with traumatic brain injury. As such, the current study examines the experiences and perceptions of TBI among treatment staff of Vinland National Center, a substance use disorder treatment facility in Minnesota. Results of this study raise awareness of the challenges of TBI in drug and alcohol treatment centers and offer tips, strategies, and solutions for professionals working with this clientele.

DOI: 10.29245/2572.942X/2019/3.1248 View / Download Pdf

Rémy Cohan2,8, Karolina A. Bearss1,2,4,6, Joseph F.X. DeSouza1-8

1Centre for Vision Research, York University, Canada

2Department of Psychology, York University, Canada

3Department of Biology, York University, Canada

4Neuroscience Graduate Diploma Program, York University, Canada

5Interdisciplinary Graduate Studies, York University, Canada

6Canadian Action and Perception Network (CAPnet), York University, Canada

7Vision: Science to Applications (VISTA) Program, York University, Canada

8Multisensory Neuroscience Laboratory, York University, Canada

Despite advancement in neuroimaging, the link between motor and cognitive processes, and the role of oscillations in motor behaviour remain unclear. Current research in neurodegenerative disorders (e.g., Parkinson’s and Alzheimer’s disease) indicates that changes in oscillatory brain rhythms (OBRs) observed from electroencephalographic (EEG) studies could be utilized to quantify and understand the neural network changes in the presence of pathology. Research suggests, that rhythmicity is a common feature amongst biological entities, and cyclic fluctuations in neurological systems in response to incoming stimuli from the environment, grant a great degree of flexibility to such systems in order to interact with their surroundings at an optimal level. This reciprocity between exogenous stimuli and endogenous mechanisms in the brain creates a two-way pathway that awards a bi-directional relationship between the environment, and the brain. Here, in this mini review we explore the role of OBRs, and review the current literature supporting the putative role of frequency-specific OBRs as potential biomarkers in neurodegenerative disorders, mainly Parkinson’s disease (PD), which in turn, may allow clinicians to identify effective therapies based on these biomarkers, expanding the armamentarium for delaying the rate of disease progression and symptom management.

DOI: 10.29245/2572.942X/2019/3.1207 View / Download Pdf

Hannah C. Saternos1 and Wissam A. AbouAlaiwi1*

1University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental Therapeutics, Toledo, Ohio, USA

DOI: 10.29245/2572.942X/2019/2.1250 View / Download Pdf

Lisa M. James1,2,3, Brian E. Engdahl1,2,4, Rachel A. Johnson1, Apostolos P. Georgopoulos1,2,3,4,5*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 5541, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

4Department of Psychology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

5Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Gulf War Illness (GWI) is a chronic multi-system condition that has affected one-third of U.S. veterans who served in the Persian Gulf. Although GWI etiology remains unclear, mounting evidence points to immune system involvement and inflammation, in particular, as underlying the host of symptoms associated with the condition. Here we investigated the association between GWI symptoms and C-reactive protein (CRP), a marker of inflammation, in 76 veterans with GWI. Results indicated a highly significant positive association between CRP and mean GWI symptom severity. At the symptom domain level, CRP was significantly and positively associated with Pain, Neurocognitive/Mood, Fatigue, and Respiratory symptom severity but not with Skin or Gastrointestinal symptom severity. These results support the premise that GWI symptoms, particularly those implicating brain involvement, are a result of neuroinflammation. The cause for inflammation is not known. We have hypothesized that at the root of GWI are harmful persistent antigens stemming from environmental exposures associated with service during the Gulf War that could not be successfully eliminated due to lack of specific immunity1,2. Work is underway in our laboratory to identify and eliminate persistent antigens in veterans with GWI which we anticipate will result in reduced inflammation and reduced GWI symptoms.

DOI: 10.29245/2572.942X/2019/2.1245 View / Download Pdf

Ashutosh Gupta1*, Suman Kushwaha2

1Department of Neurology, Institute of Human Behavior and Allied Sciences, Delhi, India

DOI: 10.29245/2572.942X/2019/2.1244 View / Download Pdf

F. Haour1*, E. Dobbelaere1,2, C. de Beaurepaire3

1EMDR France Association, 9 rue Papillon, 75009 Paris, France

2Université Paris 5, 75006 Paris, France

3EPS of Maison-Blanche, 6-10, Pierre-Bayle Street, 75020 Paris, France

DOI: 10.29245/2572.942X/2019/2.1234 View / Download Pdf

Palalle G. Tharushi Perera1, Olha Bazaka2, Kateryna Bazaka3, Dominique Appadoo4, Rodney J. Croft5, Russell J. Crawford2, Elena P. Ivanova2*

1Faculty of Science, Engineering and Technology, Swinburne University of Technology, PO Box 218, Hawthorn, Vic 3122, Australia

2School of Science, RMIT University, PO Box 2476, Melbourne, Vic 3001, Australia

3Institute for Future Environments, Queensland University of Technology, GPO Box 2434. Brisbane, QLD 4001, Australia

4THz/Far-Infrared Beamline, Australian Synchrotron, Clayton, VIC 3168, Australia

5School of Psychology, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia

Pheochromocytoma PC 12 cell line is an established model system for neurosecretion and neuronal differentiation, particular to study cellular responses to nerve growth factors (NGF) and how these lead to expression of differentiation-specific proteins and differentiation. More recently, PC 12 has become a model system for investigating cell membrane permeabilization and cell attachment on different substrata. Of particular interest is the use of PC 12 to study the fundamental responses of cells to electromagnetic fields (EMFs) of 18 GHz and THz in the range of 0.3-19.5×1012 Hz, a type of radiation treatment shown to induce membrane depolarization and transient increase in permeability with no changes in cell viability, morphology, proliferation and cellular physiology. This makes EMFs of 18 GHz and THz radiation a promising alternative to conventional poration techniques for drug and gene delivery applications. This article will review recent progress in the use of PC 12 to investigate EMF radiation-induced cell membrane permeability, as well as to study mammalian cell attachment preferences and differentiation on polymer surfaces, including those coated with high molecular weight proteins of the extracellular matrix, e.g. laminins, poly-l-lysine, fibronectin, and on novel metallic surfaces of nanostructured titanium.

DOI: 10.29245/2572.942X/2019/1.1240 View / Download Pdf

Yoshikuni Mizuno

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

In 2018, we wrote a paper on the drug treatment of Parkinson's disease. In this article, we obtained that the wearing off was observed in 77%, but the incidence of dyskinesia was 37.7% for the Parkinson?s disease patients from the onset of the disease 16-20 years. In this review article, we will discuss some of the newer treatments of Parkinson?s disease first, i.e., transplantation with induced pluripotent stem cell-derived cells, gene therapy, deep brain stimulation, levodopa/ carbidopa intrajejunal gel infusion, MRI-supported focused ultrasound, and IPX066. Then, we will discuss our opinion on the mechanism of wearing off and dyskinesia, and modifications of levodopa treatment after the wearing off sets in.

DOI: 10.29245/2572.942X/2019/1.1241 View / Download Pdf

Marianna Stamou1, Pamela J Lein2

11Department of Molecular Biosciences, School of Veterinary Medicine, 1089 Veterinary Medicine Drive, University of California, Davis, CA 95616

22ETH Zurich, Department of Health Sciences and Technology, Institute of Molecular Systems Biology, 8093 Zürich, Switzerland

DOI: 10.29245/2572.942X/2019/1.1243 View / Download Pdf

Monica Ines1, Joao Costa1,2,3*

1Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal

2Laboratório de Farmacologia Clínica e Terapêutica, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal

3Centro de Estudos de Medicina Baseada na Evidência, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal

Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is a neurological disease that affects severely patients and their families and caregivers over generations. It is a rare, progressive, and if untreated fatal autosomal dominant hereditary disorder. The disease may affect multiple organ systems and if untreated progress rapidly to death. TTR-FAP affects nearly 10,000 people worldwide, with known endemic regions in Portugal, Sweden, and Japan. Until recently only liver transplantation and tafamidis were treatment options across several world regions. Despite the worldwide use of these disease-modifying treatments to delay disease progression, challenges in clinical assessment and management remain because of disease heterogeneity, phenotypic diversity, small patient populations, incomplete natural history and uncertainty of treatment effect in survival. The two new treatment options (inotersen and patisiran) appear to provide important benefits for patients, based on clinical trials short-term evidence. In this review, we discuss the disease natural survival course and currently available treatments impact on survival. We also discuss the importance of treatment choice (and or sequence of treatments) to maximize survival, while preserving the patient’s health-related quality of life.

DOI: 10.29245/2572.942X/2019/1.1242 View / Download Pdf

Tehila Beiser, Rami Yaka*

Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel

Cocaine is a powerfully addictive psychostimulant that elevates dopamine (DA) levels in the mesolimbic system and causes a feeling of wellbeing. At the same time, cocaine leads to toxic effects in many essential organs, including the brain. The harmful effects of cocaine on the brain are the basis for the development of compulsive and irrational behaviors, an integral part of cocaine addiction. Over the last two decades, it has been suggested that the damage and reinforcing properties of cocaine are associated with increased reactive oxygen species (ROS) production. This increase impairs the endogenous defense antioxidant system, either directly by cocaine metabolites, or indirectly via increased DA metabolites, resulting in oxidative stress (OS). It was thus plausible to seek an exogenous, stable and non-toxic antioxidant, which can penetrate the blood brain barrier and counteract the oxidative damage in the brain caused by drugs of abuse such as cocaine. In this mini-review we describe studies that explore the role of antioxidants in reducing the OS state in the brain reward system and consequently reversing negative behavioral outcomes induced by cocaine.

DOI: 10.29245/2572.942X/2019/1.1239 View / Download Pdf

John Grizzanti1, Rachel Corrigan1, Spencer Servizi1, Gemma Casadesus1,2*

1School of Biomedical Sciences, Kent State University, Ohio, USA

2Department of Biological Sciences, Kent State University, Ohio, USA

Growing evidence highlights the intimate relationship between type II diabetes (T2D) and Alzheimer’s disease (AD). Importantly, these two diseases share a number of pathological similarities, including amyloid accumulation, oxidative stress, inflammation, and cell death. To date, drug therapies for AD and T2D are lacking and there is a crucial need for the discovery and development of novel therapeutics for these diseases. A number of human and rodent studies have given evidence that metabolic hormone supplementation is highly valuable for improving cognitive function and overall metabolic health in both T2D and AD. The pancreatic hormone amylin has arisen as a crucial component of the disease etiology of both T2D and AD, though the exact role that amylin plays in these diseases is not yet well understood. Here, we critically review the current literature that utilizes human amylin or its synthetic analogue, pramlintide, as well as amylin receptor antagonists for the treatment of AD.

DOI: 10.29245/2572.942X/2019/1.1212 View / Download Pdf

Genki Tohnai1, Ryoichi Nakamura1, Masahiro Nakatochi2, Naoki Atsuta1, Masahisa Katsuno1, Gen Sobue1,3*

1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Statistical Analysis Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

3Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, Nagoya, Japan

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, and the etiology of sporadic ALS is unknown. The TANK-binding kinase 1 (TBK1) gene identified as an ALS gene, contributes towards a predisposition for ALS. In this review, we analyzed variants of TBK1 found in ALS cohort studies belonging to various regions and ethnic populations. TBK1 variants tend to be enriched in patients with ALS compared to patients without ALS. The frequency of TBK1 variants is more in the familial Caucasian than that in the Asian population. However, loss of function (LoF) variant associated with sporadic ALS is almost similar among the Asian group, including Japanese population. LoF variants were frequently reported to be associated with the TBK1 biology. These findings indicate that TBK1- LoF variants are pathogenic for ALS, regardless of race or region.

DOI: 10.29245/2572.942X/2019/1.1236 View / Download Pdf

Renata M. Lataro1, Helio C. Salgado2*

1Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil

2Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

There is a consensus in the literature that the autonomic dysfunction in arterial hypertension involves the increase of sympathetic activity and, also, reduction of vagal tone. In the last years, the role played by inflammation in the development of hypertension and target organs injuries, such as heart and blood vessels, has been emphasized. Although the clinical importance of sympathetic hyperactivity and its treatment of arterial hypertension is recognized, the therapeutic benefit of increasing parasympathetic activity in hypertensive patients still requires an in-depth investigation. The increased vagal activity may produce beneficial effects on cardiovascular modulation and inflammation, preventing target organ damage. Parasympathetic neurotransmission can be improved by the inhibition of acetylcholinesterase action. Anticholinesterase agents prevent the hydrolysis of acetylcholine by acetylcholinesterase, prolonging its availability within the cholinergic cleft. This article will highlight the key concepts of the cardiac autonomic imbalance and the increase of acetylcholine availability under inflammation and control of arterial hypertension. In conclusion, significant evidence exists associating the reduction of parasympathetic activity and the occurrence of inflammation involving the pathophysiology of hypertension; suggesting that the improvement of vagal activity by the increased availability of acetylcholine has a remarkable potential for the therapeutic intervention on arterial hypertension.

DOI: 10.29245/2572.942X/2018/6.1226 View / Download Pdf

Lisa M. James1,2,3, Apostolos P. Georgopoulos1,2,3,4*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

4Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

DOI: 10.29245/2572.942X/2018/6.1235 View / Download Pdf

George Stoica1*, Heidi Martini-Stoica2

1Texas A&M University, College Station, TX,USA

2Baylor College of Medicine, Houston, TX, USA

DOI: 10.29245/2572.942X/2018/6.1231 View / Download Pdf

Hildegard M. Schuller

Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville TN, USA

DOI: 10.29245/2572.942X/2018/6.1230 View / Download Pdf

Toshiyuki Mizui1, 2*, Masami Kojima1,2,3#

Biomedical Research Inst. (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka, 563-8577 Japan

Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, 332-0012, Japan

Graduate School of Frontier Bioscience, Osaka University, Suita 565-0871, Japan

Most growth factors are initially synthesized as precursors. To produce biologically active mature peptides, the pro-domain is cleaved by proteolytic processing. However, compared with mature bioactive growth factors, the biological roles of pro-domains are poorly understood. Recent new findings on brain-derived neurotrophic factor (BDNF), a growth factor in the brain that promotes neuronal survival, differentiation, and synaptic plasticity, have been reported. Interestingly, the pro-domain (pro-peptide) of BDNF is endogenously present and localized at presynaptic termini, where it surprisingly functions as a facilitator of long-term depression (LTD). Given that BDNF elicits synaptic transmission and long-term potentiation (LTP), BDNF and its pro-peptide might exert distinct roles in synaptic plasticity in the central nervous system (CNS). In addition to reports on the BDNF pro-peptide, we review recent literature on the role of BDNF in the peripheral nervous system (PNS), and in brain-body interactions following exercise. Together, these findings provide new insight into BDNF biology.

DOI: 10.29245/2572.942X/2018/6.1228 View / Download Pdf

Ido Rippin, Hagit Eldar-Finkelman*

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel

DOI: 10.29245/2572.942X/2018/6.1227 View / Download Pdf

Qin Wang, Richard Grater*, Luisette Delva, Elvana Veizaj, Cheryl Black, Chris Rowbottom, Roger Rusesabagina, Ellen Rohde, Patricia Schroeder, Tonika Bohnert, Guangqing Xiao

Preclinical Pharmacokinetics and In Vitro ADME, Biogen Inc. 225 Binney St Cambridge, MA 02142, USA

Objective: The convective flow of CSF plays a crucial role for CNS to clear endogenous and xenobiotic substances. The objective of this study is to investigate the impact of modifying CSF flow with acetazolamide and arginine vasopressin (AVP) on the CNS clearance of ibuprofen and acetaminophen.

Results: Microdialysis studies indicated that acetaminophen AUC ratio (Kp,uu) between brain ISF and unbound plasma increased from 0.40 ± 0.14 in the vehicle control group to 0.60 ± 0.27 in the acetazolamide treated group (P < 0.05). Conversely, acetaminophen’s steady-state ISFC to unbound_plasmaC ratio (Kp,uu) decreased from 0.44 ± 0.08 to 0.36 ± 0.07 upon IV infusion of 0.3 µg/hr AVP (P < 0.05). Using CSF concentration as a surrogate of unbound brain drug concentration, AVP treatment reduced the CSFAUC0-5hr/unbound_plasmaAUC0-5hr ratio from 1.63 to 0.85 for acetaminophen, and the CSFC4hr / unbound_plasmaC4hr ratio decreased from 0.91 ± 0.27 to 0.54 ± 0.12 for ibuprofen (P < 0.05).

Conclusion: We have demonstrated that acetazolamide decreases the CNS clearance of acetaminophen, while AVP increases the CNS clearance of both acetaminophen and ibuprofen. Such changes are caused by altering the CSF production rates.

DOI: 10.29245/2572.942X/2018/5.1217 View / Download Pdf

Laxminarayan Bhat*, Marc Cantillon, and Robert Ings

Reviva Pharmaceuticals, Inc., Sunnyvale, CA, USA

Schizophrenia is a condition comprising of both treatment and comorbidity factors that both complicate its management and present multiple unmet needs. Brilaroxazine (RP5063), a dopamine (D)/serotonin (5-HT) modulator, possesses a broad in vitro pharmacology profile against D2/3/4 and 5-HT1A/2A/2B/6/7 receptors, nicotinic acetylcholine (α4β2) receptors, and the serotonin transporter. In Phase 1 and 2 clinical experience in healthy volunteers, patients with schizophrenia and schizoaffective disorder, brilaroxazine was well tolerated, with the repeated 100 mg oral dose as the maximum tolerated dose. Investigators observed no cardiometabolic, cardiovascular, prolactin, or neurologic complications. Adherence in Phase 2 was good with discontinuation rates generally less than placebo. In a Phase 2 evaluation of patients with acute exacerbations in schizophrenia and schizoaffective disorders, brilaroxazine met its primary endpoint of significance versus placebo for Total Positive and Negative Symptom Scale (PANSS) Score at Day 28 as compared to baseline. In Phase 1 multi-dose pharmacodynamic evaluation, brilaroxazine displayed clinical activity in patients with stable disease and a PANSS greater than 50, as early as Day 10 of treatment. Pharmacokinetic analyses demonstrated brilaroxazine to have a substantial and relatively rapid oral absorption, linear (dose proportional) increases in maximum concentration (Cmax) and area under the curve (AUC), lack of excessive accumulation, and a relatively long terminal half-life of about 60 hours. Early clinical findings with brilaroxazine in schizophrenia and schizoaffective disorders indicate that this compound appears to be effective, well tolerated, and possess a straightforward once-daily dosing pharmacokinetic profile.

DOI: 10.29245/2572.942X/2018/5.1225 View / Download Pdf