Abstract
Background: No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking.
Methods: Single administration of buspirone/levodopa/carbidopa (SpinalonTM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration. Results: SpinalonTM (10-35 mg buspirone/100-350 mg levodopa/25-85 mg carbidopa) displayed no sign of safety concerns - only mild nausea was found in 3 cases. At higher doses, 50 mg/500 mg/125 mg SpinalonTM was considered to have reached maximum tolerated dose (MTD) since 3 out of 4 subjects experienced related adverse events including vomiting. PK analyses showed comparable data between groups suggesting no significant drugdrug interaction with SpinalonTM. Only the SpinalonTM–treated groups displayed significant EMG activity accompanied by locomotor-like characteristics - that is with rhythmic and bilaterally alternating bursts. Conclusion: Therefore, this study provides evidence of safety and preliminary efficacy following a single administration of SpinalonTM in subjects with SCI.Keywords: Locomotion, drug treatment, paraplegia, tetraplegia, spinal locomotor neurons, Electromyographic (EMG).
Current Pharmaceutical Design
Title:Double-Blind, Placebo-Controlled, Randomized Phase I/IIa Study (Safety and Efficacy) with Buspirone/Levodopa/Carbidopa (SpinalonTM) in Subjects with Complete AIS A or Motor-Complete AIS B Spinal Cord Injury
Volume: 23 Issue: 12
Author(s): Mohan Radhakrishna*, Inge Steuer, Francois Prince, Mary Roberts, David Mongeon, Maryam Kia, Sasha Dyck, Gilbert Matte, Mario Vaillancourt and Pierre A. Guertin*
Affiliation:
- Research Institute of the McGill University Health Centre (MUHC), Department of Medicine, McGill University, Montreal, QC,Canada
- CHUQ-CHUL, Neurosciences Unit, RC-9800, 2705 Laurier Boulevard, Quebec City, QC, Canada, G1V 4G2,Canada
Keywords: Locomotion, drug treatment, paraplegia, tetraplegia, spinal locomotor neurons, Electromyographic (EMG).
Abstract: Background: No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking.
Methods: Single administration of buspirone/levodopa/carbidopa (SpinalonTM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration. Results: SpinalonTM (10-35 mg buspirone/100-350 mg levodopa/25-85 mg carbidopa) displayed no sign of safety concerns - only mild nausea was found in 3 cases. At higher doses, 50 mg/500 mg/125 mg SpinalonTM was considered to have reached maximum tolerated dose (MTD) since 3 out of 4 subjects experienced related adverse events including vomiting. PK analyses showed comparable data between groups suggesting no significant drugdrug interaction with SpinalonTM. Only the SpinalonTM–treated groups displayed significant EMG activity accompanied by locomotor-like characteristics - that is with rhythmic and bilaterally alternating bursts. Conclusion: Therefore, this study provides evidence of safety and preliminary efficacy following a single administration of SpinalonTM in subjects with SCI.Export Options
About this article
Cite this article as:
Radhakrishna Mohan*, Steuer Inge, Prince Francois, Roberts Mary, Mongeon David, Kia Maryam, Dyck Sasha, Matte Gilbert, Vaillancourt Mario and Guertin A. Pierre*, Double-Blind, Placebo-Controlled, Randomized Phase I/IIa Study (Safety and Efficacy) with Buspirone/Levodopa/Carbidopa (SpinalonTM) in Subjects with Complete AIS A or Motor-Complete AIS B Spinal Cord Injury, Current Pharmaceutical Design 2017; 23 (12) . https://dx.doi.org/10.2174/1381612822666161227152200
DOI https://dx.doi.org/10.2174/1381612822666161227152200 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Microglial Senescence
CNS & Neurological Disorders - Drug Targets Neurodegeneration with Dementia: From Fundamentals of Pathology to Clinical Imaging by MRI and SPECT.
Current Medical Imaging Zolpidem Arousing Effect in Persistent Vegetative State Patients: Autonomic, EEG and Behavioral Assessment
Current Pharmaceutical Design Editorial (Thematic Issue: Linkage of CNS and Immunology with Psychology: Searching for New Pharmacological Targets)
CNS & Neurological Disorders - Drug Targets The Role of Pericytes in Blood-Brain Barrier Function and Stroke
Current Pharmaceutical Design IAPs, their Antagonists and their Role in Neurological Disease and Cancer
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Combining Angiogenesis Inhibitors with Radiation: Advances and Challenges in Cancer Treatment
Current Pharmaceutical Design HTLV-1 Associated Neurological Disorders
Current Topics in Medicinal Chemistry Interpreting the Mechanisms by which Integrins Promote the Differentiation of Mesenchymal Stem Cells and Integrin Application Prospects
Current Stem Cell Research & Therapy A Review on Clinical Management and Pharmacological Therapy on Hereditary Haemorrhagic Telangiectasia (HHT)
Current Vascular Pharmacology Subject Index to Volume 2
Current Medicinal Chemistry - Cardiovascular & Hematological Agents Role of the Osteochondral Unit in the Pathogenesis of Osteoarthritis: Focus on the Potential Use of Clodronate
Current Rheumatology Reviews Polypeptide Delivery Across The Blood-Brain Barrier
Current Drug Targets - CNS & Neurological Disorders Biological Implications of Oxidation and Unidirectional Chiral Inversion of D-amino Acids
Current Drug Metabolism The Many Roles of Chemokine Receptors in Neurodegenerative Disorders: Emerging New Therapeutical Strategies
Current Medicinal Chemistry The Effect of Bisphosphonates on Managing Osteoporosis After Spinal Cord Injury: A Meta-Analysis
Current Pharmaceutical Design Lipidomics as Tools for Finding Biomarkers of Intestinal Pathology: From Irritable Bowel Syndrome to Colorectal Cancer
Current Drug Targets Current Update on Synopsis of miRNA Dysregulation in Neurological Disorders
CNS & Neurological Disorders - Drug Targets Organic Toxins as Tools to Understand Ion Channel Mechanisms and Structure
Current Topics in Medicinal Chemistry The Effect of Spinal Cord Injury on Beta-Amyloid Plaque Pathology in TgCRND8 Mouse Model of Alzheimer’s Disease
Current Alzheimer Research