Spinal Cord Diseases

Optimization of Microemulgel for Tizanidine Hydrochloride

Background: Tizanidine hydrochloride acts centrally as a muscle relaxant. It is used for the treatment of painful muscle spasm, spasticity associated with multiple sclerosis or spinal cord injury and treatment of muscle spasticity in spinal cord disease. Tizanidine hydrochloride belongs to BCS class II. It has low oral bioavailability and short halflife. Incorporating this drug in microemulgel is an excellent way to overcome problems associated with the drug.

Objectives: Present research work was aimed to develop and optimize a microemulsion based gel system for tizanidine hydrochloride.

Methods: Screening of oil, surfactant and co-surfactant was carried out. Ternary phase diagram was constructed to obtain concentration range of components. The prepared microemulsion was evaluated for pH, globule size, zeta potential, conductivity, density and viscosity. 32 level factorial design was applied to study the effect of concentration of carbopol 934 and HPMC K15M on % cumulative drug release and viscosity of microemulgel using software Design Expert. Microemulgel was evaluated for pH, spreadability, viscosity, syneresis, drug content, bioadhesive strength, in-vitro as well as ex-vivo diffusion study.

Results: Microemulsion was prepared by using isopropyl myristate as oil, tween 80 as a surfactant and transcutol P as cosurfactant. Largest transparent microemulsion region was found with Smix ratio of 1:1. FE-SEM showed globule size 28μm for batch B1 and zeta potential was -1.27mV indicating good stability of the microemulsion. Optimised batch was F6 which showed 92% drug release within 8 hours. It followed the Korsmeyer-Peppas model.

Conclusion: A stable, effective and elegant microemulgel formulation, exhibiting good in-vitro and ex-vivo drug release was formulated.

Evolving Insights into the Pathophysiology of Diabetic Neuropathy: Implications of Malfunctioning Glia and Discovery of Novel Therapeutic Targets

Diabetic neuropathy subsequent to chronic high blood glucose-induced nerve damage is one of the most frustrating and debilitating complications of diabetes, which affects the quality of life in patients with diabetes. Approximately 60–70% of patients with diabetes suffer from a distal symmetrical form of mild to severe neuropathy that progresses in a fiber-length-dependent pattern, with sensory and autonomic manifestations predominating. High glucose and oxidative stress-mediated damage in neurons and glial cells, as well as neuroinflammation and crosstalk between these disease processes, have garnered immense attention as the essential mechanisms underlying the development and progression of diabetic neuropathy. Although the metabolic causes of diabetic neuropathy are well understood and documented, treatment options for this disorder are still limited, highlighting the need for further studies to identify new molecular and therapeutic targets. This review covers recent advances in our knowledge of the pathophysiology of diabetic neuropathy, discusses how persistent hyperglycemic conditions and malfunctioning glia drive disease progression, and finally explores the possibilities and challenges offered by several potential novel therapeutic targets for both preventing and reversing diabetic neuropathy.

Advanced Techniques for Imaging the Human Spinal Cord: Review of Literature

Despite the high sensitivity of magnetic resonance imaging (MRI) in detecting a wide spectrum of various pathological processes, the specificity of the method to differentiate among these pathologies and its ability to predict clinical outcomes has been rather below initial expectations. The main problem arises from the fact that most of the pathologies of the spinal cord manifest with a rather nonspecific increase of water protons, reflecting local oedema or gliosis. This is a common finding in most myelopathies, which does not allow a further differential diagnostic distinction in most cases. The use of contrast media improved the specificity of the method; however, it is still challenging to differentiate types of myelopathies. Advanced imaging methodologies such as functional MRI (fMRI), diffusion-weighted and -tensor imaging (DWI/DTI), Magnetic Resonance Spectroscopy (MRS) have been used in the evaluation of neurologic diseases in the brain and have gained increased acceptance among the clinicians for improving the specificity of MR technology and for their ability to better correlate with functional disabilities and clinical symptoms thus providing predictive information about potential outcome. Preliminary results show that, quantitative parameters extracted by these techniques from the spinal cord can provide surrogate markers of disability for determining prognosis as well. In this review, we focus on implementing advanced neuroimaging methodologies (DWI/DTI, fMRI and MRS) in imaging of the human spinal cord for better clinical assessment. Additionally, we review the recent imaging literature advances in this topics and their clinical applications.

Does Erythropoietin Always Win?

The synthesis of recombinant human erythropoietin has marked a turning point in the treatment of anaemia secondary to chronic kidney disease. However, the potentially fatal cardio- and cerebrovascular complications of the intake of high-doses of ESAs (erythropoiesis-stimulating agents), such as those observed in athletes who resort to doping, reason out the ever-prevalent debate concerning the balance between the risks and benefits of ESA administration for therapeutic purposes. Hence, there is still a discussion as to what values haemoglobin should ideally be maintained at. Additional concerns arise in cancer patients due to the ability of erythropoietin to act as an angiogenic and, in general, as a cell growth factor, because this might favour the progression of neoplastic disease. We summarized the prominent points of the latest guidelines on the management of anaemia in nephropathic patients, also identifying the possible risks that may result from the tendency to aim at too low haemoglobin levels.

Numerical Analysis of Ciliary Beat in Paramecium: Increasing Ciliary Spacing as a Low Energy Cost Method for Maneuvering

In recent years, a number of patents have been devoted to designing micro robots for minimally invasive therapies inspired by Paramecium. Paramecium changes its swimming direction due to application of an external magnetic or electric field. Changing ciliary beat direction and frequency have been identified as possible methods for maneuvering through water; however, effects of variations in ciliary spacing on swimming trajectory have been poorly studied. In this work, it is aimed to analyze the effects of adjusting the ciliary spacing on swimming trajectory. For determining the swimming trajectory, Paramecium membrane is discretized to boundary elements with length of 15μm on which there are 5 cilia beating in an effective and a recovery stroke. It is observed that increasing the ciliary spacing on the upper boundary by 5% for 0.35 seconds leads to a mean 10 degrees of Paramecium rotation. This proves that even a slight error in measuring this parameter leads to great errors in determining the swimming trajectory. Also, due to lower energy consumption, variations in ciliary spacing could be an optimum means for micro robotic maneuvering.

Molecular Genetics and Biomarkers of Polyglutamine Diseases

Polyglutamine diseases are hereditary neurodegenerative disorders caused by an abnormal expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract. To date, nine polyglutamine diseases are known: Huntingtons disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubralpallidoluysian atrophy (DRPLA) and six forms of spinocerebellar ataxia (SCA). The diseases are inherited in an autosomal dominant fashion except for SBMA, which shows an X-linked pattern of inheritance. Although the causative gene varies with each disorder, polyglutamine diseases share salient genetic features as well as molecular pathogenesis. CAG repeat size correlates well with the age of onset in each disease, shows both somatic and germline instability, and has a strong tendency to further expand in successive generations. Aggregation of the mutant protein followed by the disruption of cellular functions, such as transcription and axonal transport, has been implicated in the etiology of neurodegeneration in polyglutamine diseases. Although animal studies have provided promising therapeutic strategies for polyglutamine diseases, it remains difficult to translate these disease-modifying therapies to the clinic. To optimize “proof of concept”, the process for testing candidate therapies in humans, it is of importance to identify biomarkers which can be used as surrogate endpoints in clinical trials for polyglutamine diseases.

Current Clinical Applications of Botulinum Toxin

Botulinum toxin has long been known for its paralytic effects on the human voluntary musculature via inhibition of acetylcholine release at neuromuscular junctions. Its original clinical use for the treatment of strabismus has expanded significantly to include neurological conditions related to muscle hyperactivity and/or spasticity (e.g., dystonia, spasticity, tics, tremor, dysphonia). Recently, botulinum toxin has been shown to impact autonomic disorders by acting at acceptors on glands and smooth muscle, and consequently it has been used in the management of a number of other conditions including hypersecretory disorders, pain syndromes, detrusor sphinchter dyssenergia or overactivity and gastointestinal smooth muscle/sphincter spasm; it may also reduce pain in patients for whom it is used to treat these and other primary conditions. This article will review the pharmacology and formulations of botulinum toxins as well as data from clinical trials demonstrating their efficacy for numerous conditions based on their effects on cholinergic synapses outside the motor nervous system.

Skeletal Muscle in Motor Neuron Diseases: Therapeutic Target and Delivery Route for Potential Treatments

Lower motor neuron (LMN) degeneration occurs in several diseases that affect patients from neonates to elderly and can either be genetically transmitted or occur sporadically. Among diseases involving LMN degeneration, spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (Kennedys disease, SBMA) are pure genetic diseases linked to loss of the SMN gene (SMA) or expansion of a polyglutamine tract in the androgen receptor gene (SBMA) while amyotrophic lateral sclerosis (ALS) can either be of genetic origin or occur sporadically. In this review, our aim is to put forward the hypothesis that muscle fiber atrophy and weakness might not be a simple collateral damage of LMN degeneration, but instead that muscle fibers may be the site of crucial pathogenic events in these diseases. In SMA, the SMN gene was shown to be required for muscle structure and strength as well as for neuromuscular junction formation, and a subset of SMA patients develop myopathic pathology. In SBMA, the occurence of myopathic histopathology in patients and animal models, along with neuromuscular phenotype of animal models expressing the androgen receptor in muscle only has lead to the proposal that SBMA may indeed be a muscle disease. Lastly, in ALS, at least part of the phenotype might be explained by pathogenic events occuring in skeletal muscle. Apart from its potential pathogenic role, skeletal muscle pathophysiological events might be a target for treatments and/or be a preferential route for targeting motor neurons.

Current Advances in Delivery of Biotherapeutics Across the Blood-Brain Barrier

Significant efforts through genomic approaches have been dedicated toward the identification of novel proteinprotein interactions as promising therapeutic targets for indications such as Alzheimer's disease, Parkinson's disease and neuropsychiatric disorders. Additionally, the number of biotherapeutic agents entering the Pharmaceutical sector continues to increase and according to EvaluatePharma's “World Preview 2014” report, “the compounded annual growth rate of biologics is expected to be 8.5 percent from 2008-2014, eight to 10 times greater than the growth rate of small molecules”. However, there are limited examples of success in developing biotherapeutic modalities for central nervous system (CNS) diseases in the drug development pipeline. A primary reason for the lack of application of biotherapeutics to neuroscience targets, is that the blood-brain barrier (BBB) isolates and protects CNS structures creating a unique biochemically and immunologically privileged environment, therefore passage of macromolecules across this barrier has additional challenges. An understanding of the anatomical and physiological properties of this barrier with respect to penetration of biotherapeutics is presented in this review document.

In this summary, recent advances in biotherapeutic delivery mechanisms across the BBB including transcranial brain drug delivery, focused ultrasound technology, nasal delivery, absorptive endocytosis, and receptor mediated endocytosis are evaluated using an industrial perspective. With acknowledgement that each approach has advantages and disadvantages, this review discusses the opportunities and challenges that are encountered during application of these methods across a variety of therapeutic areas such as, pain, obesity, neuroscience, and oncology. Utilizing an industrial perspective, including consideration of cost of goods and commercial feasibility for these approaches, this review highlights technology features which would enable industry investments toward novel BBB delivery technologies for biologics. Through continued development and improvement of such technology, new therapeutic options to treat and potentially cure central nervous system diseases could eventually evolve.