Frontiers in Clinical Drug Research - CNS and Neurological Disorders

Affecting more than 50 million people worldwide and with high global costs annually, neurological disorders such as Alzheimer's disease (AD) and Parkinson’s disease (PD) are a growing challenge all over the world. Globally, only in 2018, AD costs reached an astonishing $ 1 trillion and, since the annual costs of AD are rapidly increasing, the projections estimate that these numbers will double by 2030. Considering the industrial perspective, the costs related to the development of new drugs are extremely high when compared to the expected financial return. One of the aggravating factors is the exorbitant values for the synthesis of chemical compounds, hindering the process of searching for new drug candidates. In the last 10-year period, an average of 20 to 40 new drugs were approved per year, representing a success rate of less than 6%. However, the number of referrals for new drug orders and/or applications remained at approximately 700 each year, reinforcing the difficulty in the process of identifying and developing novel drugs. Regarding neurodegenerative diseases, the FDA (USA) approved 53 new therapies in 2019, including 48 new molecules and, from these, three are medicines and two are vaccines. The main drugs recommended for the treatment of these disorders are included in the following classes: Dopamine supplement (Levodopa), Monoamine oxidase (MAO) inhibitor (Selegiline, Rasagiline), Dopamine agonist (Apomorphine, Pramipexole), and Acetylcholinesterase inhibitor (Donepezil, Rivastigmine, Galantamine). Additionally, the current pharmacological treatments are not able to cure these patients and considering the etiological complexity and the prevalence of neurological disorders, scientists have a great challenge in exploring new therapies and new molecules to find an adequate and viable treatment for these diseases. Clinical trials are essential in this process and thus, this chapter describes the most important drugs that were targets of phase III and IV clinical studies in the last five years, associated with the most common neurological disorders worldwide, AD and PD. Information about mechanisms of action, experimental studies in other diseases that support their use, and chemical structure of the drugs are included in this chapter. Additionally, nature as a source of valuable chemical entities for PD and AD therapeutics was also revised, as well as future advances in the field regarding tracking new drugs to get successful results and critical opinions in the research and clinical investigation.

Placebo is defined as the therapeutic response to inert treatment. However, this is a bit simplistic because comprehending the biological basis of the placebo effect requires understanding the entire therapeutic context and the patient immersed in it. Placebo does not cure the disease but alleviates symptoms. The placebo impact must be seen in the context of the recipients’ cultural milieu, psychosocial background, the tone and tenor of the accompanying verbal communication (caring, indifferent, unfriendly), therapeutic rituals (e.g., tablet, injection, or a procedure, including diagnostic tests), symbols (white coat, syringe, the diagnostic paraphernalia), and its meanings to the patient (past experiences and personal hope). Placebo is the inert treatment juxtaposed against the broad context of the accompanying sensory and sociocultural inputs that signal benefit. It could also be the harm in the case of nocebo. A major objective of a standard clinical trial is to eliminate or at least minimise the influence of placebo. Many methods have been devised to measure and eliminate placebo responders in the trial populations. The neurological basis of the placebo effect is complex and must have an evolutionary basis because the susceptibility to placebos may be traced back to animals and birds. The placebo effect probably owes its evolutionary origin to signalling sickness and the ability to draw comfort from winning sympathetic attention and care from conspecifics. Pain being a complex sensory experience with a strong affective component, the neuronal pathways that reflect both sensory experience and the affective components have been explored in the study of the placebo effect. Placebo research, having expanded from psychology to neurology, presently involves research tools that include pharmacology, brain imaging, genetics, animal models, etc. This review will discuss multiple dimensions of the placebo effect, including evolutionary, cultural, psychosocial, and neurological aspects, in addition to providing cues for transformational implications in clinical trials and therapeutic modalities that benefit society. Contemporary medicine is demonising placebo because it is a confounder in clinical trials. It would be much more useful if the healthcare system can harness the therapeutic potential of the placebo effect by manipulating the therapeutic context.

The prevalence of neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple sclerosis (MS) are growing in the world, but their pathogenesis is unclear and effective treatment does not exist. Neuroinflammation is associated with many neurodegenerative mechanisms involved in neurodegenerative diseases. The human gut microbiota is an aggregate of microorganisms that live in the gastrointestinal tract (GIT) that plays a crucial role in maintaining human health and the pathogenesis disease condition. The microbiota can affect neuronal function through neurotransmitters, vitamins, and neuroactive microbial metabolites like shortchain fatty acids. The change in gut microbiota architecture causes increased permeability of the intestine and immune system activation, contributing to systemic inflammation, neurological injury, and eventually neurodegeneration. Available data suggest that the microbiota send signals to the central nervous system (CNS) by activating afferent neurons of the vagus nerve via neuroendocrine and neuroimmune pathways. The molecular interaction between the gut/microbiome and CNS is complex and bidirectional, ensuring gut homeostasis and proper digestion. Evidence suggests that dysfunction of the gut-brain axis could be a significant factor leading to many disorders of CNS. In this chapter, we explore how the gut microbiome may affect brain function and the development of neurological disorders. In addition, we are also trying to highlight the recent advances in improving neurological disease by supplemental probiotics and faecal microbiota transplantation via the concept of the gut-brain axis to combat brain-related dysfunction.

Pediatric tumors of the central nervous system (CNS) are the second most common type of solid childhood cancer. As such, they have a major effect on the rates of morbidity and mortality in children. CNS tumors originate from abnormal cells in the brain and/or spinal cord, which can be classified as either benign or malignant. They can be further subdivided into different categories based on several principal aspects, such as tumor location, histopathology, and developmental age. Among these various characteristics, age is one of the most consequential determinants for CNS tumors. Specific groups between 0 and 21 years of age, for instance, have radically divergent landscapes in terms of their tumor incidence and unique biology. Depending on the age of the child, key case features may differ like the clinical evaluation, medical diagnosis and prognosis, recommended therapy and treatment courses, anticipated responses and tolerability to treatment, and management of side effects. Effective teamwork is another crucial component for the successful management of pediatric CNS tumors. In patient-and-family-centered care, ensuring a detailed education of the children and their families, as well as their involvement in the decision-making process where appropriate, is imperative. To determine the best available options for the patient, multidisciplinary medical teams will often deliberate over all of the possible procedures. The holistic care provided by these interprofessional collaborations for this vulnerable population will depend on the age of the child, in addition to the level of patient and family participation. Evidence shows that support and counseling of the patient and their family during the entire treatment process can have a significant impact on outcomes. This chapter will review the essential diagnostic and prognostic considerations of childhood CNS tumors, with special emphasis placed on favorable therapies and treatments, including in-depth discussions around the multi-faceted responses to treatment and the management of its side effects. In particular, this content will highlight the critical role that age, and interdisciplinary healthcare teams play in comprehensive disease management.

Central Nervous System (CNS) disorders are a massive burden on the global health system, including a broad range of clinical conditions, such as epilepsies, depression, dementia, multiple sclerosis, and Parkinson’s disease. Permanent efforts are being made to find early, non-invasive, and effective diagnostic methods, as well as efficient and safe drug-based treatments for CNS conditions. Nevertheless, many patients displaying these clinical conditions still face the lack of an effective pharmacotherapy to cure the diseases or at least to properly control the progression of symptoms. Currently, epilepsies present an estimated prevalence of 0.5%–1% worldwide, and around 30% of the patients remain refractory to the available drug treatment. The comorbidities that affect epileptic patients, such as cognitive impairment and depression, are major public health challenges. This scenario highlights the urgent need for approving new therapeutic tools for CNS diseases. A successful development process of a new compound presenting therapeutic potential can range up to 20 years and cost hundreds of millions of US dollars, from the initial characterization of the in vitro chemical and biological properties until clinical trials. Additionally, drug development has a low success rate in the case of CNS conditions. In this context, drug repurposing (or drug repositioning, DR) is an alternative way to reduce the cost and accelerate the process of a drug-based treatment approach since it identifies a novel clinical application for an existing compound already approved for a distinct indication. In the present chapter, we aim to describe recent outcomes of DR aiming at CNS pathological conditions, especially discussing the recent clinical trials and their impacts on future endeavors in the search for the management of epilepsies and related comorbidities.

Nowadays, organophosphorus poisoning is the most common emergency throughout the world. Two functionally different types of drugs are used in common to treat such intoxication cases. The first type includes the reactivators of acetylcholinesterase (AChE)-oximes, which have the capability to restore the physiological function of inhibited AChE. The second type includes anticholinergic, such as atropine that antagonizes the effects of excessive ACh by blocking muscarinic receptors. Alternatively, anticholinergic and reactivators may be co-administered to get synergistic effects. At muscarinic and nicotinic synapses, organophosphorus compounds inhibit AChE release by phosphoryl group deposition at the enzyme's active site very quickly. AChE regenerative process can be accelerated by detaching the OP compound at -OH group of the enzyme. OP compound combines with the AChE enzyme forming a complex and making it inactive. After ageing of the inactive state of AChE, it is difficult to break the complex to regenerate the enzyme resulting in acetylcholine accumulation at synapses. To counter the effect of OP compound, oximes catalyse the reactivation of active AChE by exerting nucleophilic attack on the phosphoryl group. Oximes theoretically remove OP compound from the complex by acting on phosphoryl bond resulting in enzyme reactivation. Reactivation of AChE inhibited by OP compounds through the above mentioned approach poses certain limitations. There is no universal antidote capable of effectively restoring AChE inhibited by wide-ranging OP compounds. The oxime reactivators are efficient only when administered before the “ageing” of AChE-OP complex. Anticholinergic drugs, like atropine, are effective only on muscarinic receptors but not on nicotinic receptors (nAChRs).