Frontiers in Clinical Drug Research - CNS and Neurological Disorders: Volume 12 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Serie: Frontiers in Clinical Drug Research - CNS and Neurological Disorders
- Sprache: Englisch
- Veröffentlichungsjahr: 2024
Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system (CNS) and other nerve disorders. The scope of the book series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of contemporary molecular targets involved in neurological and CNS disorders. Reviews presented in the series are mainly focused on clinical and therapeutic aspects of novel drugs intended for these targets. Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in neurology and allied disciplines.
The twelfth volume of this series features these reviews:
Chapter 1: Recent Drugs Tested in Clinical Trials for Alzheimer's and Parkinson's Diseases Treatment: Current Approaches in Tracking New Drugs
Chapter 2: Neurobiology of Placebo: Interpreting Its Evolutionary Origin, Meaning, Mechanisms, Monitoring, and Implications in Therapeutics
Chapter 3: Role of Gut Microbiota in Neuroinflammation and Neurological Disorders
Chapter 4: The Role of Age in Pediatric Tumors of the Central Nervous System
Chapter 5: Drug Repurposing in CNS and Clinical Trials: Recent Achievements and Perspectives Focusing on Epilepsy and Related Comorbidities
Chapter 6: Progress on the Development of Oxime Derivatives as a Potential Antidote for Organophosphorus Poisoning
Readership
Pharmaceutical scientists, clinical researchers, medical consultants and allied healthcare professionals interested in neuropharmacology and neurology
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PREFACE
Syuichi KoaradaBrain disorders are a major public health and economic concern. The causes of these disorders are heterogeneous, and so as the treatment options. State-of-the-art advances in scientific techniques, evolving clinical observations, and diagnostic accuracies to study the neurobiology of different diseases are very illuminating, and assist in not only deciphering the physiology of brain disorders but also the mechanisms that make people more vulnerable to these disorders.
As our understanding is evolving, our knowledge is expanding, and so is our book series Frontiers in Clinical Drug Research - CNS and Neurological Disorders. The organization and content of volume 12 of our book series like its predecessors sets the physiology of the brain by outlining the pathology of neurodegenerative disorders, the role of neuroinflammation in neurological disorders, aging in brain tumors, comorbidities in epilepsy as well as placebo effect based on available empirical evidence by actively formulating, synthesizing, and analyzing these pieces of evidence. The relationships between these medical illnesses are complex, multifactorial, and bidirectional.
Since the aim of the series is to include current advancements in the field, rather covering the materials exhaustively, this volume also precisely educates readers about the salient examples of the latest advancement happening in the translational research of various brain aliments, encompassing neurodegenerative disorders and neurological disorders. The volume also contextualizes the engaging and accessible introduction to drug repurposing for neurological disorders. The last chapter of the volume also discusses the organophosphorus poisoning or intoxication emergency, a very scarcely discussed topic, with reference to neuroactive drugs that can be used to treat it.
Briefly, Chapter 1 highlights the current approaches used for tracking the new drugs by reviewing recent drugs tested in clinical trials for the treatment of Alzheimer’s and Parkinson’s diseases. Chapter 2 summarizes an intellectual and conceptual framework for understanding the neurobiology of placebo by interpreting its evolutionary origin, meanings, mechanisms, monitoring, and implications from therapeutics’ perspective. Chapter 3 discusses the role of gut microbiota in neuroinflammation and neurological disorders. Chapter 4 glances the role of age in pediatric tumors of the central nervous system. Chapter 5 comprehensively and critically assesses the current knowledge about epilepsy when it is comorbid with the full range of medical disorders with reference to drug repurposing in clinical trials. Chapter 6 reviews the progress on the development of oxime derivatives as a potential antidote for organophosphorus poisoning.
Therefore, each chapter in the book very ostensibly introduces beginners in the basic science to the primary as well as advanced knowledge in the field. At the same time, these chapters are equally valuable not just for other mental health professionals, and psychiatrists but also for a wide range of medical specialists as well. Besides, it offers researchers, postdoctoral fellows, and students in diverse fields of neurobiology, neurology and neuroscience the tools they need to obtain a fundamental background in the major neurodegenerative, and neurological disorders. In conclusion, the volume provides a glimpse into the future that we are moving toward by exploring a greater understanding of the common pathways that mediate neuropathological illnesses, symptoms, and the relevant pathophysiological and neurophysiological phenomenon.
The timely assistance provided by the editorial staff; Mr. Mahmood Alam (Director Publications), and Ms. Asma Ahmed (Senior Manager Publications) at Bentham Science Publishers is highly appreciated.
List of Contributors
Recent Drugs Tested in Clinical Trials for Alzheimer´s and Parkinson´s Diseases Treatment: Current Approaches in Tracking New Drugs
Fernanda Majolo1,Lavynia Ferreira Hoffmann1,Wilian Luan Pilatti Sant’Ana2,Celso Alves3,Joana Silva3,Alice Martins3,Rui Pedrosa3,Bruno Dahmer1,Guilherme Liberato da Silva1,Luís Fernando Saraiva Macedo Timmers1,2,Márcia Inês Goettert1,2,*Abstract
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.
INTRODUCTION
Neurological diseases (ND) are a heavy burden carried by patients, their families, communities, and governments [1]. As the world population grows old, especially in developed nations, the combined annual costs of ND are rapidly rising [2]. In the United States, the social burden of ND is up to $ 800 billion, and disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and other dementias represent more than one-third of these ND [2]. For elderly, ND can dramatically increase health care costs due to other associated comorbidities, such as Idiopathic Parkinson's Syndrome (IPS) disease and fall-related fractures [3]. It is estimated that about 61% of the IPS patients will have at least one fall during the course of the disease, and 39% will suffer multiple falls, generating high disease-specific costs [3]. In 2015, German data showed that IPS patients' treatment cost was more than € 3.2 billion, which amounted to about 1% of Germany's total annual medical expenses [3]. Projections estimate that by 2050 only AD dementia will have a devastating impact, affecting 131 million people worldwide [4]. In 2018, AD costs were nearly $ 1 trillion and, since the annual costs of AD are rapidly increasing, the projections estimate that these numbers will double by 2030 [4].
To reduce this social burden related to ND as a whole, not only for AD and PD, a global effort towards discovering new drug therapies that may reduce these costs is welcome. That is a concern mainly because many ND still have poorly defined or even undefined etiopathogenesis [5]. In addition, many ND present subjective and context-dependent clinical manifestations, making the sample selection for treatment trials, using clinical criteria, inevitably heterogeneous [5]. Due to this heterogeneity, the inclusion criteria for the studies are often more rigorous, adding to the time, cost, and risk to the drug development process [6]. All these aspects, when combined, reflect the success rates of new drugs for ND, which are the lowest for any therapeutic area [6]. For example, in the early 2010 decade, less than 10% of the potential drugs that started clinical testing reached the market, and from the compounds that eventually moved on to phase III testing, less than 50% got approval [6]. This scenario explains why clinical research programs for ND tend to be longer and more complex than those for other diseases [6].
In 2008, Pharmaceutical Research and Manufacturers of America (PhRMA) presented a report that contained more than five hundred drugs for neurological disorders, which were still in the development stage [6]. When analyzed in detail, the reports data demonstrated that the research and development (R&D) pipeline contained previously known drugs, undergoing repurposing processes, i.e., tested for new indications [6].
Regarding the pipeline of drugs and biologics in clinical trials for the treatment of AD, a recent study that has utilized a survey of annual pipeline reports of the past five years provided a longitudinal insight into clinical trials and drug development for AD [4]. According to the Common Alzheimer's and Related Dementias Research Ontology (CADRO) for classifying treatment targets and mechanisms of action, the results revealed that, in 2020, there were 121 agents in clinical trials to treat AD [4]. Among them, there were 29 agents in phase 3, 65 in phase 2, and 27 in phase I trials. Also, the data showed testing of twelve agents in trials targeting cognitive enhancement, twelve intended to treat neuropsychiatric and behavioral symptoms, and 97 agents in disease modification trials [4]. For example, compared to the 2019 pipeline, these data showed a growth in the number of disease-modifying agents targeting pathways other than the amyloid or the tau pathways [4]. Finally, the clinical trials' data from the last five years showed a progressive emphasis on non-amyloid targets. Those candidate treatments aim at targets involving mechanisms like inflammation, synapse, neuronal protection, vascular factors, neurogenesis, and interventions on epigenetics [4]. Also, data revealed significant growth in the repurposed agents' pipeline as well [4].
In recent years, several drugs with the potential to modify the disease and with neuroprotective effects are being evaluated in preclinical and clinical studies. The United States stands out for conducting the largest number of phase III and phase IV clinical studies, both for AD and PD Fig (1). Thus, this chapter summarizes the most important drugs that were targets of clinical studies from 2015 to 2020, associated with the most common neurological disorders worldwide: AD and PD. The approached clinical studies are related to phase III and IV studies registered on clinicaltrials.gov. Data like mechanisms of action, experimental studies in other diseases that support their use, and chemical structure of the drugs are included in this chapter. Also, a revision focused on nature as a source of valuable chemical entities for PD and AD therapeutics is also reported. Finally, future adv-
ances in the field regarding tracking new drugs to get successful results in the research and clinical investigation are highlighted.
Fig. (1)) Illustrative map indicating the number of clinical studies (phases III and IV) carried out from 2015 to 2020 related to Alzheimer's and Parkinson's diseases.ALZHEIMER'S DISEASE
Alzheimer's disease (AD) is a neurodegenerative dysfunction which causes and pathogenesis are not fully understood. It is the most frequent cause of dementia [8], representing 60% to 80% of cases [8], affecting essentially older adults. Several primary studies, including a moderate-quality systematic review, reported that age significantly predicts AD incidence [7]. Dementia is a general term that describes neurocognitive symptoms like difficulties with memory and language, diminished problem-solving capabilities, and other thinking-related skills that directly impact the ability to perform daily activities [8].
Etiopathogenesis and Physiopathology
Alzheimer's is a gradually progressive brain disease that starts years before its symptoms appearance [8]. AD dementia has multiple etiopathogeneses, such as autosomal dominant forms, primarily attributable to mutations in proteases that release the amyloid-beta (Aβ) peptide or familial AD amyloid precursor protein (APP) mutations, further implicating amyloid metabolism [9]. Other invoked mechanisms to explain the stereotypical AD spread within the brain are the prion-like seeding of amyloid fibrils and neurofibrillary tangles [9]. AD's pathological hallmark feature is the accumulation of the beta-amyloid protein fragments (plaques) outside brain neurons and tau protein twisted strands (tangles) inside neurons [8]. These changes are associated with neuron death and brain tissue damage [8]. In addition, an up-to-date meta-analysis result, which included several recent studies that aimed at the association of levels of homocysteine and folic acid and the development of AD, has shown that homocysteine and folic acid are potential predictors for both occurrence and development of AD [8, 9].
Diagnosis
Alzheimer's dementia is a clinical syndrome that results from the AD pathophysiological process [10]. This process encompasses the antemortem biological changes manifested in the postmortem neuropathological diagnosis of AD [10]. For obvious reasons, the diagnosis of AD dementia must first meet all-cause dementia criteria, which fits to comprise the spectrum of severity, ranging from the mildest to the most severe stages of dementia [10]. According to these criteria, the diagnosis of all-cause dementia requires some degree of interference in the individual's ability to function at work or usual activities, representing a decline from a previous level of functioning and performing, which not explains itself by delirium or major psychiatric disorder [10].
The differentiation between dementia and mild cognitive impairment rests on determining whether there is a significant disturbance in functioning at work or in habitual daily activities [10]. Inherently, this is a clinical judgment made by a trained clinician based on the patient's circumstances and the description of day-to-day affairs of the patient [10]. Patients and knowledgeable informants are necessary to obtain the clinical information [10]. A combination of history-taking from the patient and a knowledgeable informant, and an objective cognitive assessment, either a bedside mental status examination or neuropsychological testing, are the basis of detection and diagnosis of cognitive impairment [10].
Two of the following domains, at least, must be present to characterize cognitive or behavioral impairment: acquiring and remembering new information ability impairment, impaired reasoning and handling of complex tasks; poor judgment, impaired visuospatial abilities, impaired language functions, changes in personality, behavior, or comportment [10]. A series of criteria established by the National Institute on Aging and the Alzheimer's Association (NIA-AA), most recently updated in 2011, is the currently proposed method to diagnose and classify AD dementia [10]. This classification encompasses three possibilities: (1) Probable AD dementia, (2) Possible AD dementia, and (3) Probable or possible AD dementia with evidence of the AD pathophysiological process [10]. The first two are fitted for clinical settings usage, while the third one currently fits the research field [10].
Treatment – Approved Drugs
Until today, there is no available pharmacological treatment capable to delay or arrest the injury and loss of neurons that cause AD manifestations and make the condition fatal [8]. Nevertheless, the U.S. Food and Drug Administration (FDA) already approved some drugs for AD treatment — galantamine, rivastigmine, memantine, donepezil, and memantine combined with donepezil [8]. Except for memantine, these drugs temporarily improve the cognitive symptoms by increasing neurotransmitters in the brain [8]. Memantine acts by blocking excess stimulation in specific receptors in the brain that can injure nerve cells [8]. The effectiveness of these drugs varies from person to person and is limited in duration [8]. Also, with US approval, in 2021, aducanumab can be prescribed for the treatment of AD in those with mild cognitive impairment or mild dementia stage, the population in which treatment was initiated in clinical trials [11].
The FDA approves explicitly no drugs to treat behavioral and psychiatric symptoms that may develop in the moderate and severe stages of AD dementia [8]. If non-pharmacologic treatment is not successful, and there is the possibility that these symptoms may harm the individual or others, physicians are authorized to prescribe drugs approved for similar symptoms in people with other diseases [8].
Prevention
The primary prevention of AD refers to prevent resulting dementia in cognitively normal subjects and is the final purpose for AD management [11]. AD has numerous well-instituted risk factors [12]. Some are not modifiable, like age, sex, and genotype, but other are potentially modifiable, such as vascular risk factors and traumatic brain injury [8, 12]. In contrast, there are suggested protective factors involving pharmacological mechanisms, like the use of antihypertensives, non-steroidal anti-inflammatories, statins, and hormone replacement therapy [12]. There are also environmental and behavioral factors, like diet, physical activity, high education, and engagement in social and intellectual activities [12]. However, how modifying these factors will reduce the risk of dementia is not yet known [12]. The secondary prevention of AD refers to preventing AD development in non-demented subjects with some evidence of cognitive impairment [12]. In this regard, the most often studied groups are those with Mild Cognitive Impairment (MCI), but there are no treatments that have demonstrated efficacy for preventing or delaying AD in MCI subjects until now [12]. At the same time, evidence shows that cholinesterase inhibitors, Vitamin E, Ginkgo biloba, and anti-inflammatories are not substantively helpful [12].
Clinical Trials
Below, we address individually the drugs used in clinical trials (phases III and IV) in the last 5 years related to studies that have ended normally, and participants are no longer being examined or treated (that is, the last participant's last visit has occurred) Table 1. The chemical structures of these drugs can be found in (Fig. 2). Additionally, Table 2 shows all the ongoing clinical trials in the last 5 years, from phases III and IV to treat this disease.
Donepezil
Mechanisms of Action: Currently, the piperidine-based drug Donepezil is the most used pharmacological agent for the treatment of AD, being a reversible inhibitor of acetylcholinesterase, centrally acting in a rapid way This pharmacological compound exerts its neuroprotective property through the upregulation of the nicotinic receptors in the cortical neurons, inhibiting voltage-activated sodium currents reversibly and delaying rectifier potassium currents and fast transient potassium currents. The cholinergic transmission is enhanced when Donepezil causes the hydrolysis of acetylcholine, thus increasing the availability of acetylcholine at the synapses [13-15].
The use of Donepezil is approved by FDA in mild, moderate, and severe AD, when initially it was tested for patients with mild-to-moderate AD [16-18]. This type of drug (cholinesterase inhibitors) was the first category approved by the FDA for this indication [19]. Until now, no evidence proves that Donepezil can alter the progression of AD but can improve the symptoms such as cognition and behavior [13-20]. Donepezil is a benefit to patients that show the two ends of the AD spectrum: moderate-to-severe impairment [21] and those very mild, early-stage disease [22] and, in this case, patients can be included in nursing homes [23].
Experimental Studies in other Diseases that Support their Use: The cholinesterase inhibitor Donepezil is suggested to be effective in other diseases, such as vascular dementia [24, 25], dementia associated with PD [26, 27] and other conditions [28]. Although not still approved by FDA, the use of Donepezil includes dementia associated with PD, vascular dementia, and Lewy body dementia, where some studies show the improvement of cognition and executive function. Additionally, the use for traumatic brain injury was tested and it was observed an improvement in memory dysfunction in patients.
The clinical trial performed by Jia et al. (2020) concluded that donepezil (10 mg/day) can be tolerated and is effective in patients with mild-to-moderate AD (ClinicalTrials.gov NCT02787746) [29].
Methylphenidate
Mechanisms of Action: The mechanism of action of Methylphenidate is still unclear to researchers but it is important to many therapeutic effects [30]. It is known that this drug causes the increasing of extracellular dopamine levels by the binding to the dopamine transporter in the presynaptic cell membrane, thus blocking the uptake of dopamine [31-34]. Also, Methylphenidate binds to the specific transporter of serotonin and norepinephrine, blocking the uptake too [35]. It’s worth mentioning that the effects are weaker on serotonin that dopamine [36].
For more than 50 years the psychostimulant Methylphenidate has been considered the first-line pharmacological treatment for the Attention-Deficit/Hyperactivity Disorder (ADHD) patients [37, 38]. The drug presents favorable effects on reducing the core symptoms of excessive hyperactivity, impulsivity, and inattention in children and adolescents with ADHD [39].
Experimental Studies in other Diseases that Support their Use: Some evidence gives support to the use of Methylphenidate not only to ADHD but on physical and psychological symptoms in cancer patients. The prognostic is unclear, but some findings suggest that Methylphenidate improve cognitive symptoms and reduction of fatigue in cancer patients. It's worth mentioning that the results could vary according to the profile of population, outcomes measures, and study design. Also, it is approached in Depression treatment, but evidences are insufficient [40].
Patients with brain tumors that present cognitive abnormalities are frequent, and some studies suggested that the use of Methylphenidate improves those conditions. Meyers et al. (1998) [41] reported that half of the patients with malignant gliomas evidenced an improvement in cognitive function receiving this psychostimulant during nonrandomized studies. A study on children with brain tumors or acute lymphocytic leukemia that displayed association with neurologic injury, the use of methylphenidate presented an improvement in language skills, attention, memory, and academic performance in 10 of 12 pediatric patients [42].
The improvement of cognitive conditions using Methylphenidate were observed in patients with advanced cancer and hypoactive delirium [43-46]. Another symptom frequently observed by cancer patients is fatigue [47]. Studies reporting the effect of Methylphenidate on fatigue in cancer patients concluded that this drug improved significantly several skills following the Brief Fatigue Inventory (BFI), like anxiety, appetite, pain, nausea, depression, and drowsiness [48].
The clinical trial performed by Mintzer et al. (2021) suggested that Methylphenidate is an efficacious medication and can be considered safe to use in the treatment of apathy in AD (ClinicalTrials.gov Identifier: NCT02346201) [49].
Rivastigmine
Mechanisms of Action: Rivastigmine acts in postsynaptic clefts, inhibiting the metabolism of acetylcholine, and it has been considered a selective cholinesterase inhibitor, thus enhancing cholinergic neurotransmission. Rivastigmine is different from other cholinesterase inhibitors because it inhibits both enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). This fact results in an increase of acetylcholine levels. AChE is mainly present in areas of the cerebral cortex that have high activity and at synaptic nerve junctions. However, the BuChE helps mediate cholinergic activity being found in the glial cells of the brain. In neurological disorders like AD and PD, it is observed the upregulation of these cholinesterase enzymes, being higher than in normal conditions [50].
This drug was approved by FDA to treat mild to moderate dementia of Alzheimer’s type. Also, it can be used for the treatment of mild to moderate dementia in PD [51].
Experimental Studies in other Diseases that Support their Use: Rivastigmine influences gain stability, reducing the risk of falls in patients with PD [52] and other studies proved that this drug, in older patients, decreases the incidence of postoperative delirium [53]. In multiple sclerosis patients it was tested the effectiveness of rivastigmine in order to check if the cognitive dysfunction was improved, but the studies showed no significant benefits for cognitive function when compared with placebo [54]. However, studies using Rivastigmine demonstrated cognition improvements in patients with Lewy bodies when compared to the placebo group. Such patients that received rivastigmine showed an improvement of 30% or more, as well as overall fewer episodes of hallucinations and anxiety [55].
The clinical trial (Identifier: NCT02703636) has no results published until this moment, where this work aims to evaluate the efficacy of rivastigmine on cognitive function in the total score of MMSE in mild to moderate AD patients who failed to benefit from other cholinesterase inhibitors (ChEIs).
Suvorexant
Mechanisms of Action: Suvorexant is a basic diazepane structure considered dual orexin receptor antagonist and has a function for blocks of both OX1R and OX2R. Through this block occurs the inhibition of orexin A and B that promote wakefulness. The orexins are neuropeptides and their receptors are blocked using suvorexant, inducing sleep. The drug is hepatically metabolized mainly by CYP3A from two hours after ingestion during the half-life of 12 h [56]. These orexin neurons (more than 70,000), located in the perifornical lateral hypothalamus in the human brain, send signals to the spinal cord and spread to the brain [57, 58].
Experimental Studies in other Diseases that Support their Use: Studies demonstrated the benefits, but side effects were observed, for example fatigue, next day somnolence, xerostomia and peripheral oedema being rarely reported cases of hallucinations, sleep paralysis and somnambulism. Suvorexant is expensive and has not been trailed against other hypnotics. It’s worth mentioning that it is very useful to insomnia but in patients with psychiatric disorders the real action is still unclear. The use of suvorexant should be considered where the established treatments demonstrated to be inappropriate [56].
Outcomes from clinical trials using suvorexant in the prevention of delirium during the acute hospitalization have been positive [59]. The use of suvorexant can improve subjective sleep quality without inducing delirium in acute stroke patients during the ramelteon therapy [60].
The clinical trial performed by Herring et al. (2020) [61] reported that suvorexant improved total sleep time (TST) in patients with clinical diagnostic criteria suggesting AD dementia and insomnia (ClinicalTrials.gov NCT02750306) [61].
Zolpidem
Mechanisms of Action: Zolpidem is FDA approved for short-term treatment of insomnia mainly to patients with difficulty to start sleep and is a non-benzodiazepine receptor modulator [62-64]. The medication is an imidazo-pyridine compound that acts like a GABAA receptor chloride channel modulator/agonist that increases GABA inhibitory effects by interaction with Omega-1 receptor subtype, upregulating these receptors leading to sedative effects and deep sleep [65, 66]. It also has other properties as anticonvulsant, anxiolytic, and minor myorelaxant, consequently increasing sleep duration in patients with insomnia [67, 68]. The use of Zolpidem does not cause any residual cognitive impairment in the next morning due to its pharmacokinetic profile [65].
However, due to the high potential for abuse, this drug is not recommended for the general population as first-line treatment. Other drugs like controlled release melatonin and doxepin could be used as first line and still are recommended for sleep hygiene and cognitive behavioral therapy [69, 70].
The clinical efficacy of this drug has been characterized by a rapid action on sleep-maintenance parameters, increasing stage 2 and slow-wave sleep, decreasing sleep-onset latency, thus, significantly improves sleep quality and duration, and reduces night-time awakenings [71]. Therefore, to patients that present troubles to achieving sustained sleep, zolpidem can be considered an appropriate treatment [65].
Experimental Studies in other Diseases that Support their Use: Zolpidem has frequently been related to treatment of a variety of neurologic disorders such as movement disorders and disorders of consciousness [72]. Other improvements related to effects of Zolpidem are on JFK Coma Recovery Scale-Revised, the Unified Parkinson´s Disease Rating Scale, and the Burke-Fahn-Marsden Dystonia Rating Scale [72].
Zolpidem did not show positive effects in patients with traumatic brain injury or post-anoxic encephalopathy, however, on brain functions in patients with non-brain stem injuries it was observed an improvement. Also, it was not detected a consistent positive effect of zolpidem in patients with disorders of consciousness [73].
Zopiclone
Mechanisms of Action: Zopiclone is considered a cyclopyrrolone agent indicated for use in short-term insomnia that improves the sleep time, awakenings, sleep quality and latency [74]. The drug involves allosteric modulation of the GABAA receptor, displacing the binding of [(3)H]-flunitrazepam with an affinity of 28 nM, and enhances the binding of the channel blocker [(35)S]-TBPS. This medication is metabolized by the cytochrome P450 enzymes CYP3A4 and CYP2C8 generating several metabolites (SPC). The consequence of this interaction with the GABAA receptor is to potentiate responses to GABA, as can be demonstrated by electrophysiological methods [75, 76].
Experimental Studies in other Diseases that Support their Use: Zopiclone improves sleep quality in patients with chronic obstructive pulmonary disease [76]. In addition, it was proved that Zopiclone demonstrated positive aspects on early morning performance and residual sedative activity [77-79].
The clinical trial performed by Louzada et al. (2022) [80] evaluated the use of zolpidem and zopiclone by AD patients considered insomniacs, suggesting that the short-term use appears to be clinically helpful, but it is worth mentioned that safety and tolerance remain subjects to be discussed and personalized in healthcare settings and in future investigations (ClinicalTrials.gov Identifier: NCT03075241) [80].
AXS-05
Mechanisms of Action: According to Axsome (2017) [81], the compound AXS-05 is composed of dextromethorphan and bupropion. The bioavailability of dextromethorphan following the inhibition of CYP2D6 is affected by addition of bupropion. AXS-05 is also in phase III studies being tested in patients with treatment resistant depression (TRD). A Fast Track Designation has been addressed this compound to TRD and AD.
AXS-05 has been granted U.S. Food and Drug Administration Breakthrough Therapy designation for major depressive disorder, Fast Track Designation for treatment resistant depression, and Breakthrough Therapy and Fast Track designations for AD agitation. AXS-05 is not approved by the FDA.
Experimental Studies in other Diseases that Support their Use: There are no experimental studies in other diseases.
The clinical trial (Identifier: NCT03226522) has no results posted until this moment aiming to evaluate the effectiveness and safety of AXS-05 use in the treatment of Agitation in AD patients with Dementia.
Umibecestat (CNP520)
Mechanisms of Action: Umibecestat (named CNP520) is an orally active inhibitor of beta-site amyloid precursor protein (APP) cleaving enzyme (BACE) that is involved in APP processing and has approximately 3-fold selectivity for BACE-1 over BACE-2 and no relevant off-target binding or activity [82].
Experimental Studies in other Diseases that Support their Use: Following single and multiple dose administration of CNP520 in animals and humans, Aβ concentrations in cerebrospinal fluid were reduced by up to 95% compared with baseline, and results of toxicology studies have not raised major safety concerns [83].
The clinical trial (Identifier: NCT03131453) was terminated due to safety issues where the main objective was to evaluate the effects of CNP520 on cognition, global clinical status, and underlying AD pathology.
PARKINSON'S DISEASE
Multiple anatomical structures degeneration within the brain is the hallmark of a neurodegenerative disorder that manifests as Parkinsonism [84]. Human postmortem studies show that individuals have a neuronal loss in the substantia nigra pars compacta, locus coeruleus, and other neuronal populations [85]. It is a clinical syndrome based on three cardinal motor manifestations, which present themselves with any combination of bradykinesia, rest tremor, and rigidity [86]. These features must be observable and not attributable to confounding factors [86]. Postural instability and other motor and non-motor symptoms may also be present [85]. The most prevalent form of parkinsonism is PD, with an incidence rate of 14.2 per 100,000 person-years [86]. The incidence and the duration of illness are the determinants of its prevalence—the incidence of PD links to the risk factors and protective ones [87].
Etiopathogenesis and Physiopathology
There is a debate about the pathogenesis of PD and the relative contribution of genetics, environmental, and lifestyle factors [85]. PD's most critical risk factor is age, with a median onset of 60 years old [85]. The frequency is higher in men than in women (ratio ranges from 1.3 to 2.0), but differences in the prevalence of cigarette smoking behavior, postmenopausal hormones, and caffeine intake may influence the incidence [85]. As in other neurodegenerative disorders, age-related biological dysfunction may support and clear the way for neuronal demise [85]. These factors include ubiquitin-proteasome and autophagy-lysosomal system disturbances, mitochondrial defects, telomere dysfunction, genomic instability, and epigenetic changes [85]. In addition, several gene mutations are genetic risk factors for developing PD, like SNCA, PINK1, PARK2, PARK7, PLA2G6, FBXO7, ATP13A2, and LRRK2 [88].
The association of industrial chemicals and pollutants, such as pesticides and solvents, exposure to heavy metals, living in rural areas, agricultural occupation, consumption of dairy products, history of melanoma, traumatic head injury, type 2 diabetes mellitus, among many other factors, have already been identified as risk factors [85, 87]. However, despite this long list, PD's most critical risk factor is age [87].
The increasing longevity of societies also translates into longer disease duration, but the factors that interfere in the disease course are less well-known [87]. As stunning as it may sound, some data suggest that smoking is associated with a decreased risk of PD, but whether this association is causal is debatable [87]. Therefore, as societies grow in aging, industrialization increases globally, and smoking decreases in some regions, the prevalence of PD seems inclined to increase [87].
Diagnosis
Clinical features are the basis for PD diagnosis, and its diagnosis remains a clinical one [87]. However, during life, total diagnostic certainty is virtually impossible [86]. Between 75% and 95% of patients diagnosed with PD by experts have their diagnosis confirmed on autopsy [86]. Although the basis of PD diagnosis during life is its distinctive clinical features discerned by the history and neurologic examination, there is an inherent conflict between sensitivity and specificity of the clinical diagnosis [86].
When considering only the initial diagnosis, the misdiagnosis is even higher since the diagnostic accuracy improves over time, during follow-up visits, with a continuous diagnostic re-evaluation process [87]. Unlike the common opinion that detecting PD is an easy task, seminal clinicopathological studies have shown that up to one-fourth of patients diagnosed with PD during life have an alternative diagnosis at postmortem [86].
The Movement Disorder Society (MDS) recently proposed updated diagnostic criteria, intending to use them as the official “The International Parkinson and MDS Clinical Diagnostic Criteria for Parkinson's disease” (MDS-PD Criteria) [86]. MDS-PD Criteria encompass the presence of parkinsonism and its cardinal manifestations, like bradykinesia, rigidity, and rest tremor [86].
Treatment – Approved Drugs
It is a central clinical issue to approach the relative effectiveness of first-line treatments for PD motor symptoms, e.g., amantadine, dopamine agonists (DA), levodopa, and monoamine oxidase B (MAO-B) inhibitors, considering that their comparative effectiveness is unclear [89]. No known theoretical reasons show one class of drugs to be more effective than another [89]. Levodopa approaches the dopamine loss of PD when converted into dopamine by the human metabolism [89]. Therefore, it helps to enhance dopamine availability [88]. DA stimulate neuronal cells similarly to dopamine [89]. MAO-Bs, in turn, break down the enzyme responsible for dopamine metabolism within the brain increasing dopamine availability [89]. Lastly, amantadine both enhances dopamine release and hinders dopamine reuptake [89]. Levodopa is the most prescribed drug to treat motor symptoms of PD [89]. However, its effectiveness declines over time, and crucial adverse motor complications may arise [89]. Therefore, clinicians often aim to keep the dose of levodopa as low as possible to maintain good function and reduce motor complications [89]. In extension to the drugs above described (dopamine agonists, MAO-Bs, and amantadine), catechol-O-methyltransferase (COMT) inhibitors and anticholinergics have also been used in the treatment pathway [89]. COMT inhibitors prolong levodopa effects by blocking an enzyme that breaks down, thereby allowing lower levodopa doses [89]. Anticholinergics intend to improve motor symptoms, most commonly in the earlier stages of PD [89].
For monotherapy of early PD, non-ergot dopamine agonists, oral levodopa preparations, selegiline, and rasagiline are clinically helpful [89]. In early/stable PD, non-ergot dopamine agonists, rasagiline, and zonisamide are clinically helpful as adjunct therapy [90]. Selegiline and rasagiline are used as monotherapy in the early stages of Parkinson's disease. In PD patients, these monoamine oxidase B inhibitors exhibit antiprotective properties and patients targeting dopamine metabolising, thus increasing the time available for dopamine neurotransmission, thus increasing the time that dopamine is available for neurotransmission [91]. Zonisamide is a reversible MAO-B inhibitor. It is used as a complementary treatment to overcome the deficiencies of general therapies used to solve motor and non-motor problems of PD [92]. Rivastigmine is possibly helpful as an adjunct therapy in optimized PD for general or specific motor symptoms, including gait, and physiotherapy is clinically useful; exercise-based movement strategy training and formalized patterned exercises are possibly helpful [90]. Most non-ergot dopamine agonists, including pergolide, levodopa ER, levodopa intestinal infusion, entacapone, opicapone, rasagiline, zonisamide, safinamide, and bilateral subthalamic nucleus (STN) and GPi deep brain stimulation (DBS) are clinically useful to treat motor fluctuations [90].
As for the non-motor symptoms, there are clinically practical or possibly useful interventions to treat depression, psychosis, apathy, dementia, insomnia, daytime sleepiness, impulse control, fatigue, orthostatic hypotension, pain, erection and urinary dysfunctions [93].
Prevention
There are no clinically helpful interventions to prevent or delay PD progression nor differences in the outcomes for the prevention/delay of motor complications [90].
Clinical Trials
Below, we address individually the drugs used in clinical trials in the last 5 years related to studies that have ended normally, and participants are no longer being examined or treated (that is, the last participant's last visit has occurred) from phases III and IV (Table 1). The chemical structure of these drugs can be found in (Fig. 3). In addition, Table 2 shows all the ongoing clinical trials of the last 5 years, from phases III and IV.
Fig. (3)) Chemical structures of target drugs submitted to clinical studies from 2015 to 2020 (phases III and IV) related to Parkinson's disease that have ended normally, and participants are no longer being examined or treated.Inosine
Mechanisms of Action: Inosine is a purine naturally formed from the degradation of adenosine by adenosine deaminase [94]. It can bind to adenosine receptors and initiates intracellular signaling effects. Furthermore, it can also affect cell function via receptor-independent pathways, increases uric acid production, inhibits poly (ADP ribose) polymerase, and upregulates GAP-43 in neurons [95
