Status of ALS Treatment, Insights into Therapeutic Challenges and Dilemmas

Khamaysa, Mohammed

doi:10.3390/jpm12101601

Cited by 14 publications

(11 citation statements)

References 126 publications

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“…[46] Third, RZ facilitates glutamate reuptake by increasing the activity of glutamate transporters (EAAT receptors) expressed on astrocytes, modulating glutamate clearance from the synaptic cleft. [47] RZ is the only drug approved by both the FDA and EMA to slow down the progression of ALS [48] and provide modest survival by slowing down the progression of disease by 2-3 months. [49] However, RZ has several limitations, such as variable pharmacokinetic metabolism following oral dosing in humans not observed in animal models.…”

Section: Multi-target Ligand Approach: Riluzole-rasagiline Hybridsmentioning

confidence: 99%

“…RZ is the only drug approved by both the FDA and EMA to slow down the progression of ALS [48] and provide modest survival by slowing down the progression of disease by 2–3 months [49] . However, RZ has several limitations, such as variable pharmacokinetic metabolism following oral dosing in humans not observed in animal models.…”

Section: Multi–target Ligand Approach: Riluzole–rasagiline Hybridsmentioning

confidence: 99%

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Current Small Molecule–Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics

Sanghai,

Vuong,

Burak Berk

et al. 2024

ChemMedChem

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Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) possess multifactorial aetiologies. In recent years, our understanding of the biochemical and molecular pathways across NDDs has increased, however, new advances in small molecule‐based therapeutic strategies targeting NDDs are obscure and scarce. Moreover, NDDs have been studied for more than five decades, however, there is a paucity of drugs that can treat NDDs. Considering the highly complex nature of NDDs, the association of multiple risk factors, and the challenges to overcome the BBB junction, medicinal chemists have developed small organic molecule‐based novel approaches to target NDDs, such as designing lipophilic molecules, applying prodrug strategies and utilizing a multitarget approach to modulate different biochemical molecular pathways involved in NDDs, in addition to, medicinal chemists making better decisions in identifying optimized drug candidates for the central nervous system (CNS) by using web‐based computational tools. Further, to increase the clinical success of these drug candidates, an in vitro assay modeling the BBB has been utilized by medicinal. Herein, we examine some of the intriguing strategies taken by medicinal chemists to design small organic molecules to combat NDDs and to increase our awareness of neurodegenerative therapeutics.

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Section: Multi-target Ligand Approach: Riluzole-rasagiline Hybridsmentioning

confidence: 99%

Section: Multi–target Ligand Approach: Riluzole–rasagiline Hybridsmentioning

confidence: 99%

Current Small Molecule–Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics

Sanghai,

Vuong,

Burak Berk

et al. 2024

ChemMedChem

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show abstract

“…Bryan then did the difficult work to find the precise mutation on the genome that was producing the signal: an expansion of the C9ORF72 gene consisting of a repeated six-nucleotide-long sequence [59] [10.1016/S1474-4422(10)70184-8]. Later, it was found that this mutation accounts for about 30% of inherited cases of ALS, and treatments based on this finding are now in clinical trials [46].…”

Section: Applications: Fun With Uncertainty Decision Making and Graph...mentioning

confidence: 99%

Heckerthoughts

Heckerman¹

2023

Preprint

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In 1987, Eric Horvitz, Greg Cooper, and I visited I.J. Good at Virginia Polytechnic and State University. The three of us were at a conference in Washington DC and made the short drive to see him. The primary reason we wanted to see him was not because he worked with Alan Turing to help win WWII by decoding encrypted messages from the Germans, although that certainly intrigued us. Rather, we wanted to see him because we had just finished reading his book "Good Thinking" [24], which summarized his life's work in Probability and its Applications. We were delighted that he was willing to have lunch with us. We were young graduate students at Stanford working in Artificial Intelligence (AI), and were amazed that his thinking was so similar to ours, having worked decades before us and coming from such a seemingly different perspective not involving AI. We had lunch and talked about many topics of shared interest including Bayesian probability, graphical models, decision theory, AI (he was interested by then), how the brain works, and the nature of the universe. Before we knew it, it was dinner time. We took a brief stroll around the beautiful campus and sat down again for dinner and more discussion. Figure 1 is a photo taken just before we reluctantly departed.This story is a fitting introduction this manuscript. Now having years to look back on my work, to boil it down to its essence, and to better appreciate its significance (if any) in the evolution of AI and Machine Learning (ML), I realized it was time to put my work in perspective, providing a roadmap to any who would like to explore it in more detail. After I had this realization, it occurred to me that this is what I.J. Good did in his book.This manuscript is for those who want to understand basic concepts central to ML and AI, and to learn about early applications of these concepts. Ironically, after I finished writing this manuscript, I realized that a lot of the concepts that I included are missing in modern courses on ML. I hope this work will help to make up for these omissions. The presentation gets somewhat technical in parts, but I've tried to keep the math to the bare minimum to convey the fundamental concepts.In addition to the technical presentations, I include stories about how the ideas came to be and the effects they have had. When I was a student in physics, I was given dry texts to read. In class, however, several of my physics professors would tell stories around the work, such as Einstein's thinking that led to his general theory of relativity. Those stories fascinated me and really made the theory stick. So here, I do my best to present both the fundamental ideas and the stories behind them.As for the title, "Heckerman Thinking" doesn't have the same ring to it as that of Good's book. I chose "Heckerthoughts," because my rather odd last name has been humorous fodder for friends and colleagues for naming things related to me such as "Heckerperson," "Heckertalk," and "Heckerpaper"-you get the idea. Ironically, a distant relative of mine who co...

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“…Despite its ability to slow the progression of ALS, its effectiveness is limited. Another drug, edaravone, has also been approved by the FDA for oral use ( 9 ) and possesses potent antioxidant properties that mitigate the effects of oxidative stress by eliminating oxidized lipids and hydroxyl radicals, which may be a key factor in the pathogenesis and development of ALS. However, clinical studies have also suggested that edaravone may be ineffective in treating ALS ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis

Zhang

et al. 2023

Front. Neurol.

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There are trillions of different microorganisms in the human digestive system. These gut microbes are involved in the digestion of food and its conversion into the nutrients required by the body. In addition, the gut microbiota communicates with other parts of the body to maintain overall health. The connection between the gut microbiota and the brain is known as the gut–brain axis (GBA), and involves connections via the central nervous system (CNS), the enteric nervous system (ENS), and endocrine and immune pathways. The gut microbiota regulates the central nervous system bottom-up through the GBA, which has prompted researchers to pay considerable attention to the potential pathways by which the gut microbiota might play a role in the prevention and treatment of amyotrophic lateral sclerosis (ALS). Studies with animal models of ALS have shown that dysregulation of the gut ecology leads to dysregulation of brain–gut signaling. This, in turn, induces changes in the intestinal barrier, endotoxemia, and systemic inflammation, which contribute to the development of ALS. Through the use of antibiotics, probiotic supplementation, phage therapy, and other methods of inducing changes in the intestinal microbiota that can inhibit inflammation and delay neuronal degeneration, the clinical symptoms of ALS can be alleviated, and the progression of the disease can be delayed. Therefore, the gut microbiota may be a key target for effective management and treatment of ALS.

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Status of ALS Treatment, Insights into Therapeutic Challenges and Dilemmas

Cited by 14 publications

References 126 publications

Current Small Molecule–Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics

Current Small Molecule–Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics

Heckerthoughts

Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis

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