Chlorotonil

A New Hope Against Antibiotic Resistance: Dual Mechanism in Chlorotonils Identified

by with No Comment Disease & DrugsResearch

Written By: Pragati Ekamalli, B.Pharm

Reviewed By: Vikas Londhe M.Pharm (Pharmacology)

Chlorotonil

Introduction

The increase of pathogens that resist multiple drugs is a big danger to global health, making many common antibiotics useless. In an important finding, scientists from Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) have discovered the dual mechanism of action of previously known natural antibiotic called chlorotonils that work against resistant bacteria. This study, published in Cell Chemical Biology, offers new ways to fight infections that do not respond to other antibiotics

Discovery of Chlorotonils

In 2008, a group of researchers from HIPS found something interesting while looking for new antibiotics in soil bacteria. They discovered chlorotonils, the substances taken from a type of soil bacteria called Sorangium cellulosum. Chlorotonils are known for fighting bacteria, especially tough ones like Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE) and the malaria-causing parasite Plasmodium falciparum. They have a special ring shape and contain several chlorine atoms that help them work against bacteria.

However, chlorotonils are hard to dissolve and not very stable, which makes it difficult to turn them into medicines that’s why scientists later synthesized derivatives called dehalogenil to improve its properties, but so far, they have not been used in treatments.

Dual-Action Mechanism: How Chlorotonils Work

Researchers led by Dr. Jennifer Herrmann and Prof. Rolf Müller have found out how chlorotonils work. Unlike most antibiotics, chlorotonils attack bacteria in two ways. First, they attach to the bacteria’s cell wall and cause lipid-targeted membrane depolarization making it weak by causing uncontrolled efflux of potassium ions out of cell. On the other hand chlorotonil functionally inhibit two enzymes a membrane bound phosphatase YbjG and the cytoplasmic methionine amino peptidase MetAP which help the bacteria build their cell wall and proteins.

Dr. Felix Deschner, the main author of the study, explains that when chlorotonils attach to the cell membrane, potassium ions leak out of the cell. This messes up the cell’s internal balance, affecting its functions and pressure. These effects can kill bacterial cells.

By blocking the enzymes phosphatise YbjG and methionine amino peptidase MetAP at the same time; chlorotonils seriously harm the cell’s abilities to produce certain proteins required for cell to live and function, leading to its death.

This two-part approach also explains why chlorotonils work quickly. They quickly disrupt the cell membrane, making it hard for bacteria to resist. Unlike some traditional antibiotics that target specific enzymes where bacteria can adapt by making more enzymes or structurally changing the enzyme, chlorotonils’ varied attack makes it tougher for bacteria to develop resistance.

Overcoming Multidrug Resistance

The new antibiotic Chlorotonil is better than traditional antibiotics because it works in two ways, making it a strong option against antibiotic resistance bacteria.

Regular antibiotics usually focus on single bacterial function like cell wall synthesis. Bacteria can evolve our self through these challenges by doing single mutation in the target pathway.

Chlorotonil, on the other hand, attacks bacteria in two different ways. This means bacteria need to change in two places at the same time to become resistant, which is much less likely to happen. This makes it harder for bacteria to fight back.

However the dual action of Chlorotonil helps each other, making it effective even without combining it with other antibiotics. This makes treatment simpler than using several antibiotics at once.

Implications and Future Research

Researchers at the Helmholtz Centre for Infection Research (HZI) and the Hans Knoll Institute (HKI) are actively advancing the development of chlorotonil-based compounds, particularly focusing on a derivative named dehalogenil. This compound has demonstrated potent activity against both sexual and asexual stages of the malaria parasite Plasmodium falciparum, with no observed resistance under laboratory conditions.

In addition to malaria, chlorotonil derivatives are being investigated for their efficacy against persistent intestinal pathogens like Clostridioides difficile. Studies have shown that chlorotonil A (ChA) can effectively combat dormant stages of C. difficile, which are often resistant to conventional antibiotics, and does so with minimal disruption to the gut microbiome.

The future prospects for researchers at HZI and HKI include advancing dehalogenil through preclinical development, exploring its potential against other resistant pathogens, and collaborating with clinical partners to assess its efficacy in human trials. These efforts are supported by funding from initiatives like GO-Bio initial and the German Center for Infection Research (DZIF), which aim to translate promising compounds into viable therapeutic options.

Conclusion

As antibiotic resistance escalates, innovative solutions like chlorotonils offer hope. Their dual-action mechanism presents a robust strategy against MDR pathogens, reinforcing the importance of natural products in drug discovery. With further research, chlorotonils could become a critical weapon in the fight against superbugs.

References

1. Deschner, Felix et al., Natural products chlorotonils exert a complex antibacterial mechanism and address multiple targets, Cell Chemical Biology, Volume 0, Issue 0, available from https://www.cell.com/action/showPdf?pii=S2451-9456%2825%2900095-9

2. Chlorotonils: Naturals antibiotics’ dual-action mechanism against multidrug-resistant pathogens uncovered, Phys Org, 15 April 2025, available from https://phys.org/news/2025-04-chlorotonils-naturals-antibiotics-dual-action.html

3. W. Hofer, F. Deschner, G. Jézéquel, L. Functionalization of Chlorotonils: Dehalogenil as promising lead compound in vivo application, Angew. Chem. Int. Ed. 2024, 63, e202319765.  https://doi.org/10.1002/anie.202319765

4. Chlorotonil: Game-Changer in the Fight against Multidrug-Resistant Pathogens, Helmholtz Centre for Infection Research, 15 April 2025, available from https://www.helmholtz-hzi.de/en/media-center/newsroom/news-detail/chlorotonil-game-changer-in-the-fight-against-multidrug-resistant-pathogens/

lariocidin

Scientists Discover Lariocidin, a Potent Lasso Shaped Antibiotic in Garden Soil

by with No Comment Disease & DrugsResearch

Written By: Lavanya Chavhan B.Pharm

Reviewed by Vikas Londhe M.Pharm (Pharmacology)

lariocidin

In a remarkable twist of scientific serendipity, researchers have discovered a powerful new antibiotic in an unexpected place a soil sample taken from a technician’s garden. The compound, named lariocidin, belongs to a rare class of antibiotics known as lasso peptides, and has shown promising results in combating drug-resistant bacteria.

A Backyard Breakthrough

Researchers from McMaster University in Ontario, Canada, and the University of Illinois, Chicago, led by Gerry Wright, worked together to discover lariocidin a compound shown to be effective against drug-resistant bacteria.

The discovery came during routine screening of soil samples for potential antimicrobial agents. One particular sample, taken from a home garden, yielded a previously unknown strain of bacteria that produced a unique antimicrobial compound. Upon further study, scientists isolated and characterized lariocidin, a small, intricately folded peptide that adopts a lasso-like structure.

Lasso peptides are named for their distinctive topology — a loop formed by the peptide backbone is threaded by its tail and locked into place, forming a mechanically constrained molecule. This unique structure often contributes to their stability and resistance to degradation, making them particularly appealing as drug candidates.

Lasso Peptide

A lasso peptide is a type of ribosomally synthesized and post-translationally modified peptide (RiPP) that has a unique and highly stable three-dimensional structure, resembling a lasso or slipknot.

Lasso peptides are characterized by A macrolactam ring (a circular peptide structure) at the N-terminus. A tail segment that threads through this ring during synthesis. The tail is “locked” in place by bulky amino acid residues or disulfide bonds, preventing it from slipping back out much like a rope threaded through a loop and pulled tight, hence the name lasso.

This structure is thermodynamically stable and resistant to heat, enzymatic degradation, and extreme pH conditions.

Targeting the Ribosome: A Novel Mechanism

What sets lariocidin apart is its mechanism of action. Unlike many antibiotics that attack bacterial cell walls or DNA replication, lariocidin targets bacterial ribosomes the machinery responsible for protein synthesis. It binds tightly to the ribosome and disrupts translation, halting the production of essential proteins needed for bacterial survival and replication.

Structural studies revealed that lariocidin latches onto a previously underexplored site on the ribosome, a feature that likely contributes to its efficacy against multi-drug resistant strains. This includes pathogens such as Staphylococcus aureus, Enterococcus faecium, and certain strains of Pseudomonas aeruginosa, which have become increasingly difficult to treat with conventional antibiotics.

A Weapon against Superbugs

The rise of antibiotic resistance is a global public health crisis. Each year, antimicrobial-resistant infections claim hundreds of thousands of lives worldwide. The emergence of lariocidin offers a glimmer of hope, especially since it belongs to a relatively untapped class of natural antibiotics with novel mechanisms of action.

Early laboratory studies have demonstrated that lariocidin is not only potent but also exhibits low toxicity to human cells, an essential step toward potential clinical development. Researchers are now working to synthesize analogs of lariocidin, optimize its pharmacokinetics, and assess its efficacy in animal models of infection.

Current status of Lariocidin

In preclinical testing, lariocidin showed strong antibacterial effects without exhibiting toxicity to human cells. In mouse models infected with A. baumannii, the antibiotic significantly lowered bacterial levels and improved survival outcomes.

At present, scientists are working to optimize lariocidin’s potency and are developing scalable production methods to support future clinical use. Although the results so far are encouraging, additional research and clinical trials are essential to confirm its safety and effectiveness in humans.

Nature Still Has Secrets to Reveal

The story of lariocidin is a potent reminder that nature, even in the soil of a backyard garden remains a vast and largely unexplored resource for life-saving compounds. With rising antibiotic resistance threatening global health, the discovery underscores the importance of continued investment in natural product research and microbial biodiversity.

If further studies validate its safety and effectiveness, lariocidin could represent the first in a new class of antibiotics, one that might help turn the tide against resistant bacterial infections.

References

1.Jangra, M., Travin, D.Y., Aleksandrova, E.V. et al.A broad-spectrum lasso peptide antibiotic targeting the bacterial ribosome. Nature(2025). https://doi.org/10.1038/s41586-025-08723-7

2. New lasso-shaped antibiotic kills drug-resistant bacteria, Nature Podcast, Nature, 26 March 2025

3. Julian D. Hegemann, Marcel Zimmermann, Xiulan Xie et al, Lasso Peptides: An Intriguing Class of Bacterial Natural Products, Accounts of Chemical ResearchVol 48, Issue 7 2015

4. Cheng Cheng, Zi-Chun Hua et al, Lasso Peptides: Heterologous Production and Potential Medical Application, Front. Bioeng. Biotechnol. Volume 8 – 2020 https://doi.org/10.3389/fbioe.2020.571165

5. Digging in the dirt: Scientists discover a new antibiotic compound from an old source, University of Minnesota, 31 March 2025

6.Molecule Discovered In Backyard Soil Can Fight Drug Resistant Bacteria, Technology Networks Immunology and Microbiology, 28 March 2025

 

epv

Earth Day Spotlight: How Ecopharmacovigilance Protects the Planet from Pharmaceutical Pollution

by with No Comment Disease & DrugsResearch

Medically Written and Reviewed by Vikas Londhe M.Pharm (Pharmacology)

epv

As we honour Earth Day and reflect on our collective duty to protect the environment, a lesser-known but critical issue deserves the spotlight: Ecopharmacovigilance. In the era where much attention is given to industrial emissions and plastic waste, Very few people are aware of the silent threat created by pharmaceuticals entering the ecosystems. That’s where ecopharmacovigilance comes in

What is Ecopharmacovigilance?

Pharmaceuticals are meant to be developed for the consumption of humans; however, once humans consume pharmaceuticals, the by-products or remains are excreted into the environment in different ways, and once they enter the environment, they start polluting nature and harming the aquatic animals and other species, including soil and trees. Hence, where pharmacovigilance is the detection and understanding of the side effects of pharmaceuticals on humans, ecopharmacovigilance refers to the science and activities related to the detection, evaluation, understanding, and prevention of adverse effects or other problems related to the presence of pharmaceuticals in the environment. On a broader scale, it is monitoring the presence of pharmaceuticals in the environment, assessing the impact on non-target organisms, understanding it thoroughly, and developing the preventive strategies in a way that any harm to nature due to the presence of pharmaceuticals in the environment should be avoided timely and appropriately.

According to the World Health Organization, treated sewage water, surface water, drinking water, groundwater, sediment, soil, and biota contain hundreds of pharmaceuticals. Increasing use of drugs worldwide, and some of them are resistant to degradation, are the main reasons behind their presence in harmful quantities in nature. The most notable pathways of these pharmaceuticals are excretion of used drugs, drug manufacturing, industrial and home wastewater, aquaculture, manure application, landfills, and incineration.

Why Should We Care?

While pharmaceuticals are essential for human and animal health, their unintended environmental footprint is becoming increasingly evident. Studies have shown:

Increasing Antibiotic Resistance: Antibiotic resistance, or antimicrobial resistance (AMR), poses a global threat due to the irrational use of antibiotics; however, the presence of antibiotics in the environment makes the condition worse, as the exposed antibiotics in open environments make bacterial infections hard to treat. AMR caused an estimated 1.27 million deaths globally in 2019.

Effect on aquatic life: As most of the drugs end up in aquatic bodies like rivers, streams, ponds, and oceans through pathways mentioned above, they are not designed to be there or show a positive effect on wildlife present in waters. They show a negative effect on aquatic animals like fish and affect their ability to reproduce, cause behavior changes, or have direct toxic effects. Hormonal drugs, like estrogens from contraceptives, are supposed to be causing these types of effects. Some reports show that male fish were feminized by ethinyl estradiol and frogs were killed by contraceptive tablets. Psychiatric and cardiovascular drugs have been linked to altered behavior and physiological changes in aquatic animals. Some reports related to it show that aggression is caused in lobsters due to antidepressants and spawning in shellfish by fluoxetine.

Current Status of Ecopharmacovigilance

Regulatory Recognition

The OECD report Pharmaceutical Residues in Freshwater: Hazards and Policy Responses highlights the growing concern over pharmaceutical contamination in global freshwater systems due to human and veterinary use, manufacturing, and improper disposal.

The report emphasizes the need for a life cycle, multi-sectoral approach involving source-directed, use-oriented, and end-of-pipe solutions. This includes better monitoring, green pharmaceutical design, responsible prescription and use, proper disposal systems, and advanced wastewater treatment.

International Cooperation Needed: The report also emphasizes the importance of data sharing, international standards, public education, and financial strategies to implement sustainable pharmaceutical pollution control.

EMA and FDA integrated environmental risk assessments (ERAs) into the drug approval process

The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have taken significant steps to integrate Environmental Risk Assessments (ERAs) into the drug approval process, marking a growing recognition of the environmental impact of pharmaceuticals.

Environmental risk assessments evaluate the potential environmental impact of a pharmaceutical substance once it enters ecosystems, typically through human excretion, improper disposal, or manufacturing waste. These assessments analyze factors such as persistence in the environment, bioaccumulation in wildlife, toxicity to aquatic and terrestrial organisms, and potential for environmental transformation into harmful by-products.

Since 2005, the EMA has required ERAs for all new marketing authorization applications in the EU.

The FDA has also implemented environmental reviews under the National Environmental Policy Act (NEPA). For human drugs, applicants typically submit an Environmental Assessment (EA) or a claim for categorical exclusion, depending on the drug’s characteristics. The FDA assesses factors such as expected introduction into the environment, manufacturing and disposal practices, and the cumulative impact of widespread use.

As awareness of pharmaceutical pollution grows, both agencies are expected to tighten guidelines, enhance transparency, and collaborate internationally on standardized ERA methodologies. This reflects a shift toward sustainable drug development that balances therapeutic benefit with environmental responsibility.

What Can You Do?

On Earth Day and every day individuals can play a role in supporting ecopharmacovigilance:

Proper Medication Disposal

Don’t flush unused meds in the toilet or sink.

Use take-back programs: Many pharmacies and communities have medication disposal programs.

If no programs are available, follow the FDA’s or local authority’s guidelines for trash disposal (e.g., mix with unpalatable substances like coffee grounds or cat litter, then seal in a bag).

Buy Only What You Need

Avoid stockpiling medications. It reduces waste and environmental load from expired drugs.

Use Medications Responsibly

Follow prescriptions exactly—using less or more than necessary not only harms health but also leads to excess drugs in the environment.

Spread Awareness

Talk to friends and family about why proper disposal matters

Share posts or articles about EPV and pharmaceutical pollution.

Ask Your Pharmacist

If unsure about disposal or environmentally safer alternatives, ask to your pharmacist. Pharmacist is the healthcare provider who is easily accessible compare to other HCPs. Added to it possesses good knowledge about medicine use and disposal. So some may offer eco-friendly info or take-back services.

Support Green Pharmacies

Support pharmacies and drug companies who are committed to reducing environmental impact (e.g., sustainable packaging, greener drug production).

Advocate for Change

Encourage local governments and health organizations to implement and promote better environmental drug policies.

Avoid Unnecessary Use of Over-the-Counter Drugs

Many people take OTC drugs like painkillers or antacids unnecessarily. This leads to increased production, use, and environmental excretion.

Looking Ahead

Ecopharmacovigilance is still evolving, but it’s becoming an essential part of environmental health strategies. With collaborative efforts from the healthcare industry, regulators, and the public, we can reduce the ecological footprint of lifesaving medicines.

References:

1. Ecopharmacovigilance: Ensuring Environmental Safety from Pharmaceuticals, Uppsala Reports, 15 Oct 2024, available form https://uppsalareports.org/articles/ecopharmacovigilance-ensuring-environmental-safety-from-pharmaceuticals/

2. The Impact of Pharmaceuticals Released to the Environment, United state environmental Protection Agency.

3. Dutta A, Banerjee A, Chaudhry S. Ecopharmacovigilance: Need of the hour. Indian J Pharm Pharmacol 2022;9(2):77-80.

4. Eapen JV, Thomas S, Antony S, George P, Antony J. A review of the effects of pharmaceutical pollutants on humans and aquatic ecosystem. Explor Drug Sci. 2024; 2:484–507. https://doi.org/10.37349/eds.2024.00058

5. OECD (2019), Pharmaceutical Residues in Freshwater: Hazards and Policy Responses, OECD Studies on Water, OECD Publishing, Paris, https://doi.org/10.1787/c936f42d-en

6. Paut Kusturica M, Jevtic M and Ristovski JT (2022), minimizing the environmental impact of unused pharmaceuticals: Review focused on prevention. Front. Environ. Sci. 10:1077974. Doi: 10.3389/fenvs.2022.1077974

7. Guideline on the environmental risk assessment of medicinal products for human use, Committee for Medicinal Products for Human Use (CHMP), European Medicine Agency.

8. Environmental Impact Review at CDER, 07 Jan 2025, US Food and Drug Administration, available fromhttps://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/environmental-impact-review-cder

MS

Could High-Dose Vitamin D Help Fight Early Multiple Sclerosis? New Evidence Says Yes

by with No Comment Disease & DrugsResearch

Written and Reviewed by Vikas Londhe M.Pharm (Pharmacology)

MS

A recent study published in JAMA on March 10, 2025, titled “High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial,” investigated the efficacy of high-dose cholecalciferol (vitamin D) as a monotherapy in reducing disease activity in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). This randomized clinical trial enrolled participants diagnosed with CIS, a condition characterized by a single episode of neurological symptoms indicative of MS. The objective was to determine whether high-dose vitamin D supplementation could delay or prevent the progression from CIS to clinically definite MS.​ The trial’s results indicated that participants receiving high-dose vitamin D exhibited a significant reduction in disease activity compared to those in the placebo group. Specifically, MRI scans revealed fewer new or enlarging lesions in the vitamin D group, suggesting a potential neuroprotective effect of high-dose cholecalciferol in the early stages of MS.

Link between Vitamin D and MS

Multiple sclerosis (MS) is a long-term disease that affects the central nervous system by damaging the protective covering of nerves (myelin). This damage disrupts nerve signals, causing symptoms that vary from mild fatigue to severe paralysis and cognitive issues. The exact cause is unknown, but it likely involves both genetics and environmental factors. MS affects over 2.8 million people worldwide and is a major cause of disability in young adults.

Vitamin D is a fat-soluble vitamin that is important for strong bones and maintaining calcium levels in the body. It also plays a role in regulating the immune system. Vitamin D works by interacting with a specific receptor Vitamin D receptor (VDR) found in many immune cells. Research suggests that it can affect the immune system by reducing the growth of certain T cells, supporting regulatory T cells, and influencing the production of inflammatory substances like cytokines. Because of these effects, scientists are interested in studying whether vitamin D supplements could help manage multiple sclerosis (MS), a disease linked to immune system dysfunction.

The D-Lay MS Trial (NCT01817166): The D-Lay MS trial was a rigorous, double-blind, placebo-controlled study conducted across 36 MS centers in France. Recruitment spanned from July 2013 to December 2020, with final follow-ups completed in January 2023. The study aimed to determine whether high-dose cholecalciferol (vitamin D3) could reduce disease activity in individuals diagnosed with CIS or early-stage relapsing-remitting MS (RRMS).

A total of 316 patients aged 18–55 years, diagnosed with CIS within the previous 90 days, were enrolled. Inclusion criteria required a serum vitamin D concentration below 100 nmol/L and MRI findings consistent with the 2010 MS diagnostic criteria. Notably, participants had not received any prior disease-modifying treatments.

Intervention and Study Groups: Participants were randomly assigned to one of two groups:

High-dose cholecalciferol (100,000 IU) every two weeks (n = 163)

Placebo group receiving a matching supplement (n = 153)

The intervention period lasted 24 months, during which disease activity and clinical outcomes were closely monitored.

Key Outcomes and Findings The primary endpoint of the study was disease activity, defined as the occurrence of relapses and/or MRI activity (new or contrast-enhancing lesions). Secondary outcomes included MRI-based disease activity measures, clinical relapses, and safety assessments.

Primary Outcome Results

60.3% of patients in the vitamin D group experienced disease activity, compared to 74.1% in the placebo group. The time to disease activity was significantly longer in the vitamin D group (432 days) compared to the placebo group (224 days).

MRI-Based Findings: Patients in the vitamin D group demonstrated significant reductions in MRI-based disease activity: MRI activity: 57.1% in the vitamin D group vs. 65.3% in the placebo group.

New lesion occurrence: 46.2% in the vitamin D group vs. 59.2% in the placebo group.

Contrast-enhancing lesions: 18.6% in the vitamin D group vs. 34.0% in the placebo group.

Clinical Outcomes and Safety While MRI-based improvements were evident, no significant differences in relapse rates were observed:

17.9% of patients in the vitamin D group experienced relapses vs. 21.8% in the placebo group

Regarding safety, severe adverse events were reported in 17 patients in the vitamin D group and 13 patients in the placebo group. However, none of the adverse events were directly attributed to vitamin D supplementation.

Interpretation and Clinical Implications

This study provides strong evidence that high-dose vitamin D can reduce MRI-based disease activity in CIS and early MS. These findings suggest potential neuroprotective and immunomodulatory effects, possibly delaying progression to clinically definite MS. However, the lack of significant impact on relapse rates indicates that vitamin D supplementation may not be a stand-alone treatment but could serve as an adjunct to existing disease-modifying therapies.

Conclusion and Future Directions

The D-Lay MS trial highlights the benefits of high-dose vitamin D (100,000 IU biweekly) in reducing MRI-based disease activity. Although it did not significantly impact relapse rates, the delayed onset of disease activity suggests its potential as an early intervention strategy. Further research is needed to optimize dosing, assess long-term safety, and evaluate the role of vitamin D in combination with other MS treatments.

References

  1. Feige J, Moser T, Bieler L, et al, Vitamin D Supplementation in Multiple Sclerosis: A Critical Analysis of Potentials and Threats. Nutrients. 2020 Mar 16;12(3):783. Doi: 10.3390/nu12030783. PMID: 32188044; PMCID: PMC7146466.
  2. Aderinto, N., Olatunji, G., Kokori, E. et al.High-dose vitamin D supplementation in multiple sclerosis: a systematic review of clinical effects and future directions. Discov Med1, 12 (2024). https://doi.org/10.1007/s44337-024-00023-9
  3. Thouvenot E, Laplaud D, Lebrun-Frenay C, et al. High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial. JAMA.Published online March 10, 2025. doi:10.1001/jama.2025.1604

4. Sintzel, M.B., Rametta, M. & Reder, A.T. Vitamin D and Multiple Sclerosis: A Comprehensive Review. Neurol Ther 7, 59–85 (2018). https://doi.org/10.1007/s40120-017-0086-4