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Recent trends and emerging alternatives for combating antibiotic resistance

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By: Soumya Ranganathan, M.S.

Image by Arek Socha from Pixabay 

Antibiotic resistance is an ongoing and rising global threat. While there is a tendency for bacteria and other microbes to develop resistance to antibiotics and antimicrobials slowly over time, the overuse and abuse of antibiotics has accelerated this effect and has led to the current crisis. The new Global Antimicrobial Surveillance System (GLASS), developed by the World Health Organization (WHO), reveals antibiotic resistance is found in 500,000 people with suspected infections across 22 countries. A study supported by the UK government and the Wellcome Trust estimates that antimicrobial resistance (AMR) could lead to an annual death toll of about 10 million by 2050. It is also predicted to have a huge economic impact and could cost 100 trillion USD between 2017 and 2050

Factors underlying the non-targeted use of antibiotics

Prescribing the right antibiotic for an infection takes about a week due to the process of identifying the infectious agent. To avoid the spread of infection, physicians are forced to make a prognosis prior to agent identification, and typically prescribe a broad-spectrum antibiotic. Since the broad-spectrum antibiotics act against a wide range of bacterial strains, their rampant use has led to the emergence of bacterial strains which are resistant to even the most potent antibiotics available. This trend has caused difficulty in treating previously curable hospital acquired infections and other benign infections. Not only is the discovery of new antibiotics is complicated (only one new class of antibiotics has been developed in the past three decades), the development of antibiotics, from discovery to medicine,  also in general takes about 1 to 2 decades. Here we will explore certain alternative strategies scientists all around the world are pursuing in their fight against antibiotic resistance. 

Antibiotic Susceptibility Test  

Reducing the time between a patient becoming ill and receiving treatment is critical for containing and effectively treating the infection. A part of this process that is currently required entails making improvements to the antibiotic susceptibility testing (AST) system, which typically has two steps: (i) Identifying the infectious agent and (ii) Identifying the most effective antibiotic to treat the infection.

Conceptually, new and rapid AST systems have been proposed and developed thanks to advancements in phenotyping methods, digital imaging and genomic approaches. But a plethora of factors act as roadblocks for implementing rigorous and standardized AST systems worldwide. A recently published consensus statement explores the major roadblocks for the development and effective implementation of these technologies while also suggesting ways to move past this stalemate. The major points of the statement are summarized below. 

  • Regulation– Since different regions and countries have their own requirements for marketing and validating a diagnostic method, the onus is on the developers to meet various demands. This also requires harmonization and cooperation among policy makers to formulate and agree on a standard set of rules.
  • Collection and dissemination of information regarding various strains and antibiotics– Antibiograms are a summary of antimicrobial susceptibility rates for selected pathogens to a variety of antimicrobial drugs, provide comprehensive information about the local antibiotic resistance. The challenge here lies in making the data available in real time and in developing a “smart antibiogram”.This is necessary to perform quicker analysis of samples and to reduce the time to treat which eventually translates to increase in lives saved. 
  • Cost involved in developing new, sensitive, and faster diagnostics– Though current diagnostics are cheap they are slow in identifying pathogenic bacteria. The transition to more advanced and sensitive diagnostics has been slow since their developmenttake time and incur more cost. However, this scenario is likely to change soon with the rising levels of antibiotic resistance that are making existing diagnostics obsolete, effectuating more investment in this sector. 

Antivirulence therapy

Small molecules are gaining prominence as an alternative or as adjuvants to antibiotic treatments. Recently, researchers from Case Western University have developed two small molecules F19 and F12 that show promise in the treatment of methicillin resistant Staphylococcus aureus(MRSA) infection in mouse models. The small molecules bind to a Staph. aureustranscription factor called AgrA, deterring it from making toxic proteins and rendering the bacteria harmless. Treatment with F19 on its own resulted in 100% survival rate in a murine MRSA bacteremia/sepsis model while only 30% of untreated mice survived. This kind of antivirulence therapy allows the immune system to clear the pathogens (since the bacteria are essentially harmless) without increasing pressure to develop resistance. When used as an adjuvant with antibiotic, F19 resulted in 10X times lesser bacteria in the mouse bloodstream than treatment with antibiotic alone. This kind of combination therapy can be used on immunocompromised patients. It has also been effective against other bacterial species such as Staph. epidermidis, Strep. pyogenes, and Strep. pneumoniaeand may act as arsenal for a broad variety of gram-positive bacterial infections. Overall the small molecule approach could also bring many of the previously shelved antibiotics back to use as they provide means to improve their efficacy in treating bacterial infections. Another class of engineered proteins called Centyrins show promise to treat Staph. aureusinfection using a similar mechanism, as they bind to the bacterial toxins and prevent them from disrupting the immune system. 

Molecular Boosters

Stanford University chemists (study published in Journal of the American Chemical Society) have developed a booster molecule called r8 which when used in combination with vancomycin (first line antibiotic used for MRSA infections), helps the antibiotic penetrate the biofilm and remain for a long time, enabling it to attack pathogens once they resurge from their dormant stage. This small molecule booster approach could be pursued further to provide existing antibiotics with additional abilities in sieging the pathogens and arresting the spread of infections.

Photobleaching

A recent collaborative effort by scientists from Purdue University and Boston University has resulted in an innovative light-based approach called photobleaching (using light to alter the activity of molecules) to treat certain bacterial infections. Photobleaching of MRSA using low-level blue (460nm) light has been found to lead to the breakdown of STX, an antioxidant (pigment) found in the membrane of bacteria. Since STX protects the bacteria against neutrophils (a class of white blood cells involved in body’s immune mechanism), prior attempts have been made using medication to eliminate the STX but those efforts have been futile. Photolysis of STX leads to transient increase in the permeability of bacterial membrane, rendering them more susceptible to even mild antiseptics like hydrogen peroxide and other reactive oxygen species. Since pigmentation is a “hallmark of multiple pathogenic microbes” this technology could be extended for use in other microbes to tackle resistance. In addition to advantages such as ease of use and development, photobleaching could also be used with minimal or no adverse side effects. 

Antisense Therapy

One of the consequences of the non-targeted use of antibiotics to treat infections has been the occurrence of C.difficileinfection in the colon. This condition is due to the elimination of useful bacteria along with the harmful bacteria in the gut. To tackle this infection, Dr. Stewart’s team from the University of Arizona has developed an antisense therapy which act by silencing genes responsible for the survival of pathogenic bacteria while sparing other useful bacteria in the gut. This strategy involves using molecules with two components – an antisense oligonucleotide moiety that targets the genetic material in C.diffand a carrier compound to transport the genetic material into the bacterium. Though this treatment approach shows potential in providing a targeted, less-toxic, nimble and cost-effective alternative against existing and evolving pathogens, clinical trials must be undertaken to see its effects in practice.

Future perspectives

In addition to the aforementioned strategies, the scientific community is pursuing immune modulation therapy, host-directed therapy, and probiotics to deal with the current AMR crisis. The problem with developing new antibiotics is that microbes will eventually develop resistance to them. Though time will reveal the approaches that are truly effective in evading antibiotic resistance, the looming threat must be dealt with prudently. A holistic approach to restrict and channel the targeted use of antibiotics while pursuing alternative therapies must be adopted by the clinicians, researchers, companies, global health experts, public and policy makers to curb the resistance emergency.

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Written by sciencepolicyforall

April 26, 2019 at 4:35 pm

Posted in Essays

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The need for regulation of artificial intelligence

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By: Jayasai Rajagopal, Ph.D.


Source: Wikimedia

The development and improvement of artificial intelligence (AI) portends change and revolution in many fields. A quick glance at the Wikipedia article on applications of artificial intelligence highlights the breadth of fields that have already been affected by these developments: healthcare, marketing, finance, music and may others. As these algorithms increase their complexity and grow in their ability to solve more diverse problems, the need to define rules by which AI is developed becomes more and more important.

            Before explaining the potential pitfalls of AI, a brief explanation of the technology is required. Attempting to define artificial intelligence begs the question of what is meant by intelligence in the first place. Poole, Mackworth and Goebel clarify that for an agent to be considered intelligent, they must adapt to their surrounding circumstances, learn from changes in those circumstances, and apply that experience in pursuit of a particular goal. A machine that is able to adapt to changing parameters, adjust its programming, and continue to pursue a specified directive is an example of artificial intelligence. While such simulacra are found throughout science fiction, dating back to Mary Shelly’s Frankenstein, they are a more recent phenomenon in the real world. 

            Development of AI technology has taken off within the last few decades, as computer processing power has increased. Computers began successfully competing against humans in chess as early as 1997 with DeepBlue’s victory over Garry Kasparov. In recent years, computers have started to earn victories in even more complex games such as Go and even video games such as Dota 2. Artificial intelligence programs have become common place for many companies which use them to monitor their products and improve the performance of their services. A report in 2017 found that one in five companies employed some form of AI in their workings. Such applications are only going to become more commonplace in the future.

In the healthcare field, the prominence of AI is readily visible. A report by BGV predicted a total of $6.6 billion invested into AI within healthcare by the year of 2021. Accenture found that this could lead to saving of up to $150 billion by 2026. With the recent push towards personalized and precision medicine, AI can greatly improve the treatment and quality of care. 

However, there are pitfalls associated with AI. At the forefront, AI poses a potential risk for abuse by bad actors. Companies and websites are frequently reported in the news for being hacked and losing customer’s personal information. The 2017 WannaCry attack crippled the UK’s healthcare system, as regular operations at many institutions were halted due to their compromised data infrastructures. While cyberdefenses will evolve with the use of AI, there is a legitimate fear that bad actors could just as easily utilize AI in their attacks. Regulation of use and development of AI can limit the number of such actors that could access those technologies.

Another concern with AI is the privacy question associated with the amount of data required. Neural networks, which seek to imitate the neurological processing of the human brain, require large amounts of data to reliably generate their conclusions. Such large amounts of data need to be curated carefully to make sure that identifying information that could compromise the privacy of citizens is not easily divulged. Additionally, data mining and other AI algorithms could information that individuals may not want revealed. In 2012, a coupon suggestion algorithm used by Target was able to discern the probability that some of their shoppers were pregnant. This proved problematic for one teenager, whose father wanted to know why Target was sending his daughter coupons for maternity clothes and baby cribs. As with the cyberwarfare concern, regulation is a critical component in protecting the privacy of citizens.

Finally, in some fields including healthcare, there is an ever present concern that artificial intelligence may replace some operations entirely. For example, in radiology, there is a fear that improvements in image analysis and computer-aided diagnosis by the use of neural networks could replace clinicians. For the healthcare field in particular, this raises several important ethical questions. What if the diagnosis of an algorithm disagrees with a clinician? As the knowledge an algorithm has is limited by the information it is exposed to, how will it react when a unique case is presented? From this perspective, regulation of AI is important not only to address practical concerns, but also pre-emptively answer ethical questions.

While regulation as strict as the Asmiov’s Three Laws may not be required, a more uniform set of rules governing AI is required. At the international level, there is much debate among the members of the United Nations as to how to address the issue of cyber security. Other organizations, such as the European Union, have made more progress. A document recently released by the EU highlights some ethical guidelines which may serve as the foundation for future regulations. At the domestic level, there has been a push from scientists and leaders in the field towards harnessing the development of artificial intelligence for the good of all. In particular, significant headway has been made in the regulation of self-driving cars. Laws passed in California restrict how the cars can be tested and by 2014, four states already had legislation applying to these kinds of cars. 

Moreover, the FDA recently released a statement expressing their approach to the regulation of artificial intelligence in the context of medical devices. At the time of this writing, there is a discussion paper that is open for commentary describing the proposed approach that the FDA may take. They note that the conventional methods of acquiring pre-market clearance for devices may not apply to artificial intelligence. The newly proposed framework adapts existing practices to the context of software improvements.  

Regulation must also be handled with care. Over-limitation of the use and research in artificial intelligence could lead to stifling of development. Laws must be made with knowledge of the potential benefits of new technological advancements could cause. As noted by Gurkaynak, Yilmaz, and Haksever, lawmakers must strike a balance between preserving the interests of humanity and the benefits of technological improvement. Indeed, artificial intelligence poses many challenges for legal scholars.

In the end, artificial intelligence is an exciting technological development that can change the way we go about our daily business. With proper regulation, legislation, and research focus, this technology can be harnessed in a way that benefits the human experience while preserving development and the security of persons.

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April 18, 2019 at 2:25 pm

Science Policy Around the Web – April 2, 2019

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By: Patrice J. Persad Ph.D.

Image by Jason Gillman from Pixabay

Worrisome nonstick chemicals are common in U.S. drinking water, federal study suggests

What lurks in our drinking water—and all its effects on organismal health—may be more of a mystery than what resides in the deep recesses of our oceans. In a recent investigation conducted by the United States Geological Survey and the Environmental Protection Agency (EPA), manmade per- and polyfluroalkyl substances (PFAS) tainted drinking water samples were analyzed. PFAS, which put the “proof” in water-proof items, are substances of concern, or, more aptly, contaminants of emerging concern (CECs), given their potential carcinogenicity and permanence in ecosystems. Perfluorooctane acid (PFOA), a PFAS discontinued in production domestically, was at a concentration over 70 nanograms per liter (ng/l) in a sample. A trio of other PFAS surpassed this concentration level, as well. A standard level issued by federal agencies has yet to transpire. However, the Centers for Control of Disease(CDC) attests that the existing cut-off of 70 ng/l is unacceptable in that it is not sufficiently low, or conservative, with respect to human health. 

The Environmental Working Group(EWG) suspects that over 100 million individuals in the U.S. drink water with PFAS. Citizens currently advocate for authorities to test drinking water samples and disclose PFAS concentrations. Without setting standards, accountability for future detriments to health is up in the air. Only through discussion with the public, policy makers, the research community, and parties formerly or currently producing PFAS can we set safeguards to protect our water supply plus well-being. 

(Natasha Gilbert, Science)


To Protect Imperiled Salmon, Fish Advocates Want To Shoot Some Gulls

In recreating the fundamental question “Who stole the cookies from the cookie jar?”, nature’s version spins off as “Who stole the juvenile salmon from Miller Island?” In this spiraling whodunit mystery, an unexpected avian culprit surfaces: the gull. According to avian predation coordinator Blaine Parker, surveys revealed that a fifth of imperiled salmon were whisked away by gulls near channels flowing out of dams. Gulls also spirited away these juvenile fish from other avian predators, such as Caspian terns. Parker maintains that not every gull is a perpetrator of decreasing the species’ numbers; gulls can assist with the population control of other birds who feast on the juveniles. Therefore, he supports killing the individual gulls disturbing juvenile salmon booms—lethal management.

Although there has been precedent of sacrificing avian species for the security of juvenile salmon, several entities denounce lethal management of wayward gulls affecting the young fish’s survival rates. The Audubon Society of Portlandpoint out that the Army Corps. of Engineers’ modifications to dams for warding away gulls, or other airborne predators, are slipshod and ineffective, if not inexistent. The U.S. Army Corps., despite this criticism, avows that killing specific gulls is only a final resort. From Parker and these organizations’ opposing viewpoints, a new mystery migrates to the surface. Will killing avian predators populating dams and waterways have a significant impact on the endangered salmons’ survival? Research collaboration on ecological impacts may be a way to tell or reassess the futures of both juvenile salmon and gulls. 

(Courtney Flatt, Northwest Public Broadcasting/National Public Radio



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April 3, 2019 at 10:32 am

Science Policy Around the Web – March 26, 2019

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By: Neetu M. Gulati Ph.D.

Image by Dimitris Vetsikas from Pixabay

Sunscreen ban aimed at protecting coral reefs spark debate – among scientists

Corals around the world have begun “bleaching,” turning white and expelling the algae that live within them. After a 2015 study found that oxybenzone can harm corals, environmentalists have worked to bar the sale of sunscreens containing the chemical. Last year, Hawaii was the first US state to ban sale of sunscreens containing oxybenzone, as well as another harmful chemical octinoxate, which are found in up to 75% of sunscreens on the US market. The ban will go into effect in 2021. Florida and California are considering similar laws. However, while some are fighting to limit the use of these toxic chemicals, others say the major issue is not sunscreen – it’s climate change.

Evidence indicates that harmful chemicals and warming oceans due to climate change are both damaging corals and leading to bleaching. Scientists agree that the major contributing factor is climate change and the chemicals play a lesser role. Nevertheless, they disagree about what should be done. C. Mark Eakin, an oceanographer and the coordinator for NOAA’s Coral Reef Watch program, commented “if we don’t deal with climate change, it won’t matter what we do about sunscreens.” Furthermore, some people believe there is not enough clear evidence explaining how damaging these chemicals can be. While many scientists share this viewpoint, others think that every step towards saving the corals matters. Some lawmakers agree with this philosophy; Teri Johnston, the mayor of Key West, Florida, said of banning the harmful chemicals, “if it’s something we can do to minimize damage to reefs, it’s one small step we’re going to take.” The city of Key West banned the sale of sunscreens containing oxybenzone and octinoxate last month, an act that will go into effect in 2021.

Damage to coral reefs is a complicated issue, with multiple stressors likely to be involved: not only climate change and sunscreens, but also pollution and other harmful chemicals. While many are worried about protecting the reefs, there is also concern as to how these bans will affect human health. In response to the Hawaii ban, the Skin Cancer Foundation put out a statement which said, “by removing access to a significant number of products, this ban will give people another excuse to skip sun protection, putting them at greater risk for skin cancer.” 

One possible solution is to expand the number of ingredients permitted in sunscreen, to allow for other protective chemicals that are less harmful to the environment. The FDA has not expanded its list of approved ingredients in approximately 20 years. Comparatively, Europe allows for more chemicals, hopeful that any one single chemical will have a less harmful environmental impact when more diversity of ingredients is allowed. Towards this end, the FDA recently proposed new regulationsto improve American sunscreens.

(Rebecca Beitsch, Washington Post

In a first, U.S. private sector employs nearly as many Ph.D.s as schools do 

The career landscape for burgeoning PhDs has changed drastically in the last 20 years; while the number of PhDs awarded has increased, especially in the fields of life and health sciences, the proportion of PhDs employed in tenured and tenure-track positions has declined. This is in contrast to what some current faculty members, who may assume that tenure track positions are the standard path for PhDs, and other career paths are “alternative.” According to the Survey of Doctorate Recipients from the US National Science Foundation (NSF), in 2017, for the first time, private sector employment of PhDs (42%) is nearly equivalent to employment by educational institutions (43%). This is in stark contrast to 1997, when educational institutions employed 11% more PhDs than the private sector. While the survey takes into consideration all PhDs under the age of 76 who are employed full-time in the US, it is expected that newer PhDs are less likely to secure tenure-track positions. 

As career trajectories change, some universities are using new information about PhD outcomes to improve programming for current graduate and prospective students. According to the Coalition for Next Generation Life Science, ten academic institutions have released data onlineabout the career outcomes of their PhD graduates, with more institutions planning to release similar data by the end of next year. The data indicates the traditional model of training, which treats graduate school like an apprenticeship to becoming faculty, is outdated. Other skills that transfer beyond educational institutions, may be necessary to successfully train the next generation of PhDs. 

(Katie Langin, Science)



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March 26, 2019 at 5:00 pm

Science Policy Around the Web – March 22, 2019

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By: Caroline Duncombe.

Image by 1388843 from Pixabay

FDA Approves First Drug for Postpartum Depression

In the USA, about 400,000 women develop post-partum depression (PPD) each year. Up until Tuesday, there was no FDA approved pharmaceutical treatment designed specifically for PPD. In attempts to alleviate PPD episodes, doctors previously prescribed drugs designed for general depression, such as selective serotonin-reuptake inhibitors (SSRIs). Such drugs were not specifically designed for PPD which involves distinct mechanisms of action that are directly related to pregnancy and childbirth. SSRIs often take months to achieve remission or adequate response, if ever. Such deficiencies are supposedly addressed by the new drug, brexanolone, marketed at Zulresso, which was designed specifically to address post-partum depression and acheives rapid onset of response alleviation.

Although brexanolone is the first FDA approved treatment for PPD, the long infusion period, the high cost of the treatment, and lacking evidence on the effectiveness of this treatment demonstrate the long road ahead before PPD treatment is ubiquitous and operational. The Brexanolone treatment is not simple: it involves a continuous intravenous (IV) infusion over the course of 60 hours. Due to the risk of the treatment, patients will be required to stay within an in-patient unit of a hospital for those 2.5 days. Considering that the treatment alone cost $34,000 for a full course, the additional cost of in-patient care would make this treatment inaccessible for many who demonstrate severe PPD. Some insurance providers may decide to cover the treatment cost, but for those who do not have insurance or are denied coverage this treatment will be inaccessible.

Additionally, the FDA approval application was largely informed by a flawed phase III clinical trial funded by Sage Pharmaceuticals, the producer of Zulresso. The trial only included 246 participants, which is a relatively small sample size for a phase III trial. A large sample size is important to providing a conclusive clinical trial result on drug side-effects. This is crucial because if a severe side effect is found within 1 in every 1000 participants (or 1 in 10,000, etc) that level of risk would most likely not be detected within a trial only enrolling 246 participants. Additionally, this specific trial compared participants to a placebo, and not existing treatment standards of anti-depressants like SSRIs. The trail also only assessed the women volunteers over a 30-day follow-up period post infusion, which means that the lasting effects beyond the first month of Brexanolone are still unknown.

Further research on Brexanolone will be necessary to definitively assess its impact of reducing PPD. At this moment Sage Therapeutics is also implementing a phase III trialon a PPD treatment drug that is structurally similar to Bexanolone but is capable of being administered via a pill. If successful, such a drug could make treatment for post-partum depression more accessible to all. 

(Pam Belluck, New York Times)



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March 22, 2019 at 5:24 pm

Taming the “Natural” – Regulating Dietary Supplements and Botanicals in the US

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By: Katelyn Lavrich, Ph.D.

Image by Seksak Kerdkanno from Pixabay

Taking supplements is a part of the American culture, as three out of four Americans use a dietary supplement. An estimated 50,000-80,000 unique supplements are on the market, with over 20,000 botanical supplements in the U.S. marketplace. Dietary supplements are defined as a product intended for ingestion but not representing a complete or conventional food source.  They are marketed in many different forms, including powders, capsules, gummies, and teas. Botanical and herbal supplements are a subset of dietary supplements containing whole plants, parts of plants, powdered plant material or plant extracts. Dietary supplements are usually marketed as beneficial for health and often recommended by physicians, especially as we age. 

In February 2019, the FDA announced“one of the most significant modernizations of dietary supplement regulation and oversight in more than 25 years.” Though plants and herbal remedies have been used in therapeutics since the beginning of civilization, companies are now capitalizing on our obsession with health using ‘natural’ products. The dietary supplement industry is estimated to be over $40 billion a yearand rapidly growing, with some estimates that it could hit over $278 billion by 2024. Of that market, an estimated $7.5 billionwas spent on botanical supplements in 2016. 

As part of the FDA’s announcement, 17 warning letters were sent to companies for illegally marketing products to prevent, treat, or cure Alzheimer’s disease, diabetes, and cancer. This highlights a key distinction between dietary supplements and pharmaceutical drugs. Dietary supplements are substances that are used to add nutrients to the diet or lower the risk of health problems but have not been rigorously tested to help specific diseases. Pharmaceutical drugs go through years of testing for safety and efficacy before ever making it to market. Dietary supplements are regulated in the U.S. under the Dietary Supplement Health and Education Act of 1994 (DSHEA). This law establishes the FDA’s role in regulating safety of botanical supplements once the product is on the market. The FDA can only take action against a misbranded or adulterated supplement after the product is already on the market. The agency tracks side effects reported by consumers and supplement companies, and can take legal action against a manufacturer or distributor if a product is found unsafe. They can also issue a warning or require that the product be removed from the marketplace. DHSEA places the liability on the company to have evidence of safety prior to introducing a drug on the market. No organization must prove efficacy of the product, and the FDA strictly prohibits health claims. This leaves thousands of supplements on the market with little idea of their safety before people consume them.

Dietary supplement safety is not straightforward, especially when evaluating botanical supplements. Botanicals are complex mixtures of chemical constituents and these mixtures can be highly variable based on the plant background and how the plant is processed. In contrast to pharmaceutical drugs that usually only have one active chemical in them, botanical supplements may have several active chemicals in them that can interfere with multiple biological functions all at once to different degrees. Manufacturing processes add a high degree of variability to safety testing of botanical supplements as many are proprietary, and often differ between companies. 

Contaminants can be introduced into botanical products during the manufacturing process. Intentional adulteration of botanical products is a serious concern worldwide. There have been documented cases of botanicals being spiked with pharmaceutical additives to enhance the marketed effect. For examples, stimulants, antidepressants, appetite suppressants, and laxatives have all been found in weight-loss supplements. And phosphodiesterase-5 inhibitors, such as Viagra, have been found in botanical supplements marketed for sexual performance. While intentional adulteration is a concern for the botanical industry, more common are likely non-pharmaceutical contaminants introduced unintentionally during the manufacturing process. 

The FDA is taking steps to improve how they regulate dietary supplements. They’re developing a tool to rapidly alert the public of when products have been shown to contain unlawful or potentially dangerous ingredients. The tool would also alert manufacturers to avoid making or selling these ingredients. The FDA is establishing guidelines requiring the submission of new dietary ingredient (NDI) notifications, giving the agency an opportunity to evaluate the safety of a new ingredient before it comes on market. While these are positives steps to improve safety knowledge to all stakeholders for single ingredients, these actions fail to take into account the potential synergistic effects ofthe mixture of ingredients together in dietary supplements.

Standardization is needed to measure and adjust the ratio of key components to help control batch-to-batch variability. Plant identification is complicated, because many features are lost during the manufacturing process. Several standards have been released including the United States Pharmacopeia (USP), the European Pharmacopoeia and the Pharmacopoeia of the P eople’s Republic of China. While these resources set out guidelines for specifications and tests in Good Manufacturing Practice settings, they are not mandatory for dietary supplements in the U.S.

Because of the high variability between products, reproducibility in research studies using botanical supplements is a major issue. NIH’s National Center for Complementary and Integrative Health released a natural product integrity policy in 2007 to require that all NIH grants address composition of research materials. Any clinical research that is evaluating the efficacy of a botanical product in “curing, treating, or mitigating a disease” shifts the research to the pharmaceutical approval track. Researches must submit an Investigational New Drug (IND) application, forcing exhaustive analysis of the product. However, the IND process makes the composition of botanicals proprietary. Better reporting and more transparency is needed in preclinical research using botanicals. The National Institute of Neurological Disorders and Stroke released a 2012 report recommending better reporting of samples size, randomization methods, and data analysis details. Of the studies they reviewed ,only 15% of clinical trials on popular botanicals (e.g. Echinacea, Ginkgo Biloba, St. John’s Wort) reported that they tested the content of the botanical, and only 4% provided enough information to compare the measure content to the expected content. 

Manufacturers of botanicals are under numerous legal obligations to ensure their products are not adulterated. Some manufacturers pursue external certification from U.S. Pharmacopeia (USP) or NSF international, though USP has only verified 139 productsto date. There is a zero-tolerance policy for all foods imported from outside the US, including botanicals. If any level of pesticide residue is detected, even if it is extremely low, it will be rejected at US ports of entry, even if the botanical is of the highest quality standards and would be allowed on the European market. Manufacturers are urging the EPA to set tolerances for pesticides on imported botanicals, as the zero-tolerance standard is nearly impossible to obtain, especially with new technology enabling extremely low limits of quantitation. 

The rapid growth of the dietary supplement industry is from the increased demand for health and wellness products. Often touted as a “healthy” alternative to pharmaceutical drugs, dietary supplements are plagued by a lack of safety regulations and manufacturing standards. Due to their complexity, toxicologists and risk assessors are alike still working out best practices to measure and interpret findings from mixtures. Collaboration between manufacturing, production, and research agencies is essential to learn how to best provide safe supplements and more information to consumers.

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March 15, 2019 at 10:46 am

Science Policy Around the Web – February 15, 2019

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By: Saurav Seshadri Ph.D.

Source: Pixabay

Hundreds protest against Washington state vaccine bill that would require measles shots

With over 58 people infected so far, the measles outbreak affecting the Pacific Northwest since January is a genuine public health emergency.  Still, local lawmakers are finding that they may have an even bigger challenge to overcome in preventing the next one.  The epicenter of the outbreak, Clark County, has one of the lowest vaccination rates in the country, with fewer than 80% of children receiving the recommended two doses of the measles-mumps-rubella (MMR) vaccine (far below the herd immunity threshold of 93-95%).  A bill sponsored by state Rep. Paul Harris, which aims to rectify this by limiting vaccine exemptions for non-medical reasons, was recently met with stiff opposition from anti-vaccination activists, who are particularly prominent in the region and turned out in the hundreds to protest.  Activists argue that the legislation would force parents to expose their children to risky medical procedures.  Such opposition, from groups such as Informed Choice Washington, prevented a similar bill introduced in 2015 from even making it to a vote.

However, while activists have been the most vocal and visible opponents of the bill, they may not be representative of the parents who are actually opting not to vaccinate in Clark County.  Portland is home to a large number of families from the former Soviet Union, many of whom are wary of vaccines for cultural or religious reasons.  Some Russian-language schools have vaccine exemption rates of over 50%.  The strain of measles in Clark County is the same one that recently sickened over 40,000 people in Ukraine, suggesting that the current outbreak may have originated within this community.  Any legislative solution may therefore have to tread carefully to avoid singling out a specific ethnic group.  

Furthermore, it’s unclear whether the proposed bill would be effective in promoting vaccination.  After a measles outbreak in 2015 that sickened 147 people, California eliminated ‘personal belief’ exemptions in both public and private schools; since then, medical exemptions (often issued with little justification and/or in exchange for a fee) have more than tripled.  While old studies linking vaccines to autism have been thoroughly debunked, their core message, that vaccines are inherently unsafe, has been tougher to eradicate.  This is partly because it bears a grain of truth: the CDC acknowledges that side effects of the MMR vaccine can include seizures and brain damage, and lists several scenarios in which its administration is contraindicated.  Despite these risks, in the wake of a potentially deadly outbreak, many will likely agree that public health must be prioritized and voluntary vaccination will resume.  If not, parents who truly fear the consequences of vaccination may be left with no other option but to educate their children at home.

(Ashley May, USA Today

Antidepressant based on party drug gets backing from FDA advisory groupT

Since 2006, scientists have known that the anesthetic ketamine is shockingly effective in treating depression.  Moreover, it can improve mood within hours, and is mechanistically distinct from existing antidepressants, meaning it can potentially help patients who are currently suicidal or whose depression is treatment-resistant.  While ketamine itself has been used as an anesthetic since the 1960s and cannot be patented, these findings were promising enough to motivate several drug companies to try to develop marketable variants.  One such compound, esketamine (produced by Johnson and Johnson), has just gotten a step closer to FDA approval: an independent advisory panel has voted to recommend its use for treating depression, based on the results of five phase III trials and several other supporting studies. The drug had previously received a Breakthrough Therapy Designation by the FDA, and an official decision from the agency is expected by early March.     

Ketamine is also a hallucinogen, a club drug known as Special K, a potential drug of abuse, and described by the DEA as ‘sometimes used to facilitate sexual assault crimes’.  Its transition to respectable pharmaceutical is therefore somewhat surprising, and could be indicative of a change in how such compounds are perceived by the government and society in general.  Medical marijuana is often prescribed to treat seizures, and last year, the FDA approved the first drug containing an active (though not psychoactive) ingredient derived from marijuana.  A more relevant example may be psilocybin, the active component of magic mushrooms.  The DEA describes psilocybin as a hallucinogenic drug of abuse, whose side effects include panic attacks, psychosis, and death; yet the FDA recently granted Breakthrough Designation to psilocybin therapy for treatment-resistant depression (a large-scale clinical trial, conducted by COMPASS Pathways, will take place this year).    

While the overall clinical efficacy reported by J&J for esketamine was modest, at least some panelists were convinced to approve the drug based on patient reports that its effects were worth any side effects.  As we enter the seventh decade since the discovery of the last novel antidepressant (or antipsychotic), such feedback may play a larger role in convincing regulatory bodies to try new treatments, even if they have been previously stigmatized or their mechanisms of action are unclear.  By allowing supervised administration, patient registration, monitoring, and research, bringing such drugs out of the shadows could provide welcome relief for people suffering from mental illness.  

(Sara Reardon, Nature)

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Written by sciencepolicyforall

February 15, 2019 at 3:23 pm