tag:theconversation.com,2011:/ca/topics/drug-side-effects-30990/articlesDrug side effects – The Conversation2023-09-15T12:31:41Ztag:theconversation.com,2011:article/2093122023-09-15T12:31:41Z2023-09-15T12:31:41ZCan at-home DNA tests predict how you’ll respond to your medications? Pharmacists explain the risks and benefits of pharmacogenetic testing<figure><img src="https://images.theconversation.com/files/545852/original/file-20230831-15-xftd5k.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2070%2C1449&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Pharmacogenetic testing is a form of precision medicine, using your genes to personalize your care.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/medicine-concept-royalty-free-image/815702424">D3Damon/E+ via Getty Images</a></span></figcaption></figure><p>Have you ever wondered why certain medications <a href="https://theconversation.com/why-prescription-drugs-can-work-differently-for-different-people-168645">don’t seem to work as well</a> for you as they do for others? This variability in drug response is what pharmacogenomic testing hopes to explain by looking at the genes within your DNA. </p>
<p><a href="https://www.cdc.gov/genomics/disease/pharma.htm">Pharmacogenomics, or PGx</a>, is the study of how genes affect your response to medications. <a href="https://www.genome.gov/genetics-glossary/Gene">Genes are segments of DNA</a> that serve as an instruction manual for cells to make proteins. Some of these proteins break down or transport certain medications through the body. Others are proteins that medications target to generate a desired effect.</p>
<p><a href="https://www.pharmacy.pitt.edu/people/kayla-rowe">As pharmacists</a> <a href="https://scholar.google.com/citations?user=9Np7_DYAAAAJ&hl=en">who see</a> <a href="https://scholar.google.com/citations?user=LKG31OkAAAAJ&hl=en">patients who</a> have stopped multiple medications because of side effects or ineffectiveness, we believe pharmacogenomic testing has the potential to help guide health care professionals to more precise dosing and prescribing.</p>
<h2>How do PGx tests work?</h2>
<p><a href="https://medlineplus.gov/lab-tests/pharmacogenetic-tests/">PGx tests</a> look for variations within the genes of your DNA to predict drug response. For instance, the presence of one genetic variant might predict that the specific protein it codes for is unable to break down a particular medication. This could potentially lead to increased drug levels in your body and an increased risk of side effects. The presence of another genetic variant might predict the opposite: It might predict that the protein it codes for is breaking down a medication more rapidly than expected, which may decrease the drug’s effectiveness.</p>
<p>For example, <a href="https://doi.org/10.1002/cpt.2903">citalopram is an antidepressant</a> broken down by a protein called CYP2C19. Patients with genetic variants that code for a version of this protein with a reduced ability to break down the drug may have an increased risk of side effects.</p>
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<figcaption><span class="caption">PGx is a form of personalized or precision medicine.</span></figcaption>
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<p>Currently, there are over 80 medications with <a href="https://cpicpgx.org/">prescribing recommendations</a> based on PGx results, including treatments for depression, cancer and heart disease. There are commercially available PGx tests that patients can have sent directly to their doorstep with or without the involvement of a health care professional. These direct-to-consumer PGx tests collect DNA from either a saliva sample or cheek swab that is then sent to the laboratory. Results can take anywhere from a few days to a few weeks depending on the company. </p>
<p>Some companies <a href="https://doi.org/10.1038%2Fnature15817">require a consultation</a> with a health care provider, often a pharmacist or genetic counselor, who can facilitate a test order and discuss any medication changes once the results come back. </p>
<h2>Limitations of PGx testing</h2>
<p>PGx testing will not be able to predict how you will respond to all medications for several reasons.</p>
<p>First, most PGx tests <a href="https://doi.org/10.3390/genes11121456">do not look for every possible variant</a> of every gene in the human genome. Instead, they look only at a limited number of genes and variants strongly linked to specific drugs. PGx tests can predict how you will respond only to medications associated with the genes it tests for. </p>
<p>Some drugs are broken down in very complicated pathways entailing multiple proteins and byproducts, and the usefulness of PGx testing for them remains unclear. For example, the <a href="https://www.pharmgkb.org/pathway/PA166170276">antidepressant bupropion</a> has three major pathways involved in its breakdown and forms three active byproducts that can interact with other drugs or body processes. This makes predicting how you will respond to the drug much more challenging because there is more than one variable involved. In many cases, there also isn’t conclusive data to confidently predict the general function of a protein and how it would affect your response to a drug.</p>
<p>The applicability of PGx test results is additionally limited by a <a href="https://theconversation.com/uncovering-the-genetic-basis-of-mental-illness-requires-data-and-tools-that-arent-just-based-on-white-people-this-international-team-is-collecting-dna-samples-around-the-globe-185997">lack of diversity of study participants</a>. Typically, populations of European ancestry are overrepresented in clinical trials. An ongoing research initiative by the National Institutes of Health called the <a href="https://allofus.nih.gov/">All of Us Research Program</a> aims to address this issue by collecting genetic samples from people of diverse backgrounds. </p>
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<figcaption><span class="caption">The All of Us research program seeks to conduct research that is more representative of a diverse population.</span></figcaption>
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<p>Another limitation of direct-to-consumer PGx tests is that they can predict drug response based only on your genetics. <a href="https://my.clevelandclinic.org/health/diagnostics/21093-pharmacogenomics">Lifestyle and environmental factors</a> such as your age, liver or kidney function, tobacco use, drug interactions and other diseases can heavily influence how you may respond to medication. For example, leafy greens with high amounts of vitamin K can <a href="https://www.pennmedicine.org/updates/blogs/heart-and-vascular-blog/2015/june/consistency-not-avoidance-the-truth-about-blood-thinners-leafy-greens-and-vitamin-k">lower the effectiveness</a> of the blood thinner warfarin. But PGx tests don’t take these factors into account.</p>
<p>Finally, your PGx results may predict that you may respond to medications differently, but this does not guarantee that the medication won’t have its intended effect. In other words, PGx testing is predictive rather than deterministic.</p>
<h2>Risks of PGx testing</h2>
<p>PGx testing carries the risk of not telling the whole story of drug response. If variations within the gene are not found, the testing company often assumes the proteins those genes code for function normally. Because of this assumption, someone carrying a rare or unknown variant may receive inaccurate results.</p>
<p>It may be tempting for some people to see their results and want to change their dose or discontinue their medications. However, this can be dangerous. Abruptly stopping some medications may cause withdrawal effects. Never change the way you take your medications without consulting your pharmacist and physician first.</p>
<p>Sharing your PGx test results with all the clinicians involved in your care can help prevent medication failure and improve safety. Pharmacists are increasingly trained in pharmacogenomics and can serve as a resource to address medication-related questions or concerns.</p>
<p>PGx tests that are not authorized by the Food and Drug Administration cannot be clinically interpreted and therefore cannot be used to inform prescribing. Results from these tests should not be added to your medical record.</p>
<h2>Benefits of PGx testing</h2>
<p>Direct-to-consumer PGx testing can empower patients to advocate for themselves and be an active participant in their health care by increasing access to and knowledge of their genetic information.</p>
<p>Patients’ knowledge of their PGx genetic profile has the potential to improve treatment safety. For example, a 2023 study of over 6,000 patients in Europe found that those who used their PGx results to guide medication therapy were <a href="https://doi.org/10.1016/s0140-6736(22)01841-4">30% less likely</a> to experience adverse drug reactions.</p>
<p>Most PGx test results stay valid throughout a patient’s life, and <a href="https://mhealthfairview.org/services/pharmacogenomics">retesting is not needed</a> unless additional genes or variants need to be evaluated. As more research on gene variants is conducted, prescribing recommendations may be updated. </p>
<p>Overall, genetic information from direct-to-consumer PGx tests can help you collaborate with health care professionals to select more effective medications with a lower risk of side effects.</p><img src="https://counter.theconversation.com/content/209312/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Genetic testing can help take the guesswork out of finding the right treatment. For certain diseases. To an extent.Kayla B. Rowe, Fellow in Clinical Pharmacogenomics, University of PittsburghLucas A. Berenbrok, Associate Professor of Pharmacy and Therapeutics, University of PittsburghPhilip Empey, Associate Professor of Pharmacogenomics, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2045222023-05-30T12:24:11Z2023-05-30T12:24:11ZYour body naturally produces opioids without causing addiction or overdose – studying how this process works could help reduce the side effects of opioid drugs<figure><img src="https://images.theconversation.com/files/528436/original/file-20230525-27-cw53qp.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2309%2C1299&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Opioid neurotransmitters are located in many areas of the body, including the brain, spine and gut.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/neurotransmitter-release-mechanisms-royalty-free-image/1396888608">ALIOUI Mohammed Elamine/iStock via Getty Images Plus</a></span></figcaption></figure><p>Opioid drugs such as morphine and fentanyl are like the two-faced Roman god Janus: The kindly face delivers pain relief to millions of sufferers, while the grim face drives an opioid abuse and overdose crisis that <a href="https://www.cdc.gov/drugoverdose/deaths/index.html">claimed nearly 70,000 lives</a> in the U.S. in 2020 alone. </p>
<p><a href="https://scholar.google.com/citations?user=LXVL7f0AAAAJ&hl=en">Scientists like me who study pain and opioids</a> have been seeking a way to separate these two seemingly inseparable faces of opioids. Researchers are trying to design drugs that deliver effective pain relief without the risk of side effects, including addiction and overdose.</p>
<p>One possible path to achieving that goal lies in understanding the molecular pathways opioids use to carry out their effects in your body.</p>
<h2>How do opioids work?</h2>
<p>The <a href="https://pubmed.ncbi.nlm.nih.gov/16082232/">opioid system in your body</a> is a set of neurotransmitters your brain naturally produces that enable communication between neurons and activate protein receptors. These neurotransmitters include small proteinlike molecules like <a href="https://doi.org/10.1124/mol.120.119388">enkephalins and endorphins</a>. These molecules regulate a tremendous number of functions in your body, including pain, pleasure, memory, the movements of your digestive system and more.</p>
<p>Opioid neurotransmitters activate receptors that are <a href="https://www.ncbi.nlm.nih.gov/books/NBK546642/">located in a lot of places</a> in your body, including pain centers in your spinal cord and brain, reward and pleasure centers in your brain, and throughout the neurons in your gut. Normally, opioid neurotransmitters are released in only small quantities in these exact locations, so your body can use this system in a balanced way to regulate itself.</p>
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<figcaption><span class="caption">The opioids your body produces and opioid drugs bind to the same receptors.</span></figcaption>
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<p>The problem comes when you take an opioid drug like morphine or fentanyl, especially at high doses for a long time. These drugs <a href="https://theconversation.com/how-do-drugs-know-where-to-go-in-the-body-a-pharmaceutical-scientist-explains-why-some-medications-are-swallowed-while-others-are-injected-182488">travel through the bloodstream</a> and can activate every opioid receptor in your body. You’ll get pain relief through the pain centers in your spinal cord and brain. But you’ll also get a euphoric high when those drugs hit your brain’s reward and pleasure centers, and that could <a href="https://doi.org/10.1016%2FS2215-0366(16)00104-8">lead to addiction</a> with repeated use. When the drug hits your gut, you may develop constipation, along with other common <a href="https://www.asahq.org/madeforthismoment/pain-management/opioid-treatment/what-are-opioids/">opioid side effects</a>.</p>
<h2>Targeting opioid signal transduction</h2>
<p>How can scientists design opioid drugs that won’t cause side effects?</p>
<p>One approach my research team and I take is to understand how cells respond when they receive the message from an opioid neurotransmitter. Neuroscientists call this process <a href="https://doi.org/10.1097%2FALN.0b013e318238bba6">opioid receptor signal transduction</a>. Just as neurotransmitters are a communication network within your brain, each neuron also has a communication network that connects receptors to proteins within the neuron. When these connections are made, they trigger specific effects like pain relief. So, after a natural opioid neurotransmitter or a synthetic opioid drug activates an opioid receptor, it activates proteins within the cell that carry out the effects of the neurotransmitter or the drug.</p>
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<figcaption><span class="caption">Cells communicate with one another in multiple ways.</span></figcaption>
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<p>Opioid signal transduction is complex, and scientists are just starting to figure out how it works. However, one thing is clear: Not every protein involved in this process does the same thing. Some are more important for pain relief, while some are more important for side effects like <a href="https://theconversation.com/pain-and-anxiety-are-linked-to-breathing-in-mouse-brains-suggesting-a-potential-target-to-prevent-opioid-overdose-deaths-174187">respiratory depression</a>, or the decrease in breathing rate that makes overdoses fatal.</p>
<p>So what if we target the “good” signals like pain relief, and avoid the “bad” signals that lead to addiction and death? Researchers are tackling this idea in different ways. In fact, in 2020 the U.S. Food and Drug Administration <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-new-opioid-intravenous-use-hospitals-other-controlled-clinical-settings">approved the first opioid drug based on this idea</a>, oliceridine, as a painkiller with fewer respiratory side effects.</p>
<p>However, relying on just one drug has downsides. That drug might not work well for all people or for all types of pain. It could also have other side effects that show up only later on. Plenty of options are needed to treat all patients in need.</p>
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<a href="https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="drawing depicting a tangle of red, blue and yellow curly and straight lines" src="https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=800&fit=crop&dpr=1 600w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=800&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=800&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1006&fit=crop&dpr=1 754w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1006&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/528435/original/file-20230525-23265-15id3l.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1006&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This figure shows the structure of Hsp90.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/heat-shock-protein-90-chaperone-complex-royalty-free-illustration/185759601">Laguna Design/Science Photo Library via Getty Images</a></span>
</figcaption>
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<p>My research team is targeting a protein called <a href="https://doi.org/10.1007/128_2012_356">Heat shock protein 90, or Hsp90</a>, which has many functions inside each cell. Hsp90 has been a hot target in the <a href="https://doi.org/10.3390/ijms221910317">cancer field</a> for years, with researchers developing Hsp90 inhibitors as a treatment for many cancer types. </p>
<p>We’ve found that Hsp90 is also really important in regulating opioid signal transduction. <a href="https://doi.org/10.1074/jbc.m116.769489">Blocking Hsp90 in the brain</a> blocked opioid pain relief. However, <a href="https://doi.org/10.1126/scisignal.aaz1854">blocking Hsp90 in the spinal cord</a> increased opioid pain relief. Our recently published work uncovered more details on exactly how <a href="https://doi.org/10.1126/scisignal.ade2438">inhibiting Hsp90 leads to increased pain relief</a> in the spinal cord.</p>
<p>Our work shows that manipulating opioid signaling through Hsp90 offers a path forward to improve opioid drugs. Taking an Hsp90 inhibitor that targets the spinal cord along with an opioid drug could improve the pain relief the opioid provides while decreasing its side effects. With improved pain relief, you can take less opioid and reduce your risk of addiction. We are <a href="https://reporter.nih.gov/search/zF-FuD_ZC0CFwl6deU7tQw/project-details/10294366">currently developing</a> a new generation of Hsp90 inhibitors that could help realize this goal. </p>
<p>There may be many paths to developing an improved opioid drug without the burdensome side effects of current drugs like morphine and fentanyl. Separating the kindly and grim faces of the opioid Janus could help provide pain relief we need without addiction and overdose.</p><img src="https://counter.theconversation.com/content/204522/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>John Streicher receives funding from the National Institutes of Health, the Arizona Biomedical Research Commission, the Flinn Foundation, and the University of Arizona. He is an equity holder in Teleport Pharmaceuticals, LLC, and Botanical Results, LLC, however, no company products or interests were discussed in this article. </span></em></p>Unlike opioid drugs like morphine and fentanyl that travel throughout the body, the opioids your body produces are released in small quantities to specific locations.John Michael Streicher, Associate Professor of Pharmacology, University of Arizona Health SciencesLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1964712022-12-15T19:00:18Z2022-12-15T19:00:18ZAnti-cancer CAR-T therapy reengineers T cells to kill tumors – and researchers are expanding the limited types of cancer it can target<figure><img src="https://images.theconversation.com/files/501134/original/file-20221214-14385-pkk4by.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2048%2C1364&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Killer T cells (green and red), or cytotoxic T cells, surround a cancer cell (blue, center).</span> <span class="attribution"><a class="source" href="https://flic.kr/p/LDRpJN">NICHD/J. Lippincott-Schwartz</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span></figcaption></figure><p>Teaching the body’s immune cells to recognize and fight cancer is one of the holy grails in medicine. Over the past two decades, researchers <a href="https://doi.org/10.1084%2Fjem.20182395">have developed new immunotherapy drugs</a> that stimulate a patient’s immune cells to significantly shrink or even eliminate tumors. These treatments often focus on increasing the cancer-killing ability of <a href="https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_Biology_(Kimball)/15%3A_The_Anatomy_and_Physiology_of_Animals/15.04%3A_Immune_System/15.4I%3A_Cytotoxic_T_lymphocytes_(CTL)">cytotoxic T cells</a>. However, these treatments appear to only work for the <a href="https://doi.org/10.1056/nejmoa1501824">small group of patients</a> who already have T cells within their tumors. One 2019 study estimated that <a href="https://doi.org/10.1001%2Fjamanetworkopen.2019.2535">under 13%</a> of cancer patients responded to immunotherapy.</p>
<p>To bring the benefits of immunotherapy to more patients, scientists have turned to <a href="https://www.genome.gov/about-genomics/policy-issues/Synthetic-Biology">synthetic biology</a>, a new field of study that seeks to redesign nature with new and more useful functions. Researchers have been developing a novel type of therapy that directly gives patients a new set of T cells engineered to attack tumors: chimeric antigen receptor T cells, or CAR-T cells for short.</p>
<p>As an <a href="https://scholar.google.com/citations?user=qkIs7VUAAAAJ&hl=en">oncology physician and researcher</a>, I believe that CAR-T cell therapy has the potential to transform cancer treatment. It’s already being used to treat <a href="https://doi.org/10.1056/NEJMoa1708566">lymphoma</a> and <a href="https://doi.org/10.1056/NEJMoa1817226">multiple myeloma</a>, and has shown remarkable response rates where other treatments have failed.</p>
<p>However, similar success against certain types of tumors such as lung or pancreatic cancer has been slower to develop because of the unique obstacles they put up against T cells. In our <a href="https://www.science.org/doi/10.1126/science.aba1624">newly published research</a>, my colleagues and I have found that adding a synthetic circuit to CAR-T cells could potentially help them bypass the barriers that tumors put up and enhance their ability to eliminate more types of cancer. </p>
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<figcaption><span class="caption">CAR-T cell therapy is currently only used for certain types of blood cancers.</span></figcaption>
</figure>
<h2>How does CAR-T cell therapy work?</h2>
<p>CAR-T cell therapy starts with doctors isolating a patient’s T cells from a sample of their blood. These T cells are then taken back to the lab, where they are genetically engineered to produce a <a href="https://doi.org/10.1056/NEJMra1706169">chimeric antigen receptor, or CAR</a>. </p>
<p>CARs are synthetic receptors specifically designed to redirect T cells from their usual targets have them recognize and hone in on tumor cells. On the outside of a CAR is a binder that allows the T cell to stick to tumor cells. Binding to a tumor cell activates the engineered T cell to kill and produce <a href="https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/cytokines.html">inflammatory cytokines</a> proteins that support T cell growth and function and boost their cancer-killing abilities.</p>
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<a href="https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Digram of CAR-T therapy process" src="https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=605&fit=crop&dpr=1 600w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=605&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=605&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=760&fit=crop&dpr=1 754w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=760&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=760&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">CAR-T therapy involves engineering a patient’s own T cells to attack their cancer.</span>
<span class="attribution"><a class="source" href="https://visualsonline.cancer.gov/details.cfm?imageid=12069">National Cancer Institute (NCI)</a></span>
</figcaption>
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<p>These CAR-T cells are then stimulated to divide into large numbers over seven to 10 days, then given back to the patient via infusion. The infusion process usually takes place at a hospital where clinicians can monitor for signs of an <a href="https://doi.org/10.1186%2Fs40425-018-0343-9">overactive immune response</a> against tumors, which can be deadly for the patient.</p>
<h2>Driving T cells into solid tumors</h2>
<p>While CAR-T cell therapy has seen success in blood cancers, it has faced hurdles when fighting what are called solid tumor cancers like pancreatic cancer and melanoma. Unlike cancers that begin in the blood, these types of cancers grow into a solid mass that produces a <a href="https://doi.org/10.1016/j.omto.2022.03.009">microenvironment</a> of molecules, cells and structures that prevent T cells from entering into the tumor and triggering an immune response. Here, even CAR-T cells engineered to specifically target a patient’s unique tumor are unable to access it, suppressing their ability to kill tumor cells.</p>
<p>For the synthetic biology community, the failures of the first generation of CAR-T cell therapy was a call to action to develop a new family of synthetic receptors to tackle the unique challenges solid tumors posed. In 2016, my colleagues in the <a href="https://limlab.ucsf.edu">Lim Lab</a> at the University of California, San Francisco developed a new synthetic receptor that could complement the first CAR design. This receptor, called <a href="https://doi.org/10.1016/j.cell.2016.01.012">synthetic Notch receptor, or synNotch</a>, is based on the natural form of Notch in the body, which plays an important role in organ development across many species. </p>
<p>Similar to CARs, the outside of synNotch has a binder that allows T cells to stick to tumor cells. Unlike CARs, the inside of synNotch has a protein that is released when a T cell binds to the tumor. This protein, or transcription factor, allows researchers to better control the T cell by inducing it to produce a specific protein. </p>
<p>For example, one of the most useful applications of synNotch thus far has been to use it to ensure that engineered T cells are only activated when bound to a tumor cell and not healthy cells. Because a CAR may bind to both tumor and healthy cells and induce T cells to kill both, my colleagues engineered T cells that are only activated when <a href="https://doi.org/10.1016/j.cell.2016.01.011">both synNotch and CAR</a> are bound to the tumor cell. Because T cells now require both CAR and synNotch receptors to recognize tumors, this increases the precision of T cell killing.</p>
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<figcaption><span class="caption">Researchers are engineering CAR-T cells to be more precise, and subsequently reduce side effects.</span></figcaption>
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<p>We wondered if we could use synNotch to improve CAR-T cell activity against solid tumors by inducing them to produce more of the inflammatory cytokines, such as IL-2, that enable them to kill tumor cells. Researchers have made many attempts to provide extra IL-2 to help CAR-T cells clear tumors. But because these cytokines are <a href="https://doi.org/10.4049/jimmunol.1490019">highly toxic</a>, there is a limit to how much IL-2 a patient can safely tolerate, limiting their use as a drug.</p>
<p>So we designed CAR-T cells to <a href="https://www.science.org/doi/10.1126/science.aba1624">produce IL-2 using synNotch</a>. Now, when a CAR-T cell encounters a tumor, it produces IL-2 within the tumor instead of outside it, avoiding causing harm to surrounding healthy cells. Because synNotch is able to bypass the barriers tumors put up, it is able to help T cells amp up and maintain the amount of IL-2 they can make, allowing the T cells to keep functioning even in a hostile microenvironment.</p>
<p>We tested our CAR-T cells modified with synNotch on mice with pancreatic cancer and melanoma. We found that CAR-T cells with synNotch-induced IL-2 were able to produce enough extra IL-2 to overcome the tumors’ defensive barriers and fully activate, completely eliminating the tumors. While all of the mice receiving synNotch modified CAR-T cells survived, none of the CAR-T-only mice did.</p>
<p>Furthermore, our synNotch modified CAR-T cells were able to trigger IL-2 production without causing toxicity to healthy cells in the rest of the body. This suggests that our method of engineering T cells to produce this toxic cytokine only where it is needed can help improve the effectiveness of CAR-T cells against cancer while reducing side effects.</p>
<h2>Next steps</h2>
<p>Fundamental questions remain on how this work in mice will translate to people. Our group is currently conducting more studies on using CAR-T cells with synNotch to produce IL-2, with the goal of entering early stage clinical trials to examine its safety and efficacy in patients with pancreatic cancer. </p>
<p>Our findings are one example of how advances in synthetic biology make it possible to engineer solutions to the most fundamental challenges in medicine.</p><img src="https://counter.theconversation.com/content/196471/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gregory Allen receives funding from NIH/NCI and Jane Coffin Childs Memorial Fund for Medical Research. </span></em></p>Immunotherapy has the potential to eliminate tumors, but works best for select patients. Engineering T cells to bypass cancer’s defenses could help expand treatment eligibility to more patients.Gregory Allen, Assistant Professor of Medicine, University of California, San FranciscoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1869072022-07-18T20:06:30Z2022-07-18T20:06:30ZCOVID drugs in Australia: what’s available and how to get them<figure><img src="https://images.theconversation.com/files/474478/original/file-20220718-22-ph1am8.jpg?ixlib=rb-1.1.0&rect=29%2C44%2C4962%2C3285&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://image.shutterstock.com/image-photo/izmir-turkey-november-5-2021-600w-2091989473.jpg">Shutterstock</a></span></figcaption></figure><p>With <a href="https://www.abc.net.au/news/2022-07-14/covid-cases-in-hospital-across-australia/101227156">COVID case numbers expected to rise</a> in Australia over the coming weeks and months there is significant concern the numbers of severely sick patients may overwhelm hospitals.</p>
<p>Thankfully, over time <a href="https://theconversation.com/covid-pandemic-2nd-anniversary-3-things-we-got-wrong-and-3-things-to-watch-out-for-177618">we are learning more about COVID</a> and now have a range of medicines that are effective in treating it, including antivirals. </p>
<p>Which medicine a patient receives, if they even need one at all, will depend on the severity of their symptoms and whether they have any underlying health problems.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/how-are-australia-and-nz-managing-the-rising-covid-winter-wave-and-is-either-getting-it-right-187020">How are Australia and NZ managing the rising COVID winter wave – and is either getting it right?</a>
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<h2>Here is what we have in our COVID arsenal</h2>
<p>When the COVID pandemic began, we didn’t have any drugs to treat the virus. Instead, we had to rely on drugs that could treat COVID symptoms while the body healed itself. </p>
<p>Now we have a range of <a href="https://www.health.gov.au/health-alerts/covid-19/treatments/about">recommended COVID medicines</a> that are either antivirals or antibody-based drugs. These are suitable for both hospitalised and at-home patients and include <a href="https://www.nps.org.au/radar/articles/molnupiravir-lagevrio-for-mild-to-moderate-covid-19">lagevrio</a>, <a href="https://www.nps.org.au/australian-prescriber/articles/remdesivir-for-covid-19">remdesivir</a>, <a href="https://www.tga.gov.au/sites/default/files/paxlovid-pi.pdf">paxlovid</a>, <a href="https://www.health.gov.au/resources/publications/evusheld-fact-sheet-for-health-professionals">evusheld</a> and <a href="https://www.fda.gov/media/149534/download">sotrovimab</a>.</p>
<p>In Australia, there are other antibody drugs available but they are not currently widely used. This includes <a href="https://www.tga.gov.au/covid-19-treatment-roche-products-pty-ltd-casirivimab-imdevimab-ronapreve">ronapreve</a>, which is <a href="https://covid19evidence.net.au/news/taskforce-notes-concerns-about-potential-ronapreve-effectiveness-and-omicron/">less effective</a> against the omicron strain of the virus, and <a href="https://www.tga.gov.au/covid-19-treatment-celltrion-healthcare-australia-pty-ltd-regdanvimab-regkirona">regkirona</a> which is still being explored in <a href="https://app.magicapp.org/#/guideline/L4Q5An/section/nBdr9j">clinical trials</a>.</p>
<p>Other drugs are also used for COVID but, again, they don’t treat the virus. Instead they are mostly used to reduce inflammation in the lungs. </p>
<p>These medicines have all been shown to work in human clinical trials and are either fully or provisionally approved by the Australian <a href="http://tga.gov.au">Therapeutic Goods Administration</a> for the treatment of COVID. </p>
<p>Each COVID medicine works in a different way. Evusheld and sotrovimab comprise antibody molecules that neutralise the virus and block its entry into human cells, whereas paxlovid works by stopping a key enzyme the virus needs to replicate. Both lagevrio and remdesivir work by getting incorporated into the virus’ genetic material and causing mutations to stop the virus from replicating. </p>
<p>Paxlovid and lagevrio come in tablet form while remdesivir, sotrovimab, and evusheld come as injections that need to be administered by a doctor.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/474480/original/file-20220718-4540-ry3cxy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="older man sick in bed with tissue" src="https://images.theconversation.com/files/474480/original/file-20220718-4540-ry3cxy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/474480/original/file-20220718-4540-ry3cxy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/474480/original/file-20220718-4540-ry3cxy.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/474480/original/file-20220718-4540-ry3cxy.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/474480/original/file-20220718-4540-ry3cxy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/474480/original/file-20220718-4540-ry3cxy.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/474480/original/file-20220718-4540-ry3cxy.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Who you are and whether you are at home or in hospital will determine your treatment.</span>
<span class="attribution"><a class="source" href="https://image.shutterstock.com/image-photo/coronavirus-covid19-old-people-senior-600w-1499094236.jpg">Shutterstock</a></span>
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Read more:
<a href="https://theconversation.com/australia-approves-two-new-medicines-in-the-fight-against-covid-how-can-you-get-them-and-are-they-effective-against-omicron-175321">Australia approves two new medicines in the fight against COVID. How can you get them and are they effective against Omicron?</a>
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<h2>The right drug for the right patient</h2>
<p><a href="https://covid19evidence.net.au/wp-content/uploads/DECISION-TOOL-DT-FOR-ADULTS.pdf?=220606-214608">Clinical guidelines</a> direct health staff as to which drug they need to administer to each patient. </p>
<p>Most people who test positive for COVID will not need treatment with an antiviral drug, as current COVID variants tend to induce mild symptoms that can be managed with rest and isolation at home. </p>
<p>For some patients managing COVID at home, certain health factors mean their doctor will prescribe a COVID drug. This includes people who have a poor functioning immune system, those who are not vaccinated or are not up-to-date with vaccinations, and those who are at a high risk of severe disease. </p>
<p>These <a href="https://www.health.gov.au/health-alerts/covid-19/advice-for-groups-at-risk/risk-factors-for-more-serious-illness#:%7E:text=Older%20people%2C%20especially%20those%20aged,someone%20you%20care%20for%2C%20safe.">risk factors</a> include respiratory conditions such as asthma, cardiovascular diseases including high blood pressure, obesity, diabetes and kidney failure. </p>
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<h2>Where you’re treated</h2>
<p>If a patient is sick enough to need hospitalisation, specialist doctors will decide if and what COVID drug to prescribe. </p>
<p>If a COVID drug is needed for an at-home patient both <a href="https://www.health.gov.au/ministers/the-hon-greg-hunt-mp/media/new-covid-19-oral-treatment-on-pbs">lagevrio and paxlovid are available on the Pharmaceutical Benefits Scheme (PBS)</a> for <a href="https://www.pbs.gov.au/publication/factsheets/covid-19-treatments/Factsheet-prescribers-and-pharmacists-COVID-19-treatments-July-2022.pdf">specific people</a> including those over 70, or those over 50 who have one of the risk factors mentioned earlier. </p>
<p>Immunocompromised people over the age of 18, and people who identify as Aboriginal or Torres Strait Islander origin who are over 30 and at high risk, are also eligible for PBS-subsidised lagevrio or paxlovid. </p>
<p>These drugs can be prescribed by a general practitioner (GP) and accessed through a local community pharmacy. If a patient is not able to see their GP in person, a COVID drug can be prescribed by booking a <a href="https://www.health.gov.au/health-topics/health-technologies-and-digital-health/about/telehealth">telehealth appointment</a> with a doctor. The drug can then be delivered to their home from their local pharmacy. Importantly, these drugs must be started within <a href="https://www.tga.gov.au/media-release/tga-provisionally-approves-two-oral-covid-19-treatments-molnupiravir-lagevrio-and-nirmatrelvir-ritonavir-paxlovid">five days of symptom onset</a>.</p>
<p>In some instances an at-home COVID patient may require an injection-only drug such as remdesivir or evusheld, which are only available through the patient’s local hospital network. Sotrovimab is another COVID drug that is only administered in healthcare facilities. This is because patients need to be monitored after they receive the infusion. General practitioners will refer their patients to a local hospital for these treatments.</p>
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Read more:
<a href="https://theconversation.com/i-have-mild-covid-should-i-take-the-antiviral-paxlovid-183913">I have mild COVID – should I take the antiviral Paxlovid?</a>
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<h2>What about side effects?</h2>
<p>All medicines have side effects, even common medications like paracetamol and aspirin. </p>
<p>If patients do experience side effects, these are likely to be specific to the drug being taken. Some of the possible side effects of <a href="https://www.nps.org.au/radar/articles/molnupiravir-lagevrio-for-mild-to-moderate-covid-19">lagevrio</a> include mild to moderate diarrhoea, nausea and dizziness in less than 2% of those trialled.</p>
<p>For <a href="https://www.nps.org.au/radar/articles/nirmatrelvir-and-ritonavir-paxlovid-for-mild-to-moderate-covid-19#r5">paxlovid</a>, side effects can include changes in taste, diarrhoea, headache, and vomiting. Serious side effects, which affect <a href="https://www.tga.gov.au/sites/default/files/paxlovid-pi.pdf">fewer than 2% of patients</a>, include liver problems which can cause prolonged nausea or vomiting, loss of appetite, stomach pain, yellowing eyes or skin, and <a href="https://www.webmd.com/drugs/2/drug-183241/paxlovid-eua-oral/details">dark urine</a>. </p>
<p>Some of the <a href="https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2020-CMI-01929-1&d=20220718172310101">side effects of remdesivir</a> include rash, sweating, fever, shortness of breath, swelling, changes in blood pressure or heart rate, nausea, and shivering.</p>
<p>Patients who experience side effects while taking a COVID drug should see their doctor if they are concerned. If a patient experiences any severe side effects, such as signs of liver problems, then they should call their doctor immediately or go straight to their local hospital.</p><img src="https://counter.theconversation.com/content/186907/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Associate Professor Wheate in the past has received funding from the ACT Cancer Council, Tenovus Scotland, Medical Research Scotland, Scottish Crucible, and the Scottish Universities Life Sciences Alliance. He is a Fellow of the Royal Australian Chemical Institute, a member of the Australasian Pharmaceutical Science Association, and member of the Australian Institute of Company Directors. Nial is the science director of Canngea Pty Ltd, chief scientific officer of Vairea Skincare LLC, and a Standards Australia panel member for sunscreen agents.</span></em></p><p class="fine-print"><em><span>Elise Schubert is a registered pharmacist and a PhD Candidate receiving scholarship from the University of Sydney and Canngea Pty Ltd.</span></em></p><p class="fine-print"><em><span>Dr Pegah Varamini has received funding from the National Breast Cancer Foundation, Therapeutic Innovation Australia (TIA), Pipeline Accelerator Grant, SPARK Oceania, Tour de Cure, Sydney Catalyst, Controlled Release Society, and Australian Pain Society. She is a lecturer and the head of Breast Cancer Targeting & Drug Delivery laboratory at the University of Sydney Pharmacy School. Pegah is affiliated with the World Health Organisation as a scientific advisor within the Global Breast Cancer Initiative and is the Co-Chair of NanoPharma cluster within NanoHealth Initiative at the Sydney Nano Institute.</span></em></p>After testing positive for COVID, your medicine prescription will depend on the severity of your symptoms and any other health conditions you have.Nial Wheate, Associate Professor of the Sydney Pharmacy School, University of SydneyElise Schubert, Pharmacist and PhD Candidate, University of SydneyPegah Varamini, Lecturer in Pharmacy and Pharmacology-Head of Breast Cancer Targeting and Drug Delivery Laboratory, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1849222022-07-11T12:29:55Z2022-07-11T12:29:55ZMany medications affect more than one target in the body – some drug designers are embracing the ‘side effects’ that had been seen as a drawback<figure><img src="https://images.theconversation.com/files/473235/original/file-20220708-14-kbl694.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2035%2C1471&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Depending on how you look at it, drugs that can act on multiple targets could be a boon instead of a challenge.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/multi-exposure-photogram-of-molecular-structure-of-royalty-free-image/886907874">Andrew Brookes/Image Source via Getty Images</a></span></figcaption></figure><p>Drugs don’t always behave exactly as expected. While researchers may develop a drug to perform one specific function that’s perhaps tailored to work for a specific genetic profile, sometimes the drug might perform several other functions outside of its intended purpose. </p>
<p>This concept of drugs having multiple functions, called <a href="https://doi.org/10.1021/acs.jmedchem.8b00760">polypharmacology</a>, may lead to unintended consequences. This is a common occurrence for <a href="https://doi.org/10.1126/scitranslmed.aaw8412">cancer drugs in clinical trials</a> that can have <a href="https://doi.org/10.1586/ecp.12.74">harmful side effects and treatment toxity</a>. </p>
<p>But polypharmacology may in fact be the norm for most drugs, not the exception. So rather than seeing a drug’s ability to perform many functions as a flaw, <a href="https://scholar.google.com/citations?user=iDKZaA4AAAAJ&hl=en">biomedical data scientists like me</a> and my <a href="https://www.waysciencelab.com/">lab colleagues</a> believe that it can be used to our advantage in designing drugs that address the full complexity of biology.</p>
<h2>Drugs often multitask in cells</h2>
<p>When scientists talk about drugs, they like to refer to its <a href="https://www.verywellmind.com/meaning-of-mechanism-of-action-in-health-care-425245">mechanism of action, or MOA</a> – essentially, exactly what a drug does when it enters the body. A drug’s official MOA, however, may not actually include all the ways it can affect cells.</p>
<p>For example, the mechanism of action of a drug labeled as a <a href="https://www.drugs.com/drug-class/vegf-vegfr-inhibitors.html">VEGF inhibitor</a> is to block the activity of a protein called VEGF, or vascular endothelial growth factor, in a cell. While VEGF plays an important role making new blood vessels, a process that’s integral to healthy tissue development, it can also be a <a href="https://doi.org/10.1016/j.cell.2011.02.013">hallmark of cancer</a>. <a href="https://www.webmd.com/cancer/cancer-angiogenesis-inhibitors">Blocking VEGF</a> can stop the formation of new blood vessels that supply nutrients to tumors and prevent the growth and spread of many types of cancers.</p>
<p>There are currently <a href="https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet">14 drugs inhibiting new blood vessel formation</a> approved in the U.S. to treat cancer, and most target VEGF. You may be wondering why there are so many different drugs available if they’re all inhibiting the same protein. The answer comes down to polypharmacology: While they all most likely work by blocking VEGF in some way, each likely has some other function that may be unique to that drug. That alternative function might cause side effects, or only work in certain conditions. </p>
<p>VEGF belongs to a larger group of proteins called <a href="https://doi.org/10.3390/cancers12030731">receptor tyrosine kinases, or RTKs</a>, that are challenging to target individually. Many drugs that target one type of RTK, like VEGF, also end up indiscriminately <a href="https://pubmed.ncbi.nlm.nih.gov/29888050/">targeting other RTKs</a> because they share a <a href="https://doi.org/10.1016/j.chembiol.2018.11.005">similar chemical structure</a>, potentially causing unwanted side effects.</p>
<p>For example, in 1999, scientists discovered that the infamous morning sickness drug thalidomide also worked as a VEGF inhibitor to <a href="https://doi.org/10.1056/nejm199911183412102">treat multiple myeloma</a>, a type of blood cancer. This was a triumph for a drug that, just 70 years prior, was banned worldwide after causing severe birth detects in an estimated <a href="https://doi.org/10.1016/s0140-6736(04)16308-3">10,000 infants</a>, not including miscarriages and stillbirths.</p>
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<figcaption><span class="caption">As in the case of thalidomide, a slight difference in chemical structure can make a huge difference in how a drug affects the body.</span></figcaption>
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<p>Like thalidomide, many chemicals affect the body in many different ways, and their full mechanism of action still isn’t fully understood. Even some approved drugs like lithium, acetaminophen and many antidepressants still have an <a href="https://doi.org/10.1016/j.isci.2020.101487">unclear MOA</a>.</p>
<p>Perhaps the most famous example of the serendipity of polypharmacology is <a href="https://www.history.com/this-day-in-history/fda-approves-viagra">Viagra</a>, a drug that was originally developed for cardiovascular problems but was later approved for erectile dysfunction. Interestingly, there is emerging evidence that Viagra also works as a <a href="https://doi.org/10.1111%2Fj.1582-4934.2008.00319.x">VEGF activator</a>, which may help treat stroke or heart attack. </p>
<h2>Taking advantage of polypharmacology</h2>
<p>The problem is that when you take a drug with multiple functions, you can’t isolate one desired effect from all the others – you get all of them all at once. Researchers can react to polypharmacology in two ways. Scientists can try to design better drugs that home in on just one specific target. Alternatively, scientists can instead embrace the complexity of biology and try to leverage the multifaceted effects drugs can offer.</p>
<p>Many existing drugs have unknown mechanisms that can be harnessed as a strength, rather than a weakness. Researchers can use polypharmacology to <a href="https://theconversation.com/repurposing-generic-drugs-can-reduce-time-and-cost-to-develop-new-treatments-but-low-profitability-remains-a-barrier-174874">repurpose existing drugs</a> to use for other conditions, reducing the time and cost of developing new treatments. There is an entire industry of doctors and scientists currently trying to do exactly that. Chemists and drug designers are also purposefully <a href="https://doi.org/10.1021/acs.jmedchem.8b00760">designing drugs with multiple functions</a> to combat complex diseases like cancer and type 2 diabetes, which may have multiple targets that can escape single-function treatments.</p>
<p>But in order to take advantage of the polypharmacology of existing drugs, researchers require a way to measure it. Typically, chemists study drug mechanisms through laborious experiments that test drugs one at a time and don’t always lead to conclusive answers. However, new experimental approaches, like <a href="https://doi.org/10.1038/s41573-022-00472-w">phenotypic drug screening</a>, that measure the overall effect of the drug instead of trying to narrow down its mechanism of action, allow researchers to measure thousands of different drugs in a single experiment.</p>
<p>My colleagues and I <a href="https://doi.org/10.1371/journal.pcbi.1009888">used this approach</a> to predict all the effects of specific drugs, using nothing but images of cells. We collected 159 million snapshots of cells reacting to over 1,300 different drugs, then applied a machine learning algorithm to identify important patterns in the images. Instead of teaching the algorithm to look for specific details, we allowed it to search for pieces of data in the pictures that allowed it to better predict how a cell would react to different types of drugs. </p>
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<figcaption><span class="caption">Machine learning can help predict how the chemical structure of any particular drug might affect the body.</span></figcaption>
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<p>Our model repurposed an approach called <a href="http://dx.doi.org/10.48550/arXiv.1511.06434">latent space arithmetic</a>, originally developed using pictures of human faces, to predict drugs with polypharmacology. Just as the original algorithm could simulate a picture of a man wearing glasses, we could simulate what a cell looks like when treated with a drug that has multiple mechanisms of action.</p>
<p>Our model was far from perfect, though. Many drug mechanisms of action could not be simulated well, and we were limited by existing, likely incomplete, knowledge about how different drugs worked. Additional work to demystify how different drug mechanisms affect cells in a wider context could help improve predicting all of a drug’s potential functions, leading to more treatment possibilities for each compound. </p>
<p>I believe that embracing polypharmacology as an unavoidable consequence of using drugs to treat diseases can help researchers reimagine the drug discovery process. Could we design a drug that targets all the receptors going haywire in a specific patient’s tumor? Could we use artificial intelligence to simulate how such a potential drug compound might look and behave in the body? Could polypharmacology actually be the answer to precision medicine instead of one of its biggest challenges? A shift in mindset might be the first step to answering these questions.</p><img src="https://counter.theconversation.com/content/184922/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gregory Way does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Many approved drugs work on the body in ways that researchers still aren’t entirely clear about. Seeing this as an opportunity instead of a flaw may lead to better treatments for complex conditions.Gregory Way, Assistant Professor of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1835882022-06-01T12:14:37Z2022-06-01T12:14:37Z‘Masked’ cancer drug stealthily trains immune system to kill tumors while sparing healthy tissues, reducing treatment side effects<figure><img src="https://images.theconversation.com/files/466370/original/file-20220531-14-t0h7ly.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2048%2C2048&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Dendritic cells (green) produce cytokines like IL-12, which can train T cells (pink) to attack tumors.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/JRzxEb">Victor Segura Ibarra and Rita Serda/National Cancer Institute via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>Many cancer treatments are notoriously savage on the body. Drugs often attack both healthy cells and tumor cells, causing a plethora of side effects. <a href="https://www.cancer.gov/about-cancer/treatment/types/immunotherapy">Immunotherapies</a> that help the immune system recognize and attack cancer cells are no different. Though they have <a href="https://doi.org/10.1001/jamanetworkopen.2019.2535">prolonged the lives of countless patients</a>, they work in only a subset of patients. One study found that <a href="https://doi.org/10.3389/fonc.2020.600573">fewer than 30% of breast cancer patients</a> respond to one of the most common forms of immunotherapy. </p>
<p>But what if drugs could be engineered to attack only tumor cells and spare the rest of the body? To that end, <a href="https://pme.uchicago.edu/group/hubbell-lab">my colleagues</a> <a href="https://scholar.google.com/citations?user=7KTLoToAAAAJ&hl=en&oi=ao">and I</a> at the University of Chicago’s <a href="https://pme.uchicago.edu/">Pritzker School of Molecular Engineering</a> have <a href="https://doi.org/10.1038/s41551-022-00888-0">designed a method</a> to keep one promising cancer drug from wreaking havoc by “masking” it until it reaches a tumor.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/K09xzIQ8zsg?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Immunotherapies help the immune system recognize and target cancer cells.</span></figcaption>
</figure>
<h2>The promise of IL-12</h2>
<p><a href="https://doi.org/10.1038/s41416-018-0328-y">Cytokines</a> are proteins that can modulate how the immune system responds to threats. One way they do this is by activating <a href="https://doi.org/10.1038/nri819">killer T cells</a>, a type of white blood cells that can attack cancer cells. Because cytokines can train the immune system to kill tumors, this makes them very promising as cancer treatments.</p>
<p>One such cytokine is interleukin-12, or IL-12. Though it was <a href="https://doi.org/10.1084%2Fjem.2045fta">discovered more than 30 years ago</a>, IL-12 still isn’t an FDA-approved therapy for cancer patients because of its <a href="https://doi.org/10.1126/science.270.5238.908.a">severe side effects</a>, such as liver damage. This is in part because IL-12 instructs immune cells to produce a large amount of inflammatory molecules that can damage the body.</p>
<p>Scientists have since been working to reengineer IL-12 to be more tolerable while retaining its powerful cancer-killing effects.</p>
<h2>Masking the killer</h2>
<p>To create a safer version of IL-12, my colleagues and I took advantage of one of the main differences between healthy and cancerous tissue: an excess of growth-promoting enzymes in cancers. Because cancer cells proliferate very rapidly, they overproduce <a href="https://doi.org/10.1186/s12885-019-5768-0">certain enzymes</a> that help them invade the nearby healthy tissue and <a href="https://doi.org/10.1007/s002800051097">metastasize to other parts of the body</a>. Healthy cells grow at a much slower pace and produce fewer of these enzymes.</p>
<p>With this in mind, we “masked” IL-12 with a cap that covers the part of the molecule that normally binds to immune cells to activate them. The cap is removed only when it comes into contact with enzymes found in the vicinity of tumors. When these enzymes chop off the cap, IL-12 is reactivated and spurs nearby killer T cells to attack the tumor.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&rect=0%2C0%2C540%2C360&q=45&auto=format&w=1000&fit=clip"><img alt="Killer T cells surrounding a cancer cell" src="https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&rect=0%2C0%2C540%2C360&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Killer T cells (green and red) can attach to cancer cells (blue, center) and kill them by releasing toxic chemicals (red), a move scientists have dubbed ‘the kiss of death.’</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/xuSZkh">NIH/Flickr</a></span>
</figcaption>
</figure>
<p>When we applied these masked IL-12 molecules to both healthy and tumor tissue donated by melanoma and breast cancer patients, our results confirmed that only the tumor samples were able to remove the cap. This indicated that masked IL-12 could potentially drive a strong immune response against tumors without causing damage to healthy organs.</p>
<p>We then examined how safe masked IL-12 is by measuring <a href="https://www.mayoclinic.org/tests-procedures/liver-function-tests/about/pac-20394595">liver damage biomarkers</a> in mice. We found that immune-related side effects typically <a href="https://doi.org/10.1177%2F019262339902700112">associated with IL-12</a> were notably absent in mice treated with masked IL-12 over a period of several weeks, indicating improved safety.</p>
<p>In breast cancer models, our masked IL-12 resulted in a 90% cure rate, while treatment with a commonly used immunotherapy called a <a href="https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/immunotherapy/types/checkpoint-inhibitors">checkpoint inhibitor</a> resulted in only a 10% cure rate. In a model of colon cancer, masked IL-12 showed a 100% cure rate.</p>
<p>Our next step is to test the modified IL-12 in cancer patients. While it <a href="https://theconversation.com/from-the-research-lab-to-your-doctors-office-heres-what-happens-in-phase-1-2-3-drug-trials-138197">will take time</a> to bring this encouraging development directly to patients, we believe a promising new treatment is on the horizon.</p><img src="https://counter.theconversation.com/content/183588/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Aslan Mansurov consults to and owns shares in Arrow Immune Inc, which is developing the technology presented in the article. </span></em></p>One promising cancer treatment has been in the works for decades, but severe side effects have kept it out of the clinic. A reengineered version may offer a way to safely harness its potent effects.Aslan Mansurov, Postdoctoral Researcher in Molecular Engineering, University of Chicago Pritzker School of Molecular EngineeringLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1475472020-11-17T15:50:55Z2020-11-17T15:50:55ZAntibiotics in cold and flu season: Potentially harmful and seldom helpful<figure><img src="https://images.theconversation.com/files/368064/original/file-20201107-17-ynhp4y.jpg?ixlib=rb-1.1.0&rect=677%2C201%2C5432%2C3884&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Antibiotics do not shorten or reduce the severity of colds or flu, but they could produce adverse effects that make you feel even worse.</span> <span class="attribution"><span class="source">(Pexels/Andrea Piacquadio)</span></span></figcaption></figure><p>Antibiotics are <a href="https://doi.org/10.1503/cmaj.109-5742">over-prescribed in Canada</a> and <a href="https://doi.org/10.1001/jama.2016.4151">worldwide</a>, often for infections that do not need their help, <a href="https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a1.htm">particularly respiratory conditions</a>. While these unnecessary prescriptions may contribute to the development of <a href="https://theconversation.com/antibiotic-resistant-infections-could-destroy-our-way-of-life-new-report-126670">resistant bacteria</a>, there is another reason to be cautious about antibiotics: Direct harms caused by these drugs.</p>
<p>Our group — a family physician, an infectious disease specialist and a health sciences student — has published <a href="https://www.cfp.ca/content/66/9/651">a review of the evidence about adverse effects of antibiotics commonly used in the community</a>. Even though two of us are experienced physicians, and knew about many problems with drugs, we were surprised by the frequency and severity of some of these effects.</p>
<h2>Gut reactions, allergies and skin rashes</h2>
<p>The review showed that for many antibiotics, over 10 per cent of patients get gut reactions, such as stomach pain, discomfort or diarrhea. This is particularly common in children given antibiotics for ear and throat infections.</p>
<p>Every antibiotic causes allergic reactions in some people. A few allergic reactions cause swelling of the mouth and airways, needing immediate treatment with adrenalin and other drugs. </p>
<p>Other allergic reactions are just a skin rash, but this is often very irritating, and in some it may progress to cause severe blistering. Such severe reactions can be caused by sulfonamide drugs, often used to treat urinary tract infections. In Canada, a medication combining the antibiotic trimethoprim and a sulfa drug is often used for this purpose. However, using trimethoprim alone — a common practice in Europe — reduces the risk of allergic reactions.</p>
<figure class="align-center ">
<img alt="Red and white pill capsules scattered on a white surface beside a glass of water." src="https://images.theconversation.com/files/368066/original/file-20201107-17-a4sy62.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/368066/original/file-20201107-17-a4sy62.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/368066/original/file-20201107-17-a4sy62.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/368066/original/file-20201107-17-a4sy62.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/368066/original/file-20201107-17-a4sy62.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/368066/original/file-20201107-17-a4sy62.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/368066/original/file-20201107-17-a4sy62.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">In mononucleosis patients, amoxycillin can cause a severe skin rash that looks just like an allergy.</span>
<span class="attribution"><span class="source">(Piqsels)</span></span>
</figcaption>
</figure>
<p>A severe skin rash occurs in as many as one-third of people given amoxycillin for infectious mononucleosis (glandular fever), a common cause of sore throat in adolescents and young adults. This looks just like an allergy, so these people may be told they are allergic, which prevents use of penicillins even when they would be the best drug to use. A skin test can show that it is not an allergy, in which case penicillins may be used in future.</p>
<p>In rare cases, antibiotics cause other serious reactions, including some that are fatal. They can cause serious damage to lungs, liver, kidneys, nerves and joints. For example quinolones, a common group of antibiotics (the most well known is ciprofloxacin), can cause ruptured tendons and damage to nerves that causes tingling and numbness. Minocycline, often used to treat acne, can cause <a href="https://doi.org/10.1503/cmaj.200012">dark pigmentation of the face, as well as neurological effects</a>.</p>
<h2>Benefits vs. risks</h2>
<p>With antibiotics, the likelihood of benefit must be balanced against the chance of harm they may cause. When someone has a serious infection, it is worth taking the risk of harms, to gain the benefits of cure. But for a mild infection that the immune system will defeat by itself, there is no benefit from the antibiotic, only a chance of harm. So a prescription for antibiotics can be worse than useless.</p>
<p>Antibiotics are among our most commonly used drugs. However, they should not be thought of as necessary to cure any infection. For most infections, they only help to tip the balance in favour of our immune system.</p>
<p>Antibiotics work on bacterial infections such as pneumonia or cellulitis, and these illnesses improve faster with the right antibiotic.</p>
<figure class="align-right ">
<img alt="Half-sphere cross-section of a flu virus showing interior and exterior." src="https://images.theconversation.com/files/368065/original/file-20201107-17-l5tdr9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/368065/original/file-20201107-17-l5tdr9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=793&fit=crop&dpr=1 600w, https://images.theconversation.com/files/368065/original/file-20201107-17-l5tdr9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=793&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/368065/original/file-20201107-17-l5tdr9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=793&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/368065/original/file-20201107-17-l5tdr9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=997&fit=crop&dpr=1 754w, https://images.theconversation.com/files/368065/original/file-20201107-17-l5tdr9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=997&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/368065/original/file-20201107-17-l5tdr9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=997&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">3-D illustration of a flu virus. There is no value in taking antibiotics for viral infections.</span>
<span class="attribution"><span class="source">(NIAID)</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>But most coughs and colds, sinusitis, influenza and even COVID-19 are viral infections that the immune system will overcome. While some bacteria may be present, they are not the cause, so there is no value in taking an antibiotic. They do not shorten these infections, nor do they reduce their severity, but they could produce adverse effects that only make matters worse. For coughs and colds, it’s better to seek advice from a physician or pharmacist about treatments that reduce fever, aches and pains, and coughs, while the immune system does its job.</p>
<p>As the fall and winter <a href="https://www.cp24.com/news/doctors-brace-for-viral-overload-between-cold-and-flu-season-and-covid-19-1.5070966">respiratory infection season approaches</a>, both prescribers and patients must remember how harmful these drugs can be. Antibiotic use should be minimized, and used only when there is good reason. They must be chosen carefully, and when prescribed, they should be taken for the minimum effective time. So rather than visiting a doctor asking for antibiotics, ask whether one could help, and what other treatments will soothe symptoms and reduce the misery.</p>
<p>Using antibiotics cautiously not only means decreasing the risk of allergic reactions or other harms, but also decreasing the risk of bacterial resistance. That means that when an antibiotic is really needed, the appropriate drug will be safe and effective.</p><img src="https://counter.theconversation.com/content/147547/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>James Dickinson receives funding from Alberta Health to run the Alberta community Influenza surveillance program. </span></em></p><p class="fine-print"><em><span>Ranjani Somayaji has received funding from Cystic Fibrosis Canada, Cystic Fibrosis Foundation, Canadian Institute for Health Research and Alberta Innovates-Health Solutions. </span></em></p><p class="fine-print"><em><span>Samiha Tarek Ah Mohsen does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Resistant bacteria aren’t the only risk posed by overprescribing antibiotics. A more immediate risk is side-effects and reactions, which a new review shows are surprisingly frequent and often severe.James Dickinson, Professor of Family Medicine, University of CalgaryRanjani Somayaji, Assistant Professor in the Department of Medicine, University of CalgarySamiha Tarek Ah Mohsen, Research Assistant at Department of Critical Care Medicine, University of CalgaryLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1316482020-02-13T04:53:21Z2020-02-13T04:53:21ZI’m taking glucosamine for my arthritis. So what’s behind the new advice to stop?<figure><img src="https://images.theconversation.com/files/315132/original/file-20200213-41665-1c7dsys.jpg?ixlib=rb-1.1.0&rect=1%2C4%2C997%2C661&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/arthritis-old-person-elderly-woman-female-757210732">Shutterstock</a></span></figcaption></figure><p>The Australian Rheumatology Association <a href="https://www.smh.com.au/national/hundreds-harmed-by-glucosamine-as-doctors-warn-stop-taking-it-20200129-p53vq1.html">this week warned</a> people not to take the supplement glucosamine for their osteoarthritis due to possible allergic side-effects.</p>
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<figcaption>The Australian Rheumatology Association warns against taking glucosamine to ease arthritis symptoms. Credit: 7 News Sydney</figcaption>
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<p>What’s the evidence behind this latest advice? And do you really need to stop taking it?</p>
<h2>How did we get here?</h2>
<p>For years, glucosamine has been marketed as a treatment for <a href="https://arthritisaustralia.com.au/types-of-arthritis/osteoarthritis/">osteoarthritis</a>, which can occur when the protective cartilage in the joints wears down over time.</p>
<p>This is despite <a href="https://theconversation.com/science-or-snake-oil-is-glucosamine-good-for-joints-98470">conflicting evidence</a> on whether the supplement works. Yet many patients may buy glucosamine, presuming that even if it doesn’t help, at least it’s “natural” and so won’t do any harm.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/arthritis-isnt-just-a-condition-affecting-older-people-it-likely-starts-much-earlier-67698">Arthritis isn't just a condition affecting older people, it likely starts much earlier</a>
</strong>
</em>
</p>
<hr>
<p>But an <a href="https://pmj.bmj.com/content/early/2019/10/09/postgradmedj-2019-136957.long">Australian study</a>, which has been online since last year and was cited in one of this <a href="https://www.smh.com.au/national/hundreds-harmed-by-glucosamine-as-doctors-warn-stop-taking-it-20200129-p53vq1.html">week’s media reports</a>, has given us more information about glucosamine’s safety.</p>
<p>The study found hundreds of allergic reactions to glucosamine have been reported to Australia’s medicines watchdog, the Therapeutic Goods Administration (TGA).</p>
<p>So is it safe for you to take glucosamine? In short, if it works for you and you haven’t had any side-effects, and your doctor and pharmacist know you are taking it, it is likely to be safe based on the multiple trials conducted to date.</p>
<h2>What is glucosamine?</h2>
<p>Glucosamine is a naturally occurring substance the body uses to help build joint tissue, such as cartilage and tendons. In a supplement, the glucosamine can be made from the shells of prawns and other crustaceans, or it can be made synthetically in a factory.</p>
<p>Whether it works to manage osteoarthritis seems open to debate. The <a href="https://bjsm.bmj.com/content/52/3/167.abstract?casa_token=PYOOQN-X5ZQAAAAA:8bJwh7qncNLBS-QzvwIvX65KZpx55Rm-wXQ8xEeAtxLOls-zVHE-7XIdobVUjAcCkDA_m9nZ-y2a">most recent evidence</a> suggests little to no clinical benefit.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/science-or-snake-oil-is-glucosamine-good-for-joints-98470">Science or Snake Oil: is glucosamine good for joints?</a>
</strong>
</em>
</p>
<hr>
<p>But advice to GPs <a href="https://www.racgp.org.au/clinical-resources/clinical-guidelines/key-racgp-guidelines/view-all-racgp-guidelines/hip-and-knee-osteoarthritis">about how to treat</a> osteoarthritis says the issue isn’t just confined to glucosamine.</p>
<p>When the Royal Australian College of General Practitioners looked at about 62 other medicines and possible treatments for osteoarthritis of the knee and hip (which include registered drugs and complementary medicines), none were backed by high-quality evidence to say they worked. Most of the evidence was based on low- or very low-quality studies.</p>
<h2>Is glucosamine really as dangerous as people say?</h2>
<p>The <a href="https://www.ncbi.nlm.nih.gov/pubmed/31597786">Australia study</a> found 336 cases of side-effects to glucosamine (and to another supplement used for osteoarthritis called chondroitin) were reported to the TGA over 11 years. Of these, 263 cases were allergies, which ranged from mild to severe.</p>
<p>We don’t know if these reactions included those from people with a known allergy to seafood or sulfur, as these would increase their risk of a reaction to glucosamine (glucosamine can come in different formulations, including glucosamine sulfate).</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/315133/original/file-20200213-41695-v0jo31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/315133/original/file-20200213-41695-v0jo31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/315133/original/file-20200213-41695-v0jo31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/315133/original/file-20200213-41695-v0jo31.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/315133/original/file-20200213-41695-v0jo31.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/315133/original/file-20200213-41695-v0jo31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/315133/original/file-20200213-41695-v0jo31.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/315133/original/file-20200213-41695-v0jo31.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The glucosamine in supplements can come from the shells of prawns and other crustaceans, which is thought to trigger allergic reactions in some people.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/steaming-prawns-419117911">Shutterstock</a></span>
</figcaption>
</figure>
<p>But a <a href="https://link.springer.com/article/10.1007/s12603-016-0721-2">large percentage</a> of people take glucosamine daily in Australia, with no ill effects. The cases reported to the TGA amount to just 30 people a year, with 16% of allergic reactions considered severe.</p>
<p>Beyond allergic reactions, there are other safety concerns about glucosamine. </p>
<p>For instance, if you are taking glucosamine and a medicine that thins your blood (such as warfarin after a stroke), this can <a href="https://arthritisaustralia.com.au/glucosamine-and-warfarin-alert/">increase your risk</a> of bleeding.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/weekly-dose-warfarin-the-blood-thinner-thats-still-used-as-a-rat-killer-55944">Weekly Dose: Warfarin, the blood-thinner that's still used as a rat killer</a>
</strong>
</em>
</p>
<hr>
<p>Glucosamine supplements have also been implicated in <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752575/">chronic liver disease</a> and in worsening underlying <a href="https://www.jabfm.org/content/15/6/481.short">asthma</a>. Some patients may also experience digestive symptoms such as heartburn. </p>
<p>The risks of other side-effects seem unclear, including whether it <a href="https://ard.bmj.com/content/66/2/260.short?casa_token=BBfCGMbeLwkAAAAA:k66n8x8Hc4z1gyc0gSKG6lIEES2lxHPwEWZqER1Ctwd6Iw2R3H7VV3UPgu0Wl3ftwXeUhRSNjFuM">raises</a> <a href="https://www.sciencedirect.com/science/article/abs/pii/S0002934316312530">blood glucose</a> levels in people <a href="https://doi.org/10.1016/j.amjmed.2016.11.038">with</a> or <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190977/">without</a> diabetes.</p>
<h2>Conflicting advice</h2>
<p>While the Australian Rheumatology Association has warned people to stop taking glucosamine, other advice is not so clear-cut.</p>
<p>Arthritis Australia <a href="https://arthritisaustralia.com.au/managing-arthritis/living-with-arthritis/complementary-treatments-and-therapies/glucosamine-and-chondroitin/">reports</a> glucosamine is a relatively safe treatment option for people with osteoarthritis and has relatively few side-effects compared with traditional medicines. </p>
<p>And the <a href="https://www.racgp.org.au/download/Documents/Guidelines/Musculoskeletal/guideline-for-the-management-of-knee-and-hip-oa-2nd-edition.pdf">guidelines for GPs</a> on how to manage osteoarthritis of the knee and hip makes a “conditional” recommendation not to use it, based on uncertainty over the balance of harms with potential benefit.</p>
<h2>So, what should I do?</h2>
<p>What should you do if you’re taking glucosamine? If it works for you and you want to keep using it, then do so only on the advice of your doctor. That’s especially the case if you have any underlying medical conditions including diabetes, allergies or asthma. </p>
<p>Next, let your pharmacist know so they can check for any possible interactions with your other medicines, which can increase your risk of side-effects. You are most at risk if you are also taking warfarin, or any other type of blood thinning medicine. </p>
<p>Finally, if you do have unwanted side-effects from glucosamine, stop using it immediately and report it to your doctor. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/the-best-foods-for-arthritis-symptoms-new-research-96138">The best foods for arthritis symptoms – new research</a>
</strong>
</em>
</p>
<hr>
<img src="https://counter.theconversation.com/content/131648/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Associate Professor Wheate in the past has received funding from the ACT Cancer Council, Tenovus Scotland, Medical Research Scotland, Scottish Crucible, and the Scottish Universities Life Sciences Alliance. He is Fellow of the Royal Australian Chemical Institute and a member of the Australasian Pharmaceutical Science Association. Nial is also a director of the medicinal cannabis company Canngea Pty Ltd and a Standards Australia committee member for sunscreen agents.</span></em></p><p class="fine-print"><em><span>Joanna Harnett has received funding in the past from, Sigma Pty Ltd (operating as Orphan Australia) and Bioceuticals Pty Ltd in the past to conduct probiotic research. She is a board member of the Australasian Integrative Medicine Association. </span></em></p>Many people are taking glucosamine for their osteoarthritis. But do they really need to stop in light of new safety warnings?Nial Wheate, Associate Professor | Program Director, Undergraduate Pharmacy, University of SydneyJoanna Harnett, Lecturer (Complementary Medicines) Sydney Pharmacy School, Faculty of Medicine and Health, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1051222018-10-24T22:49:13Z2018-10-24T22:49:13ZWe need answers to the thalidomide tragedy – to ensure drug safety today<figure><img src="https://images.theconversation.com/files/242108/original/file-20181024-71032-whb66m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">An animal experiment in a laboratory of the pharmaceutical company "Chemie Gruenenthal," which manufactured the drug Thalidomide, in West Germany in 1969. Thalidomide was prescribed by doctors as a mild sleeping pill and for relief of morning sickness but caused the miscarriage and birth of thousands of children with severe malformations globally.</span> <span class="attribution"><span class="source">(AP Photo/File)</span></span></figcaption></figure><p>In 2015, after decades of fruitless lobbying, Canadian survivors of thalidomide <a href="https://www.theglobeandmail.com/news/national/for-canadian-thalidomide-victims-compensation-is-fair-but-long-overdue/article24585168/">finally received compensation from the federal government</a>. </p>
<p>The drug was a supposedly mild sleeping pill, a “<a href="https://www.macleans.ca/society/health/thalidomide-was-a-disaster-and-its-available-in-canada-again/">wonder drug</a>” that helped pregnant women with the symptoms of morning sickness. It caused an estimated <a href="https://www.cbc.ca/news/health/thalidomide-explainer-1.4434746">24,000 babies to be born with severely deformed limbs</a> and other major medical problems globally.</p>
<p>Now, a new book, <em><a href="https://www.onwardsandupwards.org/the-thalidomide-catastrophe/?v=3e8d115eb4b3">The Thalidomide Catastrophe</a></em>, by three European campaigners for people affected by thalidomide raises new questions about the conduct of governments and the companies involved. </p>
<p>It only mentions Canada in passing, but the questions it poses are equally relevant here. </p>
<p>What was the basis for approving thalidomide (sold in Canada under the name Kevadon by the William S. Merrell Co.)? When did the government first learn about the side effects from thalidomide? How quickly did it act after learning about these side effects?</p>
<h2>Canada slow to act</h2>
<p>According to a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1849754/pdf/canmedaj00968-0046.pdf">history of events</a> put together by the company, Merrell submitted data on animal and clinical studies to the Department of National Health and Welfare (the predecessor of Health Canada) on Sept. 8, 1960, and received approval to market thalidomide on Nov. 22, 1960.</p>
<p>This means government officials worked their way through a 500-page document in under 11 weeks. This raises questions about how comprehensive that document was. What information did it contain?</p>
<p>April 1, 1961, saw the actual appearance of thalidomide on drugstore shelves. Merrell claims it didn’t know about birth defects until Nov. 29, 1961. According to a <em>Globe and Mail</em> story from Aug. 2, 1962, health officials were informed about this problem two days later.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=500&fit=crop&dpr=1 600w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=500&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=500&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=628&fit=crop&dpr=1 754w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=628&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=628&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Members of the Thalidomide Survivors Task Group hold a news conference on Parliament Hill, in Ottawa, December, 2017. Clockwise from left are Fiona Sampson, Mary Ryder, Alexandra Niblock and Lee Ann Dalling.</span>
<span class="attribution"><span class="source">THE CANADIAN PRESS/Fred Chartrand</span></span>
</figcaption>
</figure>
<p>However, Chemie Grünenthal, the company that discovered thalidomide and marketed it in Germany, should have had grounds for strongly suspecting problems with the drug long before that. </p>
<p><em>The Thalidomide Catastrophe</em> documents how the American company Smith, Kline and French tested the drug in 1958 with a view to licensing it from Grünenthal but declined, partly because in its testing there were deformed babies born to two women. </p>
<p>In 1959, a doctor working at Grünenthal was told about additional babies with birth defects. Was this information not given to Merrell when it licensed thalidomide for sales in Canada?</p>
<p>As the news about babies with severe birth defects due to thalidomide became increasingly difficult to ignore, it was pulled off the German market in late November 1961 and at about the same time in the United Kingdom. However, it remained available in Canada for another three months until the federal government asked Merrell to withdraw it.</p>
<p>Health Minister J. Waldo Monteith, in a <em>Globe and Mail</em> story of July 27, 1962, denied that the government had delayed taking action and claimed that the additional three months was because reports of safety problems were “sketchy.” Is it likely that two European governments would have acted on sketchy information? </p>
<p>Moreover, in December 1961, an Australian doctor named W.G. McBride <a href="https://doi.org/10.1016/S0140-6736(61)90927-8">published a letter</a> in the major British medical journal, <em>The Lancet</em>, about birth defects among women who had used thalidomide in pregnancy. How long would it have taken Canadian health officials to contact Dr. McBride?</p>
<h2>Drug safety blamed on patients</h2>
<p>One reason for the slowness of Canadian officials might be due to the person in charge of the Food and Drugs Directorate, Dr. C.A. Morrell. </p>
<p>Henning Sjöström and Robert Nilsson reported in their book, <em><a href="https://www.goodreads.com/book/show/4753228-thalidomide-and-the-power-of-the-drug-companies">Thalidomide and the Power of the Drug Companies</a></em>, that after thalidomide was removed from the Canadian market a number of doctors wrote to the government protesting the move. </p>
<p>In reply to one such letter, Morrell responded: </p>
<blockquote>
<p>“I think if the medical profession would take a stand… that there is every possibility that thalidomide could indeed be reinstated on the Canadian market and to this end I would encourage you to urge strongly your colleagues to express themselves to us on this question.”</p>
</blockquote>
<p>Subsequently, in 1964, in testimony before a House of Commons Committee, Morrell seemed to place the safety problems on the users of the drug: </p>
<blockquote>
<p>“I think the hazard is the inability to control the user of thalidomide after it is on the market. I am referring now to the medicine cabinet at home; you do not know who will take a pill today. Everyone wants to take pills.” </p>
</blockquote>
<p>After Morrell left the government in 1965, he joined the board of Ciba-Geigy (now part of Novartis), a major multinational Swiss drug company.</p>
<h2>More than 400 babies affected</h2>
<p>Did the officials at the Department of National Health and Welfare make mistakes in approving thalidomide? Did Merrell tell them everything it knew? Why did Canada wait three months longer than Germany and the U.K. to decide that thalidomide was too unsafe to be sold? </p>
<p>Some may wonder why we need answers to questions almost 60 years later. But if there were mistakes and withholding of information, we can learn from this — to prevent similar tragedies happening in the future.</p>
<p>In Canada, there were over 100 babies born with problems attributed to thalidomide, but the authors of <em>The Thalidomide Catastrophe</em> estimate that there could have been over 400 babies, many dying early in life. </p>
<p>These people and their families deserve answers. It’s the duty of the Canadian government to find out the answers.</p><img src="https://counter.theconversation.com/content/105122/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>In 2015-2018, Joel Lexchin was a paid consultant on three projects: one looking at indication-based prescribing (United States Agency for Healthcare Research and Quality), a second to develop principles for conservative diagnosis (Gordon and Betty Moore Foundation) and a third deciding what drugs should be provided free of charge by general practitioners (Government of Canada, Ontario Supporting Patient Oriented Research Support Unit and the St Michael’s Hospital Foundation). He also received payment for being on a panel that discussed a pharmacare plan for Canada (Canadian Institute, a for-profit organization), a panel at the American Diabetes Association, for a talk at the Toronto Reference Library and for writing a brief for a law firm. He is currently a member of research groups that are receiving money from the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council. He is member of the Foundation Board of Health Action International and the Board of Canadian Doctors for Medicare.</span></em></p>A new book, ‘The Thalidomide Catastrophe,’ raises new questions about the conduct of corporations involved. It is the duty of governments to find out the answers.Joel Lexchin, Professor Emeritus of Health Policy and Management, York University, Emergency Physician at University Health Network, Associate Professor of Family and Community Medicine, University of TorontoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/975002018-05-30T19:27:12Z2018-05-30T19:27:12ZRoseanne racist tweet: can sleeping pills change your behaviour?<figure><img src="https://images.theconversation.com/files/221041/original/file-20180530-120493-1818x7c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/woman-after-taking-drugs-night-horizontal-252988462?src=Sn5L40gYjIeiw9Po3-cW4A-1-71">Shutterstock</a></span></figcaption></figure><p>Roseanne Barr <a href="https://www.bbc.co.uk/news/world-us-canada-44294632">has claimed</a> that she was under the influence of the drug Ambien when she posted her already <a href="https://www.theguardian.com/culture/2018/may/30/roseanne-barr-blames-racist-tweet-on-sleeping-pills">infamous racist tweet</a> (since removed). But what do we know about Ambien and its side effects? </p>
<p>Ambien is the American tradename for zolpidem, a commonly used “hypnotic” sleeping tablet. In the UK, it is also known as Stilnoct. Sleeping pills are widely used in the UK. <a href="https://openprescribing.net/bnf/040101/">Data from the NHS</a> suggests that in England over 700,000 prescriptions for hypnotics are dispensed every month, with over 50,000 scripts for zolpidem.</p>
<p>Sleeping tablets work on certain nerve systems within the brain. Most sleeping pills work via the gamma-aminobutyric acid (GABA) nerve system to induce sleep. Other commonly used hypnotics in the UK include zopiclone and benzodiazepines, such as nitrazepam (Mogadon), diazepam (Valium) and temazepam.</p>
<p>These drugs, like all other medicines, can have side effects. Historically, insomnia was treated with benzodiazepines. But in 1988, the UK’s Committee for the Safety of Medicines <a href="https://www.benzo.org.uk/commit.htm">issued a warning</a> that benzodiazepines should only be used to treat insomnia if it was severe or disabling. And due to the risk of withdrawal effects, they should be stopped gradually.</p>
<p>The so-called “z-drugs” (zolpidem, zopiclone and <a href="http://journals.sagepub.com/doi/pdf/10.1177/875512250101700202">zaleplon</a>) were originally marketed as safer, non-addictive alternatives to benzodiazepines in the 1990s. But over time it has become apparent that they have similar problems to the earlier drugs. These problems include tolerance, dependence and drowsiness.</p>
<p>Sleeping tablets, like alcohol, are sedatives, and may cause confusion, drowsiness and falls. In older people, sedatives are <a href="https://www.sciencedirect.com/science/article/pii/S1525861014006720?via%253Dihub">associated with frailty</a>.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/221039/original/file-20180530-120514-1sp5db4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/221039/original/file-20180530-120514-1sp5db4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/221039/original/file-20180530-120514-1sp5db4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/221039/original/file-20180530-120514-1sp5db4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/221039/original/file-20180530-120514-1sp5db4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/221039/original/file-20180530-120514-1sp5db4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/221039/original/file-20180530-120514-1sp5db4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">From insomnia to drowsiness.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/stressed-asian-male-employee-sitting-office-763633048?src=MQQ17vj_NJANIKQbvFmRaw-1-0">Shutterstock</a></span>
</figcaption>
</figure>
<p>Problems, such as drowsiness, can persist to the next day resulting in a “hangover” like effect. This can reduce alertness affecting the person’s ability to drive or operate machinery. Increasing awareness of this problem led the <a href="https://www.fda.gov/drugs/drugsafety/ucm352085.htm">American (FDA)</a> and <a href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Zolpidem-containing_medicines/human_referral_prac_000030.jsp&mid=WC0b01ac05805c516f">European (EMEA)</a> regulators to issue warnings in 2013 and 2014. The European regulator recommended that patients should be warned that such medicines may increase the <a href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Zolpidem-containing_medicines/human_referral_prac_000030.jsp&mid=WC0b01ac05805c516f">risk of road traffic accidents</a>.</p>
<p>Sleeping tablets can also cause disinhibition, inappropriate behaviour and memory loss in a <a href="https://www.nps.org.au/australian-prescriber/articles/hypnotic-hazards-adverse-effects-of-zolpidem-and-other-z-drugs">similar way to alcohol</a>. Violence and aggressive behaviour has <a href="http://www.addictioneducation.co.uk/z-drugs-leaf09.pdf">also been reported</a>. Zolpidem in particular appears to be associated with bizarre and compulsive behaviour that is unexpected and difficult to predict.</p>
<p>These bizarre behaviours include sleep-eating and sleep-driving. The patient may appear to be awake, but unaware of their actions and may carry out routine activities such as driving, household tasks, cooking and eating. The next day the person may have little or no memory of their actions. Some patients have also reported sleep sex <a href="https://www.nps.org.au/australian-prescriber/articles/hypnotic-hazards-adverse-effects-of-zolpidem-and-other-z-drugs">(having sex while asleep)</a>. </p>
<p><a href="https://www.bmj.com/rapid-response/2011/11/01/neuropsychiatric-reactions-associated-zolpidem-and-zopiclone">A psychotic-like state</a> has also been reported with zolpidem, with patients reporting hearing voices or seeing things that aren’t there (auditory and visual hallucinations), as well as feeling paralysed, and very real and sometimes violent nightmares.</p>
<p>Worryingly, because these behaviours are accompanied by memory loss, it is likely that they are <a href="http://jaapl.org/content/39/4/535">underreported</a> and we don’t know how common they are.</p>
<h2>Drug abuse</h2>
<p>Even more worryingly, the z-drugs are <a href="http://www.addictioneducation.co.uk/z-drugs-leaf09.pdf">increasingly abused</a>. Zopiclone, the most commonly prescribed z-drug, has a street name (Zim-zim or Zimmers) and a street price of about £1 per tablet. The drug’s potential for abuse is now thought <a href="https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2125.2007.02861.x">to be higher</a> than previously believed. One <a href="http://www.addictioneducation.co.uk/z-drugs-leaf09.pdf">user reported</a>: “Zimmers are really addictive, and the rattle is about five times worse than the rattle from gear [heroin].”</p>
<p>The z-drugs, such as zolpidem, were originally introduced as safer, non-addictive alternatives to benzodiazepines such as Valium. But it appears that they cause similar problems. Hangover, addiction and dependence have all been reported. Zolpidem in particular appears to be associated with bizarre inappropriate behaviours that people can’t remember.</p>
<p><em>Sanofi, the company that manufactures Ambien, <a href="https://www.bbc.co.uk/news/world-us-canada-44294632">said in a statement</a> following Barr’s tweet: “While all pharmaceutical treatments have side effects, racism is not a known side effect of any Sanofi medication.”</em></p><img src="https://counter.theconversation.com/content/97500/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Maidment does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Sleeping tablets such as Ambien can have serious side effects.Ian Maidment, Senior Lecturer in Clinical Pharmacy, Aston UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/913722018-02-20T11:40:25Z2018-02-20T11:40:25Z5 questions to ask your aging parents’ doctors<figure><img src="https://images.theconversation.com/files/206659/original/file-20180215-131000-xa73ch.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Doctors' visits can be overwhelming for older people.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/medicine-age-health-care-cardiology-people-496099969?src=12bvbsCO_VUKplyyLmJreg-4-9">Syda Productions/Shutterstock.com</a></span></figcaption></figure><p>The population of seniors, or people age 65 or over, in the United States neared <a href="https://www.census.gov/newsroom/facts-for-features/2017/cb17-ff08.html">48 million</a> last year and is steadily growing. Consequently, millions of adult children find themselves taking care of their parents’ medical needs. This can be a daunting task because many older individuals have complex health conditions. According to the National Council on Aging, almost 70 percent of seniors have <a href="https://www.ncoa.org/resources/fact-sheet-healthy-aging/">two or more chronic diseases</a>. As a result, they see an average of <a href="https://www.jhsph.edu/research/centers-and-institutes/johns-hopkins-primary-care-policy-center/Publications_PDFs/A241.pdf">four</a> different specialists a year.</p>
<p>Taking a lot of different drugs can lead to troublesome side effects or drug interactions. Having specialists who do not necessarily communicate with each other can lead to other complications. What can you do to try to avoid these problems? The answer is: Learn to ask questions and become your parents’ advocate.</p>
<p>I am a professor of law and bioethics and was involved in my own parents’ care at the end of their lives. As I wrote about in my book, <a href="https://www.amazon.com/Aging-Plan-Thought-Improve-Tomorrow/dp/1440838909">“Aging with a Plan: How A Little Thought Today Can Vastly Improve Your Tomorrow,”</a> I have learned that you can do a great deal to help oversee loved ones’ health care and to avoid some of its pitfalls.</p>
<p>Here are five key questions that you should not hesitate to ask.</p>
<h2>1. Does my parent really need this many drugs?</h2>
<p>Be familiar with your loved one’s full medication list, and keep track of any changes. If the list is long and a doctor wants to add another drug, ask if it is really necessary. You should also request that your parent’s geriatrician or primary care physician review the complete medication list periodically. Does it raise any concerns? </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/206660/original/file-20180215-131016-11nov1i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/206660/original/file-20180215-131016-11nov1i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/206660/original/file-20180215-131016-11nov1i.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/206660/original/file-20180215-131016-11nov1i.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/206660/original/file-20180215-131016-11nov1i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=504&fit=crop&dpr=1 754w, https://images.theconversation.com/files/206660/original/file-20180215-131016-11nov1i.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=504&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/206660/original/file-20180215-131016-11nov1i.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=504&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Before getting a prescription for your older parent, ask the doctor whether the medication is essential.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/doctor-rx-prescription-drug-bottle-selective-62078386?src=XQMWrWaclXLiavBhv4sj4w-1-9">18percentgrey/Shutterstock.com</a></span>
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</figure>
<p>In 2012, about a year before she died, my mother suddenly seemed to lose her mental capacities. In a matter of two days, she went from being a frail but clear-minded 83-year-old to acting as though she had advanced dementia. She stopped wanting to eat, stopped communicating and slept most of the day. </p>
<p>After an agonizing period of trying to figure out what was wrong, it turned out to be a drug-drug interaction. She was 83 and weighed only 104 pounds. Yet, she had been on 12 drugs, and a doctor added an unlucky 13th. We slowly eliminated most of the drugs and got her down to five essential medicines. She slowly regained her cognitive capacities, but there were two months during which she had no memory. My mother’s story is not unique – I have since read and heard others like it. It should be a cautionary tale for anyone with a very long medication list.</p>
<h2>2. What are the side effects of the drug you are recommending?</h2>
<p>Drug side effects can cause serious discomfort and mental deterioration. You need to know about side effects and think about them when considering new drugs for your loved one. </p>
<p>My husband was diagnosed with Parkinson’s disease at the age of 55. Early on, we consulted a physician who recommended that he try a particular medication. I noticed that the doctor did not mention side effects. I asked about the medication’s side effects, and the doctor responded that most patients tolerate it beautifully. Nevertheless, I asked, “What about those who don’t tolerate it well?” The doctor acknowledged that one in five patients find that it dulls their mind. That was an unacceptable side effect for us. Andy is a computer science professor and enjoys his career, so we could not take a 20 percent chance that his mind would be dulled. But we would not have known of that possibility if I had not asked the question.</p>
<h2>3. Are there other, less aggressive alternatives we should consider first?</h2>
<p>In some cases, there is no alternative to surgery, and it will be lifesaving. However, in other instances, there are a lot of options, such as physical therapy, acupuncture and other interventions. Some experts believe that surgery and anesthesia can cause <a href="https://www.scientificamerican.com/article/can-general-anesthesia-trigger-dementia/">cognitive decline</a> in elderly patients, especially if they already have dementia. If the doctor recommends surgery or another aggressive treatment in a nonemergency situation, it is worth asking about alternatives. </p>
<h2>4. How can we reduce her or his discomfort?</h2>
<p>While patients often get too much treatment, at times they do not have their painful symptoms treated adequately. Some people do not want to complain to their doctors and ask for relief even in the face of acute suffering. They are shy about asserting themselves or do not want physicians to think less of them for being unable to tolerate discomfort. In other cases, doctors hesitate to provide additional pain relief. They fear that patients will become addicted to powerful drugs. Yet pain can <a href="http://www.worldwidewounds.com/2001/march/Pediani/Pain-relief-surgical-wounds.html">slow healing</a> and cause significant mental stress for patients and their caregivers. If you know your loved one is suffering severe pain, nausea or other discomfort, press the doctors to provide more relief.</p>
<h2>5. What would you do if this were your parent?</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/206661/original/file-20180215-131000-u2z19z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/206661/original/file-20180215-131000-u2z19z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/206661/original/file-20180215-131000-u2z19z.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/206661/original/file-20180215-131000-u2z19z.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/206661/original/file-20180215-131000-u2z19z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/206661/original/file-20180215-131000-u2z19z.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/206661/original/file-20180215-131000-u2z19z.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Sometimes, asking a doctor how she would treat her own parent can be a reminder of parental love.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/portrait-happy-asian-elderly-mother-her-613881722?src=Ofcaj13jUyu67QR67Qeqag-1-8">Szefei/Shutterstock.com</a></span>
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<p>At the same time, doctors might provide you with several options and little guidance as to the best course of action. They may say, “We can do tests to rule out various illnesses, or we can wait and see if symptoms improve. What do you want to do?” If you have no idea, consider asking, “What would you do if this were your mother?” You may be surprised by how helpful their answers are if you ask them to step into your shoes.</p>
<p>Our time with health care providers is precious and often scarce. When you see a doctor with your elderly parent, feel empowered to be an advocate, ask questions and express your needs.</p><img src="https://counter.theconversation.com/content/91372/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sharona Hoffman received financial support from Case Western Reserve University for publication of her book "Aging with a Plan: How a Little Thought Today Can Vastly Improve Your Tomorrow" (Praeger 2015). </span></em></p>More than 47 million people age 65 and older live in the US, and many need help accessing health care. Here are some questions that grown children should ask their parents’ doctors.Sharona Hoffman, Professor of Health Law and Bioethics, Case Western Reserve UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/779452017-05-19T05:14:10Z2017-05-19T05:14:10ZShould I stop taking Prozac if I’m pregnant?<figure><img src="https://images.theconversation.com/files/169884/original/file-20170518-24325-65g27r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Deciding whether or not to continue on medication in pregnancy is always a balancing act.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>Women, and perhaps their doctors, may be concerned when they <a href="http://www.dailymail.co.uk/femail/article-4516894/Antidepressants-cause-birth-defects-new-study-found.html">see reports of a study</a> showing an association between taking fluoxetine, an antidepressant also known as Prozac, during pregnancy and birth defects in children. </p>
<p>These findings aren’t new. We’ve known for some time of an <a href="https://theconversation.com/pregnant-women-taking-antidepressants-shouldnt-panic-about-birth-defect-claims-44358"><em>association</em> between taking antidepressants</a> (selective serotonin reuptake inhibitors or SSRIs, specifically fluoxetine and paroxetine) during pregnancy and a higher risk of birth malformation in babies.</p>
<p>But is a knee-jerk reaction to stop taking antidepressants when you discover you’re pregnant warranted? It’s important to take a step back – there are many factors to consider, one of which is that whether antidepressants themselves <em>cause</em> birth defects has never been proven. And stopping medication could lead the woman to relapse into depression, which can be a risk to the baby in itself. </p>
<h2>What was the recent study?</h2>
<p>Studies that have shown an association between antidepressants and birth defects have largely been <a href="https://www.ncbi.nlm.nih.gov/pubmed/21646927">observational</a>. Observational studies, in this instance, mean those following women from early pregnancy to the postpartum period (immediately after birth), recording information related to their health and that of the fetus, and later, child.</p>
<p>The recent paper published in the <a href="http://onlinelibrary.wiley.com/doi/10.1111/bcp.13321/abstract?utm_source=AusSMC+mailing+list&utm_campaign=4f179e2d4a-EMAIL_CAMPAIGN_2017_05_17&utm_medium=email&utm_term=0_90d9431cd5-4f179e2d4a-132722317">British Journal of Clinical Pharmacology</a> was a meta-analysis of such studies. This research method takes a number of similar studies (in this case 16 observational studies exploring fluoxetine use during pregnancy) and pools the results.</p>
<p>It concluded that taking fluoxetine in the first trimester of pregnancy increased the risk of birth defects in the child by 18%. These defects might include the child being born with spina bifida, or having an extra ureter (the duct though which urine passes from the kidney to the bladder). </p>
<p>More specifically, it found that heart-related defects increased by 36%. This included both septal defects (holes in the heart wall), many of which are minor and do not require intervention, and non-septal defects (such as malformations in a heart valve or vessels).</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Observational studies follow people over time recording information under observation.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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</figure>
<p>In terms of population-level risk, these percentage increases mean for every 100 women not on antidepressants who have babies with a defect, 118 women on antidepressants will have babies with a defect. And for every 100 women not on an antidepressant who have babies with a heart defect, 136 women on antidepressants will have babies with a heart defect. </p>
<p>This is a real increased risk, but it is a small increase considering the baseline risk is small. Across the general population, <a href="http://www.heart.org/HEARTORG/Conditions/CongenitalHeartDefects/UnderstandYourRiskforCongenitalHeartDefects/Understand-Your-Risk-for-Congenital-Heart-Defects_UCM_001219_Article.jsp">only eight per 1000 of all deliveries</a>, which includes the babies of women on antidepressants, will be born with a heart defect.</p>
<hr>
<p><em><strong>For more detail</strong>: <strong><a href="https://theconversation.com/what-you-need-to-know-to-understand-risk-estimates-67643">What you need to know to understand risk estimates</a></strong></em></p>
<hr>
<h2>Association isn’t causation</h2>
<p>It’s important to note, however, that none of the studies in the meta-analysis were randomised controlled trials: where one group is randomly chosen to receive the drug being tested, while another group receives a placebo or different drug.</p>
<p>Such trials would be unethical in pregnant women. So we can only “test” for outcomes in children of women who take drugs during pregnancy by observing them. Then we can only conclude whether taking the drug was <em>associated</em> with an increased risk to the baby, rather than the drug having <em>caused</em> the risk. </p>
<p>The observational studies on women and their babies cannot be considered equivalent in quality to randomised controlled trials. This is because we are not comparing two equivalent groups: women who take antidepressants and those who don’t. We are observing women who have many differences, which can sometimes also be risk factors.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=515&fit=crop&dpr=1 600w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=515&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=515&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=647&fit=crop&dpr=1 754w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=647&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=647&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Randomised controlled trials, where two similar groups are used to test a drug, are superior to observational studies.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<p>Women taking fluoxetine will be doing so due to poor mental health, which is often associated with other health issues, such as gestational diabetes. Some studies suggest <a href="https://www.ncbi.nlm.nih.gov/pubmed/17519397">gestational diabetes could lead to heart defects</a> in the fetus. Poor mental health is also associated with higher levels of smoking, alcohol and illicit drug use, which are <a href="https://www.ncbi.nlm.nih.gov/pubmed/355285">well known to adversely impact</a> fetal development.</p>
<p>Just by observing women over time, we can’t know whether it was one of these other factors that caused a higher increase in risk, or the antidepressants. And not all the studies in the meta-analysis controlled for other risk factors. </p>
<p>Studies that controlled for alcohol use, for instance, showed a lower, 13% increase in heart malformations, compared to 31% in those that did not. And none of the studies controlled for the dose of the drug women were taking. It is likely the fetuses exposed to 80mg daily of fluoxetine are going to be at higher risk of birth defects than those exposed to 20mg daily.</p>
<h2>The safest course of action</h2>
<p>Deciding whether or not to continue on medication in pregnancy is always a balancing act: the risk to the mother of being off the medication, and the effects of her being unwell on the fetus, versus the risk of medication to the fetus. </p>
<p>Australian guidelines suggest women who have been well for a year or more, only ever had one episode of depression or anxiety, were never suicidal and kept functioning (going to work for instance) when unwell, could <a href="https://www.ranzcp.org/Files/Resources/Publications/CPG/Clinician/CPG_Clinician_Full_Depression-pdf.aspx">likely stop taking their antidepressants</a> with little risk.</p>
<p>But for those with more serious, recurrent illnesses, <a href="http://www.preventionweb.net/files/670_72351.pdf">there is no risk-free option</a>. The likelihood the illness will recur when off medication is high, and this itself puts the fetus at risk.</p>
<p>Women who are unwell have poorer self-care and may be at <a href="https://www.ncbi.nlm.nih.gov/pubmed/15633850">risk of suicide</a>. Infants born to women who were unwell in pregnancy are also more likely to have higher levels of the stress hormone cortisol at birth. This continues throughout their lives and is a probable marker for a <a href="https://www.ncbi.nlm.nih.gov/pubmed/26610204">higher risk of their own mental health issues</a>.</p>
<h2>Prozac hardly used in pregnancy</h2>
<p>Authors of the recent study noted fluoxetine was the most frequently prescribed medication in pregnant women. This may be true in other countries but is unlikely to be the case in Australia. </p>
<p>We have <a href="https://www.ncbi.nlm.nih.gov/pubmed/10722179">known for some time</a> fluoxetine, as well as another SSRI paroxetine, has been linked with a small increased risk in birth defects. Fluoxetine has a long half-life, which means it stays longer in the system than other SSRIs, including in the baby after delivery. This makes it less attractive to use in pregnant women. </p>
<p>Australian guidelines advise a <a href="http://www.racgp.org.au/afp/2014/april/perinatal-mental-health/">SSRI with a shorter half-life</a>, and without the specific risk identified with fluoxetine, be prescribed for pregnant women.</p>
<p>Ideally, a woman will see her doctor when planning a pregnancy and, with her partner, will decide on the best options in their specific case. By reducing weight and stopping smoking, alcohol and illicit drugs, as well as deciding what to do about their antidepressant, women will ensure the risk to them and their babies is as low as possible.</p><img src="https://counter.theconversation.com/content/77945/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Anne Buist has received research and educational grants from numerous pharmacuetical companies over the last thirty years; in the last five years this has been Astrazeneca and Ostsuko-Lundbeck; she is doing occasional current paid talks for the latter but these talks do not include discussion of medication. </span></em></p>A study has shown an association between antidepressants in pregnancy and risk to the baby. But there are many factors to consider if deciding whether to stay on an antidepressant if you’re pregnant.Anne Buist, Director of Women’s Mental Health at Austin Health – Northpark Private Hospital, Professor, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/749892017-05-18T01:58:35Z2017-05-18T01:58:35ZHealth Check: why can you feel groggy days after an operation?<figure><img src="https://images.theconversation.com/files/164025/original/image-20170405-5739-1u2blpf.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Feeling tired or being unable to concentrate is common even days after surgery. But there are simple ways to help speed up your recovery. </span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/jjay69/5913824188/">Jason Jones/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>You have a small operation under general anaesthesia and go home the same day. Two days later you’re back at work, but you can’t concentrate and have a desperate desire to take a nap. Why does this happen and how can you prevent it?</p>
<p><a href="http://www.anzca.edu.au/patients/what-is-anaesthesia">General anaesthesia</a> is a reversible drug-induced coma, during which you are unconscious, don’t feel pain and don’t remember anything. This is precisely what you want when you’re having an invasive or painful procedure. </p>
<p>However, some people suffer <a href="http://onlinelibrary.wiley.com/doi/10.1111/aas.12381/full">lingering effects</a> in the days after anaesthesia. These include drowsiness, slowed reaction times, and difficulty concentrating, remembering new information and finishing complex tasks.</p>
<p>Thankfully, these unwanted effects usually wear off by the next day, but sometimes they last for a <a href="http://www.sciencedirect.com/science/article/pii/S0022399903006159">few more days or even weeks</a>. Then they can really disrupt your ability to work or get anything done at home.</p>
<h2>It’s easy to blame the anaesthetics</h2>
<p>The effects of general anaesthesia may appear to linger for days after surgery for many reasons. Tiredness after a procedure is commonly attributed to anaesthetics. But modern anaesthetics wear off completely in a <a href="https://www.ncbi.nlm.nih.gov/pubmed/10624999">couple of hours</a>, so the real picture is usually more complicated. </p>
<p>The surgical condition for which you had the procedure may have stopped you leading a full and active life for some time, resulting in lack of fitness and less reserve for recovery.</p>
<p>The surgery itself causes tissue injury. After surgery, your body undergoes repair and recovery, which drives a higher baseline metabolic rate and draws on your nutrient stores. So it isn’t surprising such intense activity at a cellular level results in feeling tired after surgery. </p>
<p>If you ignored your doctor’s advice to take it easy before or after surgery, that could also explain why you’re feeling tired.</p>
<p>Then there’s pain treatment <a href="http://fpm.anzca.edu.au/documents/apmse4_2015_final">before and after the procedure</a>, which can also contribute to grogginess.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/165413/original/image-20170415-25865-1h0f7fo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/165413/original/image-20170415-25865-1h0f7fo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=539&fit=crop&dpr=1 600w, https://images.theconversation.com/files/165413/original/image-20170415-25865-1h0f7fo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=539&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/165413/original/image-20170415-25865-1h0f7fo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=539&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/165413/original/image-20170415-25865-1h0f7fo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=677&fit=crop&dpr=1 754w, https://images.theconversation.com/files/165413/original/image-20170415-25865-1h0f7fo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=677&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/165413/original/image-20170415-25865-1h0f7fo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=677&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Strong painkillers you take before or after surgery, like oxycodone, can also make you feel drowsy. But side effects cease once you stop taking them.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/554771338?src=LN8q-gZZ5jerIDiN9S-odQ-1-4&size=medium_jpg">from www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>For instance, opioids (such as oxycodone) and gabapentinoids (such as pregabalin) are strong pain medicines often prescribed after surgery. They are important in ensuring a comfortable recovery and rapid return to normal life, but may result in grogginess and confusion, especially in higher doses. </p>
<p>Opioids are usually needed <a href="https://www2.health.vic.gov.au/hospitals-and-health-services/quality-safety-service/quality-use-of-medicines/opioid-risk-reduction">for only a few days after surgery</a> and these side effects stop when you stop taking them.</p>
<p>Finally, general anaesthetics <a href="https://academic.oup.com/bja/article/109/5/769/305281/Sleep-disturbances-after-fast-track-hip-and-knee">interfere with your body clock</a>. This <a href="http://www.tandfonline.com/doi/abs/10.1080/07420528.2016.1208664">could be</a> because
anaesthetics <a href="https://www.ncbi.nlm.nih.gov/pubmed/24498074">interfere</a>
with brain hormones, such as melatonin, and messenger chemicals called neurotransmitters.</p>
<p>While <a href="https://nutritionj.biomedcentral.com/articles/10.1186/1475-2891-13-106">melatonin tablets can treat jet lag</a>, which is also a disruption of the body clock, there is no good evidence to use melatonin for anaesthesia-induced body-clock disruption in humans.</p>
<h2>Can you prevent grogginess?</h2>
<p>An operation is a major life event. Make sure you get adequate rest and have enough support at work and home before your surgery.</p>
<p>A bit of anxiety is normal before surgery and can also be exhausting. You can reduce your anxiety by asking for clear explanations of what to expect, and by maintaining a warm, comfortable and calm waiting environment.</p>
<p>If you are very anxious, your <a href="http://www.anzca.edu.au/documents/what-is-an-anaesthetist.pdf">anaesthetist</a> can give you a sedative “pre-med” before you go to theatre. But the use of sedatives is a balancing act, as the calming effect before the procedure is desirable but not the “hangover” drowsiness afterwards, which may last for several hours.</p>
<p>Your anaesthetist is the medically trained specialist who can not only give you a “pre-med” but will look after you during your operation and plan your recovery. He or she will develop an individualised anaesthetic plan based on short-acting anaesthetics and a combination of pain-killings drugs.</p>
<p>Your anaesthetist will also advise you how to best control your pain after surgery and when you return home. This will often involve using simple pain medicines, such as paracetamol and anti-inflammatory drugs, as well as opioids, which you will need to treat strong pain. Using simple pain medicines will help to reduce the doses of opioids that you need, and help you to avoid the nausea, constipation and grogginess that goes with them.</p>
<h2>Get back into good sleep habits</h2>
<p>After a procedure, you can combat the disruption to your body clock by practising good <a href="https://sleepfoundation.org/sleep-topics/sleep-hygiene">“sleep hygiene”</a>. This involves <a href="https://theconversation.com/health-check-five-ways-to-get-a-better-nights-sleep-43700">maximising cues</a> to the body that it is time to sleep in the evening. These could include avoiding stimulants like caffeine and alcohol, going to bed at a similar time each night, being in a <a href="https://theconversation.com/a-dark-night-is-good-for-your-health-39161">dimly lit room</a> and engaging in calming or restful activities before sleep, like reading.</p>
<p>Making sure you are exposed to bright sunshine during the day and <a href="https://theconversation.com/booting-up-or-powering-down-how-e-readers-affect-your-sleep-36145">avoiding back-lit screens</a> on technology devices in the evening can also help.</p>
<p>Lingering grogginess after general anaesthesia is hardly ever sinister. But if it is persistent, getting worse rather than better, or is associated with confusion, weakness or numbness, then you must see your doctor.</p><img src="https://counter.theconversation.com/content/74989/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Some people can feel drowsy or can’t concentrate days after an operation. While it’s easy to blame the anaesthetics, the real picture is usually more complicated.Kate Leslie, Honorary professorial fellow, Department of Pharmacology, The University of MelbourneMegan Allen, Honorary Fellow, Anaesthesia, Perioperative and Pain Medicine Unit, Melbourne Medical School, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/650292016-09-07T20:08:20Z2016-09-07T20:08:20ZWe’re all at risk from scary medicine side effects, but we have to weigh the risks with the benefits<figure><img src="https://images.theconversation.com/files/136834/original/image-20160907-25266-lf9v7s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">When should we be warned about drug side effects, and when would it just be deterring us from taking a beneficial medicine for little risk?</span> <span class="attribution"><span class="source">from www.shutterstock.com.au</span></span></figcaption></figure><p><a href="http://www.abc.net.au/news/2016-09-06/more-stories-emerge-of-psychiatric-side-effects-of-singulair/7818670">Media reports have emerged</a> of psychotic episodes in children brought about by a common asthma medication, Singulair. The Therapeutic Goods Administration (TGA), which approves and monitors drugs in Australia, <a href="http://www.abc.net.au/news/2016-09-05/asthma-tablet-linked-to-serious-psychotic-episodes-in-children/7795474">has apparently received</a> 90 reports of psychiatric events. </p>
<p>So this leads to the question of how drugs are approved, and whether we are all at risk of harmful side effects from the medicines we take. </p>
<p>This issue is more complex than telling everyone about every possible side effect. First, there is no way to predict if an individual will be affected until they try the medication. </p>
<p>Second, to do so would be a scare campaign – as a pharmacist, I can scare anyone off taking anything if I put my mind to it, but that’s not my job. My job is to weigh risk and benefit – and taking any medication is a calculated risk.</p>
<h2>How are side effects determined?</h2>
<p>The list of side effects on the product information inside your medicine boxes is determined during clinical trials. Patients in the trial are monitored and regularly asked to report all symptoms they experience. At this stage, neither the patient nor the doctor knows if the patient is on the real (active) drug or the placebo. </p>
<p>All the reported symptoms are recorded and hence side-effect lists are developed, even if just one of the patients suffers this particular side effect once, and without knowing if they are in the active or placebo group.</p>
<p>The big thing missing in this recording process is causality – did the drug cause the effect, or was it coincidence? </p>
<p>For rare effects, the study size will probably not be large enough to pick them up. For example, a side effect that occurs in one in a million patients would be detected only about nine times if the entire Australian population (<a href="http://www.abs.gov.au/ausstats/abs@.nsf/mf/3101.0">almost 18 million adults in 2015</a>) was split into active and placebo groups for a trial.</p>
<p>So how do we find out about these effects? It happens through “pharmacovigilance”, or watching what happens once the drug is used in the general population. Only then will the rare things be seen. The Singulair® case is an excellent recent example of this – the company says tens of millions of patients have taken the drug (around the world), but the Australian market is much smaller.</p>
<p>The active drug in the medication, montelukast, has been available in Australia since 2000, and on the PBS since 2003. From listing in 2003 to December 2015, <a href="http://medicarestatistics.humanservices.gov.au/statistics/pbs_item.jsp">just over 2 million prescriptions</a> for it have been dispensed. (Available statistics do not determine number of patients, or show figures from 2000-2003 when it was a private prescription not on the PBS.)</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/136855/original/image-20160907-25257-1xis7d7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/136855/original/image-20160907-25257-1xis7d7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/136855/original/image-20160907-25257-1xis7d7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/136855/original/image-20160907-25257-1xis7d7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/136855/original/image-20160907-25257-1xis7d7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/136855/original/image-20160907-25257-1xis7d7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/136855/original/image-20160907-25257-1xis7d7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/136855/original/image-20160907-25257-1xis7d7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Singulair is an asthma medication in tablet form.</span>
<span class="attribution"><span class="source">from www.shutterstock.com</span></span>
</figcaption>
</figure>
<p>To put the new reports in context, the TGA received 90 reports of psychiatric events in just over 16 years. Out of these 90 reports, 16 were related to the specific event highlighted in the report (suicidal thoughts and depression). So 16 cases in over 2 million prescriptions makes this a truly rare effect.</p>
<p>This is not to make light of the seriousness of these effects for the people involved. Ideally, these effects would not occur. However, expecting such rare events to be included on warnings is not feasible. It was listed, however, on the <a href="http://secure.healthlinks.net.au/content/msd/pi.cfm?product=mkpsingu">medication product information</a>.</p>
<h2>When are warnings warranted?</h2>
<p>To determine if an effect is caused by a drug, the pharmacovigilance experts at the TGA need to filter the “signal” (drug-caused) effects out from the “noise” (same effect occurring in the population without the drug). </p>
<p><a href="http://www.uptodate.com/contents/suicidal-behavior-in-children-and-adolescents-epidemiology-and-risk-factors">A US study showed</a> the rate of non-fatal suicide attempts in ten- to 17-year-olds was 197 per 100,000 people over a five-year study period. Fatal suicide was 6.4 per 100,000. While the same data aren’t available in Australia, we can use the US data as a rough benchmark. </p>
<p>If we assume (albeit unrealistically) the 2.049 million scripts were evenly spread over the 12 years and each patient took the drug continuously for that period (one prescription per month), then the number of prescriptions equates to a low estimate of 14,299 patients. The US suicide study was conducted over five years, so the annual incidence of non-fatal suicide attempts would average 39 people per 100,000 people. </p>
<p>Using data from the media reports, there was approximately one report (16 reports over 16 years) of suicidal ideation or depression per year per 14,229 patients. That’s an incidence of seven per 100,000 people per year, yet the US data show a “background” rate of 39 per 100,000 people per year. Therefore it can be difficult to find this “signal” within the background “noise”.</p>
<h2>Drug risks and benefits</h2>
<p>The TGA has determined a likely connection between the drug and the psychiatric events, so parents of affected children are asking why they weren’t warned. I answered this earlier – it’s all about risk and benefit. If patients (or their parents) were provided with a list of every side effect, many people would be scared off taking useful medicines.</p>
<p>Unfortunately, the Australian population (generally) does not have sufficient health literacy to be able to put such information into context – look at the anti-vaccination and other scare campaigns. Health professionals are usually time-poor and often do not do the best (or even a good) job explaining the potential side effects to patients. </p>
<p>Patients should be empowered and encouraged to ask questions and discuss risks and benefits with their health-care professionals, about a range of issues, not just medication.</p>
<p>Sometimes an effect is deemed by the TGA to constitute a major risk to the public and a specific warning is attached to product information and even the packaging. These effects pose a significant risk to health and occur with a frequency that warrants such warnings. There are no hard and fast cut-off values. Like most things in the medical world, it’s about judgement and shades of grey.</p>
<p>The information available at the time of prescribing or starting a medicine is often not complete, so the risk-benefit balance is not a certain science. Health professionals must ethically have their patients’ best interests as their primary concern, but when we try a medicine we need to watch carefully to see if it works for that individual.</p>
<p>Yes, some side effects can be scary, but put in the context of the good medicines can do, judgement calls need to be made. People make risk-benefit decisions throughout daily life, such as crossing the road, driving a car and other dangerous daily tasks. </p>
<p>Medical decisions are no different, but people feel less empowered because a product is recommended by an “expert” or they do not have sufficient knowledge to make an informed decision. This is why it’s important for patients to empower themselves by asking questions and making all decisions shared.</p><img src="https://counter.theconversation.com/content/65029/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Greg Kyle does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Media reports have emerged of psychotic episodes in children brought about by a common asthma medication.Greg Kyle, Professor of Pharmacy, Queensland University of TechnologyLicensed as Creative Commons – attribution, no derivatives.