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FDA opens the door to biosimilar insulin
The Food and Drug Administration published Feb. 21 in the Federal Register a final rule that transitions insulin and other products from regulation as a drug to a biologic. This will provide manufacturers access to the biosimilars approval pathway and is expected to bring more competition to the insulin market. The move comes as insulin manufacturers continue to get increased scrutiny over the significantly increased pricing of their products in recent years.
The transition was required under a provision of the Biologics Price Competition and Innovation Act of 2009.
The move is expected to have no impact on the distribution of insulin and other products affected by the transition.
“In general, prescribers should continue to prescribe and order insulin and other biological products the same way they did before the transition,” the FDA said in an FAQ on the transition for physicians and other health care workers. “In general, pharmacists should continue to dispense and counsel about insulin and other biological products the same way they did before the transition. Prescribers and pharmacists should ensure their patients understand there are no changes to the product and they should continue to use the product the same way as before the transition.”
Other products affected by the transition include human growth hormone (somatropin), pancrelipase, chorionic gonadotropin, follitropin alfa, and menotropins. Information on all the transitioning products will move from the Orange Book (which lists FDA-approved drug products with therapeutic equivalent evaluations) to the Purple Book (which lists FDA-licensed biological products with reference product exclusivity data and biosimilar/interchangeability evaluations).
The FDA in the FAQ reiterated its commitment to reviewing any applications for these transition products within 12 months of submission.
The Food and Drug Administration published Feb. 21 in the Federal Register a final rule that transitions insulin and other products from regulation as a drug to a biologic. This will provide manufacturers access to the biosimilars approval pathway and is expected to bring more competition to the insulin market. The move comes as insulin manufacturers continue to get increased scrutiny over the significantly increased pricing of their products in recent years.
The transition was required under a provision of the Biologics Price Competition and Innovation Act of 2009.
The move is expected to have no impact on the distribution of insulin and other products affected by the transition.
“In general, prescribers should continue to prescribe and order insulin and other biological products the same way they did before the transition,” the FDA said in an FAQ on the transition for physicians and other health care workers. “In general, pharmacists should continue to dispense and counsel about insulin and other biological products the same way they did before the transition. Prescribers and pharmacists should ensure their patients understand there are no changes to the product and they should continue to use the product the same way as before the transition.”
Other products affected by the transition include human growth hormone (somatropin), pancrelipase, chorionic gonadotropin, follitropin alfa, and menotropins. Information on all the transitioning products will move from the Orange Book (which lists FDA-approved drug products with therapeutic equivalent evaluations) to the Purple Book (which lists FDA-licensed biological products with reference product exclusivity data and biosimilar/interchangeability evaluations).
The FDA in the FAQ reiterated its commitment to reviewing any applications for these transition products within 12 months of submission.
The Food and Drug Administration published Feb. 21 in the Federal Register a final rule that transitions insulin and other products from regulation as a drug to a biologic. This will provide manufacturers access to the biosimilars approval pathway and is expected to bring more competition to the insulin market. The move comes as insulin manufacturers continue to get increased scrutiny over the significantly increased pricing of their products in recent years.
The transition was required under a provision of the Biologics Price Competition and Innovation Act of 2009.
The move is expected to have no impact on the distribution of insulin and other products affected by the transition.
“In general, prescribers should continue to prescribe and order insulin and other biological products the same way they did before the transition,” the FDA said in an FAQ on the transition for physicians and other health care workers. “In general, pharmacists should continue to dispense and counsel about insulin and other biological products the same way they did before the transition. Prescribers and pharmacists should ensure their patients understand there are no changes to the product and they should continue to use the product the same way as before the transition.”
Other products affected by the transition include human growth hormone (somatropin), pancrelipase, chorionic gonadotropin, follitropin alfa, and menotropins. Information on all the transitioning products will move from the Orange Book (which lists FDA-approved drug products with therapeutic equivalent evaluations) to the Purple Book (which lists FDA-licensed biological products with reference product exclusivity data and biosimilar/interchangeability evaluations).
The FDA in the FAQ reiterated its commitment to reviewing any applications for these transition products within 12 months of submission.
New lipid-lowering drug earns FDA approval
The Food and Drug Administration has approved bempedoic acid (Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL cholesterol lowering.
The oral adenosine triphosphate–citrate lyase (ACL) inhibitor is indicated as an adjunct to diet and maximally tolerated statin therapy in these patients, and approved at the 180 mg once daily dose, the agency announced today.
The safety and efficacy of bempedoic acid were demonstrated over 52 weeks in two multicenter randomized, clinical trials involving 3,009 adults with HeFH or established ASCVD on maximally tolerated statin therapy.
The difference between bempedoic acid and placebo for the primary outcome of change in LDL cholesterol from baseline to week 12 was –18% in the first trial, CLEAR Harmony (95% confidence interval, –20% to –16%; P less than .001), and –17% in the second trial, CLEAR Wisdom (95% CI, –21% to –14%; P less than .001).
The label notes that the effect on cardiovascular morbidity and mortality has not been determined. The label also includes warnings stating that bempedoic acid may increase blood uric acid levels and is associated with an increased risk of tendon rupture or injury.
In clinical trials, 26% of bempedoic acid–treated patients with normal baseline uric acid values versus 9.5% of placebo-treated patients experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction versus 1.1% with placebo, according to the label. Gout was reported in 1.5% of patients treated with bempedoic acid and 0.4% of those treated with placebo.
Also in clinical trials, the risk of tendon rupture was 0.5% with bempedoic acid and 0% with placebo. Tendon rupture involved the rotator cuff, biceps tendon, or Achilles tendon, and occurred within weeks to months of starting the drug. Rupture may “occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders,” the label states.
The label also advises that patients avoid concomitant use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg because it causes an increase in statin concentrations and may increase the risk of related myopathy.
A decision is expected shortly on a new drug application submitted by Esperion for an LDL cholesterol–lowering indication for bempedoic acid 180 mg/ezetimibe 10 mg combination tablet.
Full prescribing information is available online.
This article first appeared on Medscape.com.
The Food and Drug Administration has approved bempedoic acid (Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL cholesterol lowering.
The oral adenosine triphosphate–citrate lyase (ACL) inhibitor is indicated as an adjunct to diet and maximally tolerated statin therapy in these patients, and approved at the 180 mg once daily dose, the agency announced today.
The safety and efficacy of bempedoic acid were demonstrated over 52 weeks in two multicenter randomized, clinical trials involving 3,009 adults with HeFH or established ASCVD on maximally tolerated statin therapy.
The difference between bempedoic acid and placebo for the primary outcome of change in LDL cholesterol from baseline to week 12 was –18% in the first trial, CLEAR Harmony (95% confidence interval, –20% to –16%; P less than .001), and –17% in the second trial, CLEAR Wisdom (95% CI, –21% to –14%; P less than .001).
The label notes that the effect on cardiovascular morbidity and mortality has not been determined. The label also includes warnings stating that bempedoic acid may increase blood uric acid levels and is associated with an increased risk of tendon rupture or injury.
In clinical trials, 26% of bempedoic acid–treated patients with normal baseline uric acid values versus 9.5% of placebo-treated patients experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction versus 1.1% with placebo, according to the label. Gout was reported in 1.5% of patients treated with bempedoic acid and 0.4% of those treated with placebo.
Also in clinical trials, the risk of tendon rupture was 0.5% with bempedoic acid and 0% with placebo. Tendon rupture involved the rotator cuff, biceps tendon, or Achilles tendon, and occurred within weeks to months of starting the drug. Rupture may “occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders,” the label states.
The label also advises that patients avoid concomitant use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg because it causes an increase in statin concentrations and may increase the risk of related myopathy.
A decision is expected shortly on a new drug application submitted by Esperion for an LDL cholesterol–lowering indication for bempedoic acid 180 mg/ezetimibe 10 mg combination tablet.
Full prescribing information is available online.
This article first appeared on Medscape.com.
The Food and Drug Administration has approved bempedoic acid (Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL cholesterol lowering.
The oral adenosine triphosphate–citrate lyase (ACL) inhibitor is indicated as an adjunct to diet and maximally tolerated statin therapy in these patients, and approved at the 180 mg once daily dose, the agency announced today.
The safety and efficacy of bempedoic acid were demonstrated over 52 weeks in two multicenter randomized, clinical trials involving 3,009 adults with HeFH or established ASCVD on maximally tolerated statin therapy.
The difference between bempedoic acid and placebo for the primary outcome of change in LDL cholesterol from baseline to week 12 was –18% in the first trial, CLEAR Harmony (95% confidence interval, –20% to –16%; P less than .001), and –17% in the second trial, CLEAR Wisdom (95% CI, –21% to –14%; P less than .001).
The label notes that the effect on cardiovascular morbidity and mortality has not been determined. The label also includes warnings stating that bempedoic acid may increase blood uric acid levels and is associated with an increased risk of tendon rupture or injury.
In clinical trials, 26% of bempedoic acid–treated patients with normal baseline uric acid values versus 9.5% of placebo-treated patients experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction versus 1.1% with placebo, according to the label. Gout was reported in 1.5% of patients treated with bempedoic acid and 0.4% of those treated with placebo.
Also in clinical trials, the risk of tendon rupture was 0.5% with bempedoic acid and 0% with placebo. Tendon rupture involved the rotator cuff, biceps tendon, or Achilles tendon, and occurred within weeks to months of starting the drug. Rupture may “occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders,” the label states.
The label also advises that patients avoid concomitant use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg because it causes an increase in statin concentrations and may increase the risk of related myopathy.
A decision is expected shortly on a new drug application submitted by Esperion for an LDL cholesterol–lowering indication for bempedoic acid 180 mg/ezetimibe 10 mg combination tablet.
Full prescribing information is available online.
This article first appeared on Medscape.com.
As costs for neurologic drugs rise, adherence to therapy drops
For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.
The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.
Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.
Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.
Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.
“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.
Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.
The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.
SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.
For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.
The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.
Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.
Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.
Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.
“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.
Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.
The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.
SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.
For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.
The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.
Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.
Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.
Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.
“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.
Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.
The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.
SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.
FROM NEUROLOGY
Doctors look to existing drugs in coronavirus fight
COVID-19, the infection caused by the newly identified coronavirus, is a currently a disease with no pharmaceutical weapons against it. There’s no vaccine to prevent it, and no drugs can treat it.
But researchers are racing to change that. A vaccine could be ready to test as soon as April. More than two dozen studies have already been registered on ClinicalTrials.gov, a website that tracks research. These studies aim to test everything from traditional Chinese medicine to vitamin C, stem cells, steroids, and medications that fight other viruses, like the flu and HIV. The hope is that something about how these repurposed remedies work will help patients who are desperately ill with no other prospects.
Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, says this is all part of the playbook for brand-new diseases. “There’s a lot of empiric guessing,” he says. “They’re going to propose a whole lot of drugs that already exist. They’re going to say, here’s the data that shows it blocks the virus” in a test tube. But test tubes aren’t people, and many drugs that seem to work in a lab won’t end up helping patients.
Coronaviruses are especially hard to stop once they invade the body. Unlike many other kinds of viruses, they have a fail-safe against tampering – a “proofreader” that constantly inspects their code, looking for errors, including the potentially life-saving errors that drugs could introduce.
Dr. Fauci said that researchers will be able to make better guesses about how to help people when they can try drugs in animals. “We don’t have an animal model yet of the new coronavirus. When we do get an animal model, that will be a big boon to drugs because then, you can clearly test them in a physiological way, whether they work,” he says.
Looking to drugs for HIV and flu
One of the drugs already under study is the combination of two HIV medications: lopinavir and ritonavir (Kaletra). Kaletra stops viruses by interfering with the enzymes they need to infect cells, called proteases.
One study being done at the Guangzhou Eighth People’s Hospital in China is testing Kaletra against Arbidol, an antiviral drug approved in China and Russia to treat the flu. Two groups of patients will take the medications along with standard care. A third group in the study will receive only standard care, typically supportive therapy with oxygen and IV fluids that are meant to support the body so the immune system can fight off a virus on its own.
An Ebola drug gets a second look
One repurposed drug generating a lot of buzz is an experimental infusion called remdesivir (Xembify). It was originally tested against the Ebola virus. While it didn’t work for that infection, it has been shown to shut down the new coronavirus, at least in test tubes. It’s been given to a small number of COVID-19 patients already, including one in Washington state.
In order to have better evidence of how well it may work in people, two studies in Beijing are comparing remdesivir to a dummy pill to see if the drug can help patients with both mild and severe symptoms recover from their illnesses. Viruses work by infecting cells, taking over their machinery, and getting them to crank out more copies of the virus, which then goes on to infect more cells. Remdesivir is a mimic that fools a virus into replacing one of its four building blocks with a chemical fake. Once in the virus’s blueprints, the imposter acts like a stop sign that keeps the virus from copying itself.
Other kinds of drugs in the same class – called nucleotide analogs – are used to attack cancer and other infectious viruses like hepatitis.
Last week, Chinese scientists published study showing remdesivir was effective against the new coronavirus, 2019-nCoV. Out of seven drugs tested, only remdesivir and an older drug called chloroquine (Aralen), which is used to treat malaria, worked, at least in test tubes. “It functions like a knife that just cuts off the RNA strand,” says Mark Denison, MD, a pediatric infectious disease specialist at Vanderbilt University in Nashville. “They can’t replicate any more. It stops them from doing that.” Dr. Denison is part of a team of researchers in Tennessee and North Carolina that discovered remdesivir could stop coronaviruses, like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), in test tubes and animals. He has studied coronaviruses in his lab for 30 years. He knew they would pose a threat again. “We’re shocked, but not surprised, that this has happened again,” he says of the China-based outbreak of 2019-nCoV.
After the SARS outbreak, which infected more than 8,000 people in 26 countries during 2002-2003, and MERS, which has infected nearly 2,500 people in 27 countries since 2012, researchers knew they had to start looking for treatments that would work against coronaviruses. Dr. Denison reached out to Gilead Sciences, a company best known for its antiviral medications that treat HIV and hepatitis C, and asked it to send drug candidates for him to test on coronaviruses. “The idea was that we didn’t want a drug that would just work against SARS or MERS,” he says. “We wanted drugs that worked against every coronavirus.”
Many of the agents he tried didn’t work until Dr. Denison and his team knocked out the virus’s pesky proofreader. Remdesivir seems to be able to defeat the proofreader, though Dr. Denison admits that he does not know how the drug gets around a virus’s defenses. He has a grant from the National Institutes of Health to study that. Gilead has been giving remdesivir to “a small number” of coronavirus patients in the United States and Europe on a compassionate basis.
One of those patients was a 35-year-old man in Everett, Wash., who had gotten pneumonia after being infected with the new coronavirus during a trip to see family in Wuhan, China, the epicenter of the outbreak. His doctors started IV remdesivir on the evening of his 7th day in the hospital. On the 8th day, he improved. He was well enough to stop using oxygen. Signs of pneumonia were gone. He got his appetite back. His case was recently published in the New England Journal of Medicine, igniting a firestorm of interest in the therapy.
Unfortunately, though, even Dr. Denison says a single person’s case isn’t enough proof that the medication can treat the new coronavirus. The patient, who has not been identified, was getting expert care. He may have improved on his own, despite getting the drug. He said the challenge in people will be to find out two things: whether the medication can block the spread of virus in the body and whether it can reverse the disease. “You can remove the source of injury, but you still have the injury,” he said. Other important questions include how soon the drug may need to be given after infection for it work and whether it may cause significant side effects.
A promising pill
Another drug, a nucleoside analog, that appears to be able to defeat the coronavirus proofreader, EIDD-2801, was developed by Emory University in Atlanta. It was originally intended to treat the flu but has shown some effectiveness against coronaviruses like SARS and MERS.
The FDA recently reached out to Emory asking if it had any drug candidates that might work against the new coronavirus. “It’s a good shot on goal here,” says George Painter, PhD, CEO of Drug Innovation Ventures at Emory. EIDD-2801 can be taken as a pill, which makes it easier to use outside of a hospital setting.
“The capsules for the trial are being made at the end of this month. So we’re close,” Painter says. “We’re right on the edge.”
While these early tests are just getting started, and it will be months until researchers have results, the World Health Organization has sounded a note of caution.
In new guidelines for the clinical management of COVID-19, the WHO reminded doctors and patients that there’s not enough evidence to recommend any specific treatment for infected patients.
Right now, the guidelines recommend that doctors offer supportive care to help the body fight off an infection on its own.
The organization says unlicensed treatments should be given only in the context of clinical trials that have been ethically reviewed or with strict clinical monitoring in emergencies.
This article first appeared on WebMD.com.
COVID-19, the infection caused by the newly identified coronavirus, is a currently a disease with no pharmaceutical weapons against it. There’s no vaccine to prevent it, and no drugs can treat it.
But researchers are racing to change that. A vaccine could be ready to test as soon as April. More than two dozen studies have already been registered on ClinicalTrials.gov, a website that tracks research. These studies aim to test everything from traditional Chinese medicine to vitamin C, stem cells, steroids, and medications that fight other viruses, like the flu and HIV. The hope is that something about how these repurposed remedies work will help patients who are desperately ill with no other prospects.
Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, says this is all part of the playbook for brand-new diseases. “There’s a lot of empiric guessing,” he says. “They’re going to propose a whole lot of drugs that already exist. They’re going to say, here’s the data that shows it blocks the virus” in a test tube. But test tubes aren’t people, and many drugs that seem to work in a lab won’t end up helping patients.
Coronaviruses are especially hard to stop once they invade the body. Unlike many other kinds of viruses, they have a fail-safe against tampering – a “proofreader” that constantly inspects their code, looking for errors, including the potentially life-saving errors that drugs could introduce.
Dr. Fauci said that researchers will be able to make better guesses about how to help people when they can try drugs in animals. “We don’t have an animal model yet of the new coronavirus. When we do get an animal model, that will be a big boon to drugs because then, you can clearly test them in a physiological way, whether they work,” he says.
Looking to drugs for HIV and flu
One of the drugs already under study is the combination of two HIV medications: lopinavir and ritonavir (Kaletra). Kaletra stops viruses by interfering with the enzymes they need to infect cells, called proteases.
One study being done at the Guangzhou Eighth People’s Hospital in China is testing Kaletra against Arbidol, an antiviral drug approved in China and Russia to treat the flu. Two groups of patients will take the medications along with standard care. A third group in the study will receive only standard care, typically supportive therapy with oxygen and IV fluids that are meant to support the body so the immune system can fight off a virus on its own.
An Ebola drug gets a second look
One repurposed drug generating a lot of buzz is an experimental infusion called remdesivir (Xembify). It was originally tested against the Ebola virus. While it didn’t work for that infection, it has been shown to shut down the new coronavirus, at least in test tubes. It’s been given to a small number of COVID-19 patients already, including one in Washington state.
In order to have better evidence of how well it may work in people, two studies in Beijing are comparing remdesivir to a dummy pill to see if the drug can help patients with both mild and severe symptoms recover from their illnesses. Viruses work by infecting cells, taking over their machinery, and getting them to crank out more copies of the virus, which then goes on to infect more cells. Remdesivir is a mimic that fools a virus into replacing one of its four building blocks with a chemical fake. Once in the virus’s blueprints, the imposter acts like a stop sign that keeps the virus from copying itself.
Other kinds of drugs in the same class – called nucleotide analogs – are used to attack cancer and other infectious viruses like hepatitis.
Last week, Chinese scientists published study showing remdesivir was effective against the new coronavirus, 2019-nCoV. Out of seven drugs tested, only remdesivir and an older drug called chloroquine (Aralen), which is used to treat malaria, worked, at least in test tubes. “It functions like a knife that just cuts off the RNA strand,” says Mark Denison, MD, a pediatric infectious disease specialist at Vanderbilt University in Nashville. “They can’t replicate any more. It stops them from doing that.” Dr. Denison is part of a team of researchers in Tennessee and North Carolina that discovered remdesivir could stop coronaviruses, like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), in test tubes and animals. He has studied coronaviruses in his lab for 30 years. He knew they would pose a threat again. “We’re shocked, but not surprised, that this has happened again,” he says of the China-based outbreak of 2019-nCoV.
After the SARS outbreak, which infected more than 8,000 people in 26 countries during 2002-2003, and MERS, which has infected nearly 2,500 people in 27 countries since 2012, researchers knew they had to start looking for treatments that would work against coronaviruses. Dr. Denison reached out to Gilead Sciences, a company best known for its antiviral medications that treat HIV and hepatitis C, and asked it to send drug candidates for him to test on coronaviruses. “The idea was that we didn’t want a drug that would just work against SARS or MERS,” he says. “We wanted drugs that worked against every coronavirus.”
Many of the agents he tried didn’t work until Dr. Denison and his team knocked out the virus’s pesky proofreader. Remdesivir seems to be able to defeat the proofreader, though Dr. Denison admits that he does not know how the drug gets around a virus’s defenses. He has a grant from the National Institutes of Health to study that. Gilead has been giving remdesivir to “a small number” of coronavirus patients in the United States and Europe on a compassionate basis.
One of those patients was a 35-year-old man in Everett, Wash., who had gotten pneumonia after being infected with the new coronavirus during a trip to see family in Wuhan, China, the epicenter of the outbreak. His doctors started IV remdesivir on the evening of his 7th day in the hospital. On the 8th day, he improved. He was well enough to stop using oxygen. Signs of pneumonia were gone. He got his appetite back. His case was recently published in the New England Journal of Medicine, igniting a firestorm of interest in the therapy.
Unfortunately, though, even Dr. Denison says a single person’s case isn’t enough proof that the medication can treat the new coronavirus. The patient, who has not been identified, was getting expert care. He may have improved on his own, despite getting the drug. He said the challenge in people will be to find out two things: whether the medication can block the spread of virus in the body and whether it can reverse the disease. “You can remove the source of injury, but you still have the injury,” he said. Other important questions include how soon the drug may need to be given after infection for it work and whether it may cause significant side effects.
A promising pill
Another drug, a nucleoside analog, that appears to be able to defeat the coronavirus proofreader, EIDD-2801, was developed by Emory University in Atlanta. It was originally intended to treat the flu but has shown some effectiveness against coronaviruses like SARS and MERS.
The FDA recently reached out to Emory asking if it had any drug candidates that might work against the new coronavirus. “It’s a good shot on goal here,” says George Painter, PhD, CEO of Drug Innovation Ventures at Emory. EIDD-2801 can be taken as a pill, which makes it easier to use outside of a hospital setting.
“The capsules for the trial are being made at the end of this month. So we’re close,” Painter says. “We’re right on the edge.”
While these early tests are just getting started, and it will be months until researchers have results, the World Health Organization has sounded a note of caution.
In new guidelines for the clinical management of COVID-19, the WHO reminded doctors and patients that there’s not enough evidence to recommend any specific treatment for infected patients.
Right now, the guidelines recommend that doctors offer supportive care to help the body fight off an infection on its own.
The organization says unlicensed treatments should be given only in the context of clinical trials that have been ethically reviewed or with strict clinical monitoring in emergencies.
This article first appeared on WebMD.com.
COVID-19, the infection caused by the newly identified coronavirus, is a currently a disease with no pharmaceutical weapons against it. There’s no vaccine to prevent it, and no drugs can treat it.
But researchers are racing to change that. A vaccine could be ready to test as soon as April. More than two dozen studies have already been registered on ClinicalTrials.gov, a website that tracks research. These studies aim to test everything from traditional Chinese medicine to vitamin C, stem cells, steroids, and medications that fight other viruses, like the flu and HIV. The hope is that something about how these repurposed remedies work will help patients who are desperately ill with no other prospects.
Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, says this is all part of the playbook for brand-new diseases. “There’s a lot of empiric guessing,” he says. “They’re going to propose a whole lot of drugs that already exist. They’re going to say, here’s the data that shows it blocks the virus” in a test tube. But test tubes aren’t people, and many drugs that seem to work in a lab won’t end up helping patients.
Coronaviruses are especially hard to stop once they invade the body. Unlike many other kinds of viruses, they have a fail-safe against tampering – a “proofreader” that constantly inspects their code, looking for errors, including the potentially life-saving errors that drugs could introduce.
Dr. Fauci said that researchers will be able to make better guesses about how to help people when they can try drugs in animals. “We don’t have an animal model yet of the new coronavirus. When we do get an animal model, that will be a big boon to drugs because then, you can clearly test them in a physiological way, whether they work,” he says.
Looking to drugs for HIV and flu
One of the drugs already under study is the combination of two HIV medications: lopinavir and ritonavir (Kaletra). Kaletra stops viruses by interfering with the enzymes they need to infect cells, called proteases.
One study being done at the Guangzhou Eighth People’s Hospital in China is testing Kaletra against Arbidol, an antiviral drug approved in China and Russia to treat the flu. Two groups of patients will take the medications along with standard care. A third group in the study will receive only standard care, typically supportive therapy with oxygen and IV fluids that are meant to support the body so the immune system can fight off a virus on its own.
An Ebola drug gets a second look
One repurposed drug generating a lot of buzz is an experimental infusion called remdesivir (Xembify). It was originally tested against the Ebola virus. While it didn’t work for that infection, it has been shown to shut down the new coronavirus, at least in test tubes. It’s been given to a small number of COVID-19 patients already, including one in Washington state.
In order to have better evidence of how well it may work in people, two studies in Beijing are comparing remdesivir to a dummy pill to see if the drug can help patients with both mild and severe symptoms recover from their illnesses. Viruses work by infecting cells, taking over their machinery, and getting them to crank out more copies of the virus, which then goes on to infect more cells. Remdesivir is a mimic that fools a virus into replacing one of its four building blocks with a chemical fake. Once in the virus’s blueprints, the imposter acts like a stop sign that keeps the virus from copying itself.
Other kinds of drugs in the same class – called nucleotide analogs – are used to attack cancer and other infectious viruses like hepatitis.
Last week, Chinese scientists published study showing remdesivir was effective against the new coronavirus, 2019-nCoV. Out of seven drugs tested, only remdesivir and an older drug called chloroquine (Aralen), which is used to treat malaria, worked, at least in test tubes. “It functions like a knife that just cuts off the RNA strand,” says Mark Denison, MD, a pediatric infectious disease specialist at Vanderbilt University in Nashville. “They can’t replicate any more. It stops them from doing that.” Dr. Denison is part of a team of researchers in Tennessee and North Carolina that discovered remdesivir could stop coronaviruses, like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), in test tubes and animals. He has studied coronaviruses in his lab for 30 years. He knew they would pose a threat again. “We’re shocked, but not surprised, that this has happened again,” he says of the China-based outbreak of 2019-nCoV.
After the SARS outbreak, which infected more than 8,000 people in 26 countries during 2002-2003, and MERS, which has infected nearly 2,500 people in 27 countries since 2012, researchers knew they had to start looking for treatments that would work against coronaviruses. Dr. Denison reached out to Gilead Sciences, a company best known for its antiviral medications that treat HIV and hepatitis C, and asked it to send drug candidates for him to test on coronaviruses. “The idea was that we didn’t want a drug that would just work against SARS or MERS,” he says. “We wanted drugs that worked against every coronavirus.”
Many of the agents he tried didn’t work until Dr. Denison and his team knocked out the virus’s pesky proofreader. Remdesivir seems to be able to defeat the proofreader, though Dr. Denison admits that he does not know how the drug gets around a virus’s defenses. He has a grant from the National Institutes of Health to study that. Gilead has been giving remdesivir to “a small number” of coronavirus patients in the United States and Europe on a compassionate basis.
One of those patients was a 35-year-old man in Everett, Wash., who had gotten pneumonia after being infected with the new coronavirus during a trip to see family in Wuhan, China, the epicenter of the outbreak. His doctors started IV remdesivir on the evening of his 7th day in the hospital. On the 8th day, he improved. He was well enough to stop using oxygen. Signs of pneumonia were gone. He got his appetite back. His case was recently published in the New England Journal of Medicine, igniting a firestorm of interest in the therapy.
Unfortunately, though, even Dr. Denison says a single person’s case isn’t enough proof that the medication can treat the new coronavirus. The patient, who has not been identified, was getting expert care. He may have improved on his own, despite getting the drug. He said the challenge in people will be to find out two things: whether the medication can block the spread of virus in the body and whether it can reverse the disease. “You can remove the source of injury, but you still have the injury,” he said. Other important questions include how soon the drug may need to be given after infection for it work and whether it may cause significant side effects.
A promising pill
Another drug, a nucleoside analog, that appears to be able to defeat the coronavirus proofreader, EIDD-2801, was developed by Emory University in Atlanta. It was originally intended to treat the flu but has shown some effectiveness against coronaviruses like SARS and MERS.
The FDA recently reached out to Emory asking if it had any drug candidates that might work against the new coronavirus. “It’s a good shot on goal here,” says George Painter, PhD, CEO of Drug Innovation Ventures at Emory. EIDD-2801 can be taken as a pill, which makes it easier to use outside of a hospital setting.
“The capsules for the trial are being made at the end of this month. So we’re close,” Painter says. “We’re right on the edge.”
While these early tests are just getting started, and it will be months until researchers have results, the World Health Organization has sounded a note of caution.
In new guidelines for the clinical management of COVID-19, the WHO reminded doctors and patients that there’s not enough evidence to recommend any specific treatment for infected patients.
Right now, the guidelines recommend that doctors offer supportive care to help the body fight off an infection on its own.
The organization says unlicensed treatments should be given only in the context of clinical trials that have been ethically reviewed or with strict clinical monitoring in emergencies.
This article first appeared on WebMD.com.
Zilucoplan improved efficacy outcomes in myasthenia gravis
The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.
While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.
“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote James F. Howard Jr, MD, of the University of North Carolina in Chapel Hill, and coauthors.
Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.
That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in JAMA Neurology.
A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.
Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.
Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.
The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.
Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.
Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.
Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.
Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.
SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125.
The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.
While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.
“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote James F. Howard Jr, MD, of the University of North Carolina in Chapel Hill, and coauthors.
Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.
That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in JAMA Neurology.
A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.
Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.
Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.
The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.
Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.
Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.
Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.
Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.
SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125.
The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.
While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.
“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote James F. Howard Jr, MD, of the University of North Carolina in Chapel Hill, and coauthors.
Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.
That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in JAMA Neurology.
A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.
Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.
Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.
The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.
Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.
Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.
Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.
Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.
SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125.
FROM JAMA NEUROLOGY
Lorcaserin withdrawn from U.S. market due to cancer risk
The Food and Drug Administration asked Eisai to voluntary withdraw the weight-loss drug lorcaserin (Belviq and Belviq XR) on Feb. 13 after a post-marketing trial with more than 12,000 subjects revealed an increased occurrence of cancer.
In a Drug Safety Communication, the agency said “health care professionals should stop prescribing and dispensing lorcaserin to patients. Contact patients currently taking lorcaserin, inform them of the increased occurrence of cancer seen in the clinical trial, and ask them to stop taking the medicine. Discuss alternative weight-loss medicines or strategies with your patients.”
Eisai is complying with the withdrawal request.
The decision is based on the agency’s review of the 5-year trial, which was designed to evaluate cardiac risk with the drug and ended in June 2018. In total, 7.7% of patients randomized to 10 mg lorcaserin twice daily were diagnosed with 520 primary cancers, compared with 7.1% of placebo subjects diagnosed with 470 cancers, over a median follow-up of 3 years and 3 months. There was one additional cancer observed for every 470 patients treated for 1 year.
“There was no apparent difference in the incidence of cancer over the initial months of treatment, but the imbalance increased with longer duration on lorcaserin,” FDA said. Pancreatic, colorectal, and lung cancers were among those diagnosed.
In short, “we believe that the risks of lorcaserin outweigh its benefits based on our completed review of” the data, the agency said. The FDA is not recommending special cancer screenings for patients who have taken lorcaserin.
The action follows an FDA alert in January about a possible elevated cancer risk based on its preliminary analysis of the study.
Patients were also advised Feb. 13 to stop taking the drug and talk to their providers about alternative weight-loss medications and weight-management programs.
They were also told to dispose of the pills at a drug take-back location if available, but if not, to mix them with an “unappealing substance” such as dirt, cat litter, or used coffee grounds; seal them in plastic bag; and put them in the trash.
The Food and Drug Administration asked Eisai to voluntary withdraw the weight-loss drug lorcaserin (Belviq and Belviq XR) on Feb. 13 after a post-marketing trial with more than 12,000 subjects revealed an increased occurrence of cancer.
In a Drug Safety Communication, the agency said “health care professionals should stop prescribing and dispensing lorcaserin to patients. Contact patients currently taking lorcaserin, inform them of the increased occurrence of cancer seen in the clinical trial, and ask them to stop taking the medicine. Discuss alternative weight-loss medicines or strategies with your patients.”
Eisai is complying with the withdrawal request.
The decision is based on the agency’s review of the 5-year trial, which was designed to evaluate cardiac risk with the drug and ended in June 2018. In total, 7.7% of patients randomized to 10 mg lorcaserin twice daily were diagnosed with 520 primary cancers, compared with 7.1% of placebo subjects diagnosed with 470 cancers, over a median follow-up of 3 years and 3 months. There was one additional cancer observed for every 470 patients treated for 1 year.
“There was no apparent difference in the incidence of cancer over the initial months of treatment, but the imbalance increased with longer duration on lorcaserin,” FDA said. Pancreatic, colorectal, and lung cancers were among those diagnosed.
In short, “we believe that the risks of lorcaserin outweigh its benefits based on our completed review of” the data, the agency said. The FDA is not recommending special cancer screenings for patients who have taken lorcaserin.
The action follows an FDA alert in January about a possible elevated cancer risk based on its preliminary analysis of the study.
Patients were also advised Feb. 13 to stop taking the drug and talk to their providers about alternative weight-loss medications and weight-management programs.
They were also told to dispose of the pills at a drug take-back location if available, but if not, to mix them with an “unappealing substance” such as dirt, cat litter, or used coffee grounds; seal them in plastic bag; and put them in the trash.
The Food and Drug Administration asked Eisai to voluntary withdraw the weight-loss drug lorcaserin (Belviq and Belviq XR) on Feb. 13 after a post-marketing trial with more than 12,000 subjects revealed an increased occurrence of cancer.
In a Drug Safety Communication, the agency said “health care professionals should stop prescribing and dispensing lorcaserin to patients. Contact patients currently taking lorcaserin, inform them of the increased occurrence of cancer seen in the clinical trial, and ask them to stop taking the medicine. Discuss alternative weight-loss medicines or strategies with your patients.”
Eisai is complying with the withdrawal request.
The decision is based on the agency’s review of the 5-year trial, which was designed to evaluate cardiac risk with the drug and ended in June 2018. In total, 7.7% of patients randomized to 10 mg lorcaserin twice daily were diagnosed with 520 primary cancers, compared with 7.1% of placebo subjects diagnosed with 470 cancers, over a median follow-up of 3 years and 3 months. There was one additional cancer observed for every 470 patients treated for 1 year.
“There was no apparent difference in the incidence of cancer over the initial months of treatment, but the imbalance increased with longer duration on lorcaserin,” FDA said. Pancreatic, colorectal, and lung cancers were among those diagnosed.
In short, “we believe that the risks of lorcaserin outweigh its benefits based on our completed review of” the data, the agency said. The FDA is not recommending special cancer screenings for patients who have taken lorcaserin.
The action follows an FDA alert in January about a possible elevated cancer risk based on its preliminary analysis of the study.
Patients were also advised Feb. 13 to stop taking the drug and talk to their providers about alternative weight-loss medications and weight-management programs.
They were also told to dispose of the pills at a drug take-back location if available, but if not, to mix them with an “unappealing substance” such as dirt, cat litter, or used coffee grounds; seal them in plastic bag; and put them in the trash.
Pathways to new therapeutic agents for human coronaviruses
No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.
Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.
“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.
2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
Examining extant drugs
The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.
For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.
Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.
Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
Developing new antivirals
The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.
MERS-CoV and SARS-CoV PL protease inhibitors
Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.
Replicase inhibitors
Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.
Membrane-bound viral RNA synthesis inhibitors
Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”
Host-based, anti-CoV treatment options
An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.
Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.
One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.
Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”
In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.
“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.
Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.
SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.
No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.
Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.
“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.
2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
Examining extant drugs
The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.
For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.
Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.
Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
Developing new antivirals
The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.
MERS-CoV and SARS-CoV PL protease inhibitors
Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.
Replicase inhibitors
Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.
Membrane-bound viral RNA synthesis inhibitors
Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”
Host-based, anti-CoV treatment options
An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.
Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.
One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.
Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”
In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.
“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.
Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.
SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.
No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.
Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.
“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.
2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
Examining extant drugs
The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.
For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.
Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.
Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
Developing new antivirals
The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.
MERS-CoV and SARS-CoV PL protease inhibitors
Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.
Replicase inhibitors
Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.
Membrane-bound viral RNA synthesis inhibitors
Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”
Host-based, anti-CoV treatment options
An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.
Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.
One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.
Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”
In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.
“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.
Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.
SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.
FROM DRUG DISCOVERY TODAY
Pharmacologic prophylaxis fails in pediatric migraine
Clinicians hoped that medications used in adults – such as antidepressants, antiepileptics, antihypertensive agents, calcium channel blockers, and food supplements – would find similar success in children. Unfortunately, researchers found only short-term signs of efficacy over placebo, with no benefit lasting more than 6 months.
The study, conducted by a team led by Cosima Locher, PhD, of Boston Children’s Hospital, included 23 double-blind, randomized, controlled trials with a total of 2,217 patients; the mean age was 11 years. They compared 12 pharmacologic agents with each other or with placebo in the study, published online in JAMA Pediatrics.
In a main efficacy analysis that included 19 studies, only two treatments outperformed placebo: propranolol (standardized mean difference, 0.60; 95% confidence interval, 0.03-1.17) and topiramate (SMD, 0.59; 95% CI, 0.03-1.15). There were no statistically significant between-treatment differences.
The results had an overall low to moderate certainty.
When propranolol was compared to placebo, the 95% prediction interval (–0.62 to 1.82) was wider than the significant confidence interval (0.03-1.17), and comprised both beneficial and detrimental effects. A similar result was found with topiramate, with a prediction interval of –0.62 to 1.80 extending into nonsignificant effects (95% CI, 0.03-1.15). In both cases, significant effects were found only when the prediction interval was 70%.
In a long-term analysis (greater than 6 months), no treatment outperformed placebo.
The treatments generally were acceptable. The researchers found no significant difference in tolerability between any of the treatments and each other or placebo. Safety data analyzed from 13 trials revealed no significant differences between treatments and placebo.
“Because specific effects of drugs are associated with the size of the placebo effect, the lack of drug efficacy in our NMA [network meta-analysis] could be owing to a comparatively high placebo effect in children. In fact, there is indirect evidence [from other studies] that the placebo effect is more pronounced in children and adolescents than in adults,” Dr. Locher and associates said. They suggested that studies were needed to quantify the placebo effect in pediatric migraine, and if it was large, to develop innovative therapies making use of this.
The findings should lead to some changes in practice, Boris Zernikow, MD, PhD, of Children’s and Adolescents’ Hospital Datteln (Germany) wrote in an accompanying editorial.
Pharmacological prophylactic treatment of childhood migraine should be an exception rather than the rule, and nonpharmacologic approaches should be emphasized, particularly because the placebo effect is magnified in children, he said.
Many who suffer migraines in childhood will continue to be affected in adulthood, so pediatric intervention is a good opportunity to instill effective strategies. These include: using abortive medication early in an attack and using antimigraine medications for only that specific type of headache; engaging in physical activity to reduce migraine attacks; getting sufficient sleep; and learning relaxation and other psychological approaches to counter migraines.
Dr. Zernikow had no relevant financial disclosures. One study author received grants from Amgen and other support from Grunenthal and Akelos. The study received funding from the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment; the Swiss National Science Foundation; the Schweizer-Arau-Foundation; and the Theophrastus Foundation.
SOURCES: Locher C et al. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5856; Zernikow B. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5907.
Clinicians hoped that medications used in adults – such as antidepressants, antiepileptics, antihypertensive agents, calcium channel blockers, and food supplements – would find similar success in children. Unfortunately, researchers found only short-term signs of efficacy over placebo, with no benefit lasting more than 6 months.
The study, conducted by a team led by Cosima Locher, PhD, of Boston Children’s Hospital, included 23 double-blind, randomized, controlled trials with a total of 2,217 patients; the mean age was 11 years. They compared 12 pharmacologic agents with each other or with placebo in the study, published online in JAMA Pediatrics.
In a main efficacy analysis that included 19 studies, only two treatments outperformed placebo: propranolol (standardized mean difference, 0.60; 95% confidence interval, 0.03-1.17) and topiramate (SMD, 0.59; 95% CI, 0.03-1.15). There were no statistically significant between-treatment differences.
The results had an overall low to moderate certainty.
When propranolol was compared to placebo, the 95% prediction interval (–0.62 to 1.82) was wider than the significant confidence interval (0.03-1.17), and comprised both beneficial and detrimental effects. A similar result was found with topiramate, with a prediction interval of –0.62 to 1.80 extending into nonsignificant effects (95% CI, 0.03-1.15). In both cases, significant effects were found only when the prediction interval was 70%.
In a long-term analysis (greater than 6 months), no treatment outperformed placebo.
The treatments generally were acceptable. The researchers found no significant difference in tolerability between any of the treatments and each other or placebo. Safety data analyzed from 13 trials revealed no significant differences between treatments and placebo.
“Because specific effects of drugs are associated with the size of the placebo effect, the lack of drug efficacy in our NMA [network meta-analysis] could be owing to a comparatively high placebo effect in children. In fact, there is indirect evidence [from other studies] that the placebo effect is more pronounced in children and adolescents than in adults,” Dr. Locher and associates said. They suggested that studies were needed to quantify the placebo effect in pediatric migraine, and if it was large, to develop innovative therapies making use of this.
The findings should lead to some changes in practice, Boris Zernikow, MD, PhD, of Children’s and Adolescents’ Hospital Datteln (Germany) wrote in an accompanying editorial.
Pharmacological prophylactic treatment of childhood migraine should be an exception rather than the rule, and nonpharmacologic approaches should be emphasized, particularly because the placebo effect is magnified in children, he said.
Many who suffer migraines in childhood will continue to be affected in adulthood, so pediatric intervention is a good opportunity to instill effective strategies. These include: using abortive medication early in an attack and using antimigraine medications for only that specific type of headache; engaging in physical activity to reduce migraine attacks; getting sufficient sleep; and learning relaxation and other psychological approaches to counter migraines.
Dr. Zernikow had no relevant financial disclosures. One study author received grants from Amgen and other support from Grunenthal and Akelos. The study received funding from the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment; the Swiss National Science Foundation; the Schweizer-Arau-Foundation; and the Theophrastus Foundation.
SOURCES: Locher C et al. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5856; Zernikow B. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5907.
Clinicians hoped that medications used in adults – such as antidepressants, antiepileptics, antihypertensive agents, calcium channel blockers, and food supplements – would find similar success in children. Unfortunately, researchers found only short-term signs of efficacy over placebo, with no benefit lasting more than 6 months.
The study, conducted by a team led by Cosima Locher, PhD, of Boston Children’s Hospital, included 23 double-blind, randomized, controlled trials with a total of 2,217 patients; the mean age was 11 years. They compared 12 pharmacologic agents with each other or with placebo in the study, published online in JAMA Pediatrics.
In a main efficacy analysis that included 19 studies, only two treatments outperformed placebo: propranolol (standardized mean difference, 0.60; 95% confidence interval, 0.03-1.17) and topiramate (SMD, 0.59; 95% CI, 0.03-1.15). There were no statistically significant between-treatment differences.
The results had an overall low to moderate certainty.
When propranolol was compared to placebo, the 95% prediction interval (–0.62 to 1.82) was wider than the significant confidence interval (0.03-1.17), and comprised both beneficial and detrimental effects. A similar result was found with topiramate, with a prediction interval of –0.62 to 1.80 extending into nonsignificant effects (95% CI, 0.03-1.15). In both cases, significant effects were found only when the prediction interval was 70%.
In a long-term analysis (greater than 6 months), no treatment outperformed placebo.
The treatments generally were acceptable. The researchers found no significant difference in tolerability between any of the treatments and each other or placebo. Safety data analyzed from 13 trials revealed no significant differences between treatments and placebo.
“Because specific effects of drugs are associated with the size of the placebo effect, the lack of drug efficacy in our NMA [network meta-analysis] could be owing to a comparatively high placebo effect in children. In fact, there is indirect evidence [from other studies] that the placebo effect is more pronounced in children and adolescents than in adults,” Dr. Locher and associates said. They suggested that studies were needed to quantify the placebo effect in pediatric migraine, and if it was large, to develop innovative therapies making use of this.
The findings should lead to some changes in practice, Boris Zernikow, MD, PhD, of Children’s and Adolescents’ Hospital Datteln (Germany) wrote in an accompanying editorial.
Pharmacological prophylactic treatment of childhood migraine should be an exception rather than the rule, and nonpharmacologic approaches should be emphasized, particularly because the placebo effect is magnified in children, he said.
Many who suffer migraines in childhood will continue to be affected in adulthood, so pediatric intervention is a good opportunity to instill effective strategies. These include: using abortive medication early in an attack and using antimigraine medications for only that specific type of headache; engaging in physical activity to reduce migraine attacks; getting sufficient sleep; and learning relaxation and other psychological approaches to counter migraines.
Dr. Zernikow had no relevant financial disclosures. One study author received grants from Amgen and other support from Grunenthal and Akelos. The study received funding from the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment; the Swiss National Science Foundation; the Schweizer-Arau-Foundation; and the Theophrastus Foundation.
SOURCES: Locher C et al. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5856; Zernikow B. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5907.
FROM JAMA PEDIATRICS
Shift in approach is encouraged in assessing chronic pain
In many cases, dietary interventions can lead to less inflammation
SAN DIEGO – When clinicians ask patients to quantify their level of chronic pain on a scale of 1-10, and they rate it as a 7, what does that really mean?
Robert A. Bonakdar, MD, said posing such a question as the main determinator of the treatment approach during a pain assessment “depersonalizes medicine to the point where you’re making a patient a number.” Dr. Bonakdar spoke at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
“It considers areas that are often overlooked, such as the role of the gut microbiome, mood, and epigenetics.”
Over the past two decades, the number of American adults suffering from pain has increased from 120 million to 178 million, or to 41% of the adult population, said Dr. Bonakdar, a family physician who is director of pain management at the Scripps Center for Integrative Medicine. Data from the National Institutes of Health estimate that Americans spend more than $600 billion each year on the treatment of pain, which surpasses monies spent on cancer, heart disease, and diabetes. According to a 2016 report from the United States Bone and Joint Initiative, arthritis and rheumatologic conditions resulted in an estimated 6.7 million annual hospitalizations, and the average annual cost per person for treatment of a musculoskeletal condition is $7,800.
“If we continue on our current trajectory, we are choosing to accept more prevalence and incidence of these disorders, spiraling costs, restricted access to needed services, and less success in alleviating pain and suffering – a high cost,” Edward H. Yelin, PhD, cochair of the report’s steering committee, and professor of medicine and health policy at the University of California, San Francisco, said in a prepared statement in 2016. That same year, Brian F. Mandell, MD, PhD, editor of the Cleveland Clinic Journal of Medicine, penned an editorial in which he stated that “The time has come to move past using a one-size-fits-all fifth vital sign . . . and reflexively prescribing an opioid when pain is characterized as severe” (Clev Clin J Med. 2016. Jun;83[6]:400-1). A decade earlier, authors of a cross-sectional review at a single Department of Veterans Affairs medical center set out to assess the impact of the VA’s “Pain as the 5th Vital Sign” initiative on the quality of pain management (J Gen Intern Med. 2006;21[6]:607–12). They found that patients with substantial pain documented by the fifth vital sign often had inadequate pain management. The preponderance of existing evidence suggests that a different approach is needed to prescribing opioids, Dr. Bonakdar said. “It’s coming from every voice in pain care: that what we are doing is not working,” he said. “It’s not only not working; it’s dangerous. That’s the consequence of depersonalized medicine. What’s the consequence of depersonalized nutrition? It’s the same industrialized approach.”
The typical American diet, he continued, is rife with processed foods and lacks an adequate proportion of plant-based products. “It’s basically a setup for inflammation,” Dr. Bonakdar said. “Most people who come into our clinic are eating 63% processed foods, 25% animal foods, and 12% plant foods. When we are eating, we’re oversizing it because that’s the American thing to do. At the end of the day, this process is not only killing us from heart disease and stroke as causes of death, but it’s also killing us as far as pain. The same diet that’s causing heart disease is the same diet that’s increasing pain.”
Dr. Bonakdar said that the ingestion of ultra-processed foods over time jumpstarts the process of dysbiosis, which increases gut permeability. “When gut permeability happens, and you have high levels of polysaccharides and inflammatory markers such as zonulin and lipopolysaccharide (LPS), it not only goes on to affect adipose tissue and insulin resistance, it can affect the muscle and joints,” he explained. “That is a setup for sarcopenia, or muscle loss, which then makes it harder for patients to be fully functional and active. It goes on to cause joint problems as well.”
He likened an increase in gut permeability to “a bomb going off in the gut.” Routine consumption of highly processed foods “creates this wave of inflammation that goes throughout your body affecting joints and muscles, and causes an increased amount of pain. Over time, patients make the connection but it’s much easier to say, ‘take this NSAID’ or ‘take this Cox-2 inhibitor’ to suppress the pain. But if all you’re doing is suppressing, you’re not going to the source of the pain.”
Dr. Bonakdar cited several recent articles that help to make the connection between dysbiosis and pain, including a review that concluded that dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases (Nutrients. 2019;11[8]:1707). Authors of a separate review concluded that human microbiome studies strongly suggest an incriminating role of microbes in the pathophysiology and progression of RA. Lastly, several studies have noted that pain conditions such as fibromyalgia may have microbiome “signatures” related to dysbiosis, which may pave the way for interventions, such as dietary shifting and probiotics that target individuals with microbiome abnormalities (Pain. 2019 Nov;160[11]:2589-602 and EBioMedicine. 2019 Aug 1;46:499-511).
Clinicians can begin to help patients who present with pain complaints “by listening to what their current pattern is: strategies that have worked, and those that haven’t,” he said. “If we’re not understanding the person and we’re just ordering genetic studies or microbiome studies and going off of the assessment, we sometime miss what interventions to start. In many cases, a simple intervention like a dietary shift is all that’s required.”
A survey of more than 1 million individuals found that BMI and daily pain are positively correlated in the United States (Obesity 2012;20[7]:1491-5). “This is increased more significantly for women and the elderly,” said Dr. Bonakdar, who was not affiliated with the study. “If we can change the diet that person is taking, that’s going to begin the process of reversing this to the point where they’re having less pain from inflammation that’s affecting the adipose tissue and adipokines traveling to their joints, which can cause less dysbiosis. It is very much a vicious cycle that patients follow, but if you begin to unwind it, it’s going to help multiple areas.”
In the Intensive Diet and Exercise for Arthritis (IDEA) trial, researchers randomized 450 patients with osteoarthritis to intensive dietary restriction only, exercise only, or a combination of both (BMC Musculoskelet Disord. 2009;10:93). They found that a 5% weight loss over the course of 18 months led to a 30% reduction in pain and a 24% improvement in function.
Inspired by the IDEA trial design, Dr. Bonakdar and his colleagues completed an unpublished 12-week pilot program with 12 patients with a BMI of 27 kg/m2 or greater plus comorbidities. The program consisted of weekly group meetings, including a lecture by team clinicians, dietician, and fitness staff; group support sessions with a behavioral counselor; and a group exercise session. It also included weekly 1:1 personal training sessions and biweekly 1:1 dietitian meetings. The researchers also evaluated several deficiencies linked to pain, including magnesium, vitamin D, vitamins B1, B2, and B12, folate, calcium, amino acids, omega 3s, zinc, coenzyme Q10, carnitine, and vitamin C. The goal was a weight reduction of 5%.
The intervention consisted of a 28-day detox/protein shake consumed 1-3 times per day, which contained 17 g of protein per serving. Nutritional supplementation was added based on results of individual diagnostics.
According to preliminary results from the trial, the intended weight goal was achieved. “More importantly, there were significant improvements in markers of dysbiosis, including zonulin and lipopolysaccharide, as well as the adipokine leptin, which appeared to be associated with improvement in quality of life measures and pain,” Dr. Bonakdar said.
He concluded his presentation by highlighting a pilot study conducted in an Australian tertiary pain clinic. It found that a personalized dietitian-delivered dietary intervention can improve pain scores, quality of life, and dietary intake of people experiencing chronic pain (Nutrients. 2019 Jan 16;11[1] pii: E181). “This is another piece of the puzzle showing that these dietary interventions can be done in multiple settings, including tertiary centers with nutrition staff, and that this important step can improve pain and quality of life,” he said.
Dr. Bonakdar disclosed that he receives royalties from Oxford University Press, Lippincott, and Elsevier. He is also a consultant to Standard Process.
In many cases, dietary interventions can lead to less inflammation
In many cases, dietary interventions can lead to less inflammation
SAN DIEGO – When clinicians ask patients to quantify their level of chronic pain on a scale of 1-10, and they rate it as a 7, what does that really mean?
Robert A. Bonakdar, MD, said posing such a question as the main determinator of the treatment approach during a pain assessment “depersonalizes medicine to the point where you’re making a patient a number.” Dr. Bonakdar spoke at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
“It considers areas that are often overlooked, such as the role of the gut microbiome, mood, and epigenetics.”
Over the past two decades, the number of American adults suffering from pain has increased from 120 million to 178 million, or to 41% of the adult population, said Dr. Bonakdar, a family physician who is director of pain management at the Scripps Center for Integrative Medicine. Data from the National Institutes of Health estimate that Americans spend more than $600 billion each year on the treatment of pain, which surpasses monies spent on cancer, heart disease, and diabetes. According to a 2016 report from the United States Bone and Joint Initiative, arthritis and rheumatologic conditions resulted in an estimated 6.7 million annual hospitalizations, and the average annual cost per person for treatment of a musculoskeletal condition is $7,800.
“If we continue on our current trajectory, we are choosing to accept more prevalence and incidence of these disorders, spiraling costs, restricted access to needed services, and less success in alleviating pain and suffering – a high cost,” Edward H. Yelin, PhD, cochair of the report’s steering committee, and professor of medicine and health policy at the University of California, San Francisco, said in a prepared statement in 2016. That same year, Brian F. Mandell, MD, PhD, editor of the Cleveland Clinic Journal of Medicine, penned an editorial in which he stated that “The time has come to move past using a one-size-fits-all fifth vital sign . . . and reflexively prescribing an opioid when pain is characterized as severe” (Clev Clin J Med. 2016. Jun;83[6]:400-1). A decade earlier, authors of a cross-sectional review at a single Department of Veterans Affairs medical center set out to assess the impact of the VA’s “Pain as the 5th Vital Sign” initiative on the quality of pain management (J Gen Intern Med. 2006;21[6]:607–12). They found that patients with substantial pain documented by the fifth vital sign often had inadequate pain management. The preponderance of existing evidence suggests that a different approach is needed to prescribing opioids, Dr. Bonakdar said. “It’s coming from every voice in pain care: that what we are doing is not working,” he said. “It’s not only not working; it’s dangerous. That’s the consequence of depersonalized medicine. What’s the consequence of depersonalized nutrition? It’s the same industrialized approach.”
The typical American diet, he continued, is rife with processed foods and lacks an adequate proportion of plant-based products. “It’s basically a setup for inflammation,” Dr. Bonakdar said. “Most people who come into our clinic are eating 63% processed foods, 25% animal foods, and 12% plant foods. When we are eating, we’re oversizing it because that’s the American thing to do. At the end of the day, this process is not only killing us from heart disease and stroke as causes of death, but it’s also killing us as far as pain. The same diet that’s causing heart disease is the same diet that’s increasing pain.”
Dr. Bonakdar said that the ingestion of ultra-processed foods over time jumpstarts the process of dysbiosis, which increases gut permeability. “When gut permeability happens, and you have high levels of polysaccharides and inflammatory markers such as zonulin and lipopolysaccharide (LPS), it not only goes on to affect adipose tissue and insulin resistance, it can affect the muscle and joints,” he explained. “That is a setup for sarcopenia, or muscle loss, which then makes it harder for patients to be fully functional and active. It goes on to cause joint problems as well.”
He likened an increase in gut permeability to “a bomb going off in the gut.” Routine consumption of highly processed foods “creates this wave of inflammation that goes throughout your body affecting joints and muscles, and causes an increased amount of pain. Over time, patients make the connection but it’s much easier to say, ‘take this NSAID’ or ‘take this Cox-2 inhibitor’ to suppress the pain. But if all you’re doing is suppressing, you’re not going to the source of the pain.”
Dr. Bonakdar cited several recent articles that help to make the connection between dysbiosis and pain, including a review that concluded that dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases (Nutrients. 2019;11[8]:1707). Authors of a separate review concluded that human microbiome studies strongly suggest an incriminating role of microbes in the pathophysiology and progression of RA. Lastly, several studies have noted that pain conditions such as fibromyalgia may have microbiome “signatures” related to dysbiosis, which may pave the way for interventions, such as dietary shifting and probiotics that target individuals with microbiome abnormalities (Pain. 2019 Nov;160[11]:2589-602 and EBioMedicine. 2019 Aug 1;46:499-511).
Clinicians can begin to help patients who present with pain complaints “by listening to what their current pattern is: strategies that have worked, and those that haven’t,” he said. “If we’re not understanding the person and we’re just ordering genetic studies or microbiome studies and going off of the assessment, we sometime miss what interventions to start. In many cases, a simple intervention like a dietary shift is all that’s required.”
A survey of more than 1 million individuals found that BMI and daily pain are positively correlated in the United States (Obesity 2012;20[7]:1491-5). “This is increased more significantly for women and the elderly,” said Dr. Bonakdar, who was not affiliated with the study. “If we can change the diet that person is taking, that’s going to begin the process of reversing this to the point where they’re having less pain from inflammation that’s affecting the adipose tissue and adipokines traveling to their joints, which can cause less dysbiosis. It is very much a vicious cycle that patients follow, but if you begin to unwind it, it’s going to help multiple areas.”
In the Intensive Diet and Exercise for Arthritis (IDEA) trial, researchers randomized 450 patients with osteoarthritis to intensive dietary restriction only, exercise only, or a combination of both (BMC Musculoskelet Disord. 2009;10:93). They found that a 5% weight loss over the course of 18 months led to a 30% reduction in pain and a 24% improvement in function.
Inspired by the IDEA trial design, Dr. Bonakdar and his colleagues completed an unpublished 12-week pilot program with 12 patients with a BMI of 27 kg/m2 or greater plus comorbidities. The program consisted of weekly group meetings, including a lecture by team clinicians, dietician, and fitness staff; group support sessions with a behavioral counselor; and a group exercise session. It also included weekly 1:1 personal training sessions and biweekly 1:1 dietitian meetings. The researchers also evaluated several deficiencies linked to pain, including magnesium, vitamin D, vitamins B1, B2, and B12, folate, calcium, amino acids, omega 3s, zinc, coenzyme Q10, carnitine, and vitamin C. The goal was a weight reduction of 5%.
The intervention consisted of a 28-day detox/protein shake consumed 1-3 times per day, which contained 17 g of protein per serving. Nutritional supplementation was added based on results of individual diagnostics.
According to preliminary results from the trial, the intended weight goal was achieved. “More importantly, there were significant improvements in markers of dysbiosis, including zonulin and lipopolysaccharide, as well as the adipokine leptin, which appeared to be associated with improvement in quality of life measures and pain,” Dr. Bonakdar said.
He concluded his presentation by highlighting a pilot study conducted in an Australian tertiary pain clinic. It found that a personalized dietitian-delivered dietary intervention can improve pain scores, quality of life, and dietary intake of people experiencing chronic pain (Nutrients. 2019 Jan 16;11[1] pii: E181). “This is another piece of the puzzle showing that these dietary interventions can be done in multiple settings, including tertiary centers with nutrition staff, and that this important step can improve pain and quality of life,” he said.
Dr. Bonakdar disclosed that he receives royalties from Oxford University Press, Lippincott, and Elsevier. He is also a consultant to Standard Process.
SAN DIEGO – When clinicians ask patients to quantify their level of chronic pain on a scale of 1-10, and they rate it as a 7, what does that really mean?
Robert A. Bonakdar, MD, said posing such a question as the main determinator of the treatment approach during a pain assessment “depersonalizes medicine to the point where you’re making a patient a number.” Dr. Bonakdar spoke at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
“It considers areas that are often overlooked, such as the role of the gut microbiome, mood, and epigenetics.”
Over the past two decades, the number of American adults suffering from pain has increased from 120 million to 178 million, or to 41% of the adult population, said Dr. Bonakdar, a family physician who is director of pain management at the Scripps Center for Integrative Medicine. Data from the National Institutes of Health estimate that Americans spend more than $600 billion each year on the treatment of pain, which surpasses monies spent on cancer, heart disease, and diabetes. According to a 2016 report from the United States Bone and Joint Initiative, arthritis and rheumatologic conditions resulted in an estimated 6.7 million annual hospitalizations, and the average annual cost per person for treatment of a musculoskeletal condition is $7,800.
“If we continue on our current trajectory, we are choosing to accept more prevalence and incidence of these disorders, spiraling costs, restricted access to needed services, and less success in alleviating pain and suffering – a high cost,” Edward H. Yelin, PhD, cochair of the report’s steering committee, and professor of medicine and health policy at the University of California, San Francisco, said in a prepared statement in 2016. That same year, Brian F. Mandell, MD, PhD, editor of the Cleveland Clinic Journal of Medicine, penned an editorial in which he stated that “The time has come to move past using a one-size-fits-all fifth vital sign . . . and reflexively prescribing an opioid when pain is characterized as severe” (Clev Clin J Med. 2016. Jun;83[6]:400-1). A decade earlier, authors of a cross-sectional review at a single Department of Veterans Affairs medical center set out to assess the impact of the VA’s “Pain as the 5th Vital Sign” initiative on the quality of pain management (J Gen Intern Med. 2006;21[6]:607–12). They found that patients with substantial pain documented by the fifth vital sign often had inadequate pain management. The preponderance of existing evidence suggests that a different approach is needed to prescribing opioids, Dr. Bonakdar said. “It’s coming from every voice in pain care: that what we are doing is not working,” he said. “It’s not only not working; it’s dangerous. That’s the consequence of depersonalized medicine. What’s the consequence of depersonalized nutrition? It’s the same industrialized approach.”
The typical American diet, he continued, is rife with processed foods and lacks an adequate proportion of plant-based products. “It’s basically a setup for inflammation,” Dr. Bonakdar said. “Most people who come into our clinic are eating 63% processed foods, 25% animal foods, and 12% plant foods. When we are eating, we’re oversizing it because that’s the American thing to do. At the end of the day, this process is not only killing us from heart disease and stroke as causes of death, but it’s also killing us as far as pain. The same diet that’s causing heart disease is the same diet that’s increasing pain.”
Dr. Bonakdar said that the ingestion of ultra-processed foods over time jumpstarts the process of dysbiosis, which increases gut permeability. “When gut permeability happens, and you have high levels of polysaccharides and inflammatory markers such as zonulin and lipopolysaccharide (LPS), it not only goes on to affect adipose tissue and insulin resistance, it can affect the muscle and joints,” he explained. “That is a setup for sarcopenia, or muscle loss, which then makes it harder for patients to be fully functional and active. It goes on to cause joint problems as well.”
He likened an increase in gut permeability to “a bomb going off in the gut.” Routine consumption of highly processed foods “creates this wave of inflammation that goes throughout your body affecting joints and muscles, and causes an increased amount of pain. Over time, patients make the connection but it’s much easier to say, ‘take this NSAID’ or ‘take this Cox-2 inhibitor’ to suppress the pain. But if all you’re doing is suppressing, you’re not going to the source of the pain.”
Dr. Bonakdar cited several recent articles that help to make the connection between dysbiosis and pain, including a review that concluded that dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases (Nutrients. 2019;11[8]:1707). Authors of a separate review concluded that human microbiome studies strongly suggest an incriminating role of microbes in the pathophysiology and progression of RA. Lastly, several studies have noted that pain conditions such as fibromyalgia may have microbiome “signatures” related to dysbiosis, which may pave the way for interventions, such as dietary shifting and probiotics that target individuals with microbiome abnormalities (Pain. 2019 Nov;160[11]:2589-602 and EBioMedicine. 2019 Aug 1;46:499-511).
Clinicians can begin to help patients who present with pain complaints “by listening to what their current pattern is: strategies that have worked, and those that haven’t,” he said. “If we’re not understanding the person and we’re just ordering genetic studies or microbiome studies and going off of the assessment, we sometime miss what interventions to start. In many cases, a simple intervention like a dietary shift is all that’s required.”
A survey of more than 1 million individuals found that BMI and daily pain are positively correlated in the United States (Obesity 2012;20[7]:1491-5). “This is increased more significantly for women and the elderly,” said Dr. Bonakdar, who was not affiliated with the study. “If we can change the diet that person is taking, that’s going to begin the process of reversing this to the point where they’re having less pain from inflammation that’s affecting the adipose tissue and adipokines traveling to their joints, which can cause less dysbiosis. It is very much a vicious cycle that patients follow, but if you begin to unwind it, it’s going to help multiple areas.”
In the Intensive Diet and Exercise for Arthritis (IDEA) trial, researchers randomized 450 patients with osteoarthritis to intensive dietary restriction only, exercise only, or a combination of both (BMC Musculoskelet Disord. 2009;10:93). They found that a 5% weight loss over the course of 18 months led to a 30% reduction in pain and a 24% improvement in function.
Inspired by the IDEA trial design, Dr. Bonakdar and his colleagues completed an unpublished 12-week pilot program with 12 patients with a BMI of 27 kg/m2 or greater plus comorbidities. The program consisted of weekly group meetings, including a lecture by team clinicians, dietician, and fitness staff; group support sessions with a behavioral counselor; and a group exercise session. It also included weekly 1:1 personal training sessions and biweekly 1:1 dietitian meetings. The researchers also evaluated several deficiencies linked to pain, including magnesium, vitamin D, vitamins B1, B2, and B12, folate, calcium, amino acids, omega 3s, zinc, coenzyme Q10, carnitine, and vitamin C. The goal was a weight reduction of 5%.
The intervention consisted of a 28-day detox/protein shake consumed 1-3 times per day, which contained 17 g of protein per serving. Nutritional supplementation was added based on results of individual diagnostics.
According to preliminary results from the trial, the intended weight goal was achieved. “More importantly, there were significant improvements in markers of dysbiosis, including zonulin and lipopolysaccharide, as well as the adipokine leptin, which appeared to be associated with improvement in quality of life measures and pain,” Dr. Bonakdar said.
He concluded his presentation by highlighting a pilot study conducted in an Australian tertiary pain clinic. It found that a personalized dietitian-delivered dietary intervention can improve pain scores, quality of life, and dietary intake of people experiencing chronic pain (Nutrients. 2019 Jan 16;11[1] pii: E181). “This is another piece of the puzzle showing that these dietary interventions can be done in multiple settings, including tertiary centers with nutrition staff, and that this important step can improve pain and quality of life,” he said.
Dr. Bonakdar disclosed that he receives royalties from Oxford University Press, Lippincott, and Elsevier. He is also a consultant to Standard Process.
REPORTING FROM A NATURAL SUPPLEMENTS UPDATE
FDA not recommending recalls of diabetes drug metformin
The Food and Drug Administration says it has no plans to recall any metformin products, used for the treatment of type 2 diabetes, after tests it conducted did not show any evidence of contamination with N-nitrosodimethylamine (NDMA) at levels that would cause concern.
The FDA began testing samples of metformin for the carcinogen NDMA at the end of 2019. Contamination with this substance has led to recalls of hypertension and heartburn medications within the past 2 years.
That announcement came on the heels of a recall of three versions of metformin in Singapore and the European Medicines Agency’s request that manufacturers test for NDMA.
This week, the FDA posted laboratory results in which NDMA levels in some metformin products ranged from “not detectable to low.”
“To date, no sample of metformin that FDA has tested exceeds the acceptable daily intake for NDMA. FDA has not recommended metformin recalls in the U.S.,” the agency indicates.
More than 30 million people in the United States have diabetes; 90%-95% of cases are of type 2. Metformin is the fourth most prescribed drug in the United States.
“Patients should continue taking metformin to keep their diabetes under control,” the FDA emphasized. “It could be dangerous for patients with this serious condition to stop taking their metformin without first talking to their health care professionals.”
The agency plans to post the methods used in laboratory testing of metformin in the near future. The FDA is collaborating with international regulators to share testing results for metformin, along with testing results for other drugs.
The U.S. agency says it will continue to monitor NDMA in metformin, along with other drug products, and will provide timely updates of new developments, including product recalls.
For more information about NDMA, visit the FDA’s nitrosamines webpage.
The FDA also encourages health care professionals and patients to report adverse reactions or quality problems with any human drugs to the agency’s MedWatch Adverse Event Reporting program.
This article first appeared on Medscape.com.
The Food and Drug Administration says it has no plans to recall any metformin products, used for the treatment of type 2 diabetes, after tests it conducted did not show any evidence of contamination with N-nitrosodimethylamine (NDMA) at levels that would cause concern.
The FDA began testing samples of metformin for the carcinogen NDMA at the end of 2019. Contamination with this substance has led to recalls of hypertension and heartburn medications within the past 2 years.
That announcement came on the heels of a recall of three versions of metformin in Singapore and the European Medicines Agency’s request that manufacturers test for NDMA.
This week, the FDA posted laboratory results in which NDMA levels in some metformin products ranged from “not detectable to low.”
“To date, no sample of metformin that FDA has tested exceeds the acceptable daily intake for NDMA. FDA has not recommended metformin recalls in the U.S.,” the agency indicates.
More than 30 million people in the United States have diabetes; 90%-95% of cases are of type 2. Metformin is the fourth most prescribed drug in the United States.
“Patients should continue taking metformin to keep their diabetes under control,” the FDA emphasized. “It could be dangerous for patients with this serious condition to stop taking their metformin without first talking to their health care professionals.”
The agency plans to post the methods used in laboratory testing of metformin in the near future. The FDA is collaborating with international regulators to share testing results for metformin, along with testing results for other drugs.
The U.S. agency says it will continue to monitor NDMA in metformin, along with other drug products, and will provide timely updates of new developments, including product recalls.
For more information about NDMA, visit the FDA’s nitrosamines webpage.
The FDA also encourages health care professionals and patients to report adverse reactions or quality problems with any human drugs to the agency’s MedWatch Adverse Event Reporting program.
This article first appeared on Medscape.com.
The Food and Drug Administration says it has no plans to recall any metformin products, used for the treatment of type 2 diabetes, after tests it conducted did not show any evidence of contamination with N-nitrosodimethylamine (NDMA) at levels that would cause concern.
The FDA began testing samples of metformin for the carcinogen NDMA at the end of 2019. Contamination with this substance has led to recalls of hypertension and heartburn medications within the past 2 years.
That announcement came on the heels of a recall of three versions of metformin in Singapore and the European Medicines Agency’s request that manufacturers test for NDMA.
This week, the FDA posted laboratory results in which NDMA levels in some metformin products ranged from “not detectable to low.”
“To date, no sample of metformin that FDA has tested exceeds the acceptable daily intake for NDMA. FDA has not recommended metformin recalls in the U.S.,” the agency indicates.
More than 30 million people in the United States have diabetes; 90%-95% of cases are of type 2. Metformin is the fourth most prescribed drug in the United States.
“Patients should continue taking metformin to keep their diabetes under control,” the FDA emphasized. “It could be dangerous for patients with this serious condition to stop taking their metformin without first talking to their health care professionals.”
The agency plans to post the methods used in laboratory testing of metformin in the near future. The FDA is collaborating with international regulators to share testing results for metformin, along with testing results for other drugs.
The U.S. agency says it will continue to monitor NDMA in metformin, along with other drug products, and will provide timely updates of new developments, including product recalls.
For more information about NDMA, visit the FDA’s nitrosamines webpage.
The FDA also encourages health care professionals and patients to report adverse reactions or quality problems with any human drugs to the agency’s MedWatch Adverse Event Reporting program.
This article first appeared on Medscape.com.