Is it just me? I don’t think that I have visited with a single patient this week who’s not struggling with sleep. Our heavily caffeinated, media-obsessed, melatonin-killing, computer-screen-staring, tragic work-life imbalances explain away a lot of it. Knowing that, though, patients in front of me seek immediate relief.

A prescription takes substantially less effort than does training patients on sleep hygiene or sleep restriction. The problem with “z” drugs is, of course, that tolerance can develop within 4 weeks with daily use. These drugs have been associated with mood and cognitive changes and increased mortality. Many of my patients cannot use them sparingly, because relief of insomnia is something of which they cannot get enough. Then we are either back to square one or playing the dose-escalation game.

I have always wondered how much of this is the “placebo effect” and how we could use this to our clinical advantage. This is certainly what I hear from my cynical colleagues when I recommend melatonin – which, by the way, I personally believe is an extremely effective and underutilized intervention. We should remind ourselves to be cognizant of the “if I can’t prescribe it, it can’t work that well” mentality.

Alexander Winkler and Winfried Rief of the University of Marburg, Germany, conducted a brilliant systematic review examining the effect of placebo conditions in randomized trials including polysomnography addressing primary insomnia (Sleep. 2015 Jun 1;38[6]:925-31).

The investigators identified 32 studies with almost 4,000 patients in 82 treatment conditions: The studies were published between 1992 and 2012. Of those 82 treatment conditions, 17 included hypnotic drugs.

Results suggest that 64% of drug response to medications for primary insomnia is achieved in the placebo group.

So what does this mean clinically? I think the first thing it means is that we should consider (re)launching frank discourse about the ethics surrounding the use of placebo in clinical medicine. Are we all too horrified to think that patients may get better despite us rather than because of us to dig too deeply here?

The second thing it means is that patients should be instructed to use the medications only when needed. If a minority of the drug effect for insomnia is from the drug itself, we should minimize the buildup of tolerance by using it sparingly. Studies that have alternated a hypnotic with a placebo show that this works just as well as using a hypnotic every night.

Patients should be encouraged to alternate therapy, such as trying melatonin first and resorting to a “z” drug only if sleep remains elusive. Alternating drug therapy may also enhance the efficacy of the medication.

Always try to combine pharmacotherapy with good sleep hygiene to maximize benefits.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter @jonebbert.

Is it just me? I don’t think that I have visited with a single patient this week who’s not struggling with sleep. Our heavily caffeinated, media-obsessed, melatonin-killing, computer-screen-staring, tragic work-life imbalances explain away a lot of it. Knowing that, though, patients in front of me seek immediate relief.

A prescription takes substantially less effort than does training patients on sleep hygiene or sleep restriction. The problem with “z” drugs is, of course, that tolerance can develop within 4 weeks with daily use. These drugs have been associated with mood and cognitive changes and increased mortality. Many of my patients cannot use them sparingly, because relief of insomnia is something of which they cannot get enough. Then we are either back to square one or playing the dose-escalation game.

I have always wondered how much of this is the “placebo effect” and how we could use this to our clinical advantage. This is certainly what I hear from my cynical colleagues when I recommend melatonin – which, by the way, I personally believe is an extremely effective and underutilized intervention. We should remind ourselves to be cognizant of the “if I can’t prescribe it, it can’t work that well” mentality.

Alexander Winkler and Winfried Rief of the University of Marburg, Germany, conducted a brilliant systematic review examining the effect of placebo conditions in randomized trials including polysomnography addressing primary insomnia (Sleep. 2015 Jun 1;38[6]:925-31).

The investigators identified 32 studies with almost 4,000 patients in 82 treatment conditions: The studies were published between 1992 and 2012. Of those 82 treatment conditions, 17 included hypnotic drugs.

Results suggest that 64% of drug response to medications for primary insomnia is achieved in the placebo group.

So what does this mean clinically? I think the first thing it means is that we should consider (re)launching frank discourse about the ethics surrounding the use of placebo in clinical medicine. Are we all too horrified to think that patients may get better despite us rather than because of us to dig too deeply here?

The second thing it means is that patients should be instructed to use the medications only when needed. If a minority of the drug effect for insomnia is from the drug itself, we should minimize the buildup of tolerance by using it sparingly. Studies that have alternated a hypnotic with a placebo show that this works just as well as using a hypnotic every night.

Patients should be encouraged to alternate therapy, such as trying melatonin first and resorting to a “z” drug only if sleep remains elusive. Alternating drug therapy may also enhance the efficacy of the medication.

Always try to combine pharmacotherapy with good sleep hygiene to maximize benefits.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter @jonebbert.

Is it just me? I don’t think that I have visited with a single patient this week who’s not struggling with sleep. Our heavily caffeinated, media-obsessed, melatonin-killing, computer-screen-staring, tragic work-life imbalances explain away a lot of it. Knowing that, though, patients in front of me seek immediate relief.

A prescription takes substantially less effort than does training patients on sleep hygiene or sleep restriction. The problem with “z” drugs is, of course, that tolerance can develop within 4 weeks with daily use. These drugs have been associated with mood and cognitive changes and increased mortality. Many of my patients cannot use them sparingly, because relief of insomnia is something of which they cannot get enough. Then we are either back to square one or playing the dose-escalation game.

I have always wondered how much of this is the “placebo effect” and how we could use this to our clinical advantage. This is certainly what I hear from my cynical colleagues when I recommend melatonin – which, by the way, I personally believe is an extremely effective and underutilized intervention. We should remind ourselves to be cognizant of the “if I can’t prescribe it, it can’t work that well” mentality.

Alexander Winkler and Winfried Rief of the University of Marburg, Germany, conducted a brilliant systematic review examining the effect of placebo conditions in randomized trials including polysomnography addressing primary insomnia (Sleep. 2015 Jun 1;38[6]:925-31).

The investigators identified 32 studies with almost 4,000 patients in 82 treatment conditions: The studies were published between 1992 and 2012. Of those 82 treatment conditions, 17 included hypnotic drugs.

Results suggest that 64% of drug response to medications for primary insomnia is achieved in the placebo group.

So what does this mean clinically? I think the first thing it means is that we should consider (re)launching frank discourse about the ethics surrounding the use of placebo in clinical medicine. Are we all too horrified to think that patients may get better despite us rather than because of us to dig too deeply here?

The second thing it means is that patients should be instructed to use the medications only when needed. If a minority of the drug effect for insomnia is from the drug itself, we should minimize the buildup of tolerance by using it sparingly. Studies that have alternated a hypnotic with a placebo show that this works just as well as using a hypnotic every night.

Patients should be encouraged to alternate therapy, such as trying melatonin first and resorting to a “z” drug only if sleep remains elusive. Alternating drug therapy may also enhance the efficacy of the medication.

Always try to combine pharmacotherapy with good sleep hygiene to maximize benefits.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter @jonebbert.

NEW YORK - Elderly patients with pneumonia whose need for intensive care unit (ICU) admission is uncertain actually fare better in the ICU than on the general medical ward, a new study suggests.

"Although our results should be confirmed with a randomized trial, clinicians should be aware that many patients who are borderline candidates for ICU admission may benefit from care provided in an ICU," Dr. Colin Cooke, from the University of Michigan, Ann Arbor, said.

To gauge the relationship between ICU admission and outcomes for elderly patients with pneumonia, the researchers took a look back at more than 1.1 million Medicare beneficiaries admitted to nearly 3,000 acute care hospitals with pneumonia from 2010 to 2012.

The team compared 30-day mortality between patients admitted to the ICU and those admitted solely to the hospital ward. They used instrumental variable analysis to account for selection bias inherent in this comparison.

Thirty percent of the cohort was admitted to the ICU. Patients living less than 3.3 miles of a hospital with high ICU admission were more apt to be admitted to the ICU than their peers living farther away, according to a report in the September 22/29 issue of JAMA.

For the 13 percent of patients whose ICU admission was deemed discretionary, ICU admission was associated with a significant reduction in 30-day mortality (14.8 percent for ICU care vs. 20.5 percent for general ward care, p<0.02).

There were no statistically significant differences in total costs or total Medicare payments between groups, "suggesting that ICU admission can save lives for lower-risk patients, and can do so at similar cost," note the authors of a linked editorial.

This study provides "important empirical evidence that ICU admission can benefit low-risk patients," write Dr. Ian J. Barbash and Dr. Jeremy M. Kahn, of the University of Pittsburgh School of Medicine in Pennsylvania.

The findings, they add, "argue against active efforts to reduce ICU admissions through triage guidelines or bed supply reductions, at least for older patients with pneumonia. In the current health care system, more judicious use of the ICU may well lead to higher mortality in some patient populations." Dr. Cooke said, "It would be premature for our study to warrant significant changes in clinical practice. Nevertheless, our results are intriguing and suggest that there indeed is a population of patients with pneumonia who may not be hospitalized in an ICU but who would otherwise benefit from ICU-level care. The sooner we can identify this group of patients clinically, the sooner we can begin the confirmatory studies."

NEW YORK - Elderly patients with pneumonia whose need for intensive care unit (ICU) admission is uncertain actually fare better in the ICU than on the general medical ward, a new study suggests.

"Although our results should be confirmed with a randomized trial, clinicians should be aware that many patients who are borderline candidates for ICU admission may benefit from care provided in an ICU," Dr. Colin Cooke, from the University of Michigan, Ann Arbor, said.

To gauge the relationship between ICU admission and outcomes for elderly patients with pneumonia, the researchers took a look back at more than 1.1 million Medicare beneficiaries admitted to nearly 3,000 acute care hospitals with pneumonia from 2010 to 2012.

The team compared 30-day mortality between patients admitted to the ICU and those admitted solely to the hospital ward. They used instrumental variable analysis to account for selection bias inherent in this comparison.

Thirty percent of the cohort was admitted to the ICU. Patients living less than 3.3 miles of a hospital with high ICU admission were more apt to be admitted to the ICU than their peers living farther away, according to a report in the September 22/29 issue of JAMA.

For the 13 percent of patients whose ICU admission was deemed discretionary, ICU admission was associated with a significant reduction in 30-day mortality (14.8 percent for ICU care vs. 20.5 percent for general ward care, p<0.02).

There were no statistically significant differences in total costs or total Medicare payments between groups, "suggesting that ICU admission can save lives for lower-risk patients, and can do so at similar cost," note the authors of a linked editorial.

This study provides "important empirical evidence that ICU admission can benefit low-risk patients," write Dr. Ian J. Barbash and Dr. Jeremy M. Kahn, of the University of Pittsburgh School of Medicine in Pennsylvania.

The findings, they add, "argue against active efforts to reduce ICU admissions through triage guidelines or bed supply reductions, at least for older patients with pneumonia. In the current health care system, more judicious use of the ICU may well lead to higher mortality in some patient populations." Dr. Cooke said, "It would be premature for our study to warrant significant changes in clinical practice. Nevertheless, our results are intriguing and suggest that there indeed is a population of patients with pneumonia who may not be hospitalized in an ICU but who would otherwise benefit from ICU-level care. The sooner we can identify this group of patients clinically, the sooner we can begin the confirmatory studies."

NEW YORK - Elderly patients with pneumonia whose need for intensive care unit (ICU) admission is uncertain actually fare better in the ICU than on the general medical ward, a new study suggests.

"Although our results should be confirmed with a randomized trial, clinicians should be aware that many patients who are borderline candidates for ICU admission may benefit from care provided in an ICU," Dr. Colin Cooke, from the University of Michigan, Ann Arbor, said.

To gauge the relationship between ICU admission and outcomes for elderly patients with pneumonia, the researchers took a look back at more than 1.1 million Medicare beneficiaries admitted to nearly 3,000 acute care hospitals with pneumonia from 2010 to 2012.

The team compared 30-day mortality between patients admitted to the ICU and those admitted solely to the hospital ward. They used instrumental variable analysis to account for selection bias inherent in this comparison.

Thirty percent of the cohort was admitted to the ICU. Patients living less than 3.3 miles of a hospital with high ICU admission were more apt to be admitted to the ICU than their peers living farther away, according to a report in the September 22/29 issue of JAMA.

For the 13 percent of patients whose ICU admission was deemed discretionary, ICU admission was associated with a significant reduction in 30-day mortality (14.8 percent for ICU care vs. 20.5 percent for general ward care, p<0.02).

There were no statistically significant differences in total costs or total Medicare payments between groups, "suggesting that ICU admission can save lives for lower-risk patients, and can do so at similar cost," note the authors of a linked editorial.

This study provides "important empirical evidence that ICU admission can benefit low-risk patients," write Dr. Ian J. Barbash and Dr. Jeremy M. Kahn, of the University of Pittsburgh School of Medicine in Pennsylvania.

The findings, they add, "argue against active efforts to reduce ICU admissions through triage guidelines or bed supply reductions, at least for older patients with pneumonia. In the current health care system, more judicious use of the ICU may well lead to higher mortality in some patient populations." Dr. Cooke said, "It would be premature for our study to warrant significant changes in clinical practice. Nevertheless, our results are intriguing and suggest that there indeed is a population of patients with pneumonia who may not be hospitalized in an ICU but who would otherwise benefit from ICU-level care. The sooner we can identify this group of patients clinically, the sooner we can begin the confirmatory studies."

September, October, and November are well known as the “coughing months” in any general pediatrician’s office. We all can relate to the frustration we feel when that handful of patients returns for the unrelenting cough after steroids and albuterol have failed. Codeine has been known to be a good cough suppressant, and when coupled with promethazine (antihistamine), you have a very effective cough syrup that been used as such for decades.

Unfortunately, over the last few decades, this cough syrup has gained notoriety for use other than cough, and now is under great scrutiny. This common syrup is now the main ingredient of a poplar drink among teens known as “Sizzurp” or the “Purple Drank.” Well known artists tweet about it, post pictures of it on Instagram, sing about it in their songs, and glamorize it in their videos.

The mixture is simple; promethazine with codeine, lemon-lime sodas, and hard candies has all the makings of a party drink. It is fizzy, colorful, and sweet, with no horrible aftertaste, so gulping is easy. Most teens don’t limit their drinking to just the purple drink, so now we have a mixture of codeine with alcohol and or marijuana. All of which result in respiratory depression and potentially death.

The abuse of this cough syrup has become so great that Actavis was reported to pull it from production. Already the pint-size bottle sells on the street for $800, and limited access will only skyrocket its value.

As clinicians, we must be aware of the misuse and abuse of common prescription medications because teens prey on busy practices with false or exaggerated symptoms to try to obtain a prescription. Despite the American Academy of Pediatrics’ warning against codeine’s use as an antitussive in children (Pediatrics. 1997 Jun;99[6]:918-20.), there has not been a significant decline in its use (Pediatrics 2014 May;133[5]:e1139-47). Pediatricians need to use extreme caution, and be vigilant to identify frequent flyers or teens known to be at risk for drug abuse. Prescribe nonnarcotic-containing products first, and only prescribe small amounts promethazine/codeine products to prevent leftovers from being kept around the house for unsupervised use.

Most importantly, educate parents and families about the danger of overdose with these products so they can monitor its use.

Dr. Pearce is a pediatrician in Frankfort, Ill.

September, October, and November are well known as the “coughing months” in any general pediatrician’s office. We all can relate to the frustration we feel when that handful of patients returns for the unrelenting cough after steroids and albuterol have failed. Codeine has been known to be a good cough suppressant, and when coupled with promethazine (antihistamine), you have a very effective cough syrup that been used as such for decades.

Unfortunately, over the last few decades, this cough syrup has gained notoriety for use other than cough, and now is under great scrutiny. This common syrup is now the main ingredient of a poplar drink among teens known as “Sizzurp” or the “Purple Drank.” Well known artists tweet about it, post pictures of it on Instagram, sing about it in their songs, and glamorize it in their videos.

The mixture is simple; promethazine with codeine, lemon-lime sodas, and hard candies has all the makings of a party drink. It is fizzy, colorful, and sweet, with no horrible aftertaste, so gulping is easy. Most teens don’t limit their drinking to just the purple drink, so now we have a mixture of codeine with alcohol and or marijuana. All of which result in respiratory depression and potentially death.

The abuse of this cough syrup has become so great that Actavis was reported to pull it from production. Already the pint-size bottle sells on the street for $800, and limited access will only skyrocket its value.

As clinicians, we must be aware of the misuse and abuse of common prescription medications because teens prey on busy practices with false or exaggerated symptoms to try to obtain a prescription. Despite the American Academy of Pediatrics’ warning against codeine’s use as an antitussive in children (Pediatrics. 1997 Jun;99[6]:918-20.), there has not been a significant decline in its use (Pediatrics 2014 May;133[5]:e1139-47). Pediatricians need to use extreme caution, and be vigilant to identify frequent flyers or teens known to be at risk for drug abuse. Prescribe nonnarcotic-containing products first, and only prescribe small amounts promethazine/codeine products to prevent leftovers from being kept around the house for unsupervised use.

Most importantly, educate parents and families about the danger of overdose with these products so they can monitor its use.

Dr. Pearce is a pediatrician in Frankfort, Ill.

September, October, and November are well known as the “coughing months” in any general pediatrician’s office. We all can relate to the frustration we feel when that handful of patients returns for the unrelenting cough after steroids and albuterol have failed. Codeine has been known to be a good cough suppressant, and when coupled with promethazine (antihistamine), you have a very effective cough syrup that been used as such for decades.

Unfortunately, over the last few decades, this cough syrup has gained notoriety for use other than cough, and now is under great scrutiny. This common syrup is now the main ingredient of a poplar drink among teens known as “Sizzurp” or the “Purple Drank.” Well known artists tweet about it, post pictures of it on Instagram, sing about it in their songs, and glamorize it in their videos.

The mixture is simple; promethazine with codeine, lemon-lime sodas, and hard candies has all the makings of a party drink. It is fizzy, colorful, and sweet, with no horrible aftertaste, so gulping is easy. Most teens don’t limit their drinking to just the purple drink, so now we have a mixture of codeine with alcohol and or marijuana. All of which result in respiratory depression and potentially death.

The abuse of this cough syrup has become so great that Actavis was reported to pull it from production. Already the pint-size bottle sells on the street for $800, and limited access will only skyrocket its value.

As clinicians, we must be aware of the misuse and abuse of common prescription medications because teens prey on busy practices with false or exaggerated symptoms to try to obtain a prescription. Despite the American Academy of Pediatrics’ warning against codeine’s use as an antitussive in children (Pediatrics. 1997 Jun;99[6]:918-20.), there has not been a significant decline in its use (Pediatrics 2014 May;133[5]:e1139-47). Pediatricians need to use extreme caution, and be vigilant to identify frequent flyers or teens known to be at risk for drug abuse. Prescribe nonnarcotic-containing products first, and only prescribe small amounts promethazine/codeine products to prevent leftovers from being kept around the house for unsupervised use.

Most importantly, educate parents and families about the danger of overdose with these products so they can monitor its use.

Dr. Pearce is a pediatrician in Frankfort, Ill.

Primary care clinicians have come to realize that a large percentage of patients use alternative or complementary approaches to many types of health problems, including emotional-behavioral ones.

Families often are reluctant to bring up these interventions in primary care appointments for fear that their doctor will criticize them for using unproven and sometimes risky treatments. When it comes to dietary supplements, the evidence for many is rather weak, while others have been studied in controlled trials and now may deserve a closer look. Omega-3 fatty acid supplementation for various types of psychiatric disorders and problems may be leading the pack as an alternative treatment that has earned the right to be on the radar screen of all pediatricians. This article briefly summarizes what scientific evidence exists about the efficacy of omega-3s in pediatric emotional-behavioral problems and where significant gaps in our knowledge remain.

Case summary

Samantha is an 11-year-old girl who was adopted into a loving and supportive family at the age of 4 years after having suffered a tumultuous early childhood that included domestic violence as well as physical and emotional abuse. Despite a much improved home environment, she has continued to struggle for many years with difficulties including inattention, emotional dysregulation, and aggression toward others. Samantha and her family have worked with a mental health counselor, and her pediatrician also has started her on pharmacotherapy with a stimulant medication and an alpha-agonist. Despite some gains, significant difficulties remain. At a follow-up visit, Samantha’s mother states that she has done some research on the Internet and has heard positive things about omega-3 fatty acid supplements. She wonders if this might be appropriate for Samantha and if so, how specifically the treatment would be administered.

Discussion

The possible benefits of omega-3s in the treatment of behavioral problems has been discussed for decades, and good evidence from rigorous trials has slowly been accumulating. In October 2015 at the annual meeting of the American Academy of Child and Adolescent Psychiatry, researchers in a clinical trial called Omega-3 and Therapy Studies (OATS) presented some preliminary results to see if omega-3s could augment response in children aged 7-14 years with depression and bipolar spectrum disorders who also were receiving evidence-based psychotherapy. The daily dose was 2,000 mg, consisting of 1,400 mg of eicosapentaenoic acid (EPA), 200 mg of docosahexaenoic acid (DHA), and 400 mg of other omega-3s. Significant improvement of small to medium effect was found for omega-3s, particularly for depressive symptoms, and side effects were minimal.

Another relatively recent study from 2014 used a randomized double-blind design in 200 youth between the ages of 6 and 18 years from the island nation of Mauritius, near Madagascar (J Child Psychol Psychiatry. 2015 May;56[5]:509-20). The active treatment here was 1,000 mg of omega-3s (300 mg DHA, 200 mg EPA, 500 mg of others). After subjects were followed for a year, significant and fairly large improvements were found for omega-3s, relative to placebo, across a wide range of problems including aggression in addition to anxiety and depressive symptoms. One very interesting side note of this study was that the improvement in child behavior seemed to be partially mediated by improvements in the parents’ behavior, even though parents did not receive the supplements.

In attention-deficit/hyperactivity disorder, a meta-analysis of 10 clinical trials also was positive (J Am Acad Child Adolesc Psychiatry. 2011 Oct;50[10]:991-1000). The effect size was small, but there seemed to be a dose effect with more positive trials related to higher daily doses of EPA. Side effects again were few.

The mechanism for improvement remains to be fully understood, although evidence points to changes in cell membrane fluidity and possible anti-inflammatory properties. The biggest question mark that remains from a practical standpoint is dose, both in absolute numbers and with regard to ratios of EPA to DHA. Given the vast number of suppliers of omega-3 supplementation and the wide range of quality with regard to accurate dosing and impurities, it also is important to help families identify a specific product that can be trusted.

Case follow-up

Somewhat to the surprise of Samantha’s mother, the pediatrician supports a trial of omega-3 supplementation, given the increasing evidence of efficacy and the favorable side effect profile. They discuss reasonable expectations, dosing, and ways that the family can obtain a high-quality supplement. Six months later, the family reports noticeable further improvements in Samantha’s behavior to the point that more aggressive psychopharmacologic treatment is not indicated currently.

In sum, it is reasonable to conclude at this point that evidence supporting omega-3 use for a variety of emotional-behavioral problems now equals or exceeds that for many off-label prescription medications that are now used in similar situations. This increasing evidence, combined with the low risk for most patients, would seem to warrant pediatricians considering omega-3 supplementation as a more mainstream and evidence-based intervention that deserves a place in one’s treatment algorithm for several emotional-behavioral concerns.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He will also be course director of the 10th annual Child Psychiatry in Primary Care conference on May 13, 2016, in Burlington. Follow him on Twitter @pedipsych.

Primary care clinicians have come to realize that a large percentage of patients use alternative or complementary approaches to many types of health problems, including emotional-behavioral ones.

Families often are reluctant to bring up these interventions in primary care appointments for fear that their doctor will criticize them for using unproven and sometimes risky treatments. When it comes to dietary supplements, the evidence for many is rather weak, while others have been studied in controlled trials and now may deserve a closer look. Omega-3 fatty acid supplementation for various types of psychiatric disorders and problems may be leading the pack as an alternative treatment that has earned the right to be on the radar screen of all pediatricians. This article briefly summarizes what scientific evidence exists about the efficacy of omega-3s in pediatric emotional-behavioral problems and where significant gaps in our knowledge remain.

Case summary

Samantha is an 11-year-old girl who was adopted into a loving and supportive family at the age of 4 years after having suffered a tumultuous early childhood that included domestic violence as well as physical and emotional abuse. Despite a much improved home environment, she has continued to struggle for many years with difficulties including inattention, emotional dysregulation, and aggression toward others. Samantha and her family have worked with a mental health counselor, and her pediatrician also has started her on pharmacotherapy with a stimulant medication and an alpha-agonist. Despite some gains, significant difficulties remain. At a follow-up visit, Samantha’s mother states that she has done some research on the Internet and has heard positive things about omega-3 fatty acid supplements. She wonders if this might be appropriate for Samantha and if so, how specifically the treatment would be administered.

Discussion

The possible benefits of omega-3s in the treatment of behavioral problems has been discussed for decades, and good evidence from rigorous trials has slowly been accumulating. In October 2015 at the annual meeting of the American Academy of Child and Adolescent Psychiatry, researchers in a clinical trial called Omega-3 and Therapy Studies (OATS) presented some preliminary results to see if omega-3s could augment response in children aged 7-14 years with depression and bipolar spectrum disorders who also were receiving evidence-based psychotherapy. The daily dose was 2,000 mg, consisting of 1,400 mg of eicosapentaenoic acid (EPA), 200 mg of docosahexaenoic acid (DHA), and 400 mg of other omega-3s. Significant improvement of small to medium effect was found for omega-3s, particularly for depressive symptoms, and side effects were minimal.

Another relatively recent study from 2014 used a randomized double-blind design in 200 youth between the ages of 6 and 18 years from the island nation of Mauritius, near Madagascar (J Child Psychol Psychiatry. 2015 May;56[5]:509-20). The active treatment here was 1,000 mg of omega-3s (300 mg DHA, 200 mg EPA, 500 mg of others). After subjects were followed for a year, significant and fairly large improvements were found for omega-3s, relative to placebo, across a wide range of problems including aggression in addition to anxiety and depressive symptoms. One very interesting side note of this study was that the improvement in child behavior seemed to be partially mediated by improvements in the parents’ behavior, even though parents did not receive the supplements.

In attention-deficit/hyperactivity disorder, a meta-analysis of 10 clinical trials also was positive (J Am Acad Child Adolesc Psychiatry. 2011 Oct;50[10]:991-1000). The effect size was small, but there seemed to be a dose effect with more positive trials related to higher daily doses of EPA. Side effects again were few.

The mechanism for improvement remains to be fully understood, although evidence points to changes in cell membrane fluidity and possible anti-inflammatory properties. The biggest question mark that remains from a practical standpoint is dose, both in absolute numbers and with regard to ratios of EPA to DHA. Given the vast number of suppliers of omega-3 supplementation and the wide range of quality with regard to accurate dosing and impurities, it also is important to help families identify a specific product that can be trusted.

Case follow-up

Somewhat to the surprise of Samantha’s mother, the pediatrician supports a trial of omega-3 supplementation, given the increasing evidence of efficacy and the favorable side effect profile. They discuss reasonable expectations, dosing, and ways that the family can obtain a high-quality supplement. Six months later, the family reports noticeable further improvements in Samantha’s behavior to the point that more aggressive psychopharmacologic treatment is not indicated currently.

In sum, it is reasonable to conclude at this point that evidence supporting omega-3 use for a variety of emotional-behavioral problems now equals or exceeds that for many off-label prescription medications that are now used in similar situations. This increasing evidence, combined with the low risk for most patients, would seem to warrant pediatricians considering omega-3 supplementation as a more mainstream and evidence-based intervention that deserves a place in one’s treatment algorithm for several emotional-behavioral concerns.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He will also be course director of the 10th annual Child Psychiatry in Primary Care conference on May 13, 2016, in Burlington. Follow him on Twitter @pedipsych.

Primary care clinicians have come to realize that a large percentage of patients use alternative or complementary approaches to many types of health problems, including emotional-behavioral ones.

Families often are reluctant to bring up these interventions in primary care appointments for fear that their doctor will criticize them for using unproven and sometimes risky treatments. When it comes to dietary supplements, the evidence for many is rather weak, while others have been studied in controlled trials and now may deserve a closer look. Omega-3 fatty acid supplementation for various types of psychiatric disorders and problems may be leading the pack as an alternative treatment that has earned the right to be on the radar screen of all pediatricians. This article briefly summarizes what scientific evidence exists about the efficacy of omega-3s in pediatric emotional-behavioral problems and where significant gaps in our knowledge remain.

Case summary

Samantha is an 11-year-old girl who was adopted into a loving and supportive family at the age of 4 years after having suffered a tumultuous early childhood that included domestic violence as well as physical and emotional abuse. Despite a much improved home environment, she has continued to struggle for many years with difficulties including inattention, emotional dysregulation, and aggression toward others. Samantha and her family have worked with a mental health counselor, and her pediatrician also has started her on pharmacotherapy with a stimulant medication and an alpha-agonist. Despite some gains, significant difficulties remain. At a follow-up visit, Samantha’s mother states that she has done some research on the Internet and has heard positive things about omega-3 fatty acid supplements. She wonders if this might be appropriate for Samantha and if so, how specifically the treatment would be administered.

Discussion

The possible benefits of omega-3s in the treatment of behavioral problems has been discussed for decades, and good evidence from rigorous trials has slowly been accumulating. In October 2015 at the annual meeting of the American Academy of Child and Adolescent Psychiatry, researchers in a clinical trial called Omega-3 and Therapy Studies (OATS) presented some preliminary results to see if omega-3s could augment response in children aged 7-14 years with depression and bipolar spectrum disorders who also were receiving evidence-based psychotherapy. The daily dose was 2,000 mg, consisting of 1,400 mg of eicosapentaenoic acid (EPA), 200 mg of docosahexaenoic acid (DHA), and 400 mg of other omega-3s. Significant improvement of small to medium effect was found for omega-3s, particularly for depressive symptoms, and side effects were minimal.

Another relatively recent study from 2014 used a randomized double-blind design in 200 youth between the ages of 6 and 18 years from the island nation of Mauritius, near Madagascar (J Child Psychol Psychiatry. 2015 May;56[5]:509-20). The active treatment here was 1,000 mg of omega-3s (300 mg DHA, 200 mg EPA, 500 mg of others). After subjects were followed for a year, significant and fairly large improvements were found for omega-3s, relative to placebo, across a wide range of problems including aggression in addition to anxiety and depressive symptoms. One very interesting side note of this study was that the improvement in child behavior seemed to be partially mediated by improvements in the parents’ behavior, even though parents did not receive the supplements.

In attention-deficit/hyperactivity disorder, a meta-analysis of 10 clinical trials also was positive (J Am Acad Child Adolesc Psychiatry. 2011 Oct;50[10]:991-1000). The effect size was small, but there seemed to be a dose effect with more positive trials related to higher daily doses of EPA. Side effects again were few.

The mechanism for improvement remains to be fully understood, although evidence points to changes in cell membrane fluidity and possible anti-inflammatory properties. The biggest question mark that remains from a practical standpoint is dose, both in absolute numbers and with regard to ratios of EPA to DHA. Given the vast number of suppliers of omega-3 supplementation and the wide range of quality with regard to accurate dosing and impurities, it also is important to help families identify a specific product that can be trusted.

Case follow-up

Somewhat to the surprise of Samantha’s mother, the pediatrician supports a trial of omega-3 supplementation, given the increasing evidence of efficacy and the favorable side effect profile. They discuss reasonable expectations, dosing, and ways that the family can obtain a high-quality supplement. Six months later, the family reports noticeable further improvements in Samantha’s behavior to the point that more aggressive psychopharmacologic treatment is not indicated currently.

In sum, it is reasonable to conclude at this point that evidence supporting omega-3 use for a variety of emotional-behavioral problems now equals or exceeds that for many off-label prescription medications that are now used in similar situations. This increasing evidence, combined with the low risk for most patients, would seem to warrant pediatricians considering omega-3 supplementation as a more mainstream and evidence-based intervention that deserves a place in one’s treatment algorithm for several emotional-behavioral concerns.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He will also be course director of the 10th annual Child Psychiatry in Primary Care conference on May 13, 2016, in Burlington. Follow him on Twitter @pedipsych.

Glial fibrillary acidic protein appears to be a candidate biomarker for detecting traumatic intracranial lesions on head CT after mild to moderate head trauma in youth, a study showed.

Previous studies have found that head CT scans in children less than 5 years old may contribute to the risk for brain cancer and leukemia because children are more sensitive to ionizing radiation. Ninety-nine different pediatric biomarkers have been researched for traumatic brain injury (TBI); some studies have indicated glial fibrillary acidic protein (GFAP) may be a promising biomarker for mild to moderate TBI in adults.

Dr. Linda Papa of the department of emergency medicine at Orlando Regional Medical Center and colleagues compared the GFAP level in the serum of children and youth evaluated for mild to moderate TBI with pediatric trauma patients without brain injury to see how these levels were related to evidence of traumatic lesions on head CT. Their results were published in Academic Emergency Medicine (2015 Nov;22[11]:1274-82. doi: 10.1111/acem.12795).

They conducted a prospective cohort study of 197 children and youth who presented with a Glasgow Coma Scale (GCS) score of 9-15 after blunt head trauma. The 60 control patients included those without head trauma and a GSC score of 15. A head CT scan was obtained in 152 patients, with 11% demonstrating traumatic intracranial lesions. Serum samples were drawn within 6 hours of injury, at a mean 3.3 hours in those with head injury and 4.1 hours in those without head injury.

Children with traumatic intracranial lesions on CT scan had higher median GFAP levels (1.01, interquartile range = 0.59-1.48), compared with those without lesions on CT (0.18, IQR = 0.06-0.47).

When GFAP was used to detect traumatic lesions on head CT, the area under the receiver operating characteristic curve (AUC) was 0.82 (95% confidence interval, 0.71-0.93); it was 0.80 (95% CI, 0.68-0.92) for those with a GCS of 15, and 0.83 (95% CI, 0.56-1.00) in those younger than 5 years old.

Using a cutoff level of 0.15 ng/mL for GFAP, Dr. Papa and colleagues noted a negative predictive value of 98%, a specificity of 47%, and a sensitivity of 94% for detecting intracranial lesions.

Several limitations to the study included not having research assistants available to enroll participants 24/7, a lack of long-term outcome data, and a small cohort without any participants requiring neurosurgical intervention.

The next steps would involve clinical validation with a large, multicenter study.

This study was supported by an award from the National Institute of Neurological Disorders and Stroke. Dr. Papa reported consulting for Banyan Biomarkers.

Glial fibrillary acidic protein appears to be a candidate biomarker for detecting traumatic intracranial lesions on head CT after mild to moderate head trauma in youth, a study showed.

Previous studies have found that head CT scans in children less than 5 years old may contribute to the risk for brain cancer and leukemia because children are more sensitive to ionizing radiation. Ninety-nine different pediatric biomarkers have been researched for traumatic brain injury (TBI); some studies have indicated glial fibrillary acidic protein (GFAP) may be a promising biomarker for mild to moderate TBI in adults.

Dr. Linda Papa of the department of emergency medicine at Orlando Regional Medical Center and colleagues compared the GFAP level in the serum of children and youth evaluated for mild to moderate TBI with pediatric trauma patients without brain injury to see how these levels were related to evidence of traumatic lesions on head CT. Their results were published in Academic Emergency Medicine (2015 Nov;22[11]:1274-82. doi: 10.1111/acem.12795).

They conducted a prospective cohort study of 197 children and youth who presented with a Glasgow Coma Scale (GCS) score of 9-15 after blunt head trauma. The 60 control patients included those without head trauma and a GSC score of 15. A head CT scan was obtained in 152 patients, with 11% demonstrating traumatic intracranial lesions. Serum samples were drawn within 6 hours of injury, at a mean 3.3 hours in those with head injury and 4.1 hours in those without head injury.

Children with traumatic intracranial lesions on CT scan had higher median GFAP levels (1.01, interquartile range = 0.59-1.48), compared with those without lesions on CT (0.18, IQR = 0.06-0.47).

When GFAP was used to detect traumatic lesions on head CT, the area under the receiver operating characteristic curve (AUC) was 0.82 (95% confidence interval, 0.71-0.93); it was 0.80 (95% CI, 0.68-0.92) for those with a GCS of 15, and 0.83 (95% CI, 0.56-1.00) in those younger than 5 years old.

Using a cutoff level of 0.15 ng/mL for GFAP, Dr. Papa and colleagues noted a negative predictive value of 98%, a specificity of 47%, and a sensitivity of 94% for detecting intracranial lesions.

Several limitations to the study included not having research assistants available to enroll participants 24/7, a lack of long-term outcome data, and a small cohort without any participants requiring neurosurgical intervention.

The next steps would involve clinical validation with a large, multicenter study.

This study was supported by an award from the National Institute of Neurological Disorders and Stroke. Dr. Papa reported consulting for Banyan Biomarkers.

Glial fibrillary acidic protein appears to be a candidate biomarker for detecting traumatic intracranial lesions on head CT after mild to moderate head trauma in youth, a study showed.

Previous studies have found that head CT scans in children less than 5 years old may contribute to the risk for brain cancer and leukemia because children are more sensitive to ionizing radiation. Ninety-nine different pediatric biomarkers have been researched for traumatic brain injury (TBI); some studies have indicated glial fibrillary acidic protein (GFAP) may be a promising biomarker for mild to moderate TBI in adults.

Dr. Linda Papa of the department of emergency medicine at Orlando Regional Medical Center and colleagues compared the GFAP level in the serum of children and youth evaluated for mild to moderate TBI with pediatric trauma patients without brain injury to see how these levels were related to evidence of traumatic lesions on head CT. Their results were published in Academic Emergency Medicine (2015 Nov;22[11]:1274-82. doi: 10.1111/acem.12795).

They conducted a prospective cohort study of 197 children and youth who presented with a Glasgow Coma Scale (GCS) score of 9-15 after blunt head trauma. The 60 control patients included those without head trauma and a GSC score of 15. A head CT scan was obtained in 152 patients, with 11% demonstrating traumatic intracranial lesions. Serum samples were drawn within 6 hours of injury, at a mean 3.3 hours in those with head injury and 4.1 hours in those without head injury.

Children with traumatic intracranial lesions on CT scan had higher median GFAP levels (1.01, interquartile range = 0.59-1.48), compared with those without lesions on CT (0.18, IQR = 0.06-0.47).

When GFAP was used to detect traumatic lesions on head CT, the area under the receiver operating characteristic curve (AUC) was 0.82 (95% confidence interval, 0.71-0.93); it was 0.80 (95% CI, 0.68-0.92) for those with a GCS of 15, and 0.83 (95% CI, 0.56-1.00) in those younger than 5 years old.

Using a cutoff level of 0.15 ng/mL for GFAP, Dr. Papa and colleagues noted a negative predictive value of 98%, a specificity of 47%, and a sensitivity of 94% for detecting intracranial lesions.

Several limitations to the study included not having research assistants available to enroll participants 24/7, a lack of long-term outcome data, and a small cohort without any participants requiring neurosurgical intervention.

The next steps would involve clinical validation with a large, multicenter study.

This study was supported by an award from the National Institute of Neurological Disorders and Stroke. Dr. Papa reported consulting for Banyan Biomarkers.

I recently attended an event honoring Dr. Katherine Upchurch, one of the attending rheumatologists I worked with during my fellowship at the University of Massachusetts. In her acceptance speech for the Massachusetts Arthritis Foundation chapter’s Dr. Marian Ropes Award, one thing that stood out for me was her acknowledgment of doctors who still practice “in this climate.” She did not elaborate on that, but my guess is that we all have a gnawing, if unenumerated, understanding that the practice of medicine today is quite different from even as recently as 20 years ago. I’ve witnessed some of the changes myself in the brief 6 years that I’ve been practicing.

Some changes have been tangible. For example, in 2011 the Centers for Medicare & Medicaid Services (CMS) started requiring the use of electronic health records that demonstrate so-called meaningful use. In 2013, the CMS started collecting information on quality of care by way of its Physician Quality Reporting System (PQRS). 2014 ushered in the new Maintenance of Certification requirements from the American Board of Internal Medicine, a change that has been contentious at best and onerous at worst. Most recently, Oct. 1, 2015, was the official rollout date for new ICD-10 coding, expanding our list of possible diagnoses to 68,000 (W61.1, contact with macaw, anyone?). 2015 is also the year that penalties start if a practice does not comply with meaningful use and PQRS. Every single one of these changes has made me feel like a child being told to comply “just because,” without the ability to question or argue.

There have also been more subtle changes over time that defy reduction to any specific date or agency. For instance, it was not too long ago that a doctor had more than 15 minutes for a follow-up visit. But Medicare reimbursement stagnated while inflation grew, so keeping practices open meant squeezing more and more patients in.

Meanwhile, insurance premiums and deductibles keep increasing. This imposes a burden on patients, often resulting in suboptimal care. Never mind that our patients can’t afford the biologics, they can’t even afford the copays required for physical therapy visits.

Contrary to the usual behavior of market forces, the higher cost of insurance does not seem to buy the patient more options. This further emphasizes that notwithstanding Justice Scalia, health care is not in fact just like broccoli. Instead, insurers are dictating which physicians, facilities, and pharmacies patients can use. They decide which medications and tests are covered based on algorithms, with little regard for the medical training that informs the physician’s recommendations.

These are just some of the changes that have made the practice of medicine so burdensome as to be intolerable to some. It is likely that these regulations have played at least some part in the unsustainability of small, independent practices, thereby reshaping the landscape quite dramatically. Already it feels like we are just cogs in the large wheel of corporate health care.

In China, children are actively discouraged from going to medical school because doctors are overworked and underpaid. Doctors are also often victims of violence perpetrated by disgruntled patients, probably because the overworked and underpaid doctors don’t have the means to care for their patients appropriately. I desperately hope this is not the direction our profession is headed in, because antagonism does not exactly become us.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I recently attended an event honoring Dr. Katherine Upchurch, one of the attending rheumatologists I worked with during my fellowship at the University of Massachusetts. In her acceptance speech for the Massachusetts Arthritis Foundation chapter’s Dr. Marian Ropes Award, one thing that stood out for me was her acknowledgment of doctors who still practice “in this climate.” She did not elaborate on that, but my guess is that we all have a gnawing, if unenumerated, understanding that the practice of medicine today is quite different from even as recently as 20 years ago. I’ve witnessed some of the changes myself in the brief 6 years that I’ve been practicing.

Some changes have been tangible. For example, in 2011 the Centers for Medicare & Medicaid Services (CMS) started requiring the use of electronic health records that demonstrate so-called meaningful use. In 2013, the CMS started collecting information on quality of care by way of its Physician Quality Reporting System (PQRS). 2014 ushered in the new Maintenance of Certification requirements from the American Board of Internal Medicine, a change that has been contentious at best and onerous at worst. Most recently, Oct. 1, 2015, was the official rollout date for new ICD-10 coding, expanding our list of possible diagnoses to 68,000 (W61.1, contact with macaw, anyone?). 2015 is also the year that penalties start if a practice does not comply with meaningful use and PQRS. Every single one of these changes has made me feel like a child being told to comply “just because,” without the ability to question or argue.

There have also been more subtle changes over time that defy reduction to any specific date or agency. For instance, it was not too long ago that a doctor had more than 15 minutes for a follow-up visit. But Medicare reimbursement stagnated while inflation grew, so keeping practices open meant squeezing more and more patients in.

Meanwhile, insurance premiums and deductibles keep increasing. This imposes a burden on patients, often resulting in suboptimal care. Never mind that our patients can’t afford the biologics, they can’t even afford the copays required for physical therapy visits.

Contrary to the usual behavior of market forces, the higher cost of insurance does not seem to buy the patient more options. This further emphasizes that notwithstanding Justice Scalia, health care is not in fact just like broccoli. Instead, insurers are dictating which physicians, facilities, and pharmacies patients can use. They decide which medications and tests are covered based on algorithms, with little regard for the medical training that informs the physician’s recommendations.

These are just some of the changes that have made the practice of medicine so burdensome as to be intolerable to some. It is likely that these regulations have played at least some part in the unsustainability of small, independent practices, thereby reshaping the landscape quite dramatically. Already it feels like we are just cogs in the large wheel of corporate health care.

In China, children are actively discouraged from going to medical school because doctors are overworked and underpaid. Doctors are also often victims of violence perpetrated by disgruntled patients, probably because the overworked and underpaid doctors don’t have the means to care for their patients appropriately. I desperately hope this is not the direction our profession is headed in, because antagonism does not exactly become us.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I recently attended an event honoring Dr. Katherine Upchurch, one of the attending rheumatologists I worked with during my fellowship at the University of Massachusetts. In her acceptance speech for the Massachusetts Arthritis Foundation chapter’s Dr. Marian Ropes Award, one thing that stood out for me was her acknowledgment of doctors who still practice “in this climate.” She did not elaborate on that, but my guess is that we all have a gnawing, if unenumerated, understanding that the practice of medicine today is quite different from even as recently as 20 years ago. I’ve witnessed some of the changes myself in the brief 6 years that I’ve been practicing.

Some changes have been tangible. For example, in 2011 the Centers for Medicare & Medicaid Services (CMS) started requiring the use of electronic health records that demonstrate so-called meaningful use. In 2013, the CMS started collecting information on quality of care by way of its Physician Quality Reporting System (PQRS). 2014 ushered in the new Maintenance of Certification requirements from the American Board of Internal Medicine, a change that has been contentious at best and onerous at worst. Most recently, Oct. 1, 2015, was the official rollout date for new ICD-10 coding, expanding our list of possible diagnoses to 68,000 (W61.1, contact with macaw, anyone?). 2015 is also the year that penalties start if a practice does not comply with meaningful use and PQRS. Every single one of these changes has made me feel like a child being told to comply “just because,” without the ability to question or argue.

There have also been more subtle changes over time that defy reduction to any specific date or agency. For instance, it was not too long ago that a doctor had more than 15 minutes for a follow-up visit. But Medicare reimbursement stagnated while inflation grew, so keeping practices open meant squeezing more and more patients in.

Meanwhile, insurance premiums and deductibles keep increasing. This imposes a burden on patients, often resulting in suboptimal care. Never mind that our patients can’t afford the biologics, they can’t even afford the copays required for physical therapy visits.

Contrary to the usual behavior of market forces, the higher cost of insurance does not seem to buy the patient more options. This further emphasizes that notwithstanding Justice Scalia, health care is not in fact just like broccoli. Instead, insurers are dictating which physicians, facilities, and pharmacies patients can use. They decide which medications and tests are covered based on algorithms, with little regard for the medical training that informs the physician’s recommendations.

These are just some of the changes that have made the practice of medicine so burdensome as to be intolerable to some. It is likely that these regulations have played at least some part in the unsustainability of small, independent practices, thereby reshaping the landscape quite dramatically. Already it feels like we are just cogs in the large wheel of corporate health care.

In China, children are actively discouraged from going to medical school because doctors are overworked and underpaid. Doctors are also often victims of violence perpetrated by disgruntled patients, probably because the overworked and underpaid doctors don’t have the means to care for their patients appropriately. I desperately hope this is not the direction our profession is headed in, because antagonism does not exactly become us.

Dr. Chan practices rheumatology in Pawtucket, R.I.

SAN FRANCISCO – The number of new waiting-list registrations for liver transplantation among patients with hepatitis C virus declined significantly after the introduction of second-generation direct-acting antiviral agents, according to a review of United Network for Organ Sharing data.

New waiting-list registrations (NWRs) through March 31, 2015 – based on the most recent data available as of September 2015 – ranged from 740 to 976 per month between August 2012 and March 2015, and a review of the data show that HCV-specific NWRs declined by 23% overall in the 15 months after the Food and Drug Administration approved simeprevir (Nov. 22, 2013) and sofosbuvir (Dec. 6, 2013) vs. the 15 months prior (from 34.8% to 26.8%), Dr. Ryan B. Perumpail reported at the annual meeting of the American Association for the Study of Liver Diseases.

©decade3d/ thinkstockphotos.com

Further, the proportion of HCV patients without hepatocellular carcinoma among new waiting-list registrations declined by 33% (from 23.0% to 15.4%) and there was a significant decline in NWRs for liver transplants in nonhepatocellular-carcinoma HCV patients from January 2014 to March 2015 (153 per month) vs. August 2012 to October 2013 (mean 188 per month), for a mean difference of 35.0, said Dr. Perumpail of Stanford University Medical Center, Palo Alto, Calif.

Among the HCV-related NWRs for liver transplantation, the proportion without hepatocellular carcinoma declined 12.5% (from 66.3% to 58.0%).

Direct-acting antiviral therapy has been prioritized in patients with HCV-related cirrhosis in an effort to slow clinical disease progress and to induce regression of hepatic histologic damage, Dr. Perumpail explained.

Thought limited by the retrospective design of the study, the findings suggest that the use of direct-acting antivirals contributed to a downward trend in NWRs for liver transplantation among HCV patients without hepatocellular carcinoma.

Dr. Perumpail reported having no disclosures.

[email protected]

SAN FRANCISCO – The number of new waiting-list registrations for liver transplantation among patients with hepatitis C virus declined significantly after the introduction of second-generation direct-acting antiviral agents, according to a review of United Network for Organ Sharing data.

New waiting-list registrations (NWRs) through March 31, 2015 – based on the most recent data available as of September 2015 – ranged from 740 to 976 per month between August 2012 and March 2015, and a review of the data show that HCV-specific NWRs declined by 23% overall in the 15 months after the Food and Drug Administration approved simeprevir (Nov. 22, 2013) and sofosbuvir (Dec. 6, 2013) vs. the 15 months prior (from 34.8% to 26.8%), Dr. Ryan B. Perumpail reported at the annual meeting of the American Association for the Study of Liver Diseases.

©decade3d/ thinkstockphotos.com

Further, the proportion of HCV patients without hepatocellular carcinoma among new waiting-list registrations declined by 33% (from 23.0% to 15.4%) and there was a significant decline in NWRs for liver transplants in nonhepatocellular-carcinoma HCV patients from January 2014 to March 2015 (153 per month) vs. August 2012 to October 2013 (mean 188 per month), for a mean difference of 35.0, said Dr. Perumpail of Stanford University Medical Center, Palo Alto, Calif.

Among the HCV-related NWRs for liver transplantation, the proportion without hepatocellular carcinoma declined 12.5% (from 66.3% to 58.0%).

Direct-acting antiviral therapy has been prioritized in patients with HCV-related cirrhosis in an effort to slow clinical disease progress and to induce regression of hepatic histologic damage, Dr. Perumpail explained.

Thought limited by the retrospective design of the study, the findings suggest that the use of direct-acting antivirals contributed to a downward trend in NWRs for liver transplantation among HCV patients without hepatocellular carcinoma.

Dr. Perumpail reported having no disclosures.

[email protected]

SAN FRANCISCO – The number of new waiting-list registrations for liver transplantation among patients with hepatitis C virus declined significantly after the introduction of second-generation direct-acting antiviral agents, according to a review of United Network for Organ Sharing data.

New waiting-list registrations (NWRs) through March 31, 2015 – based on the most recent data available as of September 2015 – ranged from 740 to 976 per month between August 2012 and March 2015, and a review of the data show that HCV-specific NWRs declined by 23% overall in the 15 months after the Food and Drug Administration approved simeprevir (Nov. 22, 2013) and sofosbuvir (Dec. 6, 2013) vs. the 15 months prior (from 34.8% to 26.8%), Dr. Ryan B. Perumpail reported at the annual meeting of the American Association for the Study of Liver Diseases.

©decade3d/ thinkstockphotos.com

Further, the proportion of HCV patients without hepatocellular carcinoma among new waiting-list registrations declined by 33% (from 23.0% to 15.4%) and there was a significant decline in NWRs for liver transplants in nonhepatocellular-carcinoma HCV patients from January 2014 to March 2015 (153 per month) vs. August 2012 to October 2013 (mean 188 per month), for a mean difference of 35.0, said Dr. Perumpail of Stanford University Medical Center, Palo Alto, Calif.

Among the HCV-related NWRs for liver transplantation, the proportion without hepatocellular carcinoma declined 12.5% (from 66.3% to 58.0%).

Direct-acting antiviral therapy has been prioritized in patients with HCV-related cirrhosis in an effort to slow clinical disease progress and to induce regression of hepatic histologic damage, Dr. Perumpail explained.

Thought limited by the retrospective design of the study, the findings suggest that the use of direct-acting antivirals contributed to a downward trend in NWRs for liver transplantation among HCV patients without hepatocellular carcinoma.

Dr. Perumpail reported having no disclosures.

[email protected]

Proliferating HSCs

Image by John Perry

Previous studies have shown that hematopoietic stresses—such as myelofibrosis, anemia, and myeloablation—can induce extramedullary hematopoiesis (EMH), in which hematopoietic stem cells (HSCs) are mobilized to sites outside the bone marrow.

The splenic red pulp is known to be a prominent site of EMH in both mice and humans, but not much is known about the EMH niche.

Now, investigators say they have characterized this niche.

They detailed their findings in Nature.

The team used mouse models to examine the expression patterns of 2 known niche cell factors, SCF and CXCL12.

They discovered that the hematopoietic microenvironment in the spleen is found near sinusoidal blood vessels and is created by endothelial cells and perivascular stromal cells, just like the microenvironment in the bone marrow.

“Under emergency conditions, the endothelial cells and perivascular stromal cells that reside in the spleen are induced to proliferate so they can sustain all the new blood-forming stem cells that migrate into the spleen,” explained study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center, Dallas.

“We determined that this process in the spleen is physiologically important for responding to hematopoietic stress. Without it, the mice we studied could not maintain normal blood cell counts during pregnancy or quickly regenerate blood cell counts after bleeding or chemotherapy.”

The investigators believe these findings could aid the development of therapeutic interventions to enhance blood formation following chemotherapy or HSC transplant and thus accelerate the recovery of blood cell counts.

Proliferating HSCs

Image by John Perry

Previous studies have shown that hematopoietic stresses—such as myelofibrosis, anemia, and myeloablation—can induce extramedullary hematopoiesis (EMH), in which hematopoietic stem cells (HSCs) are mobilized to sites outside the bone marrow.

The splenic red pulp is known to be a prominent site of EMH in both mice and humans, but not much is known about the EMH niche.

Now, investigators say they have characterized this niche.

They detailed their findings in Nature.

The team used mouse models to examine the expression patterns of 2 known niche cell factors, SCF and CXCL12.

They discovered that the hematopoietic microenvironment in the spleen is found near sinusoidal blood vessels and is created by endothelial cells and perivascular stromal cells, just like the microenvironment in the bone marrow.

“Under emergency conditions, the endothelial cells and perivascular stromal cells that reside in the spleen are induced to proliferate so they can sustain all the new blood-forming stem cells that migrate into the spleen,” explained study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center, Dallas.

“We determined that this process in the spleen is physiologically important for responding to hematopoietic stress. Without it, the mice we studied could not maintain normal blood cell counts during pregnancy or quickly regenerate blood cell counts after bleeding or chemotherapy.”

The investigators believe these findings could aid the development of therapeutic interventions to enhance blood formation following chemotherapy or HSC transplant and thus accelerate the recovery of blood cell counts.

Proliferating HSCs

Image by John Perry

Previous studies have shown that hematopoietic stresses—such as myelofibrosis, anemia, and myeloablation—can induce extramedullary hematopoiesis (EMH), in which hematopoietic stem cells (HSCs) are mobilized to sites outside the bone marrow.

The splenic red pulp is known to be a prominent site of EMH in both mice and humans, but not much is known about the EMH niche.

Now, investigators say they have characterized this niche.

They detailed their findings in Nature.

The team used mouse models to examine the expression patterns of 2 known niche cell factors, SCF and CXCL12.

They discovered that the hematopoietic microenvironment in the spleen is found near sinusoidal blood vessels and is created by endothelial cells and perivascular stromal cells, just like the microenvironment in the bone marrow.

“Under emergency conditions, the endothelial cells and perivascular stromal cells that reside in the spleen are induced to proliferate so they can sustain all the new blood-forming stem cells that migrate into the spleen,” explained study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center, Dallas.

“We determined that this process in the spleen is physiologically important for responding to hematopoietic stress. Without it, the mice we studied could not maintain normal blood cell counts during pregnancy or quickly regenerate blood cell counts after bleeding or chemotherapy.”

The investigators believe these findings could aid the development of therapeutic interventions to enhance blood formation following chemotherapy or HSC transplant and thus accelerate the recovery of blood cell counts.

Red blood cells

Preclinical research suggests a high-fat diet is associated with red blood cell (RBC) dysfunction and helps explain how these dysfunctional cells may mediate atherosclerosis.

The researchers believe their findings may have implications for the pathogenesis of atherosclerosis in obesity, but the work may aid the study of other health conditions as well, such as thrombosis in the context of cancer.

The team detailed their findings in Circulation.

“Obesity caused by chronic consumption of a high-calorie, high-fat diet is a worldwide epidemic, representing one of the greatest threats to global health,” said principal investigator Vladimir Bogdanov, PhD, of the University of Cincinnati in Ohio.

“White blood cells play a key role in fueling adipose tissue inflammation and insulin resistance in obesity and also promote the clogging of arteries, or atherosclerosis, setting the stage for heart attack and stroke. While these outcomes linked with a high-fat diet and fat in the blood on white blood cells have been shown in animal models and humans, the impact of high-fat diets on other bone marrow-derived cells, like red blood cells, is not well-defined.”

“Evidence is emerging that red blood cells play an important regulatory role in the development of atherosclerosis, binding pro-inflammatory proteins that cause dysfunction in the inner lining of the blood vessel wall—the endothelium. We explored how a high fat-diet causes red blood cell dysfunction in this study.”

Dr Bogdanov and his team fed a 60% high-fat diet to mice for 12 weeks and compared these animals to control mice that received a normal diet.

There was an increase in the level of chemokines bound to the RBCs of mice that received the high-fat diet. These chemokines were bound to RBCs via the Duffy antigen receptor for chemokines.

The researchers exposed RBCs from mice on the high-fat diet to an endothelial monolayer in vitro, and they observed “significantly enhanced” macrophage transendothelial migration. They said this confirms the functional importance of RBC-bound chemokines in the setting of a high-fat diet.

“In red blood cells from animal models fed a high-fat diet, there was an increase in cholesterol found in the cell membrane and phosphatidylserine levels, promoting inflammatory reactions,” Dr Bogdanov added.

“Phosphatidylserine is a phospholipid membrane component which plays a key role in the cycle of cells. When red blood cells from the animals being fed the high-fat diet were injected into a control group, eating a normal diet, there was a 3-fold increase in their spleens’ uptake of red blood cells. The spleen is involved in the removal of blood cells, as well as systemic inflammation.”

“All of these findings show that the dysfunction of red blood cells, corresponding with dysfunction of the lining of blood vessels, occurs very early in diet-induced obesity and may play a part in the formation of atherosclerosis. Diets high in saturated fat have long been associated with endothelial dysfunction, the precursor to atherosclerosis, but, to our knowledge, the effects of high-fat diet on red blood cells have not been rigorously examined.”

Dr Bogdanov noted that, in humans, high cholesterol is associated with alterations in RBCs that are improved by treatment with statins. But the majority of obese humans do not have severe high cholesterol, as was the case with the animals in this study.

The researchers are now working on translating their findings to humans.

Red blood cells

Preclinical research suggests a high-fat diet is associated with red blood cell (RBC) dysfunction and helps explain how these dysfunctional cells may mediate atherosclerosis.

The researchers believe their findings may have implications for the pathogenesis of atherosclerosis in obesity, but the work may aid the study of other health conditions as well, such as thrombosis in the context of cancer.

The team detailed their findings in Circulation.

“Obesity caused by chronic consumption of a high-calorie, high-fat diet is a worldwide epidemic, representing one of the greatest threats to global health,” said principal investigator Vladimir Bogdanov, PhD, of the University of Cincinnati in Ohio.

“White blood cells play a key role in fueling adipose tissue inflammation and insulin resistance in obesity and also promote the clogging of arteries, or atherosclerosis, setting the stage for heart attack and stroke. While these outcomes linked with a high-fat diet and fat in the blood on white blood cells have been shown in animal models and humans, the impact of high-fat diets on other bone marrow-derived cells, like red blood cells, is not well-defined.”

“Evidence is emerging that red blood cells play an important regulatory role in the development of atherosclerosis, binding pro-inflammatory proteins that cause dysfunction in the inner lining of the blood vessel wall—the endothelium. We explored how a high fat-diet causes red blood cell dysfunction in this study.”

Dr Bogdanov and his team fed a 60% high-fat diet to mice for 12 weeks and compared these animals to control mice that received a normal diet.

There was an increase in the level of chemokines bound to the RBCs of mice that received the high-fat diet. These chemokines were bound to RBCs via the Duffy antigen receptor for chemokines.

The researchers exposed RBCs from mice on the high-fat diet to an endothelial monolayer in vitro, and they observed “significantly enhanced” macrophage transendothelial migration. They said this confirms the functional importance of RBC-bound chemokines in the setting of a high-fat diet.

“In red blood cells from animal models fed a high-fat diet, there was an increase in cholesterol found in the cell membrane and phosphatidylserine levels, promoting inflammatory reactions,” Dr Bogdanov added.

“Phosphatidylserine is a phospholipid membrane component which plays a key role in the cycle of cells. When red blood cells from the animals being fed the high-fat diet were injected into a control group, eating a normal diet, there was a 3-fold increase in their spleens’ uptake of red blood cells. The spleen is involved in the removal of blood cells, as well as systemic inflammation.”

“All of these findings show that the dysfunction of red blood cells, corresponding with dysfunction of the lining of blood vessels, occurs very early in diet-induced obesity and may play a part in the formation of atherosclerosis. Diets high in saturated fat have long been associated with endothelial dysfunction, the precursor to atherosclerosis, but, to our knowledge, the effects of high-fat diet on red blood cells have not been rigorously examined.”

Dr Bogdanov noted that, in humans, high cholesterol is associated with alterations in RBCs that are improved by treatment with statins. But the majority of obese humans do not have severe high cholesterol, as was the case with the animals in this study.

The researchers are now working on translating their findings to humans.

Red blood cells

Preclinical research suggests a high-fat diet is associated with red blood cell (RBC) dysfunction and helps explain how these dysfunctional cells may mediate atherosclerosis.

The researchers believe their findings may have implications for the pathogenesis of atherosclerosis in obesity, but the work may aid the study of other health conditions as well, such as thrombosis in the context of cancer.

The team detailed their findings in Circulation.

“Obesity caused by chronic consumption of a high-calorie, high-fat diet is a worldwide epidemic, representing one of the greatest threats to global health,” said principal investigator Vladimir Bogdanov, PhD, of the University of Cincinnati in Ohio.

“White blood cells play a key role in fueling adipose tissue inflammation and insulin resistance in obesity and also promote the clogging of arteries, or atherosclerosis, setting the stage for heart attack and stroke. While these outcomes linked with a high-fat diet and fat in the blood on white blood cells have been shown in animal models and humans, the impact of high-fat diets on other bone marrow-derived cells, like red blood cells, is not well-defined.”

“Evidence is emerging that red blood cells play an important regulatory role in the development of atherosclerosis, binding pro-inflammatory proteins that cause dysfunction in the inner lining of the blood vessel wall—the endothelium. We explored how a high fat-diet causes red blood cell dysfunction in this study.”

Dr Bogdanov and his team fed a 60% high-fat diet to mice for 12 weeks and compared these animals to control mice that received a normal diet.

There was an increase in the level of chemokines bound to the RBCs of mice that received the high-fat diet. These chemokines were bound to RBCs via the Duffy antigen receptor for chemokines.

The researchers exposed RBCs from mice on the high-fat diet to an endothelial monolayer in vitro, and they observed “significantly enhanced” macrophage transendothelial migration. They said this confirms the functional importance of RBC-bound chemokines in the setting of a high-fat diet.

“In red blood cells from animal models fed a high-fat diet, there was an increase in cholesterol found in the cell membrane and phosphatidylserine levels, promoting inflammatory reactions,” Dr Bogdanov added.

“Phosphatidylserine is a phospholipid membrane component which plays a key role in the cycle of cells. When red blood cells from the animals being fed the high-fat diet were injected into a control group, eating a normal diet, there was a 3-fold increase in their spleens’ uptake of red blood cells. The spleen is involved in the removal of blood cells, as well as systemic inflammation.”

“All of these findings show that the dysfunction of red blood cells, corresponding with dysfunction of the lining of blood vessels, occurs very early in diet-induced obesity and may play a part in the formation of atherosclerosis. Diets high in saturated fat have long been associated with endothelial dysfunction, the precursor to atherosclerosis, but, to our knowledge, the effects of high-fat diet on red blood cells have not been rigorously examined.”

Dr Bogdanov noted that, in humans, high cholesterol is associated with alterations in RBCs that are improved by treatment with statins. But the majority of obese humans do not have severe high cholesterol, as was the case with the animals in this study.

The researchers are now working on translating their findings to humans.

Bloodhorn tree

A compound derived from the berries of the Bloodhorn tree has demonstrated activity against acute myeloid leukemia (AML), according to preclinical research published in Investigational New Drugs.

The compound, 7-formyl-10-methylisoellipticine, induced apoptosis in AML cells in a dose- and time-dependent manner.

It also significantly slowed tumor growth and reduced tumor mass in a mouse model of AML.

7-formyl-10-methylisoellipticine is derived from an ellipticine, which has been isolated from the berries of the Ochrosia Elliptica tree. The tree, also known as the Bloodhorn tree due to the shape and color of the berries, grows on the northeast coast of Australia and in the rainforests of Brazil.

“[We have] taken the natural product and restyled it with unique features to improve the potency and solubility,” explained Florence McCarthy, PhD, of University College Cork in Ireland.

“What is truly exceptional is that these features are not common in drugs, and so we aim to exploit this fully. There is also significant potential to apply this approach to other drugs in a similar fashion.”

For this study, Dr McCarthy and his colleagues first tested 7-formyl-10-methylisoellipticine in the AML cell line MV4-11. They tested a range of concentrations in an attempt to identify the minimum concentration that would cause significant cytotoxicity. It turned out to be 5 μM.

Over a period of 24 hours, 5 μM of 7-formyl-10-methylisoellipticine killed up to 40% of MV4-11 cells. And over 96 hours, 5 μM of 7-formyl-10-methylisoellipticine killed more than 90% of cells.

Further investigation revealed that 5 μM of 7-formyl-10-methylisoellipticine increases the sub-G1 phase of the MV4-11 cell cycle. And the compound functions, at least in part, by generating mitochondrial-derived reactive oxygen species.

The researchers then found that 7-formyl-10-methylisoellipticine is not toxic to BALB/c mice. The team injected the mice with 7-formyl-10-methylisoellipticine at a range of doses—5 mg/kg, 10 mg/kg, 25 mg/kg, and 50 mg/kg.

Regardless of the dose, the compound did not cause a change in body weight, significantly increase levels of alanine aminotransferase or aspartate aminotransferase relative to negative control, or significantly change cell morphology or tissue structure in specified major organs.

Finally, the researchers found that 7-formyl-10-methylisoellipticine has antitumor activity in an AML xenograft mouse model. Based on the toxicity experiments, the team used a dose of 25 mg/kg in these mice.

At this dose, 7-formyl-10-methylisoellipticine significantly slowed tumor growth and reduced tumor mass. Tumor growth was 4 times slower in mice treated with 7-formyl-10-methylisoellipticine than in control mice. And tumor mass was up to 7 times greater in controls than it was in treated mice.

Based on these results, the researchers said they plan to continue investigating the mechanism of action of ellipticines, which “have a clear potential clinical application.”

Bloodhorn tree

A compound derived from the berries of the Bloodhorn tree has demonstrated activity against acute myeloid leukemia (AML), according to preclinical research published in Investigational New Drugs.

The compound, 7-formyl-10-methylisoellipticine, induced apoptosis in AML cells in a dose- and time-dependent manner.

It also significantly slowed tumor growth and reduced tumor mass in a mouse model of AML.

7-formyl-10-methylisoellipticine is derived from an ellipticine, which has been isolated from the berries of the Ochrosia Elliptica tree. The tree, also known as the Bloodhorn tree due to the shape and color of the berries, grows on the northeast coast of Australia and in the rainforests of Brazil.

“[We have] taken the natural product and restyled it with unique features to improve the potency and solubility,” explained Florence McCarthy, PhD, of University College Cork in Ireland.

“What is truly exceptional is that these features are not common in drugs, and so we aim to exploit this fully. There is also significant potential to apply this approach to other drugs in a similar fashion.”

For this study, Dr McCarthy and his colleagues first tested 7-formyl-10-methylisoellipticine in the AML cell line MV4-11. They tested a range of concentrations in an attempt to identify the minimum concentration that would cause significant cytotoxicity. It turned out to be 5 μM.

Over a period of 24 hours, 5 μM of 7-formyl-10-methylisoellipticine killed up to 40% of MV4-11 cells. And over 96 hours, 5 μM of 7-formyl-10-methylisoellipticine killed more than 90% of cells.

Further investigation revealed that 5 μM of 7-formyl-10-methylisoellipticine increases the sub-G1 phase of the MV4-11 cell cycle. And the compound functions, at least in part, by generating mitochondrial-derived reactive oxygen species.

The researchers then found that 7-formyl-10-methylisoellipticine is not toxic to BALB/c mice. The team injected the mice with 7-formyl-10-methylisoellipticine at a range of doses—5 mg/kg, 10 mg/kg, 25 mg/kg, and 50 mg/kg.

Regardless of the dose, the compound did not cause a change in body weight, significantly increase levels of alanine aminotransferase or aspartate aminotransferase relative to negative control, or significantly change cell morphology or tissue structure in specified major organs.

Finally, the researchers found that 7-formyl-10-methylisoellipticine has antitumor activity in an AML xenograft mouse model. Based on the toxicity experiments, the team used a dose of 25 mg/kg in these mice.

At this dose, 7-formyl-10-methylisoellipticine significantly slowed tumor growth and reduced tumor mass. Tumor growth was 4 times slower in mice treated with 7-formyl-10-methylisoellipticine than in control mice. And tumor mass was up to 7 times greater in controls than it was in treated mice.

Based on these results, the researchers said they plan to continue investigating the mechanism of action of ellipticines, which “have a clear potential clinical application.”

Bloodhorn tree

A compound derived from the berries of the Bloodhorn tree has demonstrated activity against acute myeloid leukemia (AML), according to preclinical research published in Investigational New Drugs.

The compound, 7-formyl-10-methylisoellipticine, induced apoptosis in AML cells in a dose- and time-dependent manner.

It also significantly slowed tumor growth and reduced tumor mass in a mouse model of AML.

7-formyl-10-methylisoellipticine is derived from an ellipticine, which has been isolated from the berries of the Ochrosia Elliptica tree. The tree, also known as the Bloodhorn tree due to the shape and color of the berries, grows on the northeast coast of Australia and in the rainforests of Brazil.

“[We have] taken the natural product and restyled it with unique features to improve the potency and solubility,” explained Florence McCarthy, PhD, of University College Cork in Ireland.

“What is truly exceptional is that these features are not common in drugs, and so we aim to exploit this fully. There is also significant potential to apply this approach to other drugs in a similar fashion.”

For this study, Dr McCarthy and his colleagues first tested 7-formyl-10-methylisoellipticine in the AML cell line MV4-11. They tested a range of concentrations in an attempt to identify the minimum concentration that would cause significant cytotoxicity. It turned out to be 5 μM.

Over a period of 24 hours, 5 μM of 7-formyl-10-methylisoellipticine killed up to 40% of MV4-11 cells. And over 96 hours, 5 μM of 7-formyl-10-methylisoellipticine killed more than 90% of cells.

Further investigation revealed that 5 μM of 7-formyl-10-methylisoellipticine increases the sub-G1 phase of the MV4-11 cell cycle. And the compound functions, at least in part, by generating mitochondrial-derived reactive oxygen species.

The researchers then found that 7-formyl-10-methylisoellipticine is not toxic to BALB/c mice. The team injected the mice with 7-formyl-10-methylisoellipticine at a range of doses—5 mg/kg, 10 mg/kg, 25 mg/kg, and 50 mg/kg.

Regardless of the dose, the compound did not cause a change in body weight, significantly increase levels of alanine aminotransferase or aspartate aminotransferase relative to negative control, or significantly change cell morphology or tissue structure in specified major organs.

Finally, the researchers found that 7-formyl-10-methylisoellipticine has antitumor activity in an AML xenograft mouse model. Based on the toxicity experiments, the team used a dose of 25 mg/kg in these mice.

At this dose, 7-formyl-10-methylisoellipticine significantly slowed tumor growth and reduced tumor mass. Tumor growth was 4 times slower in mice treated with 7-formyl-10-methylisoellipticine than in control mice. And tumor mass was up to 7 times greater in controls than it was in treated mice.

Based on these results, the researchers said they plan to continue investigating the mechanism of action of ellipticines, which “have a clear potential clinical application.”