Topical synthetic epidermal growth factor serum moderately improved the appearance of atrophic acne scars in a small pilot study.

At the end of 12 weeks of twice-daily application, scar appearance improved from 2.875 to 2.38 points on a 5-point investigator global assessment scale. Mean Goodman and Baron acne scar grade fell from 3.00 to 2.75, with 3 representing moderate disease and 2 mild disease. Of eight pairs of before and after photographs given to a blinded investigator, posttreatment images were correctly identified in five. Two were assessed as 76%-100% improved, and three were assessed as 50%-75% improved (J Drugs Dermatol. 2015;14[9]:1005-1010).

The patients were an average of 38 years old, split about equally between the sexes, and racially diverse. They used a basic facial cleanser during the study, but were banned from using tretinoin and other topicals.

Previously studied topicals don’t do much for acne scars, so the usual go-to treatments are chemical peels, dermabrasion, resurfacing lasers, and percutaneous collagen needling. They all work in part by promoting collagen synthesis, but at the cost of pain and side effects. Epidermal growth factor (EGF) also promotes collagen synthesis, so the investigators thought it might help. The EGF used in the study – DNA Regeneration Serum, derived from barley – was supplied by its maker, DNA EGF Renewal in Los Angeles.

“The findings suggest EGF serum has the potential to be a modern, noninvasive treatment for an otherwise highly refractory condition. Whereas resurfacing procedures rely on skin injury to trigger [EGF] release, direct topical application offers the effects of EGF without the associated discomfort and recovery time,” said Dr. Ronald L. Moy of the University of Southern California, Los Angeles, and Rachel Seidel, a medical student at Georgetown University in Washington, D.C.

“All subjects in this study [also] noted improvements in skin texture, fine lines, and wrinkles, while the vast majority also saw a reduction in brown and age spots,” they said.

The investigators said they are interested next in seeing if topical EGF prevents scars in active acne. “We believe that, by counteracting collagen degradation during the course of the inflammatory response, significant tissue atrophy capable of causing visible scarring may be prevented,” they said.

Dr. Moy owns stock in DNA EGF Renewal and is the company’s scientific adviser.

[email protected]

Topical synthetic epidermal growth factor serum moderately improved the appearance of atrophic acne scars in a small pilot study.

At the end of 12 weeks of twice-daily application, scar appearance improved from 2.875 to 2.38 points on a 5-point investigator global assessment scale. Mean Goodman and Baron acne scar grade fell from 3.00 to 2.75, with 3 representing moderate disease and 2 mild disease. Of eight pairs of before and after photographs given to a blinded investigator, posttreatment images were correctly identified in five. Two were assessed as 76%-100% improved, and three were assessed as 50%-75% improved (J Drugs Dermatol. 2015;14[9]:1005-1010).

The patients were an average of 38 years old, split about equally between the sexes, and racially diverse. They used a basic facial cleanser during the study, but were banned from using tretinoin and other topicals.

Previously studied topicals don’t do much for acne scars, so the usual go-to treatments are chemical peels, dermabrasion, resurfacing lasers, and percutaneous collagen needling. They all work in part by promoting collagen synthesis, but at the cost of pain and side effects. Epidermal growth factor (EGF) also promotes collagen synthesis, so the investigators thought it might help. The EGF used in the study – DNA Regeneration Serum, derived from barley – was supplied by its maker, DNA EGF Renewal in Los Angeles.

“The findings suggest EGF serum has the potential to be a modern, noninvasive treatment for an otherwise highly refractory condition. Whereas resurfacing procedures rely on skin injury to trigger [EGF] release, direct topical application offers the effects of EGF without the associated discomfort and recovery time,” said Dr. Ronald L. Moy of the University of Southern California, Los Angeles, and Rachel Seidel, a medical student at Georgetown University in Washington, D.C.

“All subjects in this study [also] noted improvements in skin texture, fine lines, and wrinkles, while the vast majority also saw a reduction in brown and age spots,” they said.

The investigators said they are interested next in seeing if topical EGF prevents scars in active acne. “We believe that, by counteracting collagen degradation during the course of the inflammatory response, significant tissue atrophy capable of causing visible scarring may be prevented,” they said.

Dr. Moy owns stock in DNA EGF Renewal and is the company’s scientific adviser.

[email protected]

Topical synthetic epidermal growth factor serum moderately improved the appearance of atrophic acne scars in a small pilot study.

At the end of 12 weeks of twice-daily application, scar appearance improved from 2.875 to 2.38 points on a 5-point investigator global assessment scale. Mean Goodman and Baron acne scar grade fell from 3.00 to 2.75, with 3 representing moderate disease and 2 mild disease. Of eight pairs of before and after photographs given to a blinded investigator, posttreatment images were correctly identified in five. Two were assessed as 76%-100% improved, and three were assessed as 50%-75% improved (J Drugs Dermatol. 2015;14[9]:1005-1010).

The patients were an average of 38 years old, split about equally between the sexes, and racially diverse. They used a basic facial cleanser during the study, but were banned from using tretinoin and other topicals.

Previously studied topicals don’t do much for acne scars, so the usual go-to treatments are chemical peels, dermabrasion, resurfacing lasers, and percutaneous collagen needling. They all work in part by promoting collagen synthesis, but at the cost of pain and side effects. Epidermal growth factor (EGF) also promotes collagen synthesis, so the investigators thought it might help. The EGF used in the study – DNA Regeneration Serum, derived from barley – was supplied by its maker, DNA EGF Renewal in Los Angeles.

“The findings suggest EGF serum has the potential to be a modern, noninvasive treatment for an otherwise highly refractory condition. Whereas resurfacing procedures rely on skin injury to trigger [EGF] release, direct topical application offers the effects of EGF without the associated discomfort and recovery time,” said Dr. Ronald L. Moy of the University of Southern California, Los Angeles, and Rachel Seidel, a medical student at Georgetown University in Washington, D.C.

“All subjects in this study [also] noted improvements in skin texture, fine lines, and wrinkles, while the vast majority also saw a reduction in brown and age spots,” they said.

The investigators said they are interested next in seeing if topical EGF prevents scars in active acne. “We believe that, by counteracting collagen degradation during the course of the inflammatory response, significant tissue atrophy capable of causing visible scarring may be prevented,” they said.

Dr. Moy owns stock in DNA EGF Renewal and is the company’s scientific adviser.

[email protected]

I walked into my primary care doctor’s office the other day. I’m still young and healthy and a doctor, so making a doctor’s appointment is a rare event. As with most patients, it was symptoms that motivated me. I’m having a common, yet annoying problem: PVCs or premature ventricular contractions. I’ve had them on and off for a while, but now every time I push to my limit when exercising or double my espresso, they come back.

“Do you have them right now?” my doc asked me. “No. Just had them yesterday, though,” I replied. Dr. A is about my age and perhaps in even better shape than I am. He’s certainly smarter than I. Tall and athletic, he doesn’t wear a lab coat but is always immaculately dressed in a button-down shirt and light sweater. He walks from around his standing desk and hands me an iPhone cover. “Why don’t you try this?” Being the director of innovation, I recognized the device: It was a heart monitor. “Just download the app and track your EKG when you get symptoms,” he said.

I turned it over in my hands. It’s flimsier than I remembered from tech conferences. It’s even too small to fit on my iPhone 6+, although it doesn’t technically have to be on the phone to work. When I got home I downloaded the app and uploaded my first tracing. While right next to my phone, I gently touched the two sensors with my fingers. My tracing appeared on the screen. Wow, those are PQRS waves. (Indeed, I was a intern, too, once). The app requires that you submit the first recording for review before you can use it to verify that the tracing is normal.

The next morning, I hit the bike with everything I had, driving my heart rate to more than 170. (150 is working hard, 160 is painful, 170 is unsustainable for me. Sure enough, my PVCs returned later that day. Later that night, they were driving me crazy. I got out of bed and grabbed my phone. There, at 2 a.m., the glow of my iPhone lighting my bedroom, I could see my EKG: 1,2,3, PVC, 1,2,3, PVC. Wow! This is cool.

As the innovation director, most of the devices I review are from the viewpoint of a physician. This was different. I was clearly the patient in this story, and the device was meant to help me.

We talk about how digital medicine empowers our patients, and I suppose this is the idea. I now have access to diagnostic tools that ordinarily only my doctor would have. Yet, even though I clearly had PVCs this time, the app sends me back the same note as the first time I used it: “Normal EKG.” That’s true, technically. However, it’s easy for even a dermatologist to see that this tracing was different from the first.

I knew that quadrigeminy was a common and benign tracing, but if I wasn’t a physician (or hadn’t been trained by a great upper-level resident as an intern), then I might have been too anxious to fall back asleep.

Elizabeth Holmes in a recent Wall Street Journal article advocated for patients to be able to choose their own blood tests (and someday check their own blood, using her device, one presumes). Health care technology conferences abound with devices that promise to put the power of diagnostics in patients’ hands. But, as we all know, getting data is the easy part. It’s interpreting data – that’s why docs get the big bucks.

We also understand that often the best test is no test at all. If we randomly sampled EKGs from a population of everyone, we might find a few interesting tracings, most of which would have no meaningful consequences. Except if you’re a patient and your EKG has a funny blip on your at-home EKG device, or your iPhone dermatology app incorrectly reports a seborrheic keratosis as a possible melanoma. In such cases, these technologies have not empowered the user; rather, they’ve created needless anxiety, none of which existed before. The result is often more work for us physicians who must now spend time explaining why the patient’s finding is not important, and worse, might end up ordering more (real) tests to disconfirm what the at-home home test found.

Later, I brought my iPhone to my follow-up appointment and shared the tracings with my primary care doctor. “Looks like PVCs,” he confirmed, “and it looks normal.” But I already knew that.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

I walked into my primary care doctor’s office the other day. I’m still young and healthy and a doctor, so making a doctor’s appointment is a rare event. As with most patients, it was symptoms that motivated me. I’m having a common, yet annoying problem: PVCs or premature ventricular contractions. I’ve had them on and off for a while, but now every time I push to my limit when exercising or double my espresso, they come back.

“Do you have them right now?” my doc asked me. “No. Just had them yesterday, though,” I replied. Dr. A is about my age and perhaps in even better shape than I am. He’s certainly smarter than I. Tall and athletic, he doesn’t wear a lab coat but is always immaculately dressed in a button-down shirt and light sweater. He walks from around his standing desk and hands me an iPhone cover. “Why don’t you try this?” Being the director of innovation, I recognized the device: It was a heart monitor. “Just download the app and track your EKG when you get symptoms,” he said.

I turned it over in my hands. It’s flimsier than I remembered from tech conferences. It’s even too small to fit on my iPhone 6+, although it doesn’t technically have to be on the phone to work. When I got home I downloaded the app and uploaded my first tracing. While right next to my phone, I gently touched the two sensors with my fingers. My tracing appeared on the screen. Wow, those are PQRS waves. (Indeed, I was a intern, too, once). The app requires that you submit the first recording for review before you can use it to verify that the tracing is normal.

The next morning, I hit the bike with everything I had, driving my heart rate to more than 170. (150 is working hard, 160 is painful, 170 is unsustainable for me. Sure enough, my PVCs returned later that day. Later that night, they were driving me crazy. I got out of bed and grabbed my phone. There, at 2 a.m., the glow of my iPhone lighting my bedroom, I could see my EKG: 1,2,3, PVC, 1,2,3, PVC. Wow! This is cool.

As the innovation director, most of the devices I review are from the viewpoint of a physician. This was different. I was clearly the patient in this story, and the device was meant to help me.

We talk about how digital medicine empowers our patients, and I suppose this is the idea. I now have access to diagnostic tools that ordinarily only my doctor would have. Yet, even though I clearly had PVCs this time, the app sends me back the same note as the first time I used it: “Normal EKG.” That’s true, technically. However, it’s easy for even a dermatologist to see that this tracing was different from the first.

I knew that quadrigeminy was a common and benign tracing, but if I wasn’t a physician (or hadn’t been trained by a great upper-level resident as an intern), then I might have been too anxious to fall back asleep.

Elizabeth Holmes in a recent Wall Street Journal article advocated for patients to be able to choose their own blood tests (and someday check their own blood, using her device, one presumes). Health care technology conferences abound with devices that promise to put the power of diagnostics in patients’ hands. But, as we all know, getting data is the easy part. It’s interpreting data – that’s why docs get the big bucks.

We also understand that often the best test is no test at all. If we randomly sampled EKGs from a population of everyone, we might find a few interesting tracings, most of which would have no meaningful consequences. Except if you’re a patient and your EKG has a funny blip on your at-home EKG device, or your iPhone dermatology app incorrectly reports a seborrheic keratosis as a possible melanoma. In such cases, these technologies have not empowered the user; rather, they’ve created needless anxiety, none of which existed before. The result is often more work for us physicians who must now spend time explaining why the patient’s finding is not important, and worse, might end up ordering more (real) tests to disconfirm what the at-home home test found.

Later, I brought my iPhone to my follow-up appointment and shared the tracings with my primary care doctor. “Looks like PVCs,” he confirmed, “and it looks normal.” But I already knew that.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

I walked into my primary care doctor’s office the other day. I’m still young and healthy and a doctor, so making a doctor’s appointment is a rare event. As with most patients, it was symptoms that motivated me. I’m having a common, yet annoying problem: PVCs or premature ventricular contractions. I’ve had them on and off for a while, but now every time I push to my limit when exercising or double my espresso, they come back.

“Do you have them right now?” my doc asked me. “No. Just had them yesterday, though,” I replied. Dr. A is about my age and perhaps in even better shape than I am. He’s certainly smarter than I. Tall and athletic, he doesn’t wear a lab coat but is always immaculately dressed in a button-down shirt and light sweater. He walks from around his standing desk and hands me an iPhone cover. “Why don’t you try this?” Being the director of innovation, I recognized the device: It was a heart monitor. “Just download the app and track your EKG when you get symptoms,” he said.

I turned it over in my hands. It’s flimsier than I remembered from tech conferences. It’s even too small to fit on my iPhone 6+, although it doesn’t technically have to be on the phone to work. When I got home I downloaded the app and uploaded my first tracing. While right next to my phone, I gently touched the two sensors with my fingers. My tracing appeared on the screen. Wow, those are PQRS waves. (Indeed, I was a intern, too, once). The app requires that you submit the first recording for review before you can use it to verify that the tracing is normal.

The next morning, I hit the bike with everything I had, driving my heart rate to more than 170. (150 is working hard, 160 is painful, 170 is unsustainable for me. Sure enough, my PVCs returned later that day. Later that night, they were driving me crazy. I got out of bed and grabbed my phone. There, at 2 a.m., the glow of my iPhone lighting my bedroom, I could see my EKG: 1,2,3, PVC, 1,2,3, PVC. Wow! This is cool.

As the innovation director, most of the devices I review are from the viewpoint of a physician. This was different. I was clearly the patient in this story, and the device was meant to help me.

We talk about how digital medicine empowers our patients, and I suppose this is the idea. I now have access to diagnostic tools that ordinarily only my doctor would have. Yet, even though I clearly had PVCs this time, the app sends me back the same note as the first time I used it: “Normal EKG.” That’s true, technically. However, it’s easy for even a dermatologist to see that this tracing was different from the first.

I knew that quadrigeminy was a common and benign tracing, but if I wasn’t a physician (or hadn’t been trained by a great upper-level resident as an intern), then I might have been too anxious to fall back asleep.

Elizabeth Holmes in a recent Wall Street Journal article advocated for patients to be able to choose their own blood tests (and someday check their own blood, using her device, one presumes). Health care technology conferences abound with devices that promise to put the power of diagnostics in patients’ hands. But, as we all know, getting data is the easy part. It’s interpreting data – that’s why docs get the big bucks.

We also understand that often the best test is no test at all. If we randomly sampled EKGs from a population of everyone, we might find a few interesting tracings, most of which would have no meaningful consequences. Except if you’re a patient and your EKG has a funny blip on your at-home EKG device, or your iPhone dermatology app incorrectly reports a seborrheic keratosis as a possible melanoma. In such cases, these technologies have not empowered the user; rather, they’ve created needless anxiety, none of which existed before. The result is often more work for us physicians who must now spend time explaining why the patient’s finding is not important, and worse, might end up ordering more (real) tests to disconfirm what the at-home home test found.

Later, I brought my iPhone to my follow-up appointment and shared the tracings with my primary care doctor. “Looks like PVCs,” he confirmed, “and it looks normal.” But I already knew that.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

T cells

Image courtesy of NIAID

New research has revealed a population of T cells associated with relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT).

Patients experienced an increase in this cell population before their relapse was diagnosed clinically.

The cells also appear to be markers of T-cell exhaustion, which suggests therapies targeting T-cell exhaustion might be able to treat or prevent AML relapse after

allo-SCT.

Hong Zheng, MD, PhD, of Penn State University College of Medicine in Hershey, Pennsylvania, and her colleagues conducted this research and reported the results in Blood Cancer Journal.

The investigators noted that T cells are major players in the graft-vs-leukemia effect, but persistent antigen stimulation can lead to T-cell exhaustion.

To determine whether T-cell exhaustion is involved in relapse after allo-SCT, the team performed phenotypic and functional studies on T cells from the peripheral blood of AML transplant recipients.

Dr Zheng and her colleagues discovered that patients who relapsed after allo-SCT had significantly elevated levels of PD-1^hiTIM-3⁺ T cells.

These T cells produced fewer cytokines—interleukin 2, tumor necrosis factor-α, and interferon-γ—than normal T cells, which is a sign of T-cell exhaustion.

In addition, while other T cells mostly consisted of all 4 T-cell subsets, PD-1^hiTIM-3⁺ T cells had no naive T cells (CCR7⁺CD45RA⁺) and significantly decreased levels of terminally differentiated effector T cells (CCR7^-CD45RA⁺).

The investigators said this suggests PD-1^hiTIM-3⁺ cells are phenotypically antigen-experienced T cells that have lost functional subsets, which is consistent with a state of T-cell exhaustion.

The team believes their findings could pave the way for new treatments for AML patients undergoing allo-SCT.

The PD-1 inhibitor nivolumab has been shown to block T-cell exhaustion in patients with solid tumors. So Dr Zheng is planning a clinical trial to see if such treatment could work for AML patients as well.

She also believes that PD-1^hiTIM-3⁺ T cells could be used to diagnose relapses earlier than is currently possible.

“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Dr Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”

Dr Zheng is currently investigating the trigger for T-cell exhaustion in transplant recipients with AML.

“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”

T cells

Image courtesy of NIAID

New research has revealed a population of T cells associated with relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT).

Patients experienced an increase in this cell population before their relapse was diagnosed clinically.

The cells also appear to be markers of T-cell exhaustion, which suggests therapies targeting T-cell exhaustion might be able to treat or prevent AML relapse after

allo-SCT.

Hong Zheng, MD, PhD, of Penn State University College of Medicine in Hershey, Pennsylvania, and her colleagues conducted this research and reported the results in Blood Cancer Journal.

The investigators noted that T cells are major players in the graft-vs-leukemia effect, but persistent antigen stimulation can lead to T-cell exhaustion.

To determine whether T-cell exhaustion is involved in relapse after allo-SCT, the team performed phenotypic and functional studies on T cells from the peripheral blood of AML transplant recipients.

Dr Zheng and her colleagues discovered that patients who relapsed after allo-SCT had significantly elevated levels of PD-1^hiTIM-3⁺ T cells.

These T cells produced fewer cytokines—interleukin 2, tumor necrosis factor-α, and interferon-γ—than normal T cells, which is a sign of T-cell exhaustion.

In addition, while other T cells mostly consisted of all 4 T-cell subsets, PD-1^hiTIM-3⁺ T cells had no naive T cells (CCR7⁺CD45RA⁺) and significantly decreased levels of terminally differentiated effector T cells (CCR7^-CD45RA⁺).

The investigators said this suggests PD-1^hiTIM-3⁺ cells are phenotypically antigen-experienced T cells that have lost functional subsets, which is consistent with a state of T-cell exhaustion.

The team believes their findings could pave the way for new treatments for AML patients undergoing allo-SCT.

The PD-1 inhibitor nivolumab has been shown to block T-cell exhaustion in patients with solid tumors. So Dr Zheng is planning a clinical trial to see if such treatment could work for AML patients as well.

She also believes that PD-1^hiTIM-3⁺ T cells could be used to diagnose relapses earlier than is currently possible.

“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Dr Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”

Dr Zheng is currently investigating the trigger for T-cell exhaustion in transplant recipients with AML.

“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”

T cells

Image courtesy of NIAID

New research has revealed a population of T cells associated with relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT).

Patients experienced an increase in this cell population before their relapse was diagnosed clinically.

The cells also appear to be markers of T-cell exhaustion, which suggests therapies targeting T-cell exhaustion might be able to treat or prevent AML relapse after

allo-SCT.

Hong Zheng, MD, PhD, of Penn State University College of Medicine in Hershey, Pennsylvania, and her colleagues conducted this research and reported the results in Blood Cancer Journal.

The investigators noted that T cells are major players in the graft-vs-leukemia effect, but persistent antigen stimulation can lead to T-cell exhaustion.

To determine whether T-cell exhaustion is involved in relapse after allo-SCT, the team performed phenotypic and functional studies on T cells from the peripheral blood of AML transplant recipients.

Dr Zheng and her colleagues discovered that patients who relapsed after allo-SCT had significantly elevated levels of PD-1^hiTIM-3⁺ T cells.

These T cells produced fewer cytokines—interleukin 2, tumor necrosis factor-α, and interferon-γ—than normal T cells, which is a sign of T-cell exhaustion.

In addition, while other T cells mostly consisted of all 4 T-cell subsets, PD-1^hiTIM-3⁺ T cells had no naive T cells (CCR7⁺CD45RA⁺) and significantly decreased levels of terminally differentiated effector T cells (CCR7^-CD45RA⁺).

The investigators said this suggests PD-1^hiTIM-3⁺ cells are phenotypically antigen-experienced T cells that have lost functional subsets, which is consistent with a state of T-cell exhaustion.

The team believes their findings could pave the way for new treatments for AML patients undergoing allo-SCT.

The PD-1 inhibitor nivolumab has been shown to block T-cell exhaustion in patients with solid tumors. So Dr Zheng is planning a clinical trial to see if such treatment could work for AML patients as well.

She also believes that PD-1^hiTIM-3⁺ T cells could be used to diagnose relapses earlier than is currently possible.

“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Dr Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”

Dr Zheng is currently investigating the trigger for T-cell exhaustion in transplant recipients with AML.

“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have designed an online tool that can predict the role of proteins and genes involved in immunological diseases and processes.

The tool uses information compiled from 38,088 public experiments to predict new immune pathway interactions, mechanisms, and disease-associated genes.

Details on this publicly available tool, known as ImmuNet, were recently published in Immunity.

“This new tool unlocks the insight contained in big data, the world’s biomedical research output, to help understand immunological mechanisms and diseases,” said Stuart Sealfon, MD, of Mount Sinai Health System in New York, New York.

“The goal of ImmuNet is to accelerate the understanding of immune pathways and genes, ultimately leading to the development of improved treatment for diseases with an immunological component.”

ImmuNet enables immunology researchers without special computational training to use the statistical techniques of Bayesian data integration and machine learning algorithms to “interrogate” this compendium of public data.

“We expect the applicability of ImmuNet to wide-ranging areas of immunology will grow with the incorporation of continually increasing public big data,” said Olga Troyanskaya, PhD, of Princeton University in New Jersey.

“By enabling immune researchers from diverse backgrounds to leverage these valuable and heterogeneous data collections, ImmuNet has the potential to accelerate discovery in immunology.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have designed an online tool that can predict the role of proteins and genes involved in immunological diseases and processes.

The tool uses information compiled from 38,088 public experiments to predict new immune pathway interactions, mechanisms, and disease-associated genes.

Details on this publicly available tool, known as ImmuNet, were recently published in Immunity.

“This new tool unlocks the insight contained in big data, the world’s biomedical research output, to help understand immunological mechanisms and diseases,” said Stuart Sealfon, MD, of Mount Sinai Health System in New York, New York.

“The goal of ImmuNet is to accelerate the understanding of immune pathways and genes, ultimately leading to the development of improved treatment for diseases with an immunological component.”

ImmuNet enables immunology researchers without special computational training to use the statistical techniques of Bayesian data integration and machine learning algorithms to “interrogate” this compendium of public data.

“We expect the applicability of ImmuNet to wide-ranging areas of immunology will grow with the incorporation of continually increasing public big data,” said Olga Troyanskaya, PhD, of Princeton University in New Jersey.

“By enabling immune researchers from diverse backgrounds to leverage these valuable and heterogeneous data collections, ImmuNet has the potential to accelerate discovery in immunology.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have designed an online tool that can predict the role of proteins and genes involved in immunological diseases and processes.

The tool uses information compiled from 38,088 public experiments to predict new immune pathway interactions, mechanisms, and disease-associated genes.

Details on this publicly available tool, known as ImmuNet, were recently published in Immunity.

“This new tool unlocks the insight contained in big data, the world’s biomedical research output, to help understand immunological mechanisms and diseases,” said Stuart Sealfon, MD, of Mount Sinai Health System in New York, New York.

“The goal of ImmuNet is to accelerate the understanding of immune pathways and genes, ultimately leading to the development of improved treatment for diseases with an immunological component.”

ImmuNet enables immunology researchers without special computational training to use the statistical techniques of Bayesian data integration and machine learning algorithms to “interrogate” this compendium of public data.

“We expect the applicability of ImmuNet to wide-ranging areas of immunology will grow with the incorporation of continually increasing public big data,” said Olga Troyanskaya, PhD, of Princeton University in New Jersey.

“By enabling immune researchers from diverse backgrounds to leverage these valuable and heterogeneous data collections, ImmuNet has the potential to accelerate discovery in immunology.”

AML cells

Image by Lance Liotta

The investigational therapy SL-401 has received orphan designation to treat acute myeloid leukemia (AML) in the European Union (EU).

SL-401 targets the interleukin-3 receptor (IL-3R). It is comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 is under development to treat a range of hematologic malignancies, as IL-3R is overexpressed on cancer stem cells in multiple hematologic malignancies.

SL-401 has orphan designation from the US Food and Drug Administration (FDA) for the treatment of AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR.  Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

1. BPDCN and relapsed/refractory AML
2. AML patients in first complete remission with minimal residual disease
3. Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the EU benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

AML cells

Image by Lance Liotta

The investigational therapy SL-401 has received orphan designation to treat acute myeloid leukemia (AML) in the European Union (EU).

SL-401 targets the interleukin-3 receptor (IL-3R). It is comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 is under development to treat a range of hematologic malignancies, as IL-3R is overexpressed on cancer stem cells in multiple hematologic malignancies.

SL-401 has orphan designation from the US Food and Drug Administration (FDA) for the treatment of AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR.  Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

1. BPDCN and relapsed/refractory AML
2. AML patients in first complete remission with minimal residual disease
3. Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the EU benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

AML cells

Image by Lance Liotta

The investigational therapy SL-401 has received orphan designation to treat acute myeloid leukemia (AML) in the European Union (EU).

SL-401 targets the interleukin-3 receptor (IL-3R). It is comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 is under development to treat a range of hematologic malignancies, as IL-3R is overexpressed on cancer stem cells in multiple hematologic malignancies.

SL-401 has orphan designation from the US Food and Drug Administration (FDA) for the treatment of AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR.  Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

1. BPDCN and relapsed/refractory AML
2. AML patients in first complete remission with minimal residual disease
3. Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the EU benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Learning about death and dying in residency is perhaps one of the hardest things about being a doctor. ... This list might make it a tiny bit easier.

1. The Hippocratic oath challenges us to be teachers not only to students, but also to our patients – especially to our dying patients. Remember you are teachers.

2. Nurses spend the most time with your patients; utilize them and learn from them. Nurses will make you better teachers and physicians.

3. When a patient is dying, hold that person’s hand if family isn’t around. Touch your patient.

4. Accompany your residents, fellows, or attending physicians to deliver bad news.

5. Ask to debrief after a patient dies.

6. While discussing treatment or prognosis with families, pay attention to the emotional data in the room. Tears should prompt tissues or hand holding. A wrinkled forehead or fearful face warrants a pause in conversation for the family to absorb the content. Tears don’t mean to hurry.

7. Attempt to understand your patient’s expectations. In other words, learn what the family’s goals are for treatment.

8. When a patient dies, reflect upon it in moderation. Don’t just move on to the next task. It’s okay to feel and to grieve … you are human.

9. When families declare DNR [do not resuscitate], don’t ask them repeatedly if they are sure. Also, make certain that they know they can change their minds at any time. Respect a patient’s values and wishes.

10. Take the time to have the difficult conversations early in diagnosis so families know what to expect. This empowers decisions that are proactive as opposed to reactive. Be proactive in your role as a teacher.

11. When discussing options, talk about what you CAN do before you talk about what you CAN’T do.

12. Withdrawing treatment and forgoing treatment are the same thing ethically and legally, but not emotionally.

13. When your patient is actively dying, see it out. Stay with the family, even if it’s time to go home.

14. When the family prays, be present.

15. Palliative care is neither hospice nor social work.

16. Ask your dying patients if they are afraid of anything – if the moment presents itself. Answer questions about death or find someone who can answer their questions.

17. No patient should die in pain. The doctrine of double effect allows a caregiver to provide medication for pain even though it may hasten death.

18. For the dying child, ask the family where they want their child to die. Don’t assume the family wants the death of their child to be at home or in the hospital. Ask.

19. Transitioning from treatment-oriented management to comfort care does not ever mean “there is nothing we can do.”

20. Lastly, and most importantly, I leave you with a question that should be in the back of our minds regarding quality of life and treatment options: Just because we can, should we?

Dr. Morvant is a second-year pediatric resident at Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn. E-mail her at [email protected].

Learning about death and dying in residency is perhaps one of the hardest things about being a doctor. ... This list might make it a tiny bit easier.

1. The Hippocratic oath challenges us to be teachers not only to students, but also to our patients – especially to our dying patients. Remember you are teachers.

2. Nurses spend the most time with your patients; utilize them and learn from them. Nurses will make you better teachers and physicians.

3. When a patient is dying, hold that person’s hand if family isn’t around. Touch your patient.

4. Accompany your residents, fellows, or attending physicians to deliver bad news.

5. Ask to debrief after a patient dies.

6. While discussing treatment or prognosis with families, pay attention to the emotional data in the room. Tears should prompt tissues or hand holding. A wrinkled forehead or fearful face warrants a pause in conversation for the family to absorb the content. Tears don’t mean to hurry.

7. Attempt to understand your patient’s expectations. In other words, learn what the family’s goals are for treatment.

8. When a patient dies, reflect upon it in moderation. Don’t just move on to the next task. It’s okay to feel and to grieve … you are human.

9. When families declare DNR [do not resuscitate], don’t ask them repeatedly if they are sure. Also, make certain that they know they can change their minds at any time. Respect a patient’s values and wishes.

10. Take the time to have the difficult conversations early in diagnosis so families know what to expect. This empowers decisions that are proactive as opposed to reactive. Be proactive in your role as a teacher.

11. When discussing options, talk about what you CAN do before you talk about what you CAN’T do.

12. Withdrawing treatment and forgoing treatment are the same thing ethically and legally, but not emotionally.

13. When your patient is actively dying, see it out. Stay with the family, even if it’s time to go home.

14. When the family prays, be present.

15. Palliative care is neither hospice nor social work.

16. Ask your dying patients if they are afraid of anything – if the moment presents itself. Answer questions about death or find someone who can answer their questions.

17. No patient should die in pain. The doctrine of double effect allows a caregiver to provide medication for pain even though it may hasten death.

18. For the dying child, ask the family where they want their child to die. Don’t assume the family wants the death of their child to be at home or in the hospital. Ask.

19. Transitioning from treatment-oriented management to comfort care does not ever mean “there is nothing we can do.”

20. Lastly, and most importantly, I leave you with a question that should be in the back of our minds regarding quality of life and treatment options: Just because we can, should we?

Dr. Morvant is a second-year pediatric resident at Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn. E-mail her at [email protected].

Learning about death and dying in residency is perhaps one of the hardest things about being a doctor. ... This list might make it a tiny bit easier.

1. The Hippocratic oath challenges us to be teachers not only to students, but also to our patients – especially to our dying patients. Remember you are teachers.

2. Nurses spend the most time with your patients; utilize them and learn from them. Nurses will make you better teachers and physicians.

3. When a patient is dying, hold that person’s hand if family isn’t around. Touch your patient.

4. Accompany your residents, fellows, or attending physicians to deliver bad news.

5. Ask to debrief after a patient dies.

6. While discussing treatment or prognosis with families, pay attention to the emotional data in the room. Tears should prompt tissues or hand holding. A wrinkled forehead or fearful face warrants a pause in conversation for the family to absorb the content. Tears don’t mean to hurry.

7. Attempt to understand your patient’s expectations. In other words, learn what the family’s goals are for treatment.

8. When a patient dies, reflect upon it in moderation. Don’t just move on to the next task. It’s okay to feel and to grieve … you are human.

9. When families declare DNR [do not resuscitate], don’t ask them repeatedly if they are sure. Also, make certain that they know they can change their minds at any time. Respect a patient’s values and wishes.

10. Take the time to have the difficult conversations early in diagnosis so families know what to expect. This empowers decisions that are proactive as opposed to reactive. Be proactive in your role as a teacher.

11. When discussing options, talk about what you CAN do before you talk about what you CAN’T do.

12. Withdrawing treatment and forgoing treatment are the same thing ethically and legally, but not emotionally.

13. When your patient is actively dying, see it out. Stay with the family, even if it’s time to go home.

14. When the family prays, be present.

15. Palliative care is neither hospice nor social work.

16. Ask your dying patients if they are afraid of anything – if the moment presents itself. Answer questions about death or find someone who can answer their questions.

17. No patient should die in pain. The doctrine of double effect allows a caregiver to provide medication for pain even though it may hasten death.

18. For the dying child, ask the family where they want their child to die. Don’t assume the family wants the death of their child to be at home or in the hospital. Ask.

19. Transitioning from treatment-oriented management to comfort care does not ever mean “there is nothing we can do.”

20. Lastly, and most importantly, I leave you with a question that should be in the back of our minds regarding quality of life and treatment options: Just because we can, should we?

Dr. Morvant is a second-year pediatric resident at Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn. E-mail her at [email protected].

The Food and Drug Administration has issued a new warning and precaution for the type 2 diabetes drug canagliflozin, saying that risks of decreased bone density associated with the drug are more serious than previously stated.

Canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, will now have a revised adverse reactions section on its drug label. Taking canagliflozin can significantly increase an individual’s chances of incurring bone fractures, due to the decreased bone mineral density caused by the drug. According to the FDA, these fractures can start to appear 12 weeks after starting a canagliflozin regimen, and can lead to bone mineral density loss in the hip and lower spine.

“FDA is continuing to evaluate the risk of bone fractures with other drugs in the SGLT2 inhibitor class, including dapagliflozin (Farxiga, Xigduo XR) and empagliflozin (Jardiance, Glyxambi, Synjardy), to determine if additional label changes or studies are needed,” the FDA stated, adding that all health care providers and patients are urged to contact the FDA if they experience adverse effects while taking any of these drugs.

Canagliflozin is marketed as Invokana and Invokamet by Janssen Pharmaceuticals, and was approved by the FDA in March 2013. The FDA is advising all health care professionals to carefully assess patients’ risk for developing bone fractures before prescribing the drug. Individuals who experience side effects while taking canagliflozin should submit a report through the FDA’s MedWatch program, or contact 1-800-332-1088 for more information.

[email protected]

The Food and Drug Administration has issued a new warning and precaution for the type 2 diabetes drug canagliflozin, saying that risks of decreased bone density associated with the drug are more serious than previously stated.

Canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, will now have a revised adverse reactions section on its drug label. Taking canagliflozin can significantly increase an individual’s chances of incurring bone fractures, due to the decreased bone mineral density caused by the drug. According to the FDA, these fractures can start to appear 12 weeks after starting a canagliflozin regimen, and can lead to bone mineral density loss in the hip and lower spine.

“FDA is continuing to evaluate the risk of bone fractures with other drugs in the SGLT2 inhibitor class, including dapagliflozin (Farxiga, Xigduo XR) and empagliflozin (Jardiance, Glyxambi, Synjardy), to determine if additional label changes or studies are needed,” the FDA stated, adding that all health care providers and patients are urged to contact the FDA if they experience adverse effects while taking any of these drugs.

Canagliflozin is marketed as Invokana and Invokamet by Janssen Pharmaceuticals, and was approved by the FDA in March 2013. The FDA is advising all health care professionals to carefully assess patients’ risk for developing bone fractures before prescribing the drug. Individuals who experience side effects while taking canagliflozin should submit a report through the FDA’s MedWatch program, or contact 1-800-332-1088 for more information.

[email protected]

The Food and Drug Administration has issued a new warning and precaution for the type 2 diabetes drug canagliflozin, saying that risks of decreased bone density associated with the drug are more serious than previously stated.

Canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, will now have a revised adverse reactions section on its drug label. Taking canagliflozin can significantly increase an individual’s chances of incurring bone fractures, due to the decreased bone mineral density caused by the drug. According to the FDA, these fractures can start to appear 12 weeks after starting a canagliflozin regimen, and can lead to bone mineral density loss in the hip and lower spine.

“FDA is continuing to evaluate the risk of bone fractures with other drugs in the SGLT2 inhibitor class, including dapagliflozin (Farxiga, Xigduo XR) and empagliflozin (Jardiance, Glyxambi, Synjardy), to determine if additional label changes or studies are needed,” the FDA stated, adding that all health care providers and patients are urged to contact the FDA if they experience adverse effects while taking any of these drugs.

Canagliflozin is marketed as Invokana and Invokamet by Janssen Pharmaceuticals, and was approved by the FDA in March 2013. The FDA is advising all health care professionals to carefully assess patients’ risk for developing bone fractures before prescribing the drug. Individuals who experience side effects while taking canagliflozin should submit a report through the FDA’s MedWatch program, or contact 1-800-332-1088 for more information.

[email protected]

A powerful endogenous antioxidant found most abundantly in mammalian tissues, especially brain and skeletal muscle tissue, carnosine is a dipeptide of alanine and histidine.^1,2,3,4,5.

Carnosine was first isolated in 1900 by the Russian scientist Gulewitsch as a substance extracted from muscle tissue.^6,4. L-carnosine (beta-alanyl-L-histidine) is the synthetic version identical to the natural form alpha-alanyl-L-histidine.⁷ Carnosine has long been reputed to confer immunomodulating, wound healing, antiglycating, and antineoplastic effects.² Several reports have shown that carnosine can accelerate the healing of surface skin wounds and burns.^4,8

Wound healing

An early study by Nagai et al. in 1986 on carnosine in wound healing showed that rats treated locally with carnosine exhibited greater tensile skin strength at an incision site after hydrocortisone had been administered to hinder healing. The investigators concluded that carnosine bolsters wound healing by stimulating early effusion by histamine and of collagen biosynthesis by beta-alanine. They also found that the compound significantly augmented granulation inhibited by cortisone, mitomycin C, 5-fluorouracil, and bleomycin.⁹

Studies by Fitzpatrick and Fisher in the early 1980s revealed that carnosine acts as a histidine reserve in relation to histamine production during trauma, suggesting a role for carnosine in wound healing.^10,11

In 2012, Ansurudeen et al. examined the effects of carnosine in wound healing in a diabetic mouse model. Carnosine was applied locally and injected daily, yielding significant amelioration in wound healing, with analysis revealing elevated expression of growth factors and cytokines implicated in wound healing. The investigators also observed that carnosine supported cell viability in the presence of high glucose in human dermal fibroblasts and microvascular endothelial cells in vitro.²

Other findings with implications for cutaneous therapy

In 2006, Babizhayev reported that the L-carnosine-related peptidomimetic N-acetylcarnosine (N-acetyl-beta-alanyl-L-histidine) can act as a timed-release (carrier) stable version of L-carnosine in cosmetic preparations, including lubricants.⁶ Babizhayev et al. have since claimed that they have developed a technology using imidazole-containing dipeptide-based compounds (including L-carnosine and derivatives) that enhances protein hydration in photoaged skin.^12,13,14

A double-blind comparative study conducted by Dieamant et al. in 2008 in 124 volunteers with sensitive skin aimed to evaluate the therapeutic potential of the combination of the antioxidant L-carnosine and neuromodulatory Rhodiola rosea. For 28 days, the groups of 62 received twice-daily applications of the 1% combination formulation or placebo. Skin barrier function (reduction of transepidermal water loss) improved in the treatment group, and favorable subjective responses regarding skin dryness were reported. Discomfort after the stinging test was also reduced. In vitro results showed that the release of proopiomelanocortin peptides was spurred by treatment, with the elevated levels of neuropeptides and cytokines produced by keratinocytes exposed to UV radiation returning to normal.¹⁵

Two years later, Renner et al. showed that carnosine hindered tumor growth in vivo in an NIH3T3-HER2/neu mouse model. They contended that this naturally occurring dipeptide warrants increased consideration and study for its potential as an anticancer agent.¹⁶

In 2012, Federici et al. conducted a randomized, evaluator-blinded, controlled comparative trial over 1month to assess the efficacy of twice-daily topical urea 5% with arginine and carnosine (Ureadin Rx) as compared with twice-daily application of a glycerol-based emollient topical product (Dexeryl) in treating xerosis in 40 type 2 diabetes patients (40-75 years of age). Use of the carnosine-containing formulation yielded significantly greater hydration and an 89% decline in Dryness Areas Severity Index (DASI) scores, compared with baseline. The DASI score after 4 weeks of treatment was much lower in the treatment group than the control group. The Visual Analog Scale (VAS) score was also significantly higher in the Ureadin group than the Dexeryl group. The investigators concluded that the topical application of a urea 5%, arginine, and carnosine cream enhances skin hydration and relieves dryness in type 2 diabetic patients in comparison with a control glycerol-based emollient formulation.¹⁷

Antiaging potential

In 1993, Reeve et al. showed that dietary or topically applied carnosine potentiated the contact hypersensitivity reaction in hairless mice and prevented the systemic inhibition of this reaction after dorsal skin exposure to UVB. Carnosine was found to also prevent the systemic suppression provoked by the topical application of a lotion containing cis-urocanic acid.³

Carnosine was a key active ingredient in antiaging products evaluated by Kaczvinsky et al. in 2009 in two double-blind, randomized, controlled, split-face studies. The researchers used the Fast Optical in vivo Topometry of Human Skin (FOITS) technique to measure changes in periorbital wrinkles in the two studies in women between the ages of 30 and 70 years old (study 1, n = 42; study 2, n = 35). They reported that 4 weeks of treatment with the test products, which contained niacinamide, the peptides Pal-KT and Pal-KTTKS, and carnosine, ameliorated periorbital skin, enhancing smoothness and diminishing larger wrinkle depth.¹⁸

In 2012, Babizhayev et al. conducted a 4-month randomized, double-blind, controlled study with 42 subjects to evaluate the effects on skin aging of oral nonhydrolyzed carnosine (Can-C Plus formulation). Skin parameters exhibited a consistent and significant improvement during 3 months of supplementation in the treatment group, compared with the placebo group, with overall skin appearance enhanced and fine lines diminished based on visual inspection. There were no reports of adverse effects. The investigators concluded that supplementation with nonhydrolyzed carnosine or carcinine in patented oral formulations has potential as an agent for antiaging purposes.¹⁹

Two years later, Emanuele et al. conducted an experimental double-blind irradiation study to compare a complex novel topical product (TPF50) consisting of three active ingredients (traditional physical sunscreens, SPF 50; a liposome-encapsulated DNA repair enzymes complex – photolyase, endonuclease, and 8-oxoguanine glycosylase [OGG1]; and a robust antioxidant complex containing carnosine, arazine, and ergothionine) to available DNA repair and antioxidant and growth factor topical products. They found that the new topical agent was the most effective product in reducing three molecular markers (cyclobutane pyrimidine dimers, protein carbonylation, and 8-oxo-7,8-dihydro-2’-deoxyguanosine) in human skin biopsies. The researchers concluded that the carnosine-containing formulation enhances the genomic and proteomic integrity of skin cells after continual UV exposure, suggesting its potential efficacy in lowering the risk of UV-induced cutaneous aging and nonmelanoma skin cancer.²⁰

Conclusion

Carnosine is an intriguing compound with well-documented antioxidant and wound healing activity. While more research is necessary to determine its wider applications in dermatology, recent work in formulating topical products to impart antiaging effects appears to show promise.

References

1. Nutr. Res. Pract. 2011;5:421-8.

2. Amino Acids 2012;43:127-34.

3. Immunology 1993;78:99-104.

4. Mol. Aspects Med. 1992;13:379-444.

5. Am. J. Ther. 2012;19:e69-89.

6. Life Sci. 2006;78:2343-57.

7. J. Cosmet. Dermatol. 2004;3:26-34.

8. Nihon Yakurigaku Zasshi. 1992;100:165-72.

9. Surgery 1986;100:815-21.

10. Surgery 1982;91:430-4.

11. Surgery 1982;91:56-60.

12. Int. J. Cosmet. Sci. 2011;33:1-16.

13. Crit. Rev. Ther. Drug Carrier Syst. 2011;28:203-53.

14. Crit. Rev. Ther. Drug Carrier Syst. 2010;27:85-154.

15. J. Cosmet. Dermatol. 2008;7:112-9.

16. Mol. Cancer 2010;9:2.

17. BMC Dermatol. 2012;12:16.

18. J. Cosmet. Dermatol. 2009;8:228-33.

19. J. Dermatolog. Treat. 2012;23:345-84.

20. J. Drugs Dermatol. 2014;13:309-14.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

A powerful endogenous antioxidant found most abundantly in mammalian tissues, especially brain and skeletal muscle tissue, carnosine is a dipeptide of alanine and histidine.^1,2,3,4,5.

Carnosine was first isolated in 1900 by the Russian scientist Gulewitsch as a substance extracted from muscle tissue.^6,4. L-carnosine (beta-alanyl-L-histidine) is the synthetic version identical to the natural form alpha-alanyl-L-histidine.⁷ Carnosine has long been reputed to confer immunomodulating, wound healing, antiglycating, and antineoplastic effects.² Several reports have shown that carnosine can accelerate the healing of surface skin wounds and burns.^4,8

Wound healing

An early study by Nagai et al. in 1986 on carnosine in wound healing showed that rats treated locally with carnosine exhibited greater tensile skin strength at an incision site after hydrocortisone had been administered to hinder healing. The investigators concluded that carnosine bolsters wound healing by stimulating early effusion by histamine and of collagen biosynthesis by beta-alanine. They also found that the compound significantly augmented granulation inhibited by cortisone, mitomycin C, 5-fluorouracil, and bleomycin.⁹

Studies by Fitzpatrick and Fisher in the early 1980s revealed that carnosine acts as a histidine reserve in relation to histamine production during trauma, suggesting a role for carnosine in wound healing.^10,11

In 2012, Ansurudeen et al. examined the effects of carnosine in wound healing in a diabetic mouse model. Carnosine was applied locally and injected daily, yielding significant amelioration in wound healing, with analysis revealing elevated expression of growth factors and cytokines implicated in wound healing. The investigators also observed that carnosine supported cell viability in the presence of high glucose in human dermal fibroblasts and microvascular endothelial cells in vitro.²

Other findings with implications for cutaneous therapy

In 2006, Babizhayev reported that the L-carnosine-related peptidomimetic N-acetylcarnosine (N-acetyl-beta-alanyl-L-histidine) can act as a timed-release (carrier) stable version of L-carnosine in cosmetic preparations, including lubricants.⁶ Babizhayev et al. have since claimed that they have developed a technology using imidazole-containing dipeptide-based compounds (including L-carnosine and derivatives) that enhances protein hydration in photoaged skin.^12,13,14

A double-blind comparative study conducted by Dieamant et al. in 2008 in 124 volunteers with sensitive skin aimed to evaluate the therapeutic potential of the combination of the antioxidant L-carnosine and neuromodulatory Rhodiola rosea. For 28 days, the groups of 62 received twice-daily applications of the 1% combination formulation or placebo. Skin barrier function (reduction of transepidermal water loss) improved in the treatment group, and favorable subjective responses regarding skin dryness were reported. Discomfort after the stinging test was also reduced. In vitro results showed that the release of proopiomelanocortin peptides was spurred by treatment, with the elevated levels of neuropeptides and cytokines produced by keratinocytes exposed to UV radiation returning to normal.¹⁵

Two years later, Renner et al. showed that carnosine hindered tumor growth in vivo in an NIH3T3-HER2/neu mouse model. They contended that this naturally occurring dipeptide warrants increased consideration and study for its potential as an anticancer agent.¹⁶

In 2012, Federici et al. conducted a randomized, evaluator-blinded, controlled comparative trial over 1month to assess the efficacy of twice-daily topical urea 5% with arginine and carnosine (Ureadin Rx) as compared with twice-daily application of a glycerol-based emollient topical product (Dexeryl) in treating xerosis in 40 type 2 diabetes patients (40-75 years of age). Use of the carnosine-containing formulation yielded significantly greater hydration and an 89% decline in Dryness Areas Severity Index (DASI) scores, compared with baseline. The DASI score after 4 weeks of treatment was much lower in the treatment group than the control group. The Visual Analog Scale (VAS) score was also significantly higher in the Ureadin group than the Dexeryl group. The investigators concluded that the topical application of a urea 5%, arginine, and carnosine cream enhances skin hydration and relieves dryness in type 2 diabetic patients in comparison with a control glycerol-based emollient formulation.¹⁷

Antiaging potential

In 1993, Reeve et al. showed that dietary or topically applied carnosine potentiated the contact hypersensitivity reaction in hairless mice and prevented the systemic inhibition of this reaction after dorsal skin exposure to UVB. Carnosine was found to also prevent the systemic suppression provoked by the topical application of a lotion containing cis-urocanic acid.³

Carnosine was a key active ingredient in antiaging products evaluated by Kaczvinsky et al. in 2009 in two double-blind, randomized, controlled, split-face studies. The researchers used the Fast Optical in vivo Topometry of Human Skin (FOITS) technique to measure changes in periorbital wrinkles in the two studies in women between the ages of 30 and 70 years old (study 1, n = 42; study 2, n = 35). They reported that 4 weeks of treatment with the test products, which contained niacinamide, the peptides Pal-KT and Pal-KTTKS, and carnosine, ameliorated periorbital skin, enhancing smoothness and diminishing larger wrinkle depth.¹⁸

In 2012, Babizhayev et al. conducted a 4-month randomized, double-blind, controlled study with 42 subjects to evaluate the effects on skin aging of oral nonhydrolyzed carnosine (Can-C Plus formulation). Skin parameters exhibited a consistent and significant improvement during 3 months of supplementation in the treatment group, compared with the placebo group, with overall skin appearance enhanced and fine lines diminished based on visual inspection. There were no reports of adverse effects. The investigators concluded that supplementation with nonhydrolyzed carnosine or carcinine in patented oral formulations has potential as an agent for antiaging purposes.¹⁹

Two years later, Emanuele et al. conducted an experimental double-blind irradiation study to compare a complex novel topical product (TPF50) consisting of three active ingredients (traditional physical sunscreens, SPF 50; a liposome-encapsulated DNA repair enzymes complex – photolyase, endonuclease, and 8-oxoguanine glycosylase [OGG1]; and a robust antioxidant complex containing carnosine, arazine, and ergothionine) to available DNA repair and antioxidant and growth factor topical products. They found that the new topical agent was the most effective product in reducing three molecular markers (cyclobutane pyrimidine dimers, protein carbonylation, and 8-oxo-7,8-dihydro-2’-deoxyguanosine) in human skin biopsies. The researchers concluded that the carnosine-containing formulation enhances the genomic and proteomic integrity of skin cells after continual UV exposure, suggesting its potential efficacy in lowering the risk of UV-induced cutaneous aging and nonmelanoma skin cancer.²⁰

Conclusion

Carnosine is an intriguing compound with well-documented antioxidant and wound healing activity. While more research is necessary to determine its wider applications in dermatology, recent work in formulating topical products to impart antiaging effects appears to show promise.

References

1. Nutr. Res. Pract. 2011;5:421-8.

2. Amino Acids 2012;43:127-34.

3. Immunology 1993;78:99-104.

4. Mol. Aspects Med. 1992;13:379-444.

5. Am. J. Ther. 2012;19:e69-89.

6. Life Sci. 2006;78:2343-57.

7. J. Cosmet. Dermatol. 2004;3:26-34.

8. Nihon Yakurigaku Zasshi. 1992;100:165-72.

9. Surgery 1986;100:815-21.

10. Surgery 1982;91:430-4.

11. Surgery 1982;91:56-60.

12. Int. J. Cosmet. Sci. 2011;33:1-16.

13. Crit. Rev. Ther. Drug Carrier Syst. 2011;28:203-53.

14. Crit. Rev. Ther. Drug Carrier Syst. 2010;27:85-154.

15. J. Cosmet. Dermatol. 2008;7:112-9.

16. Mol. Cancer 2010;9:2.

17. BMC Dermatol. 2012;12:16.

18. J. Cosmet. Dermatol. 2009;8:228-33.

19. J. Dermatolog. Treat. 2012;23:345-84.

20. J. Drugs Dermatol. 2014;13:309-14.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

A powerful endogenous antioxidant found most abundantly in mammalian tissues, especially brain and skeletal muscle tissue, carnosine is a dipeptide of alanine and histidine.^1,2,3,4,5.

Carnosine was first isolated in 1900 by the Russian scientist Gulewitsch as a substance extracted from muscle tissue.^6,4. L-carnosine (beta-alanyl-L-histidine) is the synthetic version identical to the natural form alpha-alanyl-L-histidine.⁷ Carnosine has long been reputed to confer immunomodulating, wound healing, antiglycating, and antineoplastic effects.² Several reports have shown that carnosine can accelerate the healing of surface skin wounds and burns.^4,8

Wound healing

An early study by Nagai et al. in 1986 on carnosine in wound healing showed that rats treated locally with carnosine exhibited greater tensile skin strength at an incision site after hydrocortisone had been administered to hinder healing. The investigators concluded that carnosine bolsters wound healing by stimulating early effusion by histamine and of collagen biosynthesis by beta-alanine. They also found that the compound significantly augmented granulation inhibited by cortisone, mitomycin C, 5-fluorouracil, and bleomycin.⁹

Studies by Fitzpatrick and Fisher in the early 1980s revealed that carnosine acts as a histidine reserve in relation to histamine production during trauma, suggesting a role for carnosine in wound healing.^10,11

In 2012, Ansurudeen et al. examined the effects of carnosine in wound healing in a diabetic mouse model. Carnosine was applied locally and injected daily, yielding significant amelioration in wound healing, with analysis revealing elevated expression of growth factors and cytokines implicated in wound healing. The investigators also observed that carnosine supported cell viability in the presence of high glucose in human dermal fibroblasts and microvascular endothelial cells in vitro.²

Other findings with implications for cutaneous therapy

In 2006, Babizhayev reported that the L-carnosine-related peptidomimetic N-acetylcarnosine (N-acetyl-beta-alanyl-L-histidine) can act as a timed-release (carrier) stable version of L-carnosine in cosmetic preparations, including lubricants.⁶ Babizhayev et al. have since claimed that they have developed a technology using imidazole-containing dipeptide-based compounds (including L-carnosine and derivatives) that enhances protein hydration in photoaged skin.^12,13,14

A double-blind comparative study conducted by Dieamant et al. in 2008 in 124 volunteers with sensitive skin aimed to evaluate the therapeutic potential of the combination of the antioxidant L-carnosine and neuromodulatory Rhodiola rosea. For 28 days, the groups of 62 received twice-daily applications of the 1% combination formulation or placebo. Skin barrier function (reduction of transepidermal water loss) improved in the treatment group, and favorable subjective responses regarding skin dryness were reported. Discomfort after the stinging test was also reduced. In vitro results showed that the release of proopiomelanocortin peptides was spurred by treatment, with the elevated levels of neuropeptides and cytokines produced by keratinocytes exposed to UV radiation returning to normal.¹⁵

Two years later, Renner et al. showed that carnosine hindered tumor growth in vivo in an NIH3T3-HER2/neu mouse model. They contended that this naturally occurring dipeptide warrants increased consideration and study for its potential as an anticancer agent.¹⁶

In 2012, Federici et al. conducted a randomized, evaluator-blinded, controlled comparative trial over 1month to assess the efficacy of twice-daily topical urea 5% with arginine and carnosine (Ureadin Rx) as compared with twice-daily application of a glycerol-based emollient topical product (Dexeryl) in treating xerosis in 40 type 2 diabetes patients (40-75 years of age). Use of the carnosine-containing formulation yielded significantly greater hydration and an 89% decline in Dryness Areas Severity Index (DASI) scores, compared with baseline. The DASI score after 4 weeks of treatment was much lower in the treatment group than the control group. The Visual Analog Scale (VAS) score was also significantly higher in the Ureadin group than the Dexeryl group. The investigators concluded that the topical application of a urea 5%, arginine, and carnosine cream enhances skin hydration and relieves dryness in type 2 diabetic patients in comparison with a control glycerol-based emollient formulation.¹⁷

Antiaging potential

In 1993, Reeve et al. showed that dietary or topically applied carnosine potentiated the contact hypersensitivity reaction in hairless mice and prevented the systemic inhibition of this reaction after dorsal skin exposure to UVB. Carnosine was found to also prevent the systemic suppression provoked by the topical application of a lotion containing cis-urocanic acid.³

Carnosine was a key active ingredient in antiaging products evaluated by Kaczvinsky et al. in 2009 in two double-blind, randomized, controlled, split-face studies. The researchers used the Fast Optical in vivo Topometry of Human Skin (FOITS) technique to measure changes in periorbital wrinkles in the two studies in women between the ages of 30 and 70 years old (study 1, n = 42; study 2, n = 35). They reported that 4 weeks of treatment with the test products, which contained niacinamide, the peptides Pal-KT and Pal-KTTKS, and carnosine, ameliorated periorbital skin, enhancing smoothness and diminishing larger wrinkle depth.¹⁸

In 2012, Babizhayev et al. conducted a 4-month randomized, double-blind, controlled study with 42 subjects to evaluate the effects on skin aging of oral nonhydrolyzed carnosine (Can-C Plus formulation). Skin parameters exhibited a consistent and significant improvement during 3 months of supplementation in the treatment group, compared with the placebo group, with overall skin appearance enhanced and fine lines diminished based on visual inspection. There were no reports of adverse effects. The investigators concluded that supplementation with nonhydrolyzed carnosine or carcinine in patented oral formulations has potential as an agent for antiaging purposes.¹⁹

Two years later, Emanuele et al. conducted an experimental double-blind irradiation study to compare a complex novel topical product (TPF50) consisting of three active ingredients (traditional physical sunscreens, SPF 50; a liposome-encapsulated DNA repair enzymes complex – photolyase, endonuclease, and 8-oxoguanine glycosylase [OGG1]; and a robust antioxidant complex containing carnosine, arazine, and ergothionine) to available DNA repair and antioxidant and growth factor topical products. They found that the new topical agent was the most effective product in reducing three molecular markers (cyclobutane pyrimidine dimers, protein carbonylation, and 8-oxo-7,8-dihydro-2’-deoxyguanosine) in human skin biopsies. The researchers concluded that the carnosine-containing formulation enhances the genomic and proteomic integrity of skin cells after continual UV exposure, suggesting its potential efficacy in lowering the risk of UV-induced cutaneous aging and nonmelanoma skin cancer.²⁰

Conclusion

Carnosine is an intriguing compound with well-documented antioxidant and wound healing activity. While more research is necessary to determine its wider applications in dermatology, recent work in formulating topical products to impart antiaging effects appears to show promise.

References

1. Nutr. Res. Pract. 2011;5:421-8.

2. Amino Acids 2012;43:127-34.

3. Immunology 1993;78:99-104.

4. Mol. Aspects Med. 1992;13:379-444.

5. Am. J. Ther. 2012;19:e69-89.

6. Life Sci. 2006;78:2343-57.

7. J. Cosmet. Dermatol. 2004;3:26-34.

8. Nihon Yakurigaku Zasshi. 1992;100:165-72.

9. Surgery 1986;100:815-21.

10. Surgery 1982;91:430-4.

11. Surgery 1982;91:56-60.

12. Int. J. Cosmet. Sci. 2011;33:1-16.

13. Crit. Rev. Ther. Drug Carrier Syst. 2011;28:203-53.

14. Crit. Rev. Ther. Drug Carrier Syst. 2010;27:85-154.

15. J. Cosmet. Dermatol. 2008;7:112-9.

16. Mol. Cancer 2010;9:2.

17. BMC Dermatol. 2012;12:16.

18. J. Cosmet. Dermatol. 2009;8:228-33.

19. J. Dermatolog. Treat. 2012;23:345-84.

20. J. Drugs Dermatol. 2014;13:309-14.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

The prevalence of diabetes increases as patients age and gain weight. More than one-third of nursing home residents have diabetes. The overall treatment goals for elderly patients with diabetes are similar to those for younger patients, but somehow the stakes feel higher. Polypharmacy, decreased activity, shifting dietary patterns, hyperglycemia, fears of hypoglycemia leading to falls, worsening comorbid conditions, and hospitalization pose great challenges to ideal management.

Because of these concerns, caution is raised about the use of insulin or oral agents that cause hypoglycemia in frail older adults in long-term care facilities. But these agents are used, and perhaps we understand little about their comparative risks.

Dr. Francisco J. Pasquel of Emory University, Atlanta, and his colleagues conducted a randomized clinical trial evaluating the comparative safety and effectiveness of basal insulin or an oral antidiabetic drug (OAD) for 26 weeks (BMJ Open Diab Res Care. 2015;3:e000104).

A total of 150 patients, average age 79 years, with a blood glucose level greater than 180 mg/dL or a hemoglobin A_1c greater than 7.5%, treated with diet or an oral agent, were randomized to either 0.1 U/kg per day of glargine or continuation of oral agents (metformin, insulin secretagogues, thiazolidinediones, or DPP-4 inhibitors). Glargine was adjusted based on blood sugar readings.

In the OAD group, 16% of patients were treated with metformin plus sulfonylurea, 27% with a sulfonylurea alone, and 8% with sulfonylurea and a DPP-4 inhibitor.

There were 62 hypoglycemic events in the OAD group and 43 in the basal insulin group (P = .4). Overall, daily blood glucose levels did not differ between the groups. Rates of cardiovascular events, renal failure, infection, falls, emergency department visits, hospital admissions, and mortality were similar between the two groups.

Although these data are somewhat reassuring, power may have been an issue, and a larger sample size may have resulted in detection of more hypoglycemic events in the OAD group. On the other hand, the data are balanced and resonate with previous data showing that in older adults with diabetes (about 74 years of age), intensive glycemic control is associated with an increased risk of falls in insulin users but not in those treated with OADs. The goal of the current study was not intensive glycemic control.

So, for patients in a long-term care facility, metformin and the DPP-4 inhibitors will be weight neutral without risk of hypoglycemia. Therefore, these may be the “go-to” drugs if the DPP-4 inhibitors are affordable and you do not have a long way to go for control (DPP-4 inhibitors tend to be relatively mild agents, lowering HbA_1c by 0.6%). If a sulfonylurea must be used, glipizide should be chosen, because it has a shorter half-life.

Balance all of this with appropriate HbA_1c goals for your patient adjusted for medical comorbidity, goals of care, and life expectancy.

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.

The prevalence of diabetes increases as patients age and gain weight. More than one-third of nursing home residents have diabetes. The overall treatment goals for elderly patients with diabetes are similar to those for younger patients, but somehow the stakes feel higher. Polypharmacy, decreased activity, shifting dietary patterns, hyperglycemia, fears of hypoglycemia leading to falls, worsening comorbid conditions, and hospitalization pose great challenges to ideal management.

Because of these concerns, caution is raised about the use of insulin or oral agents that cause hypoglycemia in frail older adults in long-term care facilities. But these agents are used, and perhaps we understand little about their comparative risks.

Dr. Francisco J. Pasquel of Emory University, Atlanta, and his colleagues conducted a randomized clinical trial evaluating the comparative safety and effectiveness of basal insulin or an oral antidiabetic drug (OAD) for 26 weeks (BMJ Open Diab Res Care. 2015;3:e000104).

A total of 150 patients, average age 79 years, with a blood glucose level greater than 180 mg/dL or a hemoglobin A_1c greater than 7.5%, treated with diet or an oral agent, were randomized to either 0.1 U/kg per day of glargine or continuation of oral agents (metformin, insulin secretagogues, thiazolidinediones, or DPP-4 inhibitors). Glargine was adjusted based on blood sugar readings.

In the OAD group, 16% of patients were treated with metformin plus sulfonylurea, 27% with a sulfonylurea alone, and 8% with sulfonylurea and a DPP-4 inhibitor.

There were 62 hypoglycemic events in the OAD group and 43 in the basal insulin group (P = .4). Overall, daily blood glucose levels did not differ between the groups. Rates of cardiovascular events, renal failure, infection, falls, emergency department visits, hospital admissions, and mortality were similar between the two groups.

Although these data are somewhat reassuring, power may have been an issue, and a larger sample size may have resulted in detection of more hypoglycemic events in the OAD group. On the other hand, the data are balanced and resonate with previous data showing that in older adults with diabetes (about 74 years of age), intensive glycemic control is associated with an increased risk of falls in insulin users but not in those treated with OADs. The goal of the current study was not intensive glycemic control.

So, for patients in a long-term care facility, metformin and the DPP-4 inhibitors will be weight neutral without risk of hypoglycemia. Therefore, these may be the “go-to” drugs if the DPP-4 inhibitors are affordable and you do not have a long way to go for control (DPP-4 inhibitors tend to be relatively mild agents, lowering HbA_1c by 0.6%). If a sulfonylurea must be used, glipizide should be chosen, because it has a shorter half-life.

Balance all of this with appropriate HbA_1c goals for your patient adjusted for medical comorbidity, goals of care, and life expectancy.

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.

The prevalence of diabetes increases as patients age and gain weight. More than one-third of nursing home residents have diabetes. The overall treatment goals for elderly patients with diabetes are similar to those for younger patients, but somehow the stakes feel higher. Polypharmacy, decreased activity, shifting dietary patterns, hyperglycemia, fears of hypoglycemia leading to falls, worsening comorbid conditions, and hospitalization pose great challenges to ideal management.

Because of these concerns, caution is raised about the use of insulin or oral agents that cause hypoglycemia in frail older adults in long-term care facilities. But these agents are used, and perhaps we understand little about their comparative risks.

Dr. Francisco J. Pasquel of Emory University, Atlanta, and his colleagues conducted a randomized clinical trial evaluating the comparative safety and effectiveness of basal insulin or an oral antidiabetic drug (OAD) for 26 weeks (BMJ Open Diab Res Care. 2015;3:e000104).

A total of 150 patients, average age 79 years, with a blood glucose level greater than 180 mg/dL or a hemoglobin A_1c greater than 7.5%, treated with diet or an oral agent, were randomized to either 0.1 U/kg per day of glargine or continuation of oral agents (metformin, insulin secretagogues, thiazolidinediones, or DPP-4 inhibitors). Glargine was adjusted based on blood sugar readings.

In the OAD group, 16% of patients were treated with metformin plus sulfonylurea, 27% with a sulfonylurea alone, and 8% with sulfonylurea and a DPP-4 inhibitor.

There were 62 hypoglycemic events in the OAD group and 43 in the basal insulin group (P = .4). Overall, daily blood glucose levels did not differ between the groups. Rates of cardiovascular events, renal failure, infection, falls, emergency department visits, hospital admissions, and mortality were similar between the two groups.

Although these data are somewhat reassuring, power may have been an issue, and a larger sample size may have resulted in detection of more hypoglycemic events in the OAD group. On the other hand, the data are balanced and resonate with previous data showing that in older adults with diabetes (about 74 years of age), intensive glycemic control is associated with an increased risk of falls in insulin users but not in those treated with OADs. The goal of the current study was not intensive glycemic control.

So, for patients in a long-term care facility, metformin and the DPP-4 inhibitors will be weight neutral without risk of hypoglycemia. Therefore, these may be the “go-to” drugs if the DPP-4 inhibitors are affordable and you do not have a long way to go for control (DPP-4 inhibitors tend to be relatively mild agents, lowering HbA_1c by 0.6%). If a sulfonylurea must be used, glipizide should be chosen, because it has a shorter half-life.

Balance all of this with appropriate HbA_1c goals for your patient adjusted for medical comorbidity, goals of care, and life expectancy.

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.