Aesthetic Dermatology

BOSTON — Cosmetic dermatologists have the knowledge and training to choose the right fillers that will garner the best results, according to Dr. Mary Lupo.

"Every FDA-approved filler, in my opinion, has an appropriate indication. You just need to know the relative strengths and weaknesses," said Dr. Lupo, at the American Academy of Dermatology's Academy 2009 meeting.

Optimal results require an appropriate candidate, the choice of an appropriate product based on the patient's presentation, injection of a sufficient amount of product, the right complementing procedures, and maintenance of the effect with touch-ups, said Dr. Lupo, professor of dermatology at Tulane University in New Orleans.

Treating Older Patients

In general, older patients need more volume restoration, because their immune response is decreased. "So when one has an active filler, such as poly-L-lactic acid, the older patient may have less of an immune response to give you a final result," she said. However, the corollary is that the older patient may require so much volume with other fillers that it becomes financially unfeasible.

"Older patients always need complementing procedures to get a good result," she said.

When examining the defect being considered for correction, decide whether it is a line or a fold. Lines require less viscous fillers to avoid lumpiness. "When a skin fold is more redundant, however, you need a thicker, more structural filler in order to lift the fold." When working with folds, Dr. Lupo recommends improving the area superior to the fold in addition to filling the fold.

When talking with the patient, "it's important to point out that it really doesn't do much good to fill a line if the overall photoaging is so severe and the 'canvas of the skin' is so mottled and deformed that it will not give an overall improvement," she said. Fillers can be used adjunctively with other methods to achieve better results.

Filler Contraindications

Many of the hyaluronic acid (HA) fillers are manufactured from a streptococcal fermentation process, so ask about hypersensitivity to strep, she said. Some patients have sensitivity to lidocaine. If this is the case, avoid using Prevelle Silk, CosmoDerm, and CosmoPlast. Poly-L-lactic acid is a component of Vicryl sutures, so if a patient has a history of allergic reaction to these sutures, avoid using Sculptra.

The use of anticoagulants by a patient is not necessarily a contraindication, "but it certainly behooves you to discuss the incidence of bruising that might be significant in these patients," Dr. Lupo said. For smokers wanting fillers, she uses a consent form to make these patients aware of the increased risk of necrosis.

Managing Expectations

The issue of cost also should be part of the discussion. Older patients will need more filler, meaning that temporary fillers may not be as cost effective over time. Semipermanent fillers may offer more benefit and it might be worth considering permanent.

To get the most out of a filler, complementing procedures should be considered. Such procedures can include onabotulinumtoxinA (Botox), intense pulsed light, chemical peel, nonablative laser, and ablative laser. "At the end of the day, the more procedures that a patient can afford, the better they will look," Dr. Lupo noted.

The Fillers

▸ CosmoDerm and CosmoPlast (human collagen). These products are the best choice for immediate results. They are great for lining the lips and for fine perioral lines, and both are fairly painless. They have a short duration, however, and both will be discontinued in 2010, according to Dr. Lupo.

▸ Restylane (HA gel). The filler is versatile and can be reversed by using hyaluronidase. It also can be injected with a finer-gauge needle, which reduces pain and allows treatment of finer lines. One injection lasts about 6 months, but it can last longer with touch-ups. Swelling and bruising should be considered, she said.

▸ Perlane (HA gel). This filler is a larger-particle gel suspension of HA. It is typically used for nasolabial folds and cheeks, and it can be used for lips with good technique to avoid lumping. "I have not found that the duration is any better than with Restylane," said Dr. Lupo.

▸ Juvéderm Ultra and Juvéderm Ultra Plus (cross-linked HA). This product is malleable and soft. It is also great for lips; however, because it is so malleable, it is not the best choice for defining the lip border. This filler is also reversible. "It is a little bit harder to get through a 1-inch needle," she said. Duration is 7-9 months without touch-ups.

Juvéderm Ultra Plus is the same as Juvéderm Ultra, although increased crosslinking of HA results in improved longevity—up to 1 year without touch-ups. "It's never to be used in fine lines, in my opinion," Dr. Lupo said. It is best injected with a 30-gauge needle. This filler is extremely good in skin of color.

▸ Prevelle Silk (cross-linked HA and lidocaine). The added lidocaine decreases patient discomfort. There is very little swelling because of the low HA concentration, but as a result it does not last as long—3 months or less. "It's inexpensive, and it's a good introductory filler for the hesitant patient," she said.

▸ Elevess (cross-linked HA and lidocaine). Elevess has the highest concentration of HA available on the market. "My personal opinion, based on my limited experience with it, is that it tends to be highly inflammatory as a result of this high concentration of HA," she said.

▸ Radiesse (calcium hydroxylapatite). This structural filler is great for men. It does cause a lot of same-day redness. "I do routinely mix it with lidocaine, and that is now FDA approved and has been found not to decrease its longevity," she said. It's a good choice for marionette lines and the pre-jowl sulcus, but avoid using it for the lips, she said.

▸ Sculptra (poly-L-lactic acid). The FDA cleared Sculptra this year for cosmetic purposes—correction of mild-to-severe nasolabial folds and wrinkles and contour irregularities. "The optimal patient for this is a younger lipoatrophy patient, because these patients still have enough of an immune response to actually get a good bang for the buck," she said. This filler is not reversible. The most common problem with Sculptra is the presence of nodules if it is injected too superficially, said Dr. Lupo.

▸ Evolence (porcine collagen). "In my opinion, it's a stiffer, more structural filler," she said. It works well in the nasolabial folds. Dr. Lupo always mixes it with lidocaine, though this makes it flow more quickly, so she uses a 30-gauge needle. It is a good choice for men with thick skin. Evolence has a low incidence of bruising and swelling.

Dr. Lupo reported significant financial relationships with a number of pharmaceutical and skin care companies.

A patient is shown before treatment with one syringe of Restylane.

The effect was prolonged for 3.5 years by performing periodic touch-ups.

Source Photos courtesy Dr. Mary Lupo

BOSTON — Cosmetic dermatologists have the knowledge and training to choose the right fillers that will garner the best results, according to Dr. Mary Lupo.

"Every FDA-approved filler, in my opinion, has an appropriate indication. You just need to know the relative strengths and weaknesses," said Dr. Lupo, at the American Academy of Dermatology's Academy 2009 meeting.

Optimal results require an appropriate candidate, the choice of an appropriate product based on the patient's presentation, injection of a sufficient amount of product, the right complementing procedures, and maintenance of the effect with touch-ups, said Dr. Lupo, professor of dermatology at Tulane University in New Orleans.

Treating Older Patients

In general, older patients need more volume restoration, because their immune response is decreased. "So when one has an active filler, such as poly-L-lactic acid, the older patient may have less of an immune response to give you a final result," she said. However, the corollary is that the older patient may require so much volume with other fillers that it becomes financially unfeasible.

"Older patients always need complementing procedures to get a good result," she said.

When examining the defect being considered for correction, decide whether it is a line or a fold. Lines require less viscous fillers to avoid lumpiness. "When a skin fold is more redundant, however, you need a thicker, more structural filler in order to lift the fold." When working with folds, Dr. Lupo recommends improving the area superior to the fold in addition to filling the fold.

When talking with the patient, "it's important to point out that it really doesn't do much good to fill a line if the overall photoaging is so severe and the 'canvas of the skin' is so mottled and deformed that it will not give an overall improvement," she said. Fillers can be used adjunctively with other methods to achieve better results.

Filler Contraindications

Many of the hyaluronic acid (HA) fillers are manufactured from a streptococcal fermentation process, so ask about hypersensitivity to strep, she said. Some patients have sensitivity to lidocaine. If this is the case, avoid using Prevelle Silk, CosmoDerm, and CosmoPlast. Poly-L-lactic acid is a component of Vicryl sutures, so if a patient has a history of allergic reaction to these sutures, avoid using Sculptra.

The use of anticoagulants by a patient is not necessarily a contraindication, "but it certainly behooves you to discuss the incidence of bruising that might be significant in these patients," Dr. Lupo said. For smokers wanting fillers, she uses a consent form to make these patients aware of the increased risk of necrosis.

Managing Expectations

The issue of cost also should be part of the discussion. Older patients will need more filler, meaning that temporary fillers may not be as cost effective over time. Semipermanent fillers may offer more benefit and it might be worth considering permanent.

To get the most out of a filler, complementing procedures should be considered. Such procedures can include onabotulinumtoxinA (Botox), intense pulsed light, chemical peel, nonablative laser, and ablative laser. "At the end of the day, the more procedures that a patient can afford, the better they will look," Dr. Lupo noted.

The Fillers

▸ CosmoDerm and CosmoPlast (human collagen). These products are the best choice for immediate results. They are great for lining the lips and for fine perioral lines, and both are fairly painless. They have a short duration, however, and both will be discontinued in 2010, according to Dr. Lupo.

▸ Restylane (HA gel). The filler is versatile and can be reversed by using hyaluronidase. It also can be injected with a finer-gauge needle, which reduces pain and allows treatment of finer lines. One injection lasts about 6 months, but it can last longer with touch-ups. Swelling and bruising should be considered, she said.

▸ Perlane (HA gel). This filler is a larger-particle gel suspension of HA. It is typically used for nasolabial folds and cheeks, and it can be used for lips with good technique to avoid lumping. "I have not found that the duration is any better than with Restylane," said Dr. Lupo.

▸ Juvéderm Ultra and Juvéderm Ultra Plus (cross-linked HA). This product is malleable and soft. It is also great for lips; however, because it is so malleable, it is not the best choice for defining the lip border. This filler is also reversible. "It is a little bit harder to get through a 1-inch needle," she said. Duration is 7-9 months without touch-ups.

Juvéderm Ultra Plus is the same as Juvéderm Ultra, although increased crosslinking of HA results in improved longevity—up to 1 year without touch-ups. "It's never to be used in fine lines, in my opinion," Dr. Lupo said. It is best injected with a 30-gauge needle. This filler is extremely good in skin of color.

▸ Prevelle Silk (cross-linked HA and lidocaine). The added lidocaine decreases patient discomfort. There is very little swelling because of the low HA concentration, but as a result it does not last as long—3 months or less. "It's inexpensive, and it's a good introductory filler for the hesitant patient," she said.

▸ Elevess (cross-linked HA and lidocaine). Elevess has the highest concentration of HA available on the market. "My personal opinion, based on my limited experience with it, is that it tends to be highly inflammatory as a result of this high concentration of HA," she said.

▸ Radiesse (calcium hydroxylapatite). This structural filler is great for men. It does cause a lot of same-day redness. "I do routinely mix it with lidocaine, and that is now FDA approved and has been found not to decrease its longevity," she said. It's a good choice for marionette lines and the pre-jowl sulcus, but avoid using it for the lips, she said.

▸ Sculptra (poly-L-lactic acid). The FDA cleared Sculptra this year for cosmetic purposes—correction of mild-to-severe nasolabial folds and wrinkles and contour irregularities. "The optimal patient for this is a younger lipoatrophy patient, because these patients still have enough of an immune response to actually get a good bang for the buck," she said. This filler is not reversible. The most common problem with Sculptra is the presence of nodules if it is injected too superficially, said Dr. Lupo.

▸ Evolence (porcine collagen). "In my opinion, it's a stiffer, more structural filler," she said. It works well in the nasolabial folds. Dr. Lupo always mixes it with lidocaine, though this makes it flow more quickly, so she uses a 30-gauge needle. It is a good choice for men with thick skin. Evolence has a low incidence of bruising and swelling.

Dr. Lupo reported significant financial relationships with a number of pharmaceutical and skin care companies.

A patient is shown before treatment with one syringe of Restylane.

The effect was prolonged for 3.5 years by performing periodic touch-ups.

Source Photos courtesy Dr. Mary Lupo

BOSTON — Cosmetic dermatologists have the knowledge and training to choose the right fillers that will garner the best results, according to Dr. Mary Lupo.

"Every FDA-approved filler, in my opinion, has an appropriate indication. You just need to know the relative strengths and weaknesses," said Dr. Lupo, at the American Academy of Dermatology's Academy 2009 meeting.

Optimal results require an appropriate candidate, the choice of an appropriate product based on the patient's presentation, injection of a sufficient amount of product, the right complementing procedures, and maintenance of the effect with touch-ups, said Dr. Lupo, professor of dermatology at Tulane University in New Orleans.

Treating Older Patients

In general, older patients need more volume restoration, because their immune response is decreased. "So when one has an active filler, such as poly-L-lactic acid, the older patient may have less of an immune response to give you a final result," she said. However, the corollary is that the older patient may require so much volume with other fillers that it becomes financially unfeasible.

"Older patients always need complementing procedures to get a good result," she said.

When examining the defect being considered for correction, decide whether it is a line or a fold. Lines require less viscous fillers to avoid lumpiness. "When a skin fold is more redundant, however, you need a thicker, more structural filler in order to lift the fold." When working with folds, Dr. Lupo recommends improving the area superior to the fold in addition to filling the fold.

When talking with the patient, "it's important to point out that it really doesn't do much good to fill a line if the overall photoaging is so severe and the 'canvas of the skin' is so mottled and deformed that it will not give an overall improvement," she said. Fillers can be used adjunctively with other methods to achieve better results.

Filler Contraindications

Many of the hyaluronic acid (HA) fillers are manufactured from a streptococcal fermentation process, so ask about hypersensitivity to strep, she said. Some patients have sensitivity to lidocaine. If this is the case, avoid using Prevelle Silk, CosmoDerm, and CosmoPlast. Poly-L-lactic acid is a component of Vicryl sutures, so if a patient has a history of allergic reaction to these sutures, avoid using Sculptra.

The use of anticoagulants by a patient is not necessarily a contraindication, "but it certainly behooves you to discuss the incidence of bruising that might be significant in these patients," Dr. Lupo said. For smokers wanting fillers, she uses a consent form to make these patients aware of the increased risk of necrosis.

Managing Expectations

The issue of cost also should be part of the discussion. Older patients will need more filler, meaning that temporary fillers may not be as cost effective over time. Semipermanent fillers may offer more benefit and it might be worth considering permanent.

To get the most out of a filler, complementing procedures should be considered. Such procedures can include onabotulinumtoxinA (Botox), intense pulsed light, chemical peel, nonablative laser, and ablative laser. "At the end of the day, the more procedures that a patient can afford, the better they will look," Dr. Lupo noted.

The Fillers

▸ CosmoDerm and CosmoPlast (human collagen). These products are the best choice for immediate results. They are great for lining the lips and for fine perioral lines, and both are fairly painless. They have a short duration, however, and both will be discontinued in 2010, according to Dr. Lupo.

▸ Restylane (HA gel). The filler is versatile and can be reversed by using hyaluronidase. It also can be injected with a finer-gauge needle, which reduces pain and allows treatment of finer lines. One injection lasts about 6 months, but it can last longer with touch-ups. Swelling and bruising should be considered, she said.

▸ Perlane (HA gel). This filler is a larger-particle gel suspension of HA. It is typically used for nasolabial folds and cheeks, and it can be used for lips with good technique to avoid lumping. "I have not found that the duration is any better than with Restylane," said Dr. Lupo.

▸ Juvéderm Ultra and Juvéderm Ultra Plus (cross-linked HA). This product is malleable and soft. It is also great for lips; however, because it is so malleable, it is not the best choice for defining the lip border. This filler is also reversible. "It is a little bit harder to get through a 1-inch needle," she said. Duration is 7-9 months without touch-ups.

Juvéderm Ultra Plus is the same as Juvéderm Ultra, although increased crosslinking of HA results in improved longevity—up to 1 year without touch-ups. "It's never to be used in fine lines, in my opinion," Dr. Lupo said. It is best injected with a 30-gauge needle. This filler is extremely good in skin of color.

▸ Prevelle Silk (cross-linked HA and lidocaine). The added lidocaine decreases patient discomfort. There is very little swelling because of the low HA concentration, but as a result it does not last as long—3 months or less. "It's inexpensive, and it's a good introductory filler for the hesitant patient," she said.

▸ Elevess (cross-linked HA and lidocaine). Elevess has the highest concentration of HA available on the market. "My personal opinion, based on my limited experience with it, is that it tends to be highly inflammatory as a result of this high concentration of HA," she said.

▸ Radiesse (calcium hydroxylapatite). This structural filler is great for men. It does cause a lot of same-day redness. "I do routinely mix it with lidocaine, and that is now FDA approved and has been found not to decrease its longevity," she said. It's a good choice for marionette lines and the pre-jowl sulcus, but avoid using it for the lips, she said.

▸ Sculptra (poly-L-lactic acid). The FDA cleared Sculptra this year for cosmetic purposes—correction of mild-to-severe nasolabial folds and wrinkles and contour irregularities. "The optimal patient for this is a younger lipoatrophy patient, because these patients still have enough of an immune response to actually get a good bang for the buck," she said. This filler is not reversible. The most common problem with Sculptra is the presence of nodules if it is injected too superficially, said Dr. Lupo.

▸ Evolence (porcine collagen). "In my opinion, it's a stiffer, more structural filler," she said. It works well in the nasolabial folds. Dr. Lupo always mixes it with lidocaine, though this makes it flow more quickly, so she uses a 30-gauge needle. It is a good choice for men with thick skin. Evolence has a low incidence of bruising and swelling.

Dr. Lupo reported significant financial relationships with a number of pharmaceutical and skin care companies.

A patient is shown before treatment with one syringe of Restylane.

The effect was prolonged for 3.5 years by performing periodic touch-ups.

Source Photos courtesy Dr. Mary Lupo

The increasing incidence of skin cancer and the importance of early diagnosis is a challenge, which requires the development of reliable, cost-effective, noninvasive, diagnostic techniques. Several such methods based on optical imaging techniques are available and currently being investigated. A novel method in this field is multiphoton laser scanning microscopy (MPLSM). This technique is based on the nonlinear process of 2-photon excitation of endogenous fluorophores, which can be used to acquire horizontal optical sectioning of intact biological tissue samples. When studying human skin, MPLSM provides high-resolution fluorescence imaging, allowing visualization of cellular and subcellular structures of the epidermis and upper dermis. This review covers the application of MPLSM as a diagnostic tool for superficial skin cancers, such as basal cell carcinomas, squamous cell carcinoma in situ, and melanomas. MPLSM has also been applied in other research areas related to skin, which will be mentioned briefly. The morphologic features observed in MPLSM images of skin tumors are comparable to traditional histopathology. Safety issues, limitations, and further improvements are discussed. Although further investigations are required to make MPLSM a mainstream clinical diagnostic tool, MPLSM has the potential of becoming a noninvasive, bedside, histopathologic technique for the diagnosis of superficial skin cancers.

*For a PDF of the full article, click on the link to the left of this introduction.

The increasing incidence of skin cancer and the importance of early diagnosis is a challenge, which requires the development of reliable, cost-effective, noninvasive, diagnostic techniques. Several such methods based on optical imaging techniques are available and currently being investigated. A novel method in this field is multiphoton laser scanning microscopy (MPLSM). This technique is based on the nonlinear process of 2-photon excitation of endogenous fluorophores, which can be used to acquire horizontal optical sectioning of intact biological tissue samples. When studying human skin, MPLSM provides high-resolution fluorescence imaging, allowing visualization of cellular and subcellular structures of the epidermis and upper dermis. This review covers the application of MPLSM as a diagnostic tool for superficial skin cancers, such as basal cell carcinomas, squamous cell carcinoma in situ, and melanomas. MPLSM has also been applied in other research areas related to skin, which will be mentioned briefly. The morphologic features observed in MPLSM images of skin tumors are comparable to traditional histopathology. Safety issues, limitations, and further improvements are discussed. Although further investigations are required to make MPLSM a mainstream clinical diagnostic tool, MPLSM has the potential of becoming a noninvasive, bedside, histopathologic technique for the diagnosis of superficial skin cancers.

*For a PDF of the full article, click on the link to the left of this introduction.

The increasing incidence of skin cancer and the importance of early diagnosis is a challenge, which requires the development of reliable, cost-effective, noninvasive, diagnostic techniques. Several such methods based on optical imaging techniques are available and currently being investigated. A novel method in this field is multiphoton laser scanning microscopy (MPLSM). This technique is based on the nonlinear process of 2-photon excitation of endogenous fluorophores, which can be used to acquire horizontal optical sectioning of intact biological tissue samples. When studying human skin, MPLSM provides high-resolution fluorescence imaging, allowing visualization of cellular and subcellular structures of the epidermis and upper dermis. This review covers the application of MPLSM as a diagnostic tool for superficial skin cancers, such as basal cell carcinomas, squamous cell carcinoma in situ, and melanomas. MPLSM has also been applied in other research areas related to skin, which will be mentioned briefly. The morphologic features observed in MPLSM images of skin tumors are comparable to traditional histopathology. Safety issues, limitations, and further improvements are discussed. Although further investigations are required to make MPLSM a mainstream clinical diagnostic tool, MPLSM has the potential of becoming a noninvasive, bedside, histopathologic technique for the diagnosis of superficial skin cancers.

*For a PDF of the full article, click on the link to the left of this introduction.

The Food and Drug Administration's recent decision to require new generic, or “established,” names for botulinum toxins is not likely to have much of an impact on patient safety, say dermatologists.

Citing the introduction of Dysport in April as the agency's trigger, the FDA said that it was seeking to reduce confusion and the potential for prescribing errors. Dysport is a botulinum toxin A, similar to Botox.

Now, Botox will be known generically as onabotulinumtoxinA; Myobloc will be known as rimabotulinumtoxinB, and Dysport will be known as abobotulinumtoxinA.

Each product will also carry the same boxed warning of the potential for distant spreading, which can lead to life-threatening respiratory difficulties. FDA first required this warning in April, but Dysport was not then on the market.

All of the toxins also will have a Medication Guide for patients discussing the potential for adverse effects from distant spreading.

“The revised labels also emphasize that the different botulinum toxin products are not interchangeable, because the units used to measure the products are different,” the FDA said in a statement.

“With each product having a distinct established name, we believe the chance of serious medication errors is minimized,” an agency spokeswoman said in an interview.

But several dermatologists said that since botulinum toxins are generally ordered, purchased, and dispensed by physicians, the new requirement won't have much effect.

Dr. Christopher Zachary, who is chairman of the dermatology department at the University of California in Irvine, said that he supports the FDA's efforts to increase safety. But, he added, “I'd suggest from a practical point of view that people keep using trade names,” noting that these are the names that stick in the minds of physicians, staff, and patients.

Dr. Michael Kaminer, assistant clinical professor in the dermatologic surgery and oncology section at Yale University, New Haven, Conn., said in an interview, “I can't imagine this would have any impact on consumers or physicians.” Distinct established names for the toxins could make a difference when and if a generic version becomes available, added Dr. Kaminer.

Dr. Kaminer disclosed no conflict of interest. Dr. Zachary disclosed that he receives grants and research support from Allergan.

'I'd suggest from a practical point of view that people keep using trade names.'

Source DR. ZACHARY

The Food and Drug Administration's recent decision to require new generic, or “established,” names for botulinum toxins is not likely to have much of an impact on patient safety, say dermatologists.

Citing the introduction of Dysport in April as the agency's trigger, the FDA said that it was seeking to reduce confusion and the potential for prescribing errors. Dysport is a botulinum toxin A, similar to Botox.

Now, Botox will be known generically as onabotulinumtoxinA; Myobloc will be known as rimabotulinumtoxinB, and Dysport will be known as abobotulinumtoxinA.

Each product will also carry the same boxed warning of the potential for distant spreading, which can lead to life-threatening respiratory difficulties. FDA first required this warning in April, but Dysport was not then on the market.

All of the toxins also will have a Medication Guide for patients discussing the potential for adverse effects from distant spreading.

“The revised labels also emphasize that the different botulinum toxin products are not interchangeable, because the units used to measure the products are different,” the FDA said in a statement.

“With each product having a distinct established name, we believe the chance of serious medication errors is minimized,” an agency spokeswoman said in an interview.

But several dermatologists said that since botulinum toxins are generally ordered, purchased, and dispensed by physicians, the new requirement won't have much effect.

Dr. Christopher Zachary, who is chairman of the dermatology department at the University of California in Irvine, said that he supports the FDA's efforts to increase safety. But, he added, “I'd suggest from a practical point of view that people keep using trade names,” noting that these are the names that stick in the minds of physicians, staff, and patients.

Dr. Michael Kaminer, assistant clinical professor in the dermatologic surgery and oncology section at Yale University, New Haven, Conn., said in an interview, “I can't imagine this would have any impact on consumers or physicians.” Distinct established names for the toxins could make a difference when and if a generic version becomes available, added Dr. Kaminer.

Dr. Kaminer disclosed no conflict of interest. Dr. Zachary disclosed that he receives grants and research support from Allergan.

'I'd suggest from a practical point of view that people keep using trade names.'

Source DR. ZACHARY

The Food and Drug Administration's recent decision to require new generic, or “established,” names for botulinum toxins is not likely to have much of an impact on patient safety, say dermatologists.

Citing the introduction of Dysport in April as the agency's trigger, the FDA said that it was seeking to reduce confusion and the potential for prescribing errors. Dysport is a botulinum toxin A, similar to Botox.

Now, Botox will be known generically as onabotulinumtoxinA; Myobloc will be known as rimabotulinumtoxinB, and Dysport will be known as abobotulinumtoxinA.

Each product will also carry the same boxed warning of the potential for distant spreading, which can lead to life-threatening respiratory difficulties. FDA first required this warning in April, but Dysport was not then on the market.

All of the toxins also will have a Medication Guide for patients discussing the potential for adverse effects from distant spreading.

“The revised labels also emphasize that the different botulinum toxin products are not interchangeable, because the units used to measure the products are different,” the FDA said in a statement.

“With each product having a distinct established name, we believe the chance of serious medication errors is minimized,” an agency spokeswoman said in an interview.

But several dermatologists said that since botulinum toxins are generally ordered, purchased, and dispensed by physicians, the new requirement won't have much effect.

Dr. Christopher Zachary, who is chairman of the dermatology department at the University of California in Irvine, said that he supports the FDA's efforts to increase safety. But, he added, “I'd suggest from a practical point of view that people keep using trade names,” noting that these are the names that stick in the minds of physicians, staff, and patients.

Dr. Michael Kaminer, assistant clinical professor in the dermatologic surgery and oncology section at Yale University, New Haven, Conn., said in an interview, “I can't imagine this would have any impact on consumers or physicians.” Distinct established names for the toxins could make a difference when and if a generic version becomes available, added Dr. Kaminer.

Dr. Kaminer disclosed no conflict of interest. Dr. Zachary disclosed that he receives grants and research support from Allergan.

'I'd suggest from a practical point of view that people keep using trade names.'

Source DR. ZACHARY

The flavone luteolin, 3′,4′,5,7-tetrahydroxyflavone, is a polyphenol commonly found in fruits, vegetables, and medicinal herbs (Curr. Cancer Drug Targets 2008;8:634–46). Luteolin is most often present in leaves, but is also found in rinds and other parts of plants.

The flavone and its glycosides have been identified in Bryophyta, Magnoliophyta, Pinophyta, Pteridophyta, and Salvia (Mini Rev. Med. Chem. 2009;9:31–59).

Luteolin is believed to have the potential to play a significant role in health, as it is considered to exhibit broad-ranging anti-inflammatory benefits (Proc. Natl. Acad. Sci. U.S.A. 2008;105:7534–9), as well as anticarcinogenic, antimicrobial, antioxidant, and immunomodulatory effects. Cancer, hypertension, inflammation, and other conditions have been treated with luteolin-rich plants in traditional Chinese medicine (Curr. Cancer Drug Targets 2008;8:634–46).

Notably, this antioxidant is present in the typical human diet in relatively low amounts (less than 1 mg/day) (Molecules 2008;13:2628–51). Dietary sources of luteolin include carrots, chamomile tea, celery, olive oil, oregano, peppermint, peppers, perilla, rosemary, and thyme (Mini Rev. Med. Chem. 2009;9:31–59; FEBS Lett. 1998;438:220–4).

This column will focus on recent research conducted on this antioxidant, particularly studies that imply potential dermatologic applications.

Antitumor Actions

In 2002, Ueda et al. studied the effects of orally administered perilla leaf extract on mice, and found that it inhibited production of tumor necrosis factor-alpha. The in vitro phase of the study led to their identifying luteolin, caffeic acid, and rosmarinic acid as active constituents of perilla. The investigators noted that only luteolin exhibited in vivo activity, however. Luteolin was responsible not only for suppressing the production of serum tumor necrosis factor-alpha, but also for suppressing arachidonic acid-induced ear edema, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema, and oxazolone-induced allergic edema (Biol. Pharm. Bull. 2002;25:1197–202).

A year later, the same team reported on its examination of the effects of topically applied perilla leaf extract and luteolin on murine skin papillomas induced by TPA and 7,12-dimethyl- benz[a]anthracene. Significant decreases in tumor incidence and multiplicity were observed in mice topically treated with perilla leaf extract before TPA treatment, especially in mice treated with luteolin prior to TPA (Biol. Pharm. Bull. 2003;26:560–3).

Anticancer Actions

Recent reviews on the diverse benefits of luteolin suggest that the flavone exhibits anti-inflammatory and anticarcinogenic properties, not all of which can be attributed to its antioxidant activity. By protecting against carcinogenic stimuli, luteolin is believed to have the capacity, in vitro and in vivo, to delay or inhibit cancer cell development, suppress tumor proliferation, induce cell cycle arrest, and spur apoptosis through intrinsic and extrinsic signaling pathways. Interestingly, some epidemiologic evidence points to an inverse relationship between luteolin consumption and the risk of developing some types of cancer (Molecules 2008;13:2628–51).

In a recent review of the distribution and biologic activities of luteolin, López-Lázaro summarized preclinical studies of the flavone, which have demonstrated that it has wide-ranging pharmacologic activities, particularly anticancer, anti-inflammatory, antimicrobial, and antioxidant properties.

Significant cancer chemopreventive and chemotherapeutic potential is suggested by the capacity of luteolin to block angiogenesis, induce apoptosis, prevent carcinogenesis in animal models, decrease tumor growth in vivo, and sensitize tumor cells to the cytotoxic impact of some anticancer drugs. López-Lázaro also noted a wide range of potential mechanisms of action for the various biologic activities of luteolin (Mini Rev. Med. Chem. 2009;9:31–59). In fact, luteolin has been found to sensitize cancer cells to induced cytotoxicity by inhibiting cell survival pathways (e.g., phosphatidylinositol 3′-kinase, nuclear factor kappa B, and X-linked inhibitor of apoptosis protein), and by promoting apoptosis pathways, leading to, for example, the induction of tumor suppressor p53 (Curr. Cancer Drug Targets 2008;8:634–46).

Seelinger et al. compared the anticarcinogenic effects of luteolin to those of other flavonoids, and found that luteolin was typically the most effective, inhibiting tumor cell proliferation with half-maximal inhibitory concentrations (IC50) between 3 and 50 mmol in vitro and in vivo by intragastric application or as a food additive. They concluded that because luteolin has also been demonstrated to penetrate human skin, this polyphenolic compound is potentially a suitable agent for preventing and treating skin cancer and photoaging (Molecules 2008;13:2628–51).

Antioxidant Actions

In a 2004 study of the components of Zostera marina leaves, Kim et al. found that the constituents apigenin, chrysoeriol, and luteolin scavenged radicals and reactive oxygen species, specifically the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and the superoxide radical in the xanthine/xanthine oxidase system.

Luteolin also inhibited matrix metalloproteinase-1 (MMP-1) expression by up to 44%, and suppressed the synthesis of interleukin-6, a cytokine known to spur MMP-1 expression.

The investigators concluded that the antioxidant capacity of luteolin and the other Zostera marina constituents tested, as well as their ability to suppress MMP-1 expression, suggests the potential use of these compounds as agents to prevent cutaneous photoaging (Arch. Pharm. Res. 2004;27:177–83).

In 2008, Seelinger et al. conducted a literature review to clarify luteolin's antioxidant, anti-inflammatory, and antiallergic activities. They found that luteolin is a natural antioxidant that exhibits less pro-oxidant potential than the most studied flavonoid, quercetin, and that it has a better safety profile than quercetin.

Luteolin also has been shown to possess superlative radical scavenging and cytoprotective qualities, particularly in complex biological systems, where it can interact with other antioxidants. Luteolin acts as an anti-inflammatory agent by activating antioxidative enzymes, inhibiting the nuclear factor kappa B pathway, and suppressing proinflammatory compounds.

The authors concluded that more quantitative research is necessary to determine the potential therapeutic benefits of this potent antioxidant (Planta Med. 2008;74:1667–77).

Ultraviolet Protection

In 2005, Morquio et al. mixed extracts of plants known to contain potent antioxidants, specifically Achyrocline satureioides and Epilobium parviflorum, with a cosmetic base, and applied the compounds to the back skin of rabbits. Subsequently, they exposed the skin to ultraviolet irradiation for 1 hour, and intracutaneously injected the irradiated areas with sodium salicylate.

The researchers then evaluated hydroxyl radical production by measuring 2,3-dihydroxybenzoic acid (2,3-DHBA) synthesis resulting from the hydroxylation of sodium salicylate. The production of 2,3-DHBA was found to be significantly increased by the UV irradiation, but was markedly diminished in association with the application of the Achyrocline satureioides cosmetic formulation. The authors attributed this antioxidant effect to the presence of high concentrations of flavonoid aglycones, including luteolin (Phytother. Res. 2005;19:486–90).

In 2007, Sim et al. studied the structure-activity relationship of several flavonoid compounds and their antioxidant and inhibitory effects against MMP activity in vitro and in human dermal fibroblasts induced by ultraviolet A light. The compounds examined included luteolin, myricetin, quercetin, kaempferol, apigenin, and chrysin. Luteolin, with the highest number of OH groups in the B ring, was shown to have the most potent antioxidant efficacy as ascertained using the DPPH method and the xanthine/xanthine oxidase system. The authors also noted that in association with the relative antioxidant strength of the flavonoids, the compounds dose-dependently suppressed collagenase activity and MMP expression. They concluded that flavonoids with a higher number of hydroxyl groups may be the most effective at preventing UV-induced cutaneous aging (Arch. Pharm. Res. 2007;30:290–8).

Prostaglandin Inhibitor

In a 2008 study, Papaliodis et al. investigated the effect of flavonoids on niacin-induced flush in a rat model, and sought to determine whether prostaglandin D2 (PGD2) and 5-hydroxytryptamine (5-HT) were involved.

The researchers recorded three skin temperature measurements from each ear for each time point immediately before intraperitoneal injection with either niacin or a flavonoid (quercetin or luteolin). They then measured temperature every 10 minutes for 1 hour. Ear temperature was increased by niacin to a maximum of 1.9 plus or minus 0.2 °C at 45 minutes.

Quercetin and luteolin administered intraperitoneally 45 minutes before niacin blocked the niacin effect by 96% and 88%, respectively, while aspirin inhibited the niacin effect by 30%. Plasma PGD2 and 5-HT were increased twofold by niacin, while luteolin suppressed plasma PGD2 and 5-HT by 100% and 67%, respectively, and aspirin lowered only PGD2 (by 86%).

The investigators concluded that the increased skin temperature in rats caused by niacin is linked to increases in PGD2 and 5-HT, and that luteolin may be the most suitable inhibitor of niacin-induced flush because it suppresses both mediators (Br. J. Pharmacol. 2008;153:1382–7).

Currently, luteolin is included as a minor ingredient in some nutritional and herbal supplements.

Conclusion

Much more research is necessary to ascertain whether the bioactive properties of luteolin can be readily harnessed for application in dermatologic and other medical conditions. Currently, the preponderance of evidence suggests that this flavonoid is at least as promising as its fellow flavonoid quercetin.

The flavone luteolin, 3′,4′,5,7-tetrahydroxyflavone, is a polyphenol commonly found in fruits, vegetables, and medicinal herbs (Curr. Cancer Drug Targets 2008;8:634–46). Luteolin is most often present in leaves, but is also found in rinds and other parts of plants.

The flavone and its glycosides have been identified in Bryophyta, Magnoliophyta, Pinophyta, Pteridophyta, and Salvia (Mini Rev. Med. Chem. 2009;9:31–59).

Luteolin is believed to have the potential to play a significant role in health, as it is considered to exhibit broad-ranging anti-inflammatory benefits (Proc. Natl. Acad. Sci. U.S.A. 2008;105:7534–9), as well as anticarcinogenic, antimicrobial, antioxidant, and immunomodulatory effects. Cancer, hypertension, inflammation, and other conditions have been treated with luteolin-rich plants in traditional Chinese medicine (Curr. Cancer Drug Targets 2008;8:634–46).

Notably, this antioxidant is present in the typical human diet in relatively low amounts (less than 1 mg/day) (Molecules 2008;13:2628–51). Dietary sources of luteolin include carrots, chamomile tea, celery, olive oil, oregano, peppermint, peppers, perilla, rosemary, and thyme (Mini Rev. Med. Chem. 2009;9:31–59; FEBS Lett. 1998;438:220–4).

This column will focus on recent research conducted on this antioxidant, particularly studies that imply potential dermatologic applications.

Antitumor Actions

In 2002, Ueda et al. studied the effects of orally administered perilla leaf extract on mice, and found that it inhibited production of tumor necrosis factor-alpha. The in vitro phase of the study led to their identifying luteolin, caffeic acid, and rosmarinic acid as active constituents of perilla. The investigators noted that only luteolin exhibited in vivo activity, however. Luteolin was responsible not only for suppressing the production of serum tumor necrosis factor-alpha, but also for suppressing arachidonic acid-induced ear edema, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema, and oxazolone-induced allergic edema (Biol. Pharm. Bull. 2002;25:1197–202).

A year later, the same team reported on its examination of the effects of topically applied perilla leaf extract and luteolin on murine skin papillomas induced by TPA and 7,12-dimethyl- benz[a]anthracene. Significant decreases in tumor incidence and multiplicity were observed in mice topically treated with perilla leaf extract before TPA treatment, especially in mice treated with luteolin prior to TPA (Biol. Pharm. Bull. 2003;26:560–3).

Anticancer Actions

Recent reviews on the diverse benefits of luteolin suggest that the flavone exhibits anti-inflammatory and anticarcinogenic properties, not all of which can be attributed to its antioxidant activity. By protecting against carcinogenic stimuli, luteolin is believed to have the capacity, in vitro and in vivo, to delay or inhibit cancer cell development, suppress tumor proliferation, induce cell cycle arrest, and spur apoptosis through intrinsic and extrinsic signaling pathways. Interestingly, some epidemiologic evidence points to an inverse relationship between luteolin consumption and the risk of developing some types of cancer (Molecules 2008;13:2628–51).

In a recent review of the distribution and biologic activities of luteolin, López-Lázaro summarized preclinical studies of the flavone, which have demonstrated that it has wide-ranging pharmacologic activities, particularly anticancer, anti-inflammatory, antimicrobial, and antioxidant properties.

Significant cancer chemopreventive and chemotherapeutic potential is suggested by the capacity of luteolin to block angiogenesis, induce apoptosis, prevent carcinogenesis in animal models, decrease tumor growth in vivo, and sensitize tumor cells to the cytotoxic impact of some anticancer drugs. López-Lázaro also noted a wide range of potential mechanisms of action for the various biologic activities of luteolin (Mini Rev. Med. Chem. 2009;9:31–59). In fact, luteolin has been found to sensitize cancer cells to induced cytotoxicity by inhibiting cell survival pathways (e.g., phosphatidylinositol 3′-kinase, nuclear factor kappa B, and X-linked inhibitor of apoptosis protein), and by promoting apoptosis pathways, leading to, for example, the induction of tumor suppressor p53 (Curr. Cancer Drug Targets 2008;8:634–46).

Seelinger et al. compared the anticarcinogenic effects of luteolin to those of other flavonoids, and found that luteolin was typically the most effective, inhibiting tumor cell proliferation with half-maximal inhibitory concentrations (IC50) between 3 and 50 mmol in vitro and in vivo by intragastric application or as a food additive. They concluded that because luteolin has also been demonstrated to penetrate human skin, this polyphenolic compound is potentially a suitable agent for preventing and treating skin cancer and photoaging (Molecules 2008;13:2628–51).

Antioxidant Actions

In a 2004 study of the components of Zostera marina leaves, Kim et al. found that the constituents apigenin, chrysoeriol, and luteolin scavenged radicals and reactive oxygen species, specifically the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and the superoxide radical in the xanthine/xanthine oxidase system.

Luteolin also inhibited matrix metalloproteinase-1 (MMP-1) expression by up to 44%, and suppressed the synthesis of interleukin-6, a cytokine known to spur MMP-1 expression.

The investigators concluded that the antioxidant capacity of luteolin and the other Zostera marina constituents tested, as well as their ability to suppress MMP-1 expression, suggests the potential use of these compounds as agents to prevent cutaneous photoaging (Arch. Pharm. Res. 2004;27:177–83).

In 2008, Seelinger et al. conducted a literature review to clarify luteolin's antioxidant, anti-inflammatory, and antiallergic activities. They found that luteolin is a natural antioxidant that exhibits less pro-oxidant potential than the most studied flavonoid, quercetin, and that it has a better safety profile than quercetin.

Luteolin also has been shown to possess superlative radical scavenging and cytoprotective qualities, particularly in complex biological systems, where it can interact with other antioxidants. Luteolin acts as an anti-inflammatory agent by activating antioxidative enzymes, inhibiting the nuclear factor kappa B pathway, and suppressing proinflammatory compounds.

The authors concluded that more quantitative research is necessary to determine the potential therapeutic benefits of this potent antioxidant (Planta Med. 2008;74:1667–77).

Ultraviolet Protection

In 2005, Morquio et al. mixed extracts of plants known to contain potent antioxidants, specifically Achyrocline satureioides and Epilobium parviflorum, with a cosmetic base, and applied the compounds to the back skin of rabbits. Subsequently, they exposed the skin to ultraviolet irradiation for 1 hour, and intracutaneously injected the irradiated areas with sodium salicylate.

The researchers then evaluated hydroxyl radical production by measuring 2,3-dihydroxybenzoic acid (2,3-DHBA) synthesis resulting from the hydroxylation of sodium salicylate. The production of 2,3-DHBA was found to be significantly increased by the UV irradiation, but was markedly diminished in association with the application of the Achyrocline satureioides cosmetic formulation. The authors attributed this antioxidant effect to the presence of high concentrations of flavonoid aglycones, including luteolin (Phytother. Res. 2005;19:486–90).

In 2007, Sim et al. studied the structure-activity relationship of several flavonoid compounds and their antioxidant and inhibitory effects against MMP activity in vitro and in human dermal fibroblasts induced by ultraviolet A light. The compounds examined included luteolin, myricetin, quercetin, kaempferol, apigenin, and chrysin. Luteolin, with the highest number of OH groups in the B ring, was shown to have the most potent antioxidant efficacy as ascertained using the DPPH method and the xanthine/xanthine oxidase system. The authors also noted that in association with the relative antioxidant strength of the flavonoids, the compounds dose-dependently suppressed collagenase activity and MMP expression. They concluded that flavonoids with a higher number of hydroxyl groups may be the most effective at preventing UV-induced cutaneous aging (Arch. Pharm. Res. 2007;30:290–8).

Prostaglandin Inhibitor

In a 2008 study, Papaliodis et al. investigated the effect of flavonoids on niacin-induced flush in a rat model, and sought to determine whether prostaglandin D2 (PGD2) and 5-hydroxytryptamine (5-HT) were involved.

The researchers recorded three skin temperature measurements from each ear for each time point immediately before intraperitoneal injection with either niacin or a flavonoid (quercetin or luteolin). They then measured temperature every 10 minutes for 1 hour. Ear temperature was increased by niacin to a maximum of 1.9 plus or minus 0.2 °C at 45 minutes.

Quercetin and luteolin administered intraperitoneally 45 minutes before niacin blocked the niacin effect by 96% and 88%, respectively, while aspirin inhibited the niacin effect by 30%. Plasma PGD2 and 5-HT were increased twofold by niacin, while luteolin suppressed plasma PGD2 and 5-HT by 100% and 67%, respectively, and aspirin lowered only PGD2 (by 86%).

The investigators concluded that the increased skin temperature in rats caused by niacin is linked to increases in PGD2 and 5-HT, and that luteolin may be the most suitable inhibitor of niacin-induced flush because it suppresses both mediators (Br. J. Pharmacol. 2008;153:1382–7).

Currently, luteolin is included as a minor ingredient in some nutritional and herbal supplements.

Conclusion

Much more research is necessary to ascertain whether the bioactive properties of luteolin can be readily harnessed for application in dermatologic and other medical conditions. Currently, the preponderance of evidence suggests that this flavonoid is at least as promising as its fellow flavonoid quercetin.

The flavone luteolin, 3′,4′,5,7-tetrahydroxyflavone, is a polyphenol commonly found in fruits, vegetables, and medicinal herbs (Curr. Cancer Drug Targets 2008;8:634–46). Luteolin is most often present in leaves, but is also found in rinds and other parts of plants.

The flavone and its glycosides have been identified in Bryophyta, Magnoliophyta, Pinophyta, Pteridophyta, and Salvia (Mini Rev. Med. Chem. 2009;9:31–59).

Luteolin is believed to have the potential to play a significant role in health, as it is considered to exhibit broad-ranging anti-inflammatory benefits (Proc. Natl. Acad. Sci. U.S.A. 2008;105:7534–9), as well as anticarcinogenic, antimicrobial, antioxidant, and immunomodulatory effects. Cancer, hypertension, inflammation, and other conditions have been treated with luteolin-rich plants in traditional Chinese medicine (Curr. Cancer Drug Targets 2008;8:634–46).

Notably, this antioxidant is present in the typical human diet in relatively low amounts (less than 1 mg/day) (Molecules 2008;13:2628–51). Dietary sources of luteolin include carrots, chamomile tea, celery, olive oil, oregano, peppermint, peppers, perilla, rosemary, and thyme (Mini Rev. Med. Chem. 2009;9:31–59; FEBS Lett. 1998;438:220–4).

This column will focus on recent research conducted on this antioxidant, particularly studies that imply potential dermatologic applications.

Antitumor Actions

In 2002, Ueda et al. studied the effects of orally administered perilla leaf extract on mice, and found that it inhibited production of tumor necrosis factor-alpha. The in vitro phase of the study led to their identifying luteolin, caffeic acid, and rosmarinic acid as active constituents of perilla. The investigators noted that only luteolin exhibited in vivo activity, however. Luteolin was responsible not only for suppressing the production of serum tumor necrosis factor-alpha, but also for suppressing arachidonic acid-induced ear edema, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema, and oxazolone-induced allergic edema (Biol. Pharm. Bull. 2002;25:1197–202).

A year later, the same team reported on its examination of the effects of topically applied perilla leaf extract and luteolin on murine skin papillomas induced by TPA and 7,12-dimethyl- benz[a]anthracene. Significant decreases in tumor incidence and multiplicity were observed in mice topically treated with perilla leaf extract before TPA treatment, especially in mice treated with luteolin prior to TPA (Biol. Pharm. Bull. 2003;26:560–3).

Anticancer Actions

Recent reviews on the diverse benefits of luteolin suggest that the flavone exhibits anti-inflammatory and anticarcinogenic properties, not all of which can be attributed to its antioxidant activity. By protecting against carcinogenic stimuli, luteolin is believed to have the capacity, in vitro and in vivo, to delay or inhibit cancer cell development, suppress tumor proliferation, induce cell cycle arrest, and spur apoptosis through intrinsic and extrinsic signaling pathways. Interestingly, some epidemiologic evidence points to an inverse relationship between luteolin consumption and the risk of developing some types of cancer (Molecules 2008;13:2628–51).

In a recent review of the distribution and biologic activities of luteolin, López-Lázaro summarized preclinical studies of the flavone, which have demonstrated that it has wide-ranging pharmacologic activities, particularly anticancer, anti-inflammatory, antimicrobial, and antioxidant properties.

Significant cancer chemopreventive and chemotherapeutic potential is suggested by the capacity of luteolin to block angiogenesis, induce apoptosis, prevent carcinogenesis in animal models, decrease tumor growth in vivo, and sensitize tumor cells to the cytotoxic impact of some anticancer drugs. López-Lázaro also noted a wide range of potential mechanisms of action for the various biologic activities of luteolin (Mini Rev. Med. Chem. 2009;9:31–59). In fact, luteolin has been found to sensitize cancer cells to induced cytotoxicity by inhibiting cell survival pathways (e.g., phosphatidylinositol 3′-kinase, nuclear factor kappa B, and X-linked inhibitor of apoptosis protein), and by promoting apoptosis pathways, leading to, for example, the induction of tumor suppressor p53 (Curr. Cancer Drug Targets 2008;8:634–46).

Seelinger et al. compared the anticarcinogenic effects of luteolin to those of other flavonoids, and found that luteolin was typically the most effective, inhibiting tumor cell proliferation with half-maximal inhibitory concentrations (IC50) between 3 and 50 mmol in vitro and in vivo by intragastric application or as a food additive. They concluded that because luteolin has also been demonstrated to penetrate human skin, this polyphenolic compound is potentially a suitable agent for preventing and treating skin cancer and photoaging (Molecules 2008;13:2628–51).

Antioxidant Actions

In a 2004 study of the components of Zostera marina leaves, Kim et al. found that the constituents apigenin, chrysoeriol, and luteolin scavenged radicals and reactive oxygen species, specifically the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and the superoxide radical in the xanthine/xanthine oxidase system.

Luteolin also inhibited matrix metalloproteinase-1 (MMP-1) expression by up to 44%, and suppressed the synthesis of interleukin-6, a cytokine known to spur MMP-1 expression.

The investigators concluded that the antioxidant capacity of luteolin and the other Zostera marina constituents tested, as well as their ability to suppress MMP-1 expression, suggests the potential use of these compounds as agents to prevent cutaneous photoaging (Arch. Pharm. Res. 2004;27:177–83).

In 2008, Seelinger et al. conducted a literature review to clarify luteolin's antioxidant, anti-inflammatory, and antiallergic activities. They found that luteolin is a natural antioxidant that exhibits less pro-oxidant potential than the most studied flavonoid, quercetin, and that it has a better safety profile than quercetin.

Luteolin also has been shown to possess superlative radical scavenging and cytoprotective qualities, particularly in complex biological systems, where it can interact with other antioxidants. Luteolin acts as an anti-inflammatory agent by activating antioxidative enzymes, inhibiting the nuclear factor kappa B pathway, and suppressing proinflammatory compounds.

The authors concluded that more quantitative research is necessary to determine the potential therapeutic benefits of this potent antioxidant (Planta Med. 2008;74:1667–77).

Ultraviolet Protection

In 2005, Morquio et al. mixed extracts of plants known to contain potent antioxidants, specifically Achyrocline satureioides and Epilobium parviflorum, with a cosmetic base, and applied the compounds to the back skin of rabbits. Subsequently, they exposed the skin to ultraviolet irradiation for 1 hour, and intracutaneously injected the irradiated areas with sodium salicylate.

The researchers then evaluated hydroxyl radical production by measuring 2,3-dihydroxybenzoic acid (2,3-DHBA) synthesis resulting from the hydroxylation of sodium salicylate. The production of 2,3-DHBA was found to be significantly increased by the UV irradiation, but was markedly diminished in association with the application of the Achyrocline satureioides cosmetic formulation. The authors attributed this antioxidant effect to the presence of high concentrations of flavonoid aglycones, including luteolin (Phytother. Res. 2005;19:486–90).

In 2007, Sim et al. studied the structure-activity relationship of several flavonoid compounds and their antioxidant and inhibitory effects against MMP activity in vitro and in human dermal fibroblasts induced by ultraviolet A light. The compounds examined included luteolin, myricetin, quercetin, kaempferol, apigenin, and chrysin. Luteolin, with the highest number of OH groups in the B ring, was shown to have the most potent antioxidant efficacy as ascertained using the DPPH method and the xanthine/xanthine oxidase system. The authors also noted that in association with the relative antioxidant strength of the flavonoids, the compounds dose-dependently suppressed collagenase activity and MMP expression. They concluded that flavonoids with a higher number of hydroxyl groups may be the most effective at preventing UV-induced cutaneous aging (Arch. Pharm. Res. 2007;30:290–8).

Prostaglandin Inhibitor

In a 2008 study, Papaliodis et al. investigated the effect of flavonoids on niacin-induced flush in a rat model, and sought to determine whether prostaglandin D2 (PGD2) and 5-hydroxytryptamine (5-HT) were involved.

The researchers recorded three skin temperature measurements from each ear for each time point immediately before intraperitoneal injection with either niacin or a flavonoid (quercetin or luteolin). They then measured temperature every 10 minutes for 1 hour. Ear temperature was increased by niacin to a maximum of 1.9 plus or minus 0.2 °C at 45 minutes.

Quercetin and luteolin administered intraperitoneally 45 minutes before niacin blocked the niacin effect by 96% and 88%, respectively, while aspirin inhibited the niacin effect by 30%. Plasma PGD2 and 5-HT were increased twofold by niacin, while luteolin suppressed plasma PGD2 and 5-HT by 100% and 67%, respectively, and aspirin lowered only PGD2 (by 86%).

The investigators concluded that the increased skin temperature in rats caused by niacin is linked to increases in PGD2 and 5-HT, and that luteolin may be the most suitable inhibitor of niacin-induced flush because it suppresses both mediators (Br. J. Pharmacol. 2008;153:1382–7).

Currently, luteolin is included as a minor ingredient in some nutritional and herbal supplements.

Conclusion

Much more research is necessary to ascertain whether the bioactive properties of luteolin can be readily harnessed for application in dermatologic and other medical conditions. Currently, the preponderance of evidence suggests that this flavonoid is at least as promising as its fellow flavonoid quercetin.

A consumer information page, with alink to the approval letter, is posted at www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm176124.htm

Sculptra Aesthetic

(injectable poly-L-lactic acid, Sanofi-aventis)

Sculptra is an injectable filler containing microparticles of poly-L-lactic acid approved by the Food and Drug Administration in August for use in immune-competent people as a single regimen for the correction of shallow to deep nasolabial fold contour deficiencies and other facial wrinkles “in which deep dermal grid pattern (cross-hatch) injection technique is appropriate,” according to the manufacturer. The injectable was first approved in 2004 for correcting lipoatrophy in HIV patients.

▸ Recommended Usage: Injected into the deep dermis. Injection requirements for Sculptra Aesthetic are “unique,” and include “a tunneling technique in a grid pattern that is medial to the nasolabial fold contour defect” being corrected, according to prescription information.

▸ Special Considerations: Contraindicated in patients with a hypersensitivity to any of the components of this product and those with a known history of keloid formation or hypertrophic scarring. The product has not been studied in the periorbital area, but use in this area has been associated with an increased risk of papules and nodules, according to reports in the literature. Side effects can include injection site discomfort, redness, bruising, bleeding, itching, and swelling, noted the manufacturer.

▸Comment: Poly-L-lactic acid is a biodegradable synthetic polymer that has been widely used for years in dissolvable stitches, bone screws, and facial implants, according to the FDA. A randomized, multicenter, evaluator-blinded controlled study of 233 immune-competent mostly female patients (mean age 51 years) with previously untreated nasolabial fold wrinkles and wrinkle assessment scores of 2 (shallow) through 4 (deep) was conducted.

Patients were treated with bilateral injections of Sculptra Aesthetic (at 3-week intervals for up to four treatments) or with CosmoPlast (INAMED Aesthetics) for a maximum of four sessions over 9 weeks. At 13 months, those who received Sculptra had improvements in wrinkle assessment scores in correction of the contour deficiency of the nasolabial folds. Improvements were maintained among those patients followed for up to 25 months, according to the prescribing information. CosmoPlast results were maintained for up to 3 months.

In an interview, Dr. Leslie S. Baumann, director of cosmetic dermatology at the University of Miami, said that she has used Sculptra off-label for hundreds of patients since it was approved in 2004. It is not her first choice for nasolabial folds, but she likes to use it for improving cheek volume, which is similar to the HIV lipoatrophy indication.

The biggest issue with Sculptra is that patients need to have four to eight treatments before they see any improvement in cheek volume, which is more expensive initially than other treatments, she said. Also, it is difficult to predict how many treatments people will need.

Dr. Baumann tells patients that they will need four to eight treatments 1 month apart, and that they usually will not see changes until the third or fourth treatment. It is worth it, though, “because once you get them the way you want them to look, it lasts 2–3 years,” she said.

The University of Miami was among the Sculptra Aesthetic study sites, and Dr. Baumann said she has been an investigator for Dermik Laboratories (the dermatology division of sanofi-aventis) and other major cosmetic filler manufacturers.

She described Sculptra as a “dermal stimulator” rather than a filler because it stimulates the dermis to make collagen. She cautioned that it should not be used in areas where there is a lot of movement, such as the corner of the mouth, because of the risk of developing hard lumps. “I've seen people with horrible lumps under their eyes and there's nothing you can do,” she said.

Dr. Baumann stressed the need to be properly trained in how to inject Sculptra. When she trains residents, “this is the last thing I'll teach them, because they really have to get their skills down.”

A consumer information page, with alink to the approval letter, is posted at www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm176124.htm

Sculptra Aesthetic

(injectable poly-L-lactic acid, Sanofi-aventis)

Sculptra is an injectable filler containing microparticles of poly-L-lactic acid approved by the Food and Drug Administration in August for use in immune-competent people as a single regimen for the correction of shallow to deep nasolabial fold contour deficiencies and other facial wrinkles “in which deep dermal grid pattern (cross-hatch) injection technique is appropriate,” according to the manufacturer. The injectable was first approved in 2004 for correcting lipoatrophy in HIV patients.

▸ Recommended Usage: Injected into the deep dermis. Injection requirements for Sculptra Aesthetic are “unique,” and include “a tunneling technique in a grid pattern that is medial to the nasolabial fold contour defect” being corrected, according to prescription information.

▸ Special Considerations: Contraindicated in patients with a hypersensitivity to any of the components of this product and those with a known history of keloid formation or hypertrophic scarring. The product has not been studied in the periorbital area, but use in this area has been associated with an increased risk of papules and nodules, according to reports in the literature. Side effects can include injection site discomfort, redness, bruising, bleeding, itching, and swelling, noted the manufacturer.

▸Comment: Poly-L-lactic acid is a biodegradable synthetic polymer that has been widely used for years in dissolvable stitches, bone screws, and facial implants, according to the FDA. A randomized, multicenter, evaluator-blinded controlled study of 233 immune-competent mostly female patients (mean age 51 years) with previously untreated nasolabial fold wrinkles and wrinkle assessment scores of 2 (shallow) through 4 (deep) was conducted.

Patients were treated with bilateral injections of Sculptra Aesthetic (at 3-week intervals for up to four treatments) or with CosmoPlast (INAMED Aesthetics) for a maximum of four sessions over 9 weeks. At 13 months, those who received Sculptra had improvements in wrinkle assessment scores in correction of the contour deficiency of the nasolabial folds. Improvements were maintained among those patients followed for up to 25 months, according to the prescribing information. CosmoPlast results were maintained for up to 3 months.

In an interview, Dr. Leslie S. Baumann, director of cosmetic dermatology at the University of Miami, said that she has used Sculptra off-label for hundreds of patients since it was approved in 2004. It is not her first choice for nasolabial folds, but she likes to use it for improving cheek volume, which is similar to the HIV lipoatrophy indication.

The biggest issue with Sculptra is that patients need to have four to eight treatments before they see any improvement in cheek volume, which is more expensive initially than other treatments, she said. Also, it is difficult to predict how many treatments people will need.

Dr. Baumann tells patients that they will need four to eight treatments 1 month apart, and that they usually will not see changes until the third or fourth treatment. It is worth it, though, “because once you get them the way you want them to look, it lasts 2–3 years,” she said.

The University of Miami was among the Sculptra Aesthetic study sites, and Dr. Baumann said she has been an investigator for Dermik Laboratories (the dermatology division of sanofi-aventis) and other major cosmetic filler manufacturers.

She described Sculptra as a “dermal stimulator” rather than a filler because it stimulates the dermis to make collagen. She cautioned that it should not be used in areas where there is a lot of movement, such as the corner of the mouth, because of the risk of developing hard lumps. “I've seen people with horrible lumps under their eyes and there's nothing you can do,” she said.

Dr. Baumann stressed the need to be properly trained in how to inject Sculptra. When she trains residents, “this is the last thing I'll teach them, because they really have to get their skills down.”

A consumer information page, with alink to the approval letter, is posted at www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm176124.htm

Sculptra Aesthetic

(injectable poly-L-lactic acid, Sanofi-aventis)

Sculptra is an injectable filler containing microparticles of poly-L-lactic acid approved by the Food and Drug Administration in August for use in immune-competent people as a single regimen for the correction of shallow to deep nasolabial fold contour deficiencies and other facial wrinkles “in which deep dermal grid pattern (cross-hatch) injection technique is appropriate,” according to the manufacturer. The injectable was first approved in 2004 for correcting lipoatrophy in HIV patients.

▸ Recommended Usage: Injected into the deep dermis. Injection requirements for Sculptra Aesthetic are “unique,” and include “a tunneling technique in a grid pattern that is medial to the nasolabial fold contour defect” being corrected, according to prescription information.

▸ Special Considerations: Contraindicated in patients with a hypersensitivity to any of the components of this product and those with a known history of keloid formation or hypertrophic scarring. The product has not been studied in the periorbital area, but use in this area has been associated with an increased risk of papules and nodules, according to reports in the literature. Side effects can include injection site discomfort, redness, bruising, bleeding, itching, and swelling, noted the manufacturer.

▸Comment: Poly-L-lactic acid is a biodegradable synthetic polymer that has been widely used for years in dissolvable stitches, bone screws, and facial implants, according to the FDA. A randomized, multicenter, evaluator-blinded controlled study of 233 immune-competent mostly female patients (mean age 51 years) with previously untreated nasolabial fold wrinkles and wrinkle assessment scores of 2 (shallow) through 4 (deep) was conducted.

Patients were treated with bilateral injections of Sculptra Aesthetic (at 3-week intervals for up to four treatments) or with CosmoPlast (INAMED Aesthetics) for a maximum of four sessions over 9 weeks. At 13 months, those who received Sculptra had improvements in wrinkle assessment scores in correction of the contour deficiency of the nasolabial folds. Improvements were maintained among those patients followed for up to 25 months, according to the prescribing information. CosmoPlast results were maintained for up to 3 months.

In an interview, Dr. Leslie S. Baumann, director of cosmetic dermatology at the University of Miami, said that she has used Sculptra off-label for hundreds of patients since it was approved in 2004. It is not her first choice for nasolabial folds, but she likes to use it for improving cheek volume, which is similar to the HIV lipoatrophy indication.

The biggest issue with Sculptra is that patients need to have four to eight treatments before they see any improvement in cheek volume, which is more expensive initially than other treatments, she said. Also, it is difficult to predict how many treatments people will need.

Dr. Baumann tells patients that they will need four to eight treatments 1 month apart, and that they usually will not see changes until the third or fourth treatment. It is worth it, though, “because once you get them the way you want them to look, it lasts 2–3 years,” she said.

The University of Miami was among the Sculptra Aesthetic study sites, and Dr. Baumann said she has been an investigator for Dermik Laboratories (the dermatology division of sanofi-aventis) and other major cosmetic filler manufacturers.

She described Sculptra as a “dermal stimulator” rather than a filler because it stimulates the dermis to make collagen. She cautioned that it should not be used in areas where there is a lot of movement, such as the corner of the mouth, because of the risk of developing hard lumps. “I've seen people with horrible lumps under their eyes and there's nothing you can do,” she said.

Dr. Baumann stressed the need to be properly trained in how to inject Sculptra. When she trains residents, “this is the last thing I'll teach them, because they really have to get their skills down.”

BOSTON — Noninvasive fat removal is now technically possible, but media hype of new devices may lead to unrealistic expectations.

"We can absolutely remove fat without breaking the stratum corneum [using the new devices], but it's important to put context to this," Dr. Mathew M. Avram said at the American Academy of Dermatology's Academy 2009 meeting.

"While [the devices] are effective, the technology is truly limited at this point. There is a long and deserved reputation of snake oil salesmanship in the field of fat, so it is essential that we assess the new tools critically," said Dr. Avram of Harvard Medical School and Massachusetts General Hospital, Boston.

Focused ultrasound, high-intensity focused ultrasound, radiofrequency, and, most recently, cryolipolysis have shown promise as nonsurgical options for trimming fat from the hips, thighs, abdomen, and buttocks, but they are limited in what they can achieve, said Dr. Avram.

Focused ultrasound, for example, uses mechanical energy to target subcutaneous adipose tissue and break up fat cells, which are then flushed out through the liver, he said.

Clinical studies of patients treated with focused ultrasound, which has not yet received FDA approval for this indication, have demonstrated circumference reductions of 2–3 cm at the thighs, flanks, and abdomen with no associated lipid or liver function abnormalities after three treatments.

"The findings are limited, however, because none of the studies used an untreated control group for comparison and all relied on change in circumference as an outcome measure, which is an imprecise measure of improvement. To truly show a reduction in the fat layer, you really need to use MRI, which is expensive, or high-resolution ultrasound—neither of which were done in these studies." The commercial device that uses this technology is used around the world except in the United States, he said.

High-intensity focused ultrasound devices similarly target and ablate subcutaneous fat while leaving the epidermis, dermis, and surrounding tissue unharmed, but they do so by inducing thermal versus mechanical fat injury, said Dr. Avram.

The efficacy of this method of body contouring, which has also not yet received FDA approval, has yet to be demonstrated in clinical studies.

Unipolar and bipolar radiofrequency-based, nonsurgical skin tightening devices, which many clinicians use for "nonsurgical facelift," are also being used to remove localized fat deposits. These devices, which are cleared by the FDA, deliver radiofrequency energy, and sometimes infrared light energy, into fat deposits over multiple weeks to destroy the fat cell membranes and release the fatty acids for removal through the liver, said Dr. Avram. Although the devices are being used and marketed for fat removal, "at this point we're still awaiting studies to determine the efficacy of the technology."

The latest contender to enter the fat-removal ring is a concept known as cryolipolysis, developed at Massachusetts General Hospital, which cools fat to selectively cause cell breakdown without damaging the surrounding tissue ("Cryolipolysis on Track to Become First Cool Way to Remove Cellulite," April 2009, p. 11).

"The technology is based on the concept of cold panniculitis, or popsicle panniculitis, through which cold exposure causes clinically [and histologically] evident inflammation in fat. The inflammation peaks several days or weeks after the exposure with subsequent focal lipoatrophy," said Dr. Avram.

"What we believe is happening is a selective crystallization in lipids in fat cells at temperatures above freezing—in other words there is a different melting point for fat cells than for the [surrounding tissue]—and there is fat cell apoptosis, followed by slow dissolution of the cell with gradual release of lipids over a period of 2–6 weeks," he said.

The technology, which has not received FDA clearance, has shown promise in an initial human study, said Dr. Avram.

The multicenter investigation included 32 male and female subjects with visible fat on the flank (love handles) or back. The patients were treated using a prototype cryolipolysis device on one side with exposure times ranging from 30 to 45 minutes, while the contralateral side served as the untreated control. Outcome measures included fat-layer reduction as measured by ultrasound, comparison of pre- and posttreatment photographs, and physician assessment.

"At 4 months post treatment, a visible contour change was observed in most of the subjects," said Dr. Avram. Specifically, he noted, ultrasound measurements taken on a subset of 10 subjects demonstrated a fat layer reduction in all; the average reduction was 22.4%.

Among the treatment-related side effects, some of the patients experienced redness at the treatment site that lasted for minutes to hours, as well as bruising and dulling of sensation in the treatment area that resolved within 1–8 weeks, Dr. Avram said, noting that "there were no pigmentary changes, nor were there any lab abnormalities suggesting systemic side effects."

Further studies are needed to establish optimal treatment parameters, but these early results suggest that cryolipolysis will likely be best suited for localized fat removal in areas that are particularly resistant to exercise, he said.

Despite the apparent promise of the new technologies, Dr. Avram was quick to stress that the "clear but limited noninvasive fat removal achieved with these devices is in no way, shape, or form a competitor for liposuction." They are noninvasive alternatives that can achieve certain results, which should be made clear to patients.

Dr. Avram has conducted research for Candela Corp. and owns stock options in Zeltiq Aesthetics, which holds the cryolipolysis patent.

BOSTON — Noninvasive fat removal is now technically possible, but media hype of new devices may lead to unrealistic expectations.

"We can absolutely remove fat without breaking the stratum corneum [using the new devices], but it's important to put context to this," Dr. Mathew M. Avram said at the American Academy of Dermatology's Academy 2009 meeting.

"While [the devices] are effective, the technology is truly limited at this point. There is a long and deserved reputation of snake oil salesmanship in the field of fat, so it is essential that we assess the new tools critically," said Dr. Avram of Harvard Medical School and Massachusetts General Hospital, Boston.

Focused ultrasound, high-intensity focused ultrasound, radiofrequency, and, most recently, cryolipolysis have shown promise as nonsurgical options for trimming fat from the hips, thighs, abdomen, and buttocks, but they are limited in what they can achieve, said Dr. Avram.

Focused ultrasound, for example, uses mechanical energy to target subcutaneous adipose tissue and break up fat cells, which are then flushed out through the liver, he said.

Clinical studies of patients treated with focused ultrasound, which has not yet received FDA approval for this indication, have demonstrated circumference reductions of 2–3 cm at the thighs, flanks, and abdomen with no associated lipid or liver function abnormalities after three treatments.

"The findings are limited, however, because none of the studies used an untreated control group for comparison and all relied on change in circumference as an outcome measure, which is an imprecise measure of improvement. To truly show a reduction in the fat layer, you really need to use MRI, which is expensive, or high-resolution ultrasound—neither of which were done in these studies." The commercial device that uses this technology is used around the world except in the United States, he said.

High-intensity focused ultrasound devices similarly target and ablate subcutaneous fat while leaving the epidermis, dermis, and surrounding tissue unharmed, but they do so by inducing thermal versus mechanical fat injury, said Dr. Avram.

The efficacy of this method of body contouring, which has also not yet received FDA approval, has yet to be demonstrated in clinical studies.

Unipolar and bipolar radiofrequency-based, nonsurgical skin tightening devices, which many clinicians use for "nonsurgical facelift," are also being used to remove localized fat deposits. These devices, which are cleared by the FDA, deliver radiofrequency energy, and sometimes infrared light energy, into fat deposits over multiple weeks to destroy the fat cell membranes and release the fatty acids for removal through the liver, said Dr. Avram. Although the devices are being used and marketed for fat removal, "at this point we're still awaiting studies to determine the efficacy of the technology."

The latest contender to enter the fat-removal ring is a concept known as cryolipolysis, developed at Massachusetts General Hospital, which cools fat to selectively cause cell breakdown without damaging the surrounding tissue ("Cryolipolysis on Track to Become First Cool Way to Remove Cellulite," April 2009, p. 11).

"The technology is based on the concept of cold panniculitis, or popsicle panniculitis, through which cold exposure causes clinically [and histologically] evident inflammation in fat. The inflammation peaks several days or weeks after the exposure with subsequent focal lipoatrophy," said Dr. Avram.

"What we believe is happening is a selective crystallization in lipids in fat cells at temperatures above freezing—in other words there is a different melting point for fat cells than for the [surrounding tissue]—and there is fat cell apoptosis, followed by slow dissolution of the cell with gradual release of lipids over a period of 2–6 weeks," he said.

The technology, which has not received FDA clearance, has shown promise in an initial human study, said Dr. Avram.

The multicenter investigation included 32 male and female subjects with visible fat on the flank (love handles) or back. The patients were treated using a prototype cryolipolysis device on one side with exposure times ranging from 30 to 45 minutes, while the contralateral side served as the untreated control. Outcome measures included fat-layer reduction as measured by ultrasound, comparison of pre- and posttreatment photographs, and physician assessment.

"At 4 months post treatment, a visible contour change was observed in most of the subjects," said Dr. Avram. Specifically, he noted, ultrasound measurements taken on a subset of 10 subjects demonstrated a fat layer reduction in all; the average reduction was 22.4%.

Among the treatment-related side effects, some of the patients experienced redness at the treatment site that lasted for minutes to hours, as well as bruising and dulling of sensation in the treatment area that resolved within 1–8 weeks, Dr. Avram said, noting that "there were no pigmentary changes, nor were there any lab abnormalities suggesting systemic side effects."

Further studies are needed to establish optimal treatment parameters, but these early results suggest that cryolipolysis will likely be best suited for localized fat removal in areas that are particularly resistant to exercise, he said.

Despite the apparent promise of the new technologies, Dr. Avram was quick to stress that the "clear but limited noninvasive fat removal achieved with these devices is in no way, shape, or form a competitor for liposuction." They are noninvasive alternatives that can achieve certain results, which should be made clear to patients.

Dr. Avram has conducted research for Candela Corp. and owns stock options in Zeltiq Aesthetics, which holds the cryolipolysis patent.

BOSTON — Noninvasive fat removal is now technically possible, but media hype of new devices may lead to unrealistic expectations.

"We can absolutely remove fat without breaking the stratum corneum [using the new devices], but it's important to put context to this," Dr. Mathew M. Avram said at the American Academy of Dermatology's Academy 2009 meeting.

"While [the devices] are effective, the technology is truly limited at this point. There is a long and deserved reputation of snake oil salesmanship in the field of fat, so it is essential that we assess the new tools critically," said Dr. Avram of Harvard Medical School and Massachusetts General Hospital, Boston.

Focused ultrasound, high-intensity focused ultrasound, radiofrequency, and, most recently, cryolipolysis have shown promise as nonsurgical options for trimming fat from the hips, thighs, abdomen, and buttocks, but they are limited in what they can achieve, said Dr. Avram.

Focused ultrasound, for example, uses mechanical energy to target subcutaneous adipose tissue and break up fat cells, which are then flushed out through the liver, he said.

Clinical studies of patients treated with focused ultrasound, which has not yet received FDA approval for this indication, have demonstrated circumference reductions of 2–3 cm at the thighs, flanks, and abdomen with no associated lipid or liver function abnormalities after three treatments.

"The findings are limited, however, because none of the studies used an untreated control group for comparison and all relied on change in circumference as an outcome measure, which is an imprecise measure of improvement. To truly show a reduction in the fat layer, you really need to use MRI, which is expensive, or high-resolution ultrasound—neither of which were done in these studies." The commercial device that uses this technology is used around the world except in the United States, he said.

High-intensity focused ultrasound devices similarly target and ablate subcutaneous fat while leaving the epidermis, dermis, and surrounding tissue unharmed, but they do so by inducing thermal versus mechanical fat injury, said Dr. Avram.

The efficacy of this method of body contouring, which has also not yet received FDA approval, has yet to be demonstrated in clinical studies.

Unipolar and bipolar radiofrequency-based, nonsurgical skin tightening devices, which many clinicians use for "nonsurgical facelift," are also being used to remove localized fat deposits. These devices, which are cleared by the FDA, deliver radiofrequency energy, and sometimes infrared light energy, into fat deposits over multiple weeks to destroy the fat cell membranes and release the fatty acids for removal through the liver, said Dr. Avram. Although the devices are being used and marketed for fat removal, "at this point we're still awaiting studies to determine the efficacy of the technology."

The latest contender to enter the fat-removal ring is a concept known as cryolipolysis, developed at Massachusetts General Hospital, which cools fat to selectively cause cell breakdown without damaging the surrounding tissue ("Cryolipolysis on Track to Become First Cool Way to Remove Cellulite," April 2009, p. 11).

"The technology is based on the concept of cold panniculitis, or popsicle panniculitis, through which cold exposure causes clinically [and histologically] evident inflammation in fat. The inflammation peaks several days or weeks after the exposure with subsequent focal lipoatrophy," said Dr. Avram.

"What we believe is happening is a selective crystallization in lipids in fat cells at temperatures above freezing—in other words there is a different melting point for fat cells than for the [surrounding tissue]—and there is fat cell apoptosis, followed by slow dissolution of the cell with gradual release of lipids over a period of 2–6 weeks," he said.

The technology, which has not received FDA clearance, has shown promise in an initial human study, said Dr. Avram.

The multicenter investigation included 32 male and female subjects with visible fat on the flank (love handles) or back. The patients were treated using a prototype cryolipolysis device on one side with exposure times ranging from 30 to 45 minutes, while the contralateral side served as the untreated control. Outcome measures included fat-layer reduction as measured by ultrasound, comparison of pre- and posttreatment photographs, and physician assessment.

"At 4 months post treatment, a visible contour change was observed in most of the subjects," said Dr. Avram. Specifically, he noted, ultrasound measurements taken on a subset of 10 subjects demonstrated a fat layer reduction in all; the average reduction was 22.4%.

Among the treatment-related side effects, some of the patients experienced redness at the treatment site that lasted for minutes to hours, as well as bruising and dulling of sensation in the treatment area that resolved within 1–8 weeks, Dr. Avram said, noting that "there were no pigmentary changes, nor were there any lab abnormalities suggesting systemic side effects."

Further studies are needed to establish optimal treatment parameters, but these early results suggest that cryolipolysis will likely be best suited for localized fat removal in areas that are particularly resistant to exercise, he said.

Despite the apparent promise of the new technologies, Dr. Avram was quick to stress that the "clear but limited noninvasive fat removal achieved with these devices is in no way, shape, or form a competitor for liposuction." They are noninvasive alternatives that can achieve certain results, which should be made clear to patients.

Dr. Avram has conducted research for Candela Corp. and owns stock options in Zeltiq Aesthetics, which holds the cryolipolysis patent.