Psoriasis and acne appear to be susceptible to seasonal variations of clearing and worsening, with an analysis revealing both conditions maintained a significant trend of summer clearing and winter worsening, according to a research letter published in the Journal of the American Academy of Dermatology.

Using Physician’s Global Assessment scales for psoriasis and acne, Dr. Vanessa Lindsay Pascoe and Dr. Alexandra Boer Kimball, both of Massachusetts General Hospital, Boston, collected data from 5,468 psoriasis patients and 9,301 acne patients between June 2011 and May 2014 in the New England area. Among the psoriasis patient group, 16% were seen in the summer, 25% in the fall, 31% in the winter, and 28% in the spring. The trend was similar for acne patients, with 18% seen in the summer, 25% in the fall, 28% in the winter, and 29% in the spring. There were no significant seasonal differences in age or sex for either group.

©olavs/thinkstockphotos.com

The percentage of psoriasis patients with clear/almost clear disease was highest in the summer at 20.4%, while the percentage of patients with moderate/severe disease was highest in the winter at 40.5%. For acne, the percentage of patients with clear/almost clear disease was highest in the fall at 17.5%, and the percentage of patients with moderate/severe disease was highest in the winter at 45.9%. Fewer psoriasis and acne patients presented to the clinic in the summer, which the researchers suggested could be due to disease improvement.

“Although the climate of the Northeastern United States may not generalize to regions with less seasonal variation, providers may consider seasonal adjustment of acne plans as they have traditionally done for psoriasis,” the authors wrote. “For example, they may wait until after winter to taper a systemic antibiotic for acne, just as some providers may wait until spring to change systemic psoriasis treatments.”

Read the full article in the Journal of the American Academy of Dermatology.

[email protected]

Psoriasis and acne appear to be susceptible to seasonal variations of clearing and worsening, with an analysis revealing both conditions maintained a significant trend of summer clearing and winter worsening, according to a research letter published in the Journal of the American Academy of Dermatology.

Using Physician’s Global Assessment scales for psoriasis and acne, Dr. Vanessa Lindsay Pascoe and Dr. Alexandra Boer Kimball, both of Massachusetts General Hospital, Boston, collected data from 5,468 psoriasis patients and 9,301 acne patients between June 2011 and May 2014 in the New England area. Among the psoriasis patient group, 16% were seen in the summer, 25% in the fall, 31% in the winter, and 28% in the spring. The trend was similar for acne patients, with 18% seen in the summer, 25% in the fall, 28% in the winter, and 29% in the spring. There were no significant seasonal differences in age or sex for either group.

©olavs/thinkstockphotos.com

The percentage of psoriasis patients with clear/almost clear disease was highest in the summer at 20.4%, while the percentage of patients with moderate/severe disease was highest in the winter at 40.5%. For acne, the percentage of patients with clear/almost clear disease was highest in the fall at 17.5%, and the percentage of patients with moderate/severe disease was highest in the winter at 45.9%. Fewer psoriasis and acne patients presented to the clinic in the summer, which the researchers suggested could be due to disease improvement.

“Although the climate of the Northeastern United States may not generalize to regions with less seasonal variation, providers may consider seasonal adjustment of acne plans as they have traditionally done for psoriasis,” the authors wrote. “For example, they may wait until after winter to taper a systemic antibiotic for acne, just as some providers may wait until spring to change systemic psoriasis treatments.”

Read the full article in the Journal of the American Academy of Dermatology.

[email protected]

Psoriasis and acne appear to be susceptible to seasonal variations of clearing and worsening, with an analysis revealing both conditions maintained a significant trend of summer clearing and winter worsening, according to a research letter published in the Journal of the American Academy of Dermatology.

Using Physician’s Global Assessment scales for psoriasis and acne, Dr. Vanessa Lindsay Pascoe and Dr. Alexandra Boer Kimball, both of Massachusetts General Hospital, Boston, collected data from 5,468 psoriasis patients and 9,301 acne patients between June 2011 and May 2014 in the New England area. Among the psoriasis patient group, 16% were seen in the summer, 25% in the fall, 31% in the winter, and 28% in the spring. The trend was similar for acne patients, with 18% seen in the summer, 25% in the fall, 28% in the winter, and 29% in the spring. There were no significant seasonal differences in age or sex for either group.

©olavs/thinkstockphotos.com

The percentage of psoriasis patients with clear/almost clear disease was highest in the summer at 20.4%, while the percentage of patients with moderate/severe disease was highest in the winter at 40.5%. For acne, the percentage of patients with clear/almost clear disease was highest in the fall at 17.5%, and the percentage of patients with moderate/severe disease was highest in the winter at 45.9%. Fewer psoriasis and acne patients presented to the clinic in the summer, which the researchers suggested could be due to disease improvement.

“Although the climate of the Northeastern United States may not generalize to regions with less seasonal variation, providers may consider seasonal adjustment of acne plans as they have traditionally done for psoriasis,” the authors wrote. “For example, they may wait until after winter to taper a systemic antibiotic for acne, just as some providers may wait until spring to change systemic psoriasis treatments.”

Read the full article in the Journal of the American Academy of Dermatology.

[email protected]

Cryptogenic stroke patients and their caregivers recently surveyed by the American Heart Association/American Stroke Association said that they experience several negative consequences of having an undetermined cause of their stroke, and only one-fifth received information about cryptogenic stroke at the time of diagnosis.

This lack of information prompted the organization to start the Cryptogenic Stroke Initiative. The initiative will inform cryptogenic stroke patients and help “them to work with their healthcare team to prevent a second stroke,” Dr. Mary Ann Bauman, chair of the American Stroke Association Advisory Committee, said in an announcement.

©American Stroke Association

This month, the American Heart Association/American Stroke Association, with support from Medtronic, published a free informational document. This Patient Guide to Cryptogenic Stroke is the first of several guides that the American Stroke Association plans to create for cryptogenic stroke patients. This edition of the guide includes “information on cryptogenic stroke diagnosis, what happens during a stroke, secondary prevention information, questions [for patients to ask their doctor, and] support resources,” the Association said.

In the organizations’ survey, which included 309 cryptogenic stroke patients and caregivers, more than 50% reported anxiety and frustration when the cause of stroke is undetermined. Of the 20% of patients and caregivers who received information about cryptogenic stroke at the time of diagnosis, the information was verbally communicated 75% of the time.

[email protected]

Cryptogenic stroke patients and their caregivers recently surveyed by the American Heart Association/American Stroke Association said that they experience several negative consequences of having an undetermined cause of their stroke, and only one-fifth received information about cryptogenic stroke at the time of diagnosis.

This lack of information prompted the organization to start the Cryptogenic Stroke Initiative. The initiative will inform cryptogenic stroke patients and help “them to work with their healthcare team to prevent a second stroke,” Dr. Mary Ann Bauman, chair of the American Stroke Association Advisory Committee, said in an announcement.

©American Stroke Association

This month, the American Heart Association/American Stroke Association, with support from Medtronic, published a free informational document. This Patient Guide to Cryptogenic Stroke is the first of several guides that the American Stroke Association plans to create for cryptogenic stroke patients. This edition of the guide includes “information on cryptogenic stroke diagnosis, what happens during a stroke, secondary prevention information, questions [for patients to ask their doctor, and] support resources,” the Association said.

In the organizations’ survey, which included 309 cryptogenic stroke patients and caregivers, more than 50% reported anxiety and frustration when the cause of stroke is undetermined. Of the 20% of patients and caregivers who received information about cryptogenic stroke at the time of diagnosis, the information was verbally communicated 75% of the time.

[email protected]

Cryptogenic stroke patients and their caregivers recently surveyed by the American Heart Association/American Stroke Association said that they experience several negative consequences of having an undetermined cause of their stroke, and only one-fifth received information about cryptogenic stroke at the time of diagnosis.

This lack of information prompted the organization to start the Cryptogenic Stroke Initiative. The initiative will inform cryptogenic stroke patients and help “them to work with their healthcare team to prevent a second stroke,” Dr. Mary Ann Bauman, chair of the American Stroke Association Advisory Committee, said in an announcement.

©American Stroke Association

This month, the American Heart Association/American Stroke Association, with support from Medtronic, published a free informational document. This Patient Guide to Cryptogenic Stroke is the first of several guides that the American Stroke Association plans to create for cryptogenic stroke patients. This edition of the guide includes “information on cryptogenic stroke diagnosis, what happens during a stroke, secondary prevention information, questions [for patients to ask their doctor, and] support resources,” the Association said.

In the organizations’ survey, which included 309 cryptogenic stroke patients and caregivers, more than 50% reported anxiety and frustration when the cause of stroke is undetermined. Of the 20% of patients and caregivers who received information about cryptogenic stroke at the time of diagnosis, the information was verbally communicated 75% of the time.

[email protected]

There was a 2.4-fold increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), for Air Force veterans exposed to Agent Orange, according to a study reported in JAMA Oncology. Already, veterans who develop MM and were exposed to Agent Orange during military service are eligible to receive benefits, but the study further highlights the relationship.

Related: Management of Myeloma and Its Precursor Syndromes

The Agent Orange used during aerial spray missions of herbicides in the Vietnam War contained 2, 4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), as well as human carcinogen 2,3,7,8-tetrachlorodibenzo-p-doxin in variable amounts. After obtaining the laboratory data from 958 serum samples from Air Force personnel, the Air Force Health Studies questionnaire, and results from the physical exam from all participants, researchers were able to compare their findings with control group veterans.

Related: Nephrotic Syndrome Is a Marker for Occult Cancer

The researchers created 2 test groups from Air Force veterans. The first were 777 participants of Operation Ranch Hand, who conducted aerial herbicidal missions from 1962 to 1971, and the second group was made up of 1,174 participants, who had similar duties but did not participate in the missions.

The risk of MGUS was more pronounced in veterans aged > 70 years (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.27-4.44; P = .007). Among veterans aged > 70 years, there was not a significant increase in risk (OR, 1.4%; 95% CI, 0.55-3.63; P = .63). The crude prevalence of overall MGUS was 7.1% (34 of 479) in the exposed veterans, compared with 3.1% (15 of 479) in the comparison group.

Source
Landgren O, Shim YK, Michalek J, et al. JAMA Oncol. [Published online ahead of print September 3, 2015.]
doi: 10.1001/jamaoncol.2015.2938.

There was a 2.4-fold increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), for Air Force veterans exposed to Agent Orange, according to a study reported in JAMA Oncology. Already, veterans who develop MM and were exposed to Agent Orange during military service are eligible to receive benefits, but the study further highlights the relationship.

Related: Management of Myeloma and Its Precursor Syndromes

The Agent Orange used during aerial spray missions of herbicides in the Vietnam War contained 2, 4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), as well as human carcinogen 2,3,7,8-tetrachlorodibenzo-p-doxin in variable amounts. After obtaining the laboratory data from 958 serum samples from Air Force personnel, the Air Force Health Studies questionnaire, and results from the physical exam from all participants, researchers were able to compare their findings with control group veterans.

Related: Nephrotic Syndrome Is a Marker for Occult Cancer

The researchers created 2 test groups from Air Force veterans. The first were 777 participants of Operation Ranch Hand, who conducted aerial herbicidal missions from 1962 to 1971, and the second group was made up of 1,174 participants, who had similar duties but did not participate in the missions.

The risk of MGUS was more pronounced in veterans aged > 70 years (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.27-4.44; P = .007). Among veterans aged > 70 years, there was not a significant increase in risk (OR, 1.4%; 95% CI, 0.55-3.63; P = .63). The crude prevalence of overall MGUS was 7.1% (34 of 479) in the exposed veterans, compared with 3.1% (15 of 479) in the comparison group.

Source
Landgren O, Shim YK, Michalek J, et al. JAMA Oncol. [Published online ahead of print September 3, 2015.]
doi: 10.1001/jamaoncol.2015.2938.

There was a 2.4-fold increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), for Air Force veterans exposed to Agent Orange, according to a study reported in JAMA Oncology. Already, veterans who develop MM and were exposed to Agent Orange during military service are eligible to receive benefits, but the study further highlights the relationship.

Related: Management of Myeloma and Its Precursor Syndromes

The Agent Orange used during aerial spray missions of herbicides in the Vietnam War contained 2, 4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), as well as human carcinogen 2,3,7,8-tetrachlorodibenzo-p-doxin in variable amounts. After obtaining the laboratory data from 958 serum samples from Air Force personnel, the Air Force Health Studies questionnaire, and results from the physical exam from all participants, researchers were able to compare their findings with control group veterans.

Related: Nephrotic Syndrome Is a Marker for Occult Cancer

The researchers created 2 test groups from Air Force veterans. The first were 777 participants of Operation Ranch Hand, who conducted aerial herbicidal missions from 1962 to 1971, and the second group was made up of 1,174 participants, who had similar duties but did not participate in the missions.

The risk of MGUS was more pronounced in veterans aged > 70 years (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.27-4.44; P = .007). Among veterans aged > 70 years, there was not a significant increase in risk (OR, 1.4%; 95% CI, 0.55-3.63; P = .63). The crude prevalence of overall MGUS was 7.1% (34 of 479) in the exposed veterans, compared with 3.1% (15 of 479) in the comparison group.

Source
Landgren O, Shim YK, Michalek J, et al. JAMA Oncol. [Published online ahead of print September 3, 2015.]
doi: 10.1001/jamaoncol.2015.2938.

Pogostemon cablin, known in the West as patchouli or guang huo-xiang in China, is a long-time staple in traditional Chinese medicine for various indications, particularly gastrointestinal and skin disorders¹.

Patchouli oil, which contains several mono- and sesquiterpenoids, alkaloids, and flavonoids, is thought to possess significant anti-inflammatory and antioxidant qualities².In fact, it is reputed to impart antiviral, antioxidant, anti-inflammatory, and analgesic effects, and is also known to protect intestinal barrier function³. Peng et al. have found that patchouli oil exerts significant antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)^4.

After a comprehensive 2013 review, Chen et al. deemed P. cablin to have potential clinical benefits as an effective adaptogenic herbal treatment³. It is thought to have some antiacne properties as well¹. Further, P. cablin is among the Top 10 most-often-used traditional Chinese medicine prescriptions for skin care and appearance¹.

In Brazil, China, Indonesia, and Malaysia, P. cablin is cultivated for its essential oil, which plays an important role in the perfume industry. Patchouli essential oil, featured in perfumes, soaps, cosmetics, and as incense, is used by aromatherapists for its calming and reviving effects. The essential oil has also been shown to impart antioxidant activity⁵.

In 2014, Lin et al. studied the protective effects of P. cablin essential oil against ultraviolet (UV)-induced skin photoaging in mice. The researchers applied patchouli oil for 2 hours before UV exposure to the dorsal depilated skin of mice. They found that patchouli oil doses of 6 mg/mouse and 9 mg/mouse significantly suppressed skin wrinkle formation, mitigated skin elasticity impairment, and augmented collagen content (21.9% and 26.3%, respectively). The same doses also yielded significant reductions in epidermal thickness and malondialdehyde content, and blocked the disruption of collagen and elastic fibers. Patchouli oil treatment also resulted in the up-regulation of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. The investigators concluded that patchouli oil, perhaps due to its antioxidant characteristics, and sesquiterpene constituents in particular, was effective in preventing photoaging in mice, and warrants attention as a potential agent to hinder photoaging in humans¹.

Feng et al. also investigated the effects of topically applied patchouli alcohol on UV-induced photoaging in mice that year. For 9 weeks, investigators applied patchouli oil solution or a vehicle to the depilated dorsal skin of 6-week-old mice. They found that patchouli oil significantly hastened the recovery of UV-induced skin lesions, which they ascribed to the antioxidant and anti-inflammatory activity of the agent and its down-regulation of the expression of matrix metalloproteinase (MMP)-1 and MMP-3².

Antimicrobial and mosquito repellent activity

In a 2005 study by Trongtokit et al. of the mosquito-repellent activity of 38 essential oils at three concentrations (10%, 50%, or undiluted) against the mosquito Aedes aegypti under laboratory conditions using human volunteers, undiluted P. cablin oil was one of four [along with Cymbopogon nardus (citronella), Syzygium aromaticum (clove), and Zanthoxylum limonella (Thai name: makaen)] undiluted oils to yield an effect, 2 hours of full repellency. The investigators then tested the same concentrations of these oils for repellency against Culex quinquefasciatus (the Southern house mosquito) and Anopheles dirus (the mosquito considered to be a vector of malaria in Asian forested zones. The undiluted oils provided the greatest protection, with clove oil rendering the most durable repellency⁶.

Photoaging

Forest & Kim Starr/Wikimedia Commons/CC BY 3.0

Wu et al. determined the acaricidal activity of compounds extracted from patchouli oil against the house dust mite (Dermatophagoides farinae) in 2012. They isolated 2-(1,3-dihydroxy-but-2-enylidene)-6-methyl-3-oxo-heptanoic acid (DHEMH), the hydrolysate of pogostone, and 15 other constituents in patchouli oil, ultimately ascertaining that DHEMH and patchouli oil itself were the most toxic substances to D. farinae. The investigators concluded that patchouli oil and DHEMH warrant consideration and more study for their acaricidal potential as environmentally friendly, effective, and simple fumigant alternatives to chemical agents⁷.

In 2013, Yang et al. used molecular docking technology to evaluate the antibacterial activity of patchouli oil in vitro. They identified 26 compounds in patchouli oil displaying antibacterial activity, with pogostone and (-)-patchouli alcohol exhibiting the strongest activity⁸. Later that year, Yang et al. used the same technology to establish that Herba pogostemonis oil exhibited potent antibacterial effects, especially the constituents pogostone and (-)-Herba pogostemonis alcohol⁹. Raharjo and Fatchiyah also used molecular docking tools and Chimera 1.7s viewer software in a virtual screening of compounds from patchouli oil, concluding that alpha-patchouli alcohol is a potential inhibitor of the cyclo-oxygenase (COX)-1 enzyme. This is notable given the pivotal role of COX-1 in the inflammatory response¹⁰.

The next year, Peng et al. isolated one of the primary constituents of patchouli oil, pogostone, and assessed its antibacterial activity in vitro and in vivo. They found that pogostone suppressed both gram-negative and gram-positive bacteria in vitro. The researchers noted that pogostone was active against some drug-resistant bacteria (such as MRSA). Via intraperitoneal injection, pogostone displayed antibacterial activity in male and female Kunming mice against Escherichia coli and MRSA. At concentrations of 50 and 100 mg/kg, 90% of the mice infected with E. coli were protected; 60% of the mice at 25 mg/kg were protected. For mice with MRSA, 60% were protected at a dose of 100 mg/kg and 50% at a dose of 50 mg/kg. The investigators concluded that pogostone is a viable antibacterial agent for clinical use⁴.

Transdermal delivery

A 2008 study by Luo et al. showed that patchouli oil was among three volatile oils that improved the skin penetration of the flavonoids baicalin¹¹. It was less effective than several compounds, including clove oil, camphor, menthol, and oleic acid, as a transdermal enhancer in a subsequent study by Zheng et al.¹².

Conclusion

Patchouli oil continues to be used today in traditional Chinese medicine. In the West, the established literature on Pogostemon cablin is thin, but what has emerged recently, particularly studies on the protection against photoaging in mice, supports the continued investigation of this ancient herb to determine its potential role in dermatologic practice. As it is, much more research is necessary.

References

1. J Ethnopharmacol. 2014;154(2):408-18.

2. Eur J Pharm Sci. 2014;63:113-23.

3. Expert Opin Investig Drugs. 2013;22(2):245-57.

4. Chin Med J. (Engl) 2014;127(23):4001-5.

5. J Agric Food Chem. 2007;55(5):1737-42

6. Phytother Res. 2005;19(4):303-9.

7. Chem Pharm Bull (Tokyo). 2012;60(2):178-82.

8. Iran J Pharm Res. 2013 Summer;12(3):307-16.

9. Pak J Pharm Sci. 2013;26(6):1173-9.

10. Bioinformation 2013;9(6):321-4.

11. Zhong Yao Cai. 2008;31(11):1721-4

12. Zhongguo Zhong Yao Za Zhi. 2009;34(20):2599-603.

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

Pogostemon cablin, known in the West as patchouli or guang huo-xiang in China, is a long-time staple in traditional Chinese medicine for various indications, particularly gastrointestinal and skin disorders¹.

Patchouli oil, which contains several mono- and sesquiterpenoids, alkaloids, and flavonoids, is thought to possess significant anti-inflammatory and antioxidant qualities².In fact, it is reputed to impart antiviral, antioxidant, anti-inflammatory, and analgesic effects, and is also known to protect intestinal barrier function³. Peng et al. have found that patchouli oil exerts significant antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)^4.

After a comprehensive 2013 review, Chen et al. deemed P. cablin to have potential clinical benefits as an effective adaptogenic herbal treatment³. It is thought to have some antiacne properties as well¹. Further, P. cablin is among the Top 10 most-often-used traditional Chinese medicine prescriptions for skin care and appearance¹.

In Brazil, China, Indonesia, and Malaysia, P. cablin is cultivated for its essential oil, which plays an important role in the perfume industry. Patchouli essential oil, featured in perfumes, soaps, cosmetics, and as incense, is used by aromatherapists for its calming and reviving effects. The essential oil has also been shown to impart antioxidant activity⁵.

In 2014, Lin et al. studied the protective effects of P. cablin essential oil against ultraviolet (UV)-induced skin photoaging in mice. The researchers applied patchouli oil for 2 hours before UV exposure to the dorsal depilated skin of mice. They found that patchouli oil doses of 6 mg/mouse and 9 mg/mouse significantly suppressed skin wrinkle formation, mitigated skin elasticity impairment, and augmented collagen content (21.9% and 26.3%, respectively). The same doses also yielded significant reductions in epidermal thickness and malondialdehyde content, and blocked the disruption of collagen and elastic fibers. Patchouli oil treatment also resulted in the up-regulation of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. The investigators concluded that patchouli oil, perhaps due to its antioxidant characteristics, and sesquiterpene constituents in particular, was effective in preventing photoaging in mice, and warrants attention as a potential agent to hinder photoaging in humans¹.

Feng et al. also investigated the effects of topically applied patchouli alcohol on UV-induced photoaging in mice that year. For 9 weeks, investigators applied patchouli oil solution or a vehicle to the depilated dorsal skin of 6-week-old mice. They found that patchouli oil significantly hastened the recovery of UV-induced skin lesions, which they ascribed to the antioxidant and anti-inflammatory activity of the agent and its down-regulation of the expression of matrix metalloproteinase (MMP)-1 and MMP-3².

Antimicrobial and mosquito repellent activity

In a 2005 study by Trongtokit et al. of the mosquito-repellent activity of 38 essential oils at three concentrations (10%, 50%, or undiluted) against the mosquito Aedes aegypti under laboratory conditions using human volunteers, undiluted P. cablin oil was one of four [along with Cymbopogon nardus (citronella), Syzygium aromaticum (clove), and Zanthoxylum limonella (Thai name: makaen)] undiluted oils to yield an effect, 2 hours of full repellency. The investigators then tested the same concentrations of these oils for repellency against Culex quinquefasciatus (the Southern house mosquito) and Anopheles dirus (the mosquito considered to be a vector of malaria in Asian forested zones. The undiluted oils provided the greatest protection, with clove oil rendering the most durable repellency⁶.

Photoaging

Forest & Kim Starr/Wikimedia Commons/CC BY 3.0

Wu et al. determined the acaricidal activity of compounds extracted from patchouli oil against the house dust mite (Dermatophagoides farinae) in 2012. They isolated 2-(1,3-dihydroxy-but-2-enylidene)-6-methyl-3-oxo-heptanoic acid (DHEMH), the hydrolysate of pogostone, and 15 other constituents in patchouli oil, ultimately ascertaining that DHEMH and patchouli oil itself were the most toxic substances to D. farinae. The investigators concluded that patchouli oil and DHEMH warrant consideration and more study for their acaricidal potential as environmentally friendly, effective, and simple fumigant alternatives to chemical agents⁷.

In 2013, Yang et al. used molecular docking technology to evaluate the antibacterial activity of patchouli oil in vitro. They identified 26 compounds in patchouli oil displaying antibacterial activity, with pogostone and (-)-patchouli alcohol exhibiting the strongest activity⁸. Later that year, Yang et al. used the same technology to establish that Herba pogostemonis oil exhibited potent antibacterial effects, especially the constituents pogostone and (-)-Herba pogostemonis alcohol⁹. Raharjo and Fatchiyah also used molecular docking tools and Chimera 1.7s viewer software in a virtual screening of compounds from patchouli oil, concluding that alpha-patchouli alcohol is a potential inhibitor of the cyclo-oxygenase (COX)-1 enzyme. This is notable given the pivotal role of COX-1 in the inflammatory response¹⁰.

The next year, Peng et al. isolated one of the primary constituents of patchouli oil, pogostone, and assessed its antibacterial activity in vitro and in vivo. They found that pogostone suppressed both gram-negative and gram-positive bacteria in vitro. The researchers noted that pogostone was active against some drug-resistant bacteria (such as MRSA). Via intraperitoneal injection, pogostone displayed antibacterial activity in male and female Kunming mice against Escherichia coli and MRSA. At concentrations of 50 and 100 mg/kg, 90% of the mice infected with E. coli were protected; 60% of the mice at 25 mg/kg were protected. For mice with MRSA, 60% were protected at a dose of 100 mg/kg and 50% at a dose of 50 mg/kg. The investigators concluded that pogostone is a viable antibacterial agent for clinical use⁴.

Transdermal delivery

A 2008 study by Luo et al. showed that patchouli oil was among three volatile oils that improved the skin penetration of the flavonoids baicalin¹¹. It was less effective than several compounds, including clove oil, camphor, menthol, and oleic acid, as a transdermal enhancer in a subsequent study by Zheng et al.¹².

Conclusion

Patchouli oil continues to be used today in traditional Chinese medicine. In the West, the established literature on Pogostemon cablin is thin, but what has emerged recently, particularly studies on the protection against photoaging in mice, supports the continued investigation of this ancient herb to determine its potential role in dermatologic practice. As it is, much more research is necessary.

References

1. J Ethnopharmacol. 2014;154(2):408-18.

2. Eur J Pharm Sci. 2014;63:113-23.

3. Expert Opin Investig Drugs. 2013;22(2):245-57.

4. Chin Med J. (Engl) 2014;127(23):4001-5.

5. J Agric Food Chem. 2007;55(5):1737-42

6. Phytother Res. 2005;19(4):303-9.

7. Chem Pharm Bull (Tokyo). 2012;60(2):178-82.

8. Iran J Pharm Res. 2013 Summer;12(3):307-16.

9. Pak J Pharm Sci. 2013;26(6):1173-9.

10. Bioinformation 2013;9(6):321-4.

11. Zhong Yao Cai. 2008;31(11):1721-4

12. Zhongguo Zhong Yao Za Zhi. 2009;34(20):2599-603.

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

Pogostemon cablin, known in the West as patchouli or guang huo-xiang in China, is a long-time staple in traditional Chinese medicine for various indications, particularly gastrointestinal and skin disorders¹.

Patchouli oil, which contains several mono- and sesquiterpenoids, alkaloids, and flavonoids, is thought to possess significant anti-inflammatory and antioxidant qualities².In fact, it is reputed to impart antiviral, antioxidant, anti-inflammatory, and analgesic effects, and is also known to protect intestinal barrier function³. Peng et al. have found that patchouli oil exerts significant antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)^4.

After a comprehensive 2013 review, Chen et al. deemed P. cablin to have potential clinical benefits as an effective adaptogenic herbal treatment³. It is thought to have some antiacne properties as well¹. Further, P. cablin is among the Top 10 most-often-used traditional Chinese medicine prescriptions for skin care and appearance¹.

In Brazil, China, Indonesia, and Malaysia, P. cablin is cultivated for its essential oil, which plays an important role in the perfume industry. Patchouli essential oil, featured in perfumes, soaps, cosmetics, and as incense, is used by aromatherapists for its calming and reviving effects. The essential oil has also been shown to impart antioxidant activity⁵.

In 2014, Lin et al. studied the protective effects of P. cablin essential oil against ultraviolet (UV)-induced skin photoaging in mice. The researchers applied patchouli oil for 2 hours before UV exposure to the dorsal depilated skin of mice. They found that patchouli oil doses of 6 mg/mouse and 9 mg/mouse significantly suppressed skin wrinkle formation, mitigated skin elasticity impairment, and augmented collagen content (21.9% and 26.3%, respectively). The same doses also yielded significant reductions in epidermal thickness and malondialdehyde content, and blocked the disruption of collagen and elastic fibers. Patchouli oil treatment also resulted in the up-regulation of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. The investigators concluded that patchouli oil, perhaps due to its antioxidant characteristics, and sesquiterpene constituents in particular, was effective in preventing photoaging in mice, and warrants attention as a potential agent to hinder photoaging in humans¹.

Feng et al. also investigated the effects of topically applied patchouli alcohol on UV-induced photoaging in mice that year. For 9 weeks, investigators applied patchouli oil solution or a vehicle to the depilated dorsal skin of 6-week-old mice. They found that patchouli oil significantly hastened the recovery of UV-induced skin lesions, which they ascribed to the antioxidant and anti-inflammatory activity of the agent and its down-regulation of the expression of matrix metalloproteinase (MMP)-1 and MMP-3².

Antimicrobial and mosquito repellent activity

In a 2005 study by Trongtokit et al. of the mosquito-repellent activity of 38 essential oils at three concentrations (10%, 50%, or undiluted) against the mosquito Aedes aegypti under laboratory conditions using human volunteers, undiluted P. cablin oil was one of four [along with Cymbopogon nardus (citronella), Syzygium aromaticum (clove), and Zanthoxylum limonella (Thai name: makaen)] undiluted oils to yield an effect, 2 hours of full repellency. The investigators then tested the same concentrations of these oils for repellency against Culex quinquefasciatus (the Southern house mosquito) and Anopheles dirus (the mosquito considered to be a vector of malaria in Asian forested zones. The undiluted oils provided the greatest protection, with clove oil rendering the most durable repellency⁶.

Photoaging

Forest & Kim Starr/Wikimedia Commons/CC BY 3.0

Wu et al. determined the acaricidal activity of compounds extracted from patchouli oil against the house dust mite (Dermatophagoides farinae) in 2012. They isolated 2-(1,3-dihydroxy-but-2-enylidene)-6-methyl-3-oxo-heptanoic acid (DHEMH), the hydrolysate of pogostone, and 15 other constituents in patchouli oil, ultimately ascertaining that DHEMH and patchouli oil itself were the most toxic substances to D. farinae. The investigators concluded that patchouli oil and DHEMH warrant consideration and more study for their acaricidal potential as environmentally friendly, effective, and simple fumigant alternatives to chemical agents⁷.

In 2013, Yang et al. used molecular docking technology to evaluate the antibacterial activity of patchouli oil in vitro. They identified 26 compounds in patchouli oil displaying antibacterial activity, with pogostone and (-)-patchouli alcohol exhibiting the strongest activity⁸. Later that year, Yang et al. used the same technology to establish that Herba pogostemonis oil exhibited potent antibacterial effects, especially the constituents pogostone and (-)-Herba pogostemonis alcohol⁹. Raharjo and Fatchiyah also used molecular docking tools and Chimera 1.7s viewer software in a virtual screening of compounds from patchouli oil, concluding that alpha-patchouli alcohol is a potential inhibitor of the cyclo-oxygenase (COX)-1 enzyme. This is notable given the pivotal role of COX-1 in the inflammatory response¹⁰.

The next year, Peng et al. isolated one of the primary constituents of patchouli oil, pogostone, and assessed its antibacterial activity in vitro and in vivo. They found that pogostone suppressed both gram-negative and gram-positive bacteria in vitro. The researchers noted that pogostone was active against some drug-resistant bacteria (such as MRSA). Via intraperitoneal injection, pogostone displayed antibacterial activity in male and female Kunming mice against Escherichia coli and MRSA. At concentrations of 50 and 100 mg/kg, 90% of the mice infected with E. coli were protected; 60% of the mice at 25 mg/kg were protected. For mice with MRSA, 60% were protected at a dose of 100 mg/kg and 50% at a dose of 50 mg/kg. The investigators concluded that pogostone is a viable antibacterial agent for clinical use⁴.

Transdermal delivery

A 2008 study by Luo et al. showed that patchouli oil was among three volatile oils that improved the skin penetration of the flavonoids baicalin¹¹. It was less effective than several compounds, including clove oil, camphor, menthol, and oleic acid, as a transdermal enhancer in a subsequent study by Zheng et al.¹².

Conclusion

Patchouli oil continues to be used today in traditional Chinese medicine. In the West, the established literature on Pogostemon cablin is thin, but what has emerged recently, particularly studies on the protection against photoaging in mice, supports the continued investigation of this ancient herb to determine its potential role in dermatologic practice. As it is, much more research is necessary.

References

1. J Ethnopharmacol. 2014;154(2):408-18.

2. Eur J Pharm Sci. 2014;63:113-23.

3. Expert Opin Investig Drugs. 2013;22(2):245-57.

4. Chin Med J. (Engl) 2014;127(23):4001-5.

5. J Agric Food Chem. 2007;55(5):1737-42

6. Phytother Res. 2005;19(4):303-9.

7. Chem Pharm Bull (Tokyo). 2012;60(2):178-82.

8. Iran J Pharm Res. 2013 Summer;12(3):307-16.

9. Pak J Pharm Sci. 2013;26(6):1173-9.

10. Bioinformation 2013;9(6):321-4.

11. Zhong Yao Cai. 2008;31(11):1721-4

12. Zhongguo Zhong Yao Za Zhi. 2009;34(20):2599-603.

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

Lab mouse

Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.

STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.

But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.

Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.

The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.

The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh₂, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.

“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”

MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.

Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.

When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).

Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.

“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”

Lab mouse

Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.

STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.

But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.

Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.

The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.

The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh₂, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.

“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”

MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.

Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.

When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).

Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.

“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”

Lab mouse

Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.

STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.

But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.

Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.

The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.

The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh₂, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.

“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”

MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.

Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.

When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).

Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.

“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m²), reinfusion of autologous stem cells (≥2.1×10⁶ cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m²), reinfusion of autologous stem cells (≥2.1×10⁶ cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m²), reinfusion of autologous stem cells (≥2.1×10⁶ cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

Researchers in the lab

Photo by Rhoda Baer

In an attempt to crowd-source cancer research, a pair of Canadian organizations made a small molecule they developed freely available to researchers.

The goal was to fast-track the testing of new treatment strategies and facilitate sharing of the results.

Researchers have already completed preclinical studies of this molecule, a WDR5 inhibitor called OICR-9429, showing that it is active against breast cancer and acute myeloid leukemia (AML).

The organizations that developed OICR-9429 are the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC).

“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams, we have received results back from our collaborators showing that it can kill 2 different types of cancer cells,” said Cheryl Arrowsmith, PhD, of SGC Toronto in Ontario, Canada.

“Opening our chemistry capabilities to the world’s scientists allowed us to crowd-source and accelerate the research.”

A study published in Nature Chemical Biology suggested that WDR5 is a therapeutic target for a subtype of AML, and OICR-9429 could therefore be used to treat the disease.

The researchers noted that mutations in C/EBPα occur in about 9% of AML cases and lead to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30).

Their experiments revealed that C/EBPα p30 preferentially interacts with WDR5. So it was no surprise that OICR-9429 inhibited proliferation and induced differentiation in p30-expressing AML cells.

In a study published in Nature, OICR-9429 inhibited cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of p53.

Researchers said this work has implications beyond breast cancer because p53 is mutated in at least half of all cancers and is dysregulated in others.

“It is remarkable how quickly our research results were translated into discoveries by the groups around the world,” said Rima Al-awar, PhD, of OICR in Toronto.

“We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early stage drug discovery has significant advantages.”

The SGC and OICR teams said they are continuing their collaboration to identify additional molecules to advance cancer drug discovery.

Researchers in the lab

Photo by Rhoda Baer

In an attempt to crowd-source cancer research, a pair of Canadian organizations made a small molecule they developed freely available to researchers.

The goal was to fast-track the testing of new treatment strategies and facilitate sharing of the results.

Researchers have already completed preclinical studies of this molecule, a WDR5 inhibitor called OICR-9429, showing that it is active against breast cancer and acute myeloid leukemia (AML).

The organizations that developed OICR-9429 are the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC).

“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams, we have received results back from our collaborators showing that it can kill 2 different types of cancer cells,” said Cheryl Arrowsmith, PhD, of SGC Toronto in Ontario, Canada.

“Opening our chemistry capabilities to the world’s scientists allowed us to crowd-source and accelerate the research.”

A study published in Nature Chemical Biology suggested that WDR5 is a therapeutic target for a subtype of AML, and OICR-9429 could therefore be used to treat the disease.

The researchers noted that mutations in C/EBPα occur in about 9% of AML cases and lead to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30).

Their experiments revealed that C/EBPα p30 preferentially interacts with WDR5. So it was no surprise that OICR-9429 inhibited proliferation and induced differentiation in p30-expressing AML cells.

In a study published in Nature, OICR-9429 inhibited cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of p53.

Researchers said this work has implications beyond breast cancer because p53 is mutated in at least half of all cancers and is dysregulated in others.

“It is remarkable how quickly our research results were translated into discoveries by the groups around the world,” said Rima Al-awar, PhD, of OICR in Toronto.

“We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early stage drug discovery has significant advantages.”

The SGC and OICR teams said they are continuing their collaboration to identify additional molecules to advance cancer drug discovery.

Researchers in the lab

Photo by Rhoda Baer

In an attempt to crowd-source cancer research, a pair of Canadian organizations made a small molecule they developed freely available to researchers.

The goal was to fast-track the testing of new treatment strategies and facilitate sharing of the results.

Researchers have already completed preclinical studies of this molecule, a WDR5 inhibitor called OICR-9429, showing that it is active against breast cancer and acute myeloid leukemia (AML).

The organizations that developed OICR-9429 are the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC).

“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams, we have received results back from our collaborators showing that it can kill 2 different types of cancer cells,” said Cheryl Arrowsmith, PhD, of SGC Toronto in Ontario, Canada.

“Opening our chemistry capabilities to the world’s scientists allowed us to crowd-source and accelerate the research.”

A study published in Nature Chemical Biology suggested that WDR5 is a therapeutic target for a subtype of AML, and OICR-9429 could therefore be used to treat the disease.

The researchers noted that mutations in C/EBPα occur in about 9% of AML cases and lead to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30).

Their experiments revealed that C/EBPα p30 preferentially interacts with WDR5. So it was no surprise that OICR-9429 inhibited proliferation and induced differentiation in p30-expressing AML cells.

In a study published in Nature, OICR-9429 inhibited cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of p53.

Researchers said this work has implications beyond breast cancer because p53 is mutated in at least half of all cancers and is dysregulated in others.

“It is remarkable how quickly our research results were translated into discoveries by the groups around the world,” said Rima Al-awar, PhD, of OICR in Toronto.

“We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early stage drug discovery has significant advantages.”

The SGC and OICR teams said they are continuing their collaboration to identify additional molecules to advance cancer drug discovery.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

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

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

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

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

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

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

The discovery of a new therapeutic target site on the STAT3 oncoprotein – a protein that interferes with chemotherapy by halting deaths of cancerous cells – could cut down on acute myeloid leukemia (AML) relapse in chemoresistant patients, according to research published in Angewandte Chemie.

The STAT3 protein – which stands for “signal transducer and activator of transcription 3” – is a suspected factor in the relapse of nearly 40% of children with AML. A team of researchers from Rice University, working with colleagues at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center, all in Houston, developed a proximity-driven rhodium (II) catalyst known as MM-206, which blocks STAT3 function by identifying the STAT3 coiled-coil domain as a novel ligand-binding site and delivering a naphthalene sulfonamide inhibitor, thus halting the disease promoting effects of STAT3.

The effects were replicated in tumor growth models and testing in a leukemia mouse model suggest this approach can be used to shut down STAT3 activity in AML patients, according to coauthor Dr. Zachary Ball of the department of chemistry at Rice.

Read the full article here: Angew Chem Int Ed Engl. 2015 Sep 7. doi: 10.1002/anie.201506889.

[email protected]

The discovery of a new therapeutic target site on the STAT3 oncoprotein – a protein that interferes with chemotherapy by halting deaths of cancerous cells – could cut down on acute myeloid leukemia (AML) relapse in chemoresistant patients, according to research published in Angewandte Chemie.

The STAT3 protein – which stands for “signal transducer and activator of transcription 3” – is a suspected factor in the relapse of nearly 40% of children with AML. A team of researchers from Rice University, working with colleagues at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center, all in Houston, developed a proximity-driven rhodium (II) catalyst known as MM-206, which blocks STAT3 function by identifying the STAT3 coiled-coil domain as a novel ligand-binding site and delivering a naphthalene sulfonamide inhibitor, thus halting the disease promoting effects of STAT3.

The effects were replicated in tumor growth models and testing in a leukemia mouse model suggest this approach can be used to shut down STAT3 activity in AML patients, according to coauthor Dr. Zachary Ball of the department of chemistry at Rice.

Read the full article here: Angew Chem Int Ed Engl. 2015 Sep 7. doi: 10.1002/anie.201506889.

[email protected]

The discovery of a new therapeutic target site on the STAT3 oncoprotein – a protein that interferes with chemotherapy by halting deaths of cancerous cells – could cut down on acute myeloid leukemia (AML) relapse in chemoresistant patients, according to research published in Angewandte Chemie.

The STAT3 protein – which stands for “signal transducer and activator of transcription 3” – is a suspected factor in the relapse of nearly 40% of children with AML. A team of researchers from Rice University, working with colleagues at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center, all in Houston, developed a proximity-driven rhodium (II) catalyst known as MM-206, which blocks STAT3 function by identifying the STAT3 coiled-coil domain as a novel ligand-binding site and delivering a naphthalene sulfonamide inhibitor, thus halting the disease promoting effects of STAT3.

The effects were replicated in tumor growth models and testing in a leukemia mouse model suggest this approach can be used to shut down STAT3 activity in AML patients, according to coauthor Dr. Zachary Ball of the department of chemistry at Rice.

Read the full article here: Angew Chem Int Ed Engl. 2015 Sep 7. doi: 10.1002/anie.201506889.

[email protected]