Feverfew

History and Origin

Feverfew (Tanacetum parthenium) is a flower native to the Balkan Peninsula. Known also as Midsummer Daisy and Chrysanthemum parthenium, it was brought to America as an ornamental plant.

Feverfew has been used medicinally for centuries. Records dating back 2,000 years cite it as a potential treatment for headaches. Its efficacy for lowering fevers was well documented.

Other traditional uses include nerve relaxant, antispasmodic and remedy for stomach aches.

Pharmacological, chemical and clinical studies over the past 15 years have confirmed the value of feverfew for the treatment of migraines, leading Canada Health and Welfare to issue it the first Drug Identification Number for an herbal product for migraines.

Johnson & Johnson Consumer Companies, Inc.

Scientists at Johnson & Johnson Consumer Companies, Inc. sought to develop a natural ingredient that would provide a soothing and effective solution to treat skin redness and irritation of those with extra sensitive facial skin irritation.

The screening process, which began a decade ago, encompassed over 2,000 natural ingredients.

The parthenolide component of feverfew can cause skin sensitization.

Scientists at Johnson & Johnson Consumer Companies, Inc. partnership with world-recognized Phytochemists discovered and patented an extraction process that removes the majority of the parthenolide, while retaining the selective beneficial properties of Feverfew.

This extract was named Feverfew PFE.™

Activity, Properties, Chemical Structure

In laboratory testing, Feverfew PFE™ has shown to effectively diminish multiple skin-weakening inflammatory pathways, as well provide potent antioxidant activity.

Feverfew PFE™ is the first ingredient to be identified in the new Anti-Oxidant/Anti-Inflammatory ingredient class called AOI Boosters. This class of ingredients not only provides significant anti-oxidant benefits, but also enhances the ability to mitigate inflammatory reactions.

Preclinical Data

Murine macrophages were stimulated with 10ng/ml LPS in the presence or absence of Feverfew PFE™. After 16 hours, the release of pro-inflammatory mediators from activated macrophages was assayed. A reduction in nitric oxide production, prostaglandin E2 and tumor necrosis factor alpha (TNFα) was noted.¹

Feverfew PFE™ was found to inhibit 5-lipoxygenase, thus reducing the formation of a variety of proinflammatory lipid mediators. It was shown to reduce neutrophil chemotaxis, decrease the induce release of chemotactic factor, IL-8 and adhesion molecule, ICAM-1, from activated human keratinocytes and to reduce NF-κβ-dependent gene transcription.²

Human volar forearms were pre-treated with Feverfew PFE™ extracts in 0.5%, 0.75%, and 1% concentrations, or placebo for 30 minutes. Erythema was induced by the application of the vasodilator, methyl nicotinate.1 Figure 1 shows the linear dose response that was observed in erythema reduction compared to placebo. Erythema reduction was 68% with the 1% concentration of Feverfew PFE™ and 40% and 28% with the 0.75 and 0.5% concentrations, respectively. The 1% Feverfew PFE™ reduced the intensity-duration of erythema as calculated as Area Under the Curve by 32.5% compared to placebo.¹

In the mediator release model and when compared with a variety of other botanical extracts with reported anti-inflammatory activity, Feverfew PFE™ was shown to be more efficacious.² (Table 1)

View FeverFew Related Clinicals

Safety and Tolerance

As some natural ingredients have shown to elicit allergic responses or irritation, extensive clinical testing assessed the safety profile of Feverfew PFE™. The PFE feverfew-containing formulations were evaluated in topical clinical models of irritation, allergy, phototoxicity, and photoallergy.⁵

Cumulative Irritation

• Approximately 6 Feverfew PFE™ formulations were evaluated in panel sizes of approximately 200 subjects. Subjects wore patches containing one of the Feverfew PFE™ formulations for approximately 24 hours. Subjects were patched 3x per week for 3 weeks (9 patchings). Patches were monitored 24 hours prior to removal. After patch removal, sites were graded for erythema and edema prior to application of a new patch.
• After 3 weeks, negligible levels of cumulative irritation were noted with the Feverfew PFE™ formulations.
• Irritation potential was further investigated using Feverfew PFE™, a placebo containing no Feverfew PFE™, and a positive control formulation containing 0.15% vitamin A.
• The positive control formulation induced significantly high levels of irritation when compared to the Feverfew PFE™ formulations and the placebo control. The Feverfew PFE™ formulations resulted in negative irritation and were not significantly different from the placebo control.

Dermal sensitization

• Approximately 10 Feverfew PFE™ formulations were evaluated for dermal sensitization in approximately 200 subjects. Subjects wore patches containing Feverfew PFE™ for approximately 24 hours. Sites were then graded for erythema and edema prior to application of a new patch.
• During the 3-week induction phase, subjects received a total of 9 patchings followed by a 2-week rest period.
• During the challenge phase, patches containing Feverfew PFE™ formulation were applied to a new site for approximately 24 hours. Sites were graded for erythema and edema immediately after patch removal and at subsequent time points. No dermal contact sensitization was noted.

Dermal phototoxicity and photoallergy

Feverfew PFE™ forms were clinically evaluated for phototoxic or photoallergic potential in panels of 10-30 subjects.

Phototoxicity

Duplicate patches containing Feverfew PFE™ were worn for approximately 24 hours and removed. All sites were graded and one set of sites was immediately exposed to UVA irradiation. The other set of sites was not irradiated and served as controls. Both irradiated and non-irradiated sites were graded immediately and at subsequent time points post-irradiation. No contact dermal phototoxic reactions were noted.

Photoallergy

Duplicate patches containing Feverfew PFE™ were worn for approximately 24 hours and removed. All sites were graded and one set of sites was immediately exposed to UVA and UVB irradiation. The other set of sites was not irradiated and served as controls.

• Both irradiated and non-irradiated sites were graded immediately and at subsequent time points post irradiation. During the 3-week induction phase subjects received 6 induction patchings followed by a 2-week rest period. During the challenge phase patches containing Feverfew PFE™ formulation were applied to a new site for approximately 24 hours. Sites were graded for erythema and edema immediately after patch removal. One set of sites was immediately exposed to UVA irradiation only, the other set served as non-irradiated controls. The sites were graded immediately after irradiation. Both irradiated and non-irradiated sites were graded at subsequent time points post-irradiation.
• No photoallergic responses were noted.

Human Repeat Insult Patch Test	No induction of dermal sensitization
Phototoxicity	No dermal phototoxic responses
Photoallergy	No induction of dermal photoallergy
Cumulative Irritation	Negligible irritation potential

Table 3: Summary of Human Skin Safety and Tolerability Studies

Future Perspectives

In 2005, a range of Feverfew PFE™-based products were exclusively introduced across several skin care brands within Johnson & Johnson Consumer Companies.

References

1. Southall M, Saliou C, Oddos T, et al. Parthenolide-depleted tanacetum: A safe, non-irritating extract with potent anti-inflammatory activity. Poster presented at: European Academy of Dermatology and Venereology 13^th Congress; November 17-21, 2004; Florence, Italy.
2. Martin K, Southall M, Lyte P, Oddos T, Saliou C, Shapiro S. Parthenolide-free extract of feverfew: an extract with effective anti-irritant activity in vitro. Poster presented at: 63^rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, La.
3. Tierney N, Liebel F, Kurtz ES, Martin K. Daily use of a topical formulation containing parthenolide-free extract of feverfew clinically reduces the appearance of erythema due to ultraviolet exposure. Poster presented at: 63^rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, La.
4. Nebus J, Wallo W, Smith G, Nystrand G, Kurtz, ES, Leyden J. Evaluating topical preparations in sensitive skin patients. Poster Presented at: 63^rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, La.
5. Gisoldi, E, Walczak V, Tierney N, Martin K, Kurtz E, Grossman R. Parthenolide-depleted tanacetum extract: a review of safety testing for topical use. Poster presented at: European Academy of Dermatology and Venereology 13^th Congress; November 17-21, 2004; Florence, Italy.