Actinic Keratosis White Page

Patented Transdermal Verapamil Gel

For the treatment of Actinic Keratosis

Abstract:

Actinic keratosis (AK) is one of the most common skin conditions seen in an outpatient setting, with approximately 10% of all dermatology visits having a primary diagnosis of Actinic Keratosis. AK is a pre-cancerous skin condition resulting mainly from chronic UV exposure, including tanning beds.  With up to 60% of squamous cell carcinomas (SCC) arising from AKs, early and effective treatment can be imperative. Currently, there are multiple treatments available for AK – Including cryosurgery and light therapy to topical creams like 5-FU and imiquimod – with no current agreement on which is the most efficacious. Side effects beyond minor skin irritation are common with current regimens. Now there is Patented Transdermal Verapamil Gel. Transdermal Verapamil helps improve wound healing by enhancing matrix remodeling of damaged tissue and provides antioxidant and anti-inflammatory activity. In contrast to current treatments, the only side effect noted with Transdermal Verapamil Gel is localized minor skin irritation.

Introduction

Using Patented Transdermal Verapamil gel for hard-to-treat issues is not a new concept. Transdermal Verapamil Gel has been used to treat Plantar Fibromatosis and Dupuytren’s Contracture for many years. Studies have demonstrated Transdermal Verapamil Gel effective for the treatment of Peyronie’s Disease. Transdermal Verapamil’s proposed mechanism of action shows promise in dermatology, specifically as an agent for the very common dermatological condition Actinic Keratosis (AK) or Actinic keratoses (plural, AKs). AKs are diagnosed at > 10% of all dermatology visits, making them one of the most common diagnoses seen in the outpatient setting.[1]

What is Actinic Keratosis?

Actinic keratosis (AKs), also known as solar keratosis, is a rough, scaly, pre-cancerious, epidermal, keratinocytic lesion that results from chronic sun and UV light exposure (including tanning beds).[2]  The prevalence increases with age and declining immune health. AKs are thought to be carcinomas in situ, which can progress to squamous cell carcinomas if not managed early and appropriately.

The prevalence of Actinic kertatosis in the US is estimated at almost 40 million individuals and annual costs of > $1 billion. Most AKs do not progress to cancer, and as many as 26% regress spontaneously.  But up to 60% of squamous cell carcinomas (SCC) arise from AKs.[3] After progression to SCC, the risk of metastasis is estimated to be 0.5-3.3%.[4]

No two cases of actinic keratosis will look the same, but they may share the following similar features:

• Red scales
• Raised patches
• Crusty patches
• Sandpaper texture

AKs most often appear on sun-exposed areas such as the face, bald or balding scalp, ears, shoulders, neck and the back of the hands and forearms. However, they can also appear on the shins and other parts of the legs. AKs are often elevated, rough in texture and resemble warts, with most become red. Some are light colored or dark tan, white, pink and/or flesh-toned, OR a combination of these colors.

Data from a large Rotterdam Study in 2013 revealed that individuals with Fitzpatrick type I or II skin characteristics, such as fair skin, freckles, light-colored eyes (blue or green) and blonde or red hair, are more likely to develop AKs as they are more sensitive to damage from chronic sun exposure.[5]

This study also reported that lighter pigmentation and tendency to sunburn were associated with higher risk of AKs, along with male sex, baldness, age > 70 years, use of sun-protective measures, and history of melanoma or keratinocyte carcinoma (KC), particularly squamous cell carcinoma (SCC).[6]

What Causes AKs?

The main cause of Actinic Keratosis is UV radiation – chronic, unprotected exposure to the sun. Also, UV radiation from tanning “beds” can also cause AKs. Chronic X-Ray exposure and exposure to chemicals have also been reported to cause AKs.

There are several mechanisms for the formation of AKs, including: 

• Excessive oxidative stress
• Immunosuppression
• Chronic inflammation
• Altered proliferation and dysregulation of cell growth and death – DNA damage
• Human papillomavirus (HPV)

Excessive UV-A and UV-B generate a cascade of structural damage to cell’s DNA and membrane lipids due to increased oxidative stress, which leads to chronic inflammation.[7] Sun damage to the skin is cumulative, so even a brief period in the sun adds to the lifetime total. Those that work outside have an increased risk. Cloudy days aren’t safe either, because 70-80% of the sun’s ultraviolet (UV) rays can pass through clouds. These harmful rays can also bounce off sand, snow and other reflective surfaces, giving the individual extra exposure.

Though some individuals can get AKs as young as in their 20s, AKs are more common in people over age 50, with almost everyone over 80 having AKs. The incidence of AKs is higher in men presumably due to spending more time in the sun. Also, the closer to the equator one lives, the higher the incidence of AKs. Those with autoimmune or immune problems, such as AIDS, those receiving cancer chemotherapy, organ transplants, are more likely to develop AKs.

A summary of factors contributing to AKs include: 

• Age over 40 – aging increases AKs
• A long history of sunburn or extreme exposure to sun
• Living in a sunny environment
• Using tanning beds
• Working in the sun or around radiation
• Having a history of developing actinic keratosis
• Having lighter color hair or eyes
• Having a tendency to burn in the sun
• Immune problems

Current Treatments

There are multiple reasons for treatment, and there is no current agreement on the most efficacious treatment. The decision to treat can be based on cosmetic reasons, symptom relief, or, most importantly, the prevention of malignancy and metastasis. The most compelling reason and primary goal of treating actinic keratoses is to prevent malignant transformation into invasive squamous cell carcinoma. Treatment options include:[8]

• Cryosurgery: The most common treatment; can be done in practitioner’s office in a few minutes. The practitioner applies liquid nitrogen to the AK to freeze the tissue. Later, the lesion and surrounding frozen skin may blister or become crusted and fall off. Treatment is very painfull. Side effects include:[9]^,[10]
  • Changes to skin texture
  • Blisters
  • Infection
  • Scarring
  • Discoloration of the skin at site of treatment

• Curettage and desiccation: involves scraping or shaving off part or the entire lesion, then applying heat or a chemical agent to stop the bleeding and potentially killing any remaining AK cells. This treatment is also very painfull.

• Photodynamic therapy (PDT) is especially useful for widespread lesions on the face and scalp. The practitioner appliesa light-sensitizing topical agent to the lesions, then uses a strong light to activate the topical agent, destroying the AKs while sparing healthy tissue. This treatment option has one of the best cosmetic outcomes. Side effects include redness, swelling, burning, which may be felt during procedure and cause unwanted anxiety.

• Laser surgery: The practitioner uses intense light to vaporize AK tissue. If there are numerous or widespread actinic keratoses, a topical cream, gel or solution should be used. These can treat visible and invisible lesions with a minimal risk of scarring. Doctors sometimes refer to this type of therapy as “field therapy,” since the topical treatments can cover a wide field of skin as opposed to targeting isolated lesions.

• 5-fluorouracil (Carac®, Efudex®, Fluoroplex®): 5-FU is a topical chemotherapy – antineoplasctic analogue of pyrimidine; induces cell apoptosis. Side effects such as severe dermatitis accompanied by wound infection, pruritis, burning, blistering, necrosis and erosions, pain and ulceration can occur.[11] Cannot use with pregnancy due to potential teratogenic effects on the fetus.

• Chemical peel:Best known for reversing the signs of photoaging, this technique is also used to remove some superficial actinic keratoses on the face, especially when other techniques have not succeeded. The practitioner applies trichloroacetic acid and/or similar chemicals to the face, causing the top skin layers to slough off.

• Diclofenac (Solaraze®)and hyaluronic acid: COX-2 inibitor; anti-inflammatory; a combination topical therapy. Potential for adverse events is 3-5%, including desquamation, pruritis, dry skin, localized edema, parethesia, erythema, rashes and photosensitivity.[12]

• Imiquimod (Aldara®, Zyclara®): synthetic amine imidazoquinonlone having potent immune modifying activity; stimulates the immune system to produce interferon, a chemical that attacks cancerous and precancerous cells. This treatment option has one of the best cosmetic outcomes. Side effects include pruritus, erosions, burning, erythema, peeling, vesicles, exudations and crusts. Systemic reactions including angioedema, flu-like symptoms, and fatigue is also reported to occur.

• Ingenol mebutate (Picato®):A rapidly effective topical therapy derived from the plant Euphorbia peplus. An immunologic mechanism of action has been proposed. Side effects include Erythema, edema, peeling, crusting, pain, and/or superficial ulceration at the site of application have been described as possible adverse events.

Practitioners may combine therapy modalities to treat AKs. Typically, treatment regimens combine cryosurgery with photodynamic therapy (PDT) or a topical agent (such as imiquimod, diclofenac, ingenol mebutate, 5-fluorouracil). The topical medications and PDT may also be used alternately every three months, six months or year, as determined by the practitioner at follow-up skin examinations.[13]

Surgical treatments such as cryotherapy, excision and laser resurfacing, while effective against discrete lesions, may not 
address subclinical lesions, and are painful and associated
 with risks of scarring, infection and pigmentary changes.[14]^,[15]

Many AK
patients have multiple lesions, not all of which are distinct
and obvious. Suggested treatments for those patients include 
therapeutic options that treat the entire affected area of skin
such as topical treatments and photodynamic therapy. Topical treatments, inducing 5-FU, imiquimod, and dicolfenac, however, are less effective than surgical options against discrete lesions and have been associated with irritation, allergic reactions, and problems with patient compliance.[16] ^,[17]

All AK cases should be treated because of their propensity to transform into malignancy and further complicate treatment. In addition to medical or surgical care, education about sun exposure prevention remains the best and most cost-effective method for AK prevention.

The bottom line is many options are available with variable success and patient compliance rates. Although decreased sun exposure is the best way to prevent AKs, there still is a need for an effective, topical product with limited side effects as compared to current treatment options. One such product that may fill such a void is a patented, transdermal formulation containing the calcium channel blocker verapamil.

Transdermal  Verapamil – Rationale for Use

Verapamil, USP, is chemically a diphenylalkylamine, and is in the class of drugs called calcium channel blockers. Calcium channel blockers have been used as prescription drugs for decades for blood pressure and other cardiovascular indications.  

Application of Transdermal Verapamil is reported to affect the extracellular matrix by increasing the proteolytic activity of collagenase, thereby enhancing matrix remodeling of fibroblasts and vascular smooth muscle cells.[18]^,[19],[20] Calcium plays a noticeable role in wound healing, such as effects on organization of F-actinin collagen bundles by fibroblasts at injury site. Verapamil acts to block the entry of divalent calcium into cells, resulting in hematuration of fibroblast collagenase and subsequent degradation or remodeling of the fibrotic tissue.

Calcium channel blockers such as verapamil also improve wound healing by providing antioxidant activity by increasing nitric oxide production, thereby promoting angiogenesis, proliferation of fibroblasts and endothelial cells in skin-regeneration processes.[21] Verapamil has also been reported in the literature to exhibit anti-tumor activity and to enhance the effectiveness of chemotherapy.[22]^,[23]

In addition, verapamil and other calcium channel blockers affect cytokine expression associated with the early phase of wound healing and inflammation, including platelet derived growth factor, interleukin-6 and interleukin-8. It is believed that the effect on the appearance of skin by transdermal application of calcium channel blockers is in part due to the remodeling of the epidermal and dermal tissues.  Additionally, calcium channel blockers may modulate the innate and adaptive immune responses.[24] 

A 2016 laboratory animal study reported the application of a topical verapamil gel promoted faster wound closure rate in comparison with other topical agents. The numerical density of fibroblasts, volume density of collagen bundles, mean diameter and volume densities of the blood vessels in the verapamil treated group were significantly higher than others treatments. The authors concluded that topical verapamil has the ability to improve wound healing by enhancing fibroblast proliferation, collage bundle synthesis and revascularization in skin injuries.[25]

Patented Transdermal Verapamil 15% Gel

Transdermal Verapamil 15% Gel is a painless, non-invasive, treatment for fibrotic tissue disorders including Peyronie’s Disease, Plantar Fibromatosis, Dupuytren’s Contracture as well as hypertrophic scaring. Patented Transdermal Verapamil Gel was invented and developed by  W. Jerry Easterling RPH and his team at Prescription Dispensing Laboratories. PDLabs is a nationally licensed compounding pharmacy that relocated from San Antonio to Cedar Park TX in 2016. Since 1998, PD Labs Transdermal Verapamil 15% Gel has been prescribed for over 13,000 patients. It is an original and patented compounded prescription that is applied directly to the affective area twice a day.  The proprietary formula allows for minimal absorption into the circulatory system, while maximizing the concentration of verapamil in the damaged and surrounding tissue.

Studies using Patented Transdermal Verapamil Gel include:

• 2007 double-blind, placebo controlled clinical study of 57 patients with Peyronie’s Disease. This 4-armed study compared transdermal Verapamil 15% Gel to topically applied trifluoperazine and magnesium sulfate and placebo to determine efficacy and safety of the medication. After 9 months of treatment, topical verapamil was superior in eliminating pain on erection, decreasing plaque size, decreasing curvature and improving erection quality in patients with Peyronie’s Disease.[26]
• A 645 open-label study reported improvement in outcomes in Peyronie’s Disease when using the Patented Transdermal Verapamil 8% Gel.[27]
• A 214 patient open-label study evaluated the efficacy and safety of the Patented Transdermal Verapamil 8% Gel and reported it to be safe and efficacious in Peyronie’s Disease.[28]
• A skin-penetration study demonstrated the ability of the Patented Transdermal Verapamil 15% Gel to successfully penetrate to the tunica albuginea.[29]

Additional components of the gel include antioxidant agents to prevent oxidation of verapamil and penetration enhancers. A list of ingredients in the Patented Transdermal Verapamil 15% Gel include: *

• Ethoxydiglycol
• Propylene glycol
• Lecithin soya granular
• Isopropyl myristate
• Sorbic acid
• Butylated hydroxyl toluene (BHT)
• Pluronic F127
• Potassium sorbate
• Purified water
• Disodium edetate

* Note – Avoid Counterfeit Transdermal Verapamil Gels

When using the Patented Transdermal Verapamil Gel as a treatment, lesions should be evaluated monthly and include:

• Number of lesions
• Lesion area (size)
• Lesion volume
• Irritation scale
• Erythema
• Reduction in brown spots
• Local or systemic toxicity

Dosage

• Typically, patients apply 0.5 ml of the Transdermal Verapamil 15% to affected area(s), two (2) times daily.
• Patients should realistically expect to use Transdermal Verapamil 15% Gel for 8-12 weeks to complete their treatment.
• Transdermal Verapamil Gel 15% can also be used as a complementary therapy along with other treatments such as cryosurgery or photodynamic therapy.
• The addition of complementary dietary supplements may help support the effects of Transdermal Verapamil Gel.
  • Oral nicotinamide (vitamin B3) 500mg daily, was reported to reduce Actinic Keratoses in a Phase II double-blinded randomized controlled trial.^[30],[31] Preliminary human studies suggest that nicotinamide may help prevent skin cancers and enhance the regression of actinic keratoses. A topical 1% preparation of nicotinamide directly onto AKs twice daily has also been reported effective. [32]
  • Antioxidants can also be used orally to provide synergistic benefit with transdermal verapamil therapy – Vitamin C (ascorbic acid), 1,000mg daily or Grape Seed Extract 150mg 2 times daily (standardized to at least 95% proanthocyanidinds PCOs).

Potential Side Effects/Contraindications

• As with any medication, Transdermal Verapamil 15% Gel may not improve everyone’s symptoms.
• The most common side effect reported with Transdermal Verapamil 15% Gel is skin irritation. This is reported to affect approximately 3-5% of patients.
• Some individuals using the medication for the first time may experience mild itching/irritation during the first few days of treatment. This is normal and usually resolves within 3-4 days.
• Some individuals may experience more severe skin irritation, including itching, burning, redness, or swelling. If any of these occur, discontinue use and contact the practitioner.

Conclusion

PD Lab’s Patented Transdermal Verapamil Gel 15% is an effective prescription treatment option for Actinic Keratosis. With fewer side effects than current regimens, including the most popular therapy 5-FU creams, Transdermal Verapamil Gel has been reported to improve AKs with 0.5ml applied twice daily for 8-12 weeks to affected area(s). Transdermal Verapamil 15% Gel is also a painless and non-invasive treatment for fibrotic tissue disorders including Peyronie’s Disease, Plantar Fibromatosis and Dupuytren’s Disease.  It has been used for these conditions for over 2 decades. Make sure to only use PD Lab’s Patented, Prescription Transdermal Verapamil Gel, as imitations may be available on the market.

[1] Siegel JA, et al. Current perspective on acitinic keratosis: a review. Br J Dermatol. 2017;177(2):350-58.

[2] Rossi R, et al. Actinic keratosis. Int J Dermatol. 2007;46:895-904.

[3] Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988;1:795–7.

[4] Feldman SR, et al. Progression of actinic keratosis to squamous cell carcinoma revisited: clinical and treatment implications. Cutis. 2011;87(4):201-7.

[5] Flohil SC, van der Leest RJT, Dowlatshahi EA et al. Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam Study. J Invest Dermatol 2013; 133:1971–8.

[6] Flohil SC, van der Leest RJT, Dowlatshahi EA et al. Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam Study. J Invest Dermatol 2013; 133:1971–8.

[7] Zhao B, et al. Recent advances in the prevention and treatment of skin cancer using photodynamic therapy. Expert Rev Anticancer Ther. 2010;10:1797-1809.

[8] De Oliveira ECV, et al. Actinic keratosis – review for clinical practice. Int J Dermatol. 2018;[Epub ahead of print].

[9]  Thai KE, Fergin P, Freeman M, Vinciullo C, Francis D, Spelman L, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol. 2004;43:687–92.

[10] Hocutt JE Jr. Skin cryosurgery for the family physician. Am Fam Physician. 1993;48:445–52,455–6.

[11] Jorizzo J, Weiss J, Furst K, VandePol C, Levy SF. Effect of a 1-week treatment with 0.5% topical fluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized, vehicle-controlled clinical trial. Arch Dermatol. 2004;140:813–6.

[12]  Korman N, Moy R, Ling M, Matheson R, Smith S, McKane S, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol. 2005;141:467–73.

[13] Dodds A, et al. Actinic keratosis: rationale and management. Dermatol Ther Heidelb). 2014;4(1):11-31.

[14] Lober BA, et al. Optimum treatment strategies for actinic keratosis (intraepidermal squamous cell carcinoma). Am J Clin Dermatol. 2004;5(6):395-401.

[15] Jeffes EW 3^rd, et al. Actinic keratosis. Current treatment options. Am J Clin Dermatol. 2000;1(3):167-79.

[16] Jeffes EW 3^rd, et al. Actinic keratosis. Current treatment options. Am J Clin Dermatol. 2000;1(3):167-79.

[17] Siegel JA, et al. Current perspective on acitinic keratosis: a review. Br J Dermatol. 2-17;177(2):350-58.

[18] Roth M, et al. Ca2+ channel blockers modulate metabolism of collagen within the extracellular matrix. Proc Natl Acad Sci USA. 1996;93:11:5478-82.

[19] Boggio RF, et al. Effect of a calcium-channel blocker (verapamil) on the morphology, cytoskeleton and collagenase activity of human skin fibroblasts. Burns. 2011;37(4):616-25.

[20] Fitscha P, et al. The diminished extracellular matrix production induced by isradipine, a calcium channel blocker, is completely abolished by cyclooxygenase inhibition. Prostaglandins Leukot Essent Fatty Acids. 1992;45(4):289-91.

[21] Askikani-Esfahani S, et al. Verapamil, a Calcium-Channel Blocker, Improves the Wound Healing Process in Rats with Excisional Full-Thickness Skin Wounds Based on Stereological Parameters. Adv Skin Wound Care. 2016;29(8):271-4.

[22] Zhao L, et al. Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells. Int J Oncol. 2016;49(1):99-110.

[23] Gros A, et al. Verapamil enhances the antitumoral efficacy of oncolytic adenoviruses. Mol Ther. 2010;1(5):903-11.

[24] Liu W, Matsumori A. Calcium channel blockers and modulation of innate immunity. Curr Opin Infect Dis. 2011;24(3):254-8.

[25] Askikani-Esfahani S, et al. Verapamil, a Calcium-Channel Blocker, Improves the Wound Healing Process in Rats with Excisional Full-Thickness Skin Wounds Based on Stereological Parameters. Adv Skin Wound Care. 2016;29(8):271-4.

[26] Fitch WP, et al. Topical verapamil HCL, topical trifluoperazine and topical magnesium sulfate for the treatment of Peyronie’s Disease – a placebo-controlled pilot study. J Sex Med. 2007;4:477-84.

[27] Bilgutay AN, et al. Peyronie’s disease: a review of etiology, diagnosis and management. Curr Sex Health Rep. 2015;7(2):117-31.

[28] Bilgutay AN, et al. Peyronie’s disease: a review of etiology, diagnosis and management. Curr Sex Health Rep. 2015;7(2):117-31.

[29] Shaw EJ, et al. The non-surgical treatment of peyronie disease: 2013 update. World J Mens Health. 31(3):183-192.

[30] Surjana D, et al. Oral nicotinamide reduces actinic keratosis in Phase II double-blinded randomized controlled trials. J Invest Dermatol. 2012;132:1497-1500.

[31] Kim B, et al. Oral nicotinamide and actinic keratosis: a supplement success story. Curr Probl Dermatol. 2015;46:143-9.

[32] Moloney F, et al. Randomized double blinded placebo controlled study to assess the effect of topical 1% nicotinamide on actinic keratosis. Br J Dermatol. 2010;162(5):1138-9.