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Drug Monograph

Vitamin B12/Zinc Pyrithione 0.07%/0.25%
Topical Cream +/- Cardio B Capsules

DESCRIPTION

Combining Cardio B capsules (Folic Acid, B12, B6) with topical B12 (cyanocobalamin and zinc pyrithione) may offer a pharmaceutically comprehensive approach to the pathogenesis of psoriasis.

HOW SUPPLIED
Cream

Cyanocobalamin/Zinc Pyrithione is commonly compounded as a 0.07%/0.25% topical cream.

Cardio B Capsules

Pyridoxine Hydrochloride 50mg
Folate 8,500mcg DFE (5,000mcg Folic Acid)
Vitamin B12 (as Methylcobalamin) 1000mcg
Betaine 500mg

CLINICAL PHARMACOLOGY

Psoriasis is caused by a complex interplay among the immune system, genetic background, autoantigens, and environmental factors.

Recent studies have demonstrated that patients with psoriasis have a significantly higher serum homocysteine (Hcy) level and a higher prevalence of hyperhomocysteinaemia (HHcy). Insufficiency of folic acid and vitamin B12 can be a cause of HHcy and resulting pathophysiology in psoriasis. Moreover, hyperhomocysteinemia is a risk factor for cardiovascular disease, hence, psoriasis is associated with an increased risk of CVD and mortality.

Coenzymes methylene tetrahydrofolate, methylcobalamin, and pyridoxal phosphate are essential for three of the enzymes involved in the metabolism of homocysteine and are dependent on folate, vitamins B12 and B6. Hence in patients with severe psoriasis who have large areas of rapid skin turnover and increased keratinocyte activity, there is excessive consumption of folate. This in turn results in reduced breakdown and elevated serum levels of Hcy with all of its adverse effects.

Moreover, Hcy may promote the immuno-inflammatory process in the pathogenesis of psoriasis by activating Th1 and Th17 cells and neutrophils, while suppressing regulatory T cells. Hcy can drive the immuno-inflammatory process by enhancing the production of the pro-inflammatory cytokines in related to psoriasis. Case in point, Hcy can induce nuclear factor kappa B activation, which is critical in the immunopathogenesis of psoriasis.

The proinflammatory cytokines involved in psoriasis stimulate the expression of inducible nitric oxide synthase (iNOS) in keratinocytes and other cell types. High levels of iNOS have been detected in psoriatic lesions and in skin affected by atopic dermatitis and are shown to be associated with a greatly increased release of nitric oxide (NO). NO has been found to be implicated in the pathogenesis of atopic eczema and psoriasis. Application of a NO synthase inhibitor leads to a clear decrease in pruritus and erythema in atopic dermatitis.

Methyl-B12

Cobinamide, a cobalamin (vitamin B12) precursor binds to NO with high affinity and has been shown to be a potent NO-scavenger in biologic systems.

Systemic administration of vitamin B12 has been reported to decrease the immunological factors responsible for skin inflammation and cell proliferation, producing a significant improvement of symptoms and positive impact on psoriatic patients. Since the important renal excretion (nearly 90%) after parenteral administration, vitamin B12 requires high blood concentrations to reach peripheral targets which can be associated with toxicity. To avoid the possible concentration-related adverse events, transdermal application was recently considered the most appropriate way of administration.

Zinc Pyrithione

It inhibits the expression of integrins by keratinocytes and modulates the production of TNF-α and IL-6 and reduces the production of inflammatory mediators like nitric oxide. It is also proposed that it is the toll-like receptors mediated regulation of zinc homeostasis which influences dendritic cell function and immune processes.6

Folic Acid (5-MethyltTHF)

Recent case control studies have demonstrated the patients with psoriasis have lower levels of folate in comparison to normal controls.

Postulated mechanisms include the following:

(1) Decreased Gut Absorption. Alterations in gut absorption of folate due to microscopic inflammatory changes seen in the bowel mucosa of patients with active psoriasis and psoriatic arthritis.

(2) Accelerated Keratinocyte Turnover. Accelerated keratinocyte turnover as seen in patients with psoriasis results in excessive consumption of folate used to methylate DNA in these actively dividing cells thus lowering folate levels.

(3) MTHFR Polymorphism. Folic acid is converted into its metabolically active form, 5-MTHF, by the enzyme methyltetrahydrofolate reductase (MTHFR). 5-MTHF donates its methyl group to vitamin B12 (cobalamin), forming methylcobalamin. Methylcobalamin helps convert the problematic amino acid metabolite homocysteine into the amino acid methionine. As mentioned above, decrease in methylcobalamin may increase the immunoinflammatory response of higher levels of Hcy and decrease its activity as a NO scavenge, affecting the clinical picture of psoriasis.

CLINICAL EVIDENCE
Study 1 – Vit B12 Emollient Cream

24 patients with mild to moderate plaque psoriasis were enrolled in a 12-week randomized, controlled, single-blind study, followed by a 4-week observational washout period.

Patients were administered either Vitamin B12 ointment containing 0.07% cyanocobalamin with 20% avocado oil (M-treatment) and a glycerol-petrolatum emollient cream (C-treatment) twice daily to the affected skin areas on contralateral sides of their bodies.1

After 14 days, there was a statistically highly significant decrease in PASI scores in all M-treated body sides, whereas only small decrease in C-treated sides. The M-treated PASI scores remained lower than the C-treated body scores throughout the study, as well as the washout period.1

Study 2 – Vit B12

A total of 12 patients (8 males and 4 females, 21–86 years old) with manifest and treatment-resistant psoriasis (moderate to severe) were included and treated for 12 weeks.2

All patients were assigned to twice-daily treatment with a newly developed topical combination containing plant-based extracts traditionally used in skin disease as black cumin, olive oil, tea tree oil, cocoa butter completed by vitamin A and vitamin B12.2

Treatment success was determined by the Psoriasis Area and Severity Index (PASI) score, the body surface area, and the dermatology life index.

PASI reduction of >75% in 10 of the 12 treated patients (83%). The remaining two patients showed a PASI reduction of ≤50%. In 5 of the patients PASI reduction was achieved <12 weeks (between week 3–11).2

Study 3 – Vit B12 vs Calcipotriol (Vit D3 Analog)

In this randomized, prospective clinical trial, the effects of the vitamin D3 analog calcipotriol were evaluated in a trial population of 13 patients (10 men, 3 women) against those of a recently developed vitamin B12 cream containing avocado oil in an intraindividual right/left-side comparison for an observation period of 12 weeks.3

There was a more rapid development of beneficial effects with the use of calcipotriol in the initial 8 weeks, although differences in effects were significant only at the time point of therapy week 8 (p < 0.05). After 12 weeks, neither the PASI score nor 20-MHz sonography showed significant differences between the two treatments. While the efficacy of the calcipotriol preparation reached a maximum in the first 4 weeks and then began to subside, the effects of the vitamin B12 cream containing avocado oil remained at a constant level over the whole observation period.3

Study 4 – Folic Acid 4-7mg (Oral)

The daily intake of FA of 5% Americans age 50 and over and in one study of psoriatic American women is about 1 mg. A patient with plaque psoriasis on 10 mg lisinopril did not improve on oral vitamins B12 and B6 alone. When folic acid 5 mg daily was added, PASI improved 50%.4

Three cases of plaque psoriasis flared when given 1-2 mg folic acid (FA), 100 mg vitamin B6 and 1000 mcg B12 daily. When daily FA was increased to 4 to 7 mg daily, all three cases improved their disease.4

Study 5 - Folic acid combined with Vit B12

A combination of folic acid and vitamin B12 is more effective for lowering Hcy than is folic acid alone. A randomized, double-blind study with 150 women aged 20-34 years showed Hcy was significantly reduced in all treatment groups after 4 weeks compared to baselines Hcy values.5

Study 5 – Topical Zinc Pyrithione

60 participants were randomized in a double-blind clinical trial comparing zinc pyrithione 0.25% in an emollient cream versus an emollient cream alone. After 3 months of therapy, there was a significant difference in PASI scores in the participants treated with zinc, versus participants who received emollient cream only. PASI scores before and after treatment were 3.4±1.8 and 0.9±1.3 in the zinc group (p<0.01), and 4.3±2 and 3.9±1.3 in emollient only B (p>0.05).7

INDICATIONS AND USAGE

The use of high dose oral folic acid4 and topical B121,2,3/Zinc Pyrithione6 0.07/0.25% cream have been clinically studied for the use in mild to moderate chronic plaque psoriasis.

DOSING AND ADMINISTRATION

Take 1 serving of Cardio B daily.

  • Reducing or stopping folic acid (FA) 4-8 mg daily may place patient at risk for comorbid events due to the passage through FA levels that would promote pro-inflammatory side effects.

Apply Methyl-B12 0.07/0.25% topical cream to affected areas twice daily.

Do not use on the face.

ADVERSE EFFECTS
MethylFolate

- Allergic Reactions
- Abdominal Cramps
- Diarrhea
- Rash
- Sleep Disorders
- Irritability
- Confusion
- Nausea
- Stomach Upset
- Behavior Changes
- Skin Reactions
- Seizures
- Excitability

Methylcobalamin

- Mild transient diarrhea
- Polycythemia
- Itching
- Transitory exanthema
- Edema

WARNINGS AND PRECAUTIONS

A mild exacerbation of the skin inflammation may be a common initial response (2-4 days after treatment initiation) with a subsequent consistent improvement of the disease state thereafter.

Folic Acid
  1. Folic acid should be given with caution to drug-treated epileptic patients because seizure control may be affected.
  2. Folic acid may cause neurological injury when given to patients with undiagnosed pernicious anemia.
DRUG INTERACTIONS
Folic Acid
  • Fosphenytoin. Folic acid can increase fosphenytoin metabolism, decreasing its effectiveness in seizure prevention.
  • Methotrexate. Taking folic acid with methotrexate may decrease the effectiveness of methotrexate.
  • Phenobarbitol. Taking folic acid with phenobarbitol can decrease its effectiveness for seizure prevention.
  • Phenytoin. Folic acid may incrEase the metabolism of phenytoin, decreasing its effectiveness for seizure prevention.
  • Primidone. Taking folic acid with primidone may decrease itS effectiveness in preventing seizures
  • Pyrimethamine. Taking folic acid with pyrimethamine may decrease its effectiveness in treating parasitic infections.
USE IN SPECIFIC POPULATION

Vitamin B12/Zinc Pyrithione 0.07/0.25% cream is likely safe in children, pregnancy & lactation.

TOXICITY

Oral folic acid is generally regarded as not toxic for humans; however, it may cause neurological injury when given to patients with undiagnosed pernicious anemia.

STORAGE

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

REFERENCES
  1. Del Duca E, Farnetani F, De Carvalho N, Bottoni U, Pellacani G, Nisticò SP. Superiority of a vitamin B12-containing emollient compared to a standard emollient in the maintenance treatment of mild-to-moderate plaque psoriasis. Int J Immunopathol Pharmacol. 2017;30(4):439‐444.
  2. Michalsen A, Eddin O, Salama A. A case series of the effects of a novel composition of a traditional natural preparation for the treatment of psoriasis. J Traditional and Complementary Medicine. 2016 Oct; 6(4) 395-398.
  1. Stucker M, Hoffman U, Hartung J, Altmeyer P. Vitamin B12 Cream Containing Avocado Oil in the Therapy of Plaque Psoriasis. Dermatology 2001;203:141–147.
  2. Aronson PJ (2017) Cases of psoriasis improved by lowering homocysteine using 4-7 mg folic acid, vitamins B6 and B12 previously worsened using 1-2 mg daily folic acid, B6 and B12 f2,olic acid. J Transl Sci 2017; 3(5) 1-6.
  3. Quinlivan EP, McPartlin J, McNulty H, et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease (letter). Lancet 2002; 359(9302) 227-228.
  4. Kitamura H, Morikawa H, Kamon H, et al. Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nature Immunology. 2006;7(9):971–977
  5. Sadeghian G, Ziaei H, Nilforoushzadeh MA. Treatment of localized psoriasis with a topical formulation of zinc pyrithione. Acta Dermatovenerologica Alpina, Pannonica et Adriatica. 2011;20(4):187–190.
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CONTACT

Harbor Compounding Pharmacy

2000 Harbor Blvd, Suite C100
Costa Mesa, CA 92627