Common Dermatological Disorders

The skin is the body's largest organ. Fifteen percent of the average adults weight is skin, and it covers a surface area of nearly 2 square meters. The importance of this complex organ to our survival is illustrated by the high mortality rate of people who have been badly burned. Skin is a peculiar organ with regard to its microcirculation. The dermal vasculature is enriched with abundant anastomosis. It forms a single compartment where blood can be pulsed in any direction. Under various pro-inflammatory stimuli, endothelial cells express diverse adhesion molecules whose specificity leads to the intradermal collection of specific leukocyte types (T-cells). Such basic mechanism is the origin of all inflammatory dermatoses. It is possible and even probable that some antihistamines, flavonoids and antiseptics modulate in a beneficial way the expression of some adhesion molecules (1).

SKIN FUNCTION

 

•		Protection against physical trauma and harmful substances and microbes.
•		The skin plays a vital role in regulating body temperature.
•		Helps maintain fluid and electrolyte balance.
•		It is an important sensory organ that transmits sensations such as pressure, touch, warmth, cold and pain

Skin Structure (fig.1)
The skin has three main layers:
 

•		The epidermis is the thin, protective outer layer.
•		The dermis is the tough, elastic second layer.
•		The subcutaneous tissue is the layer of fatty and connective tissue beneath the dermis.

The Epidermis
It is a layered epithelium made up of five distinct cell layers:

Stratum Corneum (Horny Cell Layer)
Stratum Lucidum (Clear Cell Layer)
Stratum Granulosum (Granular Cell Layer)
Stratum Spinosum (Prickle Cell Layer or Spinous Cell Layer)
Stratum Germinativum (Basal Cell Layer)

The skin is a continuous process of self-renewal, and each epidermal layer corresponds to a specific stage in this process, which is called keratinization.

Normal keratinization and desquamation depends on the presence of healthy stratum corneum, in which cells are manufactured and shed at normal rate.

The Dermis
The dermis is 20 to 40 times thicker than the epidermis, This skin layer provides a flexible support structure and encloses blood vessels, nerves, and skin appendages (eccrine and apocrine sweat glands, hair follicles and sebaceous glands). Blood vessels in the dermis provide nutrition to the skin, help maintain a constant body temperature, and provide circulating white blood cells that help defend against infection and foreign substances. The eccrine sweat glands help regulate body temperature by manufacturing and excreting sweat onto the skin. Apocrine sweat glands, which are responsible for body odor which is produced when bacteria decomposes the apocrine sweat, which itself is odorless.

Sebaceous glands, which produce the oily substance sebum, are located deep in the dermis. These glands are most abundant on the scalp, face, upper back, and chest. Sebaceous glands are usually associated with hair follicles, forming what is called the pilosebaceous (pilary+sebaceous) unit. The pilosebaceous unit is the site of developing acne.

The Subcutaneous Tissue
It is a layer of fat that lies beneath the dermis and acts as an insulator and shock absorber. These tissues also store energy in the form of calories as a reserve nutritional source.

Dermatitis
Skin disease is seen commonly in internal medicine since many general medical disorders have cutaneous manifestations. The most common of these is dermatitis, which suggests perhaps that the most important area for internal medicine skin curricula would be the treatment of dermatitis.

Allergic contact dermatitis (Fig 3 A , B, C &D .)
Contact allergy is an allergic skin reaction from contact with a substance that is usually harmless to others. The commonest clinical manifestation is an itchy rash that develops over a few days, after skin contact with a substance. The affected area first becomes itchy, then red and swollen with vesicles (water bubbles). 
A substance that can cause contact allergy is called a contact allergen. Common contact allergens are:
 

1.		Metals e.g. nickel in watch straps, chrome in cement
2.		Skin care products e.g. fragrances, lanolin
3.		Medication e.g. flavine, neomycin

Fig (3 A, B, C&D)

Allergic contact dermatitis, also known as contact hypersensitivity, is a T-cell-dependent skin disease with the kinetics of a delayed-type hypersensitivity response. Although this disorder is rarely life threatening, the costs to society of occupation-related allergic contact dermatitis are high. If the contact-sensitizing antigen is a compound in the workplace that is impossible to avoid or that cannot be identified, the problem may lead to an inability to work in that environment (2).

ATOPIC DERMATITIS
Atopic dermatitis is a common, intensely pruritic skin disorder that is challenging and frustrating to treat (3). This disorder, primarily occurring in infants and children, is commonly seen in pediatric dermatology practice. Onset is within the 1st year of life in 60% of cases and within the first 5 years in 85%, and is thought to affect about 10-15% of the population. Atopic dermatitis clears in about 40% of children and persists in some adults as hand dermatitis. 

Atopic dermatitis is a genetic disorder influenced by environmental factors. The mode of inheritance and genes involved are not clear. The high concordance rate of 77% in monozygotyic twins (15% in dizygotic twins) and the obvious familial occurrence support the genetic theory (4). Atopic dermatitis can be viewed as an exaggerated cutaneous immune response to environmental antigens. Patients with this disorder have a humoral response characterized by IgE antibodies associated with T cells that produce type 2 cytokines.
The antigens that induce such responses are termed allergens, and the allergens frequently responsible for atopic dermatitis are derived from the house-dust mite

The function of type 2 T-cell cytokines:
 

•		Promote the growth and activation of eosinophils (interleukin-5).
•		Switch the antibody isotope from IgM to IgE (interleukin-4 and interleukin-13).
•		Cause reduction in cell-mediated immunity (interleukin-10) (5). There is a definite defect in cell-mediated immunity within the skin of patients with atopic dermatitis and increased susceptibility to cutaneous viral and fungal infections, yet these patients are not systemically immunosuppressed.

The chronically dry skin of most patients with atopic dermatitis has prompted investigators to assess epidermal lipids. There is a significant decrease in ceramide concentrations in involved and uninvolved skin (6). 

sphingomyelin acylase, an epidermal enzyme, has been identified in the stratum corneum of patients with atopic dermatitis. One of the products of this enzyme, sphingosyl-phosphorylcholine may be a potent modulator of epidermal-cell function, inducing prostaglandin-E2 synthesis and possibly contributing to inflammation in atopic dermatitis (7). 

Filaggrin, a precursor of so-called "natural moisturizing factors" has been also found to be decreased in non-lesional atopic-dermatitis skin (8). 

Atopic dermatitis occurs in three main age-related stages that may be separated by periods of remission or overlap:
 

•		The infantile stage up to age 2 years, is typified by highly pruritic, red, scaly, crusted, and sometimes weeping patches on both cheeks and on the extensor parts of the extremities. Eczematous changes of the scalp and wheal formation may also be seen. The napkin area is generally spared and early infantile atopic dermatitis may be difficult to distinguish from seborrheic dermatitis on clinical grounds alone.
•		The childhood stage from 2 years to 12 years shows papulation rather than exudation, and occurs in the flexural areas, especially the antecubital and popliteal fossae, the volar aspect of the wrists, ankles, and neck. Thickened plaques show lichenification and excoriation. In black children, follicular papular lesions are prominent and striking and hypopigmentation and hyperpigmentation may cause parents concern
•		In the adult stage, from puberty onwards, patients have had few or no skin problems since infancy or may have suffered a chronic relapsing course with periods of remission. Lichenification occurs in the flexural areas and facial involvement is common, especially the forehead and periorbital regions. The wrists, hands, ankles, feet, fingers, and toes are often involved.

Pruritis is such a cardinal feature of atopic dermatitis that its absence may suggest another diagnosis even if many of the other symptoms are strongly characteristic. Most patients with atopic dermatitis have a personal or family history of atopy (9).

Complications:
Staphylococcus aureus and beta-hemolytic streptococci commonly colonize or secondarily infect the skin of patients with atopic dermatitis. Eczema herpeticulum is a serious viral complication in which painful monomorphous vesicles suddenly develop with oozing, crusting, and erosion. Other viral complications, especially in children, are recalcitrant warts and molluscum contagiosum (10). 

Ocular complications of atopic dermatitis of long duration include periorbital pigmentary darkening, eyelid dermatitis, keratoconjunctivitis, cataracts, ocular herpes simplex, and, rarely, retinal detachment. 
Several psychological disturbances have been described in patients with atopic dermatitis that are probably reactions to the chronic disease process. Nevertheless, sleep disturbances have been shown in atopic children that have substantial effects on daytime psychological functioning (11).

ACNE VULGARIS (PIMPLES)
Acne is a common skin condition, which consists of blackheads, whiteheads, red spots, and sometimes-deeper boil-like lesions called nodules or cysts. It afflicts most people during the teenage years. However, the disease may affect women in their thirties. The exact cause is unknown. One theory is that when hormone levels increase during puberty, the skin of the acne- prone person reacts by producing excess sebum (oils). The bacteria (Propionibacterium acnes Staphylococcus aureus, and Staph. Epidermidis) found on the skin alter these oils to produce substances that cause acne. The hair follicle, the site of acne may get plugged with dead skin cells. Sebum and bacteria may accumulate and cause pimples.

SENILE PURPURA
The skin of an aged person is thinner and easily disrupted. Blood vessels, too, are easily disrupted, resulting in bruises called senile purpura. Senile purpura is commonly seen on the forearms. Its presence does not indicate vitamin deficiency or a bleeding disorder. The skin heals slowly following injury.

LICHEN PLANUS
These lesions represent another important but less common category of papulosquamous disease. Lichen planus more often involves flexural areas, particularly the flexural surface of the wrist in contrast to psoriasis, which is more typically found on extensor surfaces. The character of the scale of lichen planus also differs from that of psoriasis. The lesions of lichen planus frequently show a reticulate or lacy white pattern called Wickham's striae. Lichen planus also typically produces lesions, which are flat-topped, and polyangular (rectangular or polygonal in shape) rather than rounded papules.

XEROSIS/ASTEATOTIC ECZEMA
The skin becomes dry and flakes easily as the oil contents of skin decreases with age. Dry skin becomes itchy. Sensation of dryness is common. 

Dry skin has a rough and finely flaking or scaly surface. These are seen in the upper back and the limbs, especially the shins. Sometimes asteatotic eczema occurs in areas of dry skin. These are seen as poorly demarcated, scaly round red patches. Sometimes a distinctive appearance of red scaly fissures in an irregular netlike pattern resembling cracked porcelain is seen.

ROSACEA
Rosacea is another very common condition in primary care often mistaken for lupus. When there is prominent rhinophyma the diagnosis is relatively easy to make. However, rosacea should be considered in any patient with central facial erythema provoked by emotion, alcohol, exertion, warm meals, warm liquids, or spicy foods. 
Most patients are very fair-skinned. Some patients presents not only with erythema of rosacea, but also the papular or pastular component as well.

BLISTERING DISORDERS
Herpes Simplex: It is a viral disease. Herpetiform vesicular disease implies vesicles clustered on an Erythemetous and often indurated base. 

Herpes zoster: Is a common blistering disorder common in elderly in which reactivation of the chicken pox that an individual had when young. This presents as a band of blisters on one side of the head or body or along one limb. It can be associated with severe pain.

MONILIASIS/CANDIDIASIS
This fungal infection is common on the lip area and genitals of persons with diabetes, those taking oral steroids and on long-term antibiotics. It is itchy and the rash is red with white flakes. Females may have a genital discharge and itch.

GENERALIZED DERMATOPHYTE (TINEA CORPORIS)
Dermatophyte infection is another important category of papulosquamous disease. In the very young and in the very old or the otherwise immunocompromised, extensive tinea corporis can mimic most of the generalized papulosquamous diseases.


The pathogenesis of common skin diseases
In order to understand the pathogenesis of the common Skin disorders, one should be acquainted with the following processes that could involve the skin in various pathological disorders.

Inflammation And Immune Responses:
Inflammation and the immune response are two interrelated processes the skin manifist to defend itself and the body it encloses.

Inflammation: is a complex series of vascular and cellular changes that helps repair of damaged tissue. Dilatation of capillaries causes redness (erythema), and leakage of plasma into the skin causing swelling (edema) and heat.

Immune response: is orchestrated by the immune systems, an intricate mix of cellular (T-cells), molecular, and and antibody components (B-cells) that protects the body against invaders. An invader that the immune system recognizes as harmful is called an antigen. When the immune system recognizes a foreign antigen it responds by producing one or both of two types of defenders:
 

•		The B- lymphocytes that produce antibodies, which are molecules that circulates in the bloodstream and neutralizes antigens and is called immunglobulin (Ig). The most common blood circulating immunoglobulins are IgG, IgM and IgE (IgE antibodies increase in hypersensitivity reactions).
•		The T cell. T cells assault antigens directly by producing substances called lymphokines. Lymphocytes are able to recognize foreign antigens because they have a sort of memory, they remember an invader from a previous encounter and are programmed to destroy those cells.

However, sometimes, abnormal immune response due to abnormal immune system does occur and the immune system does mistake a harmless substance, such as pollen or wool, as harmful antigen. The subsequent immune response is called allergic reaction. Although inflammation and immune response interact to protect and defend the skin, these defenders also produce common skin problems, which send patients to dermatologists for medication to treat erythema, swelling, lesions, itching and other symptoms. The most common skin disease seen by the internest is Dermatitis.

The Role of the Cellular Immune System (T Cells) in Common Dermatological Disorders

(Fig.2)

Disruption of the skin is the primary stage that leads to the most damaging consequence that is invasion by pathogenic microorganisms.

The spectrum of insults that cause disruption of the skin are:
 

•		Chemical agents.
•		Thermal and electromagnetic radiation.
•		Mechanical trauma.

The need for an effective mean of protection against this challenge has been a fundamental force behind the evolution of the immune system. 

The role of Celluar immunity (T cells) in dermatological disorders: The T cells act in the following steps (Fig.2) (12). When an offending antigen is introduced epicutaneously through intact skin. The sensitizing antigens are typically unstable reactive molecules that can form complexes with host proteins. The cell-presenting antigen migrates to the local skin draining lymph nodes.
 

1.		The naive T cell of the immune system encounters the antigen for which it is specific on an antigen-presenting cell in a skin- draining lymph node.
2.		The naοve T cells is activated and becomes a memory T cell with the expression of cutaneous lymphocyte antigen (CLA) and a distinct although undefined set of chemokine receptors.
3.		CLA- positive T cells possess the molecular keys that allow them to migrate to skin the site where the antigen was first encountered by the host where they proliferate and express activation molecules, and undergo the transition to memory T cells (13). Thus, memory T cells in inflammatory skin diseases express CLA on their surface; in contrast, T cells in inflammatory diseases involving tissues other than skin are predominantly CLA-negative (14). These CLA positive cells, which are generated in lymph nodes draining skin and are recruited back to the skin during inflammation, mediate many common skin diseases, including allergic contact dermatitis, psoriasis, atopic dermatitis, alopecia areata, drug-related eruptions, and lichen planes. (15). The patterns of T-cell movement and migration that mediate cutaneous immune surveillance are central to an understanding of the clinical and pathological features of T-cell-mediated skin diseases.

CLA-Positive T Cells and Cutaneous Inflammation:
 

•		CLA-positive T cells represent 10 to 15 percent of all circulating T cells in peripheral blood.
•		Although they have some features in common (e.g., their expression of CLA and certain chemokine receptors), their T-cell antigen-receptor specificities are quite heterogeneous.
•		Once activated, they may be capable of producing either type 1 T-cell cytokines (interferon- (gamma), interleukin-2, and lymphotoxin) or type 2 T-cell cytokines (interleukin-4, 5, 10, and 13).

This heterogeneity of phenotype and function is likely to be important for a successful and flexible host response to the plethora of distinct pathogens encountered in skin. 

Thus, cutaneous inflammation preferentially recruits memory T cells that have been activated by skin-related antigens because circulating CLA-positive T cells have previously encountered antigens in lymph nodes draining skin (16). For T cells to perform effector functions in skin, however, they must recognize antigen through their antigen receptors. They then become activated, producing effector molecules, including type 1 or type 2 T-cell cytokines. Therefore, only CLA-positive T cells that actually encounter the antigen for which their antigen receptor is specific will be activated during a given episode of cutaneous inflammation. These cytokines (and possibly direct cell-mediated injury of keratinocytes) induce the clinical pattern of cutaneous inflammation that is characteristic of each skin disease

Colonization and infection with Staphylococcus aureus and streptococci has been reported to exacerbate Atopic Dermatitis and psoriasis. Recent studies demonstrating that bacterial toxins can act as superantigens provide mechanism(s) by which S. aureus and streptococci could mediate an inflammatory skin lesion that consists predominantly of activated T-cells and monocytes. These observations provide a new direction for the development of novel approaches for the treatment of skin inflammation (17).

The Role of The Free Radical Nitrous Oxide

The gaseous free radical nitrous oxide is an important biologic mediator with physiologic and pathophysiologic roles in nearly every organ system. Recent progress has allowed the identification of the nitrous oxide pathway in several cell types that reside in the skin, including keratinocytes, melanocytes, Langerhans cells, fibroblasts, and endothelial cells. Convincing evidence suggests that nitrous oxide synthesis in these cells can be modulated by a diverse of inflammatory and immune stimuli, and thereby contributes to the pathogenesis of several human skin diseases. Characterization of these intrinsic and extrinsic regulatory stimuli of nitrous oxide synthesis has afforded substantial insights into the role of nitrous oxide in inflammatory, hyperproliferative, and autoimmune skin diseases, as well as skin cancer, and may ultimately form the basis for therapeutic intervention (18).

Conventional treatment of atopic dermatitis

Topical Corticosteroids
Topical corticosteroids are the mainstay of conventional therapy for atopic dermatitis and may be used in conjunction with topical antibiotics. 

The potency, concentration, and the vehicle of topical corticosteroids have to be selected with regard to the localization and morphology of the lesions to be treated. Efficacy has to be weighed against potential adverse effects, which mostly manifest on the skin (such as atrophy, striae distensae, purpura, telangiectasia, cutaneous infections), and only rarely as hypercorticolism due to systemic absorption. Contact allergy to corticosteroids is not rare. Hypersensitivity occurs especially in individuals who have been suffering for years of atopic dermatitis, Oral or parenteral administration of corticosteroids to sensitive individuals causes exacerbation of pre-existing contact dermatitis or widespread allergic cutaneous drug reactions. Cross-reactions to other corticosteroids occur frequently (19). Although systemic corticosteroids are very effective for severe, acute flares of atopic dermatitis their repeated or chronic use may lead to severe adverse effects.

Oral antibiotics
It is used to treat staphylococcal colonization or infection is frequently helpful.

Oral antihistamines
It may help decreasing scratching in some patients due to its sedative effect, but their role is limited. Topical antihistamines may be used for pruritis but they may cause allergic contact dermatitis.

Phototherapy
Phototherapy is especially helpful for atopic dermatitis unresponsive to topical treatment. The combination of ultraviolet (UV) A with UVB seems to be superior to UVB therapy alone (20). 

High-dose UVA-1 therapy is especially useful in acute exacerbations of atopic dermatitis and for relief of symptoms, often with complete clearance on the face, which is very sensitive to side effects of topical steroids. The long-term effects of high-dose UVA1 are not known, and this therapy should not be used in children.

Cyclosporin
It is dramatically effective in the treatment of atopic dermatitis in children and adults, however the risk of hypertension, renal toxicity, and possible propensity for malignant disorders cannot be ignored. Therefore, the risk-benefit ratio should be carefully assessed (21). 

Azathioprine
It is also effective for the treatment of atopic dermatitis but there are no prospective controlled studies to support its use (22). One of the main drawbacks of azathioprine therapy is its slow onset of action, usually 4-6 weeks. Because of the danger of myelosuppression, strict monitoring of white blood cell and platelet counts is essential (23).

ALTERNATIVE TREATMENT OF COMMON SKIN DISEASES

Alternative treatment aims not only to minimize the patient's complaints, but also to restore the skin barrier function as quickly as possible in order to reduce the effects of irritants or allergens. 
Crusts should be first removed gently by a tepid water bath, preferably supplemented with anti-inflammatory agents (e.g., wheat bran) and bath oil, or by wet dressings. With efficient anti-inflammatory treatment itching also resolves in many cases. 

Most drugs used in dermatology are topical: they are applied to the skin surface in the form of ointments, creams, lotions, gels, and powders. 

Topical drugs have advantages over systemic drugs. They deliver the medication directly to the organ that needs treatment - sometimes called the target organ - the skin. Topicals are also less likely to provoke systemic side effects than systemic drugs are. 

A topical drug cannot be effective if it does not penetrate the skin's outer protective layer and deliver its healing medication. Penetration through the skin is affected by the condition of the skin itself and the physical and chemical properties of the two parts of a topical dermatologic drug: the active, the vehicle and the presence of skin enhancer. 
Topical herbal drugs can be an alternative for treating skin ailments if we take into consideration their benefit/risk ratio compared to synthetic drugs. Many of the well-known plants are currently widely accepted by patients because of their heeling power. The efficacy of herbal drugs, their extracts and isolated substances can be deduced from pharmacological and biochemical in vitro experiments. Clinical trials are very promising (24).

ALL PURPOSE PHYTOCORT OINTMENT

Dermatitis is a complex clinical picture that must be comprehended not merely as skin disease, but rather as disturbances of the entire organism. An alternative to academic medical treatments is therapy with natural remedies, in view of the fact that they act upon the pathological process of the diseases in accordance with the particular drug-symptom complexes involved (25). 

The skin healing formulations of Multipurpose Phytocort Cream is optimized in terms of macroscopic characteristics including spreadability, penetrability, and lipidity. Some of the ingredients are fat-soluble while others are more hydrophilic. In order for All Purpose Phytocort dermal preparation to contain the whole complex of the drug constituents, oil in water emulsion have been prepared, in which both phases of the emulsion system are enriched by the pertinent lipophilic and hydrophilic ingredients and mixed together in a latter step. A modification of the composition and a selection of the emulsifier can modify the structure, type of cream, as well as its viscosity from the aspect of achieving optimal application and effect (26). Thus the optimized formulation, which is emulsion of oil in water, results in enhanced diffusion of active ingredients. 

The ointment is usually soft, white, non-greasy, and it vanish when rubbed into the skin. Ointment is a versatile vehicle that is useful in a wide range of skin diseases. They are easy to rub in and do not feel tacky or greasy.

THE GOAL OF ALL PURPOSE PHYTOCORT OINTMENT
 

1.		Modulates the immune system.
2.		Exhibits anti-inflammatory action.
3.		Inhibits the release of proinflammatory cytokines.
4.		Increases the epidermal lipids.
5.		Exhibits moisturizing effect and maintain normal transepidermal water loss.
6.		Exhibits antibacterial, antiviral and antifungal effect.
7.		Increases the resistance of blood vessels.
8.		Exhibits Antioxidant activity (oxygen and nitrous oxide free radicals scavenger).
9.		Relieves the pruritis.
10.		Modulate fibroblast hyperproliferation during epithelial regeneration.

ACTIVE INGREDIENTS

TEA TREE OIL
Tea tree oil has been found to be useful in removing transient skin flora while suppressing but maintaining normal resident flora (27). 

Terpinen-4-ol, alpha-Terpineol and Alpha-pinene are the active constituents in tea tree oil. They were found to be active against Propionibacterium acnes, Staphylococcus aureus, and Staph. Epidermidis (28). Studies showed that 32 strains of Propionibacterium acnes are susceptible to the essential oil of Melaleuca alternifolia, tea tree oil. The minimum bactericidal concentration of tea tree oil for five strains was 0.25% or less while, for the remainder, it was 0.50% (29). Isolates of Staphylococcus aureus tested were susceptible to the Tea tree essential oil. Of the isolates tested, 64 were methicillin-resistant S. aureus and 33 were mupirocin-resistant (30).
 
The in vitro antifungal activity of tea oil, the essential oil of Melaleuca alternifolia, has been evaluated against 26 strains of various dermatophyte species, 54 yeast, among them 32 strains of Candida albicans and other Candida sp. as well as 22 different Malassezia furfur strains. Tea tree oil was found to be able to inhibit growth of all clinical fungal isolates (31).
 
Randomized clinical trial has been performed on 124 patients to evaluate the efficacy and skin tolerance of 5% tea-tree oil in the treatment of mild to moderate acne, and compared with 5% benzoyl peroxide lotion. The results of this study showed that both 5% tea-tree oil 5% benzoyl peroxide had a significant effect in ameliorating the patients' acne by reducing the number of inflamed and non-inflamed lesions (open and closed comedones) although the onset of action in the case of tea-tree oil was slower. Encouragingly, fewer side effects were experienced by patients treated with tea-tree oil (32). 

BORAGE OIL (A Source of Polyunsaturated fatty acids)
The skin epidermis displays a highly active metabolism of polyunsaturated fatty acids. Deficiency of Linoleic acid and gamma lenolenic acid precursors of arachidonic acid results in characteristic scaly skin disorder and excessive epidermal water loss. Arachidonic acid is metabolized into prostaglandins. It has been found that prostaglandins modulate normal skin physiological processes at low concentrations and inflammatory reactions at high concentration. Thus, appropriate supplementation with purified vegetable oils rich in arachidonic acid precursors may generate local cutaneous anti-inflammatory metabolites which could serve as a less toxic in vivo monotherpy or as adjuncts to standard therapeutic regimens for the management of skin inflammatory disorders (33). 

Experimental studies showed that arachidonic acid precursor fatty acids are effectively incorporated into the cellular lipid of human keratinocytes (34). Fatty acids have been studied in the hyperkeratotic stratum corneum. The results showed a defect in the maturation of fatty acids. This presents evidence that the abnormality of lipid metabolism can influence the process of desquamation in stratum corneum (35). 

Using Borage oil rich in GLA has shown to correct deficiencies in skin lipids in subgroup of patients with atopic dermatitis with clinical improvement of the symptoms (36). Topically applied fatty acid has been found to be able to penetrate to the living cells of normal epidermis, enter into metabolism and significantly modify endogenous epidermal lipids (37). 

As it has been proven by studies that gamma-Linolenic acid (GLA), a precursor of arachidonic acid, possesses physiological functions of modulating immune and inflammatory response, various techniques are employed for the enrichment and purification of GLA in borage oil. Highly purified GLA is desired both as a medicine and as an ingredient of cosmetics (38). 

Borage oil is a rich source of Essential Fatty Acids that play a fundamental role in all cell membranes of the body, and they are vital for metabolism. The fluidity and flexibility of cell membranes depend on the amount of essential Fatty Acids they have. They are also the precursors of the important short-lived regulating molecules, the prostaglandins (39). 

In a clinical study of infantile seborrheic dermatitis, daily topical application of borage oil containing 24% GLA has been studied. It has been suggested that GLA is of importance in maintaining normal transepidermal water loss (40). 

The anti-inflammatory effect of GLA-fortified borage oil is due to the modulation of polymorphonuclear-neutrophils generation of proinflammatory leukotriene B-4 (41). 

Borage oil rich in gamma linolenic acid has been tested in animals and found to induce epidermal generation of local anti-inflammatory metabolites that have leukotriene inhibition potentials. It has been concluded that it has ameliorative effects on chronic inflammatory skin disorders (42). 

Borage oil, being a rich source of arachidonic acid -derived eicosanoid is considered potent modulators of hyperproliferation and inflammation of the skin (43). 

Studies showed that Arachidonic acid and linoleic acid mediate their ability to modulate inflammation and epidermal proliferation by being incorporated into epidermal phospholipids (44). 

ANTIOXIDANTS
Modern life stress leads to persistent activation of the neuroendocrine stress axis, which causes:
 

•		Increased release of oxygen free radicals.
•		Increased release of Nitrous oxide radicals.
•		Increased release of pro-inflammatory cytokines.

For the correction of these metabolic states, an adequate supply of plant-based antioxidants, especially flavonoids are indicated. These are plant-based polyphenols, which like vitamins cannot be synthesized by the body. Vitamin E in combination with vitamin C and beta-carotene are currently considered worldwide as the standard antioxidative therapy. For a more reliable antioxidative action, adding a mixture of flavonoids seems preferable (45).

BIOFLAVONOIDS
Flavonoids continue to attract wide attention as possible very useful agents for combating free radical pathologies, i.e. the pathological states associated with free radical overproduction (46). Experimental studies showed that Flavonoids, particularly quercetin, the most abundant flavonoid in plants has cytoprotective potential as they are likely to be important in defending human DNA against oxidative attacks (47). Experimental studies have also shown that flavonoids have protective effect on the skin against carcinogenic agents (48). 

Flavonoids relieves stress through its clear anxiolytic effect and thus stops the activation of the neuroendocrine stress axis which leads to increased level of oxygen and nitrous oxide free radicals and proinflammatory leukotrienes (49). 

Flavonoids have also anti-inflammatory activity. It has been found to have in addition to the strong antioxidant activity, an eicosanoid enzyme inhibition property (50). Studies suggested that bioflavonoids may be a potential lead for a new type of anti-inflammatory agents having dual inhibitory activity of group 11 phospholipase A and cyclooxygenase. It has been proved by animal experimental studies that it has both anti-inflammatory and analgesic property (51). 

Flavonoids are natural products widely distributed in the vegetable kingdom and are capable of modulating the activity of enzymes that affect the behavior of many cell systems, suggesting that these compounds may possess significant antiallergic in addition to the anti-inflammatory activities (52). There have been numerous topical applications of plant extracts having flavonoids known as anti-inflammatory compounds. The anti-inflammatory activities, of some plants have been attributed at least in part to the inhibition of arachidonic acid cascade related enzymes by flavonoids (53). The effect of naturally occurring flavonoids on epidermal cyclooxygenas/lipoxygenase was studied. The eicosanoid generated in the epidermis are believed to be involved in various biological activities of the skin. Experimental studies showed that flavonoids inhibit cyclooxygenase and lipoxygenase in various degrees, which explains their anti-inflammatory effect (54). 

Flavonoids have been found to display significant antifungal activity (55). A group of polyphenolic bioflavonoids, Proanthocyanidins, have been reported to exhibit a wide range of biological, pharmacological and chemoprotective properties against oxygen free radicals (56). Flavonoids works better when applied topically as they are poorly absorbed from the gut and are subject to degradation by intestinal microorganisms thus the amount remains biologically available may not be of sufficient concentration (57). 

The clinical effect of bioflavonoids combined with ascorbic acid has been found to have beneficial effect in treating chronic progressive pigmented purpura as it increases capillary resistance and mediates potent antioxidative radical scavenging activities (58). Animal experimental studies showed that flavonoids have protective activity against skin vascular permeability (59). 

NATURAL VITAMIN E (ALPHA TOCOPHEROL)
The stratum corneum, the outermost barrier of the body is frequently and directly exposed to a pro-oxidative environment, including ultraviolet solar radiation. Depletion of vitamin E, being the major lipophilic antioxidant is an early and sensitive in vivo marker of UV induced photo-oxidation (60). UV radiation causes acute adverse effects like sunburn, photosensitivity reactions, or immunologic suppression, as well as long-term sequelae like photoaging or malignant skin tumors. Combined vitamins C and E reduce the sunburn reaction, which might indicate a consequent reduced risk of later sequelae (61). 

Studies showed that alpha-tocopherol inhibits UVR- induced epidermal lipid peroxidation, suggesting that this may be one mechanism by which alpha-tocopherol prevents UVR-induced local Immunosuppression. Scavenging of UVR- generated lipid peroxides and reactive oxygen may inhibit loss of cell membrane integrity preventing depletion of lymphocyte numbers, thus protecting from local Immunosuppression (62). 

However, application of alpha-tocopherol rich oil before exposure to UVR results in preservation of vitamin E (63). Animal experimental studies showed that topical application of alpha-tocopherol, the most prominent naturally occurring form of vitamin E, inhibits ultraviolet induced photocarcinogenesis and DNA photodamage. The topical application of alpha tocopherol at least 2 hours before exposure to sun is important to allow enough time for cellular uptake of alpha -tocopherol as this is necessary for their optimal photoprotection (64). Clinical studies showed that alpha-tochopherol act synergistically with Ascorbic acid and protect the skin against solar stimulated radiation induced skin inflammation and so suppress the sunburn reaction in healthy volunteers (65). 

The presence of ozone (O (3)) in photochemical smog is considered another important health concern. The stratum corneum (SC), the outermost skin layer and the permeability barrier of the skin, represents a sensitive target for O (3)-induced oxidative stress and depletion of vitamin E. Remarkably, repeated low-level O (3) exposures resulted in cumulative oxidative effects in the stratum corneum (66). It has been found that damage of the cutaneous lipids caused by ozone exposure, is an effect that can be attenuated by vitamin E application (67). 

Studies showed that vitamin E increased the stratum corneum hydration statistically significantly. There was also evidence of an enhanced water-binding capacity after treatment with vitamin E. For the hydrating effect of vitamin E its concentration is of importance. The optimum concentration turned out to be 5% (68). 

Alpha-tocopherol has been found to negatively regulate proliferation of human skin fibroblasts and reduce the signs of aging, as cell proliferation is an important event in the aging process. . When alpha-tocopherol was added to the growth medium at a physiological concentration of 50 microM, cell proliferation was inhibited by 40% in 72 h. Both the duration and concentration of the alpha-tocopherol are important parameters of controlling the proliferation process (69). 

The alpha-tocopherol topical treatment increased alpha- tocopherol levels both in the epidermis (62-fold) and the dermis (22-fold), further more it reduces the formation of epidermal lipid hydroperoxides after UV irradiation. Studies showed that topical alpha-tocopherol application enhance the level of epidermal and dermal antioxidants and prevent ultra violet oxidative damage of cutaneous tissue. The underlying mechanism of this effect involves the up-regulation of a network of enzymatic and non -enzymatic antioxidants (70). After topical application of alpha-tocopherol the stratum corneum was found to contain the highest concentration of vitamin E per micro m. thickness. The largest fraction of skin vitamin E following topical application was found in the deeper subcutaneous layer-the lowest layer, the papillary dermis and the dermis contained the major portion of the of the applied vitamin E. Although the papillary epidermis only represents about 16% of the total skin thickness, it contains sebaceous glands, lipid secretory organs and thus may account for the vitamin E affinity of this layer. Hence applied vitamin E penetrates rapidly through the skin but the highest concentrations are found in the uppermost 5 microns (71). 

Studies showed that glycolic acid could strongly potentiate the antioxidant action of vitamin E. This suggests the advantage of combining alpha-glycolic acid with these antioxidants in skin-designed preparations, both to improve penetration and availability of antioxidants to epidermal layers and to enhance their protective potential (72). 

NATURAL VITAMIN A (RETINOL AND RETINALDEHYDE)
Vitamin A is the generic term for a variety of fat-soluble substances including retinol, retinylaldhyde and retinoic acid. Vitamin A is commonly known as the anti-infective vitamin and has an essential role in cellular differentiation, the latter providing a unique core mechanism helping to explain the influence of vitamin A on epithelial barriers. Vitamin A has an influence on epithelial barrier. Alterations in the epithelial lining of vital organs occur early in deficiency, suggesting a potentially important role for the barrier function (73). 

Topical retinoic acid (RA) causes irritation of the skin. To prevent this side effect, natural precursors of retinoic acid have been proposed. The natural retinoids (retinol and retinaldehyde have been found to have a good tolerance profile, in contrast with the irritating potential of retinoic acid (74). However, retinol and retinaldhyde are metabolized by the dermis into retinoic acid. After treatment with retinol and retinaldhyde, low but significant amounts of retinoic acid could be detected in the epidermis, as well as in the dermis. In comparison, treatments with retinoic acid itself, leads to higher level of retinoic acid in the epidermis and in the dermis. Thus the low proportion of retinaldehyde, metabolized into a -tran-retenoic acid, explains the low irritancy profile of topical retinaldehyde and supports the concept of controlled delivery of ligands. Thus the action of retinol or retinaldhyde on the skin is still via a retinoic acid formation through the metabolic function of the dermis (75).

Retinaldehyde (RAL), a natural metabolite of beta-carotene and retinol (ROL), can be used topically in human skin and exerts biological activity; it may be a convenient way to deliver multipotential vitamin A activity in epidermis. Animal experiments indicated that keratinocytes metabolise topical retinaldehyde. Keratinocytes differentiating in vitro exhibit greater capacity for retinoic acid synthesis from retinol or retinaldehyde as compared to nondifferentiated cells (76). Experimental study results suggest that increasing cellular concentration of retinoic acids in in-vitro differentiating keratinocytes is achieved by a process of increased activity of the retinoic acid synthesis (77). Thus the concept of using retinaldehyde as a precursor has been confirmed. The keratinocytes predominantly channel retinaldhyde into storage forms should also be considered as a convenient way to load the epidermis with vitamin A. 

It has also been found that after experimental topical application of retinol and retinaldhyde that there was a significant amount of 14-hydroxy-4, 14-retro-ROL (14-HRR), a metabolite that could promote the growth of B lymphocytes (humeral antibodies) and activate T-lymphocytes (cellular immunity), suggests distinct potentials of topical retinol and retinaldhyde (78). 

Studies showed that topical retinol appears to improve the resistance of the stratum corneum against some chemical and physical (UV) threat. It also limits UV-induced shallow wrinkling (79). 

Retinoids was found to inhibit proliferation of melanocytes and melanoma cells and affect disorders of hypo- and hyperpigmentation. The endogenous concentrations of retinol and its metabolites in melanocytes were found to be five times those in melanoma cells. Dissimilarities in the metabolism and endogenous concentration of retinoids between benign and malignant melanocytes might play a key role in differentiation and growth regulation (80). 

NATURAL VITAMIN C (ASCORBIC & ASCORBATE)
Vitamin C (Ascorbic, Ascorbate) is an essential micronutrient involved in many biologic and biochemical functions. Humans cannot synthesize vitamin C because they lack the last enzyme in biosynthetic pathway. Known functions of vitamin C are accounted for by its action as an electron donor or reducing agent. Vitamin C is a specific electron donor for 8 enzymes (81,82). Three of them are enzymes that participate in collagen hydroxylation (important step for keeping a healthy skin. Vitamin C also has non-enzymatic-reductive functions in chemical reactions. Based on its free radical intermediate, vitamin C is a chemical reducing agent (antioxidant) in many intracellular and extracellular reactions. Vitamin c could also decrease oxidative damage in vascular walls (83,84). 

Environmental exposure to ultraviolet light B (UVB, wave lengths 290-320 nm) of the solar spectrum causes major damage, including an inflammatory response, in skin. Studies using the human keratinocyte cell line, showed that stable derivative of ascorbic acid, are able to reduce UVB damage. These data suggest that ascorbic acid shows a photoprotective effect against UVB-induced inflammation and damage in human epithelial cells (85). Topical application of ascorbic acid suppresses the cutaneous inflammation induce by ultraviolet irradiation in human and animals. Studies suggested that it prevents the acute inflammation partly through scavenging reactive oxygen species and potentiating the antioxidative activity of alpha-tocopherol (86). Experimental studies showed that ascorbic acid inhibited UVA-induced lipid peroxidation in cultured human keratinocytes in a concentration-dependent manner. 

It has also been found that ascorbic acid was able to down regulate the proinflammatory cytokines IL-alpha and IL-6. These findings indicate a major cell-protective effect of ascorbic acid on UVA-induced lipid peroxidation and the secretion of pro-inflammatory cytokines by UVA irradiated human keratinocytes (87). 

CALENDULA OFFICINALIS
Calendula Officinalis L has gained importance in the process of rediscovering natural healing forces. Increasing significance is contributed to calendula ointment, which have been used traditionally for a long time

Calendula extracts is characterized by a high level of terpenoids e.g. saponosides in the form of oleanolglycosides and triterpene alcohols. The triterpenediol-3-monoesters consist for 85% of Faradiol esters. 

Calendula extract is a rich source of carotinoids. The colour of the flowers depends on their content of carotinoids (88). 

Also remarkable is the fat oil of the seeds which predominately consists of the conjugated trienoic calendula acid (88). 

Calendula preparations are mainly used for the treatments of wounds and for cosmetical purposes (88). Dressing materials containin Calendula Officinalis ointment applied to experimental animal's wounds has been found to enhance the tissue repair (89). Topical application of Calendula Officinalis markedly stimulates physiological regeneration and epithelization. This effect is assumed to be due to more intensive metabolism of glycoproteins, nucleoproteins and collagen proteins during the regenerative period in the tissue (90). Medicinal herbs containing Calendula extract has been found to be stimulating to the wound healing process by their antifungal/antibacterial qualities. Some investigators reported that the wound-healing period for Calendula Officinalis is shorter than that of the witness (91). 

Animal experimental studies showed that the green leaf juice of C. Officinalis produced significant analgesia; pain threshold increased by 58.9 and 62.15 to that of control. It has been also found to have anti-inflammatory action (92). 

Studies proved the anti-inflammatory action of Calendula Officinalis (93). The triterpenoids has been shown to be the most important anti-inflammatory principles of Calendula extracts. The anti-inflammatory activity was proportional to their content of Faradiol monoester, which can be taken as a suitable parameter for the quality control of Calendula preparations (94, 95). Whole plant extract differ from that of the flowers by the presence of monoterpene hydrocarbons, essential oil, in addition to the alcohols

Calendula Officinalis extracts has been found to have anti-edematous activity due to its Faradiol esters content which is dose dependent activity (96). 

Calendula extract is a rich source of Flavonoids. Characteristic calendula-flavonoids are the isorhamnetin glycosides. The total flavonoids in calendula Officinalis flowers in the ligulate rayflorets and tubular disc-florets were found to be 0.88 and 0.25% respectively (97). 

The saponins isolated from Calendula Officinalis were tested for its toxic and mutagenic activities. All the saponins were found to be non-toxic and non-mutagenic for doses of 400.mu g (98). 

VIOLA TRICOLOR
In a multicentre observational study, 127 patients with various types of dermatitis were administered a homeopathic complex including viola tricolor. In 119 of 127 cases, clear improvement with no side effects was observed (99). 

Viola tricolor extract is a rich source of antioxidants. The total flavonoid contents were determined using rutin as the standard. Rutin content was highest in Viola tricolor flowers among 11 plants species collected in Turkey (100). 

Extract of viola tricolor was found to have antifungal activity and is effective against trichophyton mentagrophytes (101). 

CHAMOMILE
It exhibits antihistaminic effect. Animal experimental studies showed that en-yen dicycloether fraction of the essential oil of chamomile inhibits the release of histamine from the protamine sulphate-provoked degranulation of mast cells, which is the cause of allergic symptoms (102). 

Chamomile extract has been found to exert anti-inflammatory activity in vivo, and so it is used for the treatment of inflammatory skin diseases. Its activity is due to the Chamazulene component of the extract, which inhibits the formation of leukotriene B-4 in neutrophilic granulocytes and additional antioxidative effect lead to blocking the chemical peroxidation of arachidonic acid (103). 

It has also been proved by experimental studies that chamomile extract demonstrated clear antidermatophytic activity (104). 

Animal experimental study showed that a long-term exposure to low doses of the heteropolysaccharides from chamomile flowers enhance the immune response to bacterial infection and it has been concluded that chamomile extract has the ability to modulate the immune system (105). From the essential oil components: alpha-bisabolol and Chamazulene has the strongest activity on Gram-positive and Gram-negative bacteria and on pathogenic fungi (106). 

ROSA CANINA
The fruits of Rosa canina (Rosaceae) are very rich in carotenoids. Chromatographic analysis revealed the major carotenoids to be beta-carotene, lycopene, beta-chryptoxanthin, rubixanthin, zeaxanthin and lutein (107). 

Rosa canina contains vitamin C content is in high proportions. The analysis showed the vitamin C contents were 1200-mg/100 g in the frozen fruits and 2000 mg/100 g in the dried fruits (108). 

Extracts of Rosa canina routs showed anti-inflammatory activity. Laboratory experiments showed its in vitro inhibitory effects on interleukin-1 (IL-1alpha, IL-beta) and tumor necrosis factor (TNF- alpha) biosynthesis in various percentages depending upon the concentration that explains its anti-inflammatory effect and support their folkloric utilization (109). 

ECHINACEA
The efficacy of the Echinacea root extract as an immunomodulatory has been demonstrated in studies of viral and bacterial infection. The therapeutic superiority of the herbal immunomodulatory over placebo was confirmed as statistically significant and clinically relevant. Studies also demonstrated its efficacy as an immunobalancing agent, which is an antigen-independent mode of phytoimmunomodulation (110). 

The mother tinctures of Echinacea have shown high inhibitory effect against Staphylococcus epidermidis (111). 

Topical application of Echinacea containing ointment has been found to have good antiviral activity against both acyclovir resistant and acyclovir susceptible strains of HSV-1 and HSV-2 anti herpes simplex virus (HSV) (112). Laboratory experiments showed that macrophages cultured in concentrations of Echinacea as low as 0.012 mug/ml produced significantly higher levels of IL-1, TNF-alpha, IL-6 and IL-10 than unstimulated control cells. The high levels of IL-1, TNF-alpha, and IL-10 induced by very low levels of Echinacea are consistent with an immune activated antiviral effect (113). 

Echinacea stimulates wound-healing process by their antifungal/antibacterial qualities. Its locally applied form is well received by the tissues, without irritation, their action being primarily local rather than general as has been noticed from the paraclinic exams (114). 

The Echinacea Purpurea flowers have more anti-inflammatory activity than the routs (115). Polyunsaturated alkamides isolated from Echinacea were shown to possess inhibitory activity in in-vitro cyclooxygenase and 5- lipoxygenase (116). 

Echinacea Purpurea stimulates the neutrophil phagocytosis. Echinacea treatment of mice, immunosuppressed with immunosuppressive drugs, restored their resistance against lethal infections with the predominantly granulocyte-dependent Candida albicans through stimulating the phagocytic activity (117,118). Polysaccharides purified from Echinacea purpurea were found to have antistaphylococci activity. These substances enhanced the ability of granulocytes to kill staphylococci. Also activate monocytes to secrete TNF-alpha, IL-6 and IL-1. Altogether, as in mice, the polysaccharides could induce acute phase reactions and activation of phagocytes in human (119). 

REFERENCES:

(1) Henry F. Rakic L. Van Cromphaut I. Pierard-Franchimont C. Pierard GE. [Skin microcirculation, adherence molecules and inflammatory dermatoses]. [Review] [15 refs] [French] Revue Medicale de Liege. 53(8):479-82, 1998 Aug.
(2) Robert, Caroline; Kupper, Thomas S.Mechanisms of Disease: Inflammatory Skin Diseases, T Cells, and Immune Surveillance Volume 341(24) 9 December 1999 pp 1817-1828.

(3) Hanifin JM. Atopic dermatitis. In: Middleton E, Reed CE, Ellis EF, Adkinson NF, Yunginger JW, Busse WW, eds. Allergy principles and practice, 4th edn. St Louis: Mosby, 1993: 1581-604. Rudikoff, Donald; Lebwohl, Mark Atopic dermatitis [Seminar] Lancet 1998; 351: 1715-21.

(4) Dahl RE, Bernhisel-Broadbent J, Scanlon-Holdford S, Sampson HA, Lupo M. Sleep disturbances in childen with atopic dermatitis. Arch Pediatr Adolesc Med 1995; 149: 856-60. 

(5) Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LW. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J Immunol 1993;150:1122-36.

(6) Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano A. Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol 1991; 96: 523-26. 

(7) Murata Y, Ogata J, Higaki Y, et al. Abnormal expression of sphingomyelin acylase in atopic dermatitis: an etiologic factor for ceramide deficiency? J Invest Dermatol 1996; 106: 1242-49. 

(8) Seguchi T, Chang-Yi C, Kusuda S, Takahashi M, Aisu K, Tezuka T. Decreased expression of filaggrin in atopic skin. Arch Dermatol Res 1996; 288: 442-46. 

(9) Hanifin JM, Rakja G. Diagnostic features of atopic dermatitis. Acta Dermatovener 1980; 92 (suppl): 44-47.

(10) Aly R, Mailbach HI, Shinefield HR. Microbial flora of atopic dermatitis. Arch Dermatol 1977; 113: 780-82.

(11) Dahl RE, Bernhisel-Broadbent J, Scanlon-Holdford S, Sampson HA, Lupo M. Sleep disturbances in childen with atopic dermatitis. Arch Pediatr Adolesc Med 1995; 149: 856-60.


(12) Robert, Caroline; Kupper, Thomas S.Mechanisms of Disease: Inflammatory Skin Diseases, T Cells, and Immune Surveillance Volume 341(24) 9 December 1999 pp 1817-1828 

(13) Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996;272:60-6.
(14) Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LW. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J Immunol 1993; 150:1122-36.

(15) Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LW. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J Immunol 1993; 150:1122-36 

(16) Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LW. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J Immunol 1993; 150:1122-36.

(17) Leung, S.Y.M.; Hauk, P.; Strickland, l.;Travers, J.B.; Norris, D.A. The role of superantigens in human diseases: therapeutic implications for the treatment of skin diseases ] British Journal of Dermatology, Supplement. 139 (Supplement 53):17-29,
December 1998.
(18) Bruch-Gerharz, Daniela; Ruzicka, Thomas; Kolb-Bachofen, Victoria * Nitric Oxide in Human Skin: Current Status and Future Prospects. Journal of Investigative Dermatology. 110(1): 1-7, January 1998.


(19) de Groot AC. van Ginkel CJ. Bruynzeel DP. [Contact allergy for corticosteroids]. [Review] [22 refs] [Dutch] Nederlands Tijdschrift voor Geneeskunde. 141(32): 1559-62, 1997 Aug 9.

(20) Krutmann J. Phototherapy for atopic dermatitis. Dermatol Ther 1996; 1: 24-31.

(21) Berth-Jones J, Graham-Brown RA, Marks R, et al. Long term efficacy and safety of cyclosporin in severe adult atopic dermatitis. Br J Dermatol 1997; 136: 76-81. 

(22) Lear JT, English JSC, Jones P, Smith AG. Retrospective review of the use of azathioprine in severe atopic dermatitis. J Am Acad Dermatol 1996; 35: 642-43. 

(23) Tan BB. Azathioprine in dermatology: a survey of current practice in the UK. Br J Dermatol 1997; 136: 351-55. 

(24) Mennet-Von Eiff M. Meier B. Phytotherapy in dermatology. 9th Swiss Congress for Phytotherapy. Zeitschrift fur Phytotherapie. Vol 16(4) (pp 201-210), 1995.
(25) Bresser H. Flach D. Hartung A. Krautheimer B. Zenker C. New aspects in the treatment of neurodermatitis and dermatitis. Arztez Naturheil Verfahren. Vol 40(8) (pp 558-562), 1999.
(26) Lichnerov I. Masterova I. Formulation of creams containing extracts from calendula officinalis L. Ceska a Slovenska Farmacie. Vol 47(2) (pp 79-83), 1998.

(27) Carson C F. Riley T V. American Journal of Infection Control 24(3). 1996. 186-189).

(28) Raman A. Weir U. Bloomfield S F. Letters in Applied Microbiology 21(4). 1995. 242-245).
(29) Carson C F. Riley T V. Letters in Applied Microbiology 19 (1). 1994. 24-25.
(30) Carson C F. Cookson B D. Farrelly H D. Riley T V. Journal of Antimicrobial Chemotherapy 35(3). 1995. 421-424)
(31) Nenoff P [a]. Haustein U-F. Brandt W.Antifungal activity of the essential oil of Melaleuca alternifolia (Tea Tree Oil) against pathogenic fungi in vitro. Skin Pharmacology. 9(6). 1996. 388-394. 
(32) Bassett I B. Pannowitz D L. Barnetson R S C. Medical Journal of Australia 153 (8). 1990. 455-456, 458.

(33) Ziboh VA. The significance of polyunsaturated fatty acids in cutaneous biology. Lipids. 31 Suppl: S249-53, 1996 Mar.
(34) Punnonen K. Puustinen T. Jansen CT. Time course of incorporation of 20-carbon polyunsaturated fatty acids in a human keratinocyte cell line. Lipids. 22(3): 139-43, 1987 Mar.
(35) Nicollier M. Massengo T. Remy-Martin JP. Laurent R. Adessi GL. Free fatty acids and fatty acids of triacylglycerols in normal and hyperkeratotic human stratum corneum. Journal of Investigative Dermatology. 87(1): 68-71, 1986 Jul. 

(36) Henz B M [a]. Jablonska S. Van De Kerkhof P C M. Stingl G. Blaszczyk M. Vandervalk P G M. Veenhuizen R. Muggli R. Raederstorff D.Double-blind, multicentre analysis of the efficacy of borage oil in patients with atopic eczema. British Journal of Dermatology. 140(4). April, 1999. 685-688. 

(37) Wertz PW. Downing DT. Metabolism of topically applied fatty acid methyl esters in BALB/C mouse epidermis. Journal of Dermatological Science. 1(1):33-7, 1990 Jan.
(38) Huang Fang-Cheng. Ju Yi-Hsu [a]. Chiang Jen-Chung. gamma-Linolenic acid-rich triacylglycerols derived from borage oil via lipase-catalyzed reactions. Journal of the American Oil Chemists Society. 76(7). July 1999. 833-837. 
(39) San Juan P M F. Study of the presence of Gamma Linolenic Acid in vegetable oils. Alimentaria 29 (231). 1992. 49-52.

(40) Tollesson Anders [a]. Frithz Anders. Transepidermal water loss and water content in the stratum corneum in infantile seborrhoeic dermatitis. Acta Dermato-Venereologica. 73(1). 1993. 18-20.

(41) Ziboh V A. Fletcher M P. Dose-response effects of dietary Gamma Linolenic Acid-eriched oils on human polymorphonuclear-neutrophil biosynthesis of leukotriene B-4 American Journal of Clinical Nutrition 55 (1). 1992. 39-45.
(42) Miller C C. Tang W. Ziboh V A. Fletcher M P. Dietary supplementation with ethyl ester concetrates of fish oil N-3 and borage oil N-6 polyunsaturated fatty acids induces epidermal generation of local putative anti-inflammatory metabolites. Journal of Investigative Dermatology 96 (1). 1991. 98-103. 

(43) Belury MA. Leyton J. Patrick KE. Cumberland AG. Locniskar M. Fischer SM. Modulation of phorbol ester-elicited events in mouse epidermis by dietary n-3 and n-6 fatty acids. Prostaglandins Leukotrienes & Essential Fatty Acids. 44(1):19-26, 1991 Sep.

(44) Gron B. Iversen L. Ziboh V. Kragballe K. Distribution of monohydroxy fatty acids in specific human epidermal phospholipids. Dermatology. 2(1): 38-44, 1993 Feb.

(45) Hassig A [a]. Liang W X. Schwabl H. Stampfli K. Flavonoids and tannins: Plant-based antioxidants with vitamin character. Medical Hypotheses. 52(5). May, 1999. 479-481.

(46) Mauri Pier Luigi [a]. Iemoli Loredana. Gardana Claudio. Riso Patrizia. Simonetti Paolo. Porrini Marisa. Pietta Pier Giorgio. Liquid chromatography/electrospray ionization mass spectrometric characterization of flavonol glycosides in tomato extracts and human plasma. Rapid Communications in Mass Spectrometry. 13(10). 1999. 924-931. 

(47) Duthie S J [a]. Dobson V L. Dietary flavonoids protect human colonocyte DNA from oxidative attack in vitro. European Journal of Nutrition. 38(1). Feb., 1999. 28-34. 

(48) Jeong Hyeh-Jean. Shin Young Geun. Kim Il-Hyuk. Pezzuto John M [a]. Inhibition of aromatase activity by flavonoids. Archives of Pharmacal Research (Seoul). 22(3). June, 1999. 309-312 . 

(49) Paladini A C [a]. Marder M [a]. Viola H. Wolfman C. Wasowski C. Medina J H. Flavonoids and the central nervous system: From forgotten factors to potent anxiolytic compounds. Journal of Pharmacy & Pharmacology. 51(5). May, 1999. 519-526. 

(50) Schubert Shay Yehoshua. Lansky Ephraim Philip. Neeman Ishak [a]. Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. Journal of Ethnopharmacology. 66(1). July, 1999. 11-17.

(51) Kim Hee Kee. Son Kun Ho. Chang Hyeun Wook. Kang Sam Sik. Kim Hyun Pyo [a]. Amentoflavone, a plant biflavone: A new potential anti-inflammatory agent. Archives of Pharmacal Research (Seoul). 21(4). Aug., 1998. 406-410. 

(52) Di Carlo Giulia. Mascolo Nicola. Izzo Angelo A. Capasso Francesco [a]. Flavonoids: Old and new aspects of a class of natural therapeutic drugs. Life Sciences. 65(4). June 18, 1999. 337-353.

(53) Moon Tae Chul [a]. Park Jeong Ok [a]. Chung Kwang Won [a]. Son Keun Ho. Kim Hyun Pyo. Kang Sam Sik. Chang Hyeun Wook [a]. Chung Kyu Charn [a]. Anti-inflammatory activity of the flavonoid components of Lonicera japonica. [Korean] Yakhak Hoeji. 43(1). Feb., 1999. 117-123. 

(54) Kim HP. Mani I. Iversen L. Ziboh VA. Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs. Prostaglandins Leukotrienes & Essential Fatty Acids. 58(1):17-24, 1998 Jan.

(55) Lopes Norberto P. Kato Massuo J [a]. Yoshida Massayoshi. Antifungal constituents from roots of Virola surinamensis. Phytochemistry (Oxford). 51(1). May, 1999. 29-33. 

(56) Bagchi D. Garg A. Krohn R L. Bagchi M. Tran M X. Stohs S J [a]. Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Research Communications in Molecular Pathology & Pharmacology. 95(2). 1997.179-189. 

57) Formica J V [a]. Regelson W. Review of the biology of quercetin and related bioflavonoids. Food & Chemical Toxicology. 33(12). 1995. 1061-1080. 

(58) Reinhold U. Seiter S. Ugurel S. Tilgen W. Treatment of progressive pigmented purpura with oral bioflavonoids and ascorbic acid: an open pilot study in 3 patients. Journal of the American Academy of Dermatology. 41(2 Pt 1):207-8, 1999 Aug.

(59) Budzianowski J. Korzeniowska K. Chmara E. Mrozikiewicz A. Microvascular protective activity of flavonoid glucuronides fraction from Tulipa gesneriana. Phytotherapy Research. 13(2):166-8, 1999 Mar.

(60) Thiele JJ. Traber MG. Packer L. Depletion of human stratum corneum vitamin E: an early and sensitive in vivo marker of UV induced photo-oxidation. Journal of Investigative Dermatology. 110(5):756-61, 1998 May.

(61) Eberlein-Konig B. Placzek M. Przybilla B. Protective effect against sunburn of combined systemic ascorbic acid (vitamin C) and d-alpha-tocopherol (vitamin E). Journal of the American Academy of Dermatology. 38(1):45-8, 1998 Jan.

(62) Yuen KS. Halliday GM. alpha-Tocopherol, an inhibitor of epidermal lipid peroxidation, prevents ultraviolet radiation from suppressing the skin immune system. Photochemistry & Photobiology. 65(3):587-92, 1997 Mar.

(63) Weber C. Podda M. Rallis M. Thiele JJ. Traber MG. Packer L. Efficacy of topically applied tocopherols and tocotrienols in protection of murine skin from oxidative damage induced by UV-irradiation. Free Radical Biology & Medicine. 22(5):761-9, 1997.

(64) McVean M. Liebler DC. Prevention of DNA photodamage by vitamin E compounds and sunscreens: roles of ultraviolet absorbance and cellular uptake. Molecular Carcinogenesis. 24(3):169-76, 1999 Ma

(65) Fuchs J. Kern H. Modulation of UV-light-induced skin inflammation by D-alpha-tocopherol and L-ascorbic acid: a clinical study using solar simulated radiation. Free Radical Biology & Medicine. 25(9):1006-12, 1998 Dec.

(66) Thiele JJ. Traber MG. Polefka TG. Cross CE. Packer L. Ozone-exposure depletes vitamin E and induces lipid peroxidation in murine stratum corneum. Journal of Investigative Dermatology. 108(5):753-7, 1997 May.

(67) Thiele JJ. Traber MG. Podda M. Tsang K. Cross CE. Packer L. Ozone depletes tocopherols and tocotrienols topically applied to murine skin. FEBS Letters. 401(2-3):167-70, 1997 Jan 20.

(68) Gehring W. Fluhr J. Gloor M. Influence of vitamin E acetate on stratum corneum hydration. Arzneimittel-Forschung. 48(7):772-5, 1998 Jul. 

(69) Onat D. Boscoboinik D. Azzi A. Basaga H. Effect of alpha-tocopherol and silibin dihemisuccinate on the proliferation of human skin fibroblasts. Biotechnology & Applied Biochemistry. 29 ( Pt 3):213-5, 1999 Jun.

(70) Lopez-Torres M. Thiele JJ. Shindo Y. Han D. Packer L. Topical application of alpha-tocopherol modulates the antioxidant network and diminishes ultraviolet-induced oxidative damage in murine skin.British Journal of Dermatology. 138(2):207-15, 1998 Feb.

(71) Traber MG. Rallis M. Podda M. Weber C. Maibach HI. Packer L. Penetration and distribution of alpha-tocopherol, alpha- or gamma-tocotrienols applied individually onto murine skin. Lipids. 33(1):87-91, 1998 Jan.

(72) Morreale M. Livrea MA. Synergistic effect of glycolic acid on the antioxidant activity of alpha-tocopherol and melatonin in lipid bilayers and in human skin homogenates. Biochemistry & Molecular Biology International. 42(6):1093-102, 1997 Sep.

(73) McCullough FS. Northrop-Clewes CA. Thurnham DI. The effect of vitamin A on epithelial integrity. [Review] [37 refs] Proceedings of the Nutrition Society. 58(2):289-93, 1999 May.

(74) Fluhr JW. Vienne MP. Lauze C. Dupuy P. Gehring W. Gloor M. Tolerance profile of retinol, retinaldehyde and retinoic acid under maximized and long-term clinical conditions. Dermatology. 199 Suppl 1:57-60, 1999.

(75) Bailly J. Crettaz M. Schifflers MH. Marty JP. In vitro metabolism by human skin and fibroblasts of retinol, retinal and retinoic acid. Experimental Dermatology. 7(1):27-34, 1998 Feb. 

(76) Siegenthaler et al. 1990. Biochem. J. 268: 371-378. 

(77) Chatellard-Gruaz D. Randolph RK. Hagens G. Saurat JH. Siegenthaler G. Differentiation of human epidermal keratinocytes is accompanied by increased expression of CRABP-II and increased cellular concentration of retinoic acids: retention of newly synthesized retinoic acids by CRABP-II. Journal of Lipid Research. 39(7):1421-9, 1998 Jul. 

(78) Sass JO. Didierjean L. Carraux P. Plum C. Nau H. Saurat JH. Metabolism of topical retinaldehyde and retinol by mouse skin in vivo: predominant formation of retinyl esters and identification of 14-hydroxy-4, 14-retro-retinol. Experimental Dermatology. 5(5):267-71, 1996 Oct.

(79) Goffin V. Henry F. Pierard-Franchimont C. Pierard GE. Topical retinol and the stratum corneum response to an environmental threat. Skin Pharmacology. 10(2):85-9, 1997.

(80) Rosdahl I. Andersson E. Kagedal B. Torma H. Vitamin A metabolism and mRNA expression of retinoid-binding protein and receptor genes in human epidermal melanocytes and melanoma cells. Melanoma Research. 7(4):267-74, 1997 Aug.

(81) Levine M. New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med. 1986;314:892-902. 

(82) Levine M, Rumsey SC, Wang Y, et al. Vitamin C. In: Filer LJ, Ziegler EE, eds. Present Knowledge in Nutrition. Washington, DC: International Life Sciences Institute; 1996:146-159. 

(83) Diaz MN, Frei B, Vita JA, et al. Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997;337:408-416. 

(84) Levine M. Rumsey SC. Daruwala R. Park JB. Wang Y. Criteria and recommendations for vitamin C intake. JAMA. 281(15):1415-23, 1999 Apr 21.

(85) Miyai E. Yanagida M. Akiyama J. Yamamoto I. Ascorbic acid 2-O-alpha-glucoside, a stable form of ascorbic acid, rescues human keratinocyte cell line, SCC, from cytotoxicity of ultraviolet light B. Biological & Pharmaceutical Bulletin. 19(7):984-7, 1996 Jul.

(86) Miyai E. Yanagida M. Akiyama J. Yamamoto I. Ascorbic acid 2-O-alpha-glucoside-induced redox modulation in human keratinocyte cell line, SCC: mechanisms of photoprotective effect against ultraviolet light B. Biological & Pharmaceutical Bulletin. 20(6):632-6, 1997 Jun.

(87) Tebbe B. Wu S. Geilen CC. Eberle J. Kodelja V. Orfanos CE. L-ascorbic acid inhibits UVA-induced lipid peroxidation and secretion of IL-1alpha and IL-6 in cultured human keratinocytes in vitro. Journal of Investigative Dermatology. 108(3): 302-6, 1997 Mar.

(88) Isaac O. Calendula officinalis L. - Marigold. Zeitschrift fur Phytotherapie. Vol 15(6) (pp 356-370), 1994. 

(89) Ansari M A. Jadon N S. Singh S P. Kumar Amresh. Singh Harpal. Effect of Calendula officinalis ointment, charmil and gelatin granules on wound healing in buffaloes: A histological study. Indian Veterinary Journal. 74(7). 1997. 594-597. 

(90) Klouchek-Popova E. Popov A. Pavlova N. Krusteva S. Influence of the physiological regeneration and epithelialization using fractions isolated from Calendula officinalis. Acta Physiologica et Pharmacologica Bulgarica. 8(4):63-7, 1982. 

(91) Oana L. Mates N. Ognean I. Muste A. Aldea Maria. Neculoiu Doris. Banciu Cristina. Studies concerning the wound healing action of some medicinal herb extracts.[Romanian] Buletinul Universitatii de Stiinte Agricole Cluj-Napoca Seria Zootehnie Si Medicina Veterinara. 49(0). 1995. 461-465. 

(92) Hore S K [a]. Koley K M [a]. Maiti S K. [a] Dep. Pharmacology Toxicology, Coll. Veterinary Science A.H., Anjora, Durg 491001 India. Modulatory role of Calendula officinalis on thermal stimulus-induced nociception and carrageenin-induced inflammation in rats. Indian Veterinary Journal. 74(10). Oct., 1997. 844-846. 

(93) Kalvatchev Z. Walder R [a]. Garzaro D.Akihisa Toshihiro [a]. Yasukawa Ken. Oinuma Hirotoshi [a]. Kasahara Yoshimasa. Yamanouchi Sakae. Takido Michio. Kumaki Kunio. Tamura Toshitake [a]. Triterpene alcohols from the flowers of compositae and their anti-inflammatory effects. Phytochemistry (Oxford). 43(6). 1996. 1255-1260. 

(94) Della Loggia R [a]. Tubaro A. Sosa S. Becker H. Saar S. Isaac O. The role of triterpenoids in the topical anti-inflammatory activity of Calendula officinalis flowers. Planta Medica. 60(6). 1994. 516-520. 
(95) Chalchat J C. Garry R P. Michet A. Chemical Composition of Essential oil of Calendula-Officinalis L. Potmarigold Flavour & Fragrance Journal 6 (3). 1991. 189-192. 

(96) Zitterl-Eglseer K [a]. Sosa S. Jurenitsch J. Schubert-Zsilavecz M. Della Loggia R. Tubaro A. Bertoldi M. Franz C. Anti-oedematous activities of the main triterpenediol esters of marigold (Calendula officinalis L.). Journal of Ethnopharmacology. 57(2). 1997. 139-144. 

(97) Masterova I. Grancaiova Z. Uhrinova S. Suchy V. Ubik K. Nagy M. Flavonoids in Flowers of Calendula-Officinalis L Chemical Papers 45 (1). 1991. 105-108.
(98) Elias R. De Meo M. Vidal Ollivier E. Laget M. Balansard G. Dumenil G. Antimutagenic Activity of Some Saponins Isolated From Calendula-Officinalis L. Calendula-Arvensis L. and Hedera-Helix L. Mutagenesis 5 (4). 1990. 327-332.1.

(99) Bresser H. Flach D. Hartung A. Krautheimer B. Zenker C. New aspects in the treatment of neurodermatitis and dermatitis. ARZTEZ NATURHEILVERFAHREN, Vol 40(8) (pp 558-562), 1999.
(100) Toker, G. Turkoz, S. Erdemoglu, N. High performance liquid chromatographic analysis of rutin in plants, I. Pharmazie. 1998. 53: 7, 494-495. 11 ref. 

(101) Guerin, J.-C. Reveillere, H.-P. Antifungal activity of plant extracts used in therapy. I. Study of 41 plant extracts against 9 fungal species. [French] Annales Pharmaceutiques Francaises. 1984. 42: 6, 553-559. 12 ref. 
(102) Miller Thomas. Wittstock Ute. Lindequist Ulrike. Teuscher Eberhard [a]. Effects of some components of the essential oil of chamomile, Chamomilla recutita, on histamine release from rat mast cells. Planta Medica. 62(1). 1996. 60-61. 

(103) Safayhi H [a]. Sabieraj J. Sailer E-R. Ammon H P T. Chamazulene: An antioxidant-type inhibitor of leukotriene B-4 formation. Planta Medica. 60(5). 1994. 410-413. 

(104) Mares D. Romagnoli C. Bruni A. Antidermatophytic activity of herniarin in preparations of Chamomilla recutita (L.) Rauschert. Plantes Medicinales et Phytotherapie. 26(2). 1993. 91-100. 

(105) Laskova I L. Uteshev B S. Immunomodulating action of heteropolysaccharides isolated from chamomile flower clusters. [Russian] Antibiotiki i Khimioterapiya. 37(6). 1992. 15-18. 

(106) Kedzia B. Antimicroorganisms Activity of Ol. Chamomillae and Its Components Herba Polonica 37 (1). 1991. 29-38.

(107) Hodisan Teodor. Socaciu Carmen [a]. Ropan Ioana. Neamtu Gavril. Carotenoid composition of Rosa canina fruits determined by thin-layer chromatography and high-performance liquid chromatography. Journal of Pharmaceutical & Biomedical Analysis. 16(3). Nov., 1997. 521-528. 

(108) Yavru Ilknur. Kadioglu Asim. The effects of infusion temperatures and times on vitamin C content infused from fruits of dog rose (Rosa canina L.). Turkish Journal of Botany. 21(6). 1997. 323-327. 

(109) Yesilada Erdem [a]. Ustun Osman. Sezik Ekrem. Takaishi Yoshihisa. Ono Yukihisa. Honda Gisho. Inhibitory effects of Turkish folk remedies on inflammatory cytokines: Interleukin-1-alpha, interleukin-1-beta and tumor necrosis factor alpha. Journal of Ethnopharmacology. 58(1). 1997. 59-73. 

(110) Wuestenberg P. Henneicke-von Zepelin H-H. Koehler G [a]. Stammwitz U. Efficacy and mode of action of an immunomodulator herbal preparation containing Echinacea, wild indigo, and white cedar. Advances in Therapy. 16(1). Jan.-Feb., 1999. 51-70. 

(111) Bhatt Manoj. Chopra A K. In vitro antimicrobial efficacy of some homoeopathic drugs against Staphylococcus epidermidis. Biological Memoirs. 24(2). Dec., 1998. 31-33. 

(112) Thompson Kenneth D [a]. Antiviral activity of Viraceae against acyclovir susceptible and acyclovir resistant strains of herpes simplex virus. Antiviral Research. 39(1). July, 1998. 55-61. 

(113) Burger Roger A [a]. Torres Anthony R. Warren Reed P. Caldwell Virgil D. Hughes Bronwyn G. Echinacea-induced cytokine production by human macrophages. International Journal of Immunopharmacology. 19(7). July, 1997. 371-379. 

(114) Oana L. Mates N. Ognean I. Muste A. Aldea Maria. Neculoiu Doris. Banciu Cristina. Studies concerning the wound healing action of some medicinal herb extracts. [Romanian] Buletinul Universitatii de Stiinte Agricole Cluj-Napoca Seria Zootehnie Si Medicina Veterinara. 49(0). 1995. 461-465. 

(115) Voitenko H M. Varchenko V H. Lipkan H M. Oliinychenko P I. M'Yasoyedov D V. Mkhitaryan L S. Kutnyak V P. Obedkova N M. Kukhar I V. Yakovlyeva N Yu. Naumova M I. Effect of preparations from roots and flowers of Echinacea purpurea on the progress of inflammatory reaction in experimental conditions. [Ukrainian] Farmatsevtychnyi Zhurnal (Kiev). 0(2). 1996. 115-121. 

(116) Mueller-Jakic Barbara. Breu Walter. Proebstle Andrea. Redl Karl. Greger Harald. Bauer Rudolf [a]. In vitro inhibition of cyclooxygenase and 5-lipoxygenase by alkamides from Echinacea and Achillea species. Planta Medica. 60(1). 1994. 37-40. 

(117) Steinmuelelr Christiane [a]. Roesler Joachim. Groettrup Esther. Franke Gabriela. Wagner Hildebert. Lohmann-Matthes Marie-Louise. Polysaccharides isolates from plant cell cultures of Echinacea purpurea enhance the resistance of immunosuppressed mice against systemic infections with Candida albicans and Listeria monocytogenes. International Journal of Immunopharmacology. 15(5). 1993. 605-614. 

(118) Wagner H. Jurcic K. Immunological Studies of Plant Extract Combinations in-Vitro and in-Vivo on Stimulation of Phagocytosis. Arzneimittel-Forschung 41 (10). 1991. 1072-1076.

(119) Roesler J. Emmendoerffer A. Steinmueller C. Luettig B. Wagner H. Lohmann Matthes M L. Application of Purified Polysaccharides from Cell Cultures of The Plant Echinacea-Purpurea to Test Subjects Mediates Activation of the Phagocyte System .