Common Upper Respiratory Disorders And Alternative Treatment

Rhinitis and sinusitis are problems that primary-care physicians frequently encounter. Although these disorders are not life threatening, they can result in considerable discomfort and decrease the patient's quality of life. Nasal and sinus symptoms are the leading cause of restrictive activity and loss of productivity at work, home, and school. The treatment of rhinitis and sinusitis is costly, and these disorders can also complicate other medical illnesses, which can become more difficult to treat. Upper airway symptoms can be a manifestation of a systemic disease. The medications used to treat nasal obstruction cost about $5 billion annually, and surgical intervention is estimated to cost approximately $ 60 billions annually. These figures do not include the expense of diagnostic tests and office visits or the lost productivity at work and school (1). Herein this review article discusses the clinical management of these disorders, diagnostic tools, distinguishing characteristics of these conditions and available pharmacological and non-pharmacological treatment.

Common Cold
The common cold is a frequent, recurrent, acute upper respiratory tract infection affecting every age and race. It is a benign, self-limiting viral infection. The symptoms are stuffy and/or runny nose, sneezing, cough, sore throat, and sometimes, mild fever with generalized aches and pains. Although not a serious condition, colds have a substantial impact on time lost from work and school, general practitioner consultations and money spent on drugs - both prescription and over-the-counter (2). 

Etiology
The etiological agents are viral. More than 200 different viruses are known to cause the symptoms of the common cold. The most frequent viruses associated with respiratory infections are human rhinoviruses (HRV). Although the majority of HRV infections are mild and self-limited, HRV is an important cause of respiratory disease across all age groups. Recent studies have established the importance of HRV in predisposing to or causing otitis media, sinusitis and exacerbations of asthma, as well as other lower respiratory tract disorders. Among elderly people, infants and immunocompromised hosts HRV infections are often associated with lower respiratory tract morbidity and rarely mortality. However, the high incidence of HRV infections and their frequent association with upper and lower respiratory tract complications highlight the need for more effective means of prevention and treatment. 
Other viruses responsible for more severe illnesses cause approximately 10 to 15 percent of adult colds include: Coronaviruses, adenoviruses, coxsackieviruses, echoviruses, orthomyxoviruses (including influenza A and B viruses), paramyxoviruses (including several parainfluenza viruses), respiratory syncytial virus and enteroviruses (3). 

Viruses cause infection by overcoming the body's complex defense system: The body's first line of defense is mucus, produced by the membranes in the nose and throat. Mucus traps the material we inhale: pollen, dust, bacteria and viruses. When a virus penetrates the mucus and enters a cell, it commandeers the protein-making machinery to manufacture new viruses, which, in turn, attack surrounding cells. 

Symptoms:
Cold symptoms are probably the result of the body's immune response to the viral invasion. Virus-infected cells in the nose send out signals that recruit specialized white blood cells to the site of the infection. In turn, these cells emit a range of immune system chemicals known as kinins (pro-inflammatory chemokines and cytokines). These chemicals probably lead to the symptoms of the common cold by causing swelling and inflammation of the nasal membranes, leakage of proteins and fluid from capillaries and lymph vessels, and the increased production of mucus. This results in sneezing, nasal congestion and swelling of the sinus membranes that result in obstruction of nasal breathing. Post- nasal drip is the likely cause of the irritating cough typical of colds. The mild fever and aches reflect a generalized response to the viral infection. 

Symptoms of the common cold usually begin two to three days after infection. Fever is usually slight but can climb to 102o F in infants and young children. Cold symptoms can last from 2 to 14 days, but two-thirds of people recover in a week. If symptoms occur often or last much longer than two weeks, they may be the result of an allergy rather than a cold.

Colds occasionally can lead to secondary bacterial infections of the middle ear or sinuses. High fever, significantly swollen glands including the tonsils, severe facial pain, and a cough that produces mucus, may indicate a complication or more serious illness requiring a doctor's attention. 

The common cold is further complicated in those with a history of chronic respiratory disorder such as asthma, chronic bronchitis, and respiratory complications associated with smoking. Experimental rhinovirus infections in patients with asthma demonstrate features of exacerbation, such as lower airway symptoms, variable airways obstruction, and bronchial hyper-responsiveness. It has been proved by studies that these same viruses have been found to initiate the same inflammatory processes as seen and characterized in the asthmatic patient. This has clear implications for therapy of asthmatic patients (4).

New therapeutic interventions for upper respiratory tract infections need to be developed based on the increasing patho-physiological knowledge about the role of viruses and the antiviral immune response in common respiratory infection (5). 

Flu (Influenza)
The flu is similar to cold in that the patient may feel sore throat, muscle aches, runny nose, cough, headache, and fever - except the flu comes on much more aggressively and suddenly. If there is a fever, it will usually be higher and last longer with the flu than with a cold. The flu is a very common illness. Attack rates in children range from 10% to 40% a year. Children are more susceptible than adults. Morbidity occurs in adults 75 years and older, but rarely in the very young. Concurrent illness in elderly adults is potentially dangerous. Both sexes are equally susceptible.

There are three different types of flu:
 

•		Type A: the most common.
•		Type B: like Type A, it occurs every year. Influenza B outbreaks are generally less extensive and are associated with less severe disease than those associated with the influenza A virus.
•		Type C: it spreads rapidly through a population. It tends to occur every two to three years.

Types A and B change slightly from year to year and is considered a mutating illnesses. The vaccines developed during the fall of one year don't work the next year. 

The flu virus can survive for up to three days on its own, outside the body and can be transmitted by air or through human contact. Once contracted, the virus incubates for 18 to 72 hours.

Symptoms:
It typically comes on aggressively, with a fever of 102°F to 106° F. Because the root of the virus is seated at the mucous membranes of the upper respiratory system, distress symptoms are usually felt from this area and can include the following:
 

•		Sore throat
•		Dry cough
•		Runny nose
•		Sneezing
•		Achy muscles, frontal headache, and watery, irritated eyes.

Though flu symptoms generally run for about three to four days, one may continue to feel tired and run down for up to several weeks later.

Complications
The flu can bring on secondary bacterial and viral infections like pneumonia, bronchitis, acute sinusitis and middle-ear infections. 

Allergic Rhinitis
Allergic rhinitis is the most common allergic disorder all over the world. Patients with allergic rhinitis are hypersensitive to pollens, dust mites, animal dander, or moulds. 

Symptoms:
 

•		Bilateral nasal obstruction and nasal pruritis.
•		Sneezing.
•		Frequent eye symptoms that include irritation, lacrimation, and pruritis.
•		Associated symptom complexes can include asthma, and atopic dermatitis.

Physical findings:
 

•		Erythemetous conjunctiva.
•		Pale, boggy, bluish nasal mucosa and clear to slightly discoloured nasal secretions.

Non-allergic Rhinitis
About 10 to 20% of patients may have symptoms suggestive of allergic rhinitis, although they have no history of atopy and have negative results on allergy skin testing. In some of these patients, eosinophilia (a subtype of white blood cells increases in cases of allergy) is clearly demonstrated on nasal cytological analysis.

Vasomotor Rhinitis
Vasomotor rhinitis is a vaguely defined syndrome of upper respiratory disorder.

Symptoms:
 

•		Nasal obstruction.
•		Rhinorrhea.
•		Postnasal drainage.

Trigger factors seem to be non-specific, including irritants (strong odours and fumes), temperature changes, humidity, and air conditioning. Psycologic factors may have a major role. Allergy skin test results are negative, and other diagnoses must be excluded. 

Atrophic Rhinitis
Atrophic rhinitis is characterized by atrophy of the nasal mucosa and nasal or sinus bony structures. 

Symptoms:
 

•		Crusting and foul odour that is detectable by others.
•		Frequently, such patients experience loss of the senses of smell and taste.

Associated abnormalities:
Reported abnormalities include infection with Klebsiella ozaenae, atoxic Corynebacterium diphtheria, and deficiencies of vitamin A and iron. Secondary atrophic rhinitis can occur after a nasal or sinus operation involving extensive nasal mucosal resection.

Nasal Polyposis
Nasal polyps, most likely, develop because of chronic sinus obstruction and mucosal inflammation. The polyps are smooth grapelike benign masses that usually arise from the paranasal sinuses. The major complications are nasal and sinus obstruction, development of chronic and recurrent sinusitis, and loss of the sense of smell. Nasal polyposis can be associated with intrinsic asthma, aspirin-sensitivity asthma, and cystic fibrosis in children, and is sometimes complicated by fungal sinus infection.

Gustatory Rhinitis
Gustatory rhinitis is a common condition, especially in elderly persons, in which Rhinorrhea occurs with eating, particularly spicy and hot foods. The mechanism seems to be an exaggerated parasympathetic response, with transudation of serum to nasal secretions.

Anatomic Abnormalities
Trauma during delivery or later during life frequently causes septal deformities that can be responsible for nasal obstruction and sinus disease. The mechanism of sinus disease as a result of septal deformity is due to direct interference of drainage from the sinuses or to turbulence in the nasal flow; normal laminar flow is needed for normal drainage of the paranasal sinuses. 

Other anatomic abnormalities include nasal valvular collapse, which is frequently noted in elderly patients and in those with prior rhinoplasties, septal hematomas, abscess, neoplasm, foreign bodies, and choanal atresia (children). 

Sinusitis
Sinusitis is one of the most common health problems all over the world. Sinusitis affects people of all ages, males and females. 

It is an inflammation of any one of the eight sinuses adjacent to the nose. These sinuses are categorized in four groups. 
 

•		Frontal sinuses, just above the eyes
•		Ethmoid sinuses, between the eyes just over the nose
•		Maxillary sinuses, on either side of the nose below the eyes
•		Sphenoid sinuses, at the base of the skull behind all of the other sinus cavities

Sinusitis causes the linings of the sinuses (mucus membranes) to become swollen through contact with an allergen, virus, bacteria, or fungus. This swelling obstructs drainage and leads to a blockage that feeds bacteria, which then leads to an infection. Sinusitis may be short-lived and acute, or a long-standing, chronic condition. The duration and severity of sinusitis depends on the cause, or causes, and the predisposition of the individual.
 

Computed tomographic scan of sinuses, showing importance of anatomy of ostium of maxillary sinus. Right maxillary sinus opens to nose through narrow infundibulum, mucosa is normal, and opening is not occluded (arrow). Opening of left maxillary sinus is distorted (arrowhead), mucosa is congested, and normal drainage is obstructed.

X-rays are a form of electromagnetic radiation (like light); they are of higher energy, however, and can penetrate the body to form an image on film and are commonly used for the diagnosis of sinusitis. Structures that are dense (such as bone) will appear white, air will be black, and other structures will be shades of grey. CT scan or even MRI may be required for proper diagnosis.
Other laboratory tests include full blood picture as increased total white cell count indicate bacterial infection. Postnasal swab for bacterial culture and antibiotic sensitivity is often essential before starting antibiotic therapy.

The main features of sinusitis are:
 

•		Nasal congestion and swelling around the affected sinus area.
•		Tenderness, pain, and redness may also occur around the inflamed sinuses.
•		Discharge of a green-yellow colour (possibly blood-tinged) may accompany the early stages of sinusitis, while in later stages discharge is usually blocked, leading to an increase of pain.
•		Headaches that worsen in the morning or when bending forward, cheek pain that may resemble a toothache, and non-productive coughs can all indicate sinusitis.

A general feeling of weakness and fever or chills suggests that the infection has spread beyond the sinuses. On rare occasions, acute sinusitis can result in brain infection and serious complications.

By becoming aware of the precise symptoms, it is possible to determine which sinus area is affected. If the pain is centered over the cheeks just below the eyes, or is connected to a toothache or headache, it is most likely maxillary sinusitis. Headaches over the forehead are usually connected to frontal sinusitis. Splitting headache pain, generated from behind and between the eyes, could be produced from ethmoid sinusitis. If the pain is undefined by specific areas and is felt in the front or back of the head, it is likely to be connected to sphenoid sinusitis.

Acute bacterial sinusitis is an infection of the sinus cavities caused by bacteria. It is usually preceded by a cold, allergy attack, or irritation by environmental pollutants. Unlike a cold, or allergy, bacterial sinusitis requires a physician's diagnosis and treatment to cure the infection and prevent future complications. 

When patients have frequent sinusitis, or the infection lasts three months or more, it could be chronic sinusitis. Symptoms of chronic sinusitis may be less severe than those of acute; however, untreated chronic sinusitis can cause damage to the sinuses and cheekbones that sometimes requires surgery to repair. 

Normally, mucus collecting in the sinuses drains into the nasal passages. After having cold or allergy attack, the sinuses become inflamed and are unable to drain. This can lead to congestion and infection. Diagnosis of sinusitis usually is based on a physical examination and a discussion of the symptoms. Doctor also may use x-rays of the sinuses or obtain a sample of the nasal discharge to test for bacteria.

Complication of sinusitis:
Paranasal sinusitis can have devastating intracranial sequelae on rare conditions. Involvement of the adjacent pituitary gland and cavernous sinuses can result in serious neurological morbidity or mortality, and retrograde spread of infection through the basal venous system can result in subdural or parenchymal brain involvement. A high index of suspicion and aggressive medical and surgical treatment are crucial for patient survival, but the morbidity rate remains high (6). 

Intractable meningitis, intracranial abscess or cavernous sinus thrombosis could happen as a complication in a diabetic patient, arising from sphenoid sinusitis (7). 

Risk Factors:
Many of the risk factors are associated with exposure to contaminants, or activities that could lead to potential vulnerabilities in the immune system. 
 

•		Smoking.
•		Exposure to others in public places.
•		Illness that has lowered resistance.
•		Exposure to cold, damp weather outdoors or dry heat indoors.
•		Excessive nose blowing during an upper-respiratory infection.
•		Hard sneezing with the mouth closed.
•		Swimming in contaminated water, especially jumping into the water without holding the nose.
•		Abscess in an upper tooth.
•		Immunosuppression, as in people who have organ transplants and are taking drugs to suppress the immune function to prevent rejection.
•		Continuous positive airway pressure - used in obstructive sleep apnea to keep the upper airways open during sleep.
•		Air travel during upper respiratory infection.

It is important to stay aware of the environmental and behavioral triggers that can lead to this condition in order to prevent the recurrence of sinusitis.

Children have immature immune systems and are more prone to infections of the nose, sinus, and ears, especially in the first several years of life. These are most frequently caused by viral infections (colds), and they may be aggravated by allergies. Infection of the adenoid tissue, called adenoiditis, could cause obstruction of the back of the nose and can cause many of the symptoms that are similar to sinusitis, namely, runny nose, stuffy nose, post-nasal drip, bad breath, cough, and headache. If the child remains ill beyond the usual week to ten days, a serious sinus infection is likely. 

The risk of sinus infections could be reduced by reducing the exposure of children to known environmental allergies and pollutants such as tobacco smoke, reducing his/her time at day care, and treating stomach acid reflux disease. 

By distinguishing whether sinusitis is acute, recurrent, or chronic, the physician can determine the predisposing causes. Acute sinusitis is a frequent complication of a viral infection of the upper respiratory tract while recurrent and chronic sinusitis can result from anatomic abnormalities (some of which were previously described) and Immunological problems, most frequently allergic rhinitis. Other disorders such as humoral immunodeficiency are infrequently the cause, although they must be considered in the presence of other systemic infections or in patients whose condition fails to improve despite adequate therapy. Immotile cilia syndrome and cystic fibrosis are other possible etiologic factors. 

Common Etiological Factors of Sinusitis:

Viral infection, such as the common cold, flu: In these cases the body reacts by producing mucus and sending whit blood cells to the lining of the nose, which congest and swell the nasal passages. When this swelling involves the adjacent mucous membranes of the sinuses, air and mucus are trapped behind the narrowed opening of the sinuses. 

Bacteria infection: Some bacterial strains are normal inhabitant of the upper respiratory tract e.g. Streptococcus pneumoniae and Haemophilus influenzae. These bacteria have no ill effects until the body's defenses are weakened or drainage from the sinuses is blocked by a cold or other viral infection then they start to be virulent and cause infection of the upper respiratory tract and secondary sinusitis.

Fungal infections: Although fungi are abundant in the environment, they are usually harmless to healthy people, indicating that the human body has a natural resistance to them. Fungi, such as Aspergillus, cause serious illness in people whose immune systems are not functioning properly. Some people with fungal sinusitis have an allergic-type reaction to the fungi.

Allergic rhinitis: Inhalation of airborne allergens (substances that provoke an allergic reaction), such as dust, mold, and pollen, often set off allergic reactions (allergic rhinitis) that, in turn, may contribute to sinusitis. Hay fever may also be complicated by episodes of acute sinusitis. Patients with allergic rhinitis also often have chronic sinusitis. 

Vasomotor rhinitis, caused by humidity, cold air, alcohol, perfumes, and other environmental conditions, also may be complicated by sinus infections.

Immune deficiencies and HIV infection: Those patients are more susceptible to develop acute sinusitis than general population.

Cystic fibrosis and diseases of abnormal cilia: Acute and chronic sinusitis could happen as a result of abnormal mucus secretion or cilia movement. 

Deviated nasal septum or other obstruction of the nose due to nasal polyps may trap fluid in the sinuses. 

Aging rhinitis: As one ages, the nasal mucus loses its water content and becomes increasingly thick and sticky. Patients complain of post-nasal drip, cough, and hoarseness; the condition is best treated with nasal irrigation and increased hydration. 

Tumors: The presence of tumors in the sinuses is relatively uncommon. They are discovered with a nasal obstruction, often with heavy nosebleeds.

The Role of The Immune System in Viral Infection and Allergic Disorders Of The Upper Respiratory Tract

In order to understand the role of the immune system in viral infection and allergic disorders of the upper respiratory tract, one should be acquainted with the component of the immune system and how each of the components works. 

The Immune System
The organs of the immune system are stationed throughout the body. They are generally referred to as the lymphoid organs because they are concerned with the development, growth and deployment of lymphocytes, the white cells that are the key operatives of the immune system.

Lymphoid organs include the bone marrow and the thymus as well as lymph nodes, spleen, tonsils and adenoids, the appendix, and clumps of lymphoid tissue in the small intestine known as Peyer's patches. The blood and lymphatic vessels that carry lymphocytes to and from the other structures can also be considered lymphoid organs. 

Cells destined to become immune cells, like all other blood cells, are produced in the bone marrow, the soft tissue in the hollow shafts of long bones (stem cells). The descendants of some so-called stem cells become lymphocytes, while others develop into a second major group of immune cells typified by the large, cell-and particle-devouring white cells known as phagocytes. 

The two major classes of lymphocytes are: 

B cells complete their maturation in the bone marrow and become capable of being transformed into plasma cells upon contact with the antigen to produce the antibodies. 

T cells, on the other hand, migrate to the thymus, a multi-lobed organ that lies high behind the breastbone. There they multiply and mature into cells capable of producing immune response and become immunocompetent. In a process referred to as T cell "education," T cells in the thymus learn to distinguish self- cells from non-self cells; T cells that would react against self-antigens are normally eliminated. 

Upon exiting the bone marrow and thymus, some lymphocytes congregate in immune organs or lymph nodes. Others-both B and T cells-travel widely and continuously throughout the body. They use the blood circulation as well as a body-wide network of lymphatic vessels similar to blood vessels. 


The Lymphoid Organs


The lymph nodes: They are small bean-shaped bodies in the form of clusters in the neck, armpits, abdomen, and groin. Each lymph node contains specialized compartments that house platoons of B-lymphocytes, T lymphocytes, and other cells capable of enmeshing antigen and presenting it to T cells. Thus, the lymph node brings together the several components needed to spark an immune response. 

The spleen, too, provides a meeting ground for immune defenses. Like the lymph nodes, the spleen's lymphoid tissue is subdivided into compartments that specialize in different kinds of immune cells. Microorganisms carried by the blood into the spleen become trapped by the immune cells known as macrophages. (Although people can live without a spleen, persons whose spleens have been damaged by trauma or by disease such as sickle cell anemia are highly susceptible to infection). 

Clusters of lymphoid tissue are found in many parts of the body. They are common around the mucous membranes lining the respiratory and digestive tracts-areas that serve as gateways to the body. They include the tonsils and adenoids, the appendix, and Peyer's patches. 

The lymphatic vessels carry the lymph, which transport a mix of lymphocytes, macrophages, and foreign antigens to lymph nodes, where antigens can be filtered out and presented to immune cells. 

Additional lymphocytes reach the lymph nodes (and other immune tissues) through the bloodstream. An artery and a vein supply each node; lymphocytes enter the node by traversing the walls of the very small, specialized veins. 
All lymphocytes exit lymph nodes in lymph via outgoing lymphatic vessels. At the base of the neck, large lymphatic vessels merge into the thoracic duct, which empties its contents into the bloodstream. 

Once in the bloodstream, the lymphocytes and other assorted immune cells are transported to tissues throughout the body. They patrol everywhere for foreign antigens, then gradually drift back into the lymphatic vessels, to begin the cycle all over again. 

Antiviral Immunity
Viruses are small, obligate intracellular parasites, which cause infection by invading cells of the body and multiplying within them. Within their life cycle they have a relatively short extracellular period, prior to infecting the cells, and a longer intracellular period during which they undergo replication. Cold virus particles, once they slip into cells of the upper respiratory tract, start copying themselves. To defend itself, the immune system pumps out chemicals called cytokines. Two of these cytokines in particular contribute to the sore throat, sneezing, and runny nose of a cold. The lecture will describe the effector mechanisms, which the immune response uses to combat viral infections, and will then place these mechanisms in the context of acute infection with influenza virus.

The immune system has mechanisms which can attack the virus in both phases of its life cycle (extracellular and intracellular phases), and which involve both non-specific and specific effector mechanisms.

Non-Specific Mechanisms
Interferons: 
Viral infection of cells directly stimulates the production of interferons (note that the "type 1" interferons which are produced non-specifically by many cell types in response to viral infection are quite distinct from the T cell cytokine gamma interferon which is produced by CD4+ and CD8+ T cells in response to antigenic stimulation). 

Interferon type 1 function
Type I interferons lead to the induction of an "antiviral state" in the cells, which is characterized by inhibition of both viral replication and cell proliferation, and also enhancement of the ability of natural killer cells to lyse virally infected cells. Indeed, the interferons may be among the most broadly active of all the immunologic and physiologic regulators. 

Natural Killer Cells:
NK cells possess the ability to recognize and lyse virally infected cells and certain tumor cells. Whilst not showing antigen specificity, they clearly exhibit some degree of selectivity in targeting "abnormal" cells for lysis (8,9). The main advantage that NK cells have over antigen-specific lymphocytes in antiviral immunity is that there is no "lag" phase of clonal expansion for NK cells to be active as effectors, as there is with antigen-specific T and B lymphocytes. Thus NK cells may be effective early in the course of viral infection, and may limit the spread of infection during this early stage, while antigen-specific lymphocytes are being recruited and clonally expanded. 

Specific Mechanisms
Both cell mediated and humoral arms of the immune response play a role as specific effector mechanisms in antiviral immunity. 

1. Cell Mediated Immunity (T Cells and Cytokines)
T- cells:
T-cells contribute to the immune defenses in two major ways.
Regulatory T cells are vital to orchestrating the elaborate system. (B cells, for instance, cannot make antibody against most substances without T cell help).

There are two types of regulatory cells:
T-cells contribute to the immune defenses in two major ways. 
 

•		Helper T cells, which are typically identifiable by the T 4-cell marker, and are essential for activating B cells and other T cells as well as natural killer cells and macrophages.
•		Suppressive T cells which release suppressive cytokines, such as TGF-b, IL-4 and IL-10 to down-regulate or suppress the immune response and keep it from going out of control by turning the helper cells off (10).

Cytotoxic T cells, (or "killer") T cells: They aggressively screen other cells for signs of infection and malignancy and secrete toxic molecules to kill any aberrant cells, thus ridding the body of cells that have been infected by viruses or transformed by cancer. They usually carry the T8 marker.


Cytokines
T cells work primarily by secreting substances known as cytokines that include Lymphokines (which are also secreted by B cells) and their relatives, and the monokines produced by monocytes and macrophages. Both types are diverse and potent chemical messengers.


Cytokine secretion

Cytokine function: A single cytokine may have many functions; conversely, several different cytokines may be able to produce the same effect. 
 

•		Binding to specific receptors on target cells, Lymphokines call into play many other cells and substances, including the elements of the inflammatory response.
•		They encourage cell growth, promote cell activation, direct cellular traffic, destroy target cells, and incite macrophages.

Cytokines include the following types:
 

1.		Interferons: It is one of the first cytokines to be discovered. It is produced by T cells and macrophages (as well as by cells outside the immune system), interferons are a family of proteins with antiviral properties. Interferon from immune cells, known as immune interferon or gamma interferon, activates macrophages. The IFN- appearing early in the infection probably arises from natural killer (NK) cells, whereas that occurring later in a more sustained lower respiratory infection would more likely arise from T cells mediating the Th1 (helper T cells) response necessary for effective resolution of the infection.
2.		Tumor Necrosis Factor alpha TNFalpha: It is made by many different cells including neutrophils, lymphocytes and Natural Killer (NK) cells.
TNF alpha function:
•		TNFalpha initiates a cascade of cytokines, which mediate an inflammatory response.
•		TNFalpha regulates the expression of many genes important for the host response to infection.
3.		Transforming Growth Factor-b (TGF-beta): It is found at highest concentration in platelets.
TGF-beta function
•		It stimulates macrophage secretion of various growth factors.
•		It inhibits activated macrophage production of reactive oxygen and reactive nitrogen metabolites.
4.		Macrophage Colony Stimulating Factor (M-CSF): It is produced by many cells including macrophages themselves.
M-CSF function
•		It is important for the survival, proliferation and differentiation of monocytes, macrophages.
•		It is responsible for the upregulation of Macrophage Scavenger Receptor activity.
5.		Interleukins: They are considered as messengers between leukocytes, or white cells. They were initially given descriptive names but, as their basic structure has been identified they are named as intereukins and they include the following types:
•		IL-1beta: It is a pro-inflammatory cytokine, which is secreted by macrophages activated by a number of stimuli including TNFalpha, bacterial endotoxin and IL-1beta itself. It exerts its effects on many different cell types locally at the site of production and systemically (at a distance) and attract different types of granulocytes and help their degranulation releasing their chemicals which causes the different disease symptoms.
•		IL-2, originally known as T cell growth factor, TCGF, is produced by antigen-activated T cells and promotes the rapid growth or differentiation of mature T cells and B cells.
•		IL-3, is a T-cell derived member of the family of protein mediators known as colony-stimulating factors (CSF); one of its many functions is to nurture the development of immature precursor cells into a variety of mature blood cells.
•		IL-4, IL-5, and IL-6 help B cells grow and differentiate; IL-4 also affects T cells, macrophages, mast cells and granulocytes. IL-6 stimulates B-lymphocytes to produce antibodies and in concert with IL-1 causes T-cell activation.
•		IL-10: It is an immunoregulatory cytokine, which can exert a wide range of different effects on different cell types. It suppresses IL-2 by helper T-cells and thus keep the immune response from going out of control and stop inflammatory fulmination. It is also a potent modulator of monocyte/macrophage function.
•		IL-12: It stimulates growth of activated Natural killer cells, CD8+ and CD4+ T- cells. Activate the T helper cell response and increase the production of tumor necrosis factor (TNF) by macrophage cells. It also suppresses IL-4 induced IgE production.
•		IL-13: Interleukin 13 has very similar biological effects on macrophages to IL-4.

2. Humoral Immunity (B-Cells "the antibody producing cells)
Antibodies
Specific antibodies are important in and may protect against viral infections. The most effective type of antiviral antibody is "neutralizing" antibody - Each B cell is programmed to make one specific antibody. For example, one B cell will make an antibody that blocks a virus that causes the common cold, while another produces antibody that zeros in on a bacterium that causes pneumonia. 

When a B cell encounters its triggering antigen (along with collaborating T cells and accessory cells), it gives rise to many large cells called plasma cells. Every plasma cell is essentially a factory for producing antibody. They manufacture millions of identical antibody molecules and pour them into the bloodstream. 

A given antibody matches an antigen much as a key matches a lock. To some degree, however, the antibody interlocks with the antigen and thereby marks it for destruction. 


The activated B-cells give rise to the plasma cells which secrets the antibodies

Antibodies belong to a family of large molecules known as immunoglobulins. Immunoglobulins are shaped to form a Y. 

Scientists have identified nine chemically distinct classes of human immunoglobulins (Ig)-four kinds of IgG and two kinds of IgA, plus IgM, IgE, and IgD. Each type plays a different role in the immune defense strategy. 
 

•		IgG:
		It the major immunoglobulin in the blood, is also able to enter tissue spaces; it works efficiently to coat microorganisms, speeding their uptake by other cells in the immune system.
•		IgM:
		It usually combines in star-shaped clusters, tends to remain in the bloodstream, where it is very effective in killing bacteria.
•		IgA:
		It concentrates in body fluids-tears, saliva, and the secretions of the respiratory and gastrointestinal tracts-guarding the entrances to the body.
•		IgE:
		Under normal circumstances, it occurs only in trace amounts, probably evolved as a defense against parasites, but it is more familiar as the immunoglobulin responsible for allergic reactions (Allergy).
•		IgD:
		It is almost exclusively found inserted into the membranes of B cells, where it somehow regulates the cell's activation.

The immune system responds to viral proteins encountered within most tissues of the body by generating helper T cells, which release inflammatory cytokines such as IL-2 and IFN-g. The response to viral proteins in mucosal tissue also stimulates the induction of TGF-ί secreting cells and regulatory T cells which secrete IL-4 and IL-10. This cascade of events results in a suppressive regulatory response as well as stimulation of B cells that secrete IgA, which may be protective against infection at these surfaces. Virus specific antibody binds to the virus, usually to the viral envelope or capsid proteins, and blocks the virus from binding and gaining entry to the host cell. Virus specific antibodies may also act as opsonins in enhancing phagocytosis of virus particles - this effect may be further enhanced by complement activation by antibody-coated virus particles and may lead to complement-mediated lysis of the infected cell, or may direct a subset of natural killer cells to lyse the infected cell through a process known as antibody-directed cellular cytotoxicity (ADCC). 

During the course of a viral infection, antibody is most effective at an early stage, before the virus has gained entry to its target cell. In this respect, antibody is relatively ineffective in primary viral infections, due mainly to the lag phase in antibody production. 


Phagocytes, Granulocytes, and Their Relatives

Phagocytes (literally, "cell eaters") are large white cells that can engulf and digest microorganisms and other antigenic particles. Some phagocytes also have the ability to present antigen to lymphocytes. 

Important phagocytes are monocytes and macrophages. Monocytes circulate in the blood, and then migrate into tissues where they develop into macrophages ("big eaters"). Macrophages are seeded throughout body tissues. Specialized macrophages include alveolar macrophages in the lungs, mesangial phagocytes in the kidneys, microglial cells in the brain, and Kupffer cells in the liver. 

Macrophages:
They are versatile cells that play many roles. 
 

•		As scavengers, they rid the body of worn-out cells, digested microorganisms and other debris.
•		It is foremost among the cells that "present" antigen to T cells, having first digested and processed it; macrophages in such way play a crucial role in initiating the immune response.
•		As secretory cells, monocytes and macrophages are vital to the regulation of immune responses and the development of inflammation; they churn out an amazing array of powerful chemical substances (monokines) including enzymes, complement proteins, and regulatory factors such as interleukin-1.

Neutrophils:
Another critical phagocyte is the neutrophils, also known as polymorphonuclear leukocytes or polymorphs. Neutrophils are not only phagocytes but also granulocytes: they contain granules filled with potent chemicals. These chemicals, in addition to destroying microorganisms, play a key role in acute inflammatory reactions. 
Granulocytes include also eosinophils and basophils. They typically "degranulate," releasing their chemicals to work on cells or microbes in their surroundings.

Mast Cells:
The mast cell is a non-circulating counterpart of the basophil. Located in the lungs, skin, tongue, and linings of the nose and intestinal tract, the mast cell is responsible for the symptoms of allergy. 

Platelets:
Another related structure is the blood platelet. Platelets, too, contain granules. In addition to promoting blood clotting and wound repair, platelets release substances that activate components of the immune system. 

Different types of white cells (phagocytes, granulocytes and their relatives

3. Complement
The complement system is made up of a series of about 25 proteins that work to "complement" the activity of antibodies in destroying bacteria, either by facilitating phagocytosis or by puncturing the bacterial cell membrane. Complement also helps to rid the body of antigen-antibody complexes. In carrying out these tasks, it induces an inflammatory response. 

Complement proteins circulate in the blood in an inactive form. When the first of the complement substances is triggered-usually by antibody interlocked with an antigen-it sets in motion ripple effect. As each component is activated in turn, it acts upon the next in a precise sequence of carefully regulated steps known as the "complement cascade" which ends in creation of a unit known as the membrane attack complex. Inserted in the wall of the target cell, the membrane attack complex constitutes a channel that allows fluids and molecules to flow in and out. The target cell rapidly swells and bursts. One byproduct causes mast cells and basophils to release their contents, producing the redness, warmth, and swelling of the inflammatory response. Another stimulates and attracts neutrophils. Another opsonizes or coats target cells so as to make them more palatable to phagocytes. 

Antibodies and complement thus affect viruses at two points in their replication cycles: during their extracellular phase antibodies can bind and neutralize the virus directly, and during the viral intracellular phase antibody and complement can interact with exposed (membrane-associated) viral proteins, leading to antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-mediated cytolysis.

Complement cascade

Viral Immune Evasion
Why we ever get infected even in the absence of immune suppression?

Every virus capable of infecting vertebrates has some means of dealing with the immune response. These methods range from the very rapid replication that may allow some viruses to complete a replication cycle before the specific immune response has a chance to develop - to the profound, such as the near-total ablation of the immune system in late-stage HIV infection. In several instances, viruses block the responses by interfering with any of the components of the immune system. 

Cytokines, mostly produced by T helper cells, are most critical in the acute phase of the immune response; interleukin-1 (IL-1), interleukin-2 (IL-2), interferon-g (IFN-g), and tumor necrosis factor (TNF) induce inflammation, recruit and stimulate other immune components, and generally induce an inhospitable environment for any kind of microbes. (11). The cytokines, IL-6 and TNF- play an important role in the pathogenesis of symptom production in influenza, while 2 other cytokines, IL-10 and IFN- , involved in the counter-regulation of the immune response to stop any fulmination of the inflammatory response. Experimental studies showed that a number of viruses secrete potent chemokine inhibitors in order to stop the protective reaction of the immune system against the virus (12,13). 
Since NK cells are also very important in the early phase of clearing infections (14) one would also expect that some viruses target these cells. Some NK effects are also mediated by cytokines, and in particular IFN-g (15). 


The Role of The Immune System In Allergic Reactions

The most common types of allergic reactions-hay fever, some kinds of asthma, and hives-are produced when the immune system respond to a false alarm. In a susceptible person, a normally harmless substance-grass pollen or house dust, for example-is perceived as a threat and is attacked. Such allergic reactions are related to the antibody known as immunoglobulin E. Like other antibodies, each IgE antibody is specific; one reacts against oak pollen, another against ragweed. 

The first time an allergy-prone person is exposed to an allergen, he or she makes large amounts of the corresponding IgE antibody. These IgE molecules attach to the surfaces of mast cells (in tissue) or basophils (in the circulation). Mast cells are plentiful in the lungs, skin, tongue, and linings of the nose and When an IgE antibody sitting on a mast cell or basophil encounters its specific allergen, the IgE antibody signals the mast cell or basophil to release the powerful chemicals stored within its granules. These chemicals include histamine, heparin, and substances that activate blood platelets and attract secondary cells such as eosinophils and neutrophils. The activated mast cell or basophil also synthesizes new mediators, including prostaglandins and leukotrienes, on the spot. 

It is such chemical mediators that cause the symptoms of allergy, including wheezing, sneezing, runny eyes, rhinorrhea and itching. They can also produce anaphylactic shock, a life-threatening allergic reaction characterized by swelling of body tissues, including the throat, and a sudden fall in blood pressure. 


Conventional Treatment of common Upper Respiratory Disorders

Treatment of uncomplicated cases of common upper respiratory disorders includes: bed rest, plenty of fluids, gargling with warm salt water, petroleum jelly for a raw nose, and aspirin or acetaminophen to relieve headache or fever (16). However any medication used for the elderly should be monitored carefully, as over-the-counter drugs are more likely to cause adverse effects in elderly individuals.

Symptomatic treatment include:
 

•		Decongestants (Alpha adrenergic agonists): These substances are potent decongestants and have been long used for treating the common cold. Both oral and nasal forms proved effective in natural and experimental cold models. These drugs are not without hazards, as prolonged use can lead to a rebound effect (rhinitis medicamentosa) (17,18). They may relieve some cold symptoms but does not prevent, cure, or even shorten the duration of illness. Care needs to be taken in patients with hypertension because of the sympathomimetic effect of these drugs.
•		Cough suppressants (codeine and dextromethorphan), Codeine is contraindicated in pregnancy as it may pose a risk to the fetus. Doctor should be consulted before taking any medication while pregnant. Moreover, most have some side effects, such as drowsiness, dizziness, insomnia, or upset stomach, and should be taken with care.
•		Antihistamines: They may have some effect in relieving inflammatory responses such as runny nose and watery eyes that are commonly associated with colds. Antihistamines are H1 and H2 receptor antagonists. They prevent antigens acting on the membranes of basophil cells. This prevents the release of histamine, which causes the symptoms typical of allergies, and similar to those of the common cold. However, it has been shown that histamine is not present in increased concentrations in people with upper respiratory tract infection (cf. allergic rhinitis). It is suggested that if antihistamines do alleviate cold symptoms, the effect may be due to their atropine-like action on the nasal mucous membranes rather than the antagonism of histamine receptors (19).
•		Analgesics: Acetaminophen (Tylenol), ibuprofen (Advil) and (aspirin) may be used to reduce fever. Do not give aspirin to anyone under 18 years age during a viral infection due to an increased risk of Reye's syndrome, a potentially life-threatening disorder. Reye's syndrome is a rare but serious illness that usually occurs in children between the ages of three and 12 years. It can affect all organs of the body, but most often injures the brain and liver. While most children who survive an episode of Reye's syndrome do not suffer any lasting consequences, the illness can lead to permanent brain damage or death. Aspirin as well as other non-steroidal anti-inflammatory drugs has been suggested to increase nasal symptoms and virus shedding and decrease serum neutralizing antibody response in volunteers infected with rhinovirus (20,21).
		Cyclo-oxygenase inhibitor: Naproxen was found to reduce headache, malaise, and cough without altering virus shedding or antibody responses in experimentally induced rhinovirus colds (22).
•		Steam inhalation: Recent studies found that this approach had no effect on the symptoms or amount of viral shedding in individuals with rhinovirus colds. But steam may temporarily relieve symptoms of congestion associated with colds. Breathing in steam from a bowl or jug is widely believed to ease the soreness and discomfort of a cold. Nasal hyperthermia (420-440C) administered for natural or experimental common colds resulted in subjective improvement of symptoms and objective increased nasal patency in some patients (23,24,25,26).
•		Antibiotics: These prescription drugs do not have antiviral effect. People receiving antibiotics did not do better in terms of cure or improvement than those on placebo There is not enough evidence of important benefits from the treatment of upper respiratory tract infections with antibiotics and there is a significant increase in adverse effects associated with antibiotic use and should be used only for bacterial complications, as intensive antibiotic therapy might be indicated in acute and chronic sinusitis after culture and sensitivity test of the post -nasal discharge to choose the proper antibiotic. Antibiotic solution irrigations are used when purulent drainage begins in cases of atrophic rhinitis. Mucosal moisturizers are indicated to prevent crusting (27,28).
•		Interferon-alpha has been studied extensively for the treatment of the common cold. Investigators have shown interferon, given in daily doses by nasal spray, can prevent infection and illness. Interferon, however, causes unacceptable side effects such as nosebleeds and does not appear useful in treating established colds (29).
•		Cold vaccine: The development of a vaccine that could prevent the common cold has reached an impasse because of the discovery of many different cold viruses. Each virus carries its own specific antigens (substances that induce the formation of specific protective proteins "antibodies" produced by the body). Until ways are found to combine many viral antigens in one vaccine, or take advantage of the antigenic cross-relationships that exist, prospects for a vaccine are dim. Evidence that changes occur in common-cold virus antigens further complicates development of a vaccine. Such changes occur in some influenza virus antigens and make it necessary to alter the influenza vaccine each year. The vaccine may, sometimes cause side effects, especially in children who previously have not been exposed to the flu virus. The most common side effect in children and adults is soreness at the site of the vaccination. Others include fever, tiredness and sore muscles that may begin 6 to 12 hours after vaccination and may last for up to 2 days. Viruses for vaccine production are grown in chicken eggs and then inactivated with a chemical so that they are no longer infectious. People who are allergic to eggs should not receive flu vaccine since some egg protein may be present in the vaccine.
•		Antiviral treatment: Some influenza virus infections have been successfully treated with drugs such as amantadine, rimantadine, and zanamivir. On the other hand, several studies using antiviral drugs against rhinovirus colds showed no appreciable clinical benefit. 10% of people on amantadine experience side effects like depression, dizziness, nausea, and insomnia and rapid development of resistance during treatment (30,31,32,33).
•		Vitamin C: The vitamin may reduce the severity or duration of symptoms, but there is no definitive evidence (34).

Alternative Treatment of Common Upper Respiratory Disorders

The use of and search for drugs and dietary supplements derived from plants have accelerated in recent years. Ethnopharmacologists, botanists, microbiologists, and natural-products chemists are combing the different phytochemicals that could be of help for the treatment of immunodeficiency and infectious diseases. Drugs derived from plants are used to treat conditions ranging from arthritis to leukemia and ovarian cancer. Some of today's treatments use herbs directly. Researchers also are studying a variety of foods for their potential medicinal benefits. More and more consumers are buying herbal medications in the form of food supplements to use as analgesics, sedatives, or immune system stimulants. Although a few plants may cause serious adverse reactions, many herbal preparations are considered to be safe and effective in moderation (39). 

Extensive study on the present state of herbal medicine in Germany showed that phytotherapeutic drugs (herbal remedies) are of considerable importance in Germany, both in self-medication and in medical prescriptions. The Federal Health Office of the German Ministry of Health has officially evaluated the efficacy and safety of approx. 300 medicinal plants used in Germany; their evaluations are used as criteria for the permission to market phytotherapeutic drugs (40). 

The American Association of Poison Control Centre, Toxic Exposure Surveillance System was manually and computer searched over a ten-year period (1983-92) to prioritize plant exposures by frequency. The data were analyzed using descriptive statistics and it has been concluded that the most common plant exposures are not significant morbidity or mortality (41). 

Studies showed that temporary weakening of the immune defense system lowers the body resistance to common cold and influenza viruses and cause most upper respiratory tract infections. Similarities in symptom presentation for upper respiratory tract infection of different viral etiology reflect a generalized profile of proinflammatory cytokine elaboration.

The local immune response to different viral infection causing common upper respiratory tract infection was studied through determining the cytokines and chemokines levels in serial nasal lavage fluid samples, from volunteers experimentally infected with influenza virus. It has been found that Interleukin (IL-6), tumor necrosis factor alpha (TNF- ), interferon gamma (IFN- ), and proinflammatory chemokines are increased in response to influenza viruses. These cytokines are responsible for inducing inflammation, recruiting and stimulating other immune components, and generally induce an inhospitable environment for the virus. 

IL 10 has been also found to be increased in the nasal lavage and is responsible for the balance of the immune response to stop inflammatory fulmination. The cytokine and chemokine level correlated statistically with the magnitude and time course of symptoms. It was concluded that there is a complex interplay of cytokines and chemokines in the development of symptoms and resolution of influenza. 

The fact that IL-10 inhibits macrophage production of TNF- and IL-6, establishes IL-10 as a major anti-inflammatory cytokine and suggests that its production early in influenza virus infection is an important mechanism by which the body controls and limits inflammation induced by such infection. It is also able to act as a terminal differentiation factor for B cells. This leads to the suggestion that IL-10 plays a role in the B cell response to influenza antigen and thus helps drive the protective antibodies that evolve during and after infection (42). 

Recent studies have documented a link between respiratory viral infections and the expression of asthma and other allergic disorders. Results from other studies have suggested that diminished production of IL-10, an anti-inflammatory cytokine, may contribute to the patho-physiologic features of these diseases.

IL-10 production was significantly diminished in subjects with allergy, as compared with subjects with no allergy, after experimental infection with influenza A virus. It has been concluded that subjects with allergy have an intrinsic inability to up-regulate IL-10 production in response to inflammatory stimuli and extend this observation to include respiratory viral infections (43). 

Thus cell-mediated immunity (CMI) has been shown, over many decades of clinical observation and bench research, to be central to the outcome of invasive infections. In recent years, understanding the role of messenger molecules (cytokines) in coordinating and augmenting cellular immunity has been ascendant. These studies have made it possible to use herbal remedies that stimulate the natural production of cytokines by the patient's blood monocytes and thus augment the cellular immunity of the body to fight various types of infections. This function of some herbal ingredient made it possible to be used in treating infections in humans, even for immunocompromised (immunodefecient) patients. Recent experimental work has lead to a better understanding of the role of cytokines and importance in therapy (44).

Cytokines also play a role in treating patient with upper respiratory allergic reactions. Experimental laboratory work showed an increase in IL-10 and IFN-gamma expression in the bronchial lavage of allergic patients with asthma treated with cortisone was corresponding to the degree of improvement of their allergic state. It has been concluded that cortisone relieves the bronchial allergic reaction through their stimulatory effect on cytokine expression such as IL-10 and IFN-gamma. This observation made it essential to consider the herbs that simulate the action of cortisone regarding the production of such cytokines in treating patients with allergy (45). Experimental studies showed data that support the role of IL-10 as a key modulator in the inhibition of the contact hypersensitivity response by whole body (46). 


The Scientists of Dermamed Pharmaceutical Company, being always enthusiastic, about finding a solution for the common health problems that affect most of the people, they formulated their unique completely natural medication for the prophylactic and therapeutic treatment of common upper respiratory tract infections. The prophylactic or therapeutic use of this formulation enhances the specific and non-specific immune system (immunomodulatory) in a mode that makes it capable of enhancing the natural body defence against various types of infections. In addition to its immunomodulatory function it helps the protection of the respiratory tract against infection through its marked inhibitory effect on viral, bacterial and fungal infection by adding the herbal extracts that are considered to be the most abundant source of a wide variety of secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids, which have been found in vitro and in vivo to have antimicrobial properties (47). 


Dermamed formulation for cold and sinusitis is the only medication, in the drug market, that can act both as immunomodulatory and antimicrobial in the same time. It is a combination of plant extract preparations that can act synergistically in different directions i.e. enhancing the specific and non- specific immune system and in the mean time inhibit the replication of any viral, bacterial or fungal infection.

The efficacy of the herbal extract preparations used for this formulation has been assessed by many immunological in vitro- and in vivo-experiments that were done by investigators at many sites of the world. The existing controlled studies on humans and in vitro experimental studies have shown positive results. Adverse effects and possible health risk of the active natural ingredients used in this medication have not been reported so far. 

The most noteworthy features observed after using dermamed formulation are: 
 

•		Diminution of recurrent infections.
•		Reduction of the duration of a disease.
•		Significant reduction of the seriousness of most of the symptoms associated with the upper respiratory tract disorders whether infectious or allergic.

The Goal of PhytoCort Cold and Sinus Treatment:
 

1.		Stimulates the natural production of cytokines by the patient's blood monocytes and thus augment the cellular immunity of the body to fight various types of infections and in the same time keep the body's immunobalancing state through the production of the immunoregulatory cytokines such as IL-10 and IL-4 which stops any inflammatory fulmination even for immunocompromised patients.
2.		Stimulates the production of cytokines, IL-10 and IFN-gamma, which helps relieving the allergic reactions and thus exhibits quick, long lasting effect in relieving seasonal allergic rhinitis symptoms
3.		Exhibits antiviral effect via stimulation of the interferon alpha, beta-production
4.		Enhances the production of specific antibodies against the viral infection and activates the complement system.
5.		Inhibits viral, bacterial and fungal replication with secondary broad-spectrum effect on the upper respiratory tract infections and thus stops complications such as sinusitis, tonsillitis, otitis media and bronchitis.
6.		Reduces the common symptoms associated with upper respiratory tract infection through its anti-inflammatory, analgesic and antipyretic activity as well as its relaxing effect on the tracheal smooth muscles. It also relieves the sinusitis symptoms such as headache, pressure pain at nerve exit points, and irritating cough through its secretolytics effect.
7.		Exhibit muscle and mental relaxing effect without interfering with the cognitive performance.
8.		Exhibits free-radical scavenging property.
9.		Inhibits the cytopathogenic effects induced by human immunodeficiency virus and thus considered helpful as alternative treatment for AIDS patients with oropharyngeal Candidiasis refractory to conventional anti-fungal treatment.
10.		It is well tolerated, showing absence of any adverse side effect.
11.		It is cost effective and has long shelf life.

ACTIVE INGREDIENTS
The strategy of Dermamed Scientists in formulating their completely natural medications is:
 

1.		The use of a combination of active herbal ingredients that proved by different experimental and clinical studies to be safe and effective in correcting the different aspect of the pathological factors involved in causing the corresponding disease.
2.		The use of the minimum effective dose of each active ingredient to avoid the side effects of any of them if ever exists.
3.		Each active ingredient acts on one or more of the pathological factors by the same or different mechanism but without interfering with each other's mode of action (act synergistically) and thus augment the benefit of each ingredient without using unnecessary high dose of any of them.
4.		The final development of new therapeutic interventions for the common upper respiratory tract disorders based on the increasing patho-physiological knowledge about the role of viruses and the antiviral immune response in common respiratory infection and the role of immune system in allergic disorders.

The herbal active ingredients include: Echinacea, Luffa Operculata, Eucalyptus, Solidago Virgaurea, Gnaphalium Viscosum, Mentha Piperita, Linden, Lavandula Vera, Maritime Pine, Rosemary, Melaleuca alternifolia, Ocimum basilicum, Atropa belladonna, Phytolacca Americana, Populus Tremula, Melissa Officinalis and Chamomile.

Echinacea
Echinacea Purpurea is a plant that was originally used by Native Americans to treat respiratory infections and is now widely used in some European countries and the USA for upper respiratory tract infections. On the German market there are at present more than 200 preparations obtainable which contain extracts of Echinacea alone or in combination with other plant extracts (48). 

Purified root extracts from Echinacea Purpurea has revealed biological activity in different immunological and virological test systems. It exhibits different activity on immunological parameters, such enhancing the specific and non-specific immune system. An antiviral activity to influenza virus was also observed. The Echinacea Purpurea extracts have shown an indirect antiviral effect via stimulation of the interferon alpha, beta-production (49). It contains many Immunologically active constituents such as: polysaccharides, glycoproteins, caffeic acid derivatives (cichoric acid) and alkamides (50). 

The analysis of alkamides in the roots of Echinacea Purpurea (L.) showed nine major alkamides in addition to other minor alkamides (51). Roots are distinguished from other plant parts by higher levels of the C12 diene-diyne alkamides (52). 

Many studies have been done to evaluate its ability to stimulate the production of cytokines by normal human peripheral blood macrophages in vitro. Different concentrations of Echinacea were tested. 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 (P < 0.05) than un-stimulated 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. These results demonstrate the immune stimulatory ability of the Echinacea Purpurea extract and offer some insight into the nature of the resulting immune response (53,54). 

Various investigators have postulated that the Echinacea extract is capable of stimulating cytokine production that can bind to specific receptors on the microbial target cells, and call into play many other cells and substances, including the elements of the inflammatory response and thus it can direct cellular traffic to destroy the microbial target cells, and stimulate the phagocytosis of the disintegrated viral particles by the activated macrophage. In the same time it stimulate the production of IL-10 which has immunoregulatory (immunobalancing) function as it is vital for orchestrating the whole immune system by suppressing the immune response after reaching the desirable effect and keeping it from going out of control by turning the helper T cells off and thus can stop any fulminating inflammatory response (55). It is also a potent modulator of monocyte / macrophage function as it significantly enhances the natural killer (NK) -function of peripheral blood mononuclear cells both from normal individuals and patients with depressed cellular immunity (56). 

Studies also showed antifungal effect for Echinacea extract as it has been found to increase the in vitro phagocytosis of Candida albicans by granulocytes and monocytes from healthy donors by 30-45% (57). 
The Echinacea extract has also significant ability to enhance the antibody response to antigenic stimulation (58). The previous study has been confirmed by clinical trial, which has showed that the Echinacea-treated patients have significant augmentation of their primary and secondary IgG response to the antigen. The results suggested that medicinal plants like Echinacea might enhance immune function by increasing antigen-specific immunoglobulin production (59). 

A recent clinical trial on 108 patients has been done to investigate the effect of using Echinacea in cold and respiratory infection, 54 patients were taking the Echinacea extract and 54 patients were taking placebo. The average number of colds and respiratory infections per patient was 0.78 in the Echinacea group, and 0.93 in the placebo group. Median duration of colds and respiratory infections was 4.5 days in the Echinacea group and 6.5 days in the placebo group. The study showed more incidence and severity of the cold and the respiratory infections in the placebo group than in the Echinacea group, despite reporting the result as statistically non- significant which may be due to the small number of patients (60). 

Another recent double blind, placebo controlled study was done to investigate the efficacy and safety of different doses and preparations of Echinacea Purpurea in the treatment of common cold. 246 recruited healthy, adult volunteers caught a common cold. The primary endpoint was the relative reduction of the complaint index defined by 12 symptoms during common cold according to the doctor's record. All treatments were significantly effective and well tolerated. It has been concluded that it is low-risk and effective alternative to the standard symptomatic medicines in the acute treatment of common cold (61). 
The efficacy of Echinacea in the treatment of Rhinorrhea has been proved by many other experimental studies and clinical trials and it has been concluded that they demonstrated high efficacy in acute viral respiratory tract infections and infections requiring antibiotics therapy and Echinacea containing preparation demonstrated therapeutic superiority over placebo (62). 

Clinical trial has been done to test the effect of the Echinacea extract on children with chronic decompensated tonsillitis due to immunodeficiency diseases. Positive effect has been found on the clinical and immune indices and also on state of microcirculation, which gives ground to advise the formulation containing the extract for the treatment of children with this disorder (63). 
In one systemic review some investigators searched the Cochran Acute Respiratory Infections Group and Complementary Medicine Field's trials registers, MEDLINE, EMBASE, PHYTODOK and reference lists of articles. They also contacted researchers and manufacturers. The results suggested that the majority of the available studies reported positive results (64). 

Animal experiments proved that the extract is non-toxic and tests for mutagenicity carried out in microorganisms and mammalian cells in vitro and in mice all gave negative results (65). 

Luffa Operculata (Cucurbitaceae)
The names Luffa operculata (L.) is applied to the Central American indigenous species of Luffa. Bryonolic acid is a pentacyclic triterpene isolated from Luffa genus (Cucurbitaceae) and has been found to have anti-allergic activity that is comparable to other known antiallergic components. It has been tested in experimental animals and has demonstrated high ability to inhibit passive cutaneous anaphylaxis and delayed hypersensitivity more strongly than other compounds. In addition it showed not only little toxicity but also no visible side effects on mice, without impairment of the activity of the hepatic enzymes involved in steroid catabolism (66). Intracellular localization of bryonolic acid was investigated with reference to the sites of its biosynthesis and accumulation. The results of cell fractionation showed that bryonolic acid was mostly located in the cell wall fraction (67). 

Experimental studies showed that bryonolic acid (3-beta-hydroxy-D: C-friedo-olean-8-en-29-oic acid) is found exclusively in the roots of the intact plants and it has been postulated that it could be a potential source of pharmacologically active compounds (68). 

More than 150 volatile components were separated and thirty-seven components were identified and quantified. The contents of essential oil were 0.05%, 0.05%, and 0.08% on a dried weight base in leaves, stem, and seeds respectively. Seed oils obtained from Luffa genus are widely abundant in palmitic (C16: 0), oleic (C18: 1) and linoleic (C18: 2) acids (69). 

However linoleic acid has been found to be the major component of most of the oils and has marked anti-inflammatory activity due to arachidonate inhibition (70). 

Twenty-six components of normal hydrocarbons in leaves, stem, seed, and unripe fruit were separated (71). 
Luffa ribosomal inhibitory protein isolated from Luffa genus has been studied and found to show moderate but significant antiviral activity. Studies showed that HIV replication was inhibited at doses in which they were non-toxic to uninfected peripheral blood mononuclear cells (72,73). 

The therapeutic success of medication containing Luffa operculata has been demonstrated in a controlled randomized double blind trial, carried out by 47 physicians in private practice with in total 152 patients with acute and chronic sinusitis. Criteria for the therapeutic result were headache, blocked nasal breathing, trigeminal tenderness, reddening and swelling of nasal mucosa and postnasal secretion. Averaged over all four groups 81% of the patients with acute sinusitis and 67% of the patients with chronic sinusitis recovered (74). 

Recently the efficacy and safety of homeopathic medication, containing Luffa operculata has been confirmed by other investigator in another open study of 119 male and female patients, 12 to 57 years of age, with the clinical sings of acute sinusitis not previously treated. At the first visit, after a mean of 4.1 days of treatment, secretolysis had increased significantly and typical sinusitis symptoms, such as headache, pressure pain at nerve exit points, and irritating cough, were reduced. Ninety-nine patients received only the test medication. Twenty patients were able to discontinue concomitant medication at the first visit. Only one patient needed an antibiotic. The average treatment duration was 2 weeks. At the end of treatment, 81.5% of patients described themselves as symptom free or significantly improved. Adverse drug effects were not reported (75,76,77). 

A clinical study to investigate the efficacy and tolerance of a homeopathic nasal spray containing Luffa operculata in cases of hay fever (seasonal allergic rhinitis) in comparison with the conventional intranasal cromolyn sodium therapy has been made on 146 outpatients with symptoms of hay fever. The results of the study demonstrated a quick and lasting effect of the homeopathic treatment, which produced a nearly complete remission of the hay fever. Adverse systemic effects did not occur. It has been concluded that, for the treatment of hay fever, the homeopathic nasal spray is as efficient and well tolerated as the conventional therapy with cromolyn sodium (78). 

Eucalyptus
Eucalyptus sp. is considered among the most frequently used medicinal plants in Mexico and many other countries (79). It is considered a rich source of biologically active compounds. Among these, are the phloroglucinol compounds such as sideroxylonals, macrocarpals, euglobals, and robustadials, which are unique to Eucalyptus species. Macrocarpals, which consist of phrologlucinol and sesquiterpene, shows very strong antibacterial activity against gram -positive bacteria. Both Macrocarpals and euglobals have also antiviral activity (80,81). 

The essential oils of Eucalyptus globules were also tested on bacteria that could cause secondary infection of viral upper respiratory tract infection and can also cause complications such as acute bronchitis, pneumonia, sinusitis, otitis media and conjunctivitis (ascending infection of the lachrymal canals) e.g. Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, Streptococcus pyogenes. The study showed that these oils presented antimicrobial activity and produced inhibition zone larger than 12 mm diameter. These results proved that eucalyptus extract exhibits strong in vitro antibacterial activity against the tested microorganisms (82,83,84). 

The essential oils of eucalyptus have been found to have broad-spectrum antifungal activity against many human pathogenic fungi (Microsporum nanum, Trichophyton mentagrophytes and T. rubrum. On comparing the minimum effective concentration of the oil with those of prevalent synthetic antifungal drugs, the oil was found to be more effective. These oils, showed maximum effect, and were found to be cost effective, had long shelf life, and showed absence of any adverse side effects (85). 

Eucalyptus extract exhibits anti-inflammatory effects, which is dose dependent and this, affirm its traditional use in inflammatory conditions (86). It has the ability to ameliorate the inflammatory processes of various infectious diseases by interacting with aggressive oxygen free radicals that accompany or initiate the pathogenesis of inflammatory processes. These activities partially allow attenuation of oxidative attack and damage introduced by infections or environmental impacts (87). 

Polycyclic aromatic hydrocarbons and phenolic fractions were isolated from eucalyptus extract was tested for genotoxicity evaluation, the results achieved showed no genotoxic effects (88). Eucalyptus oil poisoning through oral oil ingestion has been also studied in childhood and it has been concluded that eucalyptus oil was less toxic compound than it was previously believed (89)

Eucalyptus-based drugs have been tried successfully in the treatment of common cold and flue-like symptoms (90). 

It has been also tried in children with acute maxillary sinusitis, exacerbation of chronic purulent maxillary sinusitis and paratonsillar abscess. The findings indicate a good anti-inflammatory effect and it has been concluded that it can be used as a treatment of choice in children with ENT diseases (91). 

Solidago Virgaurea L
The common golden rod, Solidago virgaurea L., has been used in European phytotherapy for 700 years as an antiphlogistic remedy (92,93). 

The steam-distilled essential oil of Solidago virgaurea L. was investigated by Gas chromatography. Sixty components were identified. The main constituents are alpha-pinene, myrcene, beta-pinene, limonene, sabinene and germacrene-D (94). 

Genuine saponins of Solidago virgaurea have been investigated in view of their immunomodulating effect. It has been found that it increases TNF alpha concentration in blood when compared to the control group (95). Experimental work has been done on aqueous-ethanolic extracts from Solidago virgaurea and it demonstrated that it has also the ability to regulate the biochemical reactions involved in various inflammatory processes (96). 
S. Virgaurea extract could be useful as antifungal preparation against dermatophytes, especially against Trichophyton mentagrophytes, Microsporum gypseum and Microsporum canis (97). 

Aqueous/alcoholic extracts of Solidago virgaurea were tested on experimental animals and found to be capable of reducing the inflammation and secondary edema (98). It has been found to produce dose-dependent anti-inflammatory, analgesic and antipyretic effects, which simulates the efficacy of non-steroidal anti-inflammatory drugs (99). 

Gnaphalium Viscosum
A methanol extract of the flowers of Gnaphalium showed significant anti-inflammatory activity. Caffeoylquinic acid derivatives and flavonol glycosides were isolated as the compounds responsible for this activity (100). 
Gnaphalium viscosum of American origin, have been used for the treatment of respiratory ailments. Preliminary in vitro results provide scientific basis for the use of this plant against bacterial respiratory infections (101). 
Laboratory studies showed that it exhibited antibacterial activity. Gnaphalium viscosum was screened for activity against 3 bacteria, which cause respiratory infection (Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes). The results proved the antibacterial activity of the extract (102,103). 

Mentha Piperita L
Mentha x Piperita L. (Lamiaceae) has been known for a long period as a medical plant, and its therapeutic effects were mostly attributed to the composition of its essential oil. In addition to the essential oil, it is known that M. x Piperita contains some other pharmacologically active ingredients as well, such as tannins, bitter substances, caffeic acid and flavonoids (104). 

Peppermint leaves contained 2.4% essential oil, total polyphenolic compounds 19% and total flavonoid compounds 12% (105). The volatile oil of mature Mentha Piperita (peppermint) leaves contains as major components the oxygenated p-menthane monoterpenes l-menthol (47%) and l-menthone (24%) as well as very low levels of the monoterpene olefins limonene (1%) and terpinolene (0.1%), which are considered to be probable precursors of the oxygenated derivatives (106). 

Mentha Piperita leaves is considered also as an inexpensive and easily obtained sources of provitamin A, which is a precursor of vitamin A which is known of its protective effect on the various mucous membrane, including that of the respiratory tract, against infection with various microbes (107). 
Earlier studies proved that Oils of, Mentha Piperita, have fungistatic or fungicidal effect, depending upon the concentrations (108). 

Many animal experimental studies have been done on Mentha Piperita and investigators concluded that it possess an anti-nociceptive (reduces the sensitivity of the nerve endings to pain sensation) and anti-inflammatory property. Both effects were dose dependent. These data affirm the traditional use of some of these plants for painful and inflammatory conditions (109). 

Compared to the application of placebo, 10 % peppermint oil in ethanol solution significantly reduced the clinical headache intensity after 15 minutes (p < 0.01). The clinical trial showed no significant difference between the efficacy of 1000 mg of acetaminophen and 10% peppermint oil in ethanol solution. The patients reported no adverse events. Peppermint oil thus proved to be a well-tolerated and cost-effective alternative to usual therapies (110,111). 

Clinical trial on the combined effect of peppermint oil in ethanol and eucalyptus oil preparations has been conducted. Studying their effect on both physiological and neuro-physiological parameters has been evaluated in 32 healthy subjects in a double blind, placebo-controlled, randomized crossover design. It has been found that the combination can increase cognitive performance while having a muscle relaxing, mentally relaxing effect and significant analgesic effect with reduction in sensitivity to headache. It has been concluded that these essential plant oil preparations often used in empirical medicine can thus be shown by laboratory tests to exert significant effects on mechanisms associated with the patho-physiology of clinical headache syndromes (112). 
Another study has also proved the efficacy of the same combination of Eucalyptus and peppermint oils in reducing the symptoms of upper respiratory tract infection (113). 

Linden, Tiliaceae
Tilia is considered as a part of the traditional folk medicine. Its extract contains mucilage, flavonoids, phenolic carbon acids and essential oils. Linden extract is used nowadays as a remedy for common cold and associated cough (114) due to its sedatives and tranquilizer effect. Studies showed that it has clear anxiolytic effect (115). 
Components prepared from Tiliaceae were also found to inhibit the histamine release induced by antigen-antibody reaction, which explains its antiallergic effect (116). 

Lavandula Vera
Many studies have been done on essential oils of Lavandula Vera and it has been concluded that when inhaled they have sedative property through their significant effect on brainwaves. The effect of oils is probably transmitted through the brain via the olfactory system (the olfactory nerve and its endings which supplies the nose). Used professionally and safely, essential oils can be of great benefit (117). 

Lavender oil is a source of vegetable aromatic substances (VAS), which has significant effect upon the oxidative-restoration enzymes activity of the body. The lack of these substances causes changes in the most important enzymes of glycolysis and pentosophosphatic cycle (118). 

Samples of essential oil Lavandula Vera has been found to contain 49 components. The major components of the oil are linalool (47-22%, linalylacetate (15-22%) and terpinen--4-ol (7-21%) (119).

Sensory evaluation and physiological measurements of the sedative properties of linalool, isolated from lavender oil was studied on humans after its inhalation. The study confirmed its efficacy in sedation (120). The sedative nature of linalool, one of the lavender's major components, on inhalation, has been shown both in animals and man. Animal experimental studies also showed that it decreases the tone in the skeletal muscle preparation of the phrenic nerve-diaphragm of rats, a result that could explain its useful effect in reducing the chest symptoms that accompany upper respiratory tract infection and allergy (121). 

The sedative effect was found to be closely dependent on the exposure time to the oil (122). 
Lavender oil, used in topical formulations, helps the relief of the musculo-skeletal pain due to its hydroxyl radical scavenging properties (123). 

Animal experimental studies showed that lavender oil inhibits immediate type allergic reactions by inhibition of mast cell degranulation in-vivo and in-vitro through both topical and intradermal applications. The inhibition was concentration dependent (124). 

In addition to the sedative, analgesic and antiallergic effect of lavender oils, it has been found to be lipophilic skin penetration enhancer (125). It thus helps the skin permeation of the other active ingredients in the same formulation on topical application.

Maritime Pine
There is growing interest in the biologic activities of plant extracts such as that obtained from the bark of the French maritime pine, Pinus maritime. Pycnogenol (PYC) is a standardized extract composed of a mixture of flavonoids, mainly procyanidins and phenolic acids. Studies indicate that PYC components are highly bioavailable. Uniquely PYC displays greater biologic effects as a mixture than its purified components do individually indicating that the components interact synergistically. Investigations of the cellular mechanisms of these therapeutic effects have demonstrated that PYC has strong free radical-scavenging activity against reactive oxygen and nitrogen species. PYC also participates in the cellular antioxidant network as indicated by its ability to regenerate the ascorbyl radical and to protect endogenous vitamin E and glutathione from oxidative stress. PYC modulates NO metabolism in activated macrophages by quenching the NO radical. Various studies showed that the active nitrous oxide radical generated by activated macrophages causes a significant loss of alpha-tocopherol and glutathione level in endothelial cells. Pycnogenol fraction of Pine Park protects alpha-tocopherol and the glutathione of endothelial cells and enhances by about 15% basal endogenous level of alpha tocopherol. This affirms that flavonoids participate in the cellular antioxidant network and that Pycnogenol may play an important role in the protection of endothelium form oxidative stress induced by reactive nitrogen species. PYC can also bind to proteins, altering their structure and thereby modulating the activity of key enzymes and proteins involved in metabolic pathways (126,127,128). 

The polysaccharide (PSE) extracted from pine seed shells as an immunopotentiator was investigated. Macrophage phagocytosis has been found to be augmented by oral administration of PSE. The activated macrophages secrete cytokines into the circulation that lead to activation of the T cells (interaction of the specific and non specific immune system) (129). The pattern of activated T cells is CD4+ T helper cells (130). The antigenic response after initial supplying of pine seed oil (PSO) showed a significant increase in the splenic production of antibodies of the IgG type (131). It has been postulated that the application of PYC in immune diseases could be of good help. 

Experimental studies showed that the pinecone extract (PCE) suppress the growth of influenza virus due to interaction between virus proteins and pine cone antitumor substance of the extract, thus inhibiting the viral RNA synthesis and suppress virus multiplication (132). 

Experimental studies in mice have shown that pine seed shell extract has anti-bacterial effect against common bacterial infection of the respiratory tract. Experimental work showed that it has protective effect against lethal doses of Klebsiella pneumonia, Pseudomonas aeruginosa and staphylococcus aureus and also moderately inhibited the cytopathogenic effect induced by human immunodeficiency virus (HIV). These data suggest a medicinal potential of pine seed shell extract against opportunistic infection of HIV patients. It has also antifungal activity against Candida Albicans (133,134,135). The potent antiviral, antibacterial and antifungal effects of the antitumor substances isolated from pinecone extract by ethanol-precipitation have been explained by the presence of lignin-related structures complexed with the polysaccharides. This natural lignified substance is capable of stimulating the endogenous production of cytotoxic factor (possibly tumor necrosis factor). These data suggested the importance of conjugating lignins with polysaccharides for in vivo expression of various kinds of immunopotentiating activity (136). 

Rosemary (Rosmarinus Officinalis Linn.)
Rosemary (Rosmarinus Officinalis Linn.) is a common household plant grown in many parts of the world. It is used for flavouring food, a beverage drink, as well as in cosmetics. In folk medicine it is used in relieving respiratory disorders. Extract of rosemary relaxes smooth muscles of trachea. The most important constituents of rosemary are caffeic acid and its derivatives such as rosmarinic acid. These compounds have antioxidant effect. Rosmarinic acid is well absorbed from gastrointestinal tract and from the skin. It has anti-inflammatory effect due to the increased production of prostaglandin E2, and the inhibition of the complement system. It is concluded that rosemary and its constituents especially caffeic acid derivatives such as rosmarinic acid have a therapeutic potential in treatment or prevention of bronchial asthma, inflammatory diseases (137). 

Rosemary extract was found to scavenge O-2 in a concentration-dependent manner. The antioxidative effect observed is believed to be partly due to this radical scavenger activity (138), which is similar to Superoxide Dismutase enzyme (139). The presence of rosemary mixture in the different creams lead to significantly lower rate of decomposition of highly unsaturated fatty acids and so the mixture works as preservative in addition to its biological activity (140). 

Clinical trial, using natural concentrations of rosemary, basil, eucalyptus and Lavandula essential oils to study their effect on the system lipid peroxidation-antioxidant defence in 150 patients with chronic bronchitis demonstrated their beneficial effect for the treatment of chronic bronchitis (141). There is an increasing interest in the antiviral activity of plant products. A liquid, deodorized rosemary extract was tested for antioxidant and antiviral action in vitro. The main active components in the herbal preparations, carnosol and carnosic acid were found capable of inhibiting human immunodeficiency virus (HIV) infection (142). Carnosol and carnosic acid have been also suggested to account for over 90% of the antioxidant properties of rosemary extract (143). 

Immunological experiment to illustrate the impact of rosemary extract on splenic mononuclear cell proliferation was determined. The results suggest that although the use of rosemary might not have a generalized immuno-enhancing effect, it will probably be effective in some stressed conditions, such as protein or antioxidant deficiency (144). 

Melaleuca alternifolia (tea tree) oil
Tea-tree oil (oil of Melaleuca alternifolia) has recently received much attention as a natural remedy for bacterial and fungal infections of the skin and mucosa. As with most naturally occurring agents, several published studies have recently demonstrated tea-tree oil's antibacterial activity. The in vitro results suggest also that tea-tree oil may be useful in the treatment of yeast and fungal mucosal and skin infections even in immunodeficiency diseases (145). The antimicrobial activity of eight components of tea tree oil were evaluated using disc diffusion and broth micro-dilution methods to determine the susceptibility of a range of micro-organisms to 1,8-cineole, 1-terpinene-4-ol, rho-cymene, linalool, alpha-terpinene, gamma-terpinene, alpha-terpineol and terpinolene. The results had significant implications for later development of tea tree oil as an antimicrobial agent (146,147). 

Major components of tea-tree oil, terpinen-4-ol, alpha-terpineol and alpha-pinene were found to be active against Staphylococcus aureus (148). 66 isolates of Staphylococcus aureus tested were susceptible to the essential oil of Melaleuca alternifolia (149). 

The in-vitro activity of tea tree oil, against the yeast candida was examined. Fifty-seven Candida isolates were tested for sensitivity to tea tree oil by the agar dilution method; the minimum concentration of oil inhibiting 90% of isolates was 0.5% (150). Clinical study has been done to evaluate the efficacy of melaleuca oral solution in AIDS patients with fluconazole-resistant oropharyngeal candida infections and it has been concluded that Melaleuca oral solution appears to be effective as an alternative regimen for AIDS patients with oropharyngeal candidiasis refractory to fluconazole (151). 

The antifungal activity of tea tree oil, in vitro was compared to miconazole, an established topical antifungal. The studies suggested that the in vivo effect of tea tree oil ointment in the therapy of fungal infections of the skin and mucous membranes is due to an antifungal activity of tea tree oil (152). 

Other active compounds were isolated from the methanol extract of Melaleuca, Stilbenes, piceatannol and oxyresveratrol, were isolated as active compounds from the methanol extract of Melaleuca and it has been found that they strongly inhibited histamine release from activated mast cells, a property that might help controlling the allergic reactions (153).

Ocimum basilicum (Labiatae)
Ocimum basilicum fixed oil may be considered to be a medication of natural origin, which possesses antioxidant, antimicrobial, anti-inflammatory and anti-ulcer activity (154). 

The essential oil composition of Ocimum basilicum, and their antimicrobial and antioxidant activity were tested. The volatile oils exhibited considerable inhibitory effect against twenty-five different genera of bacteria. The oils also demonstrated antioxidant capacities, comparable with alpha-tocopherol (155). Studies showed that the highest concentration of total anthocyanins occurred just prior to flowering, although by day 8 seedlings already had accumulated all 14 anthocyanins. Comparisons were made to other anthocyanin sources; with results showing that purple basils Ocimum basilicum L is an abundant source of acylated and glycosylated anthocyanins (156). 
Eight known terpenoids were isolated from the roots and stems of Ocimum basilicum (Labiatae). These compounds included a sesquiterpene, T-cadinol (1), a monoterpene, linalool (2), and six triterpenoids, betulinic acid (3), betulin (4), pomolic acid (5), alphitolic acid (6), ursolic acid (7) and tormentic acid (8). Their structures were determined on the basis of spectral and physical data. The anti-inflammatory activities of the triterpenoids were investigated (157). It has been found that Fixed oil of O. basilicum possesses significant anti-inflammatory activity. The results of anti-inflammatory activity of O. basilicum support the dual inhibition of arachidonate metabolism, as it blocks both cyclooxygenase and lipooxygenase pathways of arachidonic acid metabolism (158). 

Ocimum basilicum extract has also showed potent anti-HIV-1 activity. The active components in the extract samples were found to be water-soluble polar substances, not non-polar compounds such as essential oils (159). 

Many investigators have studied the antifungal activity of the essential oils of Ocimum basilicum. The most abundant compounds in the oils of O. basilicum, alcohols and oxides (>40%), possess potent antifungal activity against wide range of fungi that include: Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aureobasidium pullulans, Microsporum gypseum, Trichophyton rubrum, and Trichoderma viride (160). 

Atropa Belladonna
Eight steroidal glycosides of the spirostane type have been isolated from the methanolic extract of Atropa belladonna L. seeds. They are tentatively named atroposides A, B, C, D, E, F, G, and H (according to their increase in polarity) (161). The efficacy of belladonna has been studied in a prospective observational study carried out by 1 homoeopathic and 4 conventional ENT practitioners, the 2 methods of treating acute pediatric otitis media were compared. Group A received treatment with homoeopathic single remedies Belladonna, Chamomile, whereas group B received nasal drops, antibiotics, secretolytics and/or antipyretics. The study involved 103 children in group A and 28 children in group B, aged between 6 months and 11 years in both groups. For duration of pain, the median was 2 days in group A and 3 days in group B. For duration of therapy, the median was 4 days in group A and 10 days in group B: this is due to the fact that antibiotics are usually administered over a period of 8-10 days, whereas homoeopathic treatment can be discontinued at an earlier stage once healing has started. Of the children treated, 70.7% were free of recurrence within a year in group A and 29.3% were found to have a maximum of 3 recurrences. In group B, 56.5% were free of recurrence, and 43.5% had a maximum of 6 recurrences. Out of the 103 children in group A, 5 subsequently received antibiotics, though homoeopathic treatment was carried to the healing stage in the remaining 98. No permanent sequels were observed in either group (162,163).

Studies also reached the conclusion that the airway smooth muscle contraction is a possible cause of airflow obstruction and this contraction is almost totally abolished by belladonna (anticholinergics) (164). 

Phytolacca Americana (pokeweed plant)
Pokeweed antiviral protein (PAP) of the pokeweed plant, Phytolacca Americana, is a naturally occurring single-chain ribosome-inactivating protein that inhibits viral RNA synthesis. The therapeutic antiviral potential of PAP has gained considerable interest in recent years (165). Pokeweed antiviral protein from seeds (PAP-S) has the lowest toxicity and highest inhibition activity as opposed to other pokeweed antiviral proteins (166). An antimicrobial peptide against both gram positive and gram-negative bacteria has been also isolated from the seeds of pokeweed (Phytolacca americana) (167). 

It has the capacity to modulate the antibody response as it has been proved by studies that the antibody response to type III pneumococcal polysaccharide (SSS-III) is enhanced by lectins from Phytolacca Americana (168). Recently, many investigators were able to isolate an antifungal peptide from seeds of Phytolacca Americana, designated PAFP-s. Its amino acid sequence corresponded to the amino acid sequence from chemical sequencing that exhibited a broad spectrum of antifungal activity (169). 

Experimental studies showed that it exhibited strong antifungal activity against Candida albicans and its activity was retained even after boiling for 30 minutes and treating with proteinase K (1.0mug/mug protein) (170). 
The efficacy of Phytolacca Americana used in homeopathy to treat acute tonsillitis was evaluated by clinical observation. The objective and subjective symptoms of acute tonsillitis were noted. A significant decrease in symptoms was observed as early as 2.5 days after treatment startup; no serious adverse effects were reported. It was concluded that acute tonsillitis could be treated with such a homeopathic remedy, which is characterized, by its immunomodulatory, analgesic, and anti-inflammatory properties (171). 

Populus Tremula
The efficacy of Populus Tremula extract as anti-inflammatory, analgesic and antipyretic natural remedy has been investigated both individually and in combination with other extracts by many Russian and German investigators.

Marked anti-inflammatory and anti-ulcerative properties of a Populus tremula bark extract were demonstrated in animal experiments (172). 

The phytotherapeutic preparation, containing Populus tremula, Solidago virgaurea produced dose-dependent anti-inflammatory, analgesic and antipyretic effects which were similar to those of the reference substances salicylic alcohol and indomethacin (173,174). 

Aqueous/alcoholic extracts of Populus tremula, Solidago virgaurea were tested individually and in combinations for anti-inflammatory activity (175). and it has been found that they inhibit biochemical model reactions representing inflammatory situations to various extents. It has been concluded that the extract possesses antipyretic, analgesic, anti-inflammatory and anti-rheumatic activity. The beneficial activities may at least in part be due to the reported antioxidative functions of the individual components. The anti-inflammatory and analgesic properties were shown clearly in pharmacological tests (176).

Balm, Melissa Officinalis, Labiatae
Rosmarinic acid (RA), a naturally occurring extract from Melissa Officinalis, inhibits several complement-dependent inflammatory processes (177). 

The sedative effect of Melissa Officinalis extracts was proved by quantitative EEG analysis and by self-assessment (178). 

Analytical studies showed that Melissa Officinalis contains high concentrations of total ascorbic acid (approximately equal to 300 mg/100 g FW) and relatively high ascorbate oxidase activity (10.1-21.1 micro mol min-1 g FW-1) (179). Besides acting as an important cofactor in the modulation of the biosynthesis of catecholamine, ascorbic acid modulates the secretion of immunoreactive beta-endorphin, which stimulates the brain opiate system responsible for pain control (180). 

Experimental studies showed that supplementation with ascorbic acid in humans enhances a number of aspects of lymphocyte function (blood cells responsible for the immune response) (181). 
In Europe, M. Officinalis is used to treat nervous disorders. Experimental studies showed that it exhibited significant analgesic activity (182).

Camomille, Matricaria recutita, Compositae.
It has been found that en-yne dicycloether one of the constituents of the essential oil of C. recutita) could partly inhibit protamine sulfate-induced degranulation (histamine release) of mast cells and thus inhibits allergic reactions (183). Chamomil extract also exerts anti-inflammatory activity (184). 



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