It is likely that asthma attacks triggered by different factors have different mechanisms that ultimately lead to the narrowing of air passages. Three leading theories are currently discussed to explain asthma mechanisms: 3

• The first one, and the most popular one, is that asthma is a fundamentally allergic sequence due to a wrongful response of the immune (defense) system to a challenge, e.g. by inhaled pollutants.
  
• The second theory is the "neurogenic hypothesis" that asthma attacks are precipitated by a sudden spasm of smooth muscles in the air passages due to imbalance within the nervous system, i.e. autonomous nervous system which regulates smooth muscles via ß-receptors and a-receptors.
  
• The third theory nicknamed "myogenic hypothesis" explains that white cells migrating to walls of air passages make the smooth muscles hyperactive and prone to sudden spasms leading to an asthma attack.

To understand the various mechanisms leading to asthma further, we need to discuss briefly the anatomy and physiology of the respiratory tract and the effects of allergens on respiration. (Figure 2)

The process of respiration involves inhalation and exhalation of air into and from the lungs and is effected through a complex mechanism co-ordinated by the respiratory center of the brain. The ribs, muscles attached to the rib cage, and a muscular membrane-like structure, known as diaphragm, separating the abdomen from the thorax facilitate the process of respiration, during the inhalation or exhalation of air. In addition to this mechanism, the walls of the bronchial tree is equipped with bronchial muscles that either dilate or contract the air passages. In fact, there is a circadian rhythm operating the bronchial muscles which results in maximal dilation of air passages at about 6 PM and maximal constriction of air passages at 6 AM. This explains why asthma attacks are more severe in the morning hours than in the evening. The other recognized factors that affect bronchial muscles and respiration are emotional and physical factors, such as altitude, temperature, and humidity of air, mostly by influencing the receptors called ß- and a- receptors dispersed in the walls of air passages. It is known, for example, that drugs stimulating ß-receptors cause dilation of air passages, while ß-blockers (used for treatment of high blood pressure) constrict air passages and thus are contraindicated in some pulmonary conditions. Cooling the airways may result in bronchial constriction, and exercise or hyperventilation in emotional stress may trigger asthmatic attacks, because of a lowering of the airway temperature.

The severity of asthma in a patient is judged by the presence of persistent airflow limitation which puts asthma in a group of pulmonary conditions called Chronic Obstructive Pulmonary Diseases (or COPD). The airflow can be measured by "lung volumes".

• The vital capacity, the greatest amount of air that can be expired after a maximal inspiratory effort, is clinically useful as an index of lung functions.
• The fraction of vital capacity expired in 1 second called forced expired volume in 1 second (or FEV1) is a particularly useful measurement in evaluating asthma condition.
• The peak expiratory flow (PEF) is reduced by more than 40% in asthma where the resistance of the airways is increased owing to bronchial constriction.

Surmising that asthma is related to air pollution, the human body does possess intricate protective mechanisms. The hair in the nasal cavity, often removed for aesthetic reasons, acts as a barricade to inhaled dust particles. Most of the air pollutants are trapped by the mucus covering of the nasal and pharyngeal mucosa, hence throat clearing, nose blowing, and sneezing are more common in the presence of dusty air. These are natural protective reflexes that clear the load of polluting particles from the nose and throat and make this important barrier useful for protecting our lungs. Our tonsils, which consist of lymphatic tissue, are strategically positioned in the pharynx to assist the defense system of the upper respiratory tract. Constant exposure to pollutants, including bacteria and viruses, that pass through the throat with air, drink and food, renders the tonsils susceptible to infections. This fact often prompts surgical removal of tonsils, and this procedure, unfortunately, removes an important protective barrier against pollutants entering our body.

Further down in the bronchial tree, the inhaled air is continuously screened and the presence of residual pollutants triggers the cough reflex initiated by a constriction of the air passages. This airway constriction facilitates slower air flow, preventing the polluted air from entering the alveoli (terminal structures in the lungs where the exchange of oxygen occurs). In response, we cough to force down the air (regardless of its quality) to the alveoli. This explains why coughing is not the healthy reflex of clearing something out of lungs, but rather a desperate attempt to breathe, which simultaneously forces the polluted air into the lungs. Coughing is therefore an important signal of distress from the lungs, very much like indigestion is a sign of distress from the digestive tract. Coughing along with sneezing often precedes an asthma attack and the related condition, "allergic rhinitis."

Fortunately, the polluting particles that sneak into the lower respiratory tract are flushed off by epithelial ciliae (a microscopic hairlike structure) towards pharynx. These epithelial cells are covered with a layer of mucus, which traps the polluting particles like glue and carries them out to the throat, to be either swallowed or coughed out, in a continuous process of cleaning the air passages. In an asthmatic patient, this harmonious process becomes seriously distorted in many ways. Due to a chronic inflammatory condition, the movement of ciliae is brought almost to a standstill, and the abnormally increased secretion of mucus makes airway passages close to impassable for air that we breathe.

Another rapid reaction system in our lungs to counteract pollution is made of various immune cells (or body defense cells), which literally devour the foreign particles. These cells collectively are called white cells and by their function are referred to as macrophages - the cells that eat foreign matter. The white cells are interspersed in the wall of airway passages like toll-gate soldiers, ready to stop any unwanted passerby. However, the action of white cells comes often at considerable cost to the airways themselves. When macrophages ingest large amounts of the substances contained in a cigarette smoke, or silica or asbestos particles of polluted air, they release enzymes (intended to digest the invader, i.e., antigen) which cause the inflammation of the airways and chronic, nagging cough. This is in fact a classic mechanism of a chronic inflammatory and degenerative condition of the bronchial tree, often referred to as bronchitis and too often initiating the deadly disease of emphysema. The current view of asthma is that it is "a chronic inflammatory disorder in which many white cells play a role, especially mast cells, eosinophils and T-lymphocytes". Figure 2a summarizes the changes in respiration induced during an asthma attack.

The symptoms associated with asthma are related to the pharmacologically active substances released from the granules in the process of mast cell degranulation. The active substances include histamine (ß-imidazol-ethylamine), serotonin(5-hydroxytrypta-mine), heparin (acid proteoglycan), eosinophil chemotactic factor of anaphylaxis (ECF-A), slow reacting substances that induce anaphylaxis (SRS-A) made of leukotrienes, and platelet activating factor (PAF).

Histamine released from mast cells causes constriction of air passages. Furthermore, it increases vascular permeability, which contributes to congestion of the air passages. Thus antihistaminic drugs are utilized as decongestants.

Serotonin, although involved in constriction of smooth muscles and increased vascular permeability in some experimental animals, does not play a major role in asthma in humans.

Eosinophil Chemotactic Factor of Anaphylaxis (ECF-A) consists of peptides, which attract (chemotaxis) inflammatory cells known as eosinophils. The presence of eosinophils is indicative of the antibody IgE mediated reactions. In addition, eosinophils may release chemical factors which mediate allergic reactions.

Heparin, which when released form mast cells, is involved indirectly in the chain reaction leading to asthma (recovery of mast cells after degranulation).

SRS-A includes as its main components leukotrienes LTB4, LT, C4 and LTD4, which can cause a prolonged contraction of brionchial smooth muscles.

PAF induces platelets to aggregate and prompts to release their content which include histamine, serotonin and metabolites of arachidonic acid, in particular leukotrienes.

The various inflammatory cells involved in the development of asthma is mentioned in Figure 4.

B. The role of epithelial cells in bronchial asthma
The mast cell can be considered as a central cell to the development of inflammation in airways and it is increasingly recognized that epithelial cells which line the airway passages have a pivotal role in the initiation of allergic chain of events and in maintaining continuous inflammation.

The airway epithelium appears to be more than just a physical barrier protecting the integrity of airways. In many ways, it plays a role as a communicator sending its own messengers to the organism and requesting a response to the message. The substances synthesized and released by the epithelium in asthma syndrome are like the messengers responsible for attracting inflammatory cells to the airways³. This chain of events contributes to the development of asthma syndrome ⁴.

C. The role of eosinophils in asthma
In asthma patients, the number of bronchial tree eosinophils in blood are increased during asthma attacks and tend to normalize once the patient becomes asymptomatic. Easinophils are also considered to be the major inflammatory cells in asthma since eosinophils can damage the epithelial cells lining bronchial tree^5,6.

As soon as the eosinophils are established in the airways, they themselves, like other inflammatory cells, could produce messengers of inflammation, which in turn stimulate eosinophil production, and activation. ⁷ Eosinophils play a crucial role in asthma because their presence sustain the inflammation in asthma. The night-time worsening of asthma has been associated with the increase of eosinophils in the airways as well as increased presence of the chemical messengers of inflammation ^{8, 9, 10}.

Aspirin induced asthma may be related to the increased activity by eosinophils and mast cells.^11,12 Although not fully understood, benefits of corticosteroids in the treatment of asthma may be due to their suppressing effect on eosinophils. ¹³

D. The role of T-cells in asthma development
The role of T lymphocytes in asthma syndrome can be described as regulatory or as that of a manager which regulates traffic of the infammatory cells, specifically their arrival and departure as well inflammatory activity in the airways. The overall regulatory abilities of lymphocytes T are based mainly on existence of two specific subclasses of lympocytes T, i.e., T helper lymphocytes also known as CD4 which stimulate a particular immunological reaction (e.g. inflammation), and T suppressor lymphocytes also known as CD8+ which do the opposite subduing the immunological reaction (e.g. inflammation). Upon exposure of the airways of the asthma patient to allergen CD4 T cells are being recruited from the blood and transferred to the airways. ¹⁴

Asthmatics in comparison to healthy individuals showed an elevated percentage of CD4 cells in the airways.¹⁵ In asthmatics, the percentage of CD4 cells correlate positively with the severity of the condition as well as the numbers of blood eosinophils. ^{15, 16}

The CD4, but not CD8 lymphocytes from asthmatics, may be helping in the eosinophil survival ^15,16. This is an important finding which helps to further understand how CD4 T lymphocytes regulate inflammation in asthma, and also the therapeutic approaches in asthma. For example, steroid therapy of the asthmatics improves lung function and at the same time lowers the percentages of CD4 and decreases the eosinophils survival. It should be noted, however, that the CD8 cells can also contribute to the development of asthma, but their role is less understood and recognized than that of the CD4 cells ^17.

Asthma induced by exercise provides another insight into a role of T lymphocytes in this disorder. ¹³ In experimental conditions several minutes after the end of the exercise, there was a significant FEV1 decrease only in asthmatic subjects. In the same group, the mean plasma histamine level rose significantly after the exercise, and returned to normal limits 20 min after the test. In the same group, there was also a significant decrease of T-lymphocyte count for two hours after exercise. By contrast, exercise challenge had no effect on either plasma histamine level or T-lymphocyte proliferation in the normal group. The abonormal functioning of T lymphocytes in exercise induced asthma, indicates a broad role that T cells are playing in regulating asthma syndrome.

Asthma is an abnormal condition which can be preventable to a large extent. For example, environmental pollutants should be avoided in the first place to diminish or possibly remove the cause that triggers the allergy. Also, knowing the type of asthma that a patient suffers from can help in prevention. For example, in the case of aspirin sensitive asthma, NSAID must be avoided.

Currently used effective pharmacological treatments include the following groups of drugs: ¹⁹

• Adrenoceptor stimulants (selective ß 2- stimulants, selective ß 2- agonists)
• glucocorticoids which inhibit inflammatory changes in airways
• theophylline which helps open airways and also prevents bronchitis
• cromones similar in action as glucocorticoids, but weaker
• anticholinergics which decrease airway mucus secretion.

ß2- receptor agonists stimulate cyclic AMP and inhibit release of substances (messengers) from inflammatory cells described previouslyleading to airway narrowing, i.e., leukotrienes, acetylcholine, bradykinin, prostaglandins, histamines and endothelins. ß2-agonists, particularly in inhaled form, are considered the first choice for severe asthma, and may be life saving. Adverse effects of this class of anti-asthmatic drugs include muscle tremor, palpitations and restlessness. ß2-agonists fail to reduce the inflammation in the airways, and may actually lead to increase in the inflammatory process.

Steroids (Glucocorticoids), are effective inhibitors of inflammatory messengers which directly or indirectly produce narrowing of the air passages. Glucocorticoids may also prevent expression of "inflammatory" genes. Evidence reveals that early application of inhaled steroids, when asthma is first detected, may improve lung function more than bronchodilator treatment. Unfortunately, therapy with steroids may result in serious local and systemic side effects. According to some reports steroids inhaled for 3 months increase the risk of glaucoma, cataracts, osteoporosis, growth suppression in children, skin disorders, oral candidiasis, and suppression of adrenal glands. Local deposition of steroids leads to irritation of vocal cords leading to dysphonia.

Theophylline is a third line of treatment for patients with asthma. This is used for the relief of bronchospasm. Theophylline may block the late inflammatory events after exposure to allergen, particularly by decreasing number of activated T lymphocytes. Decline in popularity of theophylline is due to its common side-effects in the form of nausea and headaches. Less common, but serious side effects of theophylline include irregularity of heart-beat and seizures.

Cromones have been credited with mast cell stabilizing (making them less susceptible to degranulation) and thus anti-inflammatory action, and are shown effective in controlling asthma induced by allergens, exercise, some drugs and sulfur dioxide. However inhaled cromones are less effective than inhaled glucocorticoid drugs. Sodium cromoglycate is used to prevent exercise induced asthma and also food allergy.

Anticholinergic drugs may be as effective in treating acute asthma as ß₂- agonists.

The drugs of significant promise in asthma that are now being tested and gradually becoming available include various inhibitors of leukotrienes biological expression. The leukotrienes are pivotal in asthma development since they are generated by virtually all inflammatory cells that are implicated in asthma, i.e. mast cells, eosinophils, basophils, macrophages, platelets and T cells. Leukotrienes exert several effects on air passages that results in syndrome of asthma. These effects include increased mucus secretion, attraction of the inflammatory cells, increased permeability of blood vessels, interference with neuronal impulse conduction, and airway smooth muscle proliferation. It seems that blocking the expression of leukotrienes in airways is particularly relevant in treatment of asthma. The following are the tested compounds currently to control leukotrienes biological expression²⁰.

• Agents blocking receptors for leukotrienes,
• 5-lipoxygenase inhibitors,
• 5-lipooxygenase-activating-protein inhibitors
• Phospholipase A2 inhibitors.

None of the existing treatments is curative and symptoms return soon after treatment is stopped. The consideration in selecting the most effective drug therapy for asthmatic patients include: efficacy of the drug, oral administration, convenience for patient, side effects, long-term outcome and costs of the treatment.




ANTI-ASTHMATIC HERBS
Ayurveda is an example of a long standing tradition that offers a unique insight into comprehensive approach to asthma management through proper care of the respiratory tract. This includes maintaining the nourishing functions of the lungs, in providing oxygen to the body. In Ayurveda, respiratory tract functions are interrelated with those of another organ that introduces nourishment to the body, viz., the stomach. It is believed there that phlegm humor or Kapha (which is one of the three basic humors) is produced in the stomach and then accumulates in the lungs. Correcting imbalances in the basic humors is critical to health and can be achieved through proper digestion and metabolism. Ayurvedic formulations used in the management of asthma therefore, judiciously combine herbs for breathing support with antioxidant herbs such as Curcuma longa, herbs to support the digestive, cardiac and nerve functions, expectorant herbs as well as soothing herbs. Ayurveda also recommends improving aeration to the lungs through Yogic breathing exercises or Pranayama. This simple exercise teaches breathing techniques for optimal aeration. The following points merit consideration:

• In the normal condition, a person at rest inhales air 12 times and exhales the air 12 times per minute. However, most of us do not expand the chest during the process of breathing-in, adequately enough to allow the expansion of the lungs.
• We instead use the diaphragm muscle preferentially (abdominal breathing) which does not ventilate the lungs sufficiently.
• Another reason for poor aeration of lungs is that we tend to rush the cycle of breathing in and out.
• The proper ratio should be exhalation for twice the time taken for inhalation.
• The most difficult part for those in Yogic training of breath is to have a steady exhalation, without holding the breath or experiencing a choking sensation.
• Proper breathing practice would not only help alleviate the symptoms of some pulmonary conditions like asthma, but would also help to improve circulatory abnormalities like hypertension as well as provide relief from mental stress and anguish.

In additon to the attention paid to the daily care for the respiratory tract (e.g. breathing exercises), Ayurveda offers materica medica which has been succrssfully used in the prevention and the treatment of respiratory tract condtions, some of which has been developed into sythetic compounds for the respiratory tract. Some of these herbs and their active chemical constituents are briefly mentioned here and discussed in detail in the later sections of this review.

Long pepper traditionally known in Sanskrit as Pippali has been used in Ayurveda and Unani medicine in the prevention and treatment of bronchial asthma.²¹

Adathoda vasica known in Ayurveda by its Sanskrit name Vasaka has been traditionally included in preparations for the relief of cough, asthma and bronchitis.²² The properties of alkaloid vasicine has been utilized in the development of the drug with brand name Bisolvon which chemically is a derivative of alkaloid vasicine. The clinical evaluation of Bisolvon (administered intravenously) confirmed that this drug can be useful in clearing the airways by decreasing the mucus secretion and opening the air passages. ²³

Tylophora indica (syn: T. asthmatica) Sanskrit - Anthrapachaka. The therapeutic properties of this herb were particularly well documented in the treatment of bronchial asthma. ²⁴

Boswellia serrata Sanskrit - Salai guggul. Boswellic acids derived from sap of the Boswellia tree are known to block the leukotriene biosynthesis by inhibiting enzyme 5-lipoxygenase. In addition, these compounds are proven to decrease the activity of human leukocyte elastase (HLA) in vitro, which may further limit the expression of leukotrienes. Although there is no clinical documentation available on the usefulness of boswellic acids in asthma, the anti-leukotriene mechanism of this compound merits to an inclusion in a new generation of anti-asthmatic nutraceutical.

Coleus forskohlii contains the diterpene derivative, forskolin, which may activate cyclic AMP. Forskolin has been successfully used in alleviation of experimentally induced asthma in human volunteers. ²⁵

The following components are normally included in the Ayurvedic approach to the management of asthma:

Essential components:

• Long term administration of pulmonary tonics to strengthen the lungs.
• Administration of relaxing expectorants to prevent the building up of sputum.
• Anti-spasmodic preparations to help mitigate the effect of the bronchospasm on the pulmonary muscles.
  

Ancillary components:

• Demulcents could be used to soothe irritation of mucous surfaces.
• Anti-microbial compounds would prevent secondary infections.
• Anti-catarrhals would prevent the overproduction of sputum in lungs or sinuses.
• Nervine support herbs are needed to enable adaptation to stress. Excessive stress or nervous debility may aggravate the symptoms of asthma.

Herbal forrmulations used in the management of asthma are prepared by combining herbs, which provide the above characteristics.

The medicinal properties of Adhatoda vasica Nees (Natural Order : Acanthaceae), called Vasa or Vasaka in Sanskrit, have been known in India and several other countries for thousands of years. The plant has been recommended by Ayurvedic physicians for the management of various types of respiratory disorders.²⁶

The leaves of the plant were found to contain an essential oil and the quinazoline alkaloids vasicine, vasicinone and deoxyvasicine. The roots contain vasicinolone, vasicol, peganine and 2’-hydroxy-4-glucosyl-oxychalcone. The flowers contain b-sitosterol-D-glucoside, kaempferol and its glucosides, as well as the bioflavonoid, namely quercetin.²⁶

The leaves are used in the treatment of respiratory disorders in Ayurveda. Research performed over the last three decades revealed that the alkaloids, vasicine and vasicinone present in the leaves, possess respiratory stimulant activity.^27,28 Vasicine, at low concentrations, induced bronchodilation and relaxation of the tracheal muscle.²⁸ At high concentrations, vasicine offered significant protection against histamine induced bronchospasm in guinea pigs. Vasicinone, the auto-oxidation product of vasicine has been reported to cause bronchodilatory effects both in vitro and in vivo.²⁹ In another study, vasicine showed appreciable bronchodilatory effect and marked respiratory stimulant activities whereas vasicinone showed relaxation of the tracheal muscle in vitro and bronchoconstriction in vivo.³⁰ Of the two alkaloids, vasicinone was found to be more potent than vasicine, with potential anti-asthmatic activity comparable to that of disodium cromoglycate.

Vasicine	Vasicinone

Preclinical Studies
A detailed preclinical study performed to assess the pharmacological effects of vasicine and vasicinone, revealed that the two alkaloids in combination are potentially useful in the management of respiratory problems. The authors²² reported that vasicinone has a synergetic effect on vasicine in the bronchiodilation, as well as an increase in ciliary movements. It was also observed that the cardiac depressent effect manifested by vasicine was corrected by vasicinone. Vasicine and vasicinone mixed in 1:1 ratio showed more bronchodilatory activity and antagonism against histamine-induced bronchoconstriction as compared with vasicine alone or theophylline. The authors concluded that the two alkaloids in combination are effective bronchodilators in anti-asthmatic formulations and the respiratory stimulant action of vasicine is mediated mainly by its action on the respiratory center and peripherally through the chemosensory fibers (by release of the neurotransmitter acetylcholine).²² Animal studies also revealed that vasicine and vasicinone up to 10 mg/kg intravenously did not show any inhibitory activity on the cough reflex induced by irritating the tracheal mucosal surface³⁰.

Subsequent studies confirmed the bronchodilatory effects of Adhatoda vasica. The alkaloids from this plant were found to offer pronounced protection against allergen-induced bronchial obstruction in guinea pigs when administered at the dosage of 10 mg/ml of aerosol.³¹

Although the precise mechanism of action of the Adhatoda vasica alkaloids remains to be elucidated, these compounds are potentially useful phytochemicals in the management of allergic disorders and bronchial asthma³². Adhatoda vasica is also accredited with antimicrobial properties with proven in vitro action against Mycobacterium tuberculosis³³ and reduction of gingival inflammation³⁴. Vasicine hydrochloride possess significant thrombopoetic action in animals and potential use in the the management of hemorrhagic disorders³⁵.

Tylophora asthmatica (Natural Order Asclepiadaceae) is a dark copper colored delicate creeper found growing wild in the plains of India and other sub-tropical regions of the world.³⁶

The medicinal properties of the plant have been known since ancient times. The roots of the plant have been employed as a substitute for Ipecacuanha in the treatment of respiratory troubles. Powder from the dried leaves, root powder, decoction of the leaves or infusion of the root bark have been used traditionally in the treatment of respiratory afflictions such as chronic bronchitis and asthma³⁷. In recent years, the leaves have been used in the treatment of bronchial asthma, based on the use of the plant in Ayurvedic medicine. Preparations containing dried, powdered plant material are available for the treatment of bronchial asthma and tropical eosinophilia.

The anti-asthamatic activity of the plant is attributed to the presence of phenanthroindolizidine alkaloids. An alkaloid mixture (0.17%) has been isolated from the aerial parts of the plant .³⁸

Tylophorine, the major alkaloid, has been studied extensively. The presence of tylophorine in the roots of the plant was first described in 1891. Subsequently, two crystalline alkaloids tylophorine and tylophorinidine were isolated.

Tylophorine

Preclinical studies
The mode of action of the leaf of Tylophora asthmatica as well as its alkaloids tylophorine and tylophorinidine has been studied in experimental animals.

A water extract of the plant was administered intraperitoneally to sensitized guinea pigs challenged with egg albumin-induced anaphylaxis. The extract showed anti-anaphylactic effect, leucopenia and inhibition of Schultz-Dale’s reaction in experimental animals⁴². The lymphocytes and eosinophils were found to be markedly reduced. The extract also showed brief, nonspecific anti-spasmodic action in isolated tissues of guinea pig ileum, rabbit duodenum, frog rectus and rat stomach wherein contractions had been induced by the administration of spasmolytic agents. Furthermore, the authors of this study postulated that the utility of this plant in the treatment of bronchial asthma could be attributed to its action on cell-mediated immunity⁴².

Dhananjayan and his co-workers⁴³ conducted an extensive study on the pharmacological effects of the plant. They observed that the plant extracts produced muscle relaxant effect, antagonism of smooth muscle stimulants and immuno-suppressive effects in different species of laboratory animals. In another study, pre-treatment with the plant extracts prevented bronchospasm induced by Freund’s adjuvant and bovine albumin in rats⁴⁴.

The plant extracts were also found to produce significant anti-inflammatory effects in rats. The inflammatory models tested included adjuvant arthritis, hind-paw edema, granuloma pouch and cotton pellet-induced edema⁴¹. In a detailed study that sought to examine the anti-inflammatory activity of various plant extracts used in traditional medicine, edema was induced in the right hind paw of Swiss albino mice by sub-cutaneous injection of 0.05 ml of 3% l-carrageenan. Extracts of Tylophora asthmatica were administered intraperitoneally, one hour before paw injection. The inhibitory effect of the extract on inflammation was compared with that of phenylbutazone, a well-established and highly toxic, but effective anti-inflammatory compound (80 mg/kg intraperitoneally administered). Tylophora asthmatica extract significantly inhibited edema. A comparison of the inhibitory effects of the extract with those of phenylbutazone is shown in Figure 5 ³⁹.

Figure 5: Comparison of the anti-inflammatory effects of Tylophora asthmatica extract and phenylbutazone

The effects of the alcoholic extract, the petroleum ether fraction and the aqueous fraction of the alcoholic extract of Tylophora asthmatica on weight of the adrenal gland and its functional activities were studied. The sites of action of Tylophora asthmatica on the pituitary-adrenal axis were determined, based on these results. The assessment was performed in terms of vitamin C content, plasma steroid and hydroxyproline content in skin.

All extracts showed similar actions (i.e. stimulation of adrenals as indicated by increase in weight and decrease in cholesterol and vitamin C contents). The plasma steroid level was increased, but skin hydroxyproline levels were not conclusive. Tylophora asthmatica was found to antagonize dexamethasone / hypophysectomy-induced suppression of pituitary on the activity of the adrenals. The authors of the study concluded that Tylophora asthmatica may act by a direct stimulation of the adrenal cortex⁴⁰. It is therefore probable that the immunosuppressive and anti-inflammatory effects are due to increased secretion of corticosteroids by the direct effect of Tylophora asthmatica components on the adrenal cortex⁴⁰.

Clinical studies
Several studies confirmed the value of Tylophora asthmatica in the treatment of bronchial asthma and allergic rhinitis. Through an unique combination of anti-inflammatory action and immunosuppressive effects, Tylophora asthmatica extracts mitigate the inflammatory as well as allergenic symptoms of asthma, providing prolonged relief to the sufferers. The plant has been reported to be beneficial in preventing from asthma attacks, rather than in controlling acute attacks⁴³.

The effect of Tylophora asthmatica on bronchial tolerance to inhalation challenges with specific allergens has also been investigated⁴⁵. To study the protective effects of Tylophora asthmatica, thirty one asthmatic patients having positive bronchial sensitivity to an antigen were treated with Tylophora asthmatica (one leaf per day for six days), prior to challenge with the antigen. Twenty-nine of the patients were followed up. They received repeating antigenic challenges every seven to ten days. These antigens exemplified atmospheric pollutants, insect fragments and fungal spores, commonly believed to trigger allergic reactions in individuals. Of the nine patients, eight continued to show protection up to 9 days, seven up to 15 days, six up to 22 days, four up to 34 days, three up to 38 days and one up to 48 days after treatment with Tylophora asthmatica⁴⁵. The scientific confirmation of its efficacy was obtained from both open and double-blind, cross-over trials⁴⁶. One group of researchers reported that the administration of one raw leaf daily for six days or 40 mg of alcoholic extract daily, for six days, gave the patient with bronchial asthma relief which lasted for several weeks. A subsequent double-blind study using powder of the dried leaf of Tylophora asthmatica revealed significant effects only in patients with the perennial type of asthma⁴⁸.

Detailed physiological (lung function) studies with Tylophora asthmatica in the treatment of bronchial asthma were performed⁴⁷. The effects of the plant were compared with those of the known bronchodilator agent, isoprenaline. Lung function tests were compared in 18 normal persons and 11 bronchial asthma patients. The lung function tests performed included the measurement of tidal volume, vital capacity, timed vital capacity, compliance, maximum ventilatory volume and peak expiratory flow rate. For comparative purposes, isoprenaline (10 mg tablet) was administered sublingually and Tylophora asthmatica was given in the form of capsules containing 100 mg of the dried leaf powder for six days, with a daily dosage of two capsules per subject. The lung function tests were performed immediately after administering isoprenaline, and on the seventh day after commencement of treatment with Tylophora asthmatica. To test the adrenocortical function, urinary 17-ketosteroids levels and absolute eosinophil counts were determined in normal subjects and bronchial asthma patients before and after the administration of Tylophora asthmatica. Tylophora asthmatica produced significant improvement in lung functions, as evidenced by the results of the lung function tests. Four significant parameters are represented in Figure 6.

The mean value of 17 ketosteroid excretion in the urine after Tylophora asthmatica administration, was significantly different both in normal individuals as well as in asthmatics. The eosinophil count decreased on treatment with Tylophora asthmatica (Figure 7).

Boswellin®
The role of 5-lipoxygenase inhibiting phytonutrient in the management of asthma

Recent studies show that asthma, even in its mildest form, is also an inflammatory disease mediated by leukotrienes. The use of antileukotrienes in managing this condition is therefore being emphasized by the medical research community in recent years. However, although the pharmacological agents currently available for the treatment of asthma are effective in controlling symptoms in an acute attack, they do not eliminate the root cause, leading to recurrent attacks. Recently, the Food and Drug Administration approved a "once-a day asthma pill", Singulair (montelukast sodium) for the prevention and treatment of chronic asthma. This drug works by blocking leukotrienes which are involved in the inflammatory processes associated with asthma⁴⁹.

Histamine release and leukotriene synthesis are common factors in the development of both allergies and asthma. However, in asthma, leukotriene levels, or more accurately, the ratio of leukotrienes to prostaglandins play a dominant role, whereas allergic reactions are primarily mediated by histamine.

Antileukotrienes have found success in clinical trials in the management of asthma. They have shown activity in various models of asthma including exercise-induced, cold-air hyperventilation-induced, allergen-induced and aspirin-induced bronchial constriction. Working synergistically with inhaled b₂-agonists, anti-leukotrienes produced reduction in asthma symptom scores, improvements in air flow obstruction and reduction in the rescue use of inhaled b₂-agonists. In addition, the antileukotrienes partially reverse spontaneous bronchoconstriction in asthmatic patients to be combined with the effects of inhaled b₂ agonists. Clinical trials have shown marked relief from the following:

• Reduction in asthma symptoms scores
• Improvements in air flow obstruction
• Reduction in the use of inhaled b₂ agonists .

Experiments reveal that inhibition of leukotriene synthesis has a beneficial effect in the treatment of both induced and spontaneous asthma. In addition, clinical studies validate the efficacy of several antileukotrienes in the management of asthma⁵⁰. Plant extracts which function as inhibitors of leukotriene synthesis by inhibiting the lipoxygenase enzyme are currently being explored. Of these, boswellic acids obtained from the gum resin of Boswellia serrata (Boswellin^®) offer the most promising phytonutritional approach as antileukotrienes. This facet of the pharmacological activity of boswellic acids was first observed in an in vitro search for new plant constituents with potential antiphlogistic and antiallergic activity. Boswellic acids were proven to be the most potent inhibitors of the classical component pathway of the inflammatory response, producing 100% inhibition at a concentration of 0.1mM³². Boswellic acids appear to be specific inhibitors of leukotriene formation, functioning by inhibiting the activity of the enzymes which leads to their formation. Boswellic acids are therefore effective in the prevention and/or control of inflammatory processes, which are typically characterized by increased leukotriene formation⁵¹.

Studies on the anti-inflammatory mechanism of boswellic acids indicate that their primary site of action is inhibition of the 5-lipoxygenase enzyme, preventing the formation of inflammatory leukotrienes. The role of boswellic acids in the arachidonic acid cascade is indicated in Figure 8⁵³.

Figure 8 Formation of leukotrienes from arachidonic acid

Boswellic acids have been found to inhibit leukotriene synthesis via inhibition of 5-lipoxygenase, but did not affect the cyclooxygenase activities. Therefore, they had no effect on the synthesis of prostaglandins.⁵²

An extract of Boswellia serrata inhibited leukotriene LTB₄ formation in the suspension of white blood cells derived from rat. White blood cells are involved in the inflammatory reactions in many ways, and are the site where the inflammatory substances like leukotrienes are produced. This experiment shows the relationship between inhibition of the enzyme 5-lipoxygenase and the anti-inflammatory activity excreted by the extracts of Boswellia serrata gum.

Recent studies revealed that in addition to this mechanism, boswellic acids also decrease the activity of human leukocyte elastase (HLE). HLE is homologous to pancreatic serine proteases including the active site and is specific for elastin which is a predominant protein of structures that are elastic in nature like large blood vessels. The presence of HLE in leucocytes correlates with their phagocytosis and digestion of bacteria, antigenic proteins and cellular debris. This dual action was found to be unique to boswellic acids. Because leukotriene formation and HLE release are increased simultaneously by neutrophil stimulation in a number of inflammation and hypersensitivity-based human diseases, the authors of this study purpose that the reported blockade of two proinflammatory enzymes by boswellic acids might be the rationale for their anti-allergic/anti-asthmatic activity.54

Coleus forskohlii belongs to the Natural Order Labiatae (Lamiaceae), a family of mints and lavenders. The plant is the only known natural source of the unique adenylate cyclase activating drug, forskolin. Forskolin helps to enhance the production of compounds that relax the bronchial muscle⁵⁵. Double blind studies have revealed that the herb is as effective as the drug fenoterol, without the side effects. The interest in alternative medications for the management of asthma was triggered by the suggestion that b₂-adregenic receptor agonists given by metered dose inhaler may have contributed to an increase in the incidence of death and near death from asthma⁵⁶. Therefore, compounds working through another mode of action or acting locally alone may result in a greater safety margin.

Coleus forskohlii contains forskolin a 7b-acetoxy-8,13-epoxy-1a,6b,9a-trihydroxylabd-14-en11-one (diterpenoid compound) which directly activates adenylate cyclase. Research carried out over the last few decades has revealed the multi-faceted pharmacological effects of forskolin. Most of these effects have been linked to the role of forskolin as an activator of adenylate cyclase. The spectrum of potential therapeutic activities is represented in Figure 8 ⁵⁷:

Figure 9

In this context, the pathophysiological mechanism of asthma has been speculated to involve a reduction in the number of b-receptors. As forskolin acts directly on adenylate cyclase, bypassing these receptors, its efficacy would not be influenced by the number of b-receptors⁵⁸.

Forskolin
Preclinical studies
Forskolin by virtue of its ability to activate adenylate cyclase has also been proven to promote the production of steroidal hormones in vitro in rat adrenal cells. Forskolin stimulated corticosterone production and potentiated the steroidogenic action as low concentrations of ACTH (adrenocorticotropic hormone)⁵⁹. As corticosteroids are used in the management of asthma, this finding also validates the use of forskolin as an anti-asthmatic agent.

Forskolin was studied for its effects on the tone of airway smooth muscle and the immunological release of leukotrienes and histamine. The bronchospasm induced by a model antigen, 0.5% ovalbumin in sensitized guinea pigs was prevented in a dose-related manner by intravenous or intratracheal administration of forskolin. Forskolin was 100 times more potent than aminophylline by the i.v. and intratracheal route to reverse an established allergic bronchospasm. Forskolin given intratracheally also inhibited the bronchospasm to i.v. histamine with a short duration of action. An in vitro study revealed that forskolin (< 1mM) inhibited contractions of lung parenchyma provoked by LTC₄ or antigen. Forskolin 1 mM also inhibited the immunologically stimulated release of LTD₄ and histamine from LTC₄ or antigen. In sensitized guinea pigs, forskolin (1 mM) inhibited the immunologically stimulated release of LTD₄ and histamine. The authors of this study concluded that the predominant effect of forskolin in vivo is probably related to a direct effect on airway smooth muscle producing bronchodilation⁶⁰.

Clinical studies
In vitro studies demonstrated the property of forskolin to inhibit the release of mediators in the human hypersensitivity reaction. Forskolin (10^-7 to 3x10^-5 moles) caused dose-related inhibition of antigen-induced histamine release from human basophil leukocytes. This inhibition was paralleled by a increase in cyclic AMP levels in human leukocyte preparations, potentiated by forskolin. The authors of this study also evaluated the effects of forskolin on histamine release (induced by antigen) from human lung tissue which was sensitized using serum from an allergic patient. Forskolin inhibited the release of histamine from human lung mast cells in a dose dependent manner. It was therefore concluded that forskolin probably modulated the release of mediators of the immediate hypersensitivity reaction through activation of adenylate cyclase in human basophils and mast cells⁶¹. A recent in vitro study employing human peripheral blood basophils demonstrated that forskolin, functioning as a phosphodiesterase inhibitor, significantly suppressed the release of the cytokines interleukin (IL-4 and IL-13) which are secreted by the basophils after cross-linking of cell surface immunoglobulins. This finding validates the capability of forskolin to regulate the release of cytokines⁶².

In another study, six male extrinsic asthmatics were challenged with methylcholine, a reversible bronchoconstrictor resulting in a fall of 30% or more in expiratory volume per second (FEV₁). When the subjects inhaled subsequently from a nebulizer containing 1 mg and 5 mg of forskolin, the respiratory volume rose and the airways resistance decreased in all six patients. There was no significant difference between the efficacy of the 1 mg and 5 mg dose, as shown in Figure 10(a) and 10(b) ²⁵.

Figure 10(a): Effect of forskolin inhalation on expiratory volume in one sec. (FEV₁) after methacholine provocation

Figure 10(b): Effect of forskolin inhalation on airway resistance after methacholine provocation.

Inhaled forskolin has been proven to be effective in increasing airway caliber. In view of these effects, the efficacy of inhaled forskolin dry powder in 16 patients with bronchial asthma was studied. A randomized , double-masked, placebo-controlled, four period cross-over trial was conducted for a 120 minute period. This trial compared the airway and tremor response, cardiovascular and potassium depleting effects of forskolin with a conventional bronchodialator, fenoterol. Fenoterol was administered in the form of single dose inhalative dry powder capsules (0.4 mg) and metered dose inhaler (0.4 mg) while forskolin was administered as dry powder capsules (10.0 mg).

All three administrations resulted in a significant increase in specific airway conductance (p < 0.05. However, forskolin dry powder capsules caused less side effects as compared to fenoterol inhaler/capsules. These side effects included marked increase in finger tremor amplitude and decrease in plasma potassium. Forskolin dry powder capsules resulted in measurable bronchodilation in patients with asthma. The onset of the effect was as rapid as the onset with the fenoterol dry powder capsules; the maximum was reached within the first five minutes. The authors of this study concluded that forskolin may offer greater safety advantages in view of its localized action and the fact that tachyphylaxis may be overcome by bypassing the surface receptor in the case of a defect in the b-adrenergic receptor. There are no clinical reports of other drugs acting directly on the catalytic subunit of the adenylate cyclase system with sufficient relaxation of the bronchial smooth muscle in patients with asthma ⁶³.

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