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Every individual is susceptible towards variety of infection in their life time. Infections may be chronic or Persistent. Among the several microorganisms that invade host cell in order to grow and replicate, viruses are prime causative agents for majority of Persistent infections cases. There are several openings through which virus invade the host cell like mouth, eyes, genital, nasal openings. Nasal and Mouth opening constitutes Nose, Larynx, Pharynx, Trachea, Sinuses which are collectively termed as Upper Respiratory Tract (URT) . Infections caused by virus in URT are due to growth of pathogen at entry site. Viruses responsible for causing chronic infections to upper respiratory tract include Rhinovirus, Par Influenza virus, Corona virus, Adenovirus, Respiratory syncytial virus, coxsackievirus, and influenza virus. Infection to URT by virus leads to severe Sore throat, Common cold, Influenza, Sinusitis and Croup. Symptoms for above disorders are nasal blockage, sore throat, discharge, sneezing . Human body has several defense mechanisms to combat incoming pathogens. When natural mechanism of human body fails to combat against pathogens we opt for other artificial therapy or remedies such as homemade therapy, antiviral drugs and homeopathic remedies. Those treatments follow several mechanisms to fight against viral infections which are discussed in detail below.
Upper respiratory tract infections are one among leading conditions for which no particular bullet to hit the target pathogen is available. This is because most of URT infections are self replicating and viral in origin and viruses due to its unique cell structure, different metabolic pathways than bacteria remains unaffected by antibiotics. Moreover virus remains integrated with host cell and antimicrobial drugs don't target host cells . However patient's expectation and pressure forced physician for frequent prescription of antibiotics. According to the estimates of a survey conducted by National center for health statistics of United States approximately 75% of patients suffering from conditions like Sinusitis, Bronchitis, Pharyngitis or non-specific URTIs are being prescribed with antimicrobials. From the statistics of survey conducted among general populations of Germany 18% and 64% of patients with common cold and sinusitis respectively out of 1,076 patients were prescribed antibiotics. This unnecessary prescription has contributed largely towards antibiotic resistance and increase in number of infections without any available treatments [4, 5].
2.2 ALTERNATIVE TO ANTIBIOTICS
URT infection can only be diagnosized basing on their typical symptoms. Since most of the disorders are of viral in origin hence antibiotics proves to be ineffective in treatment of respiratory infections. Drugs are prescribed to suppress the symptoms not to destroy the pathogens. However immune system is capable of fighting off the viruses so basic principle followed in treatment of viral infections is to enhance the cell immunity so that body can resist viral attack. Physicians often recommend supportive treatments that help in recovery from illness .
1. Drinking plenty of water which helps to get rid of waste material which is created during body fighting infections.
2. Taking rest helps in repair of cells damaged in infections and provide energy to complete the same above process.
3. Decreasing the intake of sugars and carbohydrates as those lowers the body's ability to fight infections.
4. Avoiding Stress helps to boost body's ability to combat pathogens.
2.3 HERBAL TREATMENT
Use of herbal medicines and remedies has gained widespread acceptance for viral infections to upper respiratory tract. According to recent survey about 37% of Americans prefer herbal treatment for cold and flu and 12% of Australians from 3000subjects use herbal medicines. Some of major compounds involve Echinacea and Andrographis Peniculata (Kalmegh), Eleuthero and other supportive compounds include ginger, garlic, golden seal and slippery elm . Echinacea derived from Echinacea purpurea in which major constituents include flavonoids, polysaccharides, alkylamides, chicoric acid glycosides and polyacetylenes (Figure 2.3). A recent controlled trial of 120 patients reported that symptoms and severity of infections reduced significantly. It also acts as excellent immune stimulant by activating WBC . Eleutherococcus senticosus shows adaptogenic activity that is it helps the body to adapt stress. Reduction in stress related illness helps in long term management of various disease of immune system. Ability to strengthen the immune system it has been recommended as one of most efficient remedy for cold and flu . Andrographis peniculatum is a popular agent in Scandinavia as cold and influenza remedy in thai and Chinese medicine. Pharmacological studies suggest andrographis has number of bitter constituent's which makes it antipyretic, antiviral, immunostimulatory agent. It helps to reduce symptoms of individuals suffering from common cold .
Figure 2.3 Echinacea purpurea
2.4 MECHANSIM OF ACTION OF ECHINACEA
Echinacea proves to boost immune system by stimulating production of WBC in addition it leads to increase in the production of interferon which is important in immune response to viral infections. It has potential impact on thymus and activation of T cells. A chemical component of Echinacea called Inulin helps to stimulate the macrophage to release interferon and other immune enhancing compounds such as interlukin and tumor necrosis factor . Another polysaccharide component Echinacin B helps in neutralizing Hyaluronidase which is released by virus during the entry into blood in order to break down the connective tissue made of Hyalauronic acid that surrounds cell so that it can spread infections. The inhibition of hyaluronidase activity is due to bonding of the chemical constituent with hyaluronidase in some way resulting in temporary increase in integrity of barrier. This anti hylauronidase action is combined with regeneration of connective tissue destroyed in infections [11, 12].
2.5 ANTIVIRAL DRUGS
Viruses are comparatively smaller than bacteria hence there are only limited number of metabolic functions that anti-viral drugs can target. Various antiviral drugs works by various principles which include viral cell susceptibility, viral attachment and receptor blockade, viral uncoating, viral RNA replication, and viral protein synthesis. Basic function includes strengthening of immune response to viral infection. Drugs include several types of modified interferon, immunoglobulin and vaccines. Drugs used to relieve cold symptoms are Decongestants, Antihistamines and Cough syrups. Anti-inflammatory drugs contribute relaxation . Currently only 3 agents available for the treatment of viral respiratory tract infection, Amantadine and Rimantadine for influenza A, and Ribavirin for respiratory syncytial virus infection. Among novel antiinfluenza agents zanamivir and oseltamivir is widely approved drug. Pleconaril (WIN 63843) licenced to viropharma, a newly discovered drug against rhinovirus and Picornavirus infections. However this drug is in preclinical stage. Another compound AG-7088 have similar anti-rhinoviral activity to pleconaril. Another new generation drug Tremacamra has inhibitory effect on rhinovirus. It is produced by genetic engineering of ICAM-1 receptor, which has been truncated and made soluble [14, 15]. A detailed explanation of chemical components of virus cell wall described below will help to get a deep insight into the mechanism of action of drugs on infections.
2.6 URT INFECTION BY INFLUENZA VIRUS
A viral particle called virion surrounded by envelope which has a protein sticking through it which mediates the viral entry to host cell. The protein capsid is overlayed by lipid and protein layer. The protein capsid is made of M1 protein which is virus own protein and lipoprotein which is stolen from outer host cell while budding out of infected cell. This envelope has protein spikes with sugars attached to it. This protein-sugar combination is called Glycoprotein. The virus has 3 primary glycoprotein involved in attachment Hemagglutinin (HA), Neuramidase (NA) and M2 (Figure 2.6). The immune system recognizes them and prepares antibody against them. There are 16 broad immune classes of HA glycoprotein and 9 NA glycoprotein. The hemagluttinin plays a key role in virus attachment by binding to sialic acid in epithelial membrane allowing for penetration. Neuramidase helps in penetration of virus through pharyngeal mucus layer into host cell. Amantidine and Rimantidine are two drugs used against influenza from time before its effects were known. Their mode of action is by inhibiting action of M2 protein. . The detail mechanism of action of drugs is described below.
Figure 2.6 Schematic diagram of External structure of influenza A virus with viral proteins.
2.7. MECHANISM OF ACTION OF AMANTIDINE AND RIMANTADINE
Figure 2.7.1 shows how virus enters inside host cell and regulates its replication. However to spread infections virions need to unwrap itself and release its disease causing genes into nucleus of host cell. The hemagglutinin is the main culprit which mediates the attachment of virus to respiratory epithelial cells through a receptor binding site. The host cell has a receptor molecule made of glycoprotein chain having a side chain tipped with particular kind of sugar called sialic acid. The specific sialic acid in human cell is N-Acetylneuraminic acid(NeuAc) which when attached to cell glycoprotein via another sugar called galactose makes it a potential site for attachment of influenza A virus (Figure 2.7.2) . Once the virus makes attaches it to host it regulates its entry through endosome. Among the three glycoprotein in virus the drugs target the M2 (Matrix) protein which regulates opening of ion channel permitting H+ ion to enter the virion. This resulting acidic environment causes the unwrap of virion which is necessary for replication of virus. Role of amatidine is to inhibit the M2 protein and thus stops the replication process. (Figure 2.7.3) .
Figure 2.7.1 Mechanism of entry of virus into host cell
Figure 2.7.3 Blockage of ion channel by amatidine Figure 2.7.2 Virus binding to cell surface
2.8 URT INFECTIONS BY RHINOVIRUS
Rhinovirus is the leading agent causing common cold. These belong to family Picornaviridae. The viral capsid contains 4 proteins VP1-VP4 arranged in 60 protomeric units. Destabilization of VP4 results in viral uncoating. X-ray crystallographic studies have resolved the atomic structure of rhinovirus. It reveals there is a deep cleft or canyon in center of each protomeric unit into which receptor molecule binds (Figure 2.8.1) . Pleconaril (3-(3,5-dimethly-4-[[3-methyl-5-isoxazolyl)propyl]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole) has high anti-rhinovirus and anti-picornavirus effect. This is due its ability to bind to canyon and inhibit several major functions of rhinovirus. It is a novel drug for treating rhinovirus infection by viral uncoating which leads to inhibition of viral replication and by viral attachment to host cell receptors, blocking transmission of infectious virions .
Figure 2.8.1 X-ray crystallographic view of arrangement of proteins in rhinovirus capsid.
2.9 MECHANISM OF ACTION OF PLECONARIL ON RHINOVIRUS
Pleconaril is orally bioavailable systemically acting small molecule inhibitor of rhinovirus. It is in late clinical trial due to several complication which is discussed in detail later in this report. Pleconaril are also known as Win compounds whose in vivo activity against rhinovirus starts by targeting viral proteins. Pleconaril has high affinity towards rhinovirus receptor binding site due to number of noncovalent, hydrophobic interactions it makes with side chains of the capsid of aminoacids within the cleft of rhinovirus . Win compounds coordinate its action by binding to hydrophobic pockets formed by beta barrel of VP-1 underneath the floor of canyon (Figure 2.9.2).
Figure 2.9.2 X-ray crystallographic view of Integration of Win compounds into canyon
This integration of pleconaril into hydrophobic pockets results in increasing the stability of virus making the virus more resistant to uncoating. This binding also results in reducing capsid flexibility inducing a more rigid structure of canyon. This mechanism put an effect in changing the conformation of canyon floor hence affecting the attachment of virus to host cell receptor (Figure 2.9.3) [22, 20].
. Figure 2.9.3 Conformation change of receptor Binding site due to action of drug.
2.10 SYMTOMATIC MEASURES FOR TREATMENT OF COMMON COLD
Along with the prescription of antimicrobials or antibiotics some physicians believe to prescribe some additional drugs to help relieving the symptoms of rhinovirus infections not to eliminate the pathogens. Those include:
Decongestants- There are 2 classes of decongestants Sympathomimetic amines and Imidazolines. Most popularly used drug is pseudoephedrine among symathomimetic amines. These are alpha-andrenergic agents which affects the intranasal blood vessels by their vasoconstrictive actions. They help to reduce excessive nasal drainage and relieve vascular nasal obstruction . These drugs mimic the action of symphathetic nervous system whose main function is to make release of norepinephrine (noradrenaline) into neuronal synapse from strong vesicles in presynaptic neurons. This displaced norepinephrine binds postsynaptically to alpha1 receptors causing activation of alpha-adrenergic receptor located in nasal mucosa, on the muscles lining the walls of blood vessels. Activated receptor now causes contraction of muscles which leads to constriction of blood vessels in nasal passages allowing less fluid to enter the nose, throat and sinus thus resulting in decreased mucus production and inflammation of nasal passages. However probable side effects include hypertension a symptom of rhinitis caused due to excessive intake of decongestants [23, 24].
Antihistamines- These are frequently used drugs for treatment of nasal allergies due to its anti sedative and anticholinergic mode of action. Generally histamines are prescribed along with decongestants which act as H1 receptor antagonist. It competes with histamines released by dead cells for receptor site on the effector cells of respiratory tract. This provides relief from first stage of allergic response by blocking histamine binding to cell receptor in the sense inhibiting sedative effect (Figure 2.10.2) .
Figure 2.10.2 Mechanism of action of histamine
Antitussives and Expectorants - These are the drugs used for removal of mucus and to stop or reduce coughing. Antitussives include dextromethorphan and codeine which acts by stimulating medulla oblongata of CNS a prime center which is responsible for coughing. As several evidence supports cough occurs when sensory receptors in the airways are stimulated by mechanical and chemical stimuli which include accumulated mucus and other irritant. Stimulation of sensory receptors causes transmission of impulses to cough center in medulla along afferent nerve pathways. This impulse then transmitted to abdominal, intercoastal muscles and diaphragm through efferent or motor pathways which results in cough reflex. The aforementioned drugs act on this cough reflex pathway and paralytic agents that block neuromuscular signal transmission .