| Viral diseases hold a special and important position in the long history offighting against infectious diseases, of which respiratory infectious diseasesare the most prominent. Since the winter in 2002, the epidemic of SARS inthe world and the frequent infection of avian influenza virus in Hong Kongand Southeast Asia have caused serious losses in human health, nationalsecurity and economic development. The epidemic of SARS virus is usuallyaccompanied by the infection with other acute upper respiratory tract viruses.As shown in Table 1, the viruses causing acute upper respiratory tractinfection (common cold) in adult belong to five families and are of more than200 types, excluding those causing systemic infection through respiratory tractor those causing respiratory tract infection in the patients with immunologicdeficiency. However, 70%-80% of common cold in adult is caused byrhinovirus, coronavirus, parainfluenza virus and influenza virus. At present,influenza is mainly caused by influenza virus types H3N2, H1N1 and B.Table 1 Viruses causing respiratory tract infection in humans (2003)Up to now, so many respiratory tract infections can only be prevented bynon-specific measures but not by vaccination. Human interferon is a kind ofnatural protein against viral infection. Since human interferon α2a and α2bwere firstly approved to be put into market in USA in 1986, interferon hasbeen used in more than 50 countries or regions in the world for the treatmentof more than 40 diseases, including viral diseases, neurologic diseases andmalignant tumors. Of the current interferon preparations, recombinantinterferon α2b is most widely used in the world, of which most experiences inapplication are accumulated. As an immune modulator which can not causedrug-resistance, interferon has unique advantages as compared withchemically synthetic drugs. Interferon is a kind of protein with broad spectrumantiviral, anti-cytodiaeresis and immuno-regulatory activities, which caninfluence the metabolism, growth and differentiation of cells by differentroutes. The basic study and clinical trial during the past 50 years provedinterferon as an important drug with antiviral and anti-tumor effects.The action mechanism is binding to specific cell receptor and activatingthe expression of cell gene by signal transduction.1.Antiviral activity: Interferon can inhibit the replication of viral gene.2.Anti-cell proliferation activity:Interferon can cause the change of cellmembrane and cytoskeleton, stimulate cell differentiation, regulate theexpression of growth factor, inhibit the expression of cancer gene, reverse thephenotype of deteriorative cells and activate the expression of p53 gene.3. Immuno-regulatory activity: Interferon can induce the expression ofother cytokines, activate macrophage and NK cells, positively regulate theexpression of HLA I and II and regulate the expression of tumor-relatedantigen.There are various types of interferon with different characters andpotential clinical effects, such as interferon-α,β,δ,γ,ε,κ, λ,τ,ω and limitin, ofwhich interferon-α, β and γ have been applied in clinic, and the other typesare still in study.Because of its large relative molecular weight and low fat-soluble,recombinant human interferon α2b is difficult to pass through the biologicalmembrane, so it is administered by injection in general. However, injection isinconvenient to the patients. It is necessary to develop a non-injecting route ofinterferon.As reported in documents, the non-injecting routes of polypeptide drugsinclude intranasal, respiratory, eye drip, sublingual, oral, rectal, vaginal andpercutaneous routes et al., of which percutaneous, nasal and respiratory routesare deeply studied.There are a plenty of capillary and lymphatic vessels in nasal cavity.The nasal epithele is closely connected to the wall of blood vessel, and theintercellular space of epithelial cells is large, resulting the high permeability ofnasal cavity in which the first pass effect of drug can be avoided. The proteasecontent in nasal cavity is also low as compared with those in stomach orintestine, so the drugs with low relative molecular weight are very easy to beabsorbed and to go into blood circulation. The polypeptide with high relativemolecular weight, such as calcitonin, insulin, G-CSF and EPO, can also beabsorbed with the help of appropriate absorbefacient agents. However, theirbioavailability is low. The nasal routes of drug include drip and spraying. Thebioavailability of drug by nasal spraying route is relatively high.The effectiveness and safety of recombinant human interferon a2b bysubcutaneous, intramuscular or local injection have been proved. Thepreparation of recombinant human interferon a2b for external use is more safethan that for internal use. However, there are three problems to be solved inthe development of interferon for external use, i.e. effectiveness, stability andstimulation to local mucosa.As reported in documents, the effect of recombinant human interferona2b spraying last for at least 24 hours in nasal cavity and about 17 hours inrespiratory tract. After administration by nasal/oral spraying, interferon isadsorbed through nasal and respiratory mucosa and directly gives play to theirantiviral effect. A part of the interferon entering organism is hydrolyzed byprotease, and the rest is excreted by urine.The administration of drug by nasal route is of the follow characters: 1.No degradation of drug as that in gastrointestinal tract;2. No first pass effectof drug as that in liver;3. The drug is adsorbed and takes effect rapidly;4. Thebioavailability of large molecular drugs may be improved by absorbefacientagents or other method;5. Small molecular drugs are especially suitable foradministration by nasal route;6. The drug after absorption enters the systemiccirculation directly;7. The water-soluble large molecular drugs which isdifficult to be absorbed by gastrointestinal tract may be absorbed by nasalcavity;8. Because of its good compatibility, the administration by nasal routeis especially suitable for the patients who need to be treated for a long time.As early as 1940s, the prevention of viral infection in respiratory tract byinterferon spraying has been studied abroad. Summarizing the results of 241tests reported and 230 papers published during the past 50 years, we concludethat interferon has good preventive effect on experimental infection. Theprotective rates of the drug to experimental cold and common cold were 46%(37%-54%) and 24% (21%-27%) respectively. Interferon also shortened thecourse of experimental cold. However, being limited by the technologicallevel at that time, the drug was difficult to enter market due to severe adversereaction such as bloody nasal discharge after long-term administration.Even so, spraying and mucosal administration are still of developmentvalue. Especially in the pandemic of burst upper respiratory tract viralinfection, such as SARS and avian influenza, interferon spraying is a drug offirst choice in lack of other effective and rapid preventive measures, based onits definite antiviral effect and safety as proved by clinical trial. However, animportant premise to the entering of interferon spraying into market isimproving the formula and abating the stimulation to nasal mucosa.In our study, the formula of interferon spraying is improved, and theadverse reaction such as bloody nasal discharge is avoided. Meanwhile, thesafety and stability of interferon spraying are further studied. Thesatisfactory result laid a foundation of development of interferon spraying andprevention of acute upper respiratory tract viral infection such as SARS andavian influenza.
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