Drug Screening Of Fatigue Resistance Based On The α-1-acid Glycoprotein

Backgrounds and Objectives: Fatigue may be described as the decline in the ability of anindividual to maintain a level of performance. It is a prominent disabling symptom in avariety of medical and neurologic disorders. However, the issue of fatigue in man iscomplex due to the various physiological and psychological phenomena which contributeto it. Although fatigue is the most common symptom reported by cancer patients and hasserious adverse effects on quality of life, it remains poorly understood. The complexities ofthe chronic fatigue syndrome and the methodologic problems associated with its studyindicate the need for a comprehensive, systematic, and integrated approach to theevaluation, classification, and study of persons with this condition and other fatiguingillnesses. Fatigue occurs in the majority of patients with multiple sclerosis (MS) andtherapeutic possibilities are few. Chronic fatigue syndrome is a real illness and it has beenpoorly understood and treated by doctors. They consider chronic fatigue as being like anyother illness in that its onset and course are influenced by physical, psychological, andsocial factors. Chronic fatigue (using a working definition that includes the most prominentclinical features) is common in primary and secondary care. The highly selective minoritywho are seen in specialist clinics and are most prominent in lay accounts are but one ofnumerous subgroups—subgroups which overlap with other widely recognised syndromessuch as fibromyalgia and irritable bowel. Cultures that do not accept the Westernseparation of mind and body are more successful in accepting and understanding chronicfatigue and “unexplained” physical symptoms. Aetiology cannot be seen in terms of singlephysical or psychological causes. It is multifactorial, with physiological, pathological, andpsychological variables acting to predispose, to precipitate, and to maintain symptoms.This pattern of interaction of aetiological factors is likely to vary over time: for example,various infections such as influenza and hepatitis are direct causes of acute fatigue, but,months or years later, persistent fatigue seems to be determined by secondary physiologicalconsequences such as deconditioning and psychological variables. Once fatigue isestablished, patients’ frustrations and doctors’ bewilderment are often powerful maintaining factors. Inevitably, there are associations with primary and secondarypsychiatric disorders such as depression and anxiety. This multicausal view of chronicfatigue syndromes should enable us to replace current therapeutic nihilism, which arisesfrom a lack of understanding or overly simple explanations. Discussion of chronic fatigueraises basic issues that apply to many of the unexplained medical symptoms which arecommon in all medical practice. So it would be great news for human beings if we canscreen effective anti-fatigue drugs.Methods: We already found ORM1through two dimensional gel electrophoresis (2DE).We discovered it has an anti fatigue activity through animal experiment. The Japanesescholars have found that macrolide antibiotic as erythromycin can induce the express of invivo ORM1. Our preliminary experiments confirmed by behavior experiment thaterythromycin can indeed prolonged animal swimming time significantly by increasingORM1. The purpose of this study is based on the ORM1elevated as a target for drugscreening of anti fatigue. First we observe if other macrolide antibiotics, such asErythromycin Ethylsuccinate, Acetylspiramycin, clarithromycin, roxithromycin, also havethe similar effect. They have different effect of extension animal swimming time indifferent doses. However antibiotics as anti-fatigue drugs can produce risk of overuseantibiotics. So it is necessary to modificate the structure of macrolide antibiotics. Weremove the antibacterial activity of them still retains their anti fatigue activity. Wemodificate the structure of erythromycin to obtain spiroketal. It is confirmed spiroketal hasno antibacterial activity, but it still can induce the expression of ORM1and prolong theswimming time of mice. Thus it also has the anti fatigue activity. Then we conductedstructure transformation of erythromycin into a series of compounds (510,530). Throughanimal swimming, running, climbing and other behavioral assays, we screened moreeffective anti fatigue medicine. It is reported that erythromycin can promotes gastricemptying and colonic operation. So we had to transform gastrointestinal motility test onthe effective anti-fatigue medicines. We researched on the rate of gastric emptying andsmall intestinal propulsion ratio for further study. Results:1. The screening of macrolide antibiotics on fatigue resistance(ErythromycinEthylsuccinate, Acetylspiramycin, clarithromycin, roxithromycin)It is reported that erythromycin can induce the express of ORM1in vivo. As a result,we use different doses of erythromycin to induce the expression of ORM1in mice anddetect its corresponding swimming time simultaneously. Results show that erythromycincan dose dependent up regulated serum ORM1levels in mouse. At the same time it candose-dependently prolonged swimming time of mice. If we give the mice erythromycinand interfere its synthesis of ORM1, Erythromycin’s effect of prolonging the swimmingtime of mice is reduced a lot. Therefore, we choose four kinds of macrolide antibiotics toexplore whether they have similar effects of erythromycin. We selected three differentdoses (10,30,100mg/kg) through the animal behavior experiments (swimming, climbing,running) to explore the anti fatigue effect of four drugs. Results show that erythromycinEthylsuccinate at the doses of10mg/kg, Clarithromycin at the doses of30mg/kg, Acetylspiramycin at the doses of100mg/kg, they have an obvious role of extension theswimming time of mice.2. Anti fatigue effect of spiroketal (Erythromycin structurally similar compounds)and screening anti fatigue effect of510,530(series of new compound which arefrom structure reforming of erythromycin)As a result of macrolide antibiotics as anti-fatigue drugs can produce risk of overuseantibiotics, we choose spiroketal which is similar in structure with erythromycin but has noantibacterial activity to explore its anti fatigue effect. The results showed spiroketal canalso induce ORM1synthesis in mice and prolong the swimming time of mice. The antifatigue effect of Erythromycin has no relationship with its antibacterial activity. So weconduct a series of structural modification of erythromycin to synthesis510,530series ofcompounds and use animal behavior method to screen effective anti fatigue drugs. Theresults showed that530-17and510-09have notable anti-fatigue effect.3. Gastrointestinal motility experiment of510,530series compoundsIt is reported that erythromycin can promotes gastric emptying and colonic operation. Therefore, in order to explore if510and530series of compounds also have the sameeffect we take small intestine of animals after drug administration and usethree-dimensional monitoring method to study effect on isolated intestinal contraction. Theresults showed530-21have obvious effects.Conclusions:1. Four kinds of antibiotics have varying degrees of anti fatigue effect2. New compound510-09,530-17has obvious anti fatigue effect3.530-21have obvious effect on isolated intestinal contraction.