| 1 ObjectivesStudies of chronic anal fissure have made new progress in recent years. Firstly, the studies of the traditional drugs and classic operations have obtained more reliable datas, which will provide favorable evidence to support clinical decision-making; secondly, Some new drugs such as Gonyautoxin, phosphodiesterase inhibitor, L-arginine and muscarinic agonists and angiotensin-converting enzyme inhibitors are being researched; and the improvements to the traditional operations and bold innovations of the new operations are ongoing at the same time. Although the traditional medication treatments have lower cost, the cure rate of them are not high, meanwhile the side effects and long-term recurrence rate are high, so the compliance of patients to these treatments are not very good. Al though the cure rate of surgical therapies are relatively high, there are a certain risks of fecal incontinence, and the treatment cost is also higher.Our previous studies have showed that the Guangtongxiao foam aerosol (GTX) has significant effects on pain relieving and spasmolysis in addition to certain effects of anti-inflammatory hemostatic and wound healing on a variety of anorectal diseases. The objectives of this subject are to observe the efficacy of GTX in the treatment of chronic anal fissure, and to study its mechanism of action from relieving the internal anal sphincter spasm and inhibition to the hyperalgesia of inflammatory pain.2 MethodsThis study consists of three parts. The first part is the literature research by reviewing the previous studies of GTX and the progress of treatment of chronic anal fissure and hyperalgesia research in molecular biology. We hope to find research targets in the study of mechanisms of GTX in the treatment of chronic anal fissure. The second part is the clinical efficacy research of GTX. We adopted randomized controlled approach to compare the efficacy of GTX and GTN from cure rate, pain relieving, reducing of anal resting pressure and improving to the quality of life, meanwhile we paid close attention to the side effects and and long-term recurrence rate of both drugs during the treatment and the follow-up. The third part is about the animal studies of GTX. We demonstrated the feasibility of the model of chronic anal fissure in rats by the observation of pain behaviors, pathology and bowel movement of the rats before and after the molding in experiment one; we compared the efficacy of various drugs in rats with chronic anal fissure from the perspective of pain behaviors in the second experiment; we adopted the nitrate reductase method to measure the concentration of NO in experiment three, to study the relation between GTX and the important neurotransmitter of internal anal sphincter; we adopted enzyme linked immunosorbent assay to measure concentration of PGE2 in serum in experiment four to study the relation between GTX and PGE2which is an important inflammatory factor; We adopted immunohistochemistry to detect NR2B expression in the spinal cord of rats to study the impact of GTX on the important receptor of hyperalgesia in experiment five.3 Results3.1 clinical research(1)the cure rate:The cure rate of GTX was 56.25%, while the cure rate of glyceryl trinitrate ointment (GTN) was 51.61%, and there was no significant difference between them(p=0.5838);(2)anal resting pressure:The anal resting pressures of both groups decreased significantly after the treatment (both p were less than 0.0001); and there was no significant difference between the two groups after the treatment (p=0.6843);(3) pain scores:Pain of both groups alleviated significantly after the treatment(p=0.0011, p=0.0038), but there was no significant difference (p=0.5654) between the two groups after the treatment; pain of both groups alleviated significantly (p=0.0231, p=0.0386) at the 7th day of the treatment, and the treatment group alleviated more significantly than the control group (p=0.0176); pain of both groups alleviated significantly (p=0.0178, p=0.0255) at the 14th day than those of the 7th day, and the treatment group alleviated more significantly than the control group (p=0.0148); pain of both groups alleviated significantly (p=0.0258, p=0.0169) at the 21th day than those of the 14th day, and the treatment group alleviated more significantly than the control group (p=0.0315); pain scores of the treatment group did not decreased significantly ever since the 28th day of the treatment(p=0.3265, p=0.5284, p=0.5324), but the control group decreased all the time until the end of the treatment (p=0.0232, p=0.0154, p=0.0373); but the pain scores of the treatment group were still significantly lower than those of the control group (p=0.0139, p=0.0468), no significant difference existed between the two groups at the 42th day of the treatment (p=0.5654).(4) quality of life:â‘ bodily pain:both groups decreased significantly (p=0.0159, p=0.0278) after the treatment, but no significant difference(p=0.8621)existed between the two groups after the treatment;â‘¡role physical:both groups decreased significantly (p=0.0306, p=0.0351)after the treatment, but no significant difference (p=0.9781)existed between the two groups after the treatment;â‘¢vitality:both groups decreased significantly (p=0.0387, p=0.0405) after the treatment, but no significant difference (p=0.2572) existed between the two groups after the treatment; (4) there was no significant change about the physical functioning, general health, social functioning, role emotional and mental health (all p were greater than 0.05).(5)Analysis to the relationship between efficacy of the treatment group and relevant factors:efficacy of the treatment group had relationship with duration of disease and anal fissure stage (p=0.0079, p=0.0168); no significant relationship was observed between efficacy and gender/age (p=0.9730, p=0.3295).(6)side effects:seven patients in the control group (20%) had mild headache in the course of treatment, and three of them withdrew from the study because of headache-prone. There was no significant side effects in the treatment group in the course of treatment, significant difference existed between them(p=0.0112).(7)relapse rate:the relapse rate of the control group (29.41%) was higher than that of the treatment group (11.11%)in the follow-up,but no statistical significance existed between them(p=0.2285).3.2 zoopery research(1)pain behavior testsMWT:MWT of the low-dose group of GTX did not change significantly (p=0.4059) after the treatment; MWT of the middle-dose group of GTX, large-dose group of GTX, GTN group and the indomethacin group rised significantly (p=0.0346, 0.0105, p=0.0226, p=0.0188)at the end of the treatment; there was no significant difference among the middle-dose group of GTX, GTN group and the indomethacin group (all p were greater than 0.05); MWT of the large-dose group of GTX was significantly higher than that of the indomethacin group (p=0.0454).TWL:TWL of the low-dose group of GTX didn't change significantly (p=0.1558) after the treatment; TWL of the middle-dose group of GTX, large-dose group of GTX, GTN group and the indomethacin group rised significantly (p=0.0231, p=0.0117, p=0.0265, p=0.0185) at the end of the treatment; there was no significant difference among the middle-dose group of GTX, GTN group and the indomethacin group (all p were greater than 0.05); TWL of the large-dose group of GTX was significantly higher than that of the indomethacin group (p=0.0433).(2)concentration of NO in the local organization The concentration of NO of the low-dose group of GTX, middle-dose group of GTX and the indomethacin group were not significantly different with model group (p=0.3073, p=0.1734, p=0.3317); but that of GTN group was significantly higher than those of the model group (p=0.0121) and large-dose group of GTX (p=0.0108).(3)serum concentration of PGE2 The serum concentration of PGE2 of the low-dose group of GTX, middle-dose group of GTX and the GTN group were not significantly different from model group (p=0.7760, p=0.0869, p=0.7053); but that of indomethacin group was significantly higher than those of the model group (p=0.0023) and large-dose group of GTX (p=0.0410).(4)numbers of NR2B positive neurons in the spinal cord There was no significant difference between the low-dose group of GTX and the model group (p=0.6563); and the numbers of NR2B positive neurons of the middle-dose group of GTX, the large-dose group of GTX, the GTN group and the indomethacin group were all less than the model group remarkably (p=0.0496, p=0.0125, p=0.0465, p=0.0242); the number of NR2B positive neurons of the large-dose group of GTX was less than the indomethacin group remarkably(p=0.0128); there was no significant difference between the middle-dose group of GTX and the indomethacin group (p=0.0997); and the number of NR2B positive neurons of the GTN group was more than the indomethacin group (p=0.0454).4 ConclusionsGTX and GTN could both relieve the pain of patients, reduce anal resting pressure, and improve patients'quality of life (bodily pain, role physical and vitality) significantly in treating patients with chronic anal fissure, no significant differences were observed in the cure rate. But GTX could relieve the pain more quickly and cured the chronic anal fissure in shorter course of treatment. Besides, no significant side effects were observed in the research. The analysis between efficacy and correlative factors showed that the shorter course of disease the better efficacy, and GTX was more effective in treating stageâ…¡anal fissure than stage III anal fissure.The mechanism of GTX in treating chronic anal fissure were:to alleviate sphincter spasm by increasing the local NO concentration in the internal anal sphincter; to inhibit inflammatory hyperalgesia by inhibiting the expression of inflammatory factors--PGE2 in the serum and the expression of NR2B in the spinal cord dorsal horn, and the greater the dose, the more obvious efficacy.
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