Objective To investigate the effect of the Shaofu zhuyu decoction on the changes of the body writhing behavior,inflammatory reaction and COX-2 expression of the rats with the primary dysmenorrhea. Methods Fifty SD female rats were randomly divided into blank control group,model control group,high,middle and low dose of Shaofu zhuyu decoction groups,10 in each group.Dysmenorrhea rat model was established by treating with estradiol benzoate and oxytocin.Effect of Shaofu zhuyu decoction of different doses on writhing behavior,changes of endometritis cells and COX-2 expression in uterine smooth muscle of dysmenorrhea rats were observed. Results In the model control group,latency of the body writhing behavior was shortened and the total score was high,many inflammatory cells (especially for neutrophils) infiltrated in endometrium and uterine smooth muscle,immunohistochemistry showed that brown granules were found in the cytoplasm of smooth muscle cells of uterus,and COX-2 expression was positive in uterine smooth muscle cells.As compared with the model control group,writhing latency increased,total score decreased in both the high and middle dose of Shaofu zhuyu decoction groups,and infiltration of a small number of inflammatory cells was seen in the endometrium and smooth muscle (P<0.01);COX-2 expression was decreased (P<0.01) especially for the high dose of Shaofu zhuyu decoction group.As compared with the model control group,the latency of the low dose of Shaofu zhuyu decoction group was significantly increased,and the total score was decreased (P<0.01),but there was no significant difference in inflammatory cell infiltration and COX-2 expression (P>0.05). Conclusion A potential mechanism by which Shaofu zhuyu decotion treats primary dysmenorrhea may be related with alleviating pain,inhibiting inflammatory responses,and down-regulating expression of COX-2.
Fig.1
Inflammatory cells contents in uterus endometrium of five groups of rats (HE staining,×400) A.blank control group;B.model control group;C.high-dose Shaofu zhuyu decoction group;D.medium-dose Shaofu zhuyu decoction group;E.low-dose Shaofu zhuyu decoction group
Fig.2
COX-2 expression in uterine smooth muscle of five groups of rats (immunohistochemical staining,×400) A.blank control group;B.model control group;C.high-dose Shaofu zhuyu decoction group;D.medium-dose Shaofu zhuyu decoction group;E.low-dose Shaofu zhuyu decoction group
表3
Tab.3
表3
表3
5组大鼠子宫平滑肌COX-2的表达比较
Tab.3
Comparison of COX-2 expression in uterine smooth muscle among five groups of rats x¯±s,n=10
组别
剂量/ (g·kg-1·d-1)
阳性细胞数/ 个
阳性率/ %
空白对照组
…
13.40±13.46
6.00±6.29
模型对照组
…
77.60±19.27*1
35.00±8.49*1
少腹逐瘀汤
大剂量组
4.8
41.20±5.00*2
18.40±2.41*2
中剂量组
2.4
37.80±27.82*2
17.20±12.52*2
小剂量组
1.2
73.00±12.50*2
32.80±5.54*2
F
11.81
11.85
Compared with blank control group,*1P<0.01; compared with model control group,*2P<0.01
与空白对照组比较,*1P<0.01;与模型对照组比较,*2P<0.01
表3
5组大鼠子宫平滑肌COX-2的表达比较
Tab.3
Comparison of COX-2 expression in uterine smooth muscle among five groups of rats x¯±s,n=10
SCHMAUSSC,YAKSH TL.In vivo studies on spinal opiate receptor systems mediating antinociception.II.Pharmacological profiles suggesting a differential association of mu,delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat.[J].,1984,228(1):1-12.
SUS,DUANJ,CUIW,et al.Network-based biomarkers for cold coagulation blood stasis syndrome and the therapeutic effects of Shaofu zhuyu decoction in rats[J].,2013,2013(2/4):901-943.
Abstract In this study, the reverse docking methodology was applied to predict the action targets and pathways of Shaofu Zhuyu decoction (SFZYD) bioactive ingredients. Furthermore, Traditional Chinese Medicine (TCM) cold coagulation blood stasis (CCBS) syndrome was induced in female Sprague-Dawley rats with an ice-water bath and epinephrine, and SFZYD was used to treat CCBS syndrome. A metabolomic approach was used to evaluate changes in the metabolic profiles and to analyze the pharmacological mechanism of SFZYD actions. Twenty-three potential protein targets and 15 pathways were discovered, respectively; among these, pathways are associated with inflammation and immunological stress, hormone metabolism, coagulation function, and glycometabolism. There were also changes in the levels of endogenous metabolites of LysoPCs and glucuronides. Twenty endogenous metabolites were identified. Furthermore, the relative quantities of 6 endogenous metabolites in the plasma and 5 in the urine were significantly affected by SFZYD (P < 0.05). The pharmacological mechanism of SFZYD was partially associated with glycerophospholipid metabolism and pentose and glucuronate interconversions. In conclusion, our findings demonstrated that TCM CCBS pattern induced by ice water and epinephrine was complex and related to multiple metabolic pathways. SFZYD did regulate the TCM CCBS by multitargets, and biomarkers and SFZYD should be used for the clinical treatment of CCBS syndrome.
HARELZZ.Dysmenorrhea in adolescents and young adults: from pathophysiology to pharmacological treatments and management strategies[J].,2008,9(15):2661-2672.
Abstract BACKGROUND: Dysmenorrhea is the most common gynecologic complaint among adolescent and young adult females. Dysmenorrhea is usually primary and is associated with normal ovulatory cycles and with no pelvic pathology. In approximately 10% of females with severe dysmenorrhea symptoms, pelvic abnormalities such as endometriosis or uterine anomalies may be found. OBJECTIVE: To review the current knowledge regarding the pathophysiology of dysmenorrhea, as well as review pharmacological treatments and strategies for management of dysmenorrhea in adolescent and young adult females. METHODS: Review of original articles on dysmenorrhea that have been published in the medical literature. RESULTS/CONCLUSIONS: Potent prostaglandins and potent leukotrienes play an important role in generating primary dysmenorrhea symptoms. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common pharmacologic treatment for dysmenorrhea. A loading dose of NSAIDs (typically twice the regular dose) should be used as initial treatment for dysmenorrhea, followed by a regular dose until symptoms abate. Adolescents and young adults with symptoms that do not respond to treatment with NSAIDs for three menstrual periods should be offered hormonal treatment such as combined estrogen/progestin oral contraceptive pills (OCPs) for three menstrual cycles. If dysmenorrhea does not improve within 6 months of treatment with NSAID and OCPs, a laparoscopy is indicated to look for endometriosis. The goal of pharmacological treatment for endometriosis is to block its abnormal positive feedback loop. The abnormal loop consists of high local levels of estrogen in the lesions, which induce transcription of COX-2 and synthesis of prostaglandin E(2.) This results in further expression and activity of aromatase and a further increase in estrogen.
CHAN WY,DAWOOD MY,FUCHSF.Prostaglandins in primary dysmenorrhea: comparison of prophylactic and nonprophylactic treatment with ibuprofen and use of oral contraceptives[J].,1981,70(3):535-541.
DMITROVICR,KUNSELMAN AR,LEGRO RS.Sildenafil-citrate in the treatment of pain in primary dysmenorrhea: a randomized controlled trial[J].,2013,28(11):2958-2965.
Abstract STUDY QUESTION: Is a vaginal preparation of sildenafil citrate capable of alleviating acute menstrual pain in patients with primary dysmenorrhea (PD)? SUMMARY ANSWER: A vaginal preparation of sildenafil citrate is capable of alleviating acute menstrual pain in patients with PD with no observed adverse effects. WHAT IS KNOWN ALREADY: Oral preparations of nitric oxide (NO) donor drugs augment relaxant effects of NO on myometrial cells, reverse the vasoconstriction caused by prostaglandins and successfully alleviate pain, but the incidence of side effects is too high for routine clinical use. Sildenafil citrate inhibits type 5-specific phosphodiesterase (PDE5), thus preventing the degradation of cyclic guanosine monophosphate (cGMP) in the muscle and augmenting the vasodilatory effects of NO. Therefore, by inhibiting PDE5, the tissue remains relaxed and more blood can circulate through. It has been used previously in a vaginal form with no observed side effects, and it enhances endometrial blood flow. STUDY DESIGN, SIZE, DURATION: A double-blind, randomized, controlled trial comparing vaginal preparation of sildenafil citrate (100 mg single dose) to a placebo in 62 PD patients at the time of painful menstruation was conducted. The primary outcome was total pain relief over 4 consecutive hours (TOPAR4) comparing sildenafil citrate to placebo, where higher TOPAR4 scores represent better pain relief. Secondary outcomes were pain relief as measured by the visual analog scale (VAS) and uterine artery pulsatility index (PI). Subjects were recruited from December 2007 to January 2011. The trial was stopped due to closeout of the funding for the study. PARTICIPANTS, SETTINGS, METHODS: Participants were women in good health, were aged 18-35 years and suffered from moderate to severe PD. They were randomized to either vaginal placebo or 100 mg vaginal sildenafil citrate in a 1:1 ratio using random permuted blocks having a block size of 4. At baseline and 1, 2, 3, and 4 h post-treatment, patients were asked to provide assessment of their degree of pain using two scales: (i) pain on the 5-level ordinal scale used for TOPAR4 calculation and (ii) pain level on the VAS. The study ended 4 h after treatment initiation. MAIN RESULTS AND THE ROLE OF CHANCE: Twenty-five subjects completed the study. Using the TOPAR4 score, the sildenafil citrate group had significantly better pain relief compared with the placebo group [mean (SD): 11.9 (3.2) versus 6.4 (2.1), respectively; difference in means = 5.3; 95% CI: (2.9,7.6); P < 0.001)]. On the VAS, sildenafil citrate provided better pain relief than placebo at each time point. At the 2-h time point, the PI was significantly lower in the sildenafil citrate group compared with the placebo group [mean (SD): 1.6 (0.6) versus 2.3 (0.5), respectively; difference in means = -0.7; 95% CI: (-1.2, -0.1); P = 0.01)]. LIMITATIONS, REASONS FOR CAUTION: Since we did not meet our sample size due to the loss of funding and could not confirm our primary hypothesis, larger studies of longer duration, likely multi-center, are needed to confirm the findings from this study. WIDER IMPLICATIONS OF THE FINDINGS: A number of medications have been investigated to improve the treatment options for PD, but most have proven unsuccessful or to have an unfavorable risk/benefit ratio. Since PD is a condition that most women suffer from and seek treatment for at some point in their lives, our study offers hope that vaginal sildenafil citrate is a safe and effective option for patients who do not desire or are unresponsive to treatments now available on the market. STUDY FUNDING/COMPETING INTERESTS: Funding for this study was provided by National Institutes of Health (NIH) grants RO3 TW007438 and K24 HD01476. The authors report no relevant conflicts of interest. TRIAL REGISTRATION NUMBER: NCT00123162 (Clinical trials.gov).
COOND,GULATIA,COWANC,et al.The role of cyclo-oxygenase-2 (COX-2) in inflammatory bone resorption[J].,2007,33(4):432-436.
Prostaglandin E2 (PGE(2)) is an important inflammatory mediator that plays an essential role in the development and progression of periradicular diseases. Cyclooxygenase-2 (COX-2) is the inducible enzyme responsible for increased PGE(2) levels during inflammation and other pathologic processes. The purpose of this study was to determine the role of COX-2-mediated PGE(2) synthesis in osteoclast formation in response to endodontic pathogens and materials. Primary osteoblast cultures and osteoclast cultures were prepared from COX-2 knockout (K/O) and wild-type (WT) littermates. These cultured cells were exposed to lipopolysaccharide (LPS) or root canal obturation materials including gutta-percha (GP), Resilon (RS), mineral trioxide aggregates (MTAs), and AH Plus (AH+). Osteoclast formation was evaluated using tartrate-resistant acid phosphatase (TRAP) staining. The expression of receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) was determined by real-time polymerase chain reaction (PCR) analysis. It was found that in both WT and K/O cultures, treatment with LPS led to a marked increase in osteoclast formation. The number of osteoclasts formed was significantly lower in K/O cultures compared to WT cultures. Exposure to endodontic materials did not lead to any significant osteoclast formation. LPS and endodontic materials caused a decrease in both RANKL and OPG expression in WT cells. In K/O cells, the baseline levels of RANKL and OPG expression were dramatically decreased compared to the WT cells. In conclusion, COX-2-mediated PGE(2) expression is required for LPS-induced inflammatory bone resorption and maintaining the baseline level of RANKL and OPG expression. LPS-induced osteoclast formation may be independent of the RANKL pathway.
In vivo studies on spinal opiate receptor systems mediating antinociception.II.Pharmacological profiles suggesting a differential association of mu,delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat.