Estudo de fase II de pregabalina para prevenção de náuseas e vômitos induzidos por quimioterapia / Phase II study of pregabalin for the prevention of chemotherapy induced nausea and vomiting

Para avaliar o papel da pregabalina na proteção das náuseas e vômitos induzidos pela quimioterapia, foi realizado um ensaio clínico de fase II, aleatorizado, duplamente cego, controlado por placebo, para investigar se a pregabalina poderia melhorar o controle completo das náuseas e vômitos (desfecho primário). Inscrevemos 82 pacientes virgens de quimioterapia, programados para receber quimioterapia moderadamente e altamente emetogênica. Todos os doentes receberam ondansetron 8mg por via intravenosa, dexametasona 10mg antes da quimioterapia no primeiro dia e, dexametasona 4 mg por via oral, b.d., nos dias dois e três. Os doentes foram distribuídos aleatoriamente para tomar pregabalina 75 mg ou placebo, bd, desde a noite anterior à quimioterapia até ao quinto dia. A resposta completa global não foi estatisticamente significativa entre os grupos (53,7 versus 48,8%, respetivamente, no grupo da pregabalina e no grupo de controlo (P=0,65)). Também não houve diferença estatística significativa durante a fase aguda (primeiras 24 horas) e a fase tardia (24-120h): 80,5% versus 82,9% (P=0,77), 53,7 versus 51,2% (P=0,82), respectivamente. Neste estudo não foi identificada ação da pregabalina na prevenção de náuseas e vômitos induzidos por quimioterapia. Número de registo no Clinicaltrial.gov: NCT04181346.

To evaluate the role of pregabalin in the protection of chemotherapy-induced nausea and vomiting, we performed a phase II randomized, double-blind, placebo-controlled trial to investigate whether pregabalin could improve the complete control of nausea and vomiting (primary end point). We enrolled 82 chemotherapy-naive patients, scheduled to receive moderately and highly emetogenic chemotherapy. All patients received IV ondansetron 8mg, dexamethasone 10mg before chemotherapy on day one and oral dexamethasone 4mg, b.d., on days two and three. Patients were randomly assigned to take pregabalin 75mg or placebo, bd, from the night before chemotherapy to day five. The overall complete response was not statistically significant between the groups (53.7 versus 48.8%, respectively, in the pregabalin group and the control group (P=0.65)). There was also no significant difference during the acute phase (first 24 hours) and delayed phase (24-120h): 80.5% versus 82.9% (P=0.77), 53.7 versus 51.2% (P=0.82), respectively. There is no role for pregabalin preventing chemotherapy-induced nausea and vomiting. Clinicaltrial.gov registration number: NCT04181346.

Simulation of the oxidative metabolization pattern of netupitant,an NK1 receptor antagonist,by electrochemistry coupled to mass spectrometry / 药物分析学报

Considering the frequent use of netupitant in polytherapy,the elucidation of its oxidative metabolization pattern is of major importance.However,there is a lack of published research on the redox behavior of this novel neurokinin-1 receptor antagonist.Therefore,this study was performed to simulate the intensive hepatic biotransformation of netupitant using an electrochemically driven method.Most of the known enzyme-mediated reactions occurring in the liver(i.e.,N-dealkylation,hydroxylation,and N-oxidation)were successfully mimicked by the electrolytic cell using a boron-doped diamond working electrode.The products were separated by reversed-phase high-performance liquid chromatography and identified by high-resolution mass spectrometry.Aside from its ability to pinpoint formerly unknown metabolites that could be responsible for the known side effects of netupitant or connected with any new perspective concerning future therapeutic indications,this electrochemical process also represents a facile alternative for the synthesis of oxidation products for further in vitro and in vivo studies.

Effect of neurokinin 1 receptor antagonist on airway inflammation and hyperresponsiveness in asthmatic mice / 中国小儿急救医学

Objective@#To investigate the effects of neurokinin-1 receptor antagonist WIN 62, 577 on airway inflammation and airway hyperresponsiveness in asthmatic mice.@*Methods@#Thirty-two BALB/c mice(Specific-pathogen-free grade) were randomly divided into 4 groups: control group, asthmatic group, WIN 62, 577 intervention group and dexamethasone group.The asthmatic group, the WIN 62, 577 intervention group, and the dexamethasone group were given intraperitoneal injection of 0.2 ml of OVA sensitization solution at 0 d, 7 d, and 14 d, respectively.Then the asthmatic group, WIN 62, 577 group and dexamethasone group were given OVA challenge solution(4% OVA solution) by inhalation once a day for 30 min from 21 d to 28 d for 7 consecutive days.The WIN 62, 577 intervention group was given WIN 62, 577 300 μg intraperitoneal injection 1 h before each challenge; the dexamethasone group was given intraperitoneal injection of dexamethasone 2 mg/kg 1 h before each challenge.The airway responsiveness of each group of mice was detected by non-invasive pulmonary function test.The bronchoalveolar lavage fluid(BALF) was obtained for inflammatory count.The HE staining of lung tissue was used to observe airway inflammation in mice.@*Results@#Compared with the asthmatic group, the mice in the WIN 62, 577 intervention group showed less restlessness, standing upright, crouching back, scratching the ears and scratching the cheeks, shortness of breath and cyanosis of the lips.After inhaling different concentrations of acetylcholine, the Penh value of mice in the WIN 62, 577 intervention group and the dexamethasone group was significantly lower than that in the asthmatic group(P<0.05). Compared with the asthmatic group, the number of WBC and EOS in BALF decreased significantly in the WIN 62, 577 intervention group and the dexamethasone group(P<0.01). HE staining showed that the inflammatory changes in the lung tissue of mice in the WIN 62, 577 intervention group were significantly reduced, the bronchial epithelium did not fall off significantly, the mucosal edema was not obvious, the smooth muscle proliferation was reduced, and the inflammatory cell infiltration was reduced, similar to the airway changes in the dexamethasone group.@*Conclusion@#Neurokinin-1 receptor antagonist WIN 62, 577 can reduce airway inflammation and airway hyperresponsiveness in asthmatic mice.

Advance of substance P/neurokinin receptor 1 system in cancer treatment / 解剖学报

Substance P (SP) is the first identified peptide in tachykinin family, which widespreadly distributes in both central and peripheral nervous systems of mammals and is involved in many physiological and pathological processes. Neurokinin receptors (NKRs) belong to the G-protein coupled receptor family, including NK1R, NK2R and NK3R. SP has the highest affinity and is the selectivity ligand for NK1R. Cumulative experimental results have shown that SP/NK1R system is involved in the cancer process and NK1R has the potential to be a new target for cancer treatment. In this review, we focus on the expression levels of SP/NK1R system in cancers and how to develop SP/NK1R system as a new target for cancer treatment.

Research progress in neurokinin-1 receptor antagonist aprepitant used for postoperative nausea and vomiting / 中国医师杂志

Postoperative nausea and vomiting ( PONV) is a common complication after anaesthesia, which hinders the rapid recovery of patients. Aprepitant, one of neurokinin-1 (NK-1) receptor antagonists is mainly used to prevent nausea and vomiting by blocking the binding of substance P to NK-1 receptor. It has the advantages of high selectivity, strong affinity and long half-life, and its new antiemetic target pro-vides a new choice for prophylactic treatment of PONV. This article summarize studies on the prophylaxis of aprepitant in treatment of PONV.

Effect of neurokinin-1 receptor antagonist on alcohol reward in juvenile mice / 中华行为医学与脑科学杂志

Objective To examine the effect of NK1 receptor ( NK1R) antagonist L-703,606 on ethanol-induced conditioned place preference (CPP) and levels of NK1R protein in different brain regions in juvenile mice. Methods Four-week-old male C57BL/6 mice were divided into high anxiety group and low anxiety group according to the percentage of time spent in open arms of elevated plus maze(EPM). Then the mice in the two groups were divided into control group and experimental group according to random number table,which were high anxiety control group,high anxiety experimental group,low anxiety control group and low anxiety experimental group,with 11 in each group. L-703,606 was injected intraperitoneally 40 minutes before CPP training in the high and low anxiety experimental group,while the control group received solvent treatment. After CPP test,the anxiety level of four groups of mice was detected by EPM again. The expres-sion of NK1R protein in hippocampus,prefrontal lobe and amygdala of mice was detected by Western blot. Results Compared with the high anxiety control group, the CPP value of the high anxiety experimental group was lower,and the difference was statistically significant ((77. 7 ± 9. 3) s vs (13. 6 ± 13. 0) s,P=0. 002). Compared with the low anxiety control group,the CPP value of the low anxiety experimental group was lower,and the difference was statistically significant ((113. 2±10. 3)s vs (28. 0±9. 6)s,P<0. 01). Af-ter L-703,606 treatment,there was no significant difference in the percentage of open arm time between the control group and experimental group either in high anxiety group or in low anxiety group (both P>0. 05) . Compared with the high anxiety control group,the expression of NK1R increased in hippocampus,prefrontal lobe and amygdala of mice in high anxiety experimental group (all P<0. 05). And the expression of NK1R in the above three brain regions had the same result between the low anxiety control group and the low anxiety experimental group (all P<0. 05). Conclusions L-703,606 can attenuate ethanol-induced CPP but has no effect on anxiety-like behaviors,suggesting the direct effect of NK1R in alcohol reward in juvenile mice.

The effect of miRNA-34b/c-5p on neurokinin-1 receptor-truncated expression in breast cancer / 中国肿瘤临床

Objective:To investigate the effect of miRNA-34b/c-5p on the expression of neurokinin 1 receptor-truncated(NK1R-Tr)in breast cancer and the effect of miRNA-34b/c-5p and NK1R-Tr on the migration and invasion abilities of breast cancer cells.Methods:Real-time fluorescence quantitative PCR(RT-PCR)was used to detect the expression of miRNA-34b/c-5p and NK1R-Tr in 50 breast can-cer specimens that were collected at Tianjin Medical University Cancer Institute&Hospital from February to May 2013.Western blot analysis was performed to detect the expression of miRNA-34b/c-5p and NK1R-Tr in breast cancer cell lines MDA-MB-231 and MCF-7. Scratch and Transwell assays were carried out to explore the effects of miRNA-34b/c-5p and NK1R-Tr on the migration and invasion abilities of MDA-MB-231 cells.Results:The expression of miRNA-34b/c-5p and NK1R-Tr in breast cancer tissues and cells were signifi-cantly negatively correlated.The relative expression of NK1R-Tr in breast cancer patients with lymph node metastasis was 5.75,and the relative expression of NK1R-Tr in patients with non-lymph node metastasis was 4.29.The relative expression was significantly dif-ferent between the two groups(P=0.026).Overexpression of miRNA-34b/c-5p and knockdown of NK1R-Tr could significantly inhibit the migration and invasion abilities of MDA-MB-231 cells(all P<0.001).Conclusions:The expression of miRNA-34b/c-5p and NK1R-Tr was significantly negatively correlated.MiRNA-34b/c-5p and NK1R-Tr might be potential therapeutic targets for inhibiting the invasion of breast cancer cells.

Allopregnanolone suppresses mechanical allodynia and internalization of neurokinin-1 receptors at the spinal dorsal horn in a rat postoperative pain model

BACKGROUND: To identify a new strategy for postoperative pain management, we investigated the analgesic effects of allopregnanolone (Allo) in an incisional pain model, and also assessed its effects on the activities of the primary afferent fibers at the dorsal horn. METHODS: In experiment 1, 45 rats were assigned to Control, Allo small-dose (0.16 mg/kg), and Allo large-dose (1.6 mg/kg) groups (n = 15 in each). The weight bearing and mechanical withdrawal thresholds of the hind limb were measured before and at 2, 24, 48, and 168 h after Brennan's surgery. In experiment 2, 16 rats were assigned to Control and Allo (0.16 mg/kg) groups (n = 8 in each). The degree of spontaneous pain was measured using the grimace scale after the surgery. Activities of the primary afferent fibers in the spinal cord (L6) were evaluated using immunohistochemical staining. RESULTS: In experiment 1, the withdrawal threshold of the Allo small-dose group was significantly higher than that of the Control group at 2 h after surgery. Intergroup differences in weight bearing were not significant. In experiment 2, intergroup differences in the grimace scale scores were not significant. Substance P release in the Allo (0.16 mg/kg) group was significantly lower than that in the Control group. CONCLUSIONS: Systemic administration of Allo inhibited mechanical allodynia and activities of the primary afferent fibers at the dorsal horn in a rat postoperative pain model. Allo was proposed as a candidate for postoperative pain management.

Efficacy and safety of aprepitant in prevention of nausea and vomiting induced by chemotherapy in patients with diffuse large B-cell lymphoma / 白血病·淋巴瘤

Objective To evaluate the efficacy and safety of neurokinin1 (NK1) receptor antagonist aprepitant combined with prednisone and tropisetron in prevention of nausea and vomiting (CINV) induced by R-CHOP or CHOP regimen. Methods A total of 90 patients with diffuse large B-cell lymphoma (DLBCL) who accepted R-CHOP or CHOP regimen in the People''s Hospital of Tianjin from October 2015 to January 2016 were divided into aprepitant group (45 cases) and the control group (45 cases) according to the random number table. In aprepitant group, day 1: aprepitant 125 mg 1 h before chemotherapy, prednison 100 mg, tropisetron 10 mg, and tropisetron 5 mg 2 hours after chemotherapy;day 2-3:aprepitant 80 mg and prednison 100 mg, tropisetron 10 mg; day 4-5: prednison 100 mg. In the control group, day 1: prednison 100 mg 1 h before chemotherapy, tropisetron 10 mg, and tropisetron 5 mg 2 h after chemotherapy; days 2-3: prednison 100 mg, tropisetron 10 mg; day 4-5: prednison 100 mg. Data on nausea, vomiting and remission treatment were collected every day. The complete remission (CR) rates of CINV without vomiting and remission drugs in the whole cycle were recorded. Functional living index-emesis questionnaire (FILE) was used to assess the effect of CINV on the life quality of the patients. Results CR in aprepitant group was higher than that in the control group (77.8 ％ vs. 55.6 ％, χ2= 5.000, P= 0.025). The rate of no vomiting in aprepitant regimen was higher than that in the control regimen (82.2 ％ vs. 62.2 ％, χ2 = 4.486, P= 0.034). The average scores of FILE between the two groups were (113 ±10) and (100 ±11) scores respectively, and there was a significant difference (t=12.437, P<0.001). The related adverse reactions of vomiting-stopping drugs in both groups had no statistical difference. Conclusion The aprepitant combined with tropisetron and prednisone can improve effectively nausea and vomiting induced by R-CHOP or CHOP chemotherapy regimen for DLBCL patients.

Expressions of SP and NK-1R increase in the posterior horn of the L5－S2 spinal cord in rats with chronic nonbacterial prostatitis / 中华男科学杂志

<p><b>Objective</b>To investigate the expressions of substance P (SP) and neurokinin-1 receptor (NK-1R) in the posterior horn of the L5－S2 spinal cord in the rat model of chronic nonbacterial prostatitis (CNP) at different time points of modeling.</p><p><b>METHODS</b>Forty adult male SD rats were randomly divided into four groups of equal number, control, 45 d model, 60 d model, and 90 d model, and proteins were obtained from the prostatic tissue of another 30 rats. The CNP model was made by intraperitoneal injection of 0.5 ml DPT vaccineand intradermal injection of mixed solution of 1 ml prostatein extract and complete adjuvant at a 1∶1 ratio, while the control rats were injected with the same volume of normal saline. At 45, 60, and 90 days after modeling, we measured the paw withdrawal threshold (PWT) of the rats, determined the levels of TNF-α, IL-1β, IL-2, and IL-10 in the prostate tissue by ELISA, observed the histomorphological changes in the prostate by transmission electron and light microscopy, and detected the expressions of SP and NK1-R in the L5－S2 spinal cord by immunohistochemistry.</p><p><b>RESULTS</b>The model rats showed significantly increased sensitivity to pain, with remarkably lowered PWT at 45, 60, and 90 days after modeling. The levels of TNF-α, IL-1β, IL-2, and IL-10 in the prostate tissue were markedly elevated in the CNP models as compared with those in the controls (all P<0.05), most significantly at 90 days (all P<0.05). Immunohistochemistry showed that the expressions of SP and NK-1R were remarkably higher in the CNP model groups than in the control (all P<0.05), the highest at 90 days. Light microscopy revealed no inflammatory cell infiltration in the prostate tissue of the control rats, and obvious edema and increased lymphocytes were observed with the prolonged time of modeling.Transmission electron microscopy showed inflammatory changes in the prostate tissue of the model rats and that peritubular interstitial edema was most obvious at 90 days, with widened intervals between peritubular cells and the epithelial base and increased numbers of fibroblasts and collagen fibrils.</p><p><b>CONCLUSIONS</b>The synthesis of SP and the level of NK-1R were increased in the posterior horn of the L5－S2 spinal cord in the rat model of CNP.</p>

Effect of pretreatment with botulinum toxin A on NK-1 receptor internalization in spinal dorsal horn in a rat model of incisional pain / 中华麻醉学杂志

Objective To evaluate the effect of pretreatment with botulinum toxin A injected intrath?ecally or locally at the incision site on the neurokinin?1 ( NK?1) receptor internalization in the spinal dorsal horn in a rat model of incisional pain. Methods Male Sprague?Dawley rats, weighing 280-300 g, aged 6-8 weeks, were used in the study. The experiment was performed in two parts. ExperimentⅠ Twenty?seven rats with no sign of nerve injury at day 7 after successful catheterization were selected and divided into 3 groups (n=9 each) using a random number table: control group (C1 group), incisional pain group (IP1 group) and intrathecal botulinum toxin A group (BoNT∕A1 group). At 24 h before operation, botulinum tox?in A 0.5 U ( in 10μl of normal saline) was injected intrathecally in group BoNT∕A1, and normal saline 10μl was injected intrathecally in group IP1. ExperimentⅡ Twenty?seven rats were selected and divided into 3 groups (n=9 each) using a random number table: control group (group C2), incisional pain group (IP2 group) and locally injected botulinum toxin A at the incision site group (BoNT∕A2 group). At 24 h before op?eration, botulinum toxin A 2 U ( in 0.4 ml of normal saline) was injected subcutaneously at the incision site and into the plantar surface, and normal saline 0.4 ml was injected subcutaneously at the incision site and into the plantar surface in group IP2. Six rats in each group were selected, and the cumulative pain score (CPS) was recorded, and the mechanical paw withdrawal threshold ( MWT) in the right hindpaw was measured be?fore administration, before operation, and at 3 h and 1, 3, 5 and 7 days after operation. At 3 h after opera?tion, 3 rats in each group were selected and sacrificed, and the lumbar segment ( L4,5 ) of the spinal cord was removed for determination of the expression of NK?1 receptors in the spinal dorsal horn by immunofluores?cence. Results ExperimentⅠ Compared with group C1, the CPS was significantly increased at 3 h and 1, 3, 5 and 7 days after operation, the MWT was significantly decreased at 3 h and 1 and 3 days after opera?tion, and the expression of NK?1 receptors in the spinal dorsal horn was significantly up?regulated in group IP1, and the CPS was significantly increased at 3 h and 1, 3 and 5 days after operation, the MWT was sig?nificantly decreased at 3 h after operation ( P0.05). Compared with group IP1, the CPS was significantly decreased, and the MWT was significantly increased at 3 h and 1, 3, and 5 days after oper?ation, and the expression of NK?1 receptors in the spinal dorsal horn was significantly down?regulated in group BoNT∕A1 (P0.05) . Compared with group IP2, the CPS was significantly decreased at 3 h and 1, 3, and 5 days after operation, the MWT was signifi?cantly increased at 3 h and 1 and 3 days after operation, and the expression of NK?1 receptors in the spinal dorsal horn was significantly down?regulated in group BoNT∕A2 (P<0.05). Conclusion Pretreatment with botulinum toxin A injected intrathecally or locally at the incision site can inhibit the internalization of NK?1 re?ceptors in the spinal dorsal horn in a rat model of incisional pain.

Study on the regulation of ERαon NK1R-Tr in breast cancer cells / 天津医药

Objective To analyze the regulation of estrogen receptor α (ERα) on truncated neurokinin-1 receptor (NK1R-Tr), and the influence of this regulation on cell proliferation in estrogen receptor-positive breast cancer cell lines. Methods The chromatin immune coprecipitation (CHIP) was used to observe the transcriptional regulation function of ERαon NK1R-Tr in breast cancer cells. Luciferase reporter gene assay was used to verify whether ERα played a positive regulatory role in the expression of NK1R-Tr. Western blot assay and real-time-PCR were used to detect the expression of ERα and NK1R-Tr in breast cancer cells, MCF-7 and T47D, as well as the expression of NK1R-Tr protein and mRNA level. NK1R-Tr levels were also detected after using estradiol (E2, ERα agonist) and small interfering RNA (knock out ERα). CCK-8 and clone formation experimen were used to detect the proliferation ability of breast cancer cells after knocking out NK1R-Tr with small interfering RNAs. Results CHIP test and Luciferase reporter gene assay proved that ERα can positively regulate the expression of NK1R-Tr via the ERα sequences in the upstream of the NK1R-Tr gene promoter. The expression of NK1R-Tr at both protein level and mRNA level dropped in the estrogen receptor-positive breast cancer cell line MCF-7 upon knocking out ERα. After knocking out NK1R-Tr, the proliferation ability of estrogen receptor-positive breast cancer cells was lower than that of the control group. Conclusion The ERα positively regulates the expression of NK1R-Tr, resulting in the increased cell proliferation in estrogen positive breast cancer cells.

The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs.

The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the proliferation of tumour cells, angiogenesis and the migration of tumour cells. We review the involvement of SP, the NK-1 receptor and NK-1 receptor antagonists in cancer. Tumour cells overexpress NK-1 receptors, which are involved in their viability. This overexpression suggests the possibility of specific treatment against tumour cells using NK-1 receptor antagonists, thus promoting a considerable decrease in the side effects of the treatment. This strategy opens up new approaches for cancer treatment, since these antagonists, after binding to their molecular target, induce the death of tumour cells by apoptosis, exert an antiangiogenic action and inhibit the migration of tumour cells. The use of NK-1 receptor antagonists such as aprepitant (used in clinical practice) as antitumour agents could be a promising innovation. The value of aprepitant as an antitumour agent could be determined faster than for less wellknown compounds because many studies addressing its safety and characterization have already been completed. The NK-1 receptor may be a promising target in the treatment of cancer; NK-1 receptor antagonists could act as specific drugs against tumour cells; and these antagonists could be new candidate anti-cancer drugs.

Expression of neurokinin receptors and the effect of their antago-nists on human breast cancer / 中国肿瘤临床

Objective:To determine the expression of the full-length (NK1R-FL) and truncated (NK1R-Tr) neurokinin-1 receptor (NK1R) and the neurokinin-2 receptor (NK2R) in breast cancer tissues and cell lines, as well as to study the effects of the NK1R and NK2R antagonists on the growth of breast cancer cells. Methods:Immunohistochemistry and Western blot assays were used to detect NK1R, NK1R-FL, and NK2R expression in clinical samples of primary breast cancer tissue, benign lesions, and normal breast tissue, as well as in different breast cancer cell lines. Cell proliferation and soft agar growth tests were performed on cells treated with the NK1R and NK2R antagonists to study the ectopic overexpression of NK1R-FL and NK1R-Tr in breast cancer cell lines. Results:Total NK1R expression was detected in the breast cancer tissues, benign lesions, and normal breast tissues. Compared with the normal breast epithe-lia and benign breast lesions, the expression levels of NK1R-FL and NK2R decreased in the carcinoma. These changes were also relat-ed to the carcinoma type, histological grade, lymph node metastasis, HER2 and Ki-67 expression, and estrogen and progesterone recep-tors in breast cancer. The expression levels of NK1R-FL and NK2R were high in the HBL-100 breast cell lines of para-neoplastic tis-sues, but NK1R-Tr expression was low. The MDA-MB-231, T-47D, and MCF-7 cells only expressed NK1R-Tr. NK1R-Tr or NK1R-FL overexpression caused the decreased inhibition rate or increased levels of the NK1R and NK2R antagonists in the breast cancer cells. Conclusion:NK1R-FL and NK2R are co-expressed in normal cells. NK1R-Tr is highly expressed in breast cancer cells and exerts nega-tive feedback to regulate NK1R-FL and NK2R expression in all cells, especially cancer cells.

Effects of Salidroside on expression of substance P and neurokinin-1 receptor of bone marrow cells in bone marrow depressed anemia mice / 中国免疫学杂志

Objective:To observe the effects of salidroside on the expression of substance P (SP)and neurokinin-1 receptor (NK-1R)of bone marrow cells(BMCs)in bone marrow(BM)depressed anemia mice,and to explore its roles for hematopoietic regulation.Methods:Automatic blood cell analysator was used to detected the changes of peripheral blood cells in each group ,immuno-histochemistry and reverse transcription-polymerase chain reaction ( RT-PCR) were used to analyze the expressions of SP and its receptor NK-1R of BMCs in each group respectively.Results: Peripheral blood testing results showed that the number of white blood cells (WBC),red blood cells(RBC)and hemoglobin(HB)of model group were significantly decreased when compared with control group.Compared with model group ,low-dose,middle-dose and high-dose salidroside obviously elevated the number of white blood cells ,and middle-dose salidroside obviously elevated the number of platelets.Immunohistochemistry studies showed that the expression of SP and its receptor NK-1R of BMCs was found in each group.Compared with control group , the expression of SP of BMCs was decreased obviously in model group(P0.05),and the expression of SP and its receptor NK-1R of BMCs was increased significantly in low-dose,middle-dose and high-dose salidroside groups (P<0.05).RT-PCR data showed that the expression of SP mRNA of BMCs was increased obviously in model group ,low-dose,middle-dose and high-dose salidroside groups when compared with control group (P<0.05).The expression of NK-1R mRNA of BMCs was un-detected in control group and model group.The expression level of NK-1R mRNA of BMCs was elevated gradually with the increase of salidroside dosage in low-dose,middle-dose and high-dose salidroside groups.Conclusion: The mRNA and protein expressions of SP and its receptor NK-1R of BMCs were up-regulated significantly by salidroside in dose-dependent manner.These data suggest that salidroside could participate in the recovery of hematopoietic function of BM depressed anemia mice by increasing the expression of SP and its receptor NK-1R of BMCs.

Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 μL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

The effect of aprepitant for the prevention of postoperative nausea and vomiting in patients undergoing gynecologic surgery with intravenous patient controlled analgesia using fentanyl: aprepitant plus ramosetron vs ramosetron alone / 대한마취과학회지

BACKGROUND: The purpose of this study was to evaluate the effect of an aprepitant, neurokinin-1(NK1) receptor antagonist, for reducing postoperative nausea and vomiting (PONV) for up to 24 hours in patients regarded as high risk undergoing gynecological surgery with intravenous patient-controlled analgesia (IV PCA) using fentanyl. METHODS: In this randomized, open label, case-control study 84 gynecological surgical patients receiving a standardized general anesthesia were investigated. Patients were randomly allocated to receive aprepitant 80 mg P.O. approximately 2-3 hours before operation (aprepitant group) or none (control group). All patients received ramosetron 0.3 mg IV after induction of anesthesia. The incidence of PONV, severity of nausea, and use of rescue antiemetics were evaluated for up to 24 hours postoperatively. RESULTS: The incidence of nausea was significantly lower in the aprepitant group (50.0%) compared to the control group (80.9%) during the first 24 hours following surgery. The incidence of vomiting was significantly lower in the aprepitant group (4.7%) compared to the control group (42.8%) during the first 24 hours following surgery. In addition, the severity of nausea was less among those in the aprepitant group compared with the control group over a period of 24 hours post-surgery (P < 0.05). Use of rescue antiemetics was lower in the aprepitant group than in the control group during 24 hours postoperatively (P < 0.05). CONCLUSIONS: In patients regarded as high risk undergoing gynecological surgery with IV PCA using fentanyl, the aprepitant plus ramosetron ware more effective than ramosetron alone to decrease the incidence of PONV, use of rescue antiemetics and nausea severity for up to 24 hours postoperatively.

The role of neurokinin-1 receptor in anti-nociceptive effect of inhalation anesthetics in mice / 中华麻醉学杂志

Objective To investigate the role of neurokinin-1 receptor (NK-1R) in the anti-nociceptive effect of enflurane, isoflurane and sevoflurane in mice. Methods Three hundred and twenty Kunming mice of both sexes weighing 20-25 g were randomly divided into4 groups (n =80 each): group normal saline (group NS);group enflurane (group E); group isoflurane (group I) and group sevoflurane (group S). Normal saline (NS) 1.0ml/kg, erflurane 0.5 ml/kg, isoflurane 0.4 ml/kg and sevoflurane 2.0 ml/kg were injected intraperitoneally in NS,E,I and S groups respectively. Each group was further divided into 4 subgroups receiving intrathecal NS 5 μl and Sar-SP (NK-IR agonist) 20, 40 and 80 ng respectively at 5 min after intraperitoneal injection of inhalation anesthetics. The anti-nociceptive effect of the inhalation anesthetics was assessed by tail flick latency (TFL) (the latency for removal of the tail from the path of heat source) and paw-licking time (PLT) after intraplantar formalin injection. Results lntraperitoneal enflurane, isoflurane and sevoflurane significantly prolonged TFL and shortened PLT. Intrathecal Sar-SP 20, 40 and 80 ng significantly shortened TFL dose-dependently but had no significant effeet on PLT as compared with control subgroup. Conclusion NK-1R is involved in the anti-nociceptive effect of enflurane, isoflurane and sevofluran on thermal pain but not chemical and inflammatory pain.

Prevención de adherencias peritoneales postoperatorias mediante uso de antagonista de receptores de neurokinina tipo 1 / Peritoneal adhesions prevention: neurokinin-1 receptor antagonist

Background: The fibrinolytic activity plays an important role in Peritoneal Adhesions (PA) develop-ment. It's well known that de substance P decreased the fibrinolysis by binding the neurokinin-1 receptor, improving the PA formation. Objectives: To evaluate the effectiveness of intraperitoneal treatment with a Neurokinin-1 receptor antagonist (NK-R1A) in peritoneal adhesión prevention in animal model. Materials and Methods: In 40 male wistar rats, PA were induced, and then randomly assigned to 2 groups: A group treated with Aprepitant (NK-Rl A), and a control group. The animals were killed at 7 or 14 postoperative day, and the number, severity and histopathology of PA were evaluated. Results: NK-Rl A decreased the number (40 percent less) and severity (p = 0.001) of PA when compare to control group. The NK-Rl A group had less PA in manipulated and no manipulated organs during surgery. Besides presented less fibrosis (p = 0.001), less inflamation (p = 0.005) and less vascular proliferation (p = 0.047) than control group. Conclusions: The NK-Rl A is effective as in PA prevention.

Introducción: La actividad fibrinolítica juega un papel fundamental en el desarrollo de las adherencias peritoneales (AP), y se conoce que la Sustancia P al actuar sobre receptores de neurokinina tipo 1 a nivel peritoneal, disminuye la fibrinólisis, favoreciendo la formación de las mismas. Objetivos: Evaluar la efectividad del tratamiento intraperitoneal con antagonista de receptores 1 de neurokinina (NK-R1A) en la prevención de AP en modelo animal. Materiales y Métodos: A 40 ratas wistar se les practicó cirugía formadora de AP y fueron distribuidas de forma aleatoria en 2 grupos, un grupo que recibió Aprepitant (NK-R1A), y el otro como grupo control. Los animales fueron sacrificados a los 7 ó 14 días, y se evaluó el número, severidad e histopatología de las AP. Resultados: El NK-Rl A disminuyó el número (40 por ciento menos) y severidad de las AP (p = 0,001) en relación al grupo control y presentó menos AP en órganos manipulados y no manipulados durante la cirugía. Ademßs presentó menor grado de fibrosis (p = 0,001), menor inflamación (p = 0,005) y menor proliferación vascular (p = 0,047) que el grupo control. Conclusión: El tratamiento peritoneal con NK-R1A es eficaz en la prevención de la formación de AP.

Antagonista de receptores de neurokinina tipo 1 versus ácido hialurónico/carboximetilcelulosa en la prevención de adherencias peritoneales postoperatorias: estudio experimental en modelo animal / Neurokinin 1 receptor antagonist versus hyaluronic acid-carboxymethylcellulose in the prevention of postoperative peritoneal adhesions: experimental study in biomodels

La actividad fibrinolítica juega un papel fundamental en el desarrollo de las adherencias peritoneales (AP), y se conoce que la sustancia P al actuar sobre receptores de neurokinina tipo 1 a nivel peritoneal, disminuyen la fibrinólisis, favoreciendo la formación de las mismas. La efectividad de antagonistas de estos receptores como tratamiento preventivo de AP, ha sido evaluada, obteniendose resultados favorables. Comparar la efectividad del tratamiento intraperitoneal con antagonista de receptores 1 de neurokinina (NK-RIA) versus gel de ácido hialurónico/carboximetilcelulosa (AH/CMC) en la prevención de AP en modelo animal. A 60 ratas Wistar se les practicó cirugía formadora de AP y fueron distribuidas de forma aleatoria en 3 grupos, un grupo que recibió aprepitant (NK_RIA), otro recibió gel de AH/CMC y un grupo control. Los animales fueron sacrificados a los 7 ó 14 días, y se evaluó el número, severidad e histopatología de las AP. Tanto el NK-RIA como el AC/CMC disminuyeron el número (40% y 38% respectivamente) y severidad de las AP (p=0,001 y p=0,029 rerspectivamente) en relación al grupo control, sin diferencias estadísticas entre ellos (p=0,806). El grupo de NK-RIA presentó menos AP en órganos no manipulados durante la cirugía en relación a los otros 2 grupos. Ambos tratamientos presentaron menor grado de fibrosis que el control, sin embargo el grupo de NK-RIA tuvo menor inflamación (P=0,005) y proliferación vascular (P=0,047) que el AH/CMC. El NK-RIA tiene alta eficacia previendo la formación de AP, equiparable a la gel de AH/CMC.

The fibrinolytic activity play an important role in the peritoneal adhesions (PA) development. It’s well known that of substance P decreased the fibrinolysis by binding the neurokinin-1 receptor, improving the PA formation. Lot of investigation have evaluated the efficacy in PA prevention of antagonist of these receptors, with very good result. To compare the effectivences of intraperitoneal treatment with a neurokin-1 receptor antagonist (NK-RIA) versus hyaluronic acid/carboxymethylcellulose (HA/CMC) gel, in peritoneal adhesion prevention in animal model. In 60 male Wistar rats, PA were induced, and then randomly assigned to 3 groups. A group treated with aprepitant (NK-RIA), a second group treated with HH/CMC and a control group. The animals were killed at 7 or 14 postoperative day, and the number, severity and histopathology of PA were evaluated. NK-RIA and HA/CMC decreased the number (40% and 38% respectively) and severity (p=0,001 and p=0,029 respectively) of PA when compare to control group. The NKRIA group had less PA in no manipulated organs in surgery that the others 2 groups. Both treatments presented less fibrosis that control, however the NK-RIA group presented less inflammation (p=0,005) and vascular proliferation (p=0,047) than HA/CMC group. The NK-RIA is as effective as HC/CMC in preventing PA.