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Background The current treatment program with penehyclidine hydrochloride (PHC) for acute severe organophosphorus pesticide poisoning (ASOPP) patients exerts a positive effect but with concerned adverse reactions. Objective To evaluate the treatment effect of a revised ASOPP treatment program with PHC. Methods A prospective single-blind randomized controlled trial was conducted. A total of 157 patients with ASOPP were divided into a revised treatment group (82 cases) and a conventional treatment group (75 cases) by random number table. The two groups received the same basic treatment measures including active life support, routine gastric lavage, catharsis, and pralidoxime treatment. The revised treatment group followed a revised PHC treatment protocol initiated by first a small dose of PHC and followed by small doses of PHC administration/discontinuation through frequent observations at different time points. The conventional treatment group received the conventional program. Treatment effects and incidence rates of possible adverse reactions were compared between the two groups. Results Compared with the conventional treatment group, the revised treatment group obtained delay in penetrogenation time point, higher success rate in catharsis, earlier cholinesterase-turning time, and shorter hospitalization period with statistical significance (all Ps＜0.05). No differences were found in terms of time for symptoms of poisoning to disappear, incidence rates of intermediate myasthenic syndrome and delayed polyneuropathy, mechanical ventilation time, and cure rate (all Ps＞0.05). Less adverse reactions occurred in the revised treatment group including tachycardia and delirium than in the conventional treatment control group (all Ps＜0.05). Conclusion The revised ASOPP treatment program with PHC is similar to the current recommended treatment program in treatment effects, but with less adverse reactions.
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BACKGROUND@#Penehyclidine is a newly developed anticholinergic agent. We aimed to investigate the role of penehyclidine in acute organophosphorus pesticide poisoning (OP) patients.@*METHODS@#We searched the Pubmed, Cochrane library, EMBASE, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical literature (CBM) and Wanfang databases. Randomized controlled trials (RCTs) recruiting acute OP patients were identified for meta-analysis. Main outcomesincluded cure rate, mortality rate, time to atropinization, time to 60% normal acetylcholinesterase (AchE) level, rate of intermediate syndrome (IMS) and rate of adverse drug reactions (ADR).@*RESULTS@#Sixteen RCTs involving 1,334 patients were identified. Compared with the atropine-or penehyclidine-alone groups, atropine combined with penehyclidine significantly increased the cure rate (penehyclidine+atropine vs. atropine, 0.97 vs. 0.86, RR 1.13, 95% CI [1.07–1.19]; penehyclidine+atropine vs. penehyclidine, 0.93 vs. 0.80, RR 1.08, 95% CI [1.01–1.15]) and reduced the mortality rate (penehyclidine+atropine vs. atropine, 0.015 vs. 0.11, RR 0.17, 95% CI [0.06–0.49]; penehyclidine+atropine vs. penehyclidine, 0.13 vs. 0.08, RR 0.23, 95% CI [0.04–1.28]). Atropine combined with penehyclidine in OP patients also helped reduce the time to atropinization and AchE recovery, the rate of IMS and the rate of ADR. Compared with a single dose of atropine, a single dose of penehyclidine also significantly elevated the cure rate, reduced times to atropinization, AchE recovery, and rate of IMS.@*CONCLUSION@#Atropine combined with penehyclidine benefits OP patients by enhancing the cure rate, mortality rate, time to atropinization, AchE recovery, IMS rate, total ADR and duration of hospitalization. Penehyclidine combined with atropine is likely a better initial therapy for OP patients than atropine alone.
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Objective To investigate the anti-inflammatory effect of penehyclidine hydrochloride on oleic acid-induced acute respiratory distress syndrome (ARDS) in rats.Methods According to randomize number table method, 30 adult male Sprague-Dawley (SD) rats were divided into control group, model group and treatment group. Catheters were placed in femoral vein in each group. The control group was injected with 1.1 mL/kg physiological saline; the model group was injected with 0.1 mL/kg oleic acid and then injected with 1.0 mL/kg normal saline to establish ARDS model; the treatment group was injected with 0.1 mL/kg oleic acid and then injected with 1.0 mL/kg penehyclidine hydrochloride. At 3 hours after the model was established, blood gas analysis was carried out in each group, oxygenation index (PaO2/FiO2) was calculated, and the levels of serum interleukins (IL-1, IL-6) were measured by enzyme linked immunosorbent assay (ELISA). Rats were sacrificed to harvest lung tissue, and the lung wet/dry ratio (W/D) was calculated; the morphological changes of lung tissue was observed under microscope; the superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were detected by colorimetry; the expression of tumor necrosis factor-α(TNF-α) in lung tissue was detected by immunohistochemical method. The correlations between lung W/D ratio and various indicators were analyzed using Pearson correlation test.Results Compared with the control group, PaO2/FiO2 in model group was significantly decreased, lung W/D ratio was significantly increased, serum IL-1, IL-6 levels and lung tissue MDA content were significantly increased, lung tissue SOD activity was significantly decreased; the alveolar space was filled with exudate, neutrophils and red blood cells, and there were obvious edema and broadening in pulmonary interstitial and alveolar under light microscope; the type Ⅱ alveolar epithelial cells were partly destroyed, accompanied by lamellar body degeneration and emptying phenomenon under electron microscope; and immunohistochemistry showed that the positive expression of TNF-α in lung tissue was significantly increased. Compared with the model group, PaO2/FiO2 in the treatment group was significantly improved [mmHg (1 mmHg = 0.133 kPa): 204.42±31.61 vs. 113.91±47.78,P < 0.05], the lung W/D ratio was significantly decreased (5.80±0.44 vs. 6.82±0.59,P < 0.01), serum IL-1, IL-6 levels and lung tissue MDA content were significantly decreased [IL-1 (μg/L): 18.38±0.28 vs. 20.04±0.39, IL-6 (μg/L): 12.64±0.67 vs. 14.28±1.33, MDA (nmol/mg): 3.95±0.28 vs. 5.17±0.29, allP < 0.05], the activity of SOD in lung tissue was significantly increased (U/mg: 48.75±2.41 vs. 45.09±1.69,P < 0.01), histological and pathological changes were significantly reduced, and the positive expression of TNF-α in lung tissue was significantly reduced [positive cell rate: (25.80±3.44)％ vs. (38.82±3.59)％,P < 0.01].Conclusion Penehyclidine hydrochloride can effectively improve the oxygenation, alleviate lung injury and reduce pulmonary edema in oleic acid induced ARDS rat by decreasing lung W/D ratio, inhibiting oxidative stress and inflammatory response.
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Objective To compare the lung protection roles of intraperitoneal pre-injection with penehyclidine for two kinds of rat models with pulmonary and extrapulmonary acute respiratory distress syndrome (ARDSp and ARDSexp). Methods Forty healthy adult Sprague-Dawley (SD) rats were randomly divided into five groups (each n = 8): the rats in sham group received only tracheotomy; the ARDS rat models were reproduced by intratracheal inhalation of 0.1 mol/L hydrochloric acid (HCl) 2 mL/kg to simulate ARDSexp (HCl group) and 0.15 mL/kg oleic acid (OA) intravenous injection to simulate ARDSp (OA group) after tracheotomy; and the rats in two intervention groups were intraperitoneal injected with penehyclidine 0.5 mg/kg. All rats were received mechanical ventilation immediately after model reproduction. Carotid arterial blood was collected 4 hours after model reproduction for determining the arterial partial pressure of oxygen (PaO2), and oxygenation index (PaO2/FiO2) was calculated. Carotid venous blood and lung tissues were harvested, and the levels of myeloperoxidase (MPO), interleukin-8 (IL-8) and nuclear factor-κB (NF-κB) in serum and lung tissue were determined by enzyme linked immunosorbent assay (ELISA). Pulmonary pathology was observed under optical microscope, and pathological score of Smith was calculated. Results Under optical microscope, a large number of inflammatory cells infiltration in lung tissue, obvious alveolar collapse, fibrous exudation in alveolar and alveolar hyaline were found in HCl group. In OA group, however, microvascular congestion and interstitial pulmonary edema were the main pathological changes, with alveolar structure being kept relatively intact. Compared with sham group, pathological score of Smith in HCl and OA groups were increased, oxygenation was lowered, and inflammatory factors levels in serum and lung tissue were increased with levels in lung tissue being higher than those in serum, without significant difference between the two models. When pretreated with penehyclidine, however, pathological injury induced by HCl or OA was alleviated, and pathological score of Smith was also decreased as compared with that of corresponding model groups (5.48±1.76 vs. 9.69±2.02, 3.97±2.14 vs. 8.71±2.18, both P < 0.05), PaO2/FiO2was raised significantly [mmHg (1 mmHg = 0.133 kPa): 323±55 vs. 211±27, 307±56 vs. 207±31, both P < 0.05], the inflammatory factors levels in serum and lung tissue were obviously decreased [MPO (μg/L): 11.91±1.55 vs. 14.82±1.25, 12.75±1.16 vs. 16.97±2.06 in serum, 25.80±3.36 vs. 35.18±4.01, 24.23±1.24 vs. 33.94±1.43 in lung tissue; IL-8 (ng/L): 358±30 vs. 459±25, 377±38 vs. 427±34 in serum, 736±53 vs. 866±51, 701±53 vs. 809±39 in lung tissue; NF-κB (ng/L):483±68 vs. 632±73, 514±83 vs. 685±78 in serum, 984±75 vs. 1 217±123, 944±90 vs. 1 163±105 in lung tissue;all P < 0.05]. But all parameters above were similar between the two pretreatment groups (all P > 0.05). Conclusions Inflammatory cell infiltration and alveolar collapse mainly happened in HCl induced ARDSp, while pulmonary interstitial edema and hemorrhage was mostly seen in ARDSexp rats induced by OA intravenous injection. There was no significant difference in oxygenation and inflammatory response between the two models of rats. Pre-intraperitoneal injection of penehyclidine equally improved oxygenation state, inhibited lung inflammation response, and reduced lung injury in the two kinds of ARDS, but there was no difference in protective role between two models pretreated with penehyclidine.
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Objective To investigate the preventive and therapeutic effects of different doses of penehyclidine hydrochloride preoperative medication on the catheter -related bladder discomfort during general anesthesia recovery period.Methods 160 adult patients who underwent general anesthesia for elective surgery were randomly dividided into four groups.40 patients in each group received intravenous injection 30min before surgery with penehyclidine hydrochloride 0.005mg/kg (group A),0.010mg/kg (group B),0.015mg/kg (group C),or normal saline (group D).All patients were catheterized with a 12 Fr Foley's catheter and the balloon was inflated with 8mL normal saline after anesthesia induction .The bladder discomfort was assessed during recovery in the post -anesthesia care unit .The severity of bladder discomfort was graded as mild , moderate and severe .Results The incidence of moderate and severe bladder discomfort in group B and group C (group B:20.0％,5.0％;group C:12.8％,2.5％) were significant lower compared with group A and group D ( group A:38.5％,12.8％;group D:46.0％ 15.4％) (χ2 =7.834, 6.764,8.163,14.172,8.362,6.943,15.413,17.512,all P<0.05).There was no significant difference between group B and group C , group A and group D .Conclusion Hydrochloride penehyclidine preoperative administration with 0.010mg/kg or 0.015mg/kg can effectively control the incidence of catheter discomfort during general anesthesia recovery period and 0.010mg/kg is appropriate for the elderly .
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Objective To improve the prognosis among patients with respiratory failure poisoned by organophosphorus pesticide though analyzing and discussing the emergency measures and treatment effects. Methods From January 2014 to December 2016, 86 patients with respiratory failure caused by severe organophosphorus pesticide poisoning were received in the Emergency Department in Nanchong Central Hospital.The patients were numbered according to the order of the treatment and randomly divided into control group and observation group with 43 cases in each group.All patients were treated with routine emergency measures (gastric lavage and endotracheal intubation, rehydration, and symptomatic treatment).The control group was treated with pralidoxime chloride injection and injection of atropine detoxification while the observation group was given pralidoxime chloride combined with Penehyclidine Hydrochloride Injection detoxification.We compared the alleviation of clinical symptoms and the changes of cholinesterase (CHE) and respiratory function (respiratory frequency, Pa02, Pa02/Fi02) between the two groups of patients 10 min and 30 min after administration. The statistics of atropinization time, blood purification treatment rate, tracheotomy rate, hospital mortality,complications and treatment time were recorded. Results No statistic significance was observed among the two groups of patients in gender,age, weight,body mass index (BMI),the severity of poisoning,types of organophosphorus drugs and blood cholinesterase (CHE) at the first visit (P＞0.05).Blood CHE was effectively improved among the two groups 10 min and 30 min after the treatment and significantly higher CHE was seen in the observation group compared to the control group (P＜0.05) . The overall clinical symptom rate was lower 10min and 30min after the treatment (P＜ 0.05), and the clinical symptom rate of the observation group was lower than that of the control group (P＜0.05) . The respiratory function indexes (respiratory rate, Pa02, Pa02/Fi02) were significantly improved 10 min and 30 min after the treatment in both groups compared with those before the treatment (P＜ 0.05) .The blood purification treatment rate, tracheotomy rate, complication rate, hospitalization time and atropine time of the observation group were significantly lower than those of the control group (P＜ 0.05) . No significant difference was found in mortality rate between the two groups (P＞0.05).Conclusion After giving effective respiration and circulation support, administration of penehyclidine hydrochloride combined with pralidoxime chloride detoxification can effectively restore the cholinesterase activity among patients with organophosphorus pesticide poisoning and improve respiratory function and prognosis, whichshows a high clinical value.
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Objective To explore the clinical effect of blood perfusion combined with penehyclidine hydrochloride injection in the treatment of acute severe organophosphorus pesticide poisoning.Methods 58 patients with severe organophosphorus pesticide poisoning were selected as the research subjects.By using digital table method,they were randomly divided into observation group and control group,29 cases in each group.The two groups were given conventional treatment and blood perfusion treatment after admission,the observation group was treated with penehyclidine hydrochloride injection on this base.Before and after treatment,the myocardial enzymes,liver,kidney function index,blood gas analysis,cholinesterase activity,as well as other treatment of the two groups were observed,and the results were compared.Results Compared with the control group,after treatment,the myocardial enzyme,transaminase,serum amylase and creatinine levels in the observation group were significantly lower,cholinesterase level was significantly increased,the oxygen partial pressure increased,the partial pressure of carbon dioxide decreased obviously,the differences were statistically significant(all P<0.05).The hospitalization time and cholinesterase activity recovery time of the observation group were significantly shorter than those of the control group[(12.57±2.14)d vs.(16.35±2.73)d,(5.46±2.29)d vs.(7.61±3.47)d],and the cure rate of the observation group was significantly higher than that of the control group(100.00% vs.82.76%),the differences were statistically significant(t=2.139,2.208,x2=5.472,all P<0.05).Conclusion Blood perfusion can directly adsorb organophosphorus pesticide,shorten the recovery time of cholinesterase and reduce the case fatality rate,and it combined with penehyclidine hydrochloride injection not only can improve the clinical curative effect of blood perfusion,but also can protect the organ.
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Objective To study the influence of penehyclidine hydrochloride(PHC)on inflammatory factors in patients with acute lung injury(ALI).Methods Total of 96 patients with ALI were randomly divided into treatment group(48 cases)and control group(48 cases).Patients in the treatment group were given conventional therapy,plus penehyclidine hydrochloride injection 1 mg,im,q12 h or q8h,the first dose could be doubled,at least 2 days of continuous application;Patients in the control group were received conventional therapy.Tumor necrosis factor α (TNF-α),interleukin-6 (IL-6),high sensitive C reactive protein (hs-CRP),calcitonin (PCT),oxygenation index (PaO2/FiO2),lung injury score (LIS) and acute physiology and chronic health status score (APACHE II) of patients on each time point were compared between the two groups before and after treatment,and mechanical ventilation time,intensive care (ICU) treatment time,acute respiratory distress syndrome (ARDS) and ICU mortality were recorded.Results On each time point of treatment,TNF-α,IL-6,hs-CRP,PCT,LIS,APACHE II in treatment group were significantly lower than that of control group (P<0.05),PaO2/FiO2 was significantly higher than that of control group(P<0.01).The mechanical ventilation time,ICU treatment time in treatment group were shorter than that of control group(all P<0.05),The incidence of ARDS in treatment group and control group was 20.8% and 39.6%,respectively(P<0.05);ICU mortality rate was 12.5% and 31.2%,respectively(P<0.05).Conclusion Penehyclidine hydrochloride can effectively improve the oxygen metabolism in acute lung injury,regulate the pulmonary inflammatory response and improve the prognosis of patients.
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Objective To investigate the role of M3 receptor in the effect of penehyclidine hydrochloride(PHC) upregulating β-arrestin-1 expression in lipopolysaccharide(LPS)-induced human pulmonary microvascular endothelial cell(HPMVEC) injury.Methods.M3 shRNA transfected HPMVEC and normal HPMVEC cells were randomly divided into LPS group(A),LPS+pHC group(B),LPS+ M3 shRNA transfection group(C) and PHC+ LPS+ M3 shRNA transfection group(D).The cytoskeleton change was observed by laser scanning confocal.The LDH level in cellular supernate was detected.The VCAM 1 protein expression was examined by immunofluorescence chemistry.β-arrestin-1 protein expression was determined by Western blot and β-arrestin-1mRNA expression was measured by real-time PCR.Results Compared with the group A or C,F-actin cytoskeleton arrangement in the group B or D was neat,the LDH level and VCAM-1 protein expression were decreased,and β-arrestin-1 expression was increased;compared with group A or B,F-actin cytoskeleton arrangement in the group C or D was neat,the LDH level and VCAM-1 protein expression were decreased,while the β-arrestin-1 expression had no obvious change.Conclusion Silence M3 receptor is conducive to reduce LPS-induced HPMVEC injury.But the role of PHC up-regulating β-arrestin-1 expression has no necessary connection with M3 receptor.
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OBJECTIVE:To study the affinity of penehyclidine optical isomers to muscarinic(M)receptor subtypes,and pro-vide reference for revealing the action targets and efficacy selectivity of penehyclidine. METHODS:Homology modeling,molecu-lar docking and other molecular simulation technologies were used to analyze and predict the binding energy of 4 optical isomers to M receptor subtypes and judge its affinity by comparing the binding energy of different optical isomers R1 (3R,2′R),R2 (3R, 2′S),S1(3S,2′R),S2(3S,2′S)with M receptor subtypes M1-M5. RESULTS:All the 4 optical isomers can dock into the ac-tive sites of M receptor subtypes,and different optical isomers showed great differences in the molecular docking with different M receptor subtypes. Penehyclidine isomers showed larger binding energy to M3,the binding energy of 4 optical isomers ranged in 5736.519-5907.143 kcal/mol. The binding energy of R1 to M1 was 1190.041 kcal/mol;while those of other optical isomers to each receptor subtype were lower or negative. CONCLUSIONS:R1 shows the affinity to M1 receptor. And all the 4 optical isomer show the affinity to M3.
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Objective To investigate the effects of penehyclidine hydrochloride combined with ulinastatin on postoperative cognitive function in the patients undergoing thoracic surgery.Methods One hundred and twenty patients undergoing lung cancer thoracotomic radical resection were randomly divided into hydrochloride penehyclidine composite ulinastatin group(HU group),hydrochloride penehyclidine group(H group),ulinastatin group(U group)and control group(C group).The arterial blood was collected for detecting OI,TNF-α,IL-6 and IL-8.The serum levels of S-100β and NSE were detected.The MMSE scores were evaluated.Results Compared with the H group and U group,the levels of TNF-α at T3-4 in the HU group were decreased,and the levels of IL-6 and IL-8 at T2-4 were decreased,while OI was increased(P＜0.05).Compared with the H group and U group,the serum levels of S-100β and NSE at T5-8 in the HU group were decreased(P＜0.05);compared with the H group and U group,the MMSE scores at T6-7 in the HU group were increased(P＜0.05).Conclusion Penehyclidine hydrochloride combined with ulinastatin could reduce the inflammation reaction during one lung ventilation in thoractomy and improves the postoperative cognitive function.
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Objective To compare the clinical effect of penehyclidine hydrochloride and atropine in the treatment of acute organophosphorus pesticide poisoning.Methods 86 patients with organophosphorus pesticide poisoning were selected and randomly assigned to the observation group and the control group according to the digital table,43 cases in each group.The two groups were given conventional treatment,while the control group was treated with atropine,the observation group was given penehyclidine hydrochloride.The disappearance time of main symptoms, rescue success rate and adverse reactions of the two groups were observed.Results After salvage treatment, the rescue success rate of the observation group was 97.8%,which of the control group was 88.4%,the difference was statistically significant (x2=1.433,P<0.05).The disappear time of M like symptoms,N like symptoms and central nervous system symptoms in the observation group was significantly shorter compared with the control group (all P<0.05).The number of drugs,dosage,cholinesterase recovery time and hospitalization time between the two groups had statistically significant differences (P<0.05).The incidence rates of blurred vision,restlessness,heart rate and urinary retention in the control group were significantly higher than those in the observation group (all P<0.05).Conclusion Penehyclidine hydrochloride for acute organophosphorus pesticide poisoning can significantly reduce the incidence of symptoms,shorten the disappearance time of symptoms,reduce hospitalization time,improve the efficacy of rescue,reduce the incidence of adverse reactions, it is safe,effective and has great clinical significance.
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Objective To investigate the effect of pre injection of penehyclidine hydrochloride on the airway gland secretion of children with laparoscopic inguinal hernia surgery under general anesthesia.Methods 72 cases of children undergoing laparoscopic inguinal hernia surgery under general anesthesia in pediatric surgery department in our hospital were selected and divided into two groups,grouped by random number table method,control group of 36 cases were treated with preoperative injection of atropine,the experiment group of 36 cases were treated with preoperative injection of penehyclidine hydrochloride.Heart rate on pre injection(T0),before induction of anesthesia(T1),five min after induction(T2),ten min after induction(T3)and extubation(T4),the airway gland secretion,respiratory function related indexes,and the incidence of adverse reactions were compared.Results Compared with the control group,re fixed rate of tracheal tube during operation and the incidence of choking tube at T4 time were lower,the levels of PIP、Raw were lower and the level of CL was higher on five min after intubation,the HR at T1,T2,T3,T4 time was lower,with statistical significance(P<0.05);the incidence of adverse reactions in the control group 30.56％was higher than the experiment group 11.11％,with statistical significance(P<0.05).Conclusion Pre injection of penehyclidine hydrochloride can inhibit airway gland secretion in children with laparoscopic inguinal hernia surgery under general anesthesia,protect the respiratory function,and does not increase heart rate,the safety was higher.
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OBJECTIVE:To evaluate the economics of penehyclidine hydrochloride and atropine in the treatment of acute organophosphorus poisoning (AOPP).METHODS:The information of 118 AOPP patients were collected and divided into group A (59 cases) and B (59 cases) according to therapy plan.There were 22 cases of mild poisoning,20 cases of moderate poisoning and 17 cases of severe poisoning in group A.There were 21 mild cases,21 moderate cases and 17 severe cases in group B.Based on routine treatment,group A was given Penehyclidine hydrochloride injection intramuscularly with initial dose of 1 mg (mild),2 mg (moderate) and 4 mg (severe).Group B was given Atropine sulfate injection intravenously,with initial dose of 2 mg (mild),5 mg (moderate) and 10 mg (severe).Both received maintenance treatment according to patients condition and stopped taking medicine after symptoms disappeared.Clinical efficacies,the time of acetylcholinesterase recovery and ADR were observed in 2 groups.The economics of therapy plans for mild,moderate and severe poisoning were evaluated in 2 groups by cost-effectiveness analysis.RESULTS:There was no statistical significance in total response rate of mild poisoning or the time of acetylcholinesterase recovery between 2 groups (P＞0.05).Total effective rates of moderate and severe poisoning in group A were significantly higher than group B,and the time of acetylcholinesterase recovery was significantly shorter than group B,with statistical significance (P＜0.05).There was no statistical significance in the incidence of ADR in mild,moderate and severe poisoning patients (P＞0.05).Cost-effectiveness ratio of penehyclidine hydrochloride was similar to that of atropine in mild poisoning patients;that of penehyclidine hydrochloride were significantly lower than that of atropine in moderate and severe patients.It was inline with the results of sensitivity analysis.CONCLUSIONS:Based on routine treatment,penehyclidine hydrochloride is similar to atropine in therapeutic efficacy of AOPP and the time of acetylcholinesterase recovery.For moderate and severe AOPP patients,penehyclidine hydrochloride is significantly better than atropine in improving therapeutic efficacy and the time of acetylcholinesterase recovery.The safety of 2 drugs are satisfactory;penehyclidine hydrochloride possesses cost-effectiveness advantage.
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Objective To investigate the effect of penehyclidine hydrochloride ( PHC) pretreat?ment on nuclear factor erythroid 2?related factor 2∕heme oxygenase?1 ( Nrf2∕HO?1) signaling pathway in re?nal tissues of rats with rhabdomyolysis?induced acute kidney injury ( AKI) . Methods Thirty?six pathogen?free male Sprague?Dawley rats, weighing 200-220 g, were assigned into 3 groups ( n=12 each) using a random number table: control group (group C), group AKI and PHC pretreatment group (group PHC). Rhabdomyolysis was induced by intramuscular injection of 50% glycerol 10 ml∕kg in bilateral hindlimbs. PHC 0?2 mg∕kg was injected intraperitoneally at 30 min before glycerol was injected intramuscularly in group PHC. At 1 and 6 h after glycerol injection, serum was collected for determination of blood urea nitro?gen ( BUN) and creatinine ( Cr) concentrations, and bilateral kidneys were harvested for pathological ex?amination and for determination of HO?1 activity and expression of Nrf2 mRNA and HO?1 mRNA ( by quan?titative real?time polymerase chain reaction) , Nrf2 in nucleoprotein and total protein and HO?1 in total pro?tein in renal tissues ( by Western blot) . The damage to the renal tubules was scored. Results Compared with group C, the BUN and Cr concentrations in serum and renal tubular damage scores were significantly increased, the expression of Nrf2 in nucleoprotein and total protein and HO?1 in total protein was signifi?cantly up?regulated, and HO?1 activity was significantly increased in AKI and PHC groups, the expression of HO?1 mRNA was significantly up?regulated in group AKI, and the expression of Nrf2 mRNA and HO?1 mRNA was significantly up?regulated in group PHC (P<0?01 or 0?05). Compared with group AKI, the BUN and Cr concentrations in serum and renal tubular damage scores were significantly decreased, the ex?pression of Nrf2 in nucleoprotein and total protein and HO?1 in total protein was significantly up?regulated, and HO?1 activity was significantly increased in group PHC ( P<0?01 or 0?05) . Conclusion The mecha?nism by which PHC pretreatment attenuates rhabdomyolysis?induced AKI may be related to activation of Nrf2∕HO?1 signaling pathway in renal tissues of rats.
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Objective To investigate the effects of penehyclidine hydrochloride (PHCD)on cerebral ischemia-reperfusion injury induced by intrauterine distress in fetal rats.Methods Eighty mature fetal rats weighing 4.52-4.81 g were randomly divided into four groups (n =20):sham opera-tion group(group S),PHCD control group (group S+ P),cerebral IR group (group IR),PHCD treatment group(group IR+P).Fetal rat intrauterine distress model was set up by clamping bilateral uterine horn vessels of pregnant rats.PHCD 2 mg/kg was injected in pregnant rat’s gluteus at 30 min before intrauterine distress model was set up in group IR+P,the same volume saline was injected in pregnant rat’s gluteus before shame operation in group S,the same volume PHCD was injected in pregnant rat’s gluteus before shame operation in group S+P.Fetal rats were decapitated at 12 h after the reperfusion,the peripheral blood of fetal rats was detected by blood gas analysis (including PH, PaO 2 ,PaCO 2 ,Lac);the infarct volume and the infarct volume fraction were detected by TTC stai-ning;pathological changes in lung tissue were observed by HE staining;the TNF-α,IL-6 content in the brain were detected by ELISA;the expression of NF-κB mRNA was detected by quantitative Real-time PCR,the expression of NF-κB p65 protein was detected by Western-blotting.Results The blood PH,PaO 2 in group IR and IR+P were lower than group S and S+P,the blood PH,PaO 2 in group IR+P was higher than group IR.Compared with group S and group S+P,the blood PaCO 2 , Lac,the infarct volume and the infarct volume fraction,the concentration of TNF-αand IL-6,the ex-pression of NF-κB mRNA and protein were significantly increased in group IR and IR+P (P <0.05), and those in group IR+P were lower than group IR (P <0.05 ).The pathological changes in brain tissue were significantly attenuated in group IR + P (P < 0.05 ).Conclusion Pretreatment with PHCDcouldattenuatecerebralischemia-reperfusioninjuryoffetalratsinducedbyintrauterinedistress. ThemechanismscouldrelatetotheinhibitionofNF-κBsignalingpathwayinbraintissues.
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Objective To investigate effects of penehyclidine hydrochloride (PHC)protects a-gainst acute lung injury (ALI)in heart valve replacement patients with cardiopulmonary bypass (CPB).Methods Thirty rheumatic heart disease patients,eighteen males and twelve females with NYHA Ⅱ or Ⅲ,with cardiac valve replacement undergoing CPB were enrolled in the study.All pa-tients were randomly divided into group P and group C (fifteen in each group).Patients in group P re-ceived an intravenous injection of 0.03 mg/kg PHC before anesthesia induction and those in group C received the same volume of normal saline.Blood samples were collected to monitor the concentrations of IL-6,TNF-αand NF-κB at the following time points:before anesthesia induction (T0 ),the end of the operation (T1 ),6 hours (T2 ),12 hours (T3 )and 24 hours(T4 )postoperatively,arterial blood gas analyses were detected and oxygenation index (OI)was calculated at the time of T0 ,T1 and T4 , as well as lung dynamic compliance of patients adopt at the time of soon after anesthesia induction and the end of the operation.The outcomes included duration of intubation (DOI),length of intensive care unit stay (LOI)and length of hospital stay after the surgery (LOH).Results The DOI,LOI and LOH in group P were shorter than those in group C,but there was no statistical significance between groups.The plasma levels of IL-6,TNF-α and NF-κB were higher at T1-T4 than T0 in both groups (P <0.05),and those in group P were statistically lower than group C at T1-T4 (P <0.05).The val-ues of OI at T0 and T1 were obviously lower than T4 in both groups (P <0.05),and that in group P was slightly higher than group C at T4 but without statistical significance.The lung dynamic compli-ance of patients in group P at the end of operation was obviously higher than that in group C (P <0.05).Conclusion PHC inhibits systemic inflammatory response,improves lung compliance,amel-iorates tissue oxygen supply and encourages postoperative rehabilitation in valve heart replacement pa-tients with CPB,and its mechanisms is relevant to the regulation of NF-κB signal way on the produc-tion of such proinflammatory cytokines as IL-6 and TNF-α.
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Objective To investigate the effects of penehyclidine hydrochloride(PHC)precon-ditioning on hepatic ischemia-reperfusion injury (HIRI)in rats.Methods Fifty-four male Sprague-Dawley rats,weighing 230-250 g,were randomly divided into three groups (n =18 each):sham op-eration group (group S),HIRI group (group HR)and penehyclidine hydrochloride group (group PHC).In group S,the hepatoduodenal ligaments of rats were only pulled and separated,then abdo-mens were closed.In group HR,an atraumatic vascular clip was placed on the vessels blocking the portal venous blood supply to the median and left lateral lobes of the liver for 45 minutes,which re-sulted in approximately 70% rat liver ischemia injury.In group PHC,the rats were treated with 0.45 mg/kg penehyclidine hydrochloride at 30 minutes before the portal venous and hepatic arterial were blocked like group HR.Animals were killed at 2 h (T1 ,n =6),4 h (T2 ,n =6),24 h (T3 ,n =6) after HIRI or sham surgery.Liver tissues and blood samples were taken for analysis.The serum con-centration of ALT and AST were measured as the markers of hepatic functional damage.The TNF-a and IL-1βconcentration were measured by the enzyme linked immunosorbent assay (ELISA)tech-nique.The endothelial nitric oxide synthase (eNOS ) and hypoxia-inducible factor (HIF-1α) expression were measured by immunohistochemical staining.Results Compared with group S,the expressions of ALT,AST,TNF-αand IL-1βin groups HR and PHC increased at T1-T3 (P <0.05), which were similar to the change trend of HIR-1αand eNOS expressions (P <0.05).Compared with group HR,the expression of ALT,AST,TNF-αand IL-1βin group PHC decreased at T1-T3 (P <0.05).Nevertheless expression of HIF-1αand eNOS of groups HR and HPC were increased than that of group S,and experssion of HIF-1αand eNOS of group HPC were increased than that of group HR at T1 and T2 (P < 0.05 ).Conclusion PHC preconditioning can protect the liver from HIRI.The mechanism may be associated with the up-regulation of eNOS and HIF-1α,as well as reducing the in-flammatory response.
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Objective To explore whether hydrochloride penehyclidine can inhibit rat pulmonary hypertension induced by monocrotaline and prevent or relieve the remodeling of pulmonary vascular.Methods Thirty healthy male SD rats (aged 3-4 weeks,weighing 90-100 g)were randomly divided into normal control group (group C),monocrotaline pulmonary hypertension group (group M)and hydrochloride penehyclidine treatment group (group P,n = 10 each).Rat pulmonary hyper-tension model was established by abdominally injecting 60 mg/kg monocrotaline all at once;The con-trol group was abdominally injected equal volume of normal saline all at once;the treatment group P 2 mg/kg hydrochloric penehyclidine 1 5 minutes before model building 1 mg/kg hydrochloric penehyclid-ine two days after model building;while the other two groups received equal volume of normal saline as placebo at the same time of medicine injecting,which lasted consecutively for 3 weeks.21 days af-ter model building,the haemodynamics (pulmonary artery pressure and right ventricular pressure) test was performed for all groups;Venous blood was sampled for blood biochemical tests (using ELISA method to test the content of NO and ET-1 )before executing the rats.The left lung tissue was sliced to observe the pathological morphological changes of lung tissues.The right lung tissue was cryopreserved for other tests.Results Compared with the normal control group,the pulmonary artery pressure and right ventricular pressure of monocrotaline pulmonary hypertension group notably enhanced (P <0.05);The pulmonary arterioles strongly thickened;The lumen of pulmonary arteri-oles became narrow and even blocked;The inflammatory cells of lung tissues apparently infiltrated. When compared with the monocrotaline pulmonary hypertension group, the pulmonary artery pressure and right ventricular pressure of the hydrochloride penehyclidine treatment group greatly lowered (P <0.05);Both the thickening degree of pulmonary arterioles walls and the infiltrating de-gree of inflammation cells of lung tissues lessened.When compared with the normal control group, the NO content of other groups significantly lowered and the ET-1 content apparently increased;When compared with the monocrotaline pulmonary hypertension group,the NO content of hydrochlo-ride penehyclidine treatment group was higher and the ET-1 content was lower.The differences were statistically significant (P <0.05).Conclusion The rat pulmonary hypertension model has been suc-cessfully built with the help of monocrotaline.The reducing of NO content and increasing of ET-1 was relevant to the formation of rat pulmonary hypertension induced by monocrotaline;The fact that hy-drochloric penehyclidine lowered the pulmonary artery pressure of rat pulmonary hypertension model and improved the thickening degree of pulmonary arterioles walls might involve the increasing of NO cotent and reducing of ET-1 content.
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OBJECTIVE: To explore pharmacokinetics and relative bioavailability of penehyclidine hydrochloride in healthy subjects. METHODS: This study was an open, randomized and cross-over trial design. Twelve healthy subjects were randomized to receive pharmacokinetic analysis which were performed according to the order of ABC, BCA and CAB, and then pharmacokinetic trial of multiple dose was performed following penehyclidine hydrochloride. Twenty healthy subjects were selected to receive bioavailability study following an order of BD or DB. Blood and urine samples were collected at prescribed time and then investigated by LC-MS/MS. RESULTS: The 11 of 12 cases finished the pharmacokinetic trial. The lineare ranges of penehyclidine hydrochloride in plasma and urine were 0.1-8 ng·mL-1, 1-100 ng·mL-1, respectively and accuracy of the method was within 85%-115%. The concentration-time curve of penehyclidine hydrochloride was dose dependent within the ranges of 0.4-0.8 mg after oral administration. ρmax and AUC were significantly increased (P<0.01), Vd and CL were significantly decreased (P<0.01) following multiple dose. The relative bioavailability of penehyclidine hydrochloride was (72.44±21.03)%. The average cumulative excretion rate of penehyclidine hydrochloride with original form accounted for (4.98±1.10)% of the total administered dose. CONCLUSION: The characteristic of linear pharmacokinetics of penehyclidine hydrochloride is performed in healthy subjects after oral administration. Its excretion is mostly via non-urinary system or other metabolites.