Determination of penehyclidine hydrochloride in beagle dog plasma by liquid chromatography-electrospray ionization mass spectrometry and the pharmacokinetic study

To develop a fast and sensitive liquid chromatography-mass spectrometry method for the determination of penehyclidine hydrochloride （PH） in beagle dog plasma. PH and diphenhydramine hydrochloride （internal standard, IS） were extracted with a solvent mixture of petroleum ether-ethyl ether （7：3）. Chromatographic separation was achieved on a reversed-phase Eclipse XDB-C18 column （4.6 mm × 150 mm, 5 um） using the eluent of methanol-water （5 mmol/L ammonium acetate） （90：10, v/v, pH 5.8） as mobile phase. The electrospray ionization source was set at the positive multiple reaction monitoring （MRM） mode. This method involved the use of the [M＋H]^＋ ions of PH and diphenhydramine hydrochloride at m/z 316.4- 128.2 and m/z 256.4-167.2. The calibration curve was linear in the range of 1-1000 ng/mL with a correlation coefficient of 0.9988. The lower limit of quantification was 0.05 ng/mL. The precision, accuracy and recovery of the method were acceptable. Following intravenous injection admires＇ tration at doses of 0.5, 1 and 5 mg/kg PH, the main pharmacokinetic parameters were as the followings, t1/2a 0.33 h, t1/2β 2.44 1% tmax 0.058 1% AUC and Cmax exhibited a linear increase along with the increase of dose. The two-compartment model fit the three dose groups. This method was sensitive, accurate and fast for the determination of concentration of PH in beagle dog plasma. It could be used in pharmacokinetic studies of PH.

Effects of penehyclidine hydrochloride on rat intestinal barrier function during cardiopulmonary bypass

AIM:To test the ability of penehyclidine hydrochloride (PHC) to attenuate intestinal injury in a rat cardiopulmonary bypass (CPB) model.METHODS:Male Sprague-Dawley rats were randomly divided into six groups (eight each):sham-operated control;sham-operated low-dose PHC control (0.6 mg/kg);sham-operated high-dose PHC control (2.0 mg/kg);CPB vehicle control;CPB low-dose PHC (0.6 mg/kg);and CPB high-dose PHC (2.0 mg/kg).Blood samples were collected from the femoral artery 2 h after CPB for determination of plasma diamine oxidase (DAO),D-lactate and endotoxin levels.Spleen,liver,mesenteric lymph nodes and lung were removed for biochemical analyses.Intestinal tissue ultrastructure was examined by electron microscopy.RESULTS:In the sham-operated groups,high-and low-dose-PHC had no significant impact on the levels of DAO,D-lactate and endotoxin,or the incidence of intestinal bacterial translocation (BT).Serum levels of DAO,D-lactate,endotoxin and the incidence of intestinal BT were significantly increased in the surgical groups,compared with the sham-operated groups (0.543 ± 0.061,5.697 ± 0.272,14.75 ± 2.46,and 0/40 vs 1.038 ± 0.252,9.377 ± 0.769,60.37 ± 5.63,and 30/40,respectively,all P < 0.05).PHC alleviated the biochemical and histopathological changes in a dosedependent manner.Serum levels of DAO,D-lactate,and endotoxin and the incidence of intestinal BT in the high-dose PHC group were significantly lower than in the low-dose PHC group (0.637 ± 0.064,6.972 ± 0.349,29.64 ± 5.49,and 14/40 vs 0.998 ± 0.062,7.835 ± 0.330,38.56 ± 4.28,and 6/40,respectively,all P < 0.05).CONCLUSION:PHC protects the structure and function of the intestinal mucosa from injury after CPB in rats.

Neuroprotective effect of penehyclidine hydrochloride on focal cerebral ischemia-reperfusion injury

Penehyclidine hydrochloride can promote microcirculation and reduce vascular permeability. However, the role of penehyclidine hydrochlodde in cerebral ischemia-reperfusion injury remains unclear. In this study, in vivo middle cerebral artery occlusion models were established in experimental rats, and penehyclidine hydrochloride pretreatment was given via intravenous injection prior to model establishment. Tetrazolium chloride, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and immunohistochemical staining showed that, penehyclidine hydrochloride pretreatment markedly attenuated neuronal histopathological changes in the cortex, hippocampus and striatum, reduced infarction size, increased the expression level of BcI-2, decreased the expression level of caspase-3, and inhibited neuronal apoptosis in rats with cerebral ischemia-reperfusion injury. Xanthine oxidase and thiobarbituric acid chromogenic results showed that penehyclidine hydrochloride upregulated the activity of superoxide dismutase and downregulated the concentration of malondialdehyde in the ischemic cerebral cortex and hippocampus, as well as reduced the concentration of extracellular excitatory amino acids in rats with cerebral ischemia-reperfusion injury. In addition, penehyclidine hydrochloride inhibited the expression level of the NR1 subunit in hippocampal nerve cells in vitro following oxygen-glucose deprivation, as detected by PCR. Experimental findings indicate that penehyclidine hydrochloride attenuates neuronal apoptosis and oxidative stress injury after focal cerebral ischemia-reperfusion, thus exerting a neuroprotective effect.

Penehyclidine Hydrochloride Premedication Is Not Associated with Increased Incidence of Post-Operative Cognitive Dysfunction or Delirium:A Systemic Review and Meta-Analysis

Objective Post-operative cognitive dysfunction(POCD)and post-operative delirium(POD)are two common post-operative cerebral complications.The current meta-analysis was to systematically review the effects of penehyclidine hydrochloride(PHC)on POCD and POD in surgical patients.Methods Electronic databases were searched to identify all randomized controlled trials comparing PHC with atropine/scopolamine/placebo on POCD and POD in surgical patients.Primary outcomes of interest included the incidences of POCD and POD;the secondary outcomes of interest included peri-operative minimental state examination(MMSE)scores.Two authors independently extracted peri-operative data,including patients'baseline characteristics,surgical variables,and outcome data.For dichotomous data(POCD and POD occurrence),treatment effects were calculated as odds ratio(OR)and 95%confidential interval(Cl).Each outcome was tested for heterogeneity,and randomized-effects or fixed-effects model was used in the presence or absence of significant heterogeneity.For continuous variables(MMSE scores),treatment effects were calculated as weighted mean difference(WMD)and 95%CI.Statistical significance was defined as P<0.05.Results Our search yielded 33 studies including 4017 patients.Meta-analysis showed that,the incidence of POCD in PHC group was comparable to that in saline group(OR=0.97;95%Ck 0.S8-1.64;P=0.92),scopolamine group(OR=0.78;95%CI:0.48-1.27;P=0.32)and atropine group(0R=1.20;95%Ch 0.86-1.67;P=0.29).The incidence of POD in PHC group was comparable to that in saline group(OR=1.53;95%CI:0.81-2.90;P=0.19)and scopolamine group(OR=0.53;95%CI:0.06-4.56;P=0.56),but higher than that in atropine group(OR=4.49;95%CI:1.34-15.01;P=0.01).Conclusions PHC premedication was not associated with increased incidences of POCD or POD as compared to either scopolamine or placebo.

Penehyclidine hydrochloride attenuates cerebral vasospasm after subarachnoid hemorrhage

A new cholinergic antagonist, penehyclidine hydrochloride （PHC）, was developed independently by Chinese scientists. Administration of PHC into muscle and the cisterna magna could relieve basilar artery vasospasm following subarachnoJd hemorrhage in animals. In addition, injecting PHC into the cisterna magna had better therapeutic effect. Moreover, PHC had the capability of reducing the expression of neuron specific enolase and S-1OOI3 protein in cerebrospinal fluid. There was no effect on the number of surviving neurons in the hippocampal CA1 region, or on the levels of superoxide dismutase and malondialdehyde.

The advantages of penehyclidine hydrochloride over atropine in acute organophosphorus pesticide poisoning:A meta-analysis

Background:Penehyclidine hydrochloride(PHC)has been used for many years as an anticholinergic drug for the treatment of acute organophosphorus pesticide poisoning(AOPP).The purpose of this meta-analysis was to explore whether PHC has advantages over atropine in the use of anticholinergic drugs in AOPP.Methods:We searched Scopus,Embase,Cochrane,PubMed,ProQuest,Ovid,Web of Science,China Science and Technology Journal Database(VIP),Duxiu,Chinese Biomedical literature(CBM),WanFang,and Chinese National Knowledge Infrastructure(CNKI),from inception to March 2022.After all qualified randomized controlled trials(RCTs)were included,we conducted quality evaluation,data extraction,and statistical analysis.Statistics using risk ratios(RR),weighted mean difference(WMD),and standard mean difference(SMD).Results:Our meta-analysis included 20,797 subjects from 240 studies across 242 different hospitals in China.Compared with the atropine group,the PHC group showed decreased mortality rate(RR=0.20,95%confidence intervals[CI]:0.16–0.25,P<0.001),hospitalization time(WMD=-3.89,95%CI:-4.37 to-3.41,P<0.001),overall incidence rate of complications(RR=0.35,95%CI:0.28–0.43,P<0.001),overall incidence of adverse reactions(RR=0.19,95%CI:0.17–0.22,P<0.001),total symptom disappearance time(SMD=-2.13,95%CI:-2.35 to-1.90,P<0.001),time for cholinesterase activity to return to normal value 50–60%(SMD=-1.87,95%CI:-2.03 to-1.70,P<0.001),coma time(WMD=-5.57,95%CI:-7.20 to-3.95,P<0.001),and mechanical ventilation time(WMD=-2.16,95%CI:-2.79 to-1.53,P<0.001).Conclusion:PHC has several advantages over atropine as an anticholinergic drug in AOPP.

Preventive and therapeutic effects of penehyclidine hydrochloride on morphine-induced increased bladder pressure, urinary bladder sphincter pressure and histological damage in rabbits

Background Morphine has become the preferred drug for analgesia. However, analgesic doses of morphine can result in urinary retention, which is an intractable problem in clinical practice. Though bladder catheterization is one available therapeutic option, data supporting the technique＇s effectiveness are controversial. As a novel anti-cholinergic medicine developed in China, penehyclidine hydrochloride （PHC） exhibits greater selectivity for M3/M1 receptors than M2 receptors. Therefore, this study aimed to determine the efficacy of PHC in treating urinary retention. Methods Thirty-two healthy male New Zealand white rabbits were randomly divided in four groups （n=8 each） as follows： control group （C group）, PHC low-dose group （PL group, 0.01 mg/kg of PHC intramuscularly）, PHC middle-dose group （PM group, 0.02 mg/kg of PHC intramuscularly）, and PHC high-dose group （PH group, 0.05 mg/kg of PHC intramuscularly）. All rabbits were injected intravenously with morphine （1 mg/kg） to induce urinary retention and different doses of PHC were injected intramuscularly in the PL, PM and PH groups. In the C group, 1 ml saline was administered instead of PHC. The bladder pressure and the bladder sphincter pressure were recorded at different time points. The plasma concentration of PHC was measured at different time points with high performance liquid chromatography. Arterial blood pressure and heart rate （HR） were recorded at different time points. Results Bladder pressure and urinary bladder sphincter pressure rose significantly from 30 minutes after morphine administration until the end of the experiment. PHC markedly attenuated the elevations in pressure induced by morphine. Morphometric analysis also revealed histological damage, erythrocytes and ruptures of the microcirculation in regions of the submucosa and smooth muscle. Morphometric damage was ameliorated with PHC but not with saline. Hemodynamic data （mean arterial pressure （MAP） and HR） did not differ between groups over the observation period. Conclusions This study demonstrated that intravenous morphine significantly increased bladder pressure and urinary bladder sphincter pressure and induced histological damage in the bladder and urinary bladder sphincter. Importantly, preliminary data showed that PHC could decrease the extent of these chan qes.

Enantiospecific Synthesis of Penehyclidine Hydrochloride and Its Piperidine Derivatives with R Configuration

A novel and simple procedure for the enantiospecific synthesis of penehyclidine hydrochloride （8018） isomers and the R configuration derivatives was described. The intramolecular asymmetric cyclization of the monosulfonate of compound 1,2-diol was applied to the execution of the synthesis of the key chiral building block for the first time. The aimed products were obtained with moderate yield in〉99% ee.