Reactive Cutaneous Capillary Endothelial Proliferation Caused by Camrelizumab: Sixteen Case Reports.

To investigate the regularity and characteristics of adverse drug reaction (ADR) of reactive cutaneous capillary endothelial proliferation caused by Camrelizumab, so as to provide reference for clinical rational use of drugs. Searching for case reports of Camrelizumab-induced reactive cutaneous capillary endothelial proliferation (RCCEP) in databases such as China Biology Medicine disc, VIP Database, CNKI, Wanfang Medical, PubMed, Wiley online library, Embase with "Carritzumab/Ericab," "SHR-1210," "Reactive cutaneous capillary endothelial proliferation," "Reactive capillary hemangiomas," and "Capillary proliferation" as search terms. The retrieval time is from the establishment of the database to February 2022. After eliminating clinical trials and incomplete literature, information of patients included in the literature was analyzed, which included gender, age, reason for medication, usage and dosage, time of ADR, concomitant medication, clinical manifestations, intervention measures, outcomes of patients, etc. A total of 11 articles involving 16 patients were included, including 11 males and five females, with an average age of 60.5 years. Reasons for medication included nine cases of non-small cell lung cancer (NSCLC), four cases of liver cancer, one case of small cell lung cancer (SCLC), one case of synovial sarcoma, and one case of Hodgkin lymphoma. Thirteen patients recorded in detail that the dosage of Camrelizumab was 200 mg, and the frequency of medication was q2w~q4w. Eight patients were treated with Camrelizumab alone, and eight patients were treated with combined medication. RCCEP occurred in nine patients after the first medication, and in seven patients after two-four cycles of medication, the average medication cycle was two cycles, and the average occurrence time was 12.5 days after the last medication. The main clinical manifestations were that several different sizes of growths such as red nevus-like, pearl-like, and mulberry-like growths appear on the head, face, neck, torso, limbs, and other parts of the body, all of which were grade 1-2. The RCCEP of all patients was controlled after treatment. During the treatment, 11 patients were stable and five patients were local remission. RCCEP is caused by Camrelizumabis a special skin immune response, which will not cause life-threatening to patients. However, clinicians and pharmacists should be familiar with the characteristics and regularities of the adverse reaction, to do a good job in medication monitoring and management, as for ensuring the safety of patients with medication.

Mechanistic understanding of the inhibitory effect of cytochrome P450 3A4 and 3A5 by Wuzhi tablet (Schisandra sphenanthera extract) / 药学学报

Wuzhi tablet (WZ) is a prescribed herbal medicine extracted from Schisandra sphenanthera, which is widely used to protect the liver injury and drug-induced hepatotoxicity in clinical practices. Previous studies showed that WZ significantly increased the blood concentrations of tacrolimus, cyclosporine A, paclitaxel by inhibiting the cytochrome P450 3A (CYP3A)-mediated metabolism. CYP3A4 and CYP3A5 are the most important isoenzymes among the CYP3A subfamily. However, there are some differences in the catalytic and inhibitory activities between CYP3A4 and CYP3A5, which may lead to different risk of drug-drug and herb-drug interactions, and the risks may be further amplified in vivo. Currently, few reports have compared the herbal medicine inhibitory effects between CYP3A4 and CYP3A5 mediated metabolic reactions. Therefore, detailing the inhibitory effect of WZ on CYP3A4 and CYP3A5 will help understand and predict the potential herb-drug interaction. The results showed that WZ inhibited CYP3A4 and CYP3A5 in a NADPH-, time- and concentration- dependent manner. WZ showed more potent inhibition on CYP3A5 than CYP3A4. Cautions warranted when combining WZ with other therapeutic drugs to avoid the potential herb-drug interaction.

Lower GDNF Serum Level Is a Possible Risk Factor for Constipation in Patients With Parkinson Disease: A Case-Control Study.

Background: Constipation is a significant symptom of Parkinson's disease (PD). Glial-derived neurotrophic factor (GDNF) is important for the morphogenesis of the enteric nervous system and plays a critical role in the preservation of mucosal integrity under enteric glia surveillance. The aim of this work was to evaluate the serum levels of GDNF in patients with PD with and without constipation. Methods: This work included 128 patients with PD. The patients were classified into three groups: those with PD but no constipation (nCons-PD) (n = 49), those with prodromal stage constipation (Cons-Pro-PD) (n = 48), and those with clinical stage constipation (Cons-Clinic-PD) (n = 31). The association between serum GDNF concentration and constipation was explored using logical regression. Results: The nCons-PD group's mean GDNF levels were 528.44 pg/ml, which was higher than the Cons-Pro-PD group's 360.72 pg/ml and the Cons-Clinic-PD group's 331.36 pg/ml. The results of binary logistic regression indicated that GDNF was a protective factor in the prevention of constipation. Cons-Clinic-PD group had a higher score of MDS-UPDRS-II, MDS-UPDRS-III, MDS-UPDRS-IV, and a higher H-Y staging as compared with nCons-PD group. Relative to the nCons-PD group, Cons-Clinic-PD had higher NMSS scores, lower MoCA and PDSS scores, and were more likely to have RBD. Conclusions: GDNF serum levels are lower in patients with PD who are constipated. A low GDNF level is a potential risk factor for constipation in patients with PD.

Gender Was Associated with Depression but Not with Gastrointestinal Dysfunction in Patients with Parkinson's Disease.

OBJECTIVE: To investigate the association between gender and gastrointestinal (GI) dysfunctions, as well as gender and other motor symptoms/nonmotor symptoms, in a sample of PD patients. METHODS: 186 patients with PD were recruited into this study and divided into male PD group (M-PD) and female PD group (FM-PD). Demographic and PD-related clinical information of the participants were collected by the same neurologist. PD patients were objectively assessed by a spectrum of rating scales of motor symptoms and nonmotor symptoms (including GI dysfunctions). The data were analyzed by SPSS 20 statistical software. RESULTS: Totally 95 cases (51.08%) were in the M-PD group and 91 cases (48.92%) in the FM-PD group. There were no significant differences in age, BMI, and lifestyles between the two groups (P > 0.05). Males had higher educational level (P = 0.002). Females were more likely to have early satiety and loss of appetite (P = 0.025, P = 0.001). There were no significant differences in LED disease duration, age of motor symptoms onset, types of motor symptoms onset, location of motor symptoms onset, and phenotype of motor symptoms between the two groups (P > 0.05). Females had significantly higher UPDRS-III and HAMD scores than males (P = 0.037, P = 0.034). There were no significant differences in PQSI, ESS, RLS, RBD, HAMA, HAMD, and MoCA scores between the two groups. Gender was associated with HAMD (OR = 0.682, P = 0.019). CONCLUSIONS: Gender is a risk factor for depression, but not for GI dysfunctions in patients with PD.

Depression Is Associated With Constipation in Patients With Parkinson's Disease.

Objective: Constipation is one of the most frequent non-motor symptoms (NMS) in Parkinson's disease (PD), causing great disturbance to patients. The present study investigated the prevalence and the clinical features of constipation in patients with PD and explored the difference between prodromal and clinical constipation of PD. Methods: A total of 186 patients with PD were recruited into this study. Subjective constipation was defined by ROME III criteria. Demographic and PD-related clinical information of the participants were collected. The PD patients were objectively assessed by a spectrum of rating scales of motor symptoms, non-motor symptoms, and quality of life. Results: In total, 51.61% (96/186) of PD patients suffer from constipation. Compared with patients without constipation, the patients with constipation were prone to have restless leg syndrome, depression, and anxiety and have higher scores of the non-motor symptoms scale. Among patients with constipation, 21.88% (21/96) patients had constipation in prodromal stage. Compared with patients with constipation in clinical stage, patients with prodromal constipation had a lower age of constipation onset (56.48 ± 9.63 and 65.26 ± 8.42, χ2 = 4.091, P < 0.001), longer timespan from constipation onset to motor symptom onset (6.62 ± 3.91 and 3.18 ± 2.13, χ2 = -3.877, P = 0.001). Patients with prodromal constipation were predominantly tremor onset (χ2 = 4.405, P = 0.044) and usually had a better quality of life [28 (14.50-37.5) and 40 (25.0-55.0), χ2 = 2.011, P = 0.046]. Depression was the only risk factor of constipation in PD patients. Body mass index, depression, and anxiety were factors that affected the life quality in patients with constipation. Conclusions: Our results supported the high incidence of constipation in patients with PD and that, in some patients, constipation occurred before the onset of motor symptoms. The specific clinical characteristics of patients with constipation and with prodromal constipation help to make early diagnosis, to discover the relationship between constipation and PD, and to further explore the pathogenesis of this degenerative disease.

Analysis on potential factors of small for gestational age of Zhuang ethnicity in Wuming District of Nanning / 中华疾病控制杂志

Objective To understand the prevalence of small for gestational age (SGA) in Zhuang population, and to analyze the potential factors of SGA. Methods A total of 3 839 live births in the Wuming District People’s Hospital and Wuming Maternal and Child Health Hospital from January 2016 to January 2018 were recruited. Random Forest, 2 test and Logistic regression model were used for statistical analyses. Results The incidence of SGA was 9.6% (368/3 839), and it was 6.9% (142/2 049) and 12.6% (226/1 790) for male and female infants respectively. Random Forest method showed that second-trimester intrauterine growth restriction’s importance score was the highest, but gestational week’s was the lowest. Also, seven important variables were selected by this method. Unconditional logistic regression analysis showed that parity <2, the height of mothers <1.55 m, insufficient gestational weight gain, second-trimester intrauterine growth restriction were risk factors for SGA, but pre-pregnancy BMI ≥18.5 kg/m2 and male infants were protective factors. Conclusions The incidence of SGA is slightly higher, among the Zhuang population in Guangxi. SGA is affected by many factors. Therefore, it is necessary to evaluate the status of intrauterine growth and adopt comprehensive measures to control and reduce the incidence of SGA.

Effect of six bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) on P-glycoprotein and its herb-drug interaction with digoxin / 药学学报

This study was aimed to investigate the effects of six Schisandra lignans of Wuzhi tablet (WZ, a preparation of ethanol extract of Schisandra sphenanthera) on the pharmacokinetic process of digoxin (DG, a classical P-gp substrate) after intravenous and oral administration in rats. The effect of Schisandra lignans on the transportion of DG in Caco-2 cells was further elucidated. Our data showed that the plasma concentrations of DG were increased to different extent following co-administration of schisandrin A, schisandrin B, schisandrol B and schisantherin A, respectively. Schisandrol B showed the most potent effect among the six lignans. However, schisandrin C and schisandrol A showed little effect on pharmacokinetic of DG. Schisandrol B led to 99.0% (P < 0.05) and 109.2% (P < 0.05) increase in the AUC after orally or intravenously administered of DG, suggesting that co-administration of schisandrol B induced a more potent effect on increasing hepatic bioavailability of DG than that of intestinal. Furthermore, in vitro transport experiment showed that schisandrin A, schisandrin B, schisandrol B and schisantherin A inhibited P-gp-mediated efflux of DG, suggested that these lignans inhibited the P-gp-mediated efflux of DG. In conclusion, the exposure of DG in rats was increased when co-administered with Schisandra lignans, and schisandrol B showed the strongest effect. The dramatic increase in oral bioavailability of digoxin in the presence of schisandrol B may be due to the inhibition of hepatic/renal P-gp activity.

Effect of long-term treatment of Wuzhi tablet on the expression and activity of cytochrome P450 3A in rats / 药学学报

The study aims to evaluate the effect of long-term pretreatment of the rat with Wuzhi tablet (WZ) on hepatic and intestinal CYP3A mRNA and protein expression and activity. Male Sprague-Dawley rats were orally administered of midazolam (2 mg·kg-1) with or without 14 days of pretreatment of WZ (0.25 g·kg-1) to determine CYP3A activity. Meanwhile, RNA and protein of rats liver and intestine samples were prepared 24 h after the last dose of 14 days of WZ treatment to determine CYP3A mRNA and protein expression. Long-term treatment of WZ increased the mRNA expression of hepatic Cyp3a1, Cyp3a9 and intestinal Cyp3a9 by 54.6%, 188.3% (PP<0.05), respectively;and increased the protein expression of hepatic CYP3A by 43.2%. However, after long-term treatment of WZ, the AUC of orally administered of midazolam in the WZ group was increased 29.9% (WZ pretreatment group) and 154.2% (WZ coadministered group) compared to that of control group. In conclusion, long-term treatment of WZ increased the mRNA and protein expression of CYP3A, while could inhibit the activity of CYP3A.

Determination of hepatic and small intestinal distribution of lignans of Wuzhi tablet in rats by liquid chromatography tandem mass spectrometry method / 药学学报

This study was aimed to determine the hepatic and small intestinal distribution of active lignans in rats after treated with Wuzhi tablet (WZ, Schisandra sphenanthera extract) by LC-MS/MS method. Male Sprague-Dawley rats were sacrificed at 0.25, 1.5, 4, 6, 10, 24 h after an oral administration of WZ, and then hepatic and small intestinal samples were collected for analysis. The results showed that concentrations of lignans in liver and small intestine of rats were decreased with WZ pretreated time. The concentrations of all lignans in rat liver and small intestine at 0.25 h were the highest after a single oral administration. All lignans was undetectable in all tissues 24 h after oral dosing, suggesting lignans of WZ were eliminated rapidly in rats. The concentrations of schisandrin A, schisandrol B and schisantherin A in small intestine were much higher than those in the liver, suggesting the effect of WZ on the intestinal metabolism enzyme might be more potent than that on the liver. In short, the current results suggest that lignans of WZ were not accumulated in rat liver and small intestine. The concentrations of lignans of WZ in small intestine were much higher than those in liver.

Optimization of midazolam dosage and pharmacokinetics of CYP3A probe substrate in rats / 药学学报

The study was conducted to evaluate the pharmacokinetics of midazolam (MDZ) under different oral dosages in rats, and determine the optimum oral dosage of MDZ, a CYP3A probe substrate in vivo. Male Sprague-Dawley rats were given a single oral dosages of MDZ at 1, 2, 5, 10, 15 or 20 mg·kg-1. Plasma concentrations of MDZ and its major metabolite 1-hydroxyl midazolam (1-OH MDZ) were determined at different time points using a validated LC-MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental model. The Cmax, AUC0-t and AUC0-∞ of MDZ and 1-OH MDZ were linearly increased over the dose range of 1-5 mg·kg-1 (r > 0.99), but not at the dose of 15 or 20 mg·kg-1. The AUC/Dose at 1-10 mg·kg-1 were not significant different, but that of 15 or 20 mg·kg-1 were significantly higher. No significant sedative reaction was observed in all the rats at dosages of 1-5 mg·kg-1, however loss of righting reflex was observed in rats receiving dosages of 10-20 mg·kg-1. In conclusion, the optimized oral dose of MDZ was 1-5 mg·kg-1 when MDZ is used as the CYP3A probe substrate in rats.