The Role of Extrasynaptic GABA Receptors in Postpartum Depression.

Postpartum depression is a serious disease with a high incidence and severe impact on pregnant women and infants, but its mechanism remains unclear. Recent studies have shown that GABA receptors, especially extrasynaptic receptors, are closely associated with postpartum depression. There are many different structures of GABA receptors, so different types of receptors have different functions, even though they transmit information primarily through GABA. In this review, we focus on the function of GABA receptors, especially extrasynaptic GABA receptors, and their association with postpartum depression. We have shown that the extrasynaptic GABA receptor has a significant impact on the activity and function of neurons through tonic inhibition. The extrasynaptic receptor and its ligands undergo drastic changes during pregnancy and childbirth. Abnormal changes or the body's inability to adjust and recover may be an important cause of postpartum depression. Finally, by reviewing the mechanisms of several novel antidepressants, we suggest that extrasynaptic receptors may be potential targets for the treatment of postpartum depression.

Effects of different doses of esketamine intervention on postpartum depressive symptoms in cesarean section women: A randomized, double-blind, controlled clinical study.

BACKGROUND: The optimal dosage and method of esketamine for postpartum depressive symptoms (PDS) are unclear. We conducted a randomized controlled trial (RCT) to investigate the effect of different doses of esketamine on PDS in women undergoing cesarean section, with evidence of prenatal depression. METHODS: The three groups were high- (2 mg kg-1) and low-dose (1 mg kg-1) esketamine via patient controlled intravenous analgesia (PCIA), following an initial intravenous infusion of 0.25 mg kg-1 esketamine, compared to placebo (0.9 % saline infusion). All groups also received the sufentanil (2.2 µg kg-1). The primary outcome was the incidence of PDS at 7 and 42 days postpartum. The secondary outcomes were: the remission from depression and total EPDS scores at 7 days and 42 days postpartum; mean change from baseline in the EPDS score; postoperative analgesia. RESULTS: i). 0.25 mg kg-1 of esketamine intravenous infusion combined with 1 mg kg-1 (n = 99) or 2 mg kg-1 (n = 99) esketamine PCIA reduces PDS incidence at 7 days postpartum (p < 0.05), with high-dose esketamine PCIA also reduces PDS incidence 42 days postpartum (p < 0.05), compared to placebo (n = 97). ii). Low- and high-dose esketamine PCIA lowers NRS scores at rest within 48 h postoperatively (p < 0.01), with high-dose esketamine also reducing the NRS score during movement at 48 h postoperatively (p = 0.018). iii). Neither high- nor low-dose esketamine PCIA increased postoperative adverse reactions (p > 0.05). CONCLUSIONS: Esketamine (0.25 mg kg-1) intravenous infusion combined with 1 mg kg-1 or 2 mg kg-1 esketamine PCIA seems safe and with few adverse effects in the management of PDS and pain in women undergoing cesarean section. LIMITATIONS: The tolerability and safety of esketamine requires further investigation based on more specific scales; the transient side effects of esketamine could have biased the staff and patients. TRIAL REGISTRATION: ChiCTR-ROC-2000039069.

Efficacy and safety of remimazolam besylate in bronchoscopy for adults: A multicenter, randomized, double-blind, positive-controlled clinical study.

Background: With the development of fiberoptic bronchoscopy in the diagnosis and treatment of various pulmonary diseases, the anesthesia/sedation requirements are becoming more demanding, posing great challenges for patient safety while ensuring a smooth examination/surgery process. Remimazolam, a brand-new ultra-short-acting anesthetic, may compensate for the shortcomings of current anesthetic/sedation strategies in bronchoscopy. Methods: This study was a prospective, multicenter, randomized, double-blind, parallel positive controlled phase 3 clinical trial. Subjects were randomized to receive 0.2 mg/kg remimazolam besylate or 2 mg/kg propofol during bronchoscopy to evaluate the efficacy and safety of remimazolam. Results: A total of 154 subjects were successfully sedated in both the remimazolam group and the propofol group, with a success rate of 99.4% (95%CI of the adjusted difference -6.7 × 10%-6% to -5.1 × 10%-6%). The sedative effect of remimazolam was noninferior to that of propofol based on the prespecified noninferiority margin of -5%. Compared with the propofol group, the time of loss of consciousness in the remimazolam group (median 61 vs. 48s, p < 0.001), the time from the end of study drug administration to complete awakening (median 17.60 vs. 12.80 min, p < 0.001), the time from the end of bronchoscopy to complete awakening (median 11.00 vs. 7.00 min, p < 0.001), the time from the end of study drug administration to removal of monitoring (median 19.50 vs. 14.50 min, p < 0.001), and the time from the end of bronchoscopy to removal of monitoring (median 12.70 vs. 8.60 min, p < 0.001) were slightly longer. The incidence of Adverse Events in the remimazolam group and the propofol group (74.8% vs. 77.4%, p = 0.59) was not statistically significant, and none of them had Serious Adverse Events. The incidence of hypotension (13.5% vs. 29.7%, p < 0.001), hypotension requiring treatment (1.9% vs. 7.7%, p = 0.017), and injection pain (0.6% vs. 16.8%, p < 0.001) were significantly lower in the remimazolam group than in the propofol group. Conclusion: Moderate sedation with 0.2 mg/kg remimazolam besylate is effective and safe during bronchoscopy. The incidence of hypotension and injection pain was less than with propofol, but the time to loss of consciousness and recovery were slightly longer. Clinical Trial Registration: clinicaltrials.gov, ChiCTR2000039753.

Safety, Pharmacokinetics/Pharmacodynamics, and Absolute Bioavailability of Dexmedetomidine Hydrochloride Nasal Spray in Healthy Subjects: A Randomized, Parallel, Escalating Dose Study.

Background: The present study evaluated the safety, pharmacokinetics/pharmacodynamics (PK/PD), and absolute bioavailability (Fabs) of Dex nasal spray in healthy adult subjects, which serves as a bridge for the subsequent study in children. Methods: Part 1: a double-blind, placebo-controlled, single ascending dose study was performed on 48 subjects. For 20-/40-µg groups, every 6/2 subjects received either Dex/placebo nasal spray or Dex/placebo injection in two periods. In total, 12/4 subjects each received 100 µg Dex/placebo nasal spray. Part 2: a randomized, double-blind, placebo-controlled study; 12/4 subjects received 150 µg Dex/placebo nasal spray. Part 3: a randomized, open, self-crossover study; 12 subjects received 20 µg and 100 µg Dex nasal spray in two periods alternately. The method of administration was optimized in Part 2 and Part 3. Results: In part 1, Dex nasal spray was well tolerated up to the maximum dose of 100 µg, whereas the Fabs was tolerated to only 28.9%-32.3%. In Part 2 and Part 3, the optimized nasal spray method was adopted to promote the Fabs of Dex nasal spray to 74.1%-89.0%. A severe adverse event was found in Part 2. In Part 3 (100 µg), the Ramsay score increased the most and lasted the longest, whereas the BIS score decreased most significantly. Conclusion: Using the optimized nasal spray method, a single dose of 20/100 µg of the test drug was safe and tolerable, and 100 µg may have approached or reached the plateau of sedation. In addition, it is found that the optimized method can greatly improve the bioavailability of the test drug, leading to its higher reference value.

Bioavailability and Safety of a New Highly Concentrated Midazolam Nasal Spray Compared to Buccal and Intravenous Midazolam Treatment in Chinese Healthy Volunteers.

INTRODUCTION: Buccal midazolam treatment is licensed in the European Union for prolonged acute convulsive seizures in children and adolescents, but the buccal pathway is often hampered by jaw clenching, hypersalivation, or uncontrolled swallowing. Midazolam formulations that are more secure, reliable, and faster for use are needed in the acute setting. Pharmacokinetics and comparative bioavailability of intranasally administered midazolam and two midazolam intravenous solutions administered buccally or intravenously in healthy adults were evaluated. METHODS: In this phase 1, open-label, randomized, single-dose, three-period, three-sequence crossover study, 12 healthy adults (19-41 years) were randomly assigned to receive 2.5 mg midazolam intranasally; 2.5 mg midazolam intravenously; 2.5 mg midazolam buccally. Blood samples were collected for 10 h post dose to determine pharmacokinetic profiles. Adverse events and vital signs were recorded. RESULTS: Intranasal administration of 2.5 mg midazolam demonstrated a more rapid median time to Cmax compared to buccal administration of midazolam (Tmax, 12.6 min vs. 45 min; Cmax, 38.33 ng/ml vs. 24.97 ng/ml). The antiepileptic effect of intranasal and buccal midazolam treatment lasted less than 4 h and generally did not differ from intravenously administered midazolam. No serious adverse events or deaths were reported, and no treatment-emergent adverse events led to study discontinuation. CONCLUSION: Intranasal administration of midazolam may be a preferable alternative to the currently approve buccal midazolam treatment for prolonged acute convulsive seizures in children and adolescents. TRIAL REGISTRATION: This study is registered at the Chinese Clinical Trial [ http://www.chictr.org.cn ] (ChiCTR2000032595) on 3 May, 2020.

The development and application of a prediction model for postpartum depression: optimizing risk assessment and prevention in the clinic.

BACKGROUND: Preventive intervention can significantly reduce the human and economic costs of postpartum depression (PPD) compared with treatment post-diagnosis. However, identifying women with a high PPD risk and making a judgement as to the benefits of preventive intervention is a major challenge. METHODS: This is a retrospective study of parturients that underwent a cesarean delivery. Control group was used as development cohort and validation cohort to construct the risk prediction model of PPD and determine a risk threshold. Ketamine group and development cohort were used to verify the risk classification of parturients by evaluating whether the incidence of PPD decreased significantly after ketamine treatment in high-risk for PPD population. RESULTS: The AUC for the development cohort and validation cohort of the PPD prediction model were 0.751 (95%CI:0.700-0.802) and 0.748 (95%CI:0.680-0.816), respectively. A threshold of 19% PPD risk probability was determined, with a specificity and sensitivity in the validation cohort are 0.766 and 0.604, respectively. After matching the high-risk group and the low-risk group by propensity score, the results demonstrated that PPD incidence significantly reduced in the high-risk group following ketamine, versus non-ketamine, intervention (p < 0.01). In contrast, intervention in the low-risk group showed no significant difference in PPD outcomes (p > 0.01). LIMITATION: Randomized trials are needed to further verify the feasibility of the model and the thresholds proposed. CONCLUSION: This prediction model developed in this study shows utility in predicting PPD risk. Ketamine intervention significantly lowers PPD incidence in parturients with a risk classification threshold greater than 19%.

Genetic Polymorphism of rs13306146 Affects α2AAR Expression and Associated With Postpartum Depressive Symptoms in Chinese Women Who Received Cesarean Section.

Postpartum depressive symptom (PDS) is a common psychological and mental disorder after giving birth. Our previous studies showing the application of dexmedetomidine, an α2-AR agonist, can significantly improve maternal sleep, as well as relieve and reduce the incidence of PDS. This study investigated the association between α2 A AR gene polymorphisms and PDS. A total of 568 cesarean section patients were enrolled; the incidence of PDS is 18.13% (103 with PDS, 465 with non-PDS). The Edinburgh Postpartum Depression Scale score ≥10 was used to diagnose PDS at 42 days after delivery. The single-nucleotide polymorphisms of α2AR were sequenced by pyrosequencing. The effect of rs13306146 A > G polymorphism on α2AR transcription and the regulation of miR-646 on α2AR expression were assessed by dual luciferase reporter assays or gene transfection. Increased stress during pregnancy, poor relationship between mother-in-law and daughter-in-law, spousal relationship, domestic violence, antenatal depression, self-harm ideation, and stressful life events were all associated with increased PDS incidence (p < 0.05). The logistic regression analysis found that the α2AAR rs13306146 polymorphism was associated with PDS after adjusting confounding variables. The transcriptional function of the α2AAR rs13306146 A allele was decreased compared with the G allele, and the α2AAR expression level was correspondingly decreased (p < 0.05), as the strongest binding ability of miR-646 to the α2AAR rs13306146 AA genotype. The effect of α2AAR rs13306146 A > G polymorphism may change the binding ability of miR-646 at the 3'UTR of the α2AAR gene, affecting the expression of α2AAR. This study supports the involvement of the norepinephrine system in the pathogenesis of PDS. Genotypes of α2AAR may be novel and useful biomarkers for PDS.

Correlations Between SIRT Genetic Polymorphisms and Postpartum Depressive Symptoms in Chinese Parturients Who Had Undergone Cesarean Section.

OBJECTIVE: To investigate the association of genetic polymorphisms of SIRT with postpartum depressive symptoms and analyze the risk factors for postpartum depressive symptoms in women following cesarean section. METHODS: A total of 368 Chinese woman undergoing cesarean section were enrolled in this study. A cutoff of ≥10 for the Edinburgh Postnatal Depression Scale identified postpartum depressive symptoms. Genotypes of SIRT1, SIRT 2, and SIRT 6 were determined using Sequenom MassArray single-nucleotide polymorphism (SNP) analysis. We analyzed the contribution of genetic factors (SNPs, linkage disequilibrium, and haplotype) to postpartum depressive symptoms and performed logistic regression analysis to identify all potential risk factors for postpartum depressive symptoms and define interactions between genetic and environmental factors. RESULTS: The incidence of postpartum depressive symptoms was 18.7% in this cohort. Univariate analysis suggested that SIRT2 polymorphism at rs2873703 (TT genotype) and rs4801933 ((TT genotype) and SIRT6 polymorphism at rs350846 (CC genotype) and rs107251 (TT genotype) were significantly correlated with the occurrence of postpartum depressive symptoms (p<0.05). Linkage disequilibrium was identified between SIRT6 polymorphisms rs350846 and rs107251. Incidence of postpartum depressive symptoms in cesarean-section parturients with SIRT2 haplotype CCC was decreased (OR 0.407, 95% CI 0.191-0.867; p=0.016). SIRT2 polymorphisms rs2873703 and rs4801933 were multiply collinear. Logistic regression analysis showed that SIRT2 polymorphism at rs2873703 (TT genotype) and rs4801933 (TT genotype), domestic violence, stress during pregnancy, and depressive prenatal mood were risk factors for postpartum depressive symptoms (p<0.05). CONCLUSION: Pregnant women with SIRT2 genotypes rs2873703 TT and rs4801933 TT and experiencing domestic violence, stress during pregnancy, and prenatal depression are more likely to suffer from postpartum depressive symptoms.

Association between well-characterized gene polymorphisms and the hypnosis response caused by sevoflurane-induced anaesthesia.

WHAT IS KNOWN AND OBJECTIVE: Sevoflurane is the most widely used volatile anaesthetic in clinical practice. It exhibits a hypnotic (unconsciousness) effect and causes a loss of reaction to noxious stimuli (immobility). However, to date, the mechanism of action of sevoflurane is poorly understood. In this study, we explored the effects of genetic variations on sevoflurane-induced hypnosis. METHODS: Sixty-six SNPs in 18 candidate genes were genotyped using MALDI-TOF MassARRAY in a discovery cohort containing 161 patients administered sevoflurane. Significant polymorphisms were assessed in a validation cohort containing 265 patients. RESULTS AND DISCUSSION: Three polymorphisms (GRIN1 rs28681971, rs79901440 and CHRNA7 rs72713539) were significantly associated with the time to loss of consciousness in patients treated with sevoflurane in the discovery cohort; among them, GRIN1 rs28681971 showed a significant association even after false discovery rate (FDR) correction (pFDR  = 0.039). Following the validation analysis, GRIN1 rs28681971 and rs79901440 showed statistical efficacy (pFDR  = 0.027, 0.034). Combined assessments and meta-analysis of the results of the two cohorts indicated that the C carriers of rs28681971 and T carriers of rs79901440 in GRIN1 require a longer time to achieve unconsciousness. WHAT IS NEW AND CONCLUSION: These findings suggest that GRIN1 polymorphisms are associated with sevoflurane-induced unconsciousness. Thus, the genotypes of GRIN1 may serve as novel and meaningful biomarkers for sevoflurane-induced unconsciousness.

Dexmedetomidine Alleviates Postpartum Depressive Symptoms following Cesarean Section in Chinese Women: A Randomized Placebo-Controlled Study.

OBJECTIVES: Few studies have investigated the prophylactic efficacy of dexmedetomidine (DEX) in postpartum depressive symptoms (PDS). A randomized double-blind placebo-controlled trial was conducted to investigate whether the administration of DEX, immediately after delivery and for patient-controlled intravenous analgesia (PCIA), can attenuate PDS. METHODS: A total of 600 parturients scheduled for elective cesarean delivery under spinal anesthesia were randomly allocated into the control group (infusion with 0.9% normal saline after delivery and PCIA with sufentanil) and the DEX group (DEX infusion 0.5 µg/kg after delivery and PCIA with DEX plus sufentanil). The prevalence of postpartum depressive disorders was indicated by the Edinburgh Postnatal Depression Scale (EPDS). Postoperative analgesia, sedation, and sleep quality of parturients were also assessed. RESULTS: Postpartum blues and PDS prevalence in the DEX, versus control, group were significantly lower (5.0% vs 14.1%, p<0.001; 5.7% vs 16.3%, p<0.001, respectively), especially in parturients with antenatal depression or moderate stress during pregnancy. Compared with the control group, the EPDS score at postpartum days 7 and 42 in the DEX group was significantly lower (4.23 ± 4.37 vs 1.93 ± 3.36, p<0.001; 4.68 ± 4.78 vs 1.99 ± 3.18, p<0.001, respectively), as was the incidence of postpartum self-harm ideation at postpartum days 7 and 42 in the DEX group versus the control group (1.1% vs 4.0%, p=0.03; 0.4% vs 2.9%, p=0.04, respectively). The pain score and the sleep quality in the DEX group were better than that in the control group (p<0.001). CONCLUSION: The application of DEX in the early postpartum period can significantly attenuate the incidence of postpartum depressive disorders.

Prophylactic use of ketamine reduces postpartum depression in Chinese women undergoing cesarean section✰.

This study aimed to explore the effect of prophylactic ketamine administration on postpartum depression in Chinese woman undergoing cesarean section. This randomized controlled study included 654 Chinese women undergoing cesarean section. At 10 min after child birth, patients in the ketamine group were given 0.5 mg/kg ketamine, whereas patients in the control group received standard postpartum care. At the end of operation, all patients were armed with a patient-controlled intravenous analgesia device. The primary outcome was the prevalence of postpartum depression (PPD), as assessed by the Edinburgh Postnatal Depression Scale (EPDS), and the secondary outcomes included the safety assessment and the Numerical Rating Scale (NRS) of postoperative pain. The prevalence of postpartum blues and postpartum depression were significantly lower in the ketamine group than in the control group. Logistic analysis showed that ketamine administration protected against postpartum depression, and PPD-associated risk factors included stress during pregnancy, antenatal depressive symptom and antenatal suicidal ideation. In addition, the antidepressive effect of prophylactic ketamine was stronger in mothers with a history of moderate stress during pregnancy, antenatal depressive symptom and antenatal suicidal ideation. Our findings suggest that ketamine functions as a prophylactic agent against PPD.

The promising role of PAX1 (aliases: HUP48, OFC2) gene methylation in cancer screening.

BACKGROUND: Paired-box gene 1 (PAX1), a member of the PAX family, plays a role in pattern formation during embryogenesis, and might be essential for development of the vertebral column. METHODS: PAX1 is silenced by methylation in several cancers and is considered a tumor suppressor gene. Our previous studies reported PAX1 as hypermethylated in cervical cancer tissues, thereby suggesting it as a potential screening marker. Recently, an increasing number of studies have confirmed PAX1 methylation as a promising biomarker in cervical cancer based on its excellent discriminatory ability between high-grade cervical lesions and normal tissues, resulting in a reduced necessity for referral for colposcopy and biopsy. Additionally, PAX1 is also hypermethylated in other tumors, including those associated with epithelial ovarian cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and endometrial carcinoma, and shows relatively good sensitivity and specificity for the detection of these tumors. RESULTS: This review summarizes reports of PAX1 methylation and its promising role in cancer screening, especially that associated with cervical cancer. CONCLUSION: According to current evidence, combined testing for human papillomavirus and PAX1 methylation analysis represents an efficacious cervical cancer-screening protocol.

The IDO genetic polymorphisms and postpartum depressive symptoms: an association study in Chinese parturients who underwent cesarean section.

Postpartum depressive symptoms (PDS) are not an uncommon mood disorder in postpartum women. Our previous research indicated a role for increased tryptophan (TRP) metabolism along the kynurenine pathway (KP) in the pathogenesis of PDS. Accordingly, this study was going to investigate the association of indoleamine-2,3-dioxygenase (IDO, a key enzyme of KP) genetic polymorphisms with PDS. Seven hundred twenty-five women receiving cesarean section were enrolled in this study. PDS was determined by an Edinburgh Postnatal Depression Scale (EPDS) score ≥ 13. Subsequently, 48 parturients with PDS and 48 parturients without PDS were selected for investigation of perinatal serum concentrations of TRP, kynurenine (KYN), and KYN/TRP ratio, the latter is the representative of IDO activity. In addition, seven single nucleotide polymorphisms of the IDO gene were examined. Following this genotyping, 50 parturients carrying the IDO rs10108662 AA genotype and 50 parturients carrying the IDO rs10108662 AC + CC genotype were selected for comparisons of TRP, KYN, and KYN/TRP ratio levels. This study showed the PDS incidence of 6.9% in the Chinese population, with PDS characterized by increased IDO activity (p < 0.05), versus women without PDS. We also found that the variations of IDO1 gene rs10108662 were significantly related to PDS incidence (p < 0.05). Furthermore, there was a significant difference in IDO activity between the IDO rs10108662 CA + AA, versus CC, genotypes. Our findings indicate a role of the kynurenine pathway in the development of PDS, rs10108662 genetic polymorphism resulting in changes of IDO activity might contribute to PDS pathogenesis.

The role of tryptophan metabolism in postpartum depression.

The Postpartum depression (PPD) is the most common postpartum psychiatric disorder, afflicting approximately 10%-20% of new mothers. Clinical symptoms of the PPD include depressive disorder, agitation, insomnia, anxiety and confusion, resulting in an increase in suicidal tendencies, thereby having significant impacts on the puerpera, newborn and their family. A growing body of data indicate a role for alterations in tryptophan metabolism in the PPD. The metabolism of tryptophan produces an array of crucial factors that can differentially regulate key physiological processes linked to the PPD. Importantly, an increase in stress hormones and immune-inflammatory activity drives tryptophan to the production of neuroregulatory kynurenine pathway products and away from the serotonin and melatonin pathways. This links the PPD to other disorders of depressed mood, which are classically associated with decreased serotonin and melatonin, coupled to increases in kynurenine pathway products. Several kynurenine pathway products, such as kynurenic acid and quinolinic acid, can have neuroregulatory effects, with consequences pathological underpinnings of the PPD. The current article reviews the role of alterations in tryptophan metabolism in the PPD.

Genetic variants of the kynurenine-3-monooxygenase and postpartum depressive symptoms after cesarean section in Chinese women.

BACKGROUND: New conceptualizations of depression have emphasized the role of the kynurenine pathway (KP) in the pathogenesis of postpartum depressive symptoms (PDS). Kynurenine 3-monooxygenase (KMO) is a rate-limiting enzyme of the KP, where it catalyzes the conversion of kynurenine (KYN) to 3-hydroxykynurenine (3-HK). Previous work indicates that KMO is closely linked to the pathophysiology of depressive disorders. The purpose of this study is to investigate whether variations in the KMO gene affect PDS development after cesarean section. METHODS: A total of 710 Chinese women receiving cesarean section were enrolled in this study. PDS was determined by an Edinburgh Postnatal Depression Scale (EPDS) score ≥13. Subsequently, 24 women with PDS and 48 matched women without PDS were randomly selected for investigation of perinatal serum concentrations of KYN, 3-HK and the 3-HK/KYN ratio. The 3-HK/KYN ratio indicates the activity of KMO. In addition, 6 single nucleotide polymorphisms of the KMO gene were examined. Following this genotyping, 36 puerperant women carrying the KMO rs1053230 AG genotype and 72 matched puerperant women carrying the KMO rs1053230 GG genotype were selected for comparisons of KYN, 3-HK and 3-HK/KYN ratio levels. RESULTS: The results show the incidence of PDS in the Chinese population to be 7.3%, with PDS characterized by increased serum 3-HK concentration and 3-HK/KYN ratio, versus matched postpartum women without PDS (P<0.05). Furthermore, polymorphisms of KMO rs1053230 are significantly associated with the incidence of PDS (P<0.05). The serum concentrations of 3-HK and the 3-HK/KYN ratio in postpartum women carrying the KMO rs1053230 AG genotype are significantly higher than those in matched postpartum women carrying the KMO rs1053230 GG genotype. CONCLUSIONS: The presented data highlight the contribution of alterations in the KP to the pathogenesis of postpartum depression. Heightened KMO activity, including as arising from KMO rs1053230 G/A genetic variations, are indicated as one possible mechanism driving the biological underpinnings of PDS.

Population pharmacokinetics study of dexmedetomidine in Chinese adult patients during spinal anesthesia.

OBJECTIVES: The objectives of this study were to construct a population pharmacokinetics model for dexmedetomidine used in Chinese adult patients with spinal anesthesia and to identify the key factors affecting the pharmacokinetics of dexmedetomidine. METHODS: A total of 34 subjects (elderly group: n = 15; young group: n = 19) undergoing spinal anesthesia received dexmedetomidine with a loading dose of 0.5 µg×kg(-1) for 10 minutes, followed by a maintenance dose of 0.5 µg×kg-1×h(-1) for 50 minutes. Blood samples were collected until 10 hours after dosing. Laboratory and respiratory parameters, and dexmedetomidine concentrations were measured. A population pharmacokinetic model for dexmedetomidine was constructed using a nonlinear mixed effects model (NONMEM). RESULTS: Pharmacokinetics of dexmedetomidine can be described by a three-compartment model. The respective typical values for clearance (CL), V1, V2, Q2, Q3, and V3 were 0.883 L×min(-1), 17.6 L, 51.5 L, 2.37 L×min(-1), 0.517 L×min(-1), and 44.00 L. Alanine aminotransferase (ALT), age, and body weight were key factors affecting CL, V1, and V2, respectively. CONCLUSIONS: A three-compartment model can be used to describe the pharmacokinetics processing of dexmedetomidine for Chinese adult patients during spinal anesthesia. The population pharmacokinetic of dexmedetomidine was generally in line with results from previous studies.

Pharmacokinetic and pharmacodynamic study of dexmedetomidine in elderly patients during spinal anesthesia.

OBJECTIVE: The application of dexmedetomidine in patient sedation is generally accepted, though its clinical application is limited because of the lack of information detailing the specific properties among diverse populations of patients. The aim of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between elderly and young patients during spinal anesthesia. METHODS: 34 subjects (elderly group: n = 15; young group: n = 19) with spinal anesthesia were enrolled in the present study following the inclusion/exclusion criteria detailed below. All subjects received intravenous infusion of dexmedetomidine with a loading dose of 0.5 µg x kg⁻¹ for 10 minutes and a maintenance dose of 0.5 µg x kg⁻¹ x h⁻¹ for 50 minutes. Plasma concentrations of dexmedetomidine were detected by the HPLC-MS/MS method and pharmacokinetic parameters were calculated using WinNolin software. RESULTS: There was no significant difference between the elderly and young subjects in major pharmacokinetic parameters. There was a marked gender difference in the Cmax (peak plasma concentration) and tmax (time to reach Cmax) between genders in elderly subjects, though in this cohort the other pharmacokinetic parameters were not significantly different. In the young subjects there were no noteworthy variations between genders in pharmacokinetic parameters. There was no significant difference between the two groups in BISAUC(0-t) (the area under the bispectral index-time curve from time 0 to t hours), BISmin (the minimum value of the bispectral index after drug delivery), and or tmin-BIS (bispectral index for the minimum value of time). SBP (systolic blood pressure), DBP (diastolic blood pressure), HR (heart rate), and SpO2(pulse oxygen saturation) developed substantive differences in a time-dependent manner, but there were no statistically significant differences in these four indicators in the time*group at three time points (1 hour, 2 hours, and 3 hours after drug administration); while SBP was significantly different between the groups, this differential declined in a time-dependent manner, and there were no significant attendant differences in the D-value. The observed values and D-values of DBP and HR were similar in the groups, but the observed value and D-value of SpO2did differ. There were 14 drug-related adverse events in the young group, and 26 drug-related adverse events in the elderly group, a 46% differential. The percentage of patients who requiring intervention during surgery was 68.75% (11/16) in the elderly group and 36.84% (7/19) in the young group, with no significant difference between the two groups once age was factored in (p = 0.06). None of the pharmacodynamic indices, however, correlated with the key pharmacokinetic parameters (Cmax, AUC(0→t), AUC(0→∞)) of dexmedetomidine. CONCLUSIONS: The clearance of dexmedetomidine in elderly patients showed a declining trend compared to young patients. Interventions in the elderly group were more frequent than in the young group, and the elderly group showed significant adverse effects. It is suggested that elderly patients who use dexmedetomidine may benefit from a different dose. However, further research with a larger population size is required to confirm these findings.

Immune-Mediated Metabolic Kynurenine Pathways Are Involved in the Postoperative Cognitive Dysfunction after Cardiopulmonary Bypass.

Postoperative cognitive dysfunction (POCD) after cardiopulmonary bypass is a serious complication that can lead to personality changes, memory loss, reduction in the ability to learn, and other central nervous system dysfunctions. In recent years, there have been improvements in measures to protect the brain during surgery, although the incidence of cognitive dysfunction after cardiac surgery remains high (33 to 83% short-term and 20 to 60% long-term cognitive dysfunction). Despite the large amount of basic and clinical research on the incidence of POCD, its exact pathogenesis and complexity are not clear. Many studies have shown that the kynurenine pathway (KP) and cognitive function in humans are closely related. Some reports also show that the imbalance of some metabolites of the KP such as kynurenic acid and quinolinic acid (QUIN), which act in dynamic equilibrium under physiologic conditions, have effects on the central nervous system and can significantly affect cognitive function. Further studies have shown that inflammatory mediators may act on key enzymes of the KP causing KP-induced disorders. Severe inflammatory reaction occurs in patients undergoing cardiopulmonary bypass, which triggers metabolic pathways that are closely related to changes in cognitive function. In this review, we summarize that inflammation-induced metabolic kynurenine (KYN) pathway disorders are likely to have an important role in incidence of POCD after CPB surgery.

Preoperative cognitive intervention reduces cognitive dysfunction in elderly patients after gastrointestinal surgery: a randomized controlled trial.

BACKGROUND: Preoperative conditions may play a significant role in postoperative cognitive dysfunction (POCD) development in elderly patients. We aimed to investigate whether preoperative cognitive training could lower the incidence of POCD one week after surgery. MATERIAL AND METHODS: A total of 141 ASA I-III elderly patients who underwent gastrointestinal surgery were enrolled into the study. Patients were randomized into either the Intervention group (69 analyzed) or the Control group (72 analyzed). Patients in the intervention group were instructed and trained in a cognition mnemonic skill for a total of three 1-hour sessions with the method of loci (MoL). Controls did not receive any cognitive training during hospitalization. All patients were tested using neuropsychological battery tests (NPTs) on admission and one week after surgery. RESULTS: The incidence of POCD in the intervention group (15.9%) was significantly lower than in the controls (36.1%) (P<0.05). Patients' performance in Brief Visuospatial Memory Test-Revised and Symbol-Digit Modalities Test were improved by the cognitive training. Increasing age, longer length of anesthesia and surgery, and lack of cognitive training were associated with a significantly higher risk of POCD (P<0.05). CONCLUSIONS: Cognitive training with MoL can reduce the decline of early postoperative cognitive function in elderly patients undergoing major gastrointestinal surgery.

Role of SLCO1B1, ABCB1, and CHRNA1 gene polymorphisms on the efficacy of rocuronium in Chinese patients.

This study explored the role of SLCO1B1, ABCB1, and CHRNA1 gene polymorphisms on the efficacy and duration of action of rocuronium in Chinese patients. Two hundred seven unrelated Chinese patients scheduled for elective surgery were recruited, and 200 completed the study. Their ABCB1, SLCO1B1, and CHRNA1 genotypes were determined. Demographic and clinical non-genetic data also were collected. The SLCO1B1, ABCB1, and CHRNA1 variants did not affect the onset time of rocuronium. Clinical duration and recovery time of rocuronium were prolonged in patients with the ABCB1 rs1128503TT and SLCO1B1 rs2306283 AG and GG genotypes. We demonstrate that the SLCO1B1 and ABCB1 gene variants could affect the pharmacodynamics of rocuronium. The ABCB1 rs1128503 C>T genotype was the most important factor on the efficacy of rocuronium.