The Associations Between CYP2D6*10 C188T Polymorphism and Pharmacokinetics and Clinical Outcomes of Tramadol: A Systematic Review and Meta-analysis.

BACKGROUND: Tramadol is one of the most extensively used centrally acting synthetic opioid analgesics. Recently, a number of studies have explored the associations of the CYP2D6*10 C188T polymorphism with pharmacokinetic and clinical outcomes of tramadol. However, the results of these previous reports remain controversial. Therefore, a meta-analysis was needed to reach a consensus. METHODS: PubMed, EMBASE, and the Cochrane Library were searched to identify eligible studies that explored the influence of the CYP2D6*10 C188T polymorphism on clinical outcomes of tramadol through April 2019. Articles meeting the inclusion criteria were comprehensively reviewed by two independent evaluators. A meta-analysis was performed using Review Manager 5.3. RESULTS: A total of nine studies involving 809 related subjects were included in this meta-analysis. Significant associations were found between CYP2D6*10 C188T mutation and longer serum tramadol half-lives, larger AUC0-∞, and the slower clearance rate of tramadol. In addition, we also found that CYP2D6*10 C188T had effects on the pharmacokinetic parameters of the metabolite of tramadol, O-desmethyltramadol, by sensitive analysis. Furthermore, CYP2D6*10 C188T polymorphism was associated with higher visual analog scale score, loading dose, and total consumption of tramadol. There was no significant association between CYP2D6*10 C188T polymorphism and postoperative nausea and vomiting. CONCLUSIONS: CYP2D6*10 C188T polymorphism had a significant influence on tramadol pharmacokinetics and analgesic effect, but there was insufficient evidence to demonstrate that this polymorphism was associated with incidence of nausea and vomiting.

The associations of HLA-DRB1 gene polymorphisms with late-onset myasthenia gravis: a meta-analysis.

BACKGROUND: Late-onset myasthenia gravis (LOMG) is one of the major subgroups of the MG. Intensive evidence suggested that polymorphisms in HLA-DRB1 gene were associated with LOMG risk, but the results remained inconsistent. Therefore, a meta-analysis is conducted to make a more precise evaluation between HLA-DRB1 alleles and LOMG. METHODS: The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang and Technology of Chongqing (VIP) Database were searched for eligible studies. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were applied to assess the association between HLA-DRB1 alleles and LOMG. RESULTS: A total of 11 studies involving 5513 people were included in our meta-analysis. The results showed that DRB1 07 and 0403 alleles were risk factors for LOMG (1.83 [1.12, 2.98], P = 0.02; 7.05 [2.62, 18.92], P = 0.0001, respectively), while DRB1 0301 and 1301 alleles were identified as protective factors for LOMG (0.44 [0.31, 0.62], P < 0.00001; 0.38 [0.23, 0.62], P = 0.0001, respectively). As for the HLA-DRB1 04 and 14 alleles, our subgroup analysis showed that there were significant associations between these alleles and LOMG in Caucasians (2.21 [1.14, 4.27], P = 0.02; 2.82 [1.29, 6.14], P = 0.009, respectively). CONCLUSIONS: These results confirmed the association of DRB1 alleles (0301, 04, 0403, 07, 1301, and 14) and LOMG, which might provide potential promising biomarkers for prediction of LOMG risk.

The Associations Between CYP2D6 Metabolizer Status and Pharmacokinetics and Clinical Outcomes of Venlafaxine: A Systematic Review and Meta-Analysis.

BACKGROUND: The association between CYP2D6 metabolizer status and clinical outcomes of venlafaxine was extensively investigated previously, but no widely accepted conclusion has been reached so far. To obtain a more precise estimation of the association, a systematic review by meta-analysis was conducted in the present study. METHODS: The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Technology of Chongqing, and Wan Fang Database were searched for eligible studies up to August 2018. RESULTS: Fourteen related studies involving 1035 patients were finally included. Significant associations were found among 3 CYP2D6 phenotypes (NM, IM, and PM) and most pharmacokinetic parameters of venlafaxine. However, CYP2D6 phenotypes were not associated with Hamilton Depression Rating Scale response of venlafaxine. In addition, we also found no significant association between CYP2D6 phenotype and overall rate of adverse events. CONCLUSIONS: CYP2D6 metabolizer status had significant influence on venlafaxine pharmacokinetics, but insufficient evidence demonstrated that CYP2D6 metabolizer status was associated with its therapeutic effects and overall rate of adverse events, which provided further evidence regarding the relationship between CYP2D6 metabolizer status and venlafaxine.

Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta-analysis.

PURPOSE: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Recently, increasing evidence suggested that polymorphisms in UGT2B7 gene were associated with VPA pharmacokinetics, but results remained controversial. Therefore, a meta-analysis was performed to derive a more precise evaluation between C802T, C161T, and G211T polymorphisms and plasma concentration of VPA. METHODS: The PubMed, EMBASE, and the Cochrane library databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated. The mean difference (MD) and 95% confidence interval (CI) were applied to assess the strength of the relationship. RESULTS: A total of 12 studies involving 1996 related East Asia epilepsy patients were assessed. We found that the UGT2B7 G211T polymorphism was associated with adjusted plasma VPA concentration (GG versus TT: P = 0.01, I 2 = 97%; GG versus GT: P < 0.00001, I 2 = 0%). Additionally, we also observed a significantly association between the C161T polymorphism and adjusted plasma VPA concentration (CC versus CT: P = 0.01, I 2 = 77%). Nevertheless, the pooled analysis showed that the C802T polymorphism had no significant effect on adjusted serum concentration of VPA. CONCLUSIONS: The results of this meta-analysis demonstrated that UGT2B7 G211T and C161T polymorphisms were able to affect the pharmacokinetics in epilepsy patients treated with VPA, which provide further evidence for genetic effects of UGT2B7 gene on pharmacokinetics and pharmacodynamics of VPA. Epilepsy patients with these genotypes may be necessary to increase (or decrease) VPA dose to ensure its therapeutic effect.

The permeability of puerarin loaded poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 on the blood-brain barrier and its protective effect against cerebral ischemia/reperfusion injury.

Puerarin (PUE) is a good candidate for treating stroke, but its low concentration in brain after administration limits its curative efficacy. The aim of the present work was to design and characterize PUE loaded poly(butylcyanoacrylate) nanoparticles (PBCN) coated with polysorbate 80 (Ps 80), and to evaluate the effect of PBCN on the permeability of PUE across the blood-brain barrier (BBB) and the effect of PUE loaded PBCN on the cerebral ischemia/reperfusion injury. PUE loaded PBCN were successfully prepared by anionic polymerization method with the mean particle size of 201.2 nm and the zeta potential of -7.72 mV. The in vitro release behavior of PUE from the nanoparticles showed a biphasic profile manner with an initial burst release followed by a sustained release. The results of pharmacokinetic and biodistribution to brain performed in mice after intravenous administration showed that the drug concentrations in blood and brain for PUE loaded PBCN were both greater than these for the free drug. Moreover, compared with free drug, the vein injection of PUE loaded PBCN exerted the better neuroprotective effect in rats with focal cerebral ischemic injury via significantly decreasing neurological deficit scores, increasing body weight, lowing brain water content, and reducing the infarct volume. The results indicated that this preparation may reduce the total dose required for the stroke therapy with concurrent reduction in dose related toxicity. All these findings suggest that PBCN could enhance the transport of PUE to brain and have a potential as a neuroprotective agent in the focal cerebral ischemic injury.

Targeted profiling of chlorinated transformation products and the parent micropollutants in the aquatic environment: A comparison between two coastal cities.

This study investigated chlorinated transformation products (TPs) and their parent micropollutants, aromatic pharmaceuticals and personal care products (PPCPs) in the urban water bodies of two metropolitan cities. Nine PPCPs and 16 TPs were quantitatively or semi-quantitatively determined using isotope dilution techniques and liquid chromatography-tandem mass spectrometry. TPs and most PPCPs were effectively removed by conventional wastewater treatments in a wastewater treatment plant (WWTP). Chlorinated parabens and all PPCPs (at concentrations below 1000 ng/L) were present in the waters receiving treated wastewater. By contrast, the waters receiving untreated wastewater contained higher levels of PPCPs (up to 9400 ng/L) and more species of chlorinated TPs including chlorinated parabens, triclosan, diclofenac, and bisphenol A. The very different chemical profiles between the water bodies of the two cities of similar geographical and climatic properties may be attributed to their respective uses of chemicals and policies of wastewater management. No apparent increase in the number of species or abundances of TPs was observed in either the chlorinated wastewater or the seawater rich in halogens. This is the first study to elucidate and compare the profiles of multiple TPs and their parent PPCPs in the water bodies of coastal cities from tropical islands. Our findings suggest that chlorinated derivatives of bisphenol A, diclofenac, triclosan, and parabens in the surface water originate from sources other than wastewater disinfection or marine chlorination. Although further studies are needed to identify the origins, conventional wastewater treatments may protect natural water bodies against contamination by those chlorinated substances.

Associations between UGT2B7 polymorphisms and cancer susceptibility: A meta-analysis.

BACKGROUND: UGT2B7 was recently acknowledged as a new critical enzyme involved in biotransformation of a variety of carcinogens, whose function was reported to be significantly associated with its encoding gene (UGT2B7) polymorphisms. However, results regarding the associations between single nucleotide polymorphisms (SNPs) of UGT2B7 and cancer risk still remained controversial. Therefore, a meta-analysis was conducted to further elucidate the role of UGT2B7 SNPs on cancer susceptibilities. METHODS: PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP) and Wan Fang Database were searched for eligible studies until March 2019. All analysis was carried out using the Review Manager 5.3 software. Subgroup analyses were performed by cancer types, ethnicity or source of controls. RESULTS: 13 studies with a total of 7688 cancer cases and 11,281 controls were included in this meta-analysis. The results showed that UGT2B7 rs7439366 increased the colorectal cancer risk in dominant model (OR = 0.76, 95% CI = 0.61-0.95, P = 0.02). However, as for the rs7435335 and rs12233719, we did not find their associations with cancer risk in all genetic models. In addition, the rs7441774 was found to be associated with breast cancer risk and significantly reduced papillary thyroid cancer risk in rs3924194 was also observed. Nevertheless, these findings remained to be further proven in future studies since these 2 SNPs were only respectively involved in 1 study. CONCLUSION: This meta-analysis confirmed the association of UGT2B7 rs7439366 with colorectal cancer risk, which may be a potential promising biomarker for prediction of colorectal cancer risk.

The associations of TNF-α gene polymorphisms with bone mineral density and risk of osteoporosis: A meta-analysis.

OBJECTIVE: Fracture is a common consequence of osteoporosis and is associated with high morbidity and mortality. Recently, increasing evidence has suggested that polymorphisms in tumor necrosis factor-α (TNF-α) gene were associated with osteoporosis risk and bone mineral density (BMD), but results remain conflicting. We herein performed a meta-analysis based on evidence currently available from the literature to make a more precise estimation of these relationships. METHODS: The PubMed, EMBASE, Cochrane Library, CNKI (China National Knowledge Infrastructure) and Wan Fang databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed and all available data were accumulated. The pooled odds ratios (ORs) or mean differences (MDs) and corresponding 95% confidence intervals (CIs) were applied to assess the strength of the relationships. RESULTS: A total of 15 studies involving 5273 subjects were included in our meta-analysis. The GG genotype of TNF-α G308A was associated with an increased risk of osteoporosis under a mutant model (GG vs GA+AA: OR = 0.63, 95% CI: 0.51-0.77, P < 0.0001, I2  = 31%). Additionally, we also observed a significant association between G308A polymorphism and BMD of lumbar spine (AA vs GG: P = 0.01, I2  = 53%). However, TNF-α T1031C, C857T and C863A polymorphisms had no obvious impacts on osteoporosis risk. CONCLUSIONS: The present meta-analysis demonstrated that TNF-α G308A polymorphism may act as a potential candidate biomarker for screening, diagnosis, and treatment of osteoporosis, which will help improve individualized therapy of osteoporosis patients in clinics.

Systematic screening and identification of the chlorinated transformation products of aromatic pharmaceuticals and personal care products using high-resolution mass spectrometry.

Pharmaceuticals and personal care products (PPCPs) are an emerging concern because of the large amount of PPCPs that is discharged and its potential ecological effects on the aquatic environment. Chlorination has proven efficient for removing some aromatic PPCPs from wastewater, but the formation of by-products has not been thoroughly investigated partly because of analytical difficulties. This study developed a method for systematically screening and identifying the transformation products (TPs) of multiple aromatic PPCPs through high-resolution mass spectrometry (HRMS). We spiked an environmentally relevant concentration (5000 ng/L) of three anti-inflammatory drugs, four parabens, bisphenol A, oxybenzone, and triclosan in the Milli-Q water and water containing natural organic matter (NOM). Low-dose chlorination (0.2-0.7 mg/L) was performed. We compared the chemical profiles of the chlorinated and untreated water and selected the ions to be identified based on the results of t-test and the ratio of signal intensities. Compound matching and isotopic pattern comparison were applied to characterising the molecular formulae of TPs. The fragmentation of the PPCPs and TPs was used in elucidating the structures of the TPs. The confirmation of TPs was achieved by comparing the retention time and fragment patterns of TPs with the isomer standards. In the chlorinated water, the aromatic PPCPs were substantially removed, except for the anti-inflammatory drugs (removal rates -5.2%-26%). Even with moderate chlorine dosages, all of the aromatic PPCPs, except for acetylsalicylic acid, were transformed into chlorinated derivatives in the Milli-Q water, and so were some PPCPs in the NOM-added water. The results of structure elucidation and compound confirmation as well as the increases in log Kow suggested that chlorination could transform aromatic PPCPs into more persistent, bioaccumulative, and toxic TPs. The presence of these TPs in the effluents where the PPCPs are removed through chlorination may pose increased risks to aquatic organisms.

Activation of histamine H4 receptor suppresses the proliferation and invasion of esophageal squamous cell carcinoma via both metabolism and non-metabolism signaling pathways.

Although dysregulation of histamine H4 receptor (H4R) has widely and frequently been documented in digestive carcinomas and correlates with the malignancy and proliferation of these tumors, the existence of H4R and its pathophysiological function in esophageal squamous cell carcinoma (ESCC) remains unknown. In our present study, we explored the expression and function of H4R in human ESCC samples and cell lines. H4R was overexpressed in poorly differentiated ESCC samples and cell lines and correlated with the median survival of ESCC patients. H4R activation not only significantly blocked cell proliferation, cell cycle, and invasion but also inhibited the growth of TE-2 xenografts and increased the survival of xenograft-bearing mice. According to the mechanistic experiments, both metabolism (acetyl-coenzyme A synthetase 2 (ACSS2))- and non-metabolism (mitogen-activated protein kinase (MAPK))-related pathways were involved in the effect of H4R activation on suppressing tumor proliferation and invasion. Based on these findings, H4R was overexpressed in esophageal cancer and exerted antitumor effects on ESCC proliferation and invasion, suggesting that H4R may be a novel potential target of therapies for ESCC. KEY MESSAGES: The function of H4R in ESCC and the underlying mechanisms were investigated. H4R expression was correlated with ESCC cell differentiation and patients' survival. Both metabolism (ACSS2) and non-metabolism (MAPK)-related pathways were involved. This study provided new insight into the relationship between H4R and ESCC. H4R may be a novel potential therapeutic target for ESCC.

Cardioprotective effect of histamine H2 antagonists in congestive heart failure: A systematic review and meta-analysis.

BACKGROUND: Histamine H2 antagonists (H2RAs) have long been suggested to have beneficial effects on congestive heart failure (CHF). However, full agreement about the cardioprotective effects of H2RAs is still not reached yet. Therefore, this study aims to clarify the effects of H2RAs on myocardial function in CHF patients by meta-analysis. METHODS: Electronic databases including PubMed, Embase, and Cochrane Library were retrieved. Randomized controlled trials comparing the cardiac effects of H2RAs and placebo or other medicines were collected. Pooled mean differences (MDs) with 95% confidence intervals (CIs) were calculated and meta-analysis was performed using RevMan 5.3 software. RESULTS: A total of 10 studies (472 participants) were included in this meta-analysis. H2RAs exhibited significant negative inotropic and chronotropic effects to reduce heart rate (MD: -3.90; 95%CI: -7.07 to -0.73, P = .02). Furthermore, although H2RAs did not affect the blood pressure in health volunteers, they significantly decreased the blood pressure of CHF patients. Additionally, H2RAs were also associated with significant increase in pre-ejection period and the ratio of pre-ejection period to left ventricular ejection time. CONCLUSION: In summary, these findings showed that H2RAs exerted negative inotropic and chronotropic effects to reduce heart rate and blood pressure, which, similar to beta-adrenergic receptor blockers, might decrease myocardial oxygen demand and eventually result in improvement of CHF symptoms. These data provided further evidence for the effect of H2RAs on cardiac function and novel potential strategy for treatment of CHF.

Complex effects of apoplexy secondary to pituitary adenoma.

Pituitary adenoma apoplexy is a well-known clinical syndrome induced by insulin infusion, cardiac surgery, trauma, and hypothalamic releasing factors. Pituitary apoplexy can cause secondary cerebral infarct and internal carotid artery occlusion. With blockade of tumor perfusion, apoplexy triggers a sudden onset of headache, visual impairment, cranial nerve palsy, disturbances of consciousness, eyelid ptosis, and hemiparesis. However, pituitary adenoma cells with high metabolic demand cannot survive with deficient blood supply and glucose concentrations. Moreover, a number of case reports have shown that spontaneous remission of syndromes, such as acromegaly, may be caused by pituitary adenoma after apoplexy. Therefore, understanding mechanism that underlies the balance between pituitary adenoma apoplexy and subsequent spontaneous remission of syndromes may suggest new approaches for treatment of pituitary adenoma apoplexy.