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Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.
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Objective:To analyze the clinical characteristics of late-onset epileptic spasm (LOS), thus providing basis for its early identification and treatment.Methods:Clinical data[electroencephalogram(EEG), imaging, treatment and prognosis]of LOS patient hospitalized in the Department of Pediatrics, the Second Affiliated Hospital of Xi′an Jiaotong University from January 2017 to June 2019 were retrospectively analyzed.Results:The age of onset of spasm in 35 children with LOS ranged from 18 months to 11 years old, with a median of 42 months.There were 21 cases of symptomatic LOS (60.0%) and 14 cases of cryptogenic LOS (40.0%). Epileptic spastic seizures, generalized seizures, partial seizures and myoclonic seizures as the first onset were reported in 13 cases (37.1%), 11 cases (31.4%), 10 cases (28.6%), and 1 case (2.9%), respectively.There were 15 cases (43.9%) of flexion type, 11 cases (30.4%) of extension type and 9 cases (25.7%) of mixed type.Spastic seizures can be presented as genera-lized or focal seizures.Among the 35 cases of LOS, 12 cases (34.3%) had normal EEG background, 18 cases (51.4%) had slow EEG background, and 5 cases (14.3%) had high EEG irregularity.Three cases were in accor-dance with Lennox-Gastaut syndrome and the other 32 cases were not in accordance with the defined epileptic syndrome.Eighteen cases were treated with antiepileptic drugs, and sodium channel blockers were added in 9 cases; 17 cases were treated with glucocorticoid.Eight cases did not have seizures at the last follow-up.There were 17 children with seizure reduction ≥ 50%, 3 cases with seizure reduction < 50%, and 7 cases with no reduction of seizure.Conclusions:LOS is mostly symptomatic and often associated with other types of seizures.Most of cases do not have high irregularity in the EEG, and the focal discharges are mainly in the temporal region or frontotemporal region, with refractory epilepsy mainly.The onset age, etiology and EEG characteristics of LOS differ from those of West syndrome, which should be detected and treated as soon as possible to improve the prognosis in pediatric patients.
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【Objective】 To analyze the clinical features and gene mutation characteristics of four children with pyridoxine-dependent epilepsy (PDE) in order to provide evidence for early diagnosis of this rare disease. 【Methods】 The clinical data of four cases of PDE were collected from January 2016 to June 2019 in The Second Affiliated Hospital of Xi’an Jiaotong University. We collected data of the laboratory examination, electroencephalogram, and magnetic resonance imaging (MRI). Peripheral venous blood was collected from children and parents, genomic DNA was extracted from white blood cells, and primers were designed to amplify the aldehyde dehydrogenase 7 family member A1(ALDH7A1) on the long arm of chromosome 5 using PCR; exon and the junction of exon and intron were also amplified to determine whether there is a gene mutation. 【Results】 All the 4 cases had a full-term birth and no history of birth asphyxia. ① Clinical features: onset time from 8 days after birth to 6 months after birth. Type of seizure: 1 case with myoclonus onset, then converted to spasm; 1 case for generalized seizures; 2 cases for partial seizures, then converted to generalized seizures; 3 cases were prone to epileptic seizures; 1 case was significantly worse after infection; MRI: 3 cases showed no abnormalities, 1 case showed non-specific abnormalities; EEG: One case was fragmentary hypsarrhythmia, 3 cases of multifocal epileptiform discharge; Treatment: a small dose of vitamin B6 could control the seizure, 1 of them was controlled at a tiny dose, and 3 cases were controlled by a small dose. ② Genetic analysis results: There were 4 cases of ALDH7A1 gene mutation, of which 3 cases were known gene mutations and 1 case was new mutation. 【Conclusion】 PDE has an early onset, often in the neonatal or small infancy, is prone to epilepticus and has an increased severity after infection. There is no specificity in seizure type, EEG or MRI. The analysis of ALDH7A1 gene and vitamin B6 load test can help to confirm the diagnosis, small dose of Vitamin B6 can control the seizures so as to provide reference for the dose of vitamin B6. However, the number of cases is small, and a large sample size is still needed for verification.
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Objective To investigate the effect of different doses of ioversol on renal function,and to explore early renal injury biomarkers on contrast induced kidney injury and safe ioversol dosage.Methods A total of 158 cases (98 males and 60 females) undergoing cerebral vascular intervention (CVI) in our department was selected with age ranging from 23 to 81 years old (average age 59.70 ± 12.02).Based on ioversol dosage in surgery,patients were divided into three groups:low dose group (≤ 150 ml,n =49),middle dose group (151-200 ml,n =74),and high dose group (＞200 ml,n =35).U-κ,U-λ,urinary transferrin (UTRF),urine microalbumin (UMA),urinary immunoglobulin IgG (UIgG),urine beta2-microglobulin (Uβ2-MG),Uα1-MG,urinary N-acetyl-beta-D-glucosaminidase (UNAG),plasma cystatin C (CysC) and Scr were detected by scattering turbidimetry,immune turbidimetry and fully automatic biochemical analysis pre-surgery 24 h and post-surgery 72 h.Contrast-induced acute kidney injury (CI-AKI) was defined as laboratory increase of Scr value≥44.2 μmol/L or ≥25％ from baseline measurement at 48 hours after surgery.The relationship in ioversol dosage and various factors was assessed by Single and multiple factors binary logistic regression analysis.Results According to the criterion that Scr increase value were ≥44.2 μmol/L,of 158 cases,3 cases occurred CI-AKI,the AKI incidence was 1.90％.Based on the criterion that Scr increase value was ≥25％,33 cases occurred CI-AKI,the incidence was 20.89％.The concentration of U-κ,UTRF,Uα1-MG,UNAG and plasma CysC were significantly different in high dose group compared to low ioversol dose group (P ＜ 0.05),while the other biomarkers had no significant difference (P ＞ 0.05).Conclusions The contrast media-ioversol could lead to CI-AKI;when the dosage of ioversol was more than 200 ml one-time,the concentration of U-κ,UTRF,Uα1-MG,UNAG and plasma CysC increased significantly.U-κ,UTRF,Uα1-MG,UNAG and plasma CysC could predict the early renal injury in patients who undergoing CVI.The rise of U-κ,UTRF,Uα1-MG,UNAG and plasma CysC are related to the dosage of ioversol.Furthermore,possibility of kidney injury is significantly high when ioversol dosage is more than 200 ml one-time.
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The microfluidic channels integrated with microring resonator were designed. The salt coalescence on chip surface caused by liquid volatilization in open environment was avoided and only 30 μL of reaction solution was consumed. These channels significantly reduced the experiment cost. The design, fabrication and characterization of a highly sensitive and label-free silicon-on-insulator (SOI) microring optical resonator integrated with the microfluidic channels were demonstrated. The radius of the microring was 5 μm and the straight waveguide with a width of 450 nm was employed in the microring resonator. The microring resonator device had many advantages such as high sensitivity, label-free and real-time detection. Using different concentrations of ethanol solution with known refractive indices, the refractive index detection sensitivity was 76.09 nm/RIU and the volume refractive index detection limit was 5.25×10Symbolm_4 RIU. We also demonstrated the label-free quantitative specific detections of human immunoglobulin G (IgG) solutions using an antibody-modified microring resonator by measuring the resonance wavelength shift resulting from refraction index changes causing by the immobilization of antibodies and specific recognition between antibodies and antigens, respectively. The results showed that the microring optical resonator could real-time monitor the reaction between biological molecules, the resonator could be used in the quantitative detection and biological sensing.
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Objective:To explore blood type distribution of newborns hemolytic disease ( HDN ) caused by maternal and neonatal blood type incompatibility and analyze the value of hemolysis three trials in the diagnosis of HDN.Methods:Hemolysis three trials of type O or Rh negative maternal cord blood samples and hyperbilirubinemia of the newborn blood samples from January 2014 to 2016 were detected by micro-column gel test cards.Then the results were statistically analyzed.Results:(1) There were 918 cases of maternal and neonatal blood type incompatibility in all 1350 cases.569 cases were detected HDN positive with the rate of 62%( 569/918).Among 569 cases,the positive rate of direct anti-globulin test,free antibody test and antibody released test were 27.9%(159/569),86.5%(492/569) and 100% respectively.There was statistical difference of the combination of direct anti-globulin test negative,free antibody test positive and antibody released test positive compared with other combinations ( P<0.05 ).( 2 ) There was statistical difference of HDN positive rate between ABO 73.8%(551/747) and Rh 10.5%(18/171)in 918 cases of blood type incom-patibility.(3)There was statistical difference between A positive rate of 80%(280/350) and B positive rate of 68.3%(271/397) in 747 cases of ABO incompatibility.(4)There was statistical difference among RhD positive rate of 17.7%(14/79),RhE positive rate of 6.8%(4/59) and RhC positive rate of 0(0/33).Conclusion: Antibody released test was the most sensitive test in hemolysis three trials to diagnose HDN.The probability of HDN positive caused by maternal and neonatal ABO blood type incompatibility was significantly higher than Rh.The probability of HDN positive with type A newborns was significantly higher than type B.The probability of HDN positive caused by RhD blood type incompatibility was significantly higher than RhE and RhC.
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Objective To improve the different diagnosis between autoimmune pancreatitis(AIP) and pancreatic cancer(PC) by a retrospective analysis of clinical symptoms and serological features.Methods The analysis included 36 patients who had postoperative pathological,serological findings consistent with Asian AIP standards and 95 patients who had postoperative pathological consistent with PC pathological standards.All patients were admitted by the surgery department of our hospital from January,2003 to October,2011.A retrospective comparative analysis of the clinical manifestations,serology data of these AIP and PC patients was conducted.And summary the differential diagnosis characteristics of AIP and pancreatic cancer in the clinical symptoms,the serology.Results The features of different diagnosis:(1) The age of patients with PC was higher than AIP((60.9 ±9.0) years vs.(53.56 ± 14.6) years,t =3.48,P ＜0.05),and AIP preferred to male groups (x2 =2.88,P =0.09).(2) The clinical features of AlP and PC with the age characteristics were easily confused.Both clinical features were relatively typical in younger age which could be found earlier and relatively insidious in the older age which might be found with delay.(3) AIP were often complicated by biliary system inflammations(AIP =47.2％,PC =12.6％,x2 =18.12,P ＜ 0.05),while PC were usually complicated by the cysts in liver and kidney (PC =29.5％,AIP =0,x2 =13.50,P ＜ 0.05).(4) The high titer in CA199 had a higher value in the diagnosis of PC (concentration:group AIP =20.51 (9.55,86.5) kU/L,group PC =326.50 (94.38,10393.00) kU/L; positive rate:group AIP =35.70％ (10/28),group PC =86.70％ (65/75),P =0.000).The high titers in amylase (concentration:group AIP =103.50 (72.00,252.00) U/L,group PC =46.50 (21.65,96.90) U/L; positive rate:group AIP =45.00％ (9/20),group PC =19.40％ (7/36),P =0.043),lipase(concentration:group AIP =340.50(152.05,495.80) U/L,group PC =107.40(23.40,177.26) U/L,P =0.005 ; aspartate aminotransferase (positive rate:group AIP =75.00％ (27/36),group,PC =55.90％ (52/93),P =0.046) andγ-glutamyltranspeptidase (positive rate:group AIP =79.40％ (27/34),group PC =57.10％ (52/91),P =0.022) had higher values in the diagnosis of AIP.The significant increases in CA199 were not the basis which excluding AIP.Conclusion AIP as a unique type of chronic pancreatitis can be distinguished from PC on distinctive clinical,serological characteristics.