Effects of Risk Factors for the Recurrence of Ischemic Stroke after Secondary Prevention and the Effect of Drug Intervention on the Concentration of 4-HNE / 中国药房

OBJECTIVE：To investigate the risk factors for the recurrence of ischemic stroke after secondary prevention ，and to observe the effect of glutathione on 4-HNE. METHODS ：Totally 97 patients with ischemic stroke relapse within one year were treated from Oct. 2017 to Oct. 2019 in 3 hospitals as the Second Affiliated Hospital of Shandong First Medical University due to cerebral thrombosis or cerebral embolism as observation group ，and 97 non-recurrence patients in the same period were paired as control group. The patients in the observation group were randomly divided into conventional treatment group （49 cases）and drug intervention group （48 cases）. The patients in conventional treatment group received routine treatment such as cerebral blood flow recanalization， improving circulation ， controlling blood pressure ， maintaining blood glucose ， treating hyperlipidemia and arrhythmia during hospitalization. Drug intervention group was additionally given Glutathione for injection 1.8 g intragastrically ， once a day ，on the basis of conventional treatment group. 4-HNE concentrations in plasma were determined at admission and 14 days after treatment ，the genetic type of ALDH2 and type of TAST were determined at admission. Multiple liner regression was used to analyze the factors associated with 4-HNE increasing ； conditional Logistic analysis was used to identify independent risk factors resulting to ischem ic stroke recurrence after secondary prevention. RESULTS ：The plasma concentration of 4-HNE at admission and the percentage of arte ry atherosclerosis patients in observation group were significantly higher than control group（P＜0.05）. The distribution of each ALDH2 genotype in 2 groups complied with Hardy-Weinberg genetic equilibrium （P＞ 0.05）. The proportion of patients carrying ALDH2*2 allele in observation group （50.50％）was significantly higher than control group（36.08％）（P＜0.05）. ALDH2*2 allele [ B＝2.33，95％CI（1.35，5.50），P＝0.03] and artery atherosclerosis [ B＝1.90，95％CI （1.29，3.74），P＝0.04] were significantly associated with the elevation of plasma concentration of 4-HNE；artery atherosclerosis [OR＝ 2.93，95％CI（1.84，4.67），P＜0.01]，stroke family history [OR ＝1.50，95％CI（1.18，1.90），P＝0.04]，elevated plasma concentration of 4-HNE [OR ＝1.34，95％CI（1.11，1.62），P＝0.04] were regarded as independent risk factors associating with ischemic stroke recurrence after secondary prevention. After intervention ，plasma concentration of 4-HNE in drug intervention group and conventional treatment group was significantly lower than before intervention （P＜0.05）；there was no statistical significance between 2 groups（P＞0.05）. CONCLUSIONS ：Stroke family history ，artery atherosclerosis and the elevation plasma concentration of 4-HNE are independent risk factors associating with ischemic stroke recurrence after secondary prevention. Although drug intervention can reduce the elevated plasma concentration of 4-HNE，the effect of additional use of glutathione is not more significant than that of conventional treatment.

Therapeutic drug monitoring of valproic acid

The unpredictable and unfavorable connection of dose and plasma concentration of valproic acis supports the nescessity to regularly measure its plasma concentration. The present study is drug monitoring of valproic acid and comparative evaluation of therapeutic monitoring results of valproic acid for assessment of clinical response, safety and toxicity in different age and gender groups of Chinese epileptic patients. This knowledge will help the clinicians in adjusting the drug dosages of valproic acid in various sub-groups of epileptic patients for enhancing the safety and minimizing the toxicity of valproic acid. A total of 206 plasma samples [126 males and 80 females] of epileptic patients using valproic acid were requested for therapeutic drug monitoring by neurology department of Qilu Hospital. It was found that 29% of the total samples were found in sub-therapeutic levels. 13% of the samples had toxic levels and 58% of all samples had valproic acid levels in therapeutic range. The difference in plasma concentration of valproiv acid is notably altered in gender and various age groups. However, this requires further investigation. Despite the majority of samples in the therapeutic range, there was an unfavorable clinical response. The outcomes of the current research work exposed that there was a poor correlation between the plasma concentration and clinical response. Careful attention must be applied to specific gender and particular age group on an individual basis in the interpretation of plasma concentration results, in order to facilitate the modification of doses and develop the best approach in treatment and to obtain the desired clinical response because multiple factors can effect the valproic acid plasma concentration. Through these results, it can be concluded that poor correlation exists between valproic acid plasma concentration and clinical response

Simple, rapid and highly sensitive HPLC method for measurement of Lamotrigine in human plasma and its clinical applications

Spikes in Lamotrigine concentrations levels and associated clinical toxicity may occur unpredictably. This study describes the development and validation of a simple, more rapid, highly sensitive and economical method for measuring Lamotrigine [LTG] concentration levels in human plasma using HPLC-UV and its clinical applications. Analyte from plasma was extracted with methanol [protein precipitation] and separated on the analytical column Diamonsil C[18] [150mmx4.6mm, 5 micro m] Waters-Milford, MA, United States. Mixture of 0.1% Trifluoroacetate and Methanol used as mobile phase in a 59:41 volume/volume mixture with an isocratic flow rate of 1.5 ml/min and wavelength was adjusted to 260nm. Standard curve of lamotrigine showed good linearity over the range of 1.0-50 micro g/mL [r[2]=0.9961] and LLOQ was 1.0 micro g/ml. The Specificity, Recovery, Accuracy, Stability, Robustness and RSDs for both intraday and interday precision were within acceptable limits. The highly sensitive HPLC assay for determination of LTG in human plasma was demonstrated, validated and applied in Therapeutic Drug Monitoring [TDM] of sixty seven epilepsy patients who were using LTG. The proposed method can be easily applied in routine Therapeutic monitoring of LTG, Besides TDM, stated method can be also very useful for Bioequivalence studies, Pharmacovigilance and Pharmacokinetics studies

Determination of Paraquat in Human Plasma by Solid Phase Extraction-HPLC / 中国药房

OBJECTIVE:To develop a method for the determination of paraquat in human plasma,and to provide experimen-tal evidence for the therapy and prognosis of paraquat-poisoned patients. METHODS:The human plasma samples were processed using Waters Oasis solid phase extraction column. HPLC determination was performed on DiamonsilTM C18 chromatographic column with mobile phase consisted of 0.1 mol/L phosphate buffer(containing 80 mmol/L sodium heptanesulfonate,pH adjusted to 3.0 by triethylamine)-acetonitrile (82∶18,V/V) at the flow rate of 0.9 ml/min. The detection wavelength was set at 258 nm. RESULTS:The linear range of paraquat were 20-5 000 ng/ ml;RSDs of inter-day and intra-day both were lower than 9%;average extraction recoveries were 90.72%-96.34%,and average method recoveries were 100.32%-103.10%. CONCLUSIONS:The solid phase ex-traction HPLC can determine the content of paraquat in human plasma rapidly and accurately.

Determinations of mifepristone and its metabolites and their pharmacokinetics in healthy female Chinese subjects / 药学学报

The aim of this study is to establish an HPLC method for simultaneous determinations of mifepristone and its metabolites, mono-demethylated mifepristone, di-demethylated mifepristone and C-hydroxylated mifepristone in plasma and to evaluate the pharmacokinetic characteristics of mifepristone tablet. Twenty healthy female Chinese subjects were recruited and a series of blood samples were collected before and after 0.25, 0.5, 1.0, 1.5, 2.0, 4.0, 8.0, 12.0, 24.0, 48.0, 72.0 and 96.0 hours administration by a single oral dose of 75 mg mifepristone tablet. Mifepristone and its three metabolites were extracted from plasma using ethyl acetate and determined by high performance liquid chromatography. The main pharmacokinetic parameters of mifepristone and its metabolites, including Cmax, tmax, MRT, t(1/2), V, CL, AUC(0-96 h) and AUC(0-infinity), were calculated by Drug and Statistical Software Version 2.0. The simple, accurate and stable method allows the sensitive determinations ofmifepristone and its metabolites in human plasma up to 4 days after oral administration of 75 mg mifepristone tablet and the clinical applications of their pharmacokinetic studies.

Determination of betamethasone in human plasma by liquid chromatography with tandem mass / 药学学报

A sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of betamethasone in human plasma. The analyte was isocratically eluted on a Venusil XBP C8 column (200 mm ×3.9 mm ID, 5 μm) with methanol-water with a triple quad LC-MS/MS using ESI with positive ionization. Ions monitored in the multiple reaction monitoring (MRM) mode were m/z 393.3→355.2 for betamethasone and m/z 361.3→343.2 for prednisolone (IS). Betamethasone was extracted from 0.5 mL human plasma with ethyl acetate. The validation study demonstrated excellent precision and accuracy across the calibration range of 0.5 - 80.0 injection in healthy Chinese volunteers.

Determination of paeonol in human plasma by HPLC and its pharmacokinetic studies / 中国临床药理学与治疗学

AIM: To establish a sensitive HPLC method for determining the concentrations of paeonol in human plasma and to evaluate its pharmacokinetic characteristics. METHODS: A single oral dose of 160 mg paeonol capsules was given to 24 Chinese healthy volunteers. Paeonol was separated on a XB-C18 column with tetrahydrofuran-methanol-water-phosphonic acid (6∶60∶34∶0.1, V∶V) as mobile phase. The plasma concentrations of paeonol were determined and its pharmacokinetic parameters were calculated and evaluated using DAS 2.0. RESULTS: The linear range of the paeonol was 10-500 ng/mL and the determination limit was 10 ng/mL. The main pharmacokinetic parameters, as Cmax, tmax, t1/2,AUC0-3, AUC0-∞ after a single dose of paeonol capsules were (116±46)ng/mL,(1.02±0.13) h,(1.03±0.35) h, (174±45) ng/mL, (217±56) ng/mL,respectively. CONCLUSION: The HPLC method for determining paeonol concentration in plasma is rapid, sensitive and suitable for pharmacokinetic studies.

Study on absorption and distribution of oxybutynin oral tablet and transdermal gel in rats / 中国临床药理学与治疗学

AIM: To study the absorption and distribution characteristics of oxybutynin (OXY) oral tablet and transdermal gel. METHODS: A single dose of 0.1 g OXY transdermal gel (2 mg OXY) was applied to abdominal area about 4 cm2 and 0.5 mg immediate-release tablet was orally given to 48 rats in a randomized, open-label, control design test. The plasma, bladder and liver tissue were collected, disposed and analyzed and OXY pharmacokinetic parameters were calculated and evaluated. RESULTS: The Cmax of OXY transdermal gel and oral tablets in bladder are approximately 800 and 70 times higher than those in plasma. The plasma half life of OXY gel delayed 5.99 h, tablets 2.18 h. CONCLUSION: OXY gel show better pharmacokinetic properties, characterized with long half life and high target organ concentrations than those of tablets.

Determination of loratadine in human plasma by LC-MS and its pharmacokinetic studies / 中国临床药理学与治疗学

AIM:To establish an LC-MS method for determining the concentrations of loratadine (LOR) in human plasma and to evaluate its pharmacokinetic characteristics. METHODS: A ZORBAX Eclipse XDB-C8 (5 μm, 150 mm×4.6 mm) column was used, atmospheric pressure electronic spray ionization (AP-ESI) and ion mass spectrum (m/z) of 388.2 (M+H)+ were selected to quantify LOR, and 275.1 (M+H)+ for ropivacaine (internal standard, IS). RESULTS: The linear range of LOR standard curve was 0.5-50 ng·ml-1, and the determination limit was 0.5 ng·ml-1. The pharmacokinetic parameters of LOR after a single dose of 20 mg tablet (T1), capsule (T2) and reference (R) were as follows, the half life (t1/2) 13.52±1.35, 13.14±0.98 and 14.00±1.25 h, the time to peak concentration (Tmax) 1.24±0.06, 1.18±0.12 and 1.17±0.12 h, the peak concentration (Cmax) 21.72±7.70, 21.49±8.34 and 20.50±8.65 ng·ml-1, the area under time-concentration curve (AUC0-48 and AUC0-∞) 137.24±47.84 and 146.61±51.03 ng·ml-1·h, 139.65±45.69 and 148.04±48.10 ng·ml-1·h, 134.19±49.03 and 143.70±52.08 ng·ml-1·h, the relative bioavailability of LOR tablet and capsule were (105.49±8.08)% and (102.90±10.02)%, respectively. CONCLUSION: The LC-MS method for determining the concentration of LOR in human plasma is sensitive and accurate and can be used for LOR bioavailability and pharmacokinetic studies. LOR tests and reference are bioequivalent.

Determination of concentration of nisoldipine in human plasma by HPLC-MS method and investigation of its pharmacokinetics / 中国临床药理学与治疗学

AIM: To determine the concentration of nisoldipine in human plasma by HPLC-MS method and investigate the pharmacokinetics of sustained and immediate-release preparations. METHODS: A C 18 column was used to separate nisoldipine from plasma with the mobile phase of a mixture of methanol-water-acetic acid (7525 0.1) at a flow rate of 1.0 ml?min -1. MS: atmospheric pressure electronic spray ionization (AP-ESI) and ion mass spectral (m/z) of 411 were selected to quantify nisoldipine. Internal standard (IS): atmospheric pressure electronic spray ionization and m/z of 441 for nimodipine. RESULTS: The linear range of the standard curve of nisoldipine was 0.2- 50 ?g?L -1 and the determination limit was 0.15 ?g?L -1. The recovery rate was more than 70%, and intra-day relative standard deviation (RSD) and inter-day RSD were less than 10%. After being given a single dose of 10 mg nisoldipine sustained release tablet, sustained release capsule and normal tablet, the half life(t 1/2 /h) were 6.08? 1.48, 7.06? 1.80 and 3.70? 0.25, the time to peak concentration (T peak /h) were 5.4? 0.7, 5.8? 0.4 and 2.0? 0.2, the peak concentration (C max / ?g?L -1) were 3.43? 0.55, 3.71? 0.24 and 9.18? 3.78, the area under time- concentration curve (AUC 0-t / ?g?h -1?L -1) were 31.10? 5.00, 33.63? 7.16 and 32.72? 5.09. But after being given multiple doses of nisoldipine, C max/ ?g?L -1 were 5.20? 0.27, 3.91? 0.22 and 5.30? 1.04, C min / ?g?L -1 were 0.72? 0.10, 0.77? 0.07 and 0.53? 0.07, DF were 175.00%? 16.34%, 177.10%? 18.43% and 247.92%? 57.71% respectively. The bioavailability of sustained- release tablet and capsule were 96%?12% and 102%?9% respectively. CONCLUSION: The determination of concentration of nisoldipine in human plasma by HPLC-MS method is sensitive and accurate. It can be used for the investigation of the bioavailability and pharmacokinetic of nisoldipine.

Influence of nicotinylmethylamide on the pharmacokinetic parameters of cyclosporin A by HPLC / 中国临床药理学与治疗学

AIM: To establish a simple, rapid and accurate high performance liquid chromatographic method (HPLC) for the determination of cyclosporin A (CsA) in human whole blood, and to study the influence of nicotinylmethylamide (Nic) on the pharmacokinetic parameters of cyclosporin A (CsA). METHODS: Whole blood CsA concentrations were measured by HPLC in 18 healthy volunteers administrated single CsA or co administrated Nic. The data of time blood concentrations of CsA were analyzed by 3p97 Program. The analysis of variance and two one sided t test were used to compare the main pharmacokinetic parameters of CsA in the two administrations. RESULTS: C max and AUC 0～∞ of CsA had statistically significance between the single CsA group and co administration of Nic group (P0.05). CONCLUSION: This HPLC method is simple, sensitive and accurate, and is suitable for routine determination of blood CsA levels in human. Nic can improve the absorption of CsA and increase the C max and AUC of CsA, but has no influence on the metabolism of CsA.

Bioavailability of Benproperine Sustained-release Tablets in Healthy Volunteers / 中国药房

OBJECTIVE:To compare benproperine sustained-release tablet(BP)with cofrel tablet(CF)in respect to the bioequivalence,release characteristics and correlation between in vitro dissolubility and in vivo absorption METHODS:A HPLC method was used to determine the serum benproperine concentration after single and multiple oral administration of 80mg BP and CF in a two-period cross-over test RESULTS:The T1/2(?),Tpeak,Cmax,AUC0～36,AUC0～∞ of BP after single and multiple oral administration were (11 99?1 15)h and (11 91?1 41)h,(3 80?0 42)h and (2 25?0 26)h,(0 2 787?0 03)?g/ml and (0 4 507?0 07)?g/ml,(4 1 445?0 48)?g/(ml?h)and (3 8 981?0 54)?g/(ml?h),(4 7 908?0 42)?g/(ml?h) and (4 3 278?0 55)?g/(ml?h),and those of CF were (11 68?1 24)h and (10 83?1 01)h,(3 10?0 26)h and (1 95?0 16)h,(0 4 737?0 32)?g/ml and (0 6 163?0 42)?g/ml,(9 3 954?0 80)?g/(ml?h) and (8 5 223?0 76)?g/(ml?h),(10 1 336?0 87)?g/(ml?h) and (8 8 821?0 77)?g/(ml?h),respectively The relative bioavailability of BP versus CF was(112 40?0 06)% CONCLUSION:The results show that the benproperine sustained-release tablet and cofrel are bioequivalent

Bioequivalence of brodimoprim capsules in 18 healthy volunteers / 中国临床药理学与治疗学

Aim To evaluate the bioequivalence of demestic brodimoprim capsules and imported hyprim tablets and provide experimental basis for clinical application. MethodsA single dosage of Brodimoprim or hyprim was given to 18 healthy volunteers in a randomized 2-way cross-over test and the brodimoprim concentrations in plasma were determined by HPLC with β-naphtol as internal standard. The pharmacokinetic parameters and the relative bioavailability of the two preparations were calculated and their bioequivalence was evaluated. ResultsThe major pharmacokinetic parameters of test and reference preparations were as follows respectively:t1/2(α) (2.1 + 1.0) and (1.9+± 0.9) h, t1/3(β)(43.2±4.8) and (42.4±4.3)h, Tpeak(3.4±1.6) and (3.1±1.5) h,Cmax(5.9+ 0.9) and (5.9±1.0)μg · ml-1, AUC0～132(360.2± 55.3) and (358.7±52.6) μg · h · ml-1, AUC0～∞ (423.8±56.0) and (422.5±51.1) μg · h · ml-1. The relative bioavailability(F) of brodimprim capsules was (99.7± 4.8)%。 Conclusion . The multi-factorial analysis of variance showed that there was no significant difference in AUC0- 132between the test and reference preparations (P＞ 0.05) . The bioequivalent assumption was proved by further two one-side t-test and (1～2 α) confidence interval analysis in individuals, periods and forms of these two preparations.