Pharmacovigilance in China: issues of concern identified through an analysis of the Chinese Adverse Drug Reaction Information Bulletin 2001 to 2014.

WHAT IS KNOWN AND OBJECTIVE: The Adverse Drug Reaction Information Bulletin (ADRIB), issued by China Food and Drug Administration (CFDA), is a major source of information on drugs causing safety concerns in China. As the publication is only published in Chinese, we undertook an analysis of the reports in the ADRIB since its first publication in 2001 to give international readers a better appreciation of the pharmacovigilance issues addressed. METHODS: Every issue of the ADRIB was scrutinized, and the issues addressed as well as the drugs involved are summarized and discussed. RESULTS AND DISCUSSION: From 2001 to 2014, 109 items of ADR information have been reported. The antimicrobial agents were most often the subject of discussion. There were 28 traditional Chinese medicines (TCMs) discussed. Among the ADRs addressed, the adverse reactions of the skin and its appendages were most frequent. About two-fifths of the ADRs arose from the inherent properties of the active substance, and a majority of the ADRs were caused by off-label use, irrational drug combinations and misuse in special populations. WHAT IS NEW AND CONCLUSION: Many of the pharmacovigilance issues addressed were similar to those considered by Western Drug Regulatory Agencies. The pharmacovigilance issues relating to Chinese traditional medicines are less well addressed internationally, and these would be of particular value as the use of such medicines increases in the West.

Genetic polymorphisms of debrisoquine and S-mephenytoin oxidation metabolism in Chinese populations: a meta-analysis.

Chinese data on the polymorphic metabolism of debrisoquine, metoprolol, codeine and mephenytoin were collected and re-analysed using a meta-analysis method. There were no significant differences in the incidences of poor metabolizer (PM) between the separate series of debrisoquine, metoprolol and codeine, which are the three probe drugs reflecting the same enzyme polymorphism. PMs were detected at low frequencies for debrisoquine (1.20%; 95% confidence interval, CI: 0.67-1.98%), metoprolol (0.72%; CI: 0.29-1.49%) and codeine (0.48%, CI: 0.01-2.68%). The overall estimate of PM was 0.95% (CI: 0.60-1.42%) based on the 2427 determinations of all three probe drugs. The overall mean of PM of mephenytoin was 14.32% (12.26-16.38%) in the 1117 subjects. In summary, the present meta-analysis determined the accurate incidences of the genetic deficiency of S-mephenytoin 4'-hydroxylase (cytochrome P450 2C19) and debrisoquine hydroxylase (cytochrome P450 2D6) in Chinese populations.

[Changes of osteopontin and matrix Gla protein mRNA expressions in the healing process of rat thoracic aorta damaged by balloon angioplasty].

Using Northern blot and reverse transcriptase-polymerase chain reaction (RT-PCR) the dynamic changes of osteopontin (OPN) and matrix Gla protein (MGP) mRNA expression in the healing process of rat thoracic aorta damaged by balloon angioplasty were investigated. The results showed that expression of OPN and MGP in the thoracic aorta damaged group was higher compared with normal group. 1, 7, and 14 d after thoracic aorta was damaged, expression of OPN and MGP was increased gradually, and decreased after artery damaged 21 d.

[Measurement of cytoplasmic Ca2+ activity in myocardia with Ca(2+)-sensitive microelectrode].

The improved neutral ligand ETH1001 Ca(2+)-sensitive microelectrodes (Ca-ISE, tip diameter 0.4-0.8 mumol.L-1) are highly ion selective and sensitive and therefore can be reliably used to measure cytoplasmic Ca2+ activity (alpha iCa) in myocardia. The resting alpha iCa in guinea-pig ventricular trabecula, canine ventricular myocardia and Purkinje fibers were respectively 0.19 +/- 0.01, 0.20 +/- 0.02 and 0.46 +/- 0.07 mumol.L-1. Three mumol.L-1 strophantin G increased the resting and dynamic myocardial alpha iCa by 0.18 +/- 0.02 and 6.69 +/- 2.09 mumol.L-1 respectively, as well as engendered triggered activity (TA). When pretreated with 100 mumol.L-1 dauricine (Dau), strophantin G could no longer increase alpha iCa and TA disappeared. It is suggested thus the applicability of Ca-ISE for measurement of myocardia alpha iCa and TA is obvious.

[HPLC method for determination of lorcainide hydrochloride in human serum].

An analytical method was established for determination of lorcainide hydrochloride concentration in serum using high performance liquid chromatography (HPLC). The stainless steel column was 200 mm x 5.0 mm ID, packed with YWG C18H37, 5 microns. The mobile phase consisted of methanol-water-0.625 mol.L-1 ammonium acetate. (86:13:1 v/v), adjusted to the pH 8.0 with ammonium hydroxide. The flow rate was 1 ml.min-1, using diltiazem as internal standard. Chromatography was performed with ultraviolet detector at 226 nm. The recoveries of lorcainide hydrochloride at 40, 200 and 400 micrograms.L-1 were 95.85%, 100.63% and 100.09%, respectively. The within-day and day-to-day RSD of the determinations at concentrations of 100, 200, 400 and 800 micrograms.L-1 were less than 7%. Linear calibration curve for lorcainide hydrochloride was measured within the range of 20 to 800 micrograms.L-1 with correlation coefficient of 0.9996. The detection limit was 5 micrograms.L-1 in serum. The HPLC method described is suitable for clinical monitoring and pharmacokinetic study of lorcainide hydrochloride.

[Effects of 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxy phenylethylamino) propane hydrochloride on cytosolic free calcium concentration of rabbit platelets].

The effects of 1-(2, 6-dimethylphenoxy)-2- (3,4-dimethoxyphenylethylamino) propane hydrochloride (DDPH) and verapamil on cytosolic free calcium concentration of rabbit platelets were investigated. The results showed that the elevation of cytosolic free calcium concentration ([Ca2+]i) of rabbit platelets following ionophore A23187 was significantly inhibited by DDPH and verapamil. The rates of inhibition with DDPH and verapamil were 58% and 78%, respectively, with no significant difference between the two groups (P > 0.05).

[Effects of dauricine on His-bundle electrogram and interaction with other drugs in anesthetized rabbits].

Dauricine was shown to prolong the HBE A-H, H-V intervals and the V width of anesthetized rabbits in a dose-dependent manner. Dauricine 2.5, 5 and 7.5 mg/kg iv increased the A-H interval by 11 +/- 6, 21 +/- 12 and 33 +/- 14%; prolonged the H-V interval by 22 +/- 9, 34 +/- 22 and 51 +/- 16%; and widened the V by 14 +/- 6, 22 +/- 12 and 27 +/- 11%, respectively. The effect of dauricine on the H-V interval was greater than on the A-H interval. Influence of lidocaine on the His-bundle electrogram was not significant. The effect of dauricine on the H-V interval was weakened when administered in combination with lidocaine (p less than 0.05). Dauricine 7.5 mg/kg prolonged the A-H interval at all stimulation frequencies (300, 335, 375, 430 beats/min). Dauricine increased the atrial effective refractory period (AERP) and the atrial-ventricular (A-V) node functional refractory period (AVNFRP) of the rabbits in dose-dependent manner. Isoprenaline 10 micrograms/kg iv shortened the A-H, H-V intervals and V width, and atropine 3 mg/kg iv partially reduced the A-H interval prolonged by dauricine.(ABSTRACT TRUNCATED AT 250 WORDS)

[Antagonism of daurisoline on arrhythmogenic delayed afterdepolarization].

Standard microelectrode technique was used to study the effect of daurisoline (DS) on delayed afterdepolarization (DAD) and triggered activity (TA) in guinea pig ventricular trabeculae. DS (50 mumol.L-1) abolished TA induced by ouabain or caffeine, inhibited isoprenaline-induced TA, decreased incidence of TA induced by K(+)-free and high-Ca2+ medium or phenylephrine from 100.75% to 9.1% and 22.2% respectively, and significantly suppressed DAD caused by the above induces. It is concluded that DS exert antagonistic action to DAD and TA in guinea pig trabeculae.

Frequency-dependent effects of antiarrhythmic drugs on action potential duration and refractoriness of canine cardiac Purkinje fibers.

Antiarrhythmic drugs are known to have frequency dependent effects on Vmax and conduction. The purpose of this study was to determine whether the effects of antiarrhythmic drugs on action potential duration (APD) and refractory period depend on frequency. Standard microelectrode techniques were used to measure APD and refractory period after abrupt or sustained alterations in stimulation frequency. Increases in APD95 resulting from bretylium and quinidine and decreases resulting from lidocaine were 50 to 60% attenuated (P less than .01 for each) by sustained increases in activation rate. Unlike sustained rate increases, abrupt increases in rate enhanced quinidine-induced APD prolongation (P less than .01). Quinidine increased the time constant (222 +/- 6 to 346 +/- 36 msec, P less than .01) and decreased the magnitude of the rapid phase of APD abbreviation upon premature stimulation. In contrast, bretylium increased the magnitude of APD abbreviation upon premature stimulation, reducing the tendency of bretylium to prolong premature APD compared to basic APD. Changes in refractory period parallelled changes in APD95 with the exception of the effect of quinidine after sustained rate change. Despite attenuation of its effects oN APD95, quinidine prolonged refractory period more after sustained rate increases (P less than .01), apparently because of greater depression of maximum sodium conductance. These experiments show that the effects of antiarrhythmic drugs on APD and refractoriness depend on activation frequency and that abrupt changes in rate may alter drug effects differently from sustained rate changes.

Protective and anti-arrhythmic effects of dauricine and verapamil on acute myocardial infarction in anesthetized dogs.

Dauricine (Dau) 5 mg.kg-1 and verapamil (Ver) 0.15 mg.kg-1 iv followed by infusions of 0.1 and 0.01 mg.kg-1.min-1, respectively, for 30 min, depressed the elevated coronary venous blood LDH and CPK after LAD occlusion. Dau produced antagonistic effects on acute myocardial ischemia-induced ventricular ectopic activities (VE) and ventricular tachycardia (VT). The incidences of VE and VT in Ver group and ventricular fibrillation (VF) in both groups tended to descend. The results suggested that Dau and Ver produced marked protective effects on myocardial infarction and antagonized the acute ischemic arrhythmia.

Effects of dauricine, quinidine, and sotalol on action potential duration of papillary muscles in vitro.

AIM: To compare the characteristics of dauricine, sotalol, and quinidine on action potential duration (APD). METHODS: Using intracellular microelectrode method to record APD in guinea pig papillary muscles. RESULTS: Dauricine 20 mumol.L-1 prolonged action potential at 90% repolarization, the percent of APD prolongation were 22 +/- 8, 11 +/- 6, 9 +/- 5, 7 +/- 5, 6 +/- 3, 4.3 +/- 2.8, 4.5 +/- 2.8 at the cycle lengths of 200-2000 ms, dauricine became more effective in lengthening APD at short cycle lengths. The effect of dauricine on prolonging APD exhibited normal use-dependence, whereas quinidine 1 mumol.L-1 and sotalol 10 mumol.L-1 were less effective in lengthening APD at short cycle lengths. The effect of quinidine and sotalol on APD exhibited reverse use-dependence. CONCLUSION: [corrected] The effect of dauricine on APD depends on activation frequency.

Kinetic disposition and hemodynamic effects of tetrandrine in anesthetized dogs.

The kinetic disposition and hemodynamic effects ot tetrandrine, l3 mg/kg i.v., over 30 s were studied in five anesthetized dogs during continuous monitoring of the ECG and systemic arterial pressure. Repeated determinations of cardiac output (CO) and pulmonary capillary wedge pressure (PCWP) were made via a flow-directed thermodilution catheter in the pulmonary artery. Blood samples were drawn at intervals for determination of plasma tetrandrine or erythrocyte binding of the drug. Maximal reductions in mean and diastolic arterial pressures of 23 +/- 4% were observed within 5 min of the drug infusion without a change in systolic pressure. CO was increased maximally 52% and systemic resistance reduced 5l% at l0 min, gradually returning to baseline values in l-2 h. PCWP was increased transiently at 5-l0 min. The PR interval was prolonged slightly without alteration in the R-R interval, QRS, or QTc. Changes in MAP and PR interval were correlated significantly with plasma tetrandrine concentrations over time, which followed a two-compartment kinetic model with a distribution t1/2 of 7 min and an elimination tl/2 of 88 min. The apparent volume of distribution at steady state was 57 L/kg. Plasma tetrandrine was greater than 90% bound to plasma proteins, and approximately 44% of whole blood tetrandrine was associated with erythrocytes. Tetrandrine is a potent arteriolar vasodilator drug with slight effects on AV conduction, but without significant negative inotropic effects in anesthetized dogs.

Effects of dauricine on transmembrane potential of ischemic and non-ischemic Purkinje fibers and ventricular muscles from infarcted canine hearts.

Dauricine (Dau) 1-30 mumol/L produced the concentration-dependent depression of APA, Vmax, MDP, and RP, and prolongations of APD90 of Purkinje fibers (PF) and epicardial ventricular muscles (VM) from both infarcted and non-infarcted zones. The ERP was lengthened only in non-ischemic PF and VM, and APD50 in non-ischemic PF, non- and ischemic VM. The prolonging effects of Dau on APD and ERP of ischemic PF were much less than those of non-ischemic ones, and its depressing effect on the Vmax of ischemic VM was markedly greater than that of non-ischemic VM. The results suggest that Dau exerts its anti-arrhythmic effect through further depressing conduction of ischemic zone.

Effects of dauricine and lidocaine alone or combined on electrophysiological properties of canine Purkinje fibers.

Dauricine (Dau) 1 to 30 mumol/L produced the concentration-dependent depressions in the APA, Vmax, MDP, and prolongations of APD50 and APD90 as well as ERP of the isolated canine cardiac Purkinje fibers (PF). The automaticity and excitation were significantly reduced at concentration of 30 mumol/L. The effects of Dau on all action potential parameters of PF were observed at all stimulation frequencies (60, 75, 100, 150 beats/min). Lidocaine (Lid) markedly shortened APD50 of PF at concentration of 30 mumol/L and also shortened APD90, ERP and significantly depressed APA, Vmax at 100 mumol/L. When perfused in combination with Dau, Lid appreciably shortened APD50 and APD90, and lightly abbreviated ERP prolonged by Dau.

Stereoselective steady state disposition and action of propafenone in Chinese subjects.

AIMS: To investigate the steady state disposition and action of racemic propafenone and its enantiomers and the potential for an enantiomer-enantiomer interaction in Chinese subjects. METHODS: Eight healthy male Chinese individuals received in a double-blind, randomized, cross-over study racemic propafenone (150 mg every 6 h), (S)-, and (R)-propafenone (150 mg each every 6 h) and placebo orally for 4 days. During the last dosing interval the plasma concentrations of both enantiomers of propafenone were measured and ECG, blood pressure (MAP) and heart rate were monitored. RESULTS: Whereas the apparent elimination half-life (t1/2,z), mean residence time (MRT) and time to reach peak concentrations (tmax) of (S)- and (R)-propafenone were similar and independent of the administered agent, significant differences were observed in the apparent oral clearance (CLO) of the enantiomers. During dosing with racemic propafenone CLO of (S)- and (R)-propafenone averaged (+/-s.d.) 1226+751 and 1678+625 ml min(-1), respectively (P=0.024). Following the administration of the pure enantiomers CLO of (S)-propafenone increased (P= 0.007) to 2028+/-959 ml min(-1) and that of (R)-propafenone was reduced (P= 0.042) to 1318+/-867 ml min(-1). Both enantiomers and the racemate caused about a 10% increase in the QRS duration (P<0.05) and PR-interval (P<0.01) when compared with placebo. The increase in maximum exercise heart rate was significantly (P<0.05) attenuated only at 3 h following the administration of the racemate and the S-enantiomer. MAP and QTC were not affected significantly. CONCLUSIONS: These data indicate that the stereoselective disposition of propafenone is similar in Chinese and Caucasian subjects (previously published findings), the (R)-enantiomer being cleared more rapidly. A similar enantiomer-enantiomer interaction also occurred. Thus, when the racemate was given, the elimination of (S)-propafenone was impaired and that of the (R)-form accelerated compared with single enantiomer administration. The results indicate that dosage adjustments are probably not required in Chinese patients receiving propafenone.

[First-pass effect of dauricine].

The first-pass effect of dauricine (Dau) was compared with that of lidocaine (Lid) by measuring the ventricular fibrillation threshold (VFT) and dauricine plasma concentration in rats or rabbits. After forelimb or mesenteric vein (imv) infusion of Dau at a rate of 1 mg.kg-1 x min-1 in rats, the VFT were 1.64-3.17 or 1.60-2.11 V, respectively. In the case of Lid at 2.5 mg.kg-1 x min-1, the VFT were 1.69-4.79 or 1.67-2.80 V, respectively, after ear vein (iev) or imv infusion of Dau at a rate of 0.5 mg.kg-1 x min-1 in rabbits, the VFT were 6.50-12.14 or 5.81-7.43 V, respectively. Plasma Dau concentration through iev infusion was significantly higher than that through imv route. As the dose of imv infusion increased, AUC of Dau showed a nonlinear increase. The results suggested that Dau showed a considerable first-pass effect, which was dose-dependent.

Dauricine inhibited L-type calcium current in single cardiomyocyte of guinea pig.

AIM: To study the effect of dauricine (Dau) on L-type calcium current in guinea pig ventricular myocytes. METHODS: Using whole-cell recording method to record L-type calcium current (ICa) in single ventricular cell of guinea pig. RESULTS: Dau 1, 10, and 100 mumol.L-1 markedly reduced ICa by 15.2% +/- 2.2%, 41% +/- 5%, and 82% +/- 8%, respectively. After washing out, ICa partially recovered. Dau inhibited ICa at 3 Hz and 1 Hz to a similar extent, its effect on ICa appeared to be not frequency-dependent. CONCLUSION: Dau had a calcium channel blocking effect.

Dauricine suppressed CsCl-induced early afterdepolarizations and triggered arrhythmias in rabbit heart in vivo.

AIM: To study the effect of dauricine on CsCl-induced early afterdepolarizations (EAD) and ventricular arrhythmias in rabbits. METHODS: Monophasic action potentials (MAP) of the left ventricle of the rabbit heart in situ were recorded with MAP recording technique. CsCl 1-2 mmol.kg-1 i.v. was used to induce EAD and ventricular arrhythmias. RESULTS: CsCl resulted in decrease of MAP amplitude (MAPA, P < 0.05) and prolongation of MAP duration at 90% repolarization (MAPD90, P < 0.01), QRS, and R-R duration (P < 0.05) compared with those before CsCl in the dauricine and control group. CsCl injection induced EAD that appeared within about 30 s and disappeared 5-15 min thereafter. EAD always preceded ventricular arrhythmias including ventricular premature beats and paroxysmal ventricular tachycardia. The EAD amplitude (EADA) in the dauricine group (26% +/- 9% of MAPA) was smaller than that in the control group (52% +/- 5% of MAPA, P < 0.05) and the incidence of arrhythmias in dauricine group (28%) was lower than that in control group (80%, P < 0.05). CONCLUSION: Dauricine exerted an antagonistic effect on EAD and suppressed triggered ventricular arrhythmias by decreasing EADA.