Pharmacokinetic–pharmacodynamic model for the anticholinergic effect of glycopyrrolate

OBJECTIVE: The purpose of this study was to develop and test a pharmacokinetic-pharmacodynamic (PK-PD) model for the anticholinergic effect of glycopyrrolate in eight healthy male volunteers. METHODS: First, arterial drug concentration (Cp) data after a single intravenous (i.v.) bolus injection (5 micrograms/kg) were individually fitted to a three-compartment PK model. Second, the effect of a 2-h glycopyrrolate i.v. infusion (5 micrograms/kg/h) on the mean R-R interval (RRI) and the Hayano index of the high frequency variability of RRI (HF CCV) was modelled using an effect-compartment, inhibitory sigmoidal Emax model, with the individual PK parameters from the first part as constants. Third, the developed model was tested using a computer-driven infusion which aimed at two ascending steady-state effect-site concentrations (Ce) at 1-h intervals, corresponding to 20% and 80% of the maximal effect (Emax) observed in the second part. RESULTS: Modeling of the HF CCV data yielded the following mean (+/- SD) estimates: concentration at 50% of Emax (EC50), 2.46 +/- 0.58 ng/ml, equilibration half-time (t1/2 ke0), 42.5 +/- 7.7 min, and sigmoidicity factor (gamma), 7.26 +/- 2.82. The corresponding values for RRI data were 2.79 +/- 0.52 ng/ml, 58.3 +/- 17.2 min, and 4.75 +/- 1.56. During the computer-controlled two-step infusion (performed using HF CCV as the effect variable), the measured Cp approached the targeted Ce in most of the subjects, while the observed effect appeared to surpass the targeted levels. CONCLUSION: Although we were able to develop individual PK-PD models for glycopyrrolate, maintaining a stable anticholinergic effect in the computer-driven infusion appeared to be difficult. This is probably due to intra-individual variability in the PK-PD parameters and the extremely steep concentration-effect relationship of glycopyrrolate.     

A signal transduction pharmacodynamic model of the kinetics of the parasympathomimetic activity of low-dose scopolamine and atropine in rats

We used a novel pharmacokinetic-pharmacodynamic (PK-PD) approach that had been applied for signal transduction kinetics to investigate the kinetics of the parasympathomimetic effect of scopolamine and atropine in rats. The parasympathetic tone was assessed by continuous measurement of the power of the high frequency band (HF) of electrocardiogram (ECG) R-R intervals obtained by power spectral analysis (PSA) of heart rate variability (HRV). To overcome the inherent noise of the HRV-HF data and to quantitatively identify temporal changes in the autonomic tone, a new approach of stepwise regression of the cumulative HF data was applied. The elevation of the parasympathetic tone occurred after a significant lag time (>70 min) following scopolamine administrations [0.25 and 0.5 mg/kg intravenous (iv) bolus or infusion over 100 min], followed by a gradual return to the baseline levels. A similar lag time in parasympathetic stimulation was observed following iv bolus administration of atropine (0.1 mg/kg). The plasma drug concentration versus time data were linked to the response versus time data using a signal transduction pharmacodynamic model that was fitted simultaneously to all four experimental data sets. This PK-PD model resolved the significant discrepancy between the concentration versus time and the response versus time patterns and successfully described the kinetics of the parasympathetic stimulation obtained for different drugs and different rates of administration. This work paves the way for further PK-PD preclinical investigations in this field.     

Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effects of scopolamine in healthy volunteers

Scopolamine is a muscarinic receptor antagonist commonly used as a pharmacological model substance based on the "cholinergic hypothesis" of memory loss in senile dementia of the Alzheimer type. The objective of the study was to relate pharmacodynamic electroencephalogram (EEG) changes and scopolamine serum concentration using pharmacokinetic-pharmacodynamic (PK-PD) modeling techniques. This was a randomized, three-way crossover, open-label study involving 10 healthy nonsmoking young male volunteers who received either scopolamine 0.5 mg as an intravenous (i.v.) infusion over 15 minutes or an intramuscular (i.m.) injection or a placebo. The pharmacodynamic EEG measure consists of the total power in delta, theta, alpha, and beta bands over frontal, central, and occipital brain areas. The values of the pharmacokinetic parameters of scopolamine after i.v. infusion were clearance (CL) 205 +/- 36.6 L/h, volume of distribution (Vd) 363 +/- 66.7 L, distribution half-life (t1/2 alpha) 2.9 +/- 0.67 min, and terminal half-life (t1/2 beta) 105.4 +/- 9.94 min (mean +/- SEM). Mean peak serum concentrations (Cmax) were 4.66 and 0.96 ng/ml after i.v. and i.m. administration, respectively (p < 0.05). The area under the serum concentration versus time curve (AUC) after i.m. administration (81.27 +/- 11.21 ng/ml/min) was significantly lower compared to the value after i.v. infusion (157.28 +/- 30.86 ng/ml/min) (mean +/- SEM, p < 0.05). Absolute bioavailability of scopolamine after i.m. injection was 57% +/- 0.08% (mean +/- SEM). After both i.v. and i.m. administration, scopolamine induced a decrease in EEG alpha power (7.50-11.25 Hz) over frontal, central, and occipital brain areas compared to placebo (p < 0.05). The individual concentration-EEG effect relationships determined after i.v. infusion of scopolamine were successfully characterized by a sigmoidal Emax model. The averaged values of the pharmacodynamic parameters were E0 = 0.58 microV2, Emax = 0.29 microV2, EC50 = 0.60 ng/ml, and gamma = 1.17. No time delay between serum concentrations and changes in alpha power was observed, indicating a rapid equilibration between serum and effect site. The results provide the first demonstration of a direct correlation between serum concentrations of scopolamine and changes in total power in alpha frequency band in healthy volunteers using PK-PD modeling techniques. As regards the effect on the EEG, 0.5 mg of scopolamine administered i.v. appears to be a suitable dose.     

Effects of atropine on the time and frequency domain estimates of blood pressure and heart rate variability in mice

1. Indices quantifying blood pressure (BP) and heart rate (HR) variability have been recently developed and may be used to assess the contribution of the autonomic nervous system to cardiovascular fluctuations. 2. Cardiovascular variables were measured in eight conscious mice equipped with a BP telemetric device. Each recording session was conducted when the mice were at rest and included a control period, an injection of atropine methylnitrate (2 mg/kg) and a post-treatment recording. 3. Time domain indices were the mean pulse interval (PI) and NN (the normal-to-normal intervals), mean HR, standard deviation of PI (SDNN), the square root of the mean of the sum of the squares of differences between adjacent PI (RMSSD) and the pNN8 (NN8 count divided by the number of NN intervals). Frequency domain indices of HR variability were the low frequency (LF) zone (0.15-0.60 Hz) and the high frequency (HF, respiratory sinus arrhythmia) zone (2.5-5.0 Hz) of the PI power spectrum. The time domain index of spontaneous baroreflex sensitivity (BRS) was the slope of the linear PI and systolic BP relationship obtained using the sequence technique. The frequency domain indices of BRS were the gain of the transfer function between systolic BP and PI in the LF and HF bands. 4. Atropine markedly affected these variables, illustrating vagal predominance under resting conditions in mice. The preferable time and frequency domain indices for quantifying the vagal contribution to HR variability were the pNN8 and the LF gain.     

Pharmacokinetic and pharmacodynamic population modeling of orally administered rabeprazole in healthy Chinese volunteers by the NONMEM method.

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of the proton pump inhibitor rabeprazole in healthy Chinese volunteers was characterized via a population approach. Healthy Chinese male volunteers were enrolled in the clinical trial. Subjects were divided into three groups by their CYP2C19 genotype. Serum concentrations of rabeprazole were determined using high performance liquid chromatography (HPLC). The intragastric pH values were monitored simultaneously. Data analysis was performed using nonlinear mixed-effects modeling as implemented in the NONMEM software package. The final PK-PD model incorporated a one-compartment PK model with one-order absorption from the gastroenteric trace, first-order elimination pathway with one fixed-effect genotype modeling, and a full sigmoidal Emax PD model (X +/- SE: E0 = 2.30 +/- 0.189; Emax = 7.32 +/- 0.662; EC50 = 51.3 +/- 2.142 ng/ml; Hill coefficient = 5.00 +/- 0.556). The time profiles for concentration and pH value, as well as the concentration-pH value relationship of rabeprazole in healthy Chinese volunteers were well described by the developed population PK-PD model.     

Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

The pharmacodynamics of a racemic mixture of ketamine R,S(+/-)-ketamine and of each enantiomer, S(+)-ketamine and R(-)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid Emax pharmacodynamic model, yielding estimates of both maximal effect (Emax) and sensitivity (IC50) to the racemic and enantiomeric forms of ketamine. R(-)-ketamine was not as effective as R,S(+/-)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean +/- SD) of the median frequency (Emax) for R(-)-ketamine was 4.4 +/- 0.5 Hz and was significantly different from R,S(+/-)-ketamine (7.6 +/- 1.7 Hz) and S(+)-ketamine (8.3 +/- 1.9 Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC50) was 1.8 +/- 0.5 micrograms/mL for R(-)-ketamine; 2.0 +/- 0.5 micrograms/mL for R,S(+/-)-ketamine; and 0.8 +/- 0.4 microgram/mL for S(+)-ketamine. Because the maximal effect (Emax) of the R(-)-ketamine was different from that of S(+)-ketamine and R,S(+/-)-ketamine, it was not possible to directly compare the potency (i.e., IC50) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.     

Effects of nonpeptide and selective V1 and V2 antagonists on blood pressure short-term variability in spontaneously hypertensive rats

Effects of V(1) (OPC-21268) and V(2) (OPC-31260) vasopressin antagonists on blood pressure (BP) short-term variability were investigated in adult spontaneously hypertensive rats (SHR) under basal conditions and after the stimulation of vasopressin release by hemorrhage. BP was recorded intra-arterially and sampled at 20 Hz to be analyzed on a personal computer. BP time spectra were calculated on 30 stationary overlapping 2048 point-time series. Spectral power was estimated in total (0.00976 - 3 Hz), very low frequency (VLF: 0.00976 - 0.195 Hz), low frequency (LF: 0.195 - 0.605 Hz), and high frequency (HF: 0.8 - 3 Hz) regions. Under basal conditions a V(1) antagonist (5 mg/kg, i.v.) decreased BP without affecting BP variability, while combined (V(1) + V(2)) blockade or V(2) blockade (1 mg/kg, i.v.) alone did not affect cardiovascular parameters. Mild hemorrhage (5 ml/kg per min) increased HF-BP variability, while moderate (10 ml/kg per min) and massive (15 ml/kg per min) hemorrhage did not affect it. In V(1), but not V(2), antagonist pre-treated SHR HF-BP increased significantly after moderate and massive hemorrhage. V(1) or V(2) antagonist pre-treatment also enhanced VLF-BP variability during massive hemorrhage. Moreover V(1) blockade prevented hemorrhage-induced bradycardia, while V(2) blockade potentiated it. It follows that in adult SHR, vasopressin buffers BP oscillations in HF and VLF frequency domains only in hypovolaemic conditions and that the modulation of the autonomic adjustment of the HR to hemorrhage by vasopressin is preserved.     

Pharmacokinetic-pharmacodynamic modelling of S(-)-atenolol in rats: reduction of isoprenaline-induced tachycardia as a continuous pharmacodynamic endpoint

BACKGROUND AND PURPOSE: For development of mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models, continuous recording of drug effects is essential. We therefore explored the use of isoprenaline in the continuous measurement of the cardiovascular effects of antagonists of beta-adrenoceptors (beta-blockers). The aim was to validate heart rate as a pharmacodynamic endpoint under continuous isoprenaline-induced tachycardia by means of PK-PD modelling of S(-)-atenolol. EXPERIMENTAL APPROACH: Groups of WKY rats received a 15 min i.v. infusion of 5 mg kg(-1) S(-)-atenolol, with or without i.v. infusion of 5 microg kg(-1) h(-1) isoprenaline. Heart rate was continuously monitored and blood samples were taken. KEY RESULTS: A three-compartment model best described the pharmacokinetics of S(-)-atenolol. The PK-PD relationship was described by a sigmoid Emax model and an effect compartment was used to resolve the observed hysteresis. In the group without isoprenaline, the variability in heart rate (30 b.p.m.) approximated the maximal effect (Emax=43+/-18 b.p.m.), leaving the parameter estimate of potency (EC50=28+/-27 ng ml(-1)) unreliable. Both precise and reliable parameter estimates were obtained during isoprenaline-induced tachycardia: 517+/-13 b.p.m. (E0), 168+/-15 b.p.m. (Emax), 49+/-14 ng ml(-1) (EC50), 0.042+/-0.012 min(-1) (k(eo)) and 0.95+/-0.34 (n). CONCLUSIONS AND IMPLICATIONS: Reduction of heart rate during isoprenaline-induced tachycardia is a reliable pharmacodynamic endpoint for beta-blockers in vivo in rats. Consequently this experimental approach will be used to investigate the relationship between drug characteristics and in vivo effects of different beta-blockers.     

Uniformly sized molecularly imprinted polymer for atropine and its application to the determination of atropine and scopolamine in pharmaceutical preparations containing Scopolia extract

A uniformly sized molecularly imprinted polymer (MIP) for atropine has been prepared. The MIP was prepared using 2-(trifluoromethyl) acrylic acid and ethylene glycol dimethacrylate as a functional monomer and cross-linker, respectively, by a multi-step swelling and thermal polymerization method. The selectivity factor, which is defined as the ratio of the retention factors (k) on the molecularly imprinted and non-imprinted polymers, k(imprinted)/k(non-imprinted), was 2.2 for atropine on the MIP. The obtained MIP was applied for the determination of tropane alkaloids (atropine and scopolamine) in a commercial gastrointestinal drug by a column-switching HPLC system, consisting of an MIP material as a pre-column, and a conventional cation-exchange analytical column. An interference peak was observed at the retention time of atropine derived from pre-column. However, since the peak area was less than 0.5% the peak area of atropine of a standard solution under the analytical conditions of this study (0.2 microg of atropine was loaded), this interference was negligible in the determination of atropine. On the other hand, no interference peak was observed at the retention time of scopolamine. Calibration curves of atropine and scopolamine showed good linearity in the range of 0.02-0.9 microg/ml (r=0.9999) and 0.003-0.09 microg/ml (r=0.9998), respectively. The mean recoveries of atropine and scopolamine from a placebo pharmaceutical preparation sample were 98.9 and 99.9%, respectively. The intra-day precision (measured by relative standard deviation, R.S.D. (%)) of both ingredients was less than 2.0%. The optimized column-switching system was applied successfully to the determination of atropine and scopolamine in a commercial gastrointestinal drug.     

Effects of scopolamine on immediate postural changes in heart rate and R—R variance in humans

To examine the anticholinergic effects of scopolamine, postural tests were performed in nine healthy male volunteers after they received intravenous infusions of 0.2mg of scopolamine, 0.4 mg of glycopyrrolate, or placebo on separate days under double-blind randomized conditions. Compared to the placebo and glycopyrrolate conditions, scopolamine produced a significantly exaggerated HR response to standing from supine posture. Scopolamine also produced a significant increase in R-R variance during supine deep breathing and standing conditions as compared to glycopyrrolate and placebo conditions. At the same time, scopolamine also produced a significant dry mouth. These findings suggest that the effects of scopolamine in low doses on the above cardiac variables are vagomimetic.     

Effect of cardiac vagal outflow on complexity and fractal correlation properties of heart rate dynamics

1. Cardiac vagal outflow is the major factor determining the magnitude of heart rate (HR) variability analysed by traditional time and frequency domain methods. New analysis techniques, such as fractal and complexity methods, have been developed to probe non-linear features in HR behaviour that may not be detectable by traditional methods. 2. We investigated the effects of vagal blockade (glycopyrrolate i.v. 5 microg kg-1 h-1 for 2 h, n = 8 vs. unmedicated control group, n = 8) and various breathing patterns (n = 12) on two non-linear measures of HR variability--detrended fluctuation analysis (DFA) and approximate entropy (ApEn)--in healthy male volunteers. 3. Glycopyrrolate decreased the mean (+/-SD) ApEn from 1.46 +/- 0.18 to 0.85 +/- 0.24 (P = 0.001 in comparison with the control group), and increased the short-term (alpha 1) and intermediate-term (alpha 2) fractal scaling exponents of DFA, alpha 1 from 0.96 +/- 0.19 to 1.43 +/- 0.29 (P = 0.003) and alpha 2 from 1.13 +/- 0.10 to 1.34 +/- 0.14 (P < 0.001). 4. Decrease in fixed respiration rate from 15 to 6 breaths min-1 increased alpha 1 from 0.83 +/- 0.25 to 1.18 +/- 0.27 (P < 0.001), but decreased alpha 2 from 0.88 +/- 0.09 to 0.45 +/- 0.17 (P < 0.001) and ApEn from 1.26 +/- 0.12 to 1.10 +/- 0.14 (P = 0.028). Rapid breathing (24 min-1) had no influence on these non-linear measures of HR variability. Hyperventilation (15 min-1, tidal volume increased voluntarily by 0.5 l) decreased alpha 1 from 0.83 +/- 0.25 to 0.66 +/- 0.28 (P = 0.002) but did not affect alpha 2 or ApEn. 5. To conclude, vagal blockade alters the fractal scaling properties of R-R intervals (alpha 1, alpha 2) and reduces the complexity (ApEn) of HR behaviour. Both the fractal and complexity measures of HR variability can also be influenced by changes in the breathing pattern.     

Augmentation of the behavioral effects of amphetamine by scopolamine

Summary Non-effective doses of scopolamine were found to augment the tendency of amphetamine to increase the response rates of rats working in an operant, shock-avoidance situation. This finding is presumably related to our earlier observation that the related parasympatholytic, atropine, also had this augmenting action.     

Central cholinergic modulation of blood pressure short-term variability

The role of neurally born acetylcholine in the central modulation of cardiovascular short-term variability was assessed using a pharmacological probe physostigmine, a cholinesterase inhibitor that can act centrally also. Experiments were performed in instrumented conscious rats. Equidistant sampling at 20 Hz of systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and heart rate (HR) allowed direct spectral analysis. Spectra were analysed in the whole, very-low frequency (VLF), low-frequency (LF) and high-frequency (HF) domains. Physostigmine, but not neostigmine, increased SAP, LF SAP and HF SAP variability while neostigmine, but not physostigmine, decreased HR without affecting HR variability. Atropine methyl nitrate prevented neostigmine-induced bradycardia and potentiated the effects of physostigmine on DAP, LF DAP and HF DAP variability. Atropine sulphate, hexamethonium, phentolamine and metoprolol inhibited physostigmine-induced increase of SAP and LF SAP. Pre-treatment of rats by quinapril prevented physostigmine-induced increase of SAP, but not of LF SAP, while the V(1a) antagonist prevented the increase of HF SAP. The results suggest that central cholinergic neurons facilitate but do not create LF SAP and HF SAP variability. The effect of physostigmine on LF SAP seems to be mediated via central muscarinic sites and the peripheral sympathetic system, while non-muscarinic central sites and vasopressin pathways subserve the increase of HF SAP.     

瑞芬太尼对心率影响的临床与实验研究

目的：观察瑞芬太尼对心率（HR）及心率变异性的影响,并探讨其作用机制。方法：临床部分：选择行择期手术的全麻患者40例,分为单纯应用瑞芬太尼组（R组）和阿托品预处理组（A组）,每组20例。R组患者静脉恒速泵入瑞芬太尼2μg/kg,泵速为1μg·kg^-1·min^-1;A组患者阿托品0.5 mg肌肉注射30 min后,给予瑞芬太尼方法同R组。记录用药前后各时间点的HR和低高频比值（LF/HF）。实验部分：雄性SD大鼠24只,随机分为3组（n=8）,行离体心脏灌注,C组为空白对照,R10组和R30组分别灌注瑞芬太尼10 ng/mL和30 ng/mL。记录用药前后各时间点的HR和左室发展压（LVDP）。结果：组内比较：R组患者的HR和LF/HF值在用药后各时间点均降低（P〈0.05）;A组给药后的各时间点HR和LF/HF值未出现有统计学意义的变化。组间比较：在给药后的各时间点,R组的HR和LF/HF值低于A组（P〈0.05）。动物实验部分瑞芬太尼10 ng/mL和30 ng/mL对离体鼠心的HR和LVDP均无影响。结论：通过本研究发现瑞芬太尼主要是通过抑制中枢神经系统或破坏心脏自主神经系统平衡而使HR及心率变异性明显降低,而阿托品可以拮抗瑞芬太尼的这种HR抑制作用。     

LC determination of atropine sulfate and scopolamine hydrobromide in pharmaceuticals

An accurate, simple, reproducible and sensitive method for the determination of atropine sulfate and scopolamine hydrobromide has been developed and validated. Atropine sulfate and scopolamine hydrobromide were separated using a microBondapack C(18) column by isocratic elution with flow rate 1.0 ml/min. The mobile phase composition was methanol, water, formic acid (165:35:1; v/v/v) and pH adjusted 8.3 with triethylamine. The samples were detected at 230 nm using photo-diode array detector. The linear range of detection for atropine sulfate (I) and scopolamine hydrobromide (II) were between 10.38 and 1038 microg/ml with a limit of quantification (LOQ) of 10.38, 10.00 and 1034 microg/ml with an LOQ of 10.00 microg/ml respectively. The linearity, range, peak purity, selectivity, system performance parameters, precision, accuracy, robustness and ruggedness for (I) and (II) were also shown acceptable values.     

Effects of atropine and glycopyrrolate on neuromuscular transmission in the rat phrenic nerve-diaphragm preparation

1. The effects of atropine and glycopyrrolate on neuromuscular transmission and on muscle contraction, were studied, in the rat diaphragm preparation, by analyzing their effects on the indirectly (and directly)-elicited twitch (0.2 Hz), tetanic (50 Hz for 20 sec duration), post-tetanic twitch responses (at 5 sec after the tetanus), and on the phenomenon of post-tetanic twitch potentiation (PTP), which is thought to be of a presynaptic origin, i.e. due to increased transmitter release. 2. Atropine (0.001-10 microM) increased the indirectly-elicited twitch tension by 22 +/- 2.1% (control 0.9 +/- 0.1 g, P less than 0.02), the tetanus by 15 +/- 1.1% (control 3.9 +/- 0.7 g, P less than 0.05), the post-tetanic twitch response by 33 +/- 3.1% (control 1.2 +/- 0.1 g, P less than 0.01) and the PTP value by 36 +/- 1.9% (control 33 +/- 2.3%, P less than 0.01, means +/- SEM = 6). 3. Atropine (0.001-10 microM) had little effect on the directly-elicited twitch tension, but in high concentrations (e.g. 20 microM), it blocked the twitch tension. 4. In contrast, glycopyrrolate (0.1-100 microM) had little effect on the twitch tension (direct or indirect), but it significantly reduced the tetanus (by 38 +/- 3.5%, P less than 0.01), the post-tetanic twitch response (by 17 +/- 1.2%, P less than 0.05) and the PTP values (by 24 +/- 3.1% P less than 0.02). 5. In the presence of hemicholinium (1.3 microM) the responses to atropine and glycopyrrolate were altered (decreased), indicating a possible action on presynaptic mechanism of transmission. 6. It is concluded that atropine and glycopyrrolate produce different (opposite) effects at the rat neuromuscular junction, atropine enhances whereas glycopyrrolate depresses neuromuscular transmission. The effects of these two antimuscarinic drugs may be exerted at the presynaptic nerve terminals, i.e. on presynaptic muscarinic receptors, which are involved in the feedback mechanism of transmitter release.     

蝙蝠葛碱在Beagle犬体内的药动学与其对心电图的影响

目的:建立药动学-药效学结合模型分析蝙蝠葛碱在犬体内药动学与其对心电图影响之间的关系。方法:蝙蝠葛碱6 mg·kg-1静脉注射后,8 h内定时取血,同时观察并记录心电图变化。采用反相高效液相-紫外法测定血浆中蝙蝠葛碱的浓度。应用3P97程序药动-药效参数估算程序对血药浓度和效应时间数据进行估算。结果:蝙蝠葛碱在犬体内动力学行为符合二房室开放模型,t1/2α=0.049±0.016 h;t1/2β=2.7±0.6 h。蝙蝠葛碱对HR的最大抑制率为(26.4±6.1)％,对PR,QRS,和Q-Tc间期的最大延长率分别为(33.7±10.0)％、(35.6±12.0)％和(25.5±9.4)％。效应滞后于血药浓度10~15 min。药理效应与效应室浓度之间的关系符合sigmoid-Emax模型。结论:以上模型很好地描述了蝙蝠葛碱在犬体内的血药浓度与其对心电图的药理效应之间的关系。     

Lack of association between QT dispersion and blood pressure response during dental surgery

1. It is well known that dental surgery induces increases in blood pressure. However, the factors influencing this increase are not yet fully understood. We have determined the relationship between QTc (= QT/RR(1/2), with RR being the R-R interval in seconds) dispersion, measured with a 12-lead surface electrocardiogram, and changes in blood pressure during tooth extraction. 2. Both QTc dispersion and the power spectrum of R-R variability were determined before the dental surgery was undertaken. The low-frequency (LF; 0.041-0.140 Hz), high- frequency (HF; 0.140-0.500 Hz) and total spectral powers (TF; 0.000-4.000 Hz) were calculated and the ratio of LF to HF and the percentage of HF relative to TF (%HF; HF/TF x 100) were used as indices of sympathovagal balance and parasympathetic activities, respectively. 3. In the present study, QTc dispersion failed to correlate with LF/HF and %HF. Systolic blood pressure and pulse rate increased significantly during tooth extraction; however, changes in these variables failed to correlate with QTc dispersion. 4. These results suggest that QTc dispersion is not associated with the power spectrum of R-R variability and that it does not affect the blood pressure response during tooth extraction.     

Spontaneous baroreflex sensitivity as a dynamic measure of cardiac anticholinergic drug effect

1 In this study, the analysis of spontaneous baroreflex sensitivity (BRS) was applied to the dynamic assessment of cardiac anticholinergic drug effect in healthy male volunteers. 2 The anticholinergic effects of single intravenous (i.v.) injections of atropine (10 μg kg^–1), glycopyrrolate (5 μg kg^–1) and scopolamine (5 μg kg^–1), as well as a 2‐h infusion of glycopyrrolate (5 μg kg^–1 h^–1) were investigated. Baroreflex sensitivity, a validated measure of cardiac parasympathetic reflex regulation, was repeatedly measured from 5‐min recordings of electrocardiogram (ECG) and continuous blood pressure by using the sequence technique, a method based on detection of spontaneous fluctuations in blood pressure and heart rate. 3 Single injections of atropine, glycopyrrolate and scopolamine decreased the mean BRS by 71 ± 32, 68 ± 23 and 27 ± 45%, respectively, whereas the slow glycopyrrolate infusion gradually decreased BRS (up to 83 ± 11% reduction) and increased both systolic (SAP) and diastolic arterial pressures (DAP) (on an average, by 9 mmHg). 4 During the withdrawal of the parasympathetic blockade (indicated by increasing BRS), the proportion of baroreflex sequences in the recordings increased transiently from 10 up to 20–25%, probably reflecting the restoration of the baroreflex integrity and the baroreflex‐induced attempt to counteract the blood pressure increase. 5 The sequence method to study BRS seems to be feasible in the assessment of cardiac anticholinergic drug effects, and it also provides good time resolution for the dynamic measurements.