Effect of dietary fat content on the bioavailability of a sustained release quinidine gluconate tablet

Quinidine gluconate 324 mg sustained release tablets (Quinaglute) was administered as a single dose to 15 healthy male subjects following an overnight fast, immediately following a high fat (HF) breakfast or immediately following a low fat (LF) breakfast. Serum samples were obtained over a 48 h period and analyzed for quinidine content using a high performance liquid chromatographic assay. Under the conditions of the study, both the rate and extent of quinidine bioavailability was significantly affected by food. The extent of bioavailability was statistically significantly greater (p less than 0.05) following both the HF and LF meals as compared to that in the fasted state. Rate of bioavailability was significantly enhanced following the LF meal as compared to that of the other two treatment groups. Although peak concentrations were greater and time to peak concentrations somewhat later following the HF meal versus those under fasting conditions, these differences were not statistically significant. In addition, the characteristics of the serum concentration-time profile (as defined by the number, magnitude, and time of occurrence of the multiple absorption maxima) was unique for each of the three treatment groups. Possible mechanisms underlying these results are explored.     

The effect of quinidine on the analgesic effect of codeine

Summary We have studied the hypoalgesic effect of codeine (100 mg) after blocking the hepatic O-demethylation of codeine to morphine via the sparteine oxygenase (CYP2D6) by quinidine (200 mg). The study was performed in 16 extensive metabolizers of sparteine, using a double-blind, randomized, four-way, cross-over design. The treatments given at 3 h intervals during the four sessions were placebo/placebo, quinidine/placebo, placebo/codeine, and quinidine/codeine. We measured pin-prick pain and pain tolerance thresholds to high energy argon laser stimuli before and 1, 2, and 3 h after codeine or placebo.After codeine and placebo, the peak plasma concentration of morphine was 6–62 (median 18) nmol·.l^–1. When quinidine pre-treatment was given, no morphine could be detected (<4 nmol·l^–1) after codeine. The pin-prick pain thresholds were significantly increased after placebo/codeine, but not after quinidine/codeine compared with placebo/placebo. Both placebo/codeine and quinidine/codeine increased pain tolerance thresholds significantly. Quinidine/codeine and quinidine/placebo did not differ significantly for either pin-prick or tolerance pain thresholds.These results are compatible with local CYP2D6 mediated formation of morphine in the brain, not being blocked by quinidine. Alternatively, a hypoalgesic effect of quinidine might have confounded the results.     

高钾时心室肌电——机械交替活动的分析

高钾（１２ｍｍｏｌ／Ｌ）条件下，突然增快刺激频率（１ＨＺ－４Ｈｚ），豚鼠乳头肌发生两轮２：１电－机械交替（ＥＭＡ）。第一轮ＥＭＡ历时约２２－３０ｓ宽的动作电位（ＡＰ）马低的收缩力（Ｆｃ）相对应。间隔性ＡＰ脱落期发生在两轮ＥＭＡ之间，历时约４－６ｍｉｎ。第二轮ＥＭＡ期间，高宽的ＡＰ与高的Ｆｃ相对应。ＡＰ交替消失时Ｆｃ交替也随之消失。第二轮ＥＭＡ历时２２－３４ｍｉｎ（２６±５ｍｉｎ，ｎ＝７），奎尼丁（１μｇ／ｍｌ）显著增强第二轮ＥＭＡ，异搏定（０．５μｇ／ｍｌ）则相反。提示高钾诱发的ＥＭＡ可能与Ｎａ＋，Ｃａ２＋离子流有关。     

甘草黄酮抗实验性心律失常的作用

甘草黄酮（ｇｌｙｃｙｒｒｈｅｉｃｂｒｓｓ．ＧＢ）２ｍｇ／ｋｇ能明显对抗乌头碱２０μｇ／ｋｇ，ＢａＣｌ２２ｍｇ／ｋｇ和结扎左冠状动脉前降支诱发大鼠的室性心律失常。甘草黄酮也能明显对抗ＣａＣｌ２－Ａｃｈ（ＣａＣｌ２０．６％＋Ａｃｈ０．００２５％）混合液诱发小鼠心房纤颤或扑动，ＧＢ对大鼠心电图实验，证明了有负性频率作用，负性传导作用，这些作用可能是ＧＢ抗心律失常作用的药理基础。     

Quinidine blockade of calcium-activated potassium channels in dissociated gastric smooth muscle cells

The effects of quinidine, an antiarrhythmic alkaloid, on potassium-selective channels in enzymatically dissociated gastric smooth muscle cells fromRana pipiens andBufo marinus were investigated using excised patches and the patch-clamp technique. The predominant potassium channel in these cells is the calcium- and voltage-activated maxi-K channel with a single-channel conductance > 100 pS. Applications of quinidine (100–600 M) resulted in resolvable rapid flickerings between the open and blocked states with a corresponding reduction in open channel amplitude and an increase in open channel noise. The currentvoltage curves in the presence of internal quinidine and symmetrical potassium gradients displayed inward rectification. The time-constant of open-time distributions was found to decrease with increasing quinidine concentrations and membrane depolarization. The power-density spectrum of the channel current noise induced by internal quinidine showed a second Lorentzian component with a corner frequency larger than 300 Hz, suggesting that the noise is caused by rapid fluctuations between the open and blocked states. Apparent dissociation constants of 253 M and 209 M for membrane potentials of +20 mV and –60 mV, respectively, were obtained for the quinidine-induced blockade of Ca²⁺-activated K⁺ channels in these smooth muscle cells. Another potassium-selective channel with a single-channel conductance of 40 pS was completely blocked in the presence of 100 M qunidine. However, a 15 pS potassium channel was not affected by quinidine but was reversibly blocked by tetraethylammonium. Quinidine (500 M) was also observed to decrease the opening probability of a 40 pS potassium channel fromBufo marinus without affecting its channel amplitude. Thus, quinidine appears to have diverse mechanisms of action on potassium-selective channels in smooth muscle cells, ranging from totally ineffective to highly selective, as a slow blocker for some channels and as intermediate and fast blockers for others.     

Intracellular mechanism of quinidine action on muscle contraction

Summary The mechanism of quinidine action on rabbit cardiac and skeletal muscle was examined with functionally skinned muscle-fiber preparations. By using these preparations we could correlate measurements of muscle tension with the effect of quinidine on the Ca²⁺ activation of the contractile proteins and on the Ca²⁺ uptake and release from the sarcoplasmic reticulum (SR). Effect of quinidine on the contractile proteins. Quinidine concentrations above 0.5 mmol/l increased the maximal Ca²⁺-activated tension development 12% for papillary muscle and 5% for soleus (slow-twitch). Adductor magnus (fast-twitch) showed no significant change. Quinidine (0.1–1.0 mmol/l) also increased the submaximal Ca²⁺-activated tension development for the three muscle types (papillary muscle=soleus>adductor magnus) and shifted the [Ca²⁺]-tension curves to the left in a dose-dependent fashion. Effects of quinidine on the Ca ²⁺ uptake and release from the SR. Sarcoplasmic reticulum of skinned fibers was loaded with Ca²⁺ (uptake phase), then Ca²⁺ was released by 25 mmol/l caffeine (release phase) giving a tension transient. The area under the tension transient was used to estimate the amount of Ca²⁺ released. Quinidine (>0.5 mmol/l) decreased the Ca²⁺ uptake (soleus>adductor magnus>papillary muscle) and increased the Ca²⁺ release [papillary muscle=soleus adductor magnus (only at 1.5 mmol/l, the highest concentration tested)] from the SR of all three muscles in a dose-dependent manner. Quinidine at low concentration (0.1 and 0.5 mmol/l) increased the caffeine-induced tension transient of papillary muscle and higher quinidine concentrations (1.0 and 1.5 mmol/l) decreased the caffeine-induced tension transient of soleus and adductor magnus during both the uptake and release phases. The decreased Ca²⁺ uptake of papillary muscle in 1.5 mmol/l quinidine was antagonized by increasing the free Mg²⁺ from 0.032 to 0.32 mmol/l.In summary, quinidine has similar mechanisms of action in all three muscles: increased Ca²⁺ activation of the contractile proteins, decreased Ca²⁺ uptake and increased Ca²⁺ release from the SR in functionally skinned muscle fibers. We conclude that quinidine-induced decreases in Ca²⁺ uptake by the SR could be responsible for quinidine-induced myocardial depression and that quinidine-induced increases in Ca²⁺ activation of the contractile proteins and Ca²⁺ release from the SR could be responsible for the increases in skeletal muscle contraction caused by quinidine.     

Electrocardiological profile and proarrhythmic effects of quinidine,verapamil and their combination: a mapping study

Quinidine and verapamil are widely used as antiarrhythmic agents and their combination is often used in the treatment of supraventricular tachycardia. This study was undertaken to clarify, whether these drugs exert proarrhythmic effects on the ventricles in therapeutic concentrations and whether possible arrhythmogenic effects might be enhanced by combination. Isolated rabbit hearts perfused according to the Langendorff technique were treated with increasing concentrations of quinidine (0.05 to 3.5 M) or verapamil (5 to 50 M) or of their combination (70:1 or 10:1; quinidine:verapamil) corresponding to common low, medium and high free therapeutic concentrations. The epicardial activation process was measured using a computer assisted mapping system for unipolar multichannel recording (256 channels simultaneously).Both substances prolonged the atrioventricular conduction time PQ. This effect was even more pronounced if the 70:1 combination was administered. The activation pattern was altered by both drugs and their combination to the same extent as became obvious from analysis of local activation vectors and of localisation of breakthroughpoints of epicardial activation for heart beats under control conditions and under drug treatment. The epicardial potential durations were prolonged by quinidine and to the same degree by the combinations, but not by verapamil alone. The total activation time was prolonged under the influence of quinidine and if the 70:1 combination was given. Both substances exerted a negative inotropic effect which was enhanced in an additive manner if both drugs were combined. In parallel the coronary flow was diminished.From these results it is concluded that (1) in this therapeutic concentration range quinidine possess a greater proarrhythmic risk than verapamil, (2) that both drugs' PQ prolonging effect can be enhanced by combination, (3) that combination does not enhance the proarrhythmic effects but the negative inotropic effects.     

Effects on atrio-ventricular conduction of calcium-antagonistic coronary vasodilators,local anaesthetics and quinidine injected into the posterior and the anterior septal artery of the atrio-ventricular node preparation of the dog

Summary The effects on atrio-ventricular (A-V) conduction and blood flow of calcium-antagonists (verapamil, nifedipine and diltiazem), local anaesthetics (procaine and lidocaine) and quinidine were investigated in the isolated, cross-circulated A-V node preparation of the dog. The drugs were injected individually into the posterior septal artery (PSA) through which the upper part of the A-V node is mainly perfused or into the anterior septal artery (ASA) through which the lower part of the node and the more distal conduction system are perfused. Single injections into the PSA of nifedipine (0.3–10 g), verapamil (1–30 g), diltiazem (1–30 g), quinidine (30–300 g), lidocaine (100 g–1 mg) and procaine (300 g–3 mg) produced a dose-related increase in the A-V conduction time and with higher doses of these drugs a second or third degree block of A-V conduction occurred. Nifedipine (0.3–30 g) and verapamil (1–100 g) injected into the ASA scarcely affected A-V conduction. Quinidine (30 g–1 mg) and lidocaine (100 g–3 mg) injected into the ASA prolonged the A-V conduction time in a dose-related manner, although the effects were less prominent than those produced upon injection into the PSA. High doses of quinidine (3 mg) and lidocaine (3–10 mg) injected into the ASA altered the shape of ventricular bipolar electrograms and prolonged the time interval between an electrogram of the right bundle branch and that of the ventricle. The results are consistent with the hypothesis that in excitation of A-V nodal cells a slow calcium current rather than a fast sodium current plays an important role and that in the His-Purkinje-ventricular system the fast sodium current is predominant. Single injections of the 6 drugs into the PSA produced a doserelated increase in blood flow through the PSA. All drugs but nifedipine increased the blood flow in almost the same dose range that caused impairment of A-V conduction. Nifedipine was 10 times more potent in increasing the blood flow than in impairing A-V conduction.     

莲心碱衍生物抗实验性心律失常的作用

目的:研究4种莲心碱衍生物抗心律失常的药理作用.方法:采用哇巴因、氯化钙、乌头碱3种抗心律失常模型.结果:4种莲心碱衍生物(5 mg&#8226;kg 1,iv)均能显著提高哇巴因致豚鼠、乌头碱致大鼠发生室性期前收缩(VE)、室性心动过速(VT)、心室纤颤(VF)及心脏停搏(CA)的用量,延长CaCl2诱发大鼠心律失常的出现时间,缩短生存大鼠的窦性心律恢复时间,减少死亡率.结论:4种莲心碱衍生物均有广泛的抗心律失常作用.     

二氢奎尼丁与奎尼丁对乳头肌动作电位影响的对比观察

目的：研究二氢奎尼丁（ＤＨＱ）与奎尼丁对心肌动作电位作用的区别，为临床用药提供理论依据。方法：取豚鼠乳头肌，应用常规玻璃微电极技术，记录动作电位参数，对比观察在药物不同灌注浓度、不同Ｋ~＋浓度、不同刺激频率及与地高辛协同作用下两者对动作电位的影响，实验结果以表示，采用配对ｔ检验及两随机组ｔ检验。结果：随药物浓度递增，动作电位时程逐渐延长，而０相最大除极速度（Ｖｍａｘ）则逐渐降低，但奎尼丁作用的高峰浓度在２０μｍｏｌ／Ｌ，而ＤＨＱ在１０μｍｏｌ／Ｌ。奎尼丁及ＤＨＱ两组的频率依赖反应是一致的。无论低钾还是高钾情况下，ＤＨＱ对Ｖｍａｘ抑制作用均大于奎尼丁（Ｐ＜０．０５）。地高辛６．４×１０~（－４）μｍｏｌ／Ｌ（０．５μｇ／Ｌ）能明显缩短由奎尼丁和ＤＨＱ延长的动作电位复极９０％时程（Ｐ＜０．０５）。结论：ＤＨＱ对心肌细胞动作电位的影响大于奎尼丁，从电生理上反映它为有效的抗心律失常药物。