Pharmacodynamics and pharmacokinetics of disopyramide phosphate

Based on pharmacodynamic and pharmacokinetic studies in 42 patients with paroxysmal and extrasystolic abnormalities of the rhythm it was established that disopyramide phosphate (ritmilen) is an effective antiarrhythmic agent for atrial fibrillation paroxysms. The drug exerts negative, chronotropic, dromotropic and inotropic effects, especially upon intravenous injections for removal of atrial fibrillatin paroxysms. Ritmilen moderately reduces the blood pressure. When used for removal of atrial fibrillation paroxysms ritmilen is effective in doses of 1.2-1.7 mg/kg intravenously and in doses of 2.5-3.8 mg/kg per os. In patients with chronic ventricular premature heart beat the single effective drug doses amount to 0.61-1.7 mg/kg. After oral use the ritmilen concentration in blood plasma is lower than after intravenous use in adequate doses. No relationship has been found between the drug antiarrhythmic effect and blood plasma concentration.     

In vitro study of clonazepam diffusion kinetics from solutions or hydrophilic gel

Preliminary studies were conducted to evaluate the influence of temperature, pH and ionic strength of the donor and receptor medium on the solubility, partition coefficient and diffusion rate of clonazepam across a lipophilic artificial membrane, in view of future setting up of transdermal formulation of this drug. The in vitro release of clonazepam from a carbopol hydrogel was also investigated.     

荧光标记鹿茸蛋白提取物胃肠道吸收离体实验研究

鹿茸是一种名贵的中药,含有丰富的蛋白质及多肽等活性成分,对神经、心血管、免疫、生殖系统有显著的调节作用[1]。鹿茸的传统给药方式为口服给药,给药后经消化道相关酶的降解发生一系列的变化,然而,由于检测方法的限制,目前还没有成熟的     

国产克林霉素磷酸酯体外抗菌作用研究

国产、进口克林霉素磷酸酯与盐酸克林霉素对革兰氏阳性菌和阴性菌及厌氧菌具有相似的体外抗菌活性，克林霉素磷酸酯经碱性磷酸酯酶水解后，对金葡球菌、表葡球菌抗菌活性与红霉素及氯唑西林相似，ＭＩＣ＿（５０）分别为０．０６２和０．１２５ｍｇ／Ｌ，低于盐酸林可霉素。对一些红霉素耐药的金葡球菌、表葡球菌也有一定抗菌活性，最低ＭＩＣ＿（５０）分别为０．０６２和０．５ｍｇ／Ｌ，对肺炎链球菌、化脓性链球菌具有较好的抗菌活性，ＭＩＣ＿（５０）分别为０．０３１和０．０６２ｍｇ／Ｌ，对革兰氏阳性、阴性厌氧菌具有较强的抗菌活性，ＭＩＣ＿（５０）分别为０．０６２～０．５ｍｇ／Ｌ，ＭＩＣ＿（９０）为０．２５～４ｍｇ／Ｌ。结果表明，克林霉素磷酸酯对金葡球菌、表葡球菌、肺炎链球菌、化脓链球菌ＭＢＣ＿（５０）较其ＭＩＣ＿（５０）高１～４倍，其它结果显示克林霉素磷酸酯不受ｐＨ或接种量影响。     

辣椒素脂质体在体外瘢痕组织中透皮吸收的研究

目的探讨脂质体包裹的辣椒素在体外人瘢痕组织中的透皮吸收能力。方法采用改良的Franz扩散池体外透皮实验技术 ,对通过微流法制备的辣椒素脂质体及其普通商用软膏剂进行透皮扩散。 1 2h后HPLC法测定瘢痕组织中辣椒素的含量 ,并加以比较。结果体外透皮扩散 1 2h后 ,脂质体组瘢痕组织中的辣椒素单位面积透皮药量显著高于软膏组 (1 2 3 3 3± 3 2 )、(3 5 93±2 0 2 ) μg·cm-2 ,(P <0 0 1 )。结论脂质体作为辣椒素皮肤局部给药的载体 ,能够提高对瘢痕皮肤的穿透力 ,提高作用部位的有效药物浓度。     

Food-dependent disintegration of immediate release fosamprenavir tablets: In vitro evaluation using magnetic resonance imaging and a dynamic gastrointestinal system

In the present study, we demonstrated the value of two advanced tools, the TNO gastric and small Intestinal Model (TIM-1) and magnetic resonance imaging (MRI), for the in vitro evaluation of food-dependent disintegration of immediate release fosamprenavir tablets. Upon introduction of a tablet with the nutritional drink Scandishake Mix® in the stomach compartment of TIM-1, simulating the fed state, disintegration and fosamprenavir dissolution were significantly postponed compared to the fasted state (lag time 80 ± 23 min). This resulted in a lag in the appearance of bioaccessible fosamprenavir (<5% during the first 2 h), even though the nutritional state did not significantly alter the cumulative bioaccessibility after 5 h. These results were in agreement with the previously observed postprandial delay in gastric fosamprenavir tablet disintegration and subsequent amprenavir absorption in healthy volunteers. Therefore, TIM-1 can be used in tablet development to identify food-induced disintegration issues causing unexpected clinical behavior. From a mechanistic perspective, we applied MRI to illustrate impaired water ingress in fosamprenavir tablets immersed in the nutritional drink compared to simulated gastric fluid. This effect may be attributed to both competition between nutritional components and the tablet for the available water (indicated by reduced rotational and translational diffusion) as well as the possible formation of a food-dependent precipitation layer on the HPMC-coated tablet.     

In vitro release: comparative evaluation of vertical diffusion cell system and automated procedure

In vitro release for topical drug products is carried out using a vertical diffusion cell system and a synthetic support membrane. The improvements in vertical diffusion cell design and automated procedures have been carefully studied and evaluated to establish their reproducibility and ruggedness of the experimental procedure. The data were analyzed using 90% confidence interval procedure developed and published by the US Food and Drug Administration in SUPAC-SS (Start Up and Post Approval Changes-Semi Solid) guidance.     

Lithium acetate gastrointestinal diffusion system. Part 2: Lithium acetate multi-unit gastrointestinal diffusion system: preparation and release rate studies

The method of obtaining the multi-unit gastrointestinal diffusion system (m-GDS), containing lithium acetate, consists in encapsulating the lithium acetate in a form of microballs and thereafter coating the resulting microballs with a porous membrane which controls the diffusion rats of the drug. For the coating, a water-insoluble polymer (cellulose acetate) and two types of polymer-modifying agents (cetyl alcohol and shellac) were used. In this paper in vitro studies of drug release from the unit in relation to the microballs' coating and mass, and exposed surface area of the capsules are presented. Most in vitro systems provide zero-order dry delivery by appropriate selection of manufacturing parameters.     

Lithium acetate gastrointestinal diffusion system. Part 1: Lithium acetate single-unit gastrointestinal diffusion system: preparation and release rate studies

The gastrointestinal diffusion system (GDS), containing lithium acetate (1), releases the drug by a controlled source of diffusion energy. The unit can possibly be used for all soluble drugs in which solubility is independent from the pH of the gastrointestinal contents as is the case with 1. The one-compartment unit is obtained by tabletting the drug and coating the tablets with a membrane of cellulose acetate to which soluble porofores-gum arabic, sodium chloride, 1-are added. When the pore-creating substance is dissolved out of the coating, there remains a porous film, which controls the rate of release of the drug. The release characteristics depend on membrane composition and mass. The systems reported here provided for zero-order drug delivery in vitro.     

In vitro diffusion in polyacrylamide embedded agarose microbeads

125I Sodium iodide, 125I insulin, 125I albumin, and 111indium IGG were employed to investigate release from, and penetration of different sized molecules into agarose/polyacrylamide microcapsules. The microcapsules were formed by photopolymerization of an acrylamide solution round agarose beads. The indium-chelated antibody gave a particular low background count. The different release times were explained in terms of differences in diffusion coefficient. By retarding in vitro penetration of antibodies, these microcapsules could be of value for the encapsulation of living cells in bioartificial organs.     

In vitro metabolic study of EGYT-3615 using rat liver microsomes

In vitro metabolism of EGYT-3615, a prospective new antidepressant was studied by using rat liver microsomes. The metabolite (M) found in earlier in vivo studies was unanimously found to be the product of a microsomal enzymatic process. The Michaelis-Menten constant of the reaction was calculated.     

The effect of intravenous disopyramide phosphate on recurrent paroxysmal tachycardias.

1 Reccurent paroxysmal atrial, atrioventricular and ventricular tachycardias in 50 patients without acute coronary insufficiency, heart failure or metabolic abnormlity were treated with disopyramide phosphate in a dose of 2 mg/kg body weight infused over 5 min. 2 Conversion to sinus rhythm within 10 min of the completed infusion occurred in 10 of 14 (71%) patients with paroxysmal 'lone' atrial fibrillation, 3 of 7 (43%) patients with paroxysmal atrial flutter, 6 of 9 (67%) patients with paroxysmal atrial tachycardia, 5 of 9 (56%) patients with paroxysmal atrioventricular tachycardia associated with the Wolff-Parkinson-White syndrome and 8 of 11 (73%) patients with paroxysmal ventricular tachycardia. 3 Side effects: significant systemic hypotension in 3, high grade AV block in 1, an increased ventricular response producing symptoms in 4, post conversion asystole in 1 land sinus bradycardia in 2. 4 The anti-arrhythmic effect and arrhythmogenic side effects may be related to both the direct membrane stabilizing effect and the anticholinergic effect of disopyramide.     

Pharmacokinetics of oral disopyramide phosphate in patients with renal impairment.

1 The pharmacokinetics of disopyramide were studied after the oral administration of a 300 mg dose to 11 patients with stable chronic renal impairment (creatinine clearance 2-53 ml min-1). 2 Absorption half-life and volume of distribution were similar to those seen in normal subjects. 3 Mean plasma elimination half-life in these patients was 12.7 h, which is substantially greater than that reported for normal subjects. Elimination half-life tended to increase as creatinine clearance fell, and renal clearance of disopyramide correlated significantly (r=0.814; P < 0.001) with creatinine clearance. 4 From these results, we have calculated that patients with renal impairment should be started on a dose of disopyramide 1.5 mg kg-1 thrice daily and the regimen subsequently altered according to plasma concentrations of the drug. However, further studies are needed to define the handling of the metabolites of disopyramide.     

In vitro study on fluoxetine adsorption onto charcoal using potentiometry.

This in vitro investigation was performed to study the adsorption rate constant as well as the adsorption characteristics of fluoxetine (F) to activated charcoal and its commercial formulation Carbomix powder in simulated gastric (pH 1.2) fluid environment. Ion-selective electrode (ISE) potentiometry, based on the selective, direct and continuous monitoring of F with an F-ISE constructed in our laboratory was used. The method used in the kinetic experiments consists of the rapid addition of a slurry containing the charcoal into the drug solution under stirring and continuous recording of the F-ISE potential until the establishment of equilibrium. The free ionized drug concentration at appropriate time intervals was calculated from the recorded adsorption curve and the apparent adsorption rate constant was estimated assuming pseudo first order kinetics. Within run R.S.D. of the estimates ranged from 0.24 to 11.5%, while between run R.S.D. (n=3-4) ranged from 0.90 to 13.8%. A linear relationship was found between the apparent adsorption rate constants and the amount of charcoal used with slopes (+/-S.D.) for activated charcoal and Carbomix equal to 1.14(+/-0.21) and 0.146(+/-0.009) s(-1)g(-1), respectively. Successive additions of microvolumes of F solution were made into a charcoal slurry with measurement of the F-ISE potential at equilibrium. The maximum adsorption capacity values (+/-S.D.) of activated charcoal and Carbomix were 254.8+/-1.8 and 405+/-41 mg/g, respectively while the affinity constant values (+/-S.D.) were 45.6+/-2.2 and 55.5+/-2.9 l/g, respectively. The adsorption of F to charcoals was rapid and for amounts of charcoal 10 times greater than the amount of the drug, 95% of F was adsorbed within the first 5 min. Relative to the toxic and lethal doses in cases of F intoxications, both types of charcoals tested adsorbed effectively F at gastric pH. Carbomix can be considered as appropriate charcoal formulation for medical treatment in cases of F poisoning.     

Stereoselective gastrointestinal clearance of disopyramide in rabbits treated with activated charcoal

The ability of activated charcoal to enhance the drug elimination of two enantiomers, R- and S-disopyramide, was compared in rabbits. Orally administered activated charcoal significantly decreased the area under the serum concentration curve of R-disopyramide, whereas the same treatment had no effect on that of S-disopyramide. The difference could be explained by the difference in the hepatic extraction ratio of two enantiomers in rabbits. S-Disopyramide is a drug of high hepatic extraction ratio in rabbits and R-disopyramide is of intermediate hepatic extraction ratio. Equations were derived to illustrate the influence of the hepatic extraction ratio on the apparent gastrointestinal clearance. A higher hepatic extraction ratio decreases the apparent gastrointestinal clearance of a drug. This phenomenon may explain some unsuccessful experiments of gastrointestinal dialysis. When considering the use of activated charcoal to enhance systemic drug elimination, the hepatic extraction ratio of the drug should be included.     

In vitro adsorption of doxorubicin hydrochloride on insoluble calcium phosphate.

The adsorption of doxorubicin hydrochloride, a potent antitumor agent, on solid tribasic calcium phosphate was studied in vitro. A Langmuir adsorption isotherm at pH 7.4 and the maximum adsorption capacity of tribasic calcium phosphate were established. Tribasic calcium phosphate was chosen as a model for solid bone samples, which are stained with doxorubicin in patients who have received long-term doxorubicin therapy.     

Absorption and antidysryhthmic activity of oral disopyramide phosphate after acute myocardial infarction

1 In a prophylactic, double-blind, randomized placebo-controlled trial of oral disopyramide phosphate, initiated within 12 h of suspected acute myocardial infarction (MI), antidysrhythmic effect was evaluated. The loading dose was 150, 200, or 300 mg followed 6 h later by 100, 150, or 200 mg every 6 h for patients assessed to weigh <55, 55-85, or >85 kg, respectively. After each loading dose and a maintenance dose on one of days 4-7, 2 and 6 h venous blood samples were obtained for determination of plasma disopyramide and mono-N-dealkylated disopyramide (MND) concentrations (expressed herein as levels), by a technique incorporating fluorescence photometry and thin layer chromatography. Of 121 patients entering the trial, 101 had confirmed acute MI and of these, 12 on active drug were recalled during convalescence and restudied after a loading dose.

2 In acute MI patients on disopyramide phosphate, an important degree of antidysrhythmic effect was observed (on active drug and placebo, 19% v 37%, respectively (P = 0.047), received lignocaine for `warning arrhythmias'), even though in the first 6 h post-loading dose, disopyramide and MND levels were low and variable.

3 Disopyramide levels 2 h post-loading dose were lower in acute MI than in non-MI patients (P = 0.004), and similarly in the limited within patient study corresponding levels after acute MI were lower than during convalescence (P = 0.013). At 6 h post-loading dose, the levels had increased in acute MI patients but decreased in non-MI patients, this change being significantly different (P = 0.048). A similar significant difference existed in the limited within patient data available during acute MI and convalescence (P = 0.002).

4 Acute MI patients on active drug developing `warning arrhythmias' had lower post-loading dose, 2 and 6 h levels than in those without `warning arrhythmias' (P = 0.012 and P = 0.0002, respectively).

5 One patient who developed renal insufficiency developed excessive disopyramide levels.

6 On any given dose, there was no significant correlation between disopyramide level and body weight.

7 In acute MI patients given oral disopyramide phosphate (a) there was marked interindividual variation in the ensuing drug and metabolite levels, (b) absorption of disopyramide into the circulation was delayed, (c) prophylactic antidysrhythmic activity was present at levels of about 1.5 mg/l which is about half the minimal level recommended hitherto, (d) disopyramide accumulated in renal insufficiency, (e) elaborate dosage adjustments based on body weight are not useful.