Oral kinetics and bioavailability of the cholinesterase reactivator HI-6 after administration of 2 different formulations of tablets to dogs

A one-compartment open model with first-order absorption was used for comparing new oral formulations of the potent acetylcholinesterase reactivating oxime HI-6. Although mean peak plasma levels did not differ between retard and conventional tablets (21.38 and 20.74 mumol/l), the time for reaching peak levels was significantly longer (5.5 h) with retard than with conventional tablets (2.86 h). Among other pharmacokinetic estimates only absorption half-lives and areas under the concentration-time curve (AUC) were significantly different (P less than 0.05). The AUC with retard tablets was 8.07% and that of conventional tablets 5.42% of intravenous AUC, indicating low bioavailability of oral HI-6 formulations. Potential therapeutic use of HI-6 requires, therefore, further investigations in order to improve its gastrointestinal absorption.     

Evaluation of the absorption from three ibuprofen formulations

The pharmacokinetic differences between two sustained-release 300 mg (A) and 400 mg (B) formulations and a rapid-release 400 mg ibuprofen conventional sugar-coated formulation (C) were compared after a single dose. Mean peak levels of 25.1 micrograms/ml for preparation A (2 X 300 mg), 31.3 micrograms/ml for preparation B (2 X 400 mg) and 68.5 micrograms/ml for preparation C (2 X 400 mg) were reached at 5.3, 3 and 2 hours respectively, after ingestion of the drugs. The individual plasma-level time-profiles for the majority of doses suggested prolonged absorption of product A and B. The absorption from formulations A and B was significantly slower (p less than 0.001 and p less than 0.05 respectively) than that from the conventional tablets. The bioavailability of ibuprofen from sustained-release capsules, was not found to differ significantly from that of ibuprofen from conventional tablets. The relative bioavailability was very close to 100% in almost all subjects (coefficient of variation 14% and 17%). Projections of plasma concentrations upon multiple dosing were made from single dose data. The dosage interval concentration ratio which reflects both the frequency and the entry of the drug into and from the body was much lower for sustained-release formulations (A: 3.0; B: 3.7; C: 12.9).     

Plasma levels of disopyramide after administration of conventional capsules and sustained-release tablets

A study was carried out in 33 patients with myocardial infarction and complicating arrhythmias to compare plasma levels of disopyramide attained after administration of conventional capsules or sustained-release tablets. On Day 1, 29 patients started treatment wtih 600 mg disopyramide in 3 divided doses of conventional capsules. In 18, disopyramide plasma concentrations of 3 mg/l or more were achieved within 300 minutes after the first dose. On the second day, patients were allocated at random to receive treatment double-blind for 11 days with 500 mg disopyramide daily given either as conventional capsules (17 patients) or as sustained-release tablets (16 patients). Plasma concentrations were measured just before and 3 hours after the morning dose. Mean maximum and minimum concentrations in the conventional capsule group were 4.4 mg/l and 2.8 mg/l, respectively, compared to 4.3 mg/l and 3.0 mg/l, respectively, in the sustained-release tablet group. For the next 30 days all patients continued treatment with sustained-release tablets. Mean disopyramide plasma concentration measured 15 to 18 hours after the last dose was 2.8 mg/l. Myocardial function was estimated during and 1 week after discontinuing disopyramide treatment. The mean fractional fibre shortening (echocardiography) during treatment was 23% less than that 1 week after discontinuation. The mean PEP/LVET (systolic time interval recording) was 7% higher during treatment compared with 1 week after discontinuation. In 4 cases, mean ejection fraction, measured by scintigraphic methods, during treatment was 10% less than 1 week after discontinuation. Anti-arrhythmic effect was investigated by continuous monitoring in the first 12 days and by Holter monitoring during the 30-day ambulant period and 1 week after discontinuing disopyramide. A significant reappearance of warning arrhythmias could be detected after discontinuing disopyramide sustained-release tablets. No anti-arrhythmic effect was detected in 4 patients. Six patients had to be withdrawn because of side-effects. It is concluded that disopyramide sustained-release tablets 500 mg per day in 2 divided doses gives therapeutic plasma concentrations of 3 mg/l comparable with conventional capsules. A myocardial depressive effect is noted of about 10%.     

Efficacy of a combination of acetylcholinesterase reactivators,HI-6 and obidoxime,against tabun and soman poisoning of mice

The bispyridinium oxime HI-6, 1-((((4-amino-carbonyl) pyridinio)methoxy) methyl)-2-(hydroxyimino)-methyl) pyridinium dichloride monohydrate, combined with atropine is an effective treatment for soman (pinacolyl methylphosphonofluoridate) poisoning but is relatively ineffective against tabun (ethyl N-dimethyl phosphoroamidocyanidate) poisoning in mice. This contrasts with those results obtained using the bispyridinium oxime obidoxime [1,1-(oxy bis(methylene)) bis(4-(hydroxyimino)-methyl) pyridinium dibromide]. The purpose of this study was to investigate the efficacy of the combination of HI-6 and obidoxime plus atropine against poisoning by tabun and soman in mice. The combination of ineffective single doses of obidoxime (5 or 10 mg/kg) and HI-6 (25 or 50 mg/kg) improved the treatment of tabun poisoning over either oxime alone. Combinations employing higher concentrations of obidoxime (25 or 50 mg/kg) and HI-6 (100 or 200 mg/kg) resulted in significant toxicity in the absence of organophosphate poisoning. Against soman poisoning the addition of obidoxime to HI-6 did not attenuate the efficacy of HI-6. The half-life of elimination and peak serum concentrations of HI-6 and obidoxime were not altered following administration of the combined injection. Reactivation of tabun-inhibited acetylcholinesterase was found consistently in the diaphragm but not in the brain. Using response surface methods it was possible to estimate the optimal therapy against soman and tabun poisoning (74.5 mg/kg HI-6+31.9 mg obidoxime against 1052 g/kg challenge of tabun and 129 mg/kg HI-6 +0 mg/kg obidoxime against 390 g/kg challenge of soman). It is proposed that reactivation of tabun inhibited acetylcholinesterase at the diaphragm may be responsible for the increased efficacy of the combination of HI-6 and obidoxime against tabun poisoning in mice.     

Serum quinidine levels after administration of three different quinidine preparations

Summary In a single-blind cross-over study, 6 healthy volunteers took three different formulations, each containing 0.33 g of quinidine base, every 12 h for 96 h. A mean steady state serum level of 1.8 mg/l of quinidine base was produced by bisulphate tablets that dissolved rapidly. Long-acting Quinidine Durules® (sustained-release quinidine bisulphate) produced a mean steady state serum level that was 23% lower (NS) and Longacor® (quinidine arabogalactone sulphate) led to one that was 46% lower (p<0.05). The time taken to reach a steady state was longer after Longacor® than Quinidine Durules®. The results are discussed in relation to the conventional clinical use of quinidine, methods of estimating its concentration in serum, and the relative value of different formulations of quinidine salts.     

Comparative bioavailability of sustained-release and conventional tablets of hydroxyethyltheophylline in man

The comparative bioavailability of sustained-release and conventional tablets of hydroxyethyltheophylline was studied in normal subjects. In a single dose study on 7 subjects, 3 conventional tablets or 2 sustained-release tablets were administered orally after a light breakfast and blood samples taken for 6 and 12 hours respectively. With conventional tablets the mean peak concentration (8.10 +/- 0.751 microgram/ml) was reached at 3 hours and concentrations less than 5 microgram/ml were observed in 4 out of 7 subjects at 6 hours. In contrast, with sustained-release tablets of theophylline and hydroxytheophylline complex the mean peak concentration (8.90 +/- 0.88 microgram/ml) was reached at 6 hours and levels above 5 microgram/ml were observed in 4 out of 7 cases at 12 hours. Administration of 2 sustained-release tablets twice a day produced trough plasma concentrations varying between 6.9-13.8 microgram/ml, i.e. within the therapeutic range in all the 5 subjects. It is concluded that this new oral sustained-release preparation provides therapeutic plasma theophylline concentration on a 12 hourly dosage schedule.     

Design of captopril sustained-release preparation with oily semisolid matrix intended for use in human subjects

A captopril sustained-release dosage form using oily semisolid matrix (OSSM) has been studied to develop a formulation useful in human treatment. Four OSSMs which had different in vitro dissolution rates were administered to human subjects. The resulting bioavailabilities revealed that the best OSSM suitable for humans had a faster in vitro dissolution rate than that for dogs. Another series of administrations of OSSM also showed that formulated ascorbic acid improved the bioavailability of OSSM, and that the bioavailability was sufficient for a sustained-release dosage form so long as the amount of ascorbic acid in the OSSM was more than 5 times that of the captopril by weight. Pharmacokinetic analysis was performed based on plasma concentrations of captopril in humans (n = 8) after a single oral administration of conventional tablets or OSSM reformulated for humans. Calculated areas under the curve (AUCs, 0-∞ h) of plasma captopril concentration were 250.5 for conventional tablets and 283.5 (ng·h/ml) for OSSM. The mean residence times (MRTs) obtained by both formulations were 1.75 h and 3.59 h, respectively. The duration time in which plasma captopril concentration stayed above 50% inhibitory concentration of angiotensin converting enzyme activity was calculated. Total duration time (TDT) per day of conventional tablets (12.5 mg) taken 3 times daily was calculated to be 10.95 h. The TDT of OSSM was 17.00 h when the OSSM (18.75 mg of captopril) was administered twice a day at 12-h intervals. Consequently, OSSM dosed twice a day is expected to show a greater efficiency than conventional tablets taken 3 times daily.     

Sustained-release methylphenidate: new preparations. New pharmaceutical forms: a slight advantage for a small number of children

(1) When non-drug measures don't work in severe attention-deficit/hyperactivity disorder, methylphenidate, an amphetamine, attenuates symptoms in about 75% of children, at least in the short term. (2) Two forms of sustained-release methylphenidate--tablets (Concerta LP) and microgranule-filled capsules (Ritaline LP)--are marketed in France. (3) In two cross-over trials (one week per treatment) and in a parallel-group trial lasting one month, sustained-release methylphenidate tablets (18 mg to 54 mg/day in a single dose) were no more or less effective than short-acting methylphenidate (5 mg to 15 mg three times a day), but the sustained-release formulation was significantly more effective than placebo. The rating scale used in these trials was not sensitive enough to show whether the two forms had the same duration of action. A one-year non comparative trial in 435 children suggested that initial efficacy persisted in at least half the children treated with sustained-release tablets. (4) The only clinical trial of sustained-release methylphenidate capsules--a randomised double-blind placebo controlled trial lasting two weeks--showed that sustained-release capsules were more effective than placebo. (5) All these short-term trials confirmed the known amphetamine-like adverse effects of methylphenidate. The sustained-release tablets are large and rigid. They have the potential to cause gastrointestinal obstruction. (6) The sustained-release tablets can be difficult to swallow, and must not be cut, crushed, or chewed. The capsules can be opened so the microgranules inside them can be mixed with food. (7) In practice, it is best to start with short-acting methylphenidate, which is better evaluated than sustained-release formulations. If it's effective, and if treatment needs to be simplified, the child can be switched to a sustained-release form later; capsules are less risky than tablets, and are also more convenient.     

The benefit of combination of oximes for the neuroprotective efficacy of antidotal treatment of sarin-poisoned rats

The potency of the oxime HI-6 and two combinations of oximes (HI-6 + trimedoxime, HI-6 + K203) to reduce sarin-induced acute neurotoxic signs and symptoms was evaluated in this study. Sarin-induced neurotoxicity and the neuroprotective effects of atropine alone or in combination with HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with sarin at a sublethal dose (108 μg/kg i.m.; 90% of LD(50) value) were monitored by a functional observatory battery (FOB) 24?h following sarin administration. The results indicate that both mixtures of oximes combined with atropine were able to survive sarin-poisoned rats 24?h following sarin administration while two non-treated sarin-poisoned rats and one sarin-poisoned rat treated with atropine alone or with atropine in combination with the oxime HI-6 died within 24?h following sarin poisoning. All types of antidotal treatment were able to decrease sarin-induced neurotoxic signs and symptoms but not completely. While atropine alone and atropine in combination with the oxime HI-6 were able to eliminate some sarin-induced neurotoxic signs and symptoms, the neuroprotective efficacy of both combinations of oximes with atropine was slightly higher. Thus, both tested combinations of oximes in combination with atropine bring a small benefit for the neuroprotective efficacy of antidotal treatment of acute sarin poisonings.     

The benefit of combination of oximes for the neuroprotective efficacy of antidotal treatment of sarin-poisoned rats

The potency of the oxime HI-6 and two combinations of oximes (HI-6 + trimedoxime, HI-6 + K203) to reduce sarin-induced acute neurotoxic signs and symptoms was evaluated in this study. Sarin-induced neurotoxicity and the neuroprotective effects of atropine alone or in combination with HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with sarin at a sublethal dose (108 μg/kg i.m.; 90% of LD₅₀ value) were monitored by a functional observatory battery (FOB) 24?h following sarin administration. The results indicate that both mixtures of oximes combined with atropine were able to survive sarin-poisoned rats 24?h following sarin administration while two non-treated sarin-poisoned rats and one sarin-poisoned rat treated with atropine alone or with atropine in combination with the oxime HI-6 died within 24?h following sarin poisoning. All types of antidotal treatment were able to decrease sarin-induced neurotoxic signs and symptoms but not completely. While atropine alone and atropine in combination with the oxime HI-6 were able to eliminate some sarin-induced neurotoxic signs and symptoms, the neuroprotective efficacy of both combinations of oximes with atropine was slightly higher. Thus, both tested combinations of oximes in combination with atropine bring a small benefit for the neuroprotective efficacy of antidotal treatment of acute sarin poisonings.     

延胡索乙素固体脂质纳米粒缓释片制备及工艺优化

目的：制备延胡索乙素固体脂质纳米粒缓释片，并研究延胡索乙素固体脂质纳米粒缓释片的释药模型和释药机理。方法：乳化-溶剂挥发法制备延胡索乙素固体脂质纳米粒，以乳糖作为冻干剂，羟丙基甲基纤维素（HPMC）为缓释材料进一步制备缓释片。在单因素考察的基础上，设计正交试验优化延胡索乙素固体脂质纳米粒缓释片处方，并对缓释片体外释药模型和释药机理进行探讨。结果：延胡索乙素固体脂质纳米粒缓释片最佳处方为缓释材料HPMC K4M和HPMC K15M比例为1：1，用量为40 mg，PEG 4000的用量为20 mg，硬脂酸镁用量为片芯质量的0.5%。延胡索乙素固体脂质纳米粒缓释片最佳处方的体外释放行为符合Higuchi释药模型，释药方程为：Mt/M_∞=0.286 8 t^1/2-0.073 8（r=0.990 8），12 h内累积释放度为93.56%，缓释片释药机理为扩散和溶蚀共存。结论：制备的延胡索乙素固体脂质纳米粒缓释片，工艺重复性较好，其释药行为符合Higuchi释药模型。     

褪黑素缓释片与普通片在犬体内药动学研究

目的:比较褪黑素普通片与缓释片在Beagle犬体内药动学参数。方法:6只Beagle犬随机、交叉、单剂量灌服褪黑素缓释片6mg或普通片3mg后,采用高效液相色谱法测定其血药浓度;以3p97软件计算药动学参数。结果:普通片和缓释片犬体内药-时曲线符合二室模型,Cmax分别为(11.27±3.77)、(8.31±5.11)ng/ml,tmax分别为(0.50±0.18)h、(1.00±0.37)h,t1/2ke分别为(1.21±0.52)h、(3.27±0.89)h,AUC0～t分别为(25.23±7.71)、(38.03±16.45)(ng·h)/ml。结论:与普通片比较,缓释片吸收较慢,药物达峰时间更长,峰浓度更低,消除更慢,维持时间更长。     

Formulation,Bioavailability, and Pharmacokinetics of Sustained-Release Potassium Chloride Tablets

The release of potassium chloride incorporated into hydrogenated vegetable oil and hydroxypropyl methylcellulose matrix tablets was studied in vitro. The formulations containing 20% hydrogenated vegetable oil and hydroxypropyl methylcellulose showed a sustained-release profile comparable to that of a standard commercially available sustained-release preparation, containing 8 mEq potassium chloride embedded in a wax material. The formulated and standard sustained-release potassium chloride tablets were compared to a conventional enteric-coated potassium chloride tablet in 10 healthy subjects. Mean recoveries in 24-hr urine potassium levels from four dosage forms (after subtracting normal urine potassium excretion levels) were 76 ± 32% from hydroxypropyl methylcellulose, 95 ± 22% from hydrogenated vegetable oil-incorporated matrix tablets, 91 ± 29% from commercially available sustained-release tablets, and 97 ± 13% from enteric-coated tablets. There was no significant difference (P > 0.05) in the time to reach maximum excretion rates among the three sustained-release tablets. No significant adverse effect was experienced with any of the preparations.     

Pharmcokinetics of HI-6 and atropine in anaesthetized pigs after administration by a new autoinjector

A newly developed autoinjector (Astra Tech, Sweden) containing 500 mg HI-6 and 2 mg atropine sulphate was tested in anaesthetized normal pigs. The pharmacokinetics and pharmacodynamics of the drugs after administration by the autoinjector were compared with those after conventional needle and syringe delivery intramuscularly and intravenously. Cardiopulmonary parameters were monitored and serum concentrations of oxime, atropine, and acetylcholinesterase were determined in blood samples taken at intervals over a 6h period postinjection. After injection in anaesthetized pigs, both HI-6 and atropine were absorbed rapidly and completely from the injection site. Therapeutic serum concentrations of HI-6, arbitrarily taken as 4 μg mL^?1, were reached within 1 min of intravenous and autoinjector administration, and within 5 min of intramuscular injection. The concentrations remained above this level for 3–4h. There were no significant changes in acetylcholinesterase activity, mean arterial blood pressure, or respiration frequency after injection of HI-6 and atropine sulphate. The heart rates increased significantly after administration of the two drugs (cardioacceleration defined as ? 5% increase in heart rate), regardless of the technique employed. Our results show that HI-6 and atropine sulphate can be given intramuscularly by the new autoinjector with the same effectiveness and speed as when given intravenously. Irrespective of the injection technique, no overt signs of toxicity were observed at the drug concentrations used.     

尼群地平缓释胶囊在家犬体内的药动学与相对生物利用度

目的研究尼群地平缓释胶囊在家犬体内的药代动力学与相对生物利用度。方法用高效液相色谱法测定了 6条健康家犬口服尼群地平缓释胶囊 (受试制剂 )和尼群地平普通片 (参比制剂 )后不同时间点血浆中尼群地平的浓度 ,绘制血药浓度 -时间曲线 ,计算药代动力学参数及相对生物利用度。结果受试犬口服含尼群地平 4 0mg的受试制剂和参比制剂后 ,血浆中尼群地平的tmax分别为 (6 1 7± 1 60 )和 (1 4 6± 0 5 1 )h;cmax分别为 (3 4 3 8± 1 2 2 6)和 (45 6 5± 1 0 7 4 )nmol L ;用梯形法计算 ,AUC0～t分别为 (1 93 0 1± 1 0 0 5 1 0 6)和 (1 790 8± 94 2 8)nmol·h L。以AUC计算 ,与参比制剂相比 ,受试制剂中尼群地平的相对生物利用度平均为 (1 1 0 5 9± 2 3 60 ) %。将AUC0～t经对数转换后进行方差分析 ,结果表明 ,受试制剂与参比制剂相比 ,除个体间外 ,周期间与制剂间无显著性差异 (P >0 0 5 ) ,受试制剂AUC0～t的 90 %置信区间为参比制剂的 88 5 4 %～ 1 3 1 93 %。结论尼群地平缓释胶囊与国外普通片相比 ,在犬体内具有更长的作用时间 ,且相对生物利用度相近     

盐酸环丙沙星缓释胶囊家犬体内生物利用度研究

目的检测盐酸环丙沙星缓释胶囊与普通片在家犬体内的生物利用度。方法样品用乙腈沉淀蛋白 ,然后用氯仿除去杂质。采用反相高效液相色谱法测定家犬体内的盐酸环丙沙星血药浓度。结果受试制剂及参比制剂的cmax分别为 (9 2 0± 2 0 2 )mol·L-1和 (2 2 5 1± 7 2 4)mol·L-1;tmax分别为 (6 0 0± 0 0 )h和 (2 5 0± 0 5 5 )h ;平均滞留时间 (tMR)分别为 (1 2 2 3± 2 92 )h和 (5 66±1 7)h ,2种制剂的AUC无显著性差异 ,相对生物利用度为 (97 1 0± 9 61 ) %。结论经统计学检验 ,受试制剂具有明显的缓释特征 ,2种制剂具有生物等效性 ,盐酸环丙沙星缓释胶囊体内吸收百分数与体外累积释放百分数相关性分析结果表明两者具有显著的相关性 (P <0 0 1 )。     

Pharmacokinetics of the oxime HI-6 from a mixture with atropine sulphate in dogs.

The pharmacokinetics of the oxime HI-6 from an aqueous solution and from a mixture containing HI-6 and atropine (in doses similar as proposed for their combination in an automatic injector) was studied in German shepherd dogs. A standard manual injection of mixed drugs was followed by enhanced resorption of HI-6 while the elimination curves were quite similar. A comparison of the parameters describing relative bioavailability at the 80% probability level did not reveal any significant differences between the formulations of HI-6. The increase in HI-6 level in blood of animals receiving a mixture is more likely to be attributed to the local vasodilatation than to the systemic cardiovascular effects of atropine.     

A comparison of the neuroprotective efficacy of individual oxime (HI-6) and combinations of oximes (HI-6+trimedoxime, HI-6+K203) in soman-poisoned rats

The ability of two combinations of oximes (HI-6+trimedoxime, HI-6+K203) to reduce soman-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of the oxime HI-6 alone, using a functional observational battery. Soman-induced neurotoxicity and the neuroprotective effects of HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with soman at a sublethal dose (90 μg/kg intramuscularly, i.m.; 80% of LD?? value) were monitored by the functional observational battery at 24 hours following soman administration. The results indicate that both tested oxime mixtures combined with atropine were able to allow soman-poisoned rats to survive 24 hours following soman challenge, while 4 nontreated soman-poisoned rats and 1 soman-poisoned rat treated with oxime HI-6 alone combined with atropine died within 24 hours following soman poisoning. While the oxime HI-6 alone combined with atropine treatment was able to eliminate a few soman-induced neurotoxic signs and symptoms, both oxime mixtures showed higher neuroprotective efficacy in soman-poisoned rats. Especially, the combination of HI-6 with trimedoxime was able to eliminate most soman-induced neurotoxic signs and symptoms and markedly reduce acute neurotoxicity of soman in rats. Thus, both tested mixtures of oximes combined with atropine were able to increase the neuroprotective effectiveness of antidotal treatment of acute soman poisonings, compared to the individual oxime.     

HI-6 in man: efficacy of the oxime in poisoning by organophosphorus insecticides.

The efficacy of the oxime HI-6 was studied as a treatment for organophosphorus poisoning. HI-6 was given four times daily as a single intramuscular injection of 500 mg accompanied by atropine and diazepam therapy. Oxime treatment was started on admission and continued for a minimum of 48 h and a maximum of 7 d. HI-6 rapidly reactivated human blood acetylcholinesterase inhibited by dimethoxy organophosphorus compounds, while the dimethoxy-inhibited enzyme was mainly resistant to the treatment by HI-6. Although both HI-6 and pralidoxime chloride reactivated the red blood cell cholinesterase in quinalphos-poisoned subjects, the return of enzyme activities was more rapid following the use of HI-6. The general improvement of poisoned patients, which was sometimes more rapid than the rise of acetylcholinesterase activity, pointed to direct pharmacological effects of HI-6. No undesirable side-effects were noted in patients when HI-6 plasma concentrations were maintained at levels far above the 'therapeutic' concentration for up to 7 d.     

马尼地平缓释片的制备及释药机制考察

目的:研制马尼地平缓释片,并考察其释药机制。方法:将制备的马尼地平固体分散体及乳糖、聚乙二醇、甲基纤维素分别过80目筛,按处方量称取,按等量递增原则于乳钵中充分混匀,干法直接压片即得。结果:马尼地平缓释片的处方组成为HPMC 60RT8000 40 mg,乳糖40 mg,聚乙二醇6000(PEG6000)40 mg,甲基纤维素(MC)80 mg。结论:该缓释片在8 h内呈现良好的零级释放特征,释放机制为骨架溶蚀机制;该缓释片在24 h内药物的释放更符合Higuchi方程,释放机制为非Fick扩散。