Evaluation of two new megestrol acetate tablet formulations in humans

The bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet (Megace). The tablets were administered to 24 male subjects in a three-way cross-over study, balanced for sequence, with a week between administrations. The 40 mg tablets were administered q.i.d. at 08.00, 12.00, 18.00 and 22.00 h, while the 160 mg tablets were administered once at 08.00 h. Plasma samples were collected at appropriate times out to 96 h after administration and were analysed for megestrol acetate with a validated high performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2.5 to 2.8 h), the absorption rate constant was the same for each of the tablets. Relative to the 40 mg q.i.d. dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97 per cent and 118 per cent, respectively.     

Effect of slow release nifedipine tablets in patients with essential hypertension.

The antihypertensive effect of slow release nifedipine (CAS 21829-25-4) tablets (20 mg, Adalat) administered once or twice daily was studied in patients with essential hypertension of WHO stage I or II. Ambulatory blood pressure was monitored by a finger volume oscillometric device every 5 min for 24 h before and during the treatment with nifedipine. Whether administered once or twice daily, nifedipine tablets dit not change the pattern of circadian blood pressure variation; i.e. diurnal rise and nocturnal fall. Twice daily administration induced a significant downward shift in the blood pressure pattern. In other words, further hypotensive effect was observed during the night when the blood pressure was already low. On the other hand, administration once daily in the morning lowered daytime blood pressure without affecting blood pressure during the night. The duration of action of nifedipine tablets administered once daily was 12 h or more. In the acute experiment using 20 mg tablets of nifedipine, plasma concentration of nifedipine was well correlated with the percentage change in mean blood pressure. The minimal effective plasma concentration of nifedipine was estimated to be 13.4 ng/ml. However, in chronic treatment, nifedipine lowered blood pressure at the plasma concentration of 10 ng/ml. The results indicate that nifedipine tablets administered once daily provide an effective antihypertensive regimen for controlling daytime hypertension with minimal antihypertensive effect during the night.     

Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients — a comparison of two oral formulations

Summary The single-dose and steady state kinetics of morphine given as controlled-release tablets (30 mg every 12 h) and as a solution (15 mg every 6 h) have been compared in 11 cancer patients with chronic pain. The concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were analyzed by HPLC.There were no significant differences between the tablets and solution in the mean steady state concentrations of morphine, M3G or M6G. The t_max was 3.3 h for the tablets compared to 1.1 h for the solution.After giving the controlled-release tablets every 12 h there was a significantly higher fluctuation index of the morphine concentrations than after the solution. Urinary recovery at steady state was comparable between the two preparations, with averages of 57% and 47%, respectively.Thus, no major differences were found in the pharmacokinetics of morphine and its glucuronidated metabolites after 30 mg morphine as controlled-release tablets every 12 h or 15 mg of morphine solution every 6 h, except for a significantly longer t_max and greater fluctuation in morphine concentrations after the controlled-release tablets.     

Bioavailability of propranolol hydrochloride tablet formulations: application of multiple dose crossover studies

Two multiple dose crossover pharmacokinetic studies were carried out to determine the steady-state bioavailability of newly formulated generic propranolol HCl tablets relative to Inderal tablets. In Study I, 24 healthy volunteers were dosed with 4 x 10 mg test tablets, 1 x 40 mg test tablet, 4 x 10 mg Inderal tablets, and 40 mg of propranolol HCl in solution. In Study II, 24 healthy volunteers were dosed with 1 x 80 mg test tablet, 1 x 80 mg Inderal tablet, and 80 mg of propranolol HCl in solution. Both studies were of randomized design with each formulation administered every 8 h for 15 doses. Serial plasma samples were obtained for 8 h after morning doses on Days 4 and 5 of each treatment period and assayed for propranolol using a validated HPLC method. Mean plasma concentration-time data for test tablets and reference tablets were superimposable in both studies. Pharmacokinetic parameters from Days 4 and 5 were combined for statistical analysis since subjects were determined to have reached steady-state. Mean AUC, Cmax, tmax, and Cmin values were not statistically different between test tablets and Inderal tablets in either study. Based on these findings, the test tablets demonstrated the same rate and extent of propranolol absorption as did corresponding Inderal tablets. Therefore, the test tablets and Inderal tablets were determined to be bioequivalent.     

Effect of food on the bioavailability of adinazolam from a sustained release formulation: effect of meal timing and lack of dose dumping

Food effects on adinazolam absorption from sustained release (SR) adinazolam mesylate tablets were assessed in 28 healthy male volunteers. Subjects received 15 mg SR tablets, 15 mg immediate release tablets, 15 mg oral solution, administered after an overnight fast, and 15 mg SR tablets after a high fat breakfast. Treatments were administered in a crossover design. Plasma adinazolam and N-desmethyladinazolam (NDMAD) concentrations were determined by HPLC. Adinazolam and NDMAD AUC values were unaffected by food. Cmax for SR tablets was increased 33 per cent and 18 per cent for adinazolam and NDMAD, respectively, when administered postprandially. Tmax occurred later in the fed state; no dose dumping was observed. Meal timing effects on adinazolam absorption from SR tablets were assessed in 24 healthy subjects, who received 30 mg SR tablets 1 h before, 0.5 h after, 2 h after a high fat meal, and in the fasted state. Postprandial administration had no effect on AUC, but resulted later and higher adinazolam and NDMAD Cmax. Differences in these values were less than 11 per cent. Administration of SR tablets before meals yielded Cmax and Tmax values which were similar to the fasted state. Results suggest that meal timing does not substantially affect adinazolam absorption from the SR tablet.     

Steady-state kinetics and analgesic effect of oral morphine in cancer patients

The steady-state kinetics of morphine given as tablets and solution were compared in 7 cancer patients with chronic pain. There was no accumulation of morphine (20-40 mg) when repeatedly administered every 4 to 6 h. The mean steady-state concentration of morphine during the dose interval varied between 5.9 and 68.4 ng/ml (20.7-240 nmol/l), and was linearly related to the daily dose of morphine. There were no significant differences between the tablets and the solution of morphine with regard to relative oral bioavailability or peak concentration. The time-to-maximum plasma concentrations was significantly longer for the tablets. The pain score profile, assessed by a visual analogue scale during a dose interval, showed a similar pattern after the two oral formulations of morphine. No significant linear relationship between the scores and the plasma concentrations of morphine was observed.     

Beta-blocking effect and serum levels of alprenolol in man after administration of ordinary and sustained release tablets

Summary The effect of alprenolol administered as ordinary and as sustained release tablets was compared by studies on the inhibition of the haemodynamic response to physical work. Serum levels of alprenolol were also determined. Two types of double-blind cross-over studies were performed in healthy volunteers. In one the effects of ordinary tablets, sustained release tablets and a placebo were followed for 12 h. In two other studies each preparation was given for five days. The sustained release tablets were given b.i.d., and were compared with ordinary tablets administered q.i.d., or with a placebo. A dose of 200 mg alprenolol in sustained release tablets had almost the same initial peak effect as 100 mg in ordinary tablets. The duration of the effect was longer after the sustained release tablets, and 200 mg b.i.d. gave approximately the same degree of beta-blockade during the day as 100 mg in ordinary tablets given q.i.d. The results indicated that both dosage regimens had an effect for 24 h, and that more constantive effect levels were obtained by the use of sustained release tablets. No accumulation was found in the five day study, neither in terms of the pharmacological effects nor of serum levels of alprenolol. The concentration of alprenolol in serum rarely exceeded 10 ng per ml, and approximately the same steady state level was obtained after sustained release tablets as after ordinary tablets.     

奥施康定治疗原发性肝癌肝动脉化疗栓塞术后中重度疼痛的疗效观察

目的观察奥施康定（盐酸羟考酮控释片）治疗原发性肝癌肝动脉化疗栓塞术后引起中重度肝区疼痛的近期疗效和不良反应。方法初始剂量10mg／12h,服用24h如疼痛分级下降不到1级,则第2天加量至20mg／12h。服用24h如疼痛分级仍下降不到1级,第3天加量至30mg／12h,以此类推,最多至40mg／12h。结果总有效率（CR＋Pit）为95．4％,中度疼痛组有效率为95．2％,重度疼痛组有效率为95．8％。不良反应：便秘者19例（28．8％）,恶心、呕吐者8例（12．1％）。结论服用盐酸羟考酮控释片治疗肝动脉化疗栓塞术后出现中重度肝区疼痛安全有效。     

Pharmacokinetic and pharmacodynamic characterization of OROS® and immediate-release amitriptyline

AIMS: To characterize the pharmacokinetics of amitriptyline and its metabolite nortriptyline following OROS and IR treatments, and to correlate them with anticholinergic side-effects. METHODS: The pharmacokinetics and safety of amitriptyline following administration of an osmotic controlled release tablet (OROS and an immediate release (IR) tablet were evaluated in 14 healthy subjects. In this randomized, open label, three-way crossover feasibility study, the subjects received a single 75 mg OROS tablet, three 25 mg IR tablets administered every 8 h, or 3x25 mg IR tablets administered at nighttime. In each treatment arm serial blood samples were collected for a period of 84 h after dosing. The plasma samples were analysed by gas chromatography for amitriptyline and its metabolite nortriptyline. Anticholinergic effects such as saliva output, visual acuity, and subject-rated drowsiness and dry mouth were measured on a continuous scale during each treatment period. RESULTS: Following dosing with OROS (amitriptyline hydrochloride), the mean maximal plasma amitriptyline concentration Cmax (15.3 ng ml-1 ) was lower and the mean tmax (25.7 h) was longer than that associated with the equivalent IR dose administered at nighttime (26.8 ng ml-1 and 6.3 h, respectively). The bioavailability of amitriptyline following OROS dosing was 95% relative to IR every 8 h dosing, and 89% relative to IR nighttime dosing. The metabolite-to-drug ratios after the three treatment periods were similar, suggesting no change in metabolism between treatments. The relationships between plasma amitriptyline concentration and anticholinergic effects (e.g. reduced saliva weight, dry mouth, and drowsiness) were similar with all three treatments. Of the anticholinergic effects, only decreased saliva weight and dry mouth correlated well with plasma amitriptyline concentrations; drowsiness did not. There was no apparent correlation between anticholinergic effects and the plasma nortriptyline concentration. CONCLUSIONS: The bioavailability of OROS (amitriptyline hydrochloride) was similar to that of the IR treatments and the pharmacokinetics of amitriptyline after OROS dosing may decrease the incidence of anticholinergic effects compared with that seen with nighttime dosing of the IR formulation. Therefore, this controlled-release formulation of amitriptyline may be appropriate for single daily administration.     

A new sustained-release theophylline suspension for asthmatic children: evaluation of serum theophylline concentrations

Theophylline level variability obtained with standard slow-release theophylline tablets was compared to that obtained with a new sustained-release theophylline suspension in asthmatic children. The sustained-release preparations were administered every 12 hours and serum samples were collected after ten days of treatment during the steady-state period. In this crossover study, the sequence of the two regimens (slow-release tablets versus slow-release suspension) was selected at random. Both preparations of theophylline were administered at a mean dosage (+/- s.d.) of 19.3 +/- 1 mg/kg/day. The results of our study demonstrated that theophylline serum levels remain within the therapeutic range for both preparations, but there was a greater fluctuation with theophylline suspension compared to the tablets. The tolerability of the two drugs was satisfactory.     

硫酸吗啡控释片治疗癌症疼痛的临床观察

目的:观察硫酸吗啡控释片对晚期癌症镇痛的效果。方法:采用开放试验方法,对100例中、重度癌痛患者进行治疗。硫酸吗啡控释片单片剂量为30mg,每12h给药一次,在用药过程中根据疼痛缓解程度调整剂量。结果:本组100例患者中显效65例,显效率65·0%,有效32例,有效率32·0%,无效3例,无效率3·0%,总有效率为97·0%(97/100)。结论:硫酸吗啡控释片治疗癌症疼痛疗效确切,有效率高。是中、重度癌痛的首选药品,现已应用于临床。     

Comparative bioavailability of disopyramide after multiple dosing with standard capsules and controlled-release tablets

Summary Plasma concentrations and bioavailability of disopyramide following repeated administration of standard capsules and controlled-release tablets have been compared. Ten patients were randomized into two groups; Group I received disopyramide capsules 150 mg every 6 h for five days and subsequently disopyramide controlled-release tablets 300 mg every 12 h for further five days. Group II received the same preparations in the reverse order. There was a more rapid rise in disopyramide concentration after the capsules: the maximum of 10.7±0.6 µmol/l (mean ± SEM) was reached within 1.8±0.4 h as compared to 10.6±0.4 µmol/l within 4.0±0.3 h after the controlled-release tablets. No significant difference in the fluctuations in individual plasma concentrations during each dose interval at steady state were observed after ordinary capsules compared to controlled-release tablets. The extent of bioavailability was the same. Eight patients reported some side-effects during the capsule period and nine during the controlled-release tablet period.     

Relative bioavailability of a controlled-release albuterol formulation for twice-daily use

A two-way-crossover bioavailability study was completed with 15 healthy male volunteers to evaluate the relative bioavailability of an orally administered controlled-release (CR) formulation of albuterol as compared to the immediate-release (IR) formulation of albuterol. The CR formulation of albuterol used in this study was based mechanistically on the elementary osmotic pump. Each subject received one 8 mg CR tablet every 12 h for 8 consecutive days and one 4 mg IR tablet every 6 h for 8 consecutive days, with 7 days separating each phase. During day 8 of dosing, hourly blood samples (0-12 h) were collected after the morning dose and three additional samples were obtained 16, 20 and 24 h following this dose. Plasma concentrations were measured using a gas chromatography-mass spectrometry procedure. No statistically significant differences were observed in mean steady-state values for Cmax, Cmin, AUC(0-12 h) and peak-to-trough fluctuations (PTF) in comparing the two dosage formulations. Mean steady state Tmax values were 2.6 and 6.0 h for the TR and CR formulations, respectively. It was concluded that twice daily administration of the controlled-release formulation of albuterol provides an alternative to four times daily administration of conventional (immediate-release) albuterol tablets.     

Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers

Summary The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng · ml^–1) was significantly lower than after the tablets (74.3 ng · ml^–1). The AUCs following the two treatments did not differ significantly from each other.The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).     

The comparability of dosage regimens of Lanoxin tablets and Lanoxicaps.

1 Twice daily administration of 0.25 mg digoxin tablets (Lanoxin) or of 0.2 mg digoxin in solution in soft gelatin capsules (Lanoxicaps) produced similar mean steady state plasma digoxin concentrations in ten healthy volunteers. Respective values were 1.07 +/- 0.075 and 0.95 +/- 0.048 ng ml-1. 2 During continued administration, peak plasma concentrations occurred earlier after capsules with a tendency to higher peak levels. However, area under curve determinations over 7 h were similar. 3 Approximately 10% less digoxin was recovered in urine collected in a 12 h dosage interval during the lower dosage administration of capsules. Mean percentage urinary recovery of administered dose was 57% for tablets and 65% for capsules. 4 The enhanced bioavailability of Lanoxicaps was associated with reduced between-subject variability in plasma concentration. 5 Lanoxicaps (0.2 mg) should be approximately equivalent in effect to digoxin tablets (0.25 mg) currently available in the United Kingdom, though improved consistency would be anticipated.     

Differential action of ondansetron and dexamethasone to modify cisplatin-induced acute and delayed kaolin consumption ("pica") in rats

The ability of cisplatin to induce acute (0-24 h) and delayed (24-48 and 48-72 h) phases of kaolin ingestion (pica) was investigated in the rat. Cisplatin 3 mg/kg, i.p., induced kaolin consumption during the 0-24- (P<0.001) and 48-72-h (P<0.05) periods that was antagonised by dexamethasone 1 mg/kg, i.p., administered every 12 h alone or in combination with ondansetron 2 mg/kg, i.p., administered every 12 h (P<0.05). As a single treatment, ondansetron 2 mg/kg, i.p., administered every 12 h potentiated cisplatin-induced kaolin consumption by 41% (P<0.05) during the 0-24-h period but had no action to modify the delayed response (P>0.05). Dexamethasone 1 mg/kg, i.p., administered every 12 h and cisplatin 3 and 6 mg/kg, i.p., but not ondansetron 2 mg/kg, i.p., administered every 12 h (P>0.05) reduced food consumption and decreased rat weight. The highest dose of cisplatin 6 mg/kg, i.p., induced acute (P<0.001) but not delayed kaolin ingestion (P>0.05). The action of cisplatin to induce acute and delayed pica is complicated and may be affected by drugs that modify appetite.     

Comparison of serum phenytoin levels in epileptic patients who swallowed their phenytoin tablets with or without previous chewing

Summary This cross-over study was conducted to compare serum phenytoin levels after chronic ingestion of phenytoin tablets with or without previous chewing. The phenytoin therapy was administered as 50 mg chewable Infatabs® tablets in a single morning dose of 200 mg. There was no significant difference between the two modes of ingestion as regards serum phenytoin levels measured at various times after ingestion of the phenytoin tablets. Moreover, the area under the curve did not differ significantly during the 24 h interval. Minor changes between two Dilantin® formulations, however, could influence drug availability.     

A comparison of the hypoalgesic effect of paracetamol in slow-release and plain tablets on laser-induced pain.

1. In a double-blind, three way, cross-over study 15 volunteers received plain paracetamol tablets 1000 mg every 6th hour, paracetamol slow-release tablets 2000 mg every 12th hour, and placebo. Steady state conditions were established over a 5 day period preceding each test session. 2. Plain paracetamol was given twice in the 12h test session, initially and after 6 h, and the slow-release formulation was given once at the start of the session. 3. Hypoalgesia, measured by experimentally laser-induced pain (pain threshold), and plasma concentrations of paracetamol were measured hourly for 12 h. 4. Both formulations of paracetamol were significantly superior (P = 0.0003) to placebo, but not difference in analgesic efficacy was found between the two regimens.     

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。     

Bioavailability and pharmacokinetic profile of dihydroergotoxine from a tablet and from an oral solution formulation

Dihydroergotoxine mesylate (DHETM, CAS 8067-24-1), the combination of the mesylates of four dihydrogenated ergot alkaloid derivatives (dihydroergocornine, dihydroergocristine, alpha-dihydroergocryptine and beta-dihydroergocryptine), is used mainly for age-related cognitive impairment. The bioavailability of DHETM was investigated in a cross-over study on 20 male healthy volunteers to whom two single doses of 9 mg DHETM were administered either in tablets (Orphol spezial) or in oral solution (Orphol forte). DHETM was assayed in serum with a double radioimmunoassay method displaying a satisfactory cross-reactivity with the principal components of DHETM. After administration of tablets the peak of DHETM was (mean +/- SE) 124 +/- 16 pg/ml, the tmax 1.15 +/- 0.21 h, the AUC 790 +/- 93 pg/ml x h and the terminal elimination half-life 7.54 +/- 1.23 h. After oral solution the peak of DHETM was 176 +/- 16 pg/ml, the tmax 0.50 +/- 0.04 h, the AUC 779 +/- 94 pg/ml x h and the terminal elimination half-life 6.13 +/- 0.76 h. The bioavailability of DHETM from tablets vs. that from oral solution differed only by a retard related to the dissolution time of DHETM from the tablets, but not for other pharmacokinetic parameters. The relatively high two single doses of 9 mg DHETM administered to the 20 subjects were well tolerated, causing only known and expected adverse reactions to DHETM (tiredness, headache and vertigo) that did not require discontinuation of the study.