The bioavailability and pharmacokinetics of slow release nifedipine during chronic dosing in volunteers.

Eight healthy volunteers received slow release nifedipine 20 mg 12 hourly, for six doses. A nifedipine pharmacokinetic profile was performed after the fifth dosing interval using 12 sampling times over 12 h. A specific high pressure liquid chromatography (h.p.l.c.) nifedipine assay was used. Six of the volunteers subsequently received an i.v. infusion of 3.5 mg of nifedipine after an identical period (five dosing intervals) of chronic oral dosing with slow release nifedipine 20 mg 12 hourly. An identical pharmacokinetic profile was performed after the infusion. Bioavailability, clearance (CL), apparent volume of distribution (V), apparent half life (t1/2) and area under the curve (AUC) were calculated. The geometric mean apparent t1/2 for the slow release preparation was 6.3 +/- 2.0 h. In the six volunteers, the mean bioavailability was 46% (range 29-86%), the mean CL was 588.0 +/- 67.1 ml min-1, the mean apparent V was 160.1 +/- 61.7 l. The pharmacokinetics of slow release nifedipine during chronic dosing appear similar to those derived from single dose studies.     

Clinical pharmacokinetics of slow release mesalazine

Slow release oral mesalazine (Pentasa) contains microgranules covered by a semipermeable ethylcellulose membrane. The microgranules continuously release their content from duodenum to ileum in a pH- and time-dependent way. About 75% of the microgranules pass into the colon, where further release is slower. This release pattern does not appear to be affected by food, diarrhoea or the simultaneous use of H2 antagonists. Rectal forms of mesalazine deliver active drug directly to the rectum and left colon. Plasma concentrations of mesalazine and its metabolite acetyl-5-aminosalicylic acid after oral or local administration are the result of systemic absorption and hepatic metabolism by N-acetyltransferase. Most studies report maximal plasma concentrations of less than 1 mg/L after oral administration of slow release mesalazine, much lower than those observed after uncoated mesalazine but generally higher than after azo-bound drugs such as sulfasalazine. Urinary recovery is an indicator of absorption and metabolism, and is lower after rectal administration (10 to 30%) than after oral administration (30 to 40%). Faecal recovery after oral administration of slow or delayed release mesalazine is lower than with azo-bound drugs. Mesalazine acts locally after absorption by colonic and ileal mucosa. Mean steady-state concentrations of 25.7+/-2.2 microg/kg wet weight are found in ileocolonic biopsy specimens from patients with irritable bowel syndrome treated for 1 week with slow release mesalazine 1.5 g/day. Intramucosal concentrations after slow release mesalazine differ little between healthy individuals and patients with inflammatory bowel disease. Although significant differences are found between the various aminosalicylates in release patterns and the resulting pharmacokinetic parameters, no differences in therapeutic effects have been found in comparative studies. High doses of oral mesalazine (2 to 4 g/day) are more effective than lower doses in the treatment of patients with mild to moderate active ulcerative colitis. High doses (4 g/day) are also effective in the treatment of Crohn's disease, predominantly in patients with ileitis. In contrast, no dose ranging effects were demonstrated with local treatment forms: mesalazine 1g enema seems sufficient for patients with distal colitis. Higher serum concentrations and urinary recoveries after the administration of slow or delayed release mesalazine compared with azo-bound drugs suggest a higher risk for renal adverse effects, although the reported occurrence is extremely low. Although preliminary data support an association between mucosal concentrations of mesalazine and its clinical activity, further studies are needed to correlate the effects of this drug with its pharmacokinetic parameters.     

Interaction between choline theophyllinate and salmefamol in patients with reversible airways obstruction

1 In 54 patients with reversible airways obstruction, a study of the interaction between oral choline theophyllinate (a methyl xanthine derivative) and oral salmefamol (a β₂-adrenergic receptor stimulant) showed that on peak flow their effect was additive, but failed to demonstrate synergy. The only example of statistically significant synergy was their combined effect on the patients' tremor of the hands.     

Plasma theophylline level and ventilatory function in chronic obstructive pulmonary disease during prolonged oral treatment with choline theophyllinate

Summary Plasma levels of theophylline and broncholytic activity have been studied in 12 patients with chronic obstructive pulmonary disease during prolonged oral treatment with choline theophyllinate, administered as a press-coated tablet (Brondaxin^R). The plasma levels determined immediately before and 80 minutes after each dose showed very good agreement with those calculated on the basis of data from a previous single dose study. The plasma concentration and improvement in ventilatory function were closely correlated throughout the 48 hours of the study. A tendency towards further reduction of bronchial obstruction was observed during the second day, despite essentially unchanged plasma levels of theophylline. The results provide a rational basis for determination of an optimal dose schedule for oral treatment with choline theophyllinate to reduce the symptoms of obstructive bronchial disease.     

Effect of oxotremorine and sodium pentobarbitone on the pharmacokinetics of intravenous tracer doses or radioactive choline.

The present study explains for the previous findings that oxotremorine increases and sodium pentobarbitone decreases the initial brain uptake of intravenously injected radioactive choline (3H-Ch). The effects are explained by haemodynamic changes since a corresponding increase and decrease in the plasma concentrations of 3H-Ch were found. This is important to know when 3H-Ch is used for estimation of aceytlcholine turnover in the brain. The drugs did not affect the distribution of radioactivity (3H) between plasma and erythrocytes.     

Acute and chronic ketanserin in essential hypertension: antihypertensive mechanisms and pharmacokinetics.

1. In nine patients with essential hypertension, following single and multiple doses of ketanserin, assessments were made of blood pressure and heart rate, QT interval, and pressor responses to phenylephrine and angiotensin II. 2. Significant reductions in blood pressure occurred for 6 h after the first dose, on average 23/14 mm Hg supine, and there was a comparable antihypertensive effect after 1 month's treatment. 3. There were small but significant rightward shifts (1.5 to 2-fold) in the phenylephrine pressor-response curves but no changes in the responsiveness to angiotensin II. 4. The QT interval (QTc) was significantly increased after 1 month's treatment: at 1 h after dosing 334 +/- 32 ms after 1 month of ketanserin compared with 302 +/- 31 ms after placebo. 5. The elimination half-life and AUC for ketanserin were both significantly increased at steady state compared with the first dose: respectively 13.4 vs 4.3 h for half-life and 830 vs 437 ng ml-1 h for AUC. 6. Ketanserin had no significant effects on baroreflex function, plasma renin activity, aldosterone, catecholamines and 24 h urinary excretion.     

Effect of oxotremorine and sodium pentobarbitone on the pharmacokinetics of intravenous tracer doses of radioactive choline

The present study explains for the previous findings that oxotremorine increases and sodium pentobarbitone decreases the initial brain uptake of intravenously injected radioactive choline (3H—Ch). The effects are explained by haemodynamic changes since a corresponding increase and decrease in the plasma concentrations of 3H—Ch were found. This is important to know when 3H—Ch is used for estimation of acetylcholine turnover in the brain. The drugs did not affect the distribution of radioactivity (3H) between plasma and erythrocytes.     

Treatment of chronic heart failure with slow release phentolamine

Summary The vasoconstrictor activity of four steroids, administered in solution and in the commercially available form, were compared in healthy volunteer subjects. Evaluation was based on conventional visual observations and photometric measurement of reflectance. Statistical analysis showed that halopredone acetate had less vasoconstrictor action on healthy skin than fluocinolone acetonide, beta-methasone valerate and hydrocortisone acetate. The halopredone acetate results were identical to those of the excipient, although it was found that halopredone acetate cream (Topicon^®) had a marked anti-inflammatory effect in animals and on human dermatoses. The validity of the McKenzie test, as an unequivocal screening procedure for the potency of topical steroids is discussed, and the accuracy and precision of photometric evaluation is emphasized.     

茶碱控释片血药浓度监测61例分析

目的：监测两种茶碱控释片的血药浓度。方法：应用荧光偏振免疫法检测血经浓度及ＰＫＳ软件计算药动学参数。结果：优喘平与优特舒有效率分别为８７．３％和８３．３％，两者差异无显著性（Ｐ〉０．０５）；所需日均剂量优喘平为６．８±２．０ｍｇ·ｋｇ＾－１，优特舒为８．９±３．１ｍｇ·ｋｇ＾－１（Ｐ〈０．０１），两药工物动力学参数Ｔ１／２、Ｋｅ、Ｃｌ之间差异有显著性（Ｐ值分别为〈０．０１，〈０．０５，〈０．０５）     

Steady-state pharmacokinetics of controlled release and immediate release formulations of remoxipride in patients with chronic schizophrenia

Twenty-four stable, chronic schizophrenic inpatients were entered in a double-blind crossover study designed to compare single dose and steady state pharmacokinetic profiles of an immediate release formulation (IR) 200 mg BID and a controlled release formulation (CR) of remoxipride 400 mg once daily. The rate of absorption of remoxipride CR was significantly lower than the IR formulation andt _max was prolonged from 1.3 to 7.9 h after a single dose and from 2.2 to 6.0 h after repeated dosing. Although the single dose of remoxipride CR was twice as large as the single dose of the IR, theC _max was similar for both formulations after a single dose. However, theC _max at steady state was slightly lower for CR. There was significantly less fluctuation in plasma concentrations at steady state with the CR formulation, although the average plasma concentration of remoxipride IR and CR was similar. The mean relative bioavailability with regard to the amount of remoxipride absorbed after remoxipride CR 400 mg once daily compared to IR 200 mg BID was 97%. It was concluded that the CR formulation is suitable for a once-daily administration from a pharmacokinetic point of view.     

Comparative pharmacokinetics of isosorbide nitrates after repeated doses of sustained release isosorbide dinitrate

The plasma kinetics of isosorbide dinitrate (ISDN), isosorbide-5-nitrate (IS-5-N) and isosorbide-2-nitrate (IS-2-N) were investigated in 20 healthy male and female volunteers, after b.i.d. administration over 2 days of sustained release ISDN 20 mg and 40 mg capsules (Iso Mack Retard 20 mg and 40 mg) and of a 40 mg sustained release ISDN tablet as reference formulation. The means of the individual maximum ISDN concentrations during the complete 2-day treatment amounted to 10.4 ng/ml after the 40 mg capsule, 5.3 ng/ml after the 20 mg capsule and 5.3 ng/ml after the reference tablet. The corresponding figures of the metabolically generated IS-5-N were 355.5 ng/ml, 168.8 ng/ml and 161.5 ng/ml, respectively. The measured amounts of IS-5-N are expected to contribute to the overall antianginal effect of at least the 40 mg capsule. According to the b.i.d. schedule, ISDN and the two mononitrates accumulated in the plasma after all three tested formulations. However, during the treatment with the 20 mg and the 40 mg capsules, accumulation was practically completed at the second day, while it was found to be more extended during treatment with the reference product. In terms of areas under the curve, the mean bioavailability of the 40 mg sustained release capsule relative to the reference formulation was 198% with respect to ISDN, and 197% both with respect to IS-2-N and IS-5-N. On the other hand, perfect dose-linearity of all relevant pharmacokinetic parameters of all three measured isosorbide nitrates was observed for the 20 mg and the 40 mg dose of the capsule.(ABSTRACT TRUNCATED AT 250 WORDS)     

The interaction between i.v. theophylline and chronic oral dosing with slow release nifedipine in volunteers.

Eight healthy volunteers received a 5 min i.v. infusion of lysine theophylline, equivalent to 197 mg anhydrous theophylline, both before (day 1) and during (day 5) steady state chronic oral dosing with slow release nifedipine 20 mg 12 hourly. A theophylline pharmacokinetic profile was performed on day 1 and day 5 and a nifedipine pharmacokinetic profile was performed on day 4 and day 5. The greatest difference in serum theophylline concentrations was seen at the first sampling time (5 min after completion of the infusion) with a mean concentration of 9.9 mg l-1 during nifedipine administration and 14.6 mg l-1 with theophylline alone. Thereafter, the difference fell to approximately 1 mg l-1 until 6 h when they became almost identical. Repeated measures analysis of variance using the theophylline serum concentrations at each of ten time points over 8 h as the repeated measures showed a small but significant effect of nifedipine (F(1,151) = 7.0, P less than 0.01) on serum theophylline concentrations. Mean volume of distribution (V) rose from 0.33 +/- 0.07 to 0.39 +/- 0.06 1 kg-1 corrected body weight (CBW) in the presence of nifedipine (t = 2.23, P = 0.052). Theophylline clearance, area under the curve to 8 h AUC (0-8), area under the curve to infinity AUC (0-infinity) and elimination half-life (t1/2) did not change appreciably. No statistically significant changes in nifedipine pharmacokinetics occurred in the presence of theophylline.     

Plasma level and broncholytic effect of choline theophyllinate after a single dose of a press- coated tablet formulation

Summary The broncholytic effect and plasma concentrations of theophylline in 10 asthmatic patients were studied for 8 hours after a single dose of 600 mg choline theophyllinate in press-coated 200 mg tablets. Therapeutic concentrations of theophylline were rapidly achieved and the plasma peak averaged 10.4 µg/ml after 2 hours. The broncholytic effect was closely related to the plasma level of theophylline. The largest change was in FEV₁, which was significantly increased 1 to 6 hours after the dose. No patient complained of adverse effects. A theophylline concentration of 7 µg/ml plasma was adequate for a broncholytic effect, but a higher level was required for a maximal response. The results provide a basis for further studies to establish a dosage schedule suitable for prolonged therapy.     

小剂量缓释茶碱治疗咳嗽变异性哮喘的临床研究

目的　观察以小剂量茶碱缓释片治疗小儿咳嗽变异性哮喘的临床疗效,并与常规推荐剂量的用药疗效相比较。方法　选择82例咳嗽变异性哮喘患儿,随机分两组,在其他治疗相同的前提下,推荐剂量组口服茶碱缓释片,每次5mg·kg-1,q12h ;小剂量组口服剂量每次3mg·kg-1,q12h ,疗程5d。结果　两组患儿口服不同剂量的茶碱缓释片,均能取得理想的治疗效果,临床症状的缓解情况无显著性差异。结论　口服小剂量茶碱缓释片可达到常规推荐剂量的疗效,临床上安全、方便。     

Comparison of pharmacokinetics of clodronate after single and repeated doses.

OBJECTIVE: Pharmacokinetics of orally given clodronate disodium, a drug for the treatment of hypercalcemia and bone resorption, were studied after a single dose of 400, 800 and 1600 mg given randomly to 11 healthy volunteers in a crossover manner, in 7-14 hospitalized cancer patients given 400, 800 and 1600 mg twice daily, each dosage for one week, and during the customary therapy in 15 additional cancer patients treated in hospital with 400 mg thrice daily for > or = 2 weeks. METHODS: Clodronate concentrations in serum and urine were measured by capillary gaschromatography with mass-selective detection. Pharmacokinetic parameters were calculated with a three-compartmental model. RESULTS: After a single oral dose to healthy volunteers the absolute clodronate concentrations increased almost dose-dependently. The mean cumulative excretion in urine was 1.72-2.77% of the dose, an interindividual range being from 0.92% to 5.52%. With 800 and 1600 mg twice daily for one week to cancer patients the serum drug concentrations increased almost progressively with increasing the dose. In cancer patients serum drug concentrations were clearly higher and renal drug clearances (mean 25-62 ml/min) lower than in healthy volunteers (mean 123-149 ml/min). The mean urinary excretions were 2.24-3.14% of the dose and interindividual ranges from 0.18% to 19.0%. During the routine cancer therapy with 400 mg thrice daily, the clodronate excretions in urine on two successive days were on an average 3.26% (range 0.0-10.5%). CONCLUSIONS: Absolute concentrations in serum and excretions in urine of orally given clodronate increase dose-dependently, but during the maintenance therapy in hospitalized cancer patients the renal drug clearances seem to be lower than in healthy volunteers. This and the large interindividual variation in kinetics propose therapeutic monitoring of clodronate for optimizing the oral dose of the drug.     

Population pharmacokinetics of theophylline in adult Chinese patients with asthma and chronic obstructive pulmonary disease

Background Theophylline has a narrow therapeutic range and large interindividual variability in blood levels, so a thorough understanding of its pharmacokinetic characteristics is essential. Population pharmacokinetic (PPK) approaches could achieve it and many PPK studies of theophylline have been reported in infants. However, none was conducted in Chinese adults and none has explored the effect of CYP1A2 genotypes on the PPK characteristics of theophylline in adults. Objective To evaluate the PPK characteristics of theophylline and to assess the possible influence of covariates, including CYP1A2 genotypes, on theophylline clearance in Chinese adult patients. Setting The study is conducted at the department of respiration in Zhujiang Hospital, Guangzhou, China. Methods Theophylline concentrations were obtained from eligible patients and were measured by high performance liquid chromatography. The polymorphisms of ??3860G?>?A, ??163C?>?A, C5347T (CYP1A2*1B) and G-3113A were genotyped using a direct sequencing method. Then, CYP1A2 genotypes, age, fat-free mass (FFM) and other covariates were used to develop a PPK model by NONMEM software. Bootstrap analysis was used to asses the accuracy and prediction of the PPK model. Main outcome measure The concentration and clearance of theophylline. Results A total of 134 theophylline concentrations from 95 patients were obtained. The final model was as follows: CL/F(L/h)?=?4.530?×?(FFM/56.1)^0.75 ×?0.713^CYP1A2*1B, the inter-individual variability in clearance/bioavailability (CL/F) was 44.0%, and the residual variability was 9.8%. The final model was proved to be reliable by bootstrap analysis. Conclusion Theophylline clearance was significantly associated with FFM and CYP1A2*1B genotypes in Chinese adult patients.