Analysis of the daily variation in blood pressure and pharmacokinetics after single or repeated administration of clentiazem to patients with essential hypertension.

Clentiazem (TA-3090, CAS 96125-53-0), a new benzothiazepine Ca++ antagonist, was orally administered to inpatients with essential hypertension at a dose of 30 mg at 8:00 a.m. once (n = 5) or daily for 2 weeks (n = 22). After administration of the medication, the daily variations in blood pressure and pulse rate were monitored using a portable blood pressure recorder, and plasma concentrations of clentiazem were determined by HPLC. 1. In the single administration study, an antihypertensive effect was observed between 4 and 12 h with a peak approximately 8 h after administration. After the single dose, the diurnal pulse rate was higher than the pretreatment level, but it was not correlated with the antihypertensive effect. 2. In the repeated administration study, both the systolic and diastolic blood pressures showed significant decreases after administration throughout the day (p less than 0.01). The nocturnal antihypertensive effect was weaker than the diurnal effect, and the minimum decrease/maximum decrease ratio in a day was 0.52 for both systolic and diastolic pressures. The pulse rate decreased slightly during certain time intervals after administration (p less than 0.01 or p less than 0.05), but those were slight changes. 3. As to the pharmacokinetic profile clentiazem showed a long-lasting plasma level, the tmax was 6.8 +/- 1.1 h for the single treatment and 6.9 +/- 1.6 h for the repeated treatment; the Cmax was 16.9 +/- 6.1 ng/ml and 19.3 +/- 8.8 ng/ml, respectively; and the t1/2 was 6.6 +/- 1.5 h and 12.5 +/- 5.4 h, respectively. The plasma level profiles for single and repeated administrations were similar.(ABSTRACT TRUNCATED AT 250 WORDS)     

Natriuretic and diuretic effects of felodipine and hydrochlorothiazide after single and repeated doses

The effects of the calcium antagonist, felodipine, and hydrochlorothiazide (HCTZ) on natriuresis/diuresis and blood pressure were evaluated in 12 healthy subjects. The investigation was designed as a double-blind, three-way, randomised, crossover study, and all comparisons were performed against placebo. Urine volume, urine sodium excretion, heart rate and blood pressure were measured after a single dose of felodipine 10 mg, HCTZ 12.5 mg or placebo as well as during steady-state conditions (6 days of treatment with felodipine 10 mg b.i.d., HCTZ 12.5 mg b.i.d. or placebo).A significant increase in natriuresis was seen in the first 4 h after a single dose of felodipine and HCTZ, and the effect of felodipine was approximately 40% that of HCTZ. When the entire 24-h period after a single dose was studied, there was a significant increase in natriuresis after HCTZ, but not after felodipine, compared with placebo.A significant increase in diuresis was found in the first 4 h after a single dose of HCTZ, but not after felodipine, compared with placebo.Under steady-state conditions, there were no statistically significant differences between felodipine and placebo or HCTZ and placebo when the 24-h period, as a whole was considered.Potassium excretion was not affected by any of the drugs. Felodipine caused a significant decrease in diastolic blood pressure in this study. This was not the case for HCTZ or placebo.     

Plasma metronidazole concentrations after single and repeated vaginal pessary administration.

Metronidazole concentrations in plasma were measured by h.p.l.c. in 12 healthy female volunteers after single and repeated vaginal administration of 500 mg metronidazole pessaries. The area under the plasma concentration-time curve (AUC(0,12 h) was 8.4 +/- 3.9 micrograms ml-1 h (mean +/- s.d.) on day 1 and 20.6 +/- 7.1 micrograms ml-1 h (mean +/- s.d.) on day 5. The peak plasma drug concentration on day 1 was 1.2 +/- 0.6 micrograms ml-1 (mean +/- s.d.) and on day 5 it was 2.0 +/- 0.7 micrograms ml-1 (mean +/- s.d.). The plasma concentration of metronidazole at steady state was above the minimum inhibitory concentration (MIC) for anaerobic Streptococci and Clostridium tetani. These results demonstrate much lower systemic exposure than after oral administration.     

The effect of imipramine after single and repeated administration on the apomorphine response in the acoustic startle reflex in rats.

The paper presents the results of studies into the effects of single and repeated (2 or 10 mg/kg po, twice daily for 14 days) administration of imipramine (IMI) on the behavior of male Wistar rats in an acoustic startle response test. Statistically significant attenuation of the animal reactivity was observed after 8 or 14 days administration of IMI in a dose of 10 mg/kg. Apomorphine APO (1.0 mg/kg, ip) enhanced the animals reactivity after repeated (but not single) administration of IMI in a dose of 2 mg/kg. The obtained results confirm the hypothesis about an increase of the dopaminergic system reactivity under the influence of repeated administration of tricyclic antidepressants.     

EEG profile of litoxetine after single and repeated administration in healthy volunteers.

1. Litoxetine is a selective serotonin reuptake inhibitor with antidepressant activity in animal models and in depressed patients. 2. This double-blind, cross-over, placebo-controlled study was carried out in 12 healthy young male volunteers. The aim was to assess the EEG profile of litoxetine in parallel with its pharmacokinetics after a single dose or multiple administrations for 4 days (6 doses) of two dosages (10 mg and 25 mg). Spectral analysis of four EEG leads (F4-T4, F3-T3, T4-02 and T3-01) was done up to 12 h post-dose. 3. In single or multiple doses, litoxetine induced EEG changes characterised by a dose-related increase in fast beta energies, mainly beta 2, without any changes in slow waves (delta and theta). A slight reduction in alpha activity occurred only after repeated doses. 4. EEG changes occurred after a single oral administration and lasted at least 12 h with litoxetine blood concentrations ranging from 4 to 10 ng ml-1. With repeated administrations, the pharmacodynamic steady-state was achieved as the increase in beta 2 energies was the same before and 12 h post-dose. These effects occurred with litoxetine blood concentrations ranging from 3 to 7 ng ml-1 with the 10 mg dosage and from 8 to 18 ng ml-1 with the 25 mg dosage. The EEG profile did not change after 4 days of repeated administration, indicating that tolerance did not develop. 5. Cmax and AUC showed proportionality between the administered dosages of 10 and 25 mg.(ABSTRACT TRUNCATED AT 250 WORDS)     

单剂量口服非洛地平缓释片的药动学及生物等效性

目的研究单剂量口服国产非洛地平缓释片在健康志愿者体内的药动学特征,并评估其与参比制剂之间的生物等效性。方法 20名健康男性志愿者采用两制剂双周期交叉试验设计。以尼莫地平为内标,采用LC-MS/MS法测定血中药物浓度。以BAPP 2.2计算其药动学参数,评价受试制剂与参比制剂之间的生物等效性。结果 20名受试者单剂量口服10 mg受试制剂和参比制剂后非洛地平的主要药动学参数ρmax）分别为（3.09±1.03）μg·L^-1和（2.68±0.88）μg·L^-1;tmax分别为（3.8±1.0）h和（3.5±1.4）h;t1/2分别为（14.49±2.72）h和（13.74±3.42）h;MRT为（19.87±2.62）h和（19.08±4.73）h;AUC0→48为（30.83±6.04）μg·h·L^-1和（31.42±5.78）μg·h·L^-1;AUG0→∞为（34.00±5.76）μg·h·L^-1和（34.93±6.54）μg·h·L^-1。受试制剂与参比制剂的主要药动学参数经统计学分析无明显差异。受试制剂的相对生物利用度为（98.5±11.0）%。结论国产非洛地平缓释片与其参比制剂之间具有生物等效性。     

Pharmacokinetics and bioavailability of omeprazole after single and repeated oral administration in healthy subjects.

1. Ten healthy subjects were given 20 mg omeprazole EC (enteric coated) granules once daily for 8 days. An i.v. tracer dose of [14C]-omeprazole was given simultaneously with the first and last oral doses and blood sampling was performed thereafter. In order to study the extent of absorption at minimal acid exposure, a single dose of 20 mg omeprazole was also given as a buffered solution, before and after the treatment with EC granules. 2. Kinetic parameters of omeprazole after the i.v. tracer dose were unchanged on repeated dosing while AUC increased by approximately 40% for the solution and 60% for the EC granules. 3. The increased AUC is caused by an increased systemic availability, which may be explained by a decreased first-pass elimination during repeated treatment and/or by a reduced degradation of omeprazole in the stomach secondary to the profound decrease in intragastric acidity caused by the drug. 4. The implication of these findings is that the antisecretory effect of therapeutic doses of omeprazole must be studied during repeated administration and not judged from studies using single doses only.     

Determination of methamphetamine in hair after single and repeated administration to rat

Methamphetamine in hair after p.o. administration to rat was identified and determined by mass fragmentography (MF). Rat hair was washed with HCl/methnanol, methanol and water. The hair was crushed in 0.6 M HCl, suspension was alkalized with Na2CO3, and extracted with chloroform/isopropanol. The extract obtained was purified by column chromatography on aluminium oxide. Concentrated eluate was trifluoroacetylated, and methamphetamine was identified and determined by MF. More than 20 pg of methamphetamine was detectable and less than 1 ng of that was determined by MF. Methamphetamine in hair collected from rat after p.o. administration of 20 mg/kg of the drug was detected and determined up to 8 days after. From hair of rat after 5-days or 14-days repeated administration of 20 mg/kg/day, methamphetamine was detected 25 or 45 days after the last administration, respectively.     

Treatment of essential hypertension with felodipine in combination with a diuretic

Summary In a double-blind cross-over study, the effect on blood pressure (BP), heart rate (HR) and plasma noradrenaline concentration (pNA) of placebo or felodipine given in addition to hydrochlorothiazide was studied in 12 male patients with essential hypertension, not satisfactorily controlled with the diuretic alone. The first dose of felodipine decreased BP and increased HR for about 6 h. After 4 weeks of treatment with felodipine, BP was reduced for 24 h, whereas HR was only transiently increased. The elimination half-life of felodipine was about 23 h. The plasma noradrenaline concentration increased after felodipine and serum uric acid decreased. Side-effects were few and usually mild.     

Catecholamines and the renin-angiotensin-aldosterone system during treatment with felodipine ER or hydrochlorothiazide in essential hypertension.

The neurohumoral responses after 10 mg of felodipine extended release (ER), a new dihydropyridine calcium antagonist, and 25 mg of hydrochlorothiazide (HCTZ) were compared in a randomized, double-blind, crossover trial in 28 mild to moderate hypertensives. Antihypertensive drugs were gradually discontinued. Felodipine ER, 10 mg was given once daily for 2 weeks; after another washout period of 1 week, patients were switched to 25 mg of HCTZ once daily and vice versa. Blood pressure (BP) was measured at baseline, 2.5 h after medication, and after 2 weeks of treatment (24 h postdosing) using an oscillometric device. Felodipine ER and HCTZ both lowered BP effectively. However, felodipine ER was superior in reducing systolic and diastolic BP during the short term and medium term. Treatment with felodipine ER over 2 weeks increased sympathetic outflow as indicated by elevated plasma norepinephrine levels, whereas plasma epinephrine was mainly unaffected, as were plasma renin and aldosterone levels. On the other hand, 25 mg of HCTZ increased plasma renin and aldosterone, but left catecholamines unchanged. Despite persistent increased sympathetic activity, the reduction in BP in this study was more pronounced after felodipine ER as compared to HCTZ. The lack of a difference between heart rates under both medications after 2 weeks of treatment suggests a resetting of the baroreflex by felodipine ER and furthermore that the increased norepinephrine levels may not be clinically relevant, but demonstrate the maintained baroreflex activity. HCTZ, in doses as low as 25 mg, is still capable of stimulating the renin-angiotensin-aldosterone system.     

Antihypertensive effect of spirapril and felodipine during repeated administration to spontaneously hypertensive rats

The antihypertensive activity of spirapril given alone or in combination with felodipine was investigated in spontaneously hypertensive rats (SHR) during a 3-week treatment regimen and for one week after drug withdrawal. Systolic blood pressure and heart rate were recorded once a week just before dosing and at varying time intervals up to 6 hr thereafter. Recordings were continued for one week after drug withdrawal. Spirapril alone at 1 and 5 mg/kg p.o. was found to produce dose-related antihypertensive effects throughout the treatment period. Felodipine alone at 5 mg/kg p.o. reduced blood pressure slightly more than did the low dose of spirapril. The combination of spirapril and felodipine induced a marked antihypertensive response which was greater than that observed in rats treated with either drug alone. One week after treatment withdrawal, blood pressure was at initial levels with no evidence of rebound phenomena. No significant heart rate changes were observed in the treated groups, as compared with the controls, except for an increase on the 1st day of treatment in rats given felodipine. These findings indicate that the combination of an angiotensin converting enzyme (ACE) inhibitor with a calcium antagonist leads to an effective control of hypertension over a prolonged period of treatment. Since the combination allows effectiveness with lower doses of ACE inhibitor, it is expected that the antihypertensive efficacy might be associated with a lower liability to untoward effects.     

国产复方非洛地平缓释片治疗原发性高血压的疗效和安全性

目的 评价国产复方非洛地平缓释片治疗轻、中度原发性高血压的疗效和安全性.方法 采用多中心、随机、双盲双模拟、前瞻性平行对照方法,从321例高血压患者中筛选出经非洛地平(5mg)单药治疗4wk、血压不能满意控制者217例,随机分为试验组和对照组,继续治疗8wk,分别服用复方非洛地平缓释片(由马来酸依那普利和缓释非洛地平组成,5mg/5mg)1片和非洛地平缓释片(5mg)、马来酸依那普利片(5mg)各1片.双盲治疗4wk后DBP不低于90mm Hg(1mm Hg=0.133kPa)者剂量加倍.结果 前4wk非洛地平单药治疗的有效率32.4%,降压无效而人组者血压平均下降(5.4±3.3/2.7±1.9)mm Hg.后8wk联合用药降压的总有效率试验组和对照组分别为88.3%和92.2%,血压分别进一步下降16.2/10.5mm Hg和14.8/11.4mm Hg.单药的不良反应主要为头痛、头晕、头胀、面部潮红等(12.0%).双盲试验期不良反应总发生率试验组和对照组分别为19.4%和14.7%,其中干咳发生率分别占6.5%和8.3%.结论 国产复方非洛地平缓释片治疗轻、中度原发性高血压安全、有效.     

Trazodone conventional and controlled-release formulations: pharmacodynamic effects after single and repeated administration

In a double-blind study, the pharmacodynamic effects of single and repeated doses of two formulations of trazodone were compared in 14 healthy young volunteers (6 men and 8 women). They received either 100 mg trazodone conventional capsules or 150 mg controlled-release tablets daily at 08.00 hours for two 7-day periods separated by a 'wash-out' period of 2 weeks. Blood pressure standing and lying, critical flicker fusion frequency and manual dexterity were measured on Days 1 and 7 of each session before and at intervals up to 8 hours after the dose. Manual dexterity was tested by measuring the time taken to drop 50 airgun pellets down a narrow tube. A daily pre-dose blood sample was also taken for measurement of trazodone to check compliance and to confirm that steady state had been achieved. Steady state plasma concentrations were reached by Day 2 of repeated dosing on both treatments. There was a trend towards shorter duration of the expected depressant effect of trazodone on critical flicker fusion frequency and manual dexterity on Day 7 for both treatments, which was significantly different between treatments for manual dexterity (p less than 0.001): for the controlled-release tablet, manual dexterity performance was better on Day 7 than on Day 1 at all times after dosing, whereas for the conventional capsule manual dexterity was worse on Day 7 than on Day 1 until 4 and 8 hours after dosing, when performance was better than on Day 1. In this study, both formulations of trazodone caused the expected negative effects on psychomotor function. Further studies would be required to confirm the apparent advantage of the controlled-release tablet in the test of manual dexterity.     

Toxicological profile of IQG-607 after single and repeated oral administration in minipigs: An essential step towards phase I clinical trial

IQG-607 is an anti-tuberculosis drug candidate, with a promising safety and efficacy profile in models of tuberculosis infection both in vitro and in vivo. Here, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in minipigs. Single oral administration of IQG-607 (220 mg/kg) to female and male minipigs did not result in any morbidity or mortality. No gross lesions were observed in the minipigs at necropsy. Repeated administration of IQG 607 (65, 30, or 15 mg/kg), given orally, for 90 days, in both male and female animals did not cause any mortality and no significant body mass alteration. Diarrhea and alopecia were the clinical signs observed in animals dosed with IQG-607 for 90 days. Long-term treatment with IQG-607 did not induce evident alterations of blood cell counts or any hematological parameters. Importantly, the repeated schedule of administration of IQG-607 resulted in increased cholesterol levels, increased glucose levels, decrease in the globulin levels, and increased creatinine levels over the time. Most necropsy and histopathological alterations of the organs from IQG-607-treated groups were also observed for the untreated group. In addition, pharmacokinetic parameters were evaluated. IQG-607 represents a potential candidate molecule for anti-tuberculosis drug development programs. Its promising in vivo activity and mild to moderate toxic events detected in this study suggest that IQG-607 represents a candidate for clinical development.     

Monitoring paracetamol metabolism after single and repeated administration in pediatric patients with neoplastic diseases

INTRODUCTION: Paracetamol (PCM) is frequently used in pediatric patients with neoplastic disease. It is metabolized mainly by conjugation, but at therapeutic concentrations, a small fraction of the drug undergoes oxidative metabolism via cytochrome P450 forming the hepatotoxic intermediate N-acetyl-p-benzo-quinone-imine (NAPQI) which is usually conjugated with glutathione and excreted as paracetamol mercapturate and paracetamol cysteine. OBJECTIVE: The aim of this monitoring study was to evaluate PCM metabolism with minimal intervention during routine treatment with single and repeated administration in patients undergoing antineoplastic therapy. METHOD: A total of 107 urine samples collected 4-12 h after PCM administration from 29 children undergoing antineoplastic treatment, and 10 children without antineoplastic treatment were analyzed for PCM, PCM glucuronide (PCM-G), PCM sulfate (PCM-S), PCM mercapturate (PCM-M) and PCM cysteine (PCM-C). RESULTS: The median (range) percentages for metabolites in urine were: a) in children with and without chemotherapy after the first administration: PCM: 0 (0-100) and 4 (0-11)%, PCM-G: 55 (0-88) and 51 (18 - 68)%, PCM-S: 30 (0-73) and 32 (22-57)%, PCM-(M+C): 13 (0-52) and 9 (0-24)%, respectively; b) after repeated administration in children with chemotherapy: PCM: 0 (0-51)%, PCM-G: 42 (7-100)%, PCM-S: 28 (0-70)%, PCM-(M+C): 24 (0-66)%. CONCLUSION: The pattern of PCM excretion in children undergoing antineoplastic treatment regimens is highly variable. Repeated administration is associated with a significant increase in the products of oxidative metabolism. This might indicate an increase in metabolism via the hepatotoxic NAPQI.     

应用整体自显影定量技术开展的单多次给药后大鼠组织分布比较研究

目的:应用整体自显影定量技术(QWBA),比较单次和重复多次给药后大鼠体内的组织分布情况,以指导人体放射性物质平衡试验设计.方法:按15 mg ? kg-1剂量,分别灌胃给予雄性Long-Evans(LE)大鼠0,7和14次的非放射性标记药物VPS-01(qd)24h后单次灌胃给予100 μCi/15 mg?kg-1的...     

Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

1. Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2. The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163 and 123 nmol l-1 in the younger and 309, 251 and 169 nmol l-1 in the older patients. The corresponding concentrations of morphine were 8.3, 7.4 and 4.5 nmol l-1 and 6.8, 5.5 and 2.8 nmol l-1 respectively. One patient in each age group had no detectable amounts of morphine. 3. In the four children, the rectal dose was repeated 6-hourly for four doses. The plasma concentrations of codeine and morphine following the fifth dose were similar to those after the first dose. The mean AUC(0,5 h) of morphine was 1.6% that of codeine. 4. In the infants the mean plasma half-lives of codeine and morphine were 2.6 and 2.5 h. The two infants with the lowest body weights had the longest half-lives. 5. The mean morphine/codeine concentration ratio was 4.3% in the infants and 1.6% in the children, suggesting impaired glucuronidation of morphine in the former group. The hourly concentration ratios were almost identical following the first and fifth dose in the children. 6. We conclude that at the age of 6 months infants are capable of O-demethylating codeine to morphine.     

The haemodynamic effects of long term felodipine therapy in previously untreated essential hypertension

Summary Sixteen patients with previously untreated mild/moderate hypertension (WHO Stage I) were studied: 7 women and 9 men, mean age 56.2 y. Haemodynamics, central and pulmonary blood volumes were measured by radionuclide techniques and repeated after 8 weeks felodipine therapy. To achieve a target diastolic blood pressure of < 95 mm Hg 12 patients required 5 mg bid, 2 10 mg bid and 1 2.5 mg bid; 1 withdrew after 2 weeks.Mean (SD) arterial blood pressure (mm Hg) was 189/106 before, and 182/103 after 2 weeks placebo treatment and fell to 148/84 after 8 weeks felodipine therapy. Relative systemic vascular resistance fell by 19% from 2146 to 1734 dyn.s.cm^–5. There were no significant changes in heart rate, cardiac index, total blood volume, pulmonary blood volume or left ventricular ejection fraction. Plasma renin activity did not rise significantly. Short lived vasodilator side effects occurred in 7/16 patients during initial treatment and mild ankle oedema persisted in 4/16 patients.In contrast to the haemodynamic changes seen acutely with felodipine, the only sustained changes after 8 weeks therapy are reductions in systemic vascular resistance and blood pressure.     

Behavioral sensitization and alteration in monoamine metabolism in mice after single versus repeated methamphetamine administration

To address the functional alterations of monoaminergic neuronal systems in mice after single and repeated administration of methamphetamine, we examined the tissue contents of monoamines and their metabolites in addition to locomotor activity estimated by horizontal locomotion and rearing measurements. In male ICR mice, the repeated treatment regimen (intraperitoneal administration of 1.0 mg/kg methamphetamine once per day for five consecutive days) induced hyperlocomotion with a plateau level on test day 4. The initial behavioral response (within 5 min after injection) to the drug appeared to include context-dependent sensitization. Mice after the initial repeated treatment regimen showed behavioral sensitization to the same dose of methamphetamine 5 days after the final injection (test day 11). On test day 11, the first 150 min, but not the nocturnal behavior (during the dark hours), were significantly enhanced after the drug challenge. A marked reduction of the content of L-dihydroxyphenylalanine and the ratio of 3,4-dihydroxyphenylacetic acid to dopamine was observed in the striatum+accumbens of mice after single and repeated administration of methamphetamine. As for serotonin metabolism, the ratio of 5-hydroxyindolacetic acid to serotonin significantly increased in mice after single administration of methamphetamine, although it decreased in mice after repeated administration of methamphetamine. Norepinephrine metabolism (the ratio of 3-methoxy-4-hydroxyphenylglycol to norepinephrine) was not affected in the striatum+accumbens or thalamus+hypothalamus of the mice after repeated or single methamphetamine treatment. These results suggest that dopaminergic and serotonergic neuronal activities were altered during the development of behavioral sensitization. The ratio of 3-methoxytyramine to dopamine was not affected, suggesting that the methamphetamine treatment selectively inhibited the monoamine oxidase pathway for dopamine inactivation.