Effect of microgravity on the pharmacokinetics of Ibuprofen in humans

The pharmacokinetics of ibuprofen were studied under microgravity (μG) conditions and compared with those at normal gravity (1G) in humans. Six healthy human volunteers were given 600 mg oral dose ibuprofen during 1-day simulated μG antiorthostatic bed rest position, then at normal position (1G) in a sequential design with 7 days washout time. Saliva and plasma samples were obtained up to 8 hours after dosing. Ibuprofen was not detected in all saliva samples. Pharmacokinetic parameters in plasma were calculated by either noncompartmental analysis or a 1- compartment model using the Kinetica program. Absorption kinetic parameters were then predicted by ADAM and PE modules using the Simcyp program. Results have showed an increased rate of ibuprofen dissolution and absorption and hence faster onset of action under μG conditions. However, rate of drug elimination and bioavailability was not affected by μG, suggesting no need for dose adjustment.     

Effect of physical exercise on the pharmacokinetics of digoxin during maintenance treatment

Blood samples were taken repeatedly and urine was collected for digoxin assays on two occasions from 12 healthy male volunteers after an oral maintenance dose of digoxin. On one occasion the subjects exercised intermittently on a bicycle ergometer for 8 h after the dose. On the other occasion they rested in the supine position during the study period. Thirty and 45 min after the intake of digoxin, the serum digoxin concentration was significantly higher during exercise compared with rest, indicating increased absorption rate during exercise. Two and 4 h after the intake of digoxin, the serum digoxin concentration was significantly lower during exercise than during rest. Furthermore, the intermittent bicycle exercise decreased the renal excretion of digoxin during the study period. It also increased the steady state digoxin concentration measured after a terminating standardized period of rest. The most probable reason for these changes in the pharmacokinetics is a previously described increased binding of digoxin to exercising muscles. According to the results, there is reason to believe that the daily physical activity performed by digoxin-treated patients will determine to some extent the body content of digoxin. Changes in activity from day to day may therefore cause variations in the effect of the drug.     

Effect of exercise on the serum level and urinary excretion of tetracycline,doxycycline and sulphamethizole

Summary The serum level and urinary excretion of sulphamethizole, tetracycline and doxycycline were studied in healthy volunteers subjected to intensive exercise and bed rest in a cross-over trial. Each group consisted of 7–8 subjects. The exercise or bed rest began 15 min before oral administration of the drug and was continued for the following 4 hours. During exercise serum drug concentration and the area under the serum concentration-time curve for each agent was significantly higher (p<0.05) than the corresponding values at rest. Exercise greatly suppressed the renal excretion of tetracycline and doxycycline, but the decrease alone appeared insufficient to account for the pronounced increase in serum drug concentration. Total drug excretion in urine was unchanged. Thus, it seemed most unlikely that overall absorption from the gastrointestinal tract had been altered by exercise. However, the rate of absorption appeared to be more rapid in the exercise than in the rest period. Marked haemoconcentration was not produced by the exercise. In addition to changes in absorption and elimination rates, alteration in the volume of distribution might contribute to the higher serum drug concentration during exercise. Therefore, the level of physical activity should be considered in the interpretation of pharmacokinetic data both in clinical practice and in pharmacokinetic studies.     

Factors influencing the absorption and disposition of mecillinam and pivmecillinam in man

1 In a pharmacokinetic study in six volunteers peak serum mecillinam concentrations were proportional to the oral dose of pivmecillinam at two dose levels of 200 and 400 mg.

2 Effects of bed rest, probenecid and a 6 day course of treatment with pivmecillinam on serum mecillinam concentrations after an oral dose of pivmecillinam (two 200 mg capsules) have been investigated.

3 Resting subjects had lower peak serum levels and a decreased rate of clearance than moderately active subjects, changes which are similar to those previously reported for benzylpenicillin.

4 Pretreatment with probenecid produced significantly higher serum mecillinam levels, a longer serum antibiotic half-life and a decreased rate of drug clearance which suggests that mecillinam is actively excreted by kidney tubules.

5 Plasma mecillinam level profiles obtained after the first dose of a 6 day treatment period were not significantly different from corresponding values after the first dose on the seventh day which indicates that each dose of mecillinam is eliminated in healthy young adults before succeeding doses are taken.

     

Pharmacokinetic and pharmacodynamic drug interactions between digoxin and macrogol 4000, a laxative polymer, in healthy volunteers

AIMS: The aim of this study was to examine the bioequivalence between a single oral dose of digoxin administered alone and with a coadministration of macrogol 4000 (a laxative polymer) in 18 healthy volunteers. METHODS: This was an open, randomised, two-way cross-over study, with a single dose oral administration of 0.5 mg digoxin administered alone or in combination with macrogol 4000, 20 g day-1 during 8 days. Pharmacokinetics of digoxin, heart rate and PR ECG interval at rest were assessed. RESULTS: Macrogol 4000 coadministration was associated with a 30% decrease of digoxin AUC and a 40% decrease in its Cmax (P<0.05). Digoxin tmax and t1/2,z were not significantly altered. Heart rate and PR interval did not differ during the two therapeutic sequences, digoxin alone and digoxin in combination. CONCLUSIONS: Macrogol 4000 coadministration interacts with single-dose digoxin pharmacokinetics. This is most likely due to a reduction of the intestinal absorption of digoxin. However, there was no consequence of this interaction on heart rate and AV conduction.     

Dose-response relationship and duration of action of acebutolol / investigations on heart rate behaviour and ischemic ST-segment depression

1. The dose-response relationship and duration of action of 3'-acetyl-4'-(2-hydroxy-3-isopropylaminopropyl)-butyranilide (acebutolol, Prent) were determined under double-blind conditions in 9 volunteers using heart rate at rest and during exercise as a test parameter. 2. The effect of 200 mg of acebutolol on ischemic ST-segment depression, heart rate, and blood pressure was investigated in 10 patients with coronary heart disease. 3. Heart rate at rest and while standing was most markedly reduced in the volunteers 3 h following ingestion of acebutolol 300 mg. 100 and 300 mg lowered heart rate during exercise by 9.9 and 18.9%, respectively. No significant additional effect was achieved by increasing the dosage to 500 mg. 4. 24 h after single oral doses of 300 and 500 mg of acebutolol, nearly 50% of the substance's activity was still evident. 5. In patients with coronary heart disease, maximum heart rate during exercise 3 h after oral intake of 200 mg declined by 13%. The heart rate sum during ergometry fell by 11.2%. Systolic blood pressure at rest and during exercise also was lower. 6. A single oral dose of 100-300 mg of acebutolol consistently reduces heart rate during exercise as well as exercise-induced myocardial ischemia. Since the drug remains active over a 24-h period, administration once daily should provide an adequate therapeutic effect in many patients.     

Comparison of intra-arterial and indirect blood pressures at rest and during isometric exercise in hypertensive patients before and after metoprolol.

1. Blood pressure was measured both directly and indirectly in seven hypertensive patients before and after a single oral dose of 100 mg metoprolol, at rest and during sustained handgrip. 2. Intra-arterially measured systolic and diastolic blood pressure increased linearly with time during sustained handgrip at 50% of maximal voluntary contraction. This linearity persisted for 60 s or more in most cases. Heart rate increased linearly for the first 30 s. 3. Indirectly measured blood pressure using an observer bias minimizing Auto-Manometer, under-read systolic and over-read diastolic pressure both at rest and during handgrip. 4. By exact timing of recorded values during handgrip and linear extrapolation (or interpolation) from base-line readings, mean values at 30 and 60 s of handgrip were calculated. The relationship between direct and indirect values remained the same at base-line and 30 s of handgrip. At 60 s of handgrip, this was true only for diastolic pressure. For systolic pressure, indirect and direct values almost coincided. 5. After metoprolol, directly recorded pressure fell slightly (7--12 mm Hg, 0.02 less than P less than 0.10), both at rest and during handgrip, and heart rate fell by 15--18 beats/min (P less than 0.01). The systolic blood pressure and heart rate effect of metoprolol at 1 min handgrip correlated with peak plasma drug levels. Indirectly measured blood pressure did not change significantly. 6. The rate of rise in heart rate and blood pressure from base-line to 60 s handgrip was not significantly influenced by metoprolol.     

Influence of simulated weightlessness on the intramuscular and oral pharmacokinetics of promethazine in 12 human volunteers

The National Aeronautics and Space Administration (NASA) recommends using promethazine to prevent and treat space motion sickness, but pharmacologic responses in space and on Earth are different. Twelve volunteers were given 50 mg promethazine orally or intramuscularly before and after 48 hours of bed rest to simulate weightlessness. The maximum measured plasma concentration (C(max)), time to C(max) (t(max)), and area under plasma concentration versus time curve from 0 to infinity (AUC(inf)) were determined, and the bioequivalence was tested between bed-rest and ambulatory status for the intramuscular and oral routes as well as between both routes for bed-rest and ambulatory position. Simulated weightlessness did not influence the ratio AUC(bed rest)/AUC(ambulatory) after intramuscular injection, whereas a significant increase (26%) in the ratio was seen after oral administration, probably because of a prolonged contact time between promethazine and the intestinal wall associated with an increase in the intestinal transit time. The AUC was 3-fold higher when the drug was administered by the intramuscular route during both positions. Thus, intramuscular administration could be a good alternative to the oral route.     

The effect of propranolol, prindolol, practolol and verapamil versus placebo on exercise induced tachycardia in patients with ventricular preexcitation.

Propranolol, prindolol, practolol and verapamil have been given orally in a fixed dose to subjects with preexcitation syndrome in a cross over study. The effect on exercise induced tachycardia, prevention of tachyarrhythmias and normalization of heart rate after exercise was investigated. Propranolol, practolol and prindolol significantly (p less than 0.01-0.05) reduced the heart rate at rest and during exercise and favourably influenced the normalization of the heart rate after exercise. The effect on effort tolerance (work done till the submaximal heart rate was reached) was significantly better after propranolol (versus prindolol and verapamil) and practolol (versus verapamil) only. Verapamil showed a consistent effect only given intravenously in paroxysmal tachycardia while in the majority of patients there was no difference between oral verapamil and placebo.     

Chronopharmacokinetic study of valproic acid in man: comparison of oral and rectal administration

Circadian stage-dependent changes of valproic acid (VPA) kinetics was examined after rectal administration comparing after oral dosing. Eight healthy volunteers took a single oral or rectal dose of VPA 400 mg, in a form of sodium valproate, on two occasions, at 8:30 A.M. or 8:30 P.M. Subjects were synchronized with diurnal activity and nocturnal rest as their usual life under standardized meal conditions. After oral administration, mean total VPA concentrations in plasma were significantly higher in the morning than in the evening during the absorption phase. Cmax tended to be higher, tmax was shorter (P less than 0.05) and absorption rate constant (ka) tended to be larger (0.05 less than P less than 0.1) for VPA in the morning than in the evening, although no difference was demonstrated in other pharmacokinetic values between morning and evening trials. After rectal administration, no significant difference was demonstrated in VPA kinetics between morning and evening trials. The rectal administration might have an advantage to eliminate the time-dependent changes of VPA kinetics. Thus the current practice of giving a rectal dose seems to be justified because the time-dependent changes in VPA kinetics observed after oral administration may be reduced without compromising therapeutic efficacy.     

Rapid reduction of blood pressure with acute oral labetalol.

1 The effect of acute oral administration of labetalol on intra-arterial pressures in a group of ten hypertensive patients has been evaluated. 2 A single dose of 200 mg labetalol produced a significant reduction in systolic and diastolic pressures within 1 h of administration. 3 Within 24 h of initial administration, 200 mg three times daily produced a significant reduction in ambulant arterial levels of systolic pressure for 21 h and diastolic pressure for 14 h in the day. 4 Acute therapy lowered resting levels but there was no significant reduction in systolic pressure during either isometric or dynamic exercise. 5 Acute therapy was not associated with any significant postural hypotension.     

髋关节置换与骨折内固定术治疗老年股骨颈骨折的效果对比

目的比较髋关节置换与骨折内固定术治疗老年股骨颈骨折的临床效果。方法选取本院48例老年股骨颈骨折患者,随机均分为髋关节置换组（全髋关节置换术）和骨折内固定组（切开复位内固定术）,比较两组患者的手术时间、术中出血量、术后卧床时间、住院时间、临床疗效、并发症发生率和再手术率的差异。结果两组患者手术时间、术中出血量和住院时间比较差异无统计学意义（P〉0．05）：髋关节置换组患者的术后卧床时间显著短于骨折内固定组（火0．05）。Harris评分示髋关节置换组优良率为87．5％,显著高于骨折内固定组的62．5％（P〈0．05）。髋关节置换组的并发症发生率（12．5％）和再手术率（0）显著低于骨折内固定组（41．9％及37．5％）（P〈0．05）。结论髋关节置换术治疗老年股骨颈骨折患者效果确切．能显著缩短术后卧床时间,临床疗效好．并发症发生率低。     

The effect of omeprazole on gastro-oesophageal reflux and symptoms during strenuous exercise

BACKGROUND: Strenuous exercise exacerbates gastro-oesophageal reflux and symptoms and this may be diminished by antisecretory medication with omeprazole. METHODS: Fourteen well-trained athletes (13 men, one woman), who indicated suffering from either heartburn, regurgitation or chest pain during competition running, performed two experimental trials at 2-week intervals using a randomized, double-blind, placebo-controlled crossover design. During the 6 days preceding the trial and on the trial day itself either 20 mg of omeprazole or a placebo was administered. Two hours after a low-fat breakfast and 1 h after the last study dose, the trial started with five successive 50-min periods: rest, three running periods on a treadmill, and recovery. Reflux (percentage time and number of periods oesophageal pH <4) was measured with an ambulant pH system during these periods. RESULTS: Compared to rest, reflux lasted significantly longer and occurred more frequently during the first running period, irrespective of the intervention, whereas during the second running period this effect was only observed with the placebo. Reflux occurred for longer and more frequently with the placebo than with omeprazole, but this was significant during the first two running periods only. Seven subjects reported heartburn, regurgitation and/or chest pain during exercise, irrespective of the intervention. Only a minority of the symptom periods was actually associated with acid reflux and in all cases this concerned periods with heartburn. CONCLUSIONS: Running-induced acid reflux, but not symptoms, were decreased by omeprazole, probably because most symptoms were not related to acid reflux.     

宫颈环扎术加卧床休息治疗宫颈机能不全的临床研究

目的：探讨宫颈环扎术加卧床休息治疗宫颈机能不全的效果。方法：回顾性分析34例宫颈机能不全病人,26例行宫颈环扎术＋卧床休息,8例行保守性治疗（卧床休息）,分析两组的未足月胎膜早破率、新生儿存活率。结果：手术治疗组来足月胎膜早破18例（69．2％）,新生儿存活19例（73．8％）;保守治疗组未足月胎膜早破5例（62．5％）,新生儿存活4例（50．0％）,明显低于手术治疗组（P〈0．05）。结论：宫颈环扎术＋卧床休息治疗宫颈机能不全可延长妊娠时间,提高新生儿存活率。     

Effect of nifedipine on plasma catecholamines in man at rest and during exercise

Summary Blood pressure, heart rate, and plasma catecholamine concentrations were measured in 9 normotensive volunteers during a randomized cross-over study of oral nifedipine (10 mg×5) and placebo; measurements were made at rest and during maximal anaerobic exercise. At rest nifedipine reduced blood pressure and increased heart rate and plasma noradrenaline, whereas plasma adrenaline did not change. During exercise, the blood pressure response was similar in nifedipine and placebo treated subjects; however, heart rate was significantly higher with nifedipine. Plasma noradrenaline increased more during exercise in nifedipine-treated subjects. By contrast, nifedipine inhibited the increase in plasma adrenaline induced by exercise.The results suggest that peripheral vasodilatation induced by nifedipine is responsible for increased sympathetic nerve activity, both at rest and during exercise, and that nifedipine inhibits adrenaline secretion in man.The data were presented in part at the Symposium: Calcium entry blockers and tissue protection, Rome, 1984     

瑞舒伐他汀钙早期应用治疗急性心肌梗死的临床疗效

目的：探讨早期应用瑞舒伐他汀钙治疗急性心肌梗死的临床价值。方法选取我院2009年5月～2010年12月间共173例临床确诊为急性心肌梗死的患者,随机分为治疗组（91例）和对照组（82例）,其中对照组的患者仅予常规处理,如镇静、止痛、对症治疗、卧床休息等,治疗组的患者在常规处理的基础上予每天口服10mg瑞舒伐他汀钙进行治疗。随访时间为1年,随访内容包括患者的存活率和再次心性事件发生率。结果对两组随访结果进行比较,治疗组的1年存活率明显高于对照组,差异有统计学意义（P＜0.05）,而再次心性事件发生率则明显低于对照组（P＜0.05）。结论在急性心肌梗死早期应用瑞舒伐他汀钙,可以显著改善患者预后,提高患者生存率,值得临床应用。     

维药方剂尿通卡克乃其的躯体依赖性评价

目的研究尿通卡克乃其的躯体依赖性作用,评价其安全性。方法采用大鼠自然戒断和催促戒断实验进行躯体依赖性实验。大鼠自然戒断实验,恒量给药30d,观察给药期间和停药后大鼠的一般状况和体质量变化;大鼠催促戒断实验,递增给药14d,给药第13天采用自主活动实验,测定大鼠的活动性,末次给药后2h,腹腔注射盐酸纳洛酮,评价躯体戒断症状。结果在大鼠自然戒断实验中,尿通卡克乃其低、中、高剂量组给药期间以及停药后大鼠未出现明显戒断反应和体质量下降现象;催促戒断实验中尿通卡克乃其低、中、高剂量组给药期间以及停药后大鼠未出现体质量明显下降现象,递增给药13d时,尿通卡克乃其高剂量组明显降低大鼠活动次数、活动总时间、修饰次数以及增加排便粒数,腹腔注射盐酸纳洛酮戒断后,尿通卡克乃其高剂量组的120min总评分明显升高,大鼠出现显著性催促戒断反应症状。结论尿通卡克乃其在正常口服剂量范围内,致依赖性风险低,临床应用较安全。     

Alpha- and beta-adrenoceptor blocking properties of labetalol in renin release.

The effect of labetalol, an alpha- and beta-adrenergic receptor blocking antihypertensive, on plasma renin activity (PRA) and the hemodynamics of healthy volunteers at rest and during an ergometric exercise test was studied. Oral doses of 200 and 400 mg labetalol were tested against a placebo in a crossover manner. The labetalol plasma concentrations were determined. Systolic and diastolic blood pressures in the supine position decreased after 400 mg labetalol as did the response of the heart rate to exercise. The lower dose decreased the resting heart rate, but had no effect on the heart rate during exercise. The ergometric exercise induced an increase in PRA which was partly inhibited after 200 mg labetalol in a manner similar to that induced by beta-blockers in our earlier studies. After 400 mg labetalol PRA was already increased at one hour at sitting rest and this higher basal level was maintained for four hours. After this higher dose of labetalol the reaction of PRA to exercise was not significantly inhibited. In renin release the vasodilating alpha-blockade thus dominated the beta-blocking property of labetalol at the dose which decreased the blood pressure.     

Lack of negative inotropic effects of the new calcium antagonist Ro 40-5967 in patients with stable angina pectoris.

We screened the antiischemic, hemodynamic, and inotropic effects of different dosages of the new calcium channel blocker Ro 40-5967 in 65 patients with stable effort-induced angina pectoris. In a double-blind way, patients were randomized to recieve a single oral dose of 50, 100, or 200 mg Ro 40-5967 or placebo, given as a drinking solution. Left ventricular ejection fraction (LVEF), blood pressure (BP), and heart rate (HR) were measured at rest and during a supine bicycle exercise test on day 0 (baseline) and 2 h after drug intake on day 1. Twenty-four hours later, the bicycle exercise test was repeated. Ro 40-5967 improved exercise duration and resting LVEF. After 200 mg, exercise time increased significantly from 8.4 +/- 0.8 min (mean +/- SEM) to 9.6 +/- 0.7 min (p = 0.018), and LVEF at rest increased from 54.5 +/- 2.2 to 58.1 +/- 2.6% (p = 0.045). Time to 0.1 mV ST-segment depression increased significantly from 4.3 +/- 0.8 to 5.5 +/- 0.9 min in the 100-mg group (p = 0.013) and from 4.3 +/- 1.3 to 5.4 +/- 1.5 min in the 200-mg group (p = 0.027). Maximum ST-segment depression decreased significantly at all dose levels (p = 0.01), with the maximum decrease noted in the 200-mg group (from 0.21 +/- 0.03 to 0.15 +/- 0.02 mV, p = 0.004). BP, HR, and rate-pressure product did not change significantly at rest or at maximum exercise. A single dose of Ro 40-5967 has antiischemic properties in patients with stable angina pectoris, with maximum effects obtained after 200 mg. No signs of negative inotropy were noted, and the drug was well tolerated.     

Dissociation between duration of plasma catecholamine and blood pressure responses to beta-adrenergic blockade in normotensive subjects during physical exercise

Summary The influence of acute and chronic treatment with the adrenergic beta-receptor blocking agent propranolol (P) on blood pressure (BP), heart rate (HR) and plasma catecholamine concentration (CA) was studied in 7 normotensive healthy volunteers, and in 5 normotensive patients with cardiac neurosis, at rest, during physical exercise and after sudden withdrawal of the drug. The first oral dose of P 120 mg as well as chronic treatment (3×80 mg/day for 3 months) caused a significant reduction in HR and supine BP. Resting values of CA were not changed. After sudden withdrawal of the long-term therapy with P, supine BP and HR returned to normal, and again, resting levels of CA remained unchanged. A physical exercise test, performed 2 1/2 days after withdrawal of the betablocker, was not indicative of a transient sympathetic hyper-response. Striking effects of the drug on CA were observed during acute and chronic treatment with P when physical exercise was performed (bicycle ergometer, 150 W). Exercise values of CA were about twice as high during P treatment as without the drug, when the exercise test was performed 2 h after the first oral dose. At the same time, however, exercise BP and HR were significantly reduced. Similar reactions during the exercise test were also seen during chronic treatment with P, when the test was performed 2 hours after the last dose of the drug. But, when the exercise test was undertaken during chronic treatment 8 h after drug intake, the drug effect on CA had disappeared, whereas the effects on BP and HR still were present. The dissociation during chronic treatment between the effect on the duration of plasma CA and that of the pharmacodynamic responses to beta-adrenergic blockade with P is the principal finding of the study. A hypothesis is offered for interpretation of the observations. The time interval between measurement of drug effect and drug intake must be carefully observed in assessing different or controversial drug responses.