Intravenous digoxin blunts the rise of inotropy induced by isometric exercise: a noninvasive study in healthy volunteers

Nine healthy volunteers were studied with echocardiography and systolic time intervals at rest and after 3 minutes' isometric exercise by hand grip. The recordings were repeated after intravenous administration of 1 mg digoxin before and after autonomic blockade induced with atropine and propranolol. During hand grip the heart rate rose from 61 +/- 3 (mean +/- SEM) to 73 +/- 5 bpm (p less than 0.05). Afterload, i.e. left ventricular systolic wall stress, increased by 21% from 260 +/- 19 x 10(3) dyn/cm2 (p less than 0.05). Preload, i.e. left ventricular end-diastolic diameter (LVEDD), fractional shortening and the ratio of the pre-ejection period to the left ventricular ejection time (PEP/LVET) did not change, indicating increased contractility. After digoxin heart rate rose during handgrip from 50 +/- 2 to 65 +/- 5 bpm, and wall stress increased by 19% from 274 +/- 21 x 10(3) dyn/cm2 (p less than 0.01 for both). Even though LVEDD rose from 44.8 +/- 1.4 to 46.6 +/- 1.3 mm (p less than 0.05), fractional shortening decreased from 33 +/- 2 to 30 +/- 2% (p less than 0.05) and PEP/LVET increased from 0.292 +/- 0.014 to 0.327 +/- 0.014 (p less than 0.01). This suggests that autonomic reflexes due to digoxin obscured the increase in inotropy during static exercise. Autonomic blockade raised heart rate under digoxin from 50 +/- 2 to 90 +/- 4 bpm and mean blood pressure from 87 +/- 2 to 99 +/- 3 mmHg (p less than 0.001 for both) without changes in loading conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic effects of atenolol and bopindolol at rest and during isometric exercise. A non-invasive study in healthy volunteers

Circulatory effects of bopindolol, a new nonselective beta blocking agent with intrinsic sympathomimetic activity and atenolol were compared. After baseline and first dose measurements atenolol 25 mg twice daily and bopindolol 1 mg daily were given to 10 healthy young subjects. Haemodynamic measurements were made noninvasively using echocardiography and systolic time intervals. Clinical and circulatory indices were measured at baseline, after initial dose and after one week of regular treatment at rest and at isometric handgrip exercise (IE) (HG). Atenol reduced the heart rate from 62 bpm to 49 and blunted totally the HR increase during IE (p less than 0.01). Bopindolol caused a 10% fall in heart rate (NS) at rest and a 15% fall (p less than 0.05) during IE. BP fell by 6% after atenol administration and 4% after bopindolol (NS) at rest and similarly during IE. In contrast to bopindolol, atenolol caused small increases initially in left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD). A 10% increase in FS was seen at rest after bopindolol administration (NS). With the fall in heart rate the estimated cardiac output (CO) also fell from 3.66 to 3.151/min (P less than 0.05) after atenolol but rose from 3.87 to 3.93 after bopindolol (NS) during chronic treatment. Consecutively the total peripheral resistance (TPR) was increased to some extent by atenolol, whereas bopindolol reduced it at rest and during IE. A similar response was also found in systolic time intervals PEP/LVET which were reduced during bopindolol administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a Ginkgo biloba extract on forearm haemodynamics in healthy volunteers

The aim was to validate possible vasodilating effects of a Ginkgo biloba extract with a secondary aim of finding a pharmacodynamic signal relating to the active component of these extracts. We studied the effect of G. biloba extract on forearm haemodynamics in 16 healthy subjects (nine females, seven males) with a median age of 32 years (range: 21-47). The study was conducted as a randomized, double-blinded cross-over design using oral treatment with G. biloba extract (Gibidyl Forte(R) t.i.d. or placebo for 6 weeks. Forearm blood flow and venous capacity were measured by strain-gauge plethysmography. Blood pressure was measured by standard sphygmomanometry, and forearm vascular resistance (FVR) was derived. Measurements were made at baseline and after 3, 6, 9 and 12 weeks of treatment. Forearm blood flow was significantly higher during active treatment after 3 and 6 weeks as compared with placebo treatment for 3 and 6 weeks (P<0.05). Mean arterial blood pressure was unchanged, making the calculated FVR significantly lower during active treatment (P<0.02). It is concluded that oral treatment with a G. biloba extract (Gibidyl Forte(R)) is able to dilate forearm blood vessels causing increments in regional blood flow without changing blood pressure levels in healthy subjects. The increments in blood flow may be used as a biological signal for pharmacokinetic studies.     

Lack of effect of norepinephrine on cranial haemodynamics and headache in healthy volunteers

Stress is a provoking factor for both tension-type headache and migraine attacks. In the present single-blind study, we investigated if stress induced by norepinephrine (NE) could elicit delayed headache in 10 healthy subjects and recorded the cranial arterial responses. NE at a dose of 0.025 µg kg⁻¹ min⁻¹ or placebo was infused for 90 min and the headache was followed for 14 h. Blood flow velocity in the middle cerebral artery (measured with transcranial Doppler) and diameters of the temporal artery and the radial artery (measured with ultrasound) were followed for 2 h. There were no changes in these arterial parameters after NE. In both treatment groups three subjects developed delayed headaches. Thus, stress by NE infusion did not result in delayed headache.     

Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing

OBJECTIVES: We have reported previously that 80 mg valsartan and 50 mg losartan provide less receptor blockade than 150 mg irbesartan in normotensive subjects. In this study we investigated the importance of drug dosing in mediating these differences by comparing the AT(1)-receptor blockade induced by 3 doses of valsartan with that obtained with 3 other antagonists at given doses. METHODS: Valsartan (80, 160, and 320 mg), 50 mg losartan, 150 mg irbesartan, and 8 mg candesartan were administered to 24 healthy subjects in a randomized, open-label, 3-period crossover study. All doses were given once daily for 8 days. The angiotensin II receptor blockade was assessed with two techniques, the reactive rise in plasma renin activity and an in vitro radioreceptor binding assay that quantified the displacement of angiotensin II by the blocking agents. Measurements were obtained before and 4 and 24 hours after drug intake on days 1 and 8. RESULTS: At 4 and 24 hours, valsartan induced a dose-dependent "blockade" of AT(1) receptors. Compared with other antagonists, 80 mg valsartan and 50 mg losartan had a comparable profile. The 160-mg and 320-mg doses of valsartan blocked AT(1) receptors at 4 hours by 80%, which was similar to the effect of 150 mg irbesartan. At trough, however, the valsartan-induced blockade was slightly less than that obtained with irbesartan. With use of plasma renin activity as a marker of receptor blockade, on day 8, 160 mg valsartan was equivalent to 150 mg irbesartan and 8 mg candesartan. CONCLUSIONS: These results show that the differences in angiotensin II receptor blockade observed with the various AT(1) antagonists are explained mainly by differences in dosing. When 160-mg or 320-mg doses were investigated, the effects of valsartan hardly differed from those obtained with recommended doses of irbesartan and candesartan.     

The effect of exercise on large artery haemodynamics in healthy young men

BACKGROUND: Brachial blood pressure predicts cardiovascular outcome at rest and during exercise. However, because of pulse pressure amplification, there is a marked difference between brachial pressure and central (aortic) pressure. Although central pressure is likely to have greater clinical importance, very little data exist regarding the central haemodynamic response to exercise. The aim of the present study was to determine the central and peripheral haemodynamic response to incremental aerobic exercise. MATERIALS AND METHODS: Twelve healthy men aged 31 +/- 1 years (mean +/- SEM) exercised at 50%, 60%, 70% and 80% of their maximal heart rate (HRmax) on a bicycle ergometer. Central blood pressure and estimated aortic pulse wave velocity, assessed by timing of the reflected wave (T(R)), were obtained noninvasively using pulse wave analysis. Pulse pressure amplification was defined as the ratio of peripheral to central pulse pressure and, to assess the influence of wave reflection on amplification, the ratio of peripheral pulse pressure to nonaugmented central pulse pressure (PPP : CDBP-P1) was also calculated. RESULTS: During exercise, there was a significant, intensity-related, increase in mean arterial pressure and heart rate (P < 0.001). There was also a significant increase in pulse pressure amplification and in PPP : CDBP-P(1) (P < 0.001), but both were independent of exercise intensity. Estimated aortic pulse wave velocity increased during exercise (P < 0.001), indicating increased aortic stiffness. There was also a positive association between aortic pulse wave velocity and mean arterial pressure (r = 0.54; P < 0.001). CONCLUSIONS: Exercise significantly increases pulse pressure amplification and estimated aortic stiffness.     

Myocardial velocities measured during adenosine, dobutamine and supine bicycle exercise: a tissue Doppler study in healthy volunteers

Background: Dobutamine stress echocardiography (DSE) quantified by tissue Doppler (TVI) have improved the diagnostic capacity of the procedure. Quantification of other stress modalities, e.g. adenosine stress echo (ASE) and exercise stress echocardiography (ESE) are necessary for assessing any pathophysiological differences in different forms of stress. Methods: Ten healthy individuals underwent ASE, DSE, and ESE during a span of 2–5 days. Left ventricular (LV) apical images at rest and peak stress (max) were postprocessed using TVI on a GE System FiVe equipment. ECG‐derived QRS duration (QRSD, ms), heart rate (HR, bpm), TVI‐estimated basal systolic velocities (S2V, cm s^?1), ejection time (S2T, ms) and strain (S, %) were computed off‐line and compared. Longitudinal displacement imaging, tissue tracking, was also made. Results: Data for ASE, DSE and ESE during peak stress were (HR: 84 ± 12***, 142 ± 19, 137 ± 27; P<0·001) (QRSD: 92 ± 18**, 74 ± 13, 79 ± 9; P<0·05), (S2T: 307 ± 34***, 175 ± 53, 192 ± 25; P<0·001) and (S%: 26·0 ± 3·0, 21·2 ± 7·3, 22·1 ± 5·1; P = n.s.) respectively. Velocity response, registered in the LV septum at max, was lowest during ASE (7·4 ± 1·4) highest during DSE (13·0 ± 2·7; P<0·001 versus ASE) and somewhat intermediate during ESE (11·3 ± 3·5; P<0·001 versus ASE). In contrast, strain and displacement did not differ. Conclusion: ASE evokes significantly less LV systolic response compared with both DSE and ESE. Increased velocity (P<0·05 versus rest) and strain (P>0·05) response at a much lower HR indicates that adenosine has minor effects on contraction presumably secondary to vasodilatation. Powerful chronotropic response to DSE and ESE is probably prerequisite for strong velocity response at the expense of strain and displacement. TVI‐assisted stress echocardiography thereby shows different LV systolic response in healthy individuals, depending on stress modality.     

轻中度哮喘患者与健康人的运动耐量对比研究

目的 :比较轻中度哮喘患者与健康人的运动心肺功能 ,研究运动对哮喘患者肺功能的影响 ,探讨轻中度哮喘患者提高运动耐量的可行性。方法 :采用负荷递增运动方案 ,对 2 0例轻中度哮喘患者及 2 0例健康志愿者进行了运动心肺功能试验。运动前后测一秒钟用力呼气容积 (FEV1 )、用力肺活量 (FVC)、最大呼气中段流量 (FEF 2 5 %- 75 % )、最大呼气末段流量 (FEF 75 % - 85 % )、呼气流量峰值 (PEF)等 ,运动中监测心率 (HR)、每分钟氧耗量(VO2 )、每分钟二氧化碳排出量 (VCO2 )、每分钟通气量 (VE)、氧脉搏 (O2 pulse)、呼吸频率 (BF)等。结果 :运动后 ,哮喘组与正常对照组的FVC、FEV1 、PEF、FEF 2 5 %— 75 %、FEF 75 %— 85 %均有所改善 ,有统计学意义 (P <0 .0 5) ,但两组在改善的差值上无显著意义 (P >0 .0 5)。哮喘患者的最大作功、最大氧耗量 (VO2max)、最大二氧化碳排出量 (VCO2max)、最大每分钟通气量 (VEmax)均显著低于健康人 (P <0 .0 5) ,无氧阈提前出现。结论 :轻中度哮喘患者的运动能力低于健康人 ,但通过小负荷运动可改善肺功能     

Effect of L-phenylalanine supplementation and a high-protein diet on pharmacokinetics of cefdinir in healthy volunteers: an exploratory study

BACKGROUND: Upregulation of oligopeptide transport activity by dietary protein, certain dipeptides and amino acids has been reported in the rat intestine and a human intestinal cell line. OBJECTIVE: In this study, the pharmacokinetics of cefdinir were investigated after L-phenylalanine supplementation and a high-protein diet (HPD) in humans to explore changes in the activities of intestinal and renal oligopeptide transporters. METHODS: A normal-protein diet (NPD, 73.2 +/- 2.6 g/day), NPD + l-phenylalanine (7.5 g/day), or HPD (141.3 +/- 3.7 g/day) was given to six male healthy volunteers for 12 days followed by a single dose of cefdinir after an overnight fast in a randomized three-way crossover study with a 22-day washout. Blood and urine were collected over a 12-h period after administration of cefdinir. Concentrations of cefdinir in plasma and/or urine were measured by high-performance liquid chromatography. RESULTS: Plasma concentrations and urinary excretion of the drug did not change throughout the study. Physiological variables and laboratory values did not reveal any differences between the three periods except for serum and urinary nitrogen levels and serum triglyceride. DISCUSSION: A reason for the unchanged pharmacokinetics of cefdinir may be due to lower doses of L-phenylalanine and protein in humans than in animals when converting animal effective doses to humans. CONCLUSION: In humans, L-phenylalanine supplementation and HPD do not seem to upregulate intestinal and renal oligopeptide transport in the ranges of duration and dose examined.     

Rewarming of healthy volunteers after induced mild hypothermia: a healthy volunteer study

Objectives: The study compares the efficacy of two active and one passive warming interventions in healthy volunteers with induced mild hypothermia.

Methods: Eight volunteers were studied in a random order crossover design. Each volunteer was studied during re-warming from a core temperature of 35°C with each of: a radiant warmer (Fisher & Paykel); a forced air warmer (Augustine Medical), and a polyester filled blanket, to re-warm.

Results: No significant differences in re-warming rates were observed between the three warming devices. It was found that the subject's endogenous heat production was the major contributor to the re-warming of these volunteers. Metabolic rates of over 350 W were seen during the study.

Conclusions: For patients with mild hypothermia and in whom shivering is not contraindicated our data would indicate that the rate of re-warming would be little different whether a blanket or one of the two active devices were used. In the field, this may provide the caregiver a useful choice.

     

Effect of angiotensin II infusion with and without angiotensin II type 1 receptor blockade on nitric oxide metabolism and endothelin in human beings: a placebo-controlled study in healthy volunteers

BACKGROUND: Angiotensin II has been shown to induce the synthesis of endothelium-derived relaxing factor nitric oxide (NO) and endothelin in vitro. In human beings, to our knowledge, no data on NO release in response to angiotensin II and on the influence of angiotensin II type 1 receptor blockade have been published. METHODS: In a placebo-controlled study in nine healthy volunteers, angiotensin II was administered intravenously for 6 hours with and without pretreatment with valsartan, a specific angiotensin II type 1 receptor antagonist. NO (NO2 + NO3) and endothelin plasma concentrations, clearance values for inulin and paraaminohippuric acid and NO (NO2 + NO3) excretion in urine were determined. RESULTS: During angiotensin II infusion NO plasma concentrations remained unaltered compared with placebo after 3 hours: 6.66 +/- 5.49 versus 5.56 +/- 3.09 micromol/L (P = ns) but increased after 6 hours: 18.36 +/- 20.02 versus 7.13 +/- 3.87 micromol/L (P < .04). The same was noted after pretreatment with valsartan: 7.61 +/- 5.69 versus 5.56 +/- 3.09 micromol/L (P= ns) after 3 hours, and 21.70 +/- 11.51 versus 7.13 +/- 3.87 micromol/L (P = .02) after 6 hours. In urine fractional NO excretion decreased after angiotensin II infusion: 0.87 +/- 0.72 versus 0.95 +/- 0.71 (P = .5) during the first 3 hours, and 0.44 +/- 0.39 versus 0.78 +/- 0.43 (P = .01) during the following 3 hours. After valsartan pretreatment the decrease in fractional urinary NO excretion began earlier: 0.40 +/- 0.15 versus 0.95 +/- 0.71 (P = .04) during the first 3 hours, and 0.17 +/- 0.11 versus 0.78 +/- 0.43 (P = .01) during the following 3 hours. Endothelin plasma concentrations showed no difference after angiotensin II infusion with or without valsartan. CONCLUSIONS: Our observations demonstrate for the first time that angiotensin II increases NO plasma concentrations in human beings and that this response is not mediated by angiotensin II type 1 receptor. In spite of increased NO plasma levels, urinary NO excretion decreased. Endothelin plasma levels remained unchanged during angiotensin II infusion.     

Effect of folic acid and betaine supplementation on flow-mediated dilation: a randomized, controlled study in healthy volunteers

Objectives:     

The influence of the Trendelenburg position on haemodynamics: comparison of anaesthetized patients with ischaemic heart disease and healthy volunteers

This study compared the influence of the Trendelenburg position on haemodynamics in non-anaesthetized spontaneously breathing healthy volunteers and anaesthetized, mechanically ventilated patients with ischaemic heart disease scheduled for coronary artery bypass graft (CABG) surgery. Placing the anaesthetized patients scheduled for CABG surgery in the Trendelenburg position resulted in a significant increase in cardiac output and mean arterial pressure and a non-significant decrease in heart rate. In contrast, in the non-anaesthetized healthy volunteers, heart rate increased significantly but both cardiac output and mean arterial pressure changed non-significantly. Further studies will be needed to evaluate the haemodynamics of the Trendelenburg position.     

Effect of modified bridge exercise on trunk muscle activity in healthy adults: a cross sectional study

Design

This is a cross-sectional study.

Investigation of cerebral haemodynamics by near-infrared spectroscopy in young healthy volunteers reveals posture-dependent spontaneous oscillations

Autonomic reflexes enable the cardiovascular system to respond to gravitational displacement of blood during changes in posture. Spontaneous oscillations present in the cerebral and systemic circulation of healthy subjects have demonstrated a regulatory role. This study assessed the dynamic responses of the cerebral and systemic circulation upon standing up and the posture dependence of spontaneous oscillations. In ten young healthy volunteers, blood pressure and cerebral haemodynamics were continuously monitored non-invasively using the Portapres and near-infrared spectroscopy (NIRS), respectively. Oscillatory changes in the cerebral NIRS signals and the diastolic blood pressure (DBP) signal have been identified by the fast Fourier analysis. Blood pressure increased during standing and returned to basal level when volunteers sat on a chair. The mean value of cerebral tissue oxygen index (TOI) as measured by NIRS did not demonstrate any significant changes. Oscillatory changes in DBP, oxyhaemoglobin concentration [O2Hb] and TOI showed a significant increase when subjects were standing. Investigation of the low frequency component (approximately 0.1 Hz) of these fluctuations revealed posture dependence associated with activation of autonomic reflexes. Systemic and cerebral changes appeared to preserve adequate blood flow and cerebral perfusion during standing in healthy volunteers. Oscillatory changes in [O2Hb] and TOI, which may be related to the degree of cerebral sympathetic stimulation, are posture dependent in healthy subjects.     

塞克硝唑胶囊健康人体生物等效性研究

目的研究塞克硝唑胶囊在健康志愿者中的生物等效性。方法21名男性健康志愿者随机交叉单次空腹服用试验制剂塞克硝唑胶囊和参比制剂塞克硝唑片剂。用高效液相色谱法测定血清中塞克硝唑的药物浓度。结果受试者单剂口服1000mg塞克硝唑试验药和对照药后,主要药动学参数Cmax分别为(22.69±3.60)和(23.29±3.62)mg/L;Tmax分别为(1.18±0.49)和(1.15±0.65)h;t1/2β分别为(26.43±5.77)和(27.08±5.46)h;AUC0-t分别为(701.12±123.89)和(709.93±89.06)mg·h/L;AUC0-∞分别为(761.14±147.96)和(773.71±108.23)mg·h/L。试验制剂对于参比制剂的平均相对生物利用度AUC0-∞为(98.38±12.83)%。结论受试者单剂空腹给药后塞克硝唑在体内的过程符合二室模型,AUC0-t、AUC0-∞及Cmax经统计学处理,表明试验制剂塞克硝唑胶囊和参比制剂塞克硝唑片具有生物等效性。     

Effect of fluconazole on the pharmacokinetics of halofantrine in healthy volunteers

Background: Halofantrine, an antimalarial drug used in endemic areas such as the tropics is mainly metabolized by CYP3A4 to the active metabolite N‐desbutylhalofantrine. Fluconazole, an antifungal agent and an inhibitor of CYP3A4 is an established part of the therapy in HIV patients, who in turn are prone to malaria in the tropics. This study investigated the effect of fluconazole on the pharmacokinetics of halofantrine after concurrent administration of the two drugs. Methods: The effect of fluconazole on the pharmacokinetics of the antimalarial drug halofantrine was evaluated in 15 healthy volunteers in a Latin Square crossover design. The subjects received a single oral dose of 500 mg halofantrine hydrochloride alone or with 50 mg fluconazole after an overnight fast. Venous blood samples were collected during the next 336 h and analysed by HPLC for halofantrine and its active metabolite N‐desbutylhalofantrine. Results: Co‐administration of fluconazole did not alter the pharmacokinetics of halofantrine significantly with the exception of elimination t_1/2 that was significantly increased by 25% (P < 0·05). In contrast, fluconazole significantly altered the pharmacokinetic parameters of the active metabolite by reducing C_max, AUC and metabolite ratio (N‐desbutylhalofantrine/halofantrine) between 35 and 41% (P < 0·05) while increasing t_max by 50%. The 90% confidence intervals of the ratio of the geometric means (with/without fluconazole) were contained within 80–125% for halofantrine but outside this range for N‐desbutylhalofantrine. Conclusion: The decreased plasma concentrations of the metabolite are presumably caused by metabolic inhibition of CYP3A4 by fluconazole. Although the therapeutic consequences of this interaction are not clear caution should be exercised when co‐administering both drugs to avoid accumulation and subsequent cardiotoxic effects of halofantrine.