Influence of input rates on (±)-isradipine haemodynamics and concentration-effect relationship in healthy volunteers

Summary Since the magnitude of the response to a drug may depend upon the drug input rate, the concentration-effect relationship of the new dihydropyridine (±)-isradipine was investigated using different administration modalities.Ten normotensive healthy volunteers were given, double-blind and in a crossover fashion, isradipine as a 1 mg iv infusion, 5 mg oral solution, 5 mg standard tablet, 10 mg slow release formulation, and a placebo. Blood pressure, heart rate, and plasma isradipine concentrations were recorded for 24 h.The maximal fall in diastolic blood pressure was similar after the infusion (-11.40 mmHg), the oral solution (-15.20 mmHg), and the standard tablet (-12.50 mmHg). In healthy volunteers the slow release form had no significant effect on blood pressure. The concentration-effect plots showed an increasing slope in the order infusion, solution, and tablet, and anticlockwise hysteresis. This was partly due to marked heart rate counter-regulation, the corresponding mean maximal heart rate increases being 24, 19, and 17 beats·min^–1.The pronounced counter-regulation of the heart rate implies that a slow isradipine input rate would be more effective in decreasing blood pressure.     

Effect of captopril on renal haemodynamics and the renin-angiotensin-aldosterone and osmoregulatory systems in essential hypertension

Summary The effect of captopril on renal plasma flow (RPF), glomerular filtration rate (GFR), plasma concentrations of renin, angiotensin II (Ang II), aldosterone (Aldo) and arginine vasopressin (AVP), serum osmolality (S_osm), free water clearance , fractional urinary excretion of electrolytes and blood pressure (BP), was examined in 10 patients with moderate essential hypertension. Placebo plus furosemide was given for 6 weeks, followed by a 6-week period on captopril and furosemide. The renin-angiotensin-aldosterone system was partly blocked by captopril, resulting in a 18% fall in BP. GFR was reduced by 8% during captopril treatment, whereas RPF remained unchanged. Water loading-induced suppression of Ang II and AVP was inhibited by captopril therapy. Without affecting BP in the placebo period, water loading almost abolished the captopril-induced reduction in BP. It is concluded that non-acute captopril treatment of moderate essential hypertension reduces GFR slightly, possibly by producing dilatation of efferent arterioles. The antipressor effect of captopril is lessened during volume expansion, which may be secondary to reduced activity of the renin-angiotensin-aldosterone and osmoregulatory systems.     

Metoclopramide,domperidone and dopamine in man: actions and interactions

Summary The effects of oral doses of the dopamine antagonist antiemetics metoclopramide and domperidone on baseline and dopamine stimulated renal function and systemic haemodynamics were assessed in a placebo controlled crossover study in 9 healthy volunteers.Metoclopramide did not change baseline ERPF, GFR or FF over 2 h post dosing but it significantly reduced baseline U_NaV, U_KV, urine flow, urinary dopamine excretion, supine and erect diastolic blood pressure and supine systolic blood pressure. Domperidone and placebo did not cause these effects.Metoclopramide caused a marked rise and domperidone a small fall in plasma aldosterone concentration (PAC) but placebo was without effect. Neither antiemetic altered plasma renin activity (PRA) but a small fall occurred with placebo.Two hours after pretreatment with placebo dopamine (2 g/kg/min) increased effective renal plasma flow (ERPF), glomerular filtration rate (GFR), sodium excretion rate (U_NaV), urine flow rate, urinary dopamine excretion rate, supine systolic blood pressure and supine and erect pulse rate and decreased the potassium excretion rate (U_KV), filtration fraction (FF) and supine diastolic blood pressure.Metoclopramide pretreatment, did not attenuate the dopamine induced rise in ERPF, GFR, urine flow, urinary dopamine excretion or supine systolic blood pressure but it did attenuate the rise in pulse rate, the fall in diastolic pressure, and the antikaliuretic effect of dopamine leading to a net kaliuresis when compared to placebo. Domperidone was similar to placebo.Neither metoclopramide nor domperidone given orally caused clinically important antagonism of the renal haemodynamic effects of dopamine. However the effects of metoclopramide on blood pressure and electrolyte excretion may have clinical importance.Metoclopramide has significant pharmacodynamic effects which are probably not due to DA₂ antagonism but may be mediated by DA₁ antagonism or be non-specific.Abbreviations DA dopamine - ERPF effective renal plasma flow - FF filtration fraction - GFR glomerular filtration rate - PAC plasma aldosterone concentration - PRA plasma renin activity - UV urine flow rate - U_NaV urinary sodium excretion rate (natriuresis) - U_KV urinary potassium excretion rate (kaliuresis) - HPLC high performance liquid chromatography.     

Effect of urinary pH on the plasma and urinary kinetics of remoxipride in man

Summary The influence of urinary pH on the plasma and urinary kinetics of remoxipride in man has been studied in an open crossover trial in ten healthy male volunteers. Ammonium chloride (urinary pH 5.2) and sodium hydrogen carbonate (urinary pH 7.8) were used as pretreatments on two occasions in randomized order. On each occasion remoxipride 50 mg solution was administered orally and plasma and urinary concentrations of the drug were determined by HPLC and plasma prolactin concentrations by RIA.Remoxipride was rapidly distributed in the body according to a one-compartment model. The mean plasma elimination half-life (t_1/2) was 3.6 h in the ammonium chloride experiment and 6.2 h in the sodium hydrogen carbonate experiment. The mean plasma clearance of remoxipride was 141 and 89.9 ml·min^–1 in the acidic and alkaline conditions, respectively, and the corresponding mean renal clearances were 58.5 ml·min^–1 and 11.7 ml·min^–1. The urinary excretion of remoxipride up to 72 h after drug administration was 43.1% and 12.3% following acidification and alkalinization, respectively. Remoxipride induced a similar rapid, transient elevation of plasma prolactin under both conditions.Thus, the urinary pH has a marked effect on the elimination kinetics of remoxipride. After an overdose, treatment with ammonium chloride might be valuable in hastening elimination of remoxipride from the body.     

Central serotonergic influences on renal electrolyte and water excretion

These studies examined the effects of altered activity or levels of serotonin (5-HT) in the central nervous system (CNS) on renal water and excretion of electrolytes and on arterial blood pressure. Rats were implanted with intracerebroventricular cannulae and then continuously hydrated with a hypotonie solution in order to induce a diuresis. In two separate experimental series, samples of urine were collected before and after intraventricular (i.v.t.) administrations of drug, and the effects on the excretion of sodium were determined.

In the first experimental series, 5-HT in the CNS was manipulated by intraventricular administration of p-chloroamphetamine (PCA), an agent known to increase synaptic concentrations of 5-HT. Significant increases in urinary excretion of sodium (U _a V) and the Na/K ratio were observed after the administration of p-chloroamphetamine (200–600 μg i.v.t.). p-Chloroamphetamine in large doses also increased blood pressure and antidiuresis. The natriuresis, but not the pressor or antidiuretic responses, were attenuated by pretreatment with either p-chlorophenylalanine, an inhibitor of tryptophan hydroxylase, or fluoxetine, a drug which inhibits the release of 5-HT following the administration of p-chloroamphetamine. Thus, the natriuretic response appeared to be due to a p-chloroamphetamine produced increase of synaptic 5-HT.

A further test of the role of 5-HT in the central control of sodium excretion was made in a second experimental series where hydrated rats received intraventricular injections of 5-HT. After direct application of 5-HT to the CNS, significant increases in U _aV and in the Na/K ratio were observed, concomitant with depressor effects.

Therefore, the results of these experiments suggest that central serotonergic mechanisms are involved in the control of the excretion of sodium in the hydrated rat.     

Effect of pinacidil on renal haemodynamics,tubular function and plasma levels of angiotensin II,aldosterone and atrial natriuretic peptide in healthy man

Summary The effects of pinacidil on renal haemodynamics, tubular function evaluated by the lithium clearance technique and the plasma levels of angiotensin II (Ang II), aldosterone (Aldo) and atrial natriuretic peptide (ANP) have been evaluated in 12 healthy volunteers given pinacidil 0.1 mg/kg IV in comparison with a placebo given to 13 different healthy volunteers.Pinacidil induced significant reductions in glomerular filtration rate (–5%), renal plasma flow (–12%), urine output (–35%), urinary sodium excretion (–20%), and the fractional excretion of sodium (–17%) and potassium (–29%). Lithium clearance and proximal and distal absolute and fractional reabsorption of sodium were not significantly changed. Ang II and Aldo were significantly increased (80% and 115%, respectively) and ANP was unchanged. The mean arterial blood pressure was not significantly changed by pinacidil, but the heart rate was increased (22%).It is concluded that bolus IV injection of pinacidil in healthy subjects reduced renal blood flow, urine volume and the urinary excretion of sodium and potassium, whereas segmental tubular function was unchanged. The increase in heart rate and activation of the renin-agiotensin-aldosterone system are most likely to be secondary to stimulation of the sympathetic nervous system caused by the vasodilator effect of pinacidil.     

Dissociation of renal vasodilator and natriuretic effects of dopamine during sulpiride infusion in normal man

The effect of sulpiride on dopamine-induced changes in renal function in man has been investigated. Dopamine dose-response studies were performed in 7 healthy volunteers before and after sulpiride 200 mg i.v. The same investigations were performed in 15 healthy volunteers after pretreatment with the selective alpha-1-adrenoceptor antagonist prazosin (n = 7) and the non-selective alpha-adrenoceptor-blocker phentolamine (n = 8). Infusion of dopamine 0.25 to 8 micrograms.kg-1.min-1 resulted in a dose-dependent increase in effective renal plasma flow (ERPF) and glomerular filtration rate (GFR), and a fall in filtration fraction (FF) in 7 normal volunteers. Sulpiride had no effect on base-line ERPF or GFR and did not influence the dopamine-induced renal vasodilatation in those volunteers. It did cause a fall in the fractional sodium excretion (FENa+%) from 1.7 to 1.38, and shifted the dose-response curve of the natriuretic response to a subsequent infusion of dopamine. Sulpiride enhanced the fall in diastolic blood pressure during infusion of dopamine. In 7 other volunteers pretreated with prazosin, sulpiride did not influence base-line ERPF, GFR or FF or their response to dopamine, but the sodium excretion fell markedly (FENa+% changed from 1.13 to 0.63). Administration of sulpiride to 8 volunteers after phentolamine pretreatment 20 mg.h-1 i.v. in the first hour followed by 10 mg.h-1 i.v. resulted in a fall in sodium excretion (FENa+% from 1.09 to 0.53) without affecting ERPF or FF, and it did not affect the dose-response curve in the subsequent DA infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetics and haemodynamics of BTS 49465 and its major metabolite in healthy volunteers

Summary The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60° head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.     

Drug interactions with urate excretion in man

Summary The effects of pyrazinamide and ampicillin on the uricosuric response to probenecid and benzbromarone were studied in six normal subjects. The amount of uric acid was calculated for the 24 h volume of urine and the urate and creatinine clearances were determined for each of three urinary collection periods in order to calculate the percentage C_urate/C_creatinine.Ampicillin alone caused a significant uricosuria in the 0–2 h (p<0.025) and 8–24 h (p<0.025) periods. Benzbromarone caused a significant reduction in all the parameters.These observations suggest that high concentrations ampicillin compete with uric acid for reabsorption, but that its delayed uricosuric action can be ascribed to the binding of this dipeptide to a charge-mediated receptor site on the brush border membrane of proximal tubular cells. It would also appear that benzbromarone is secreted by the pyrazinamide-sensitive mechanism for urate secretion as it can cause a paradoxical retention of urate, but leaves the other probenecid-sensitive secretory transport process unoccupied as indicated by the fact that it does not change the kinetics of ampicillin.     

Comparison of the effects of propranolol and labetalol on renal haemodynamics at rest and during exercise in essential hypertension

Summary The effect of exercise on renal haemodynamics was examined in young patients with mild essential hypertension. Four groups of subjects were studied: 13 normotensive, healthy control subjects, and 15 untreated, 11 propranolol-treated, and 6 labetalol-treated patients. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured during four consecutive periods, a pre-exercise control period, two exercise periods with loads of 450 kpm/min and 600 kpm/min, respectively, and a post-exercise control period. In the untreated patients RPF and GFR were lower during exercise than in the normotensive control subjects, whereas no significant differences were found at rest. In the propranolol-treated patients the reduction in RPF and GFR during exercise was more pronounced than in the untreated hypertensives. In the labetalol-treated patients however, RPF and GFR were reduced only to the same degree as in the untreated hypertensives. The reduced renal blood flow in propranolol-treated patients may be attributed to a compensatory increase in sympathetic activity caused by an impaired cardiac response to exercise. The lack of reduction in renal blood flow during labetalol therapy could partly be related to alpha-adrenergic blockade in the renal vascular bed induced by labetalol, and partly to the smaller reduction in cardiac output during labetalol than during propranolol therapy.     

Effect of loperamide on jejunal electrolyte and water transport,prostaglandin E 2-induced secretion and intestinal transit time in man

Summary Jejunal perfusion was performed in 12 healthy volunteers to evaluate the dose dependent effects of loperamide on intestinal absorption, stimulated secretion and transit.In 6 volunteers intestinal perfusion of the jejunal segment with isotonic NaCl solution was followed by addition of loperamide in increasing doses (2–8 mg·l^–1). The volunteers were pretreated with 1 mg·l^–1 prostaglandin E2 (PgE2) in the perfusate before addition of 4 mg·l^–1 loperamide. Phenolsulphonphtalein (PSP) boluses (2 ml) were given to measure mean transit time (MTT).Loperamide 2 mg·l^–1 converted the minor secretion after perfusion with the standard solution (water –1.45 ml·min^–1, Na –0.09 and Cl –0.04 mmol·min^–1) to absorption (water 0.93 ml·min^–1, Na 0.23, Cl 0.25 mmol·min^–1) within 15 min. Higher doses of loperamide did not increase absorption.The addition of PgE2 induced net secretion of water (–4.48 ml·min^–1) and electrolytes (Na –0.57, Cl –0.51 mmol·min^–1). Loperamide 4 mg·l^–1 significantly diminished the PgE2-induced net secretion by approximately 50%.Loperamide dose dependently increased the MTT from 6 (2 mg·l^–1) to 13.3 min (8 mg·l^–1). MTT was still delayed 60 min after a wash out period (10.5 min).It is concluded that loperamide had a dual effect or intestinal activities stimulating absorption and prolonging intestinal transit time with rising doses.     

预防性处理骨水泥反应对血液动力学和血气参数的影响

目的观察预防性处理骨水泥反应对血液动力学和血气参数的影响。方法择期行全髋人工关节置换术成年患者160例,年龄52～83岁,ASAⅠ～Ⅲ级,随机分为4组：Ⅰ组（预防用药＋髓腔排气）,Ⅱ组（预防用药＋无髓腔排气）,Ⅲ组（无预防用药＋髓腔排气）,Ⅳ组（无预防用药＋无髓腔排气）,每组40例,4组均采用轻比重布比卡因施行单侧蛛网膜下腔麻醉（腰麻）。记录麻醉前、麻醉后5min、麻醉后10min、骨水泥灌注前、灌注即刻、灌注后3、5和10min的MAP、HR、CVP,并于骨水泥灌注前、灌注即刻、灌注后5min、灌注后10min测定血气参数。结果①与麻醉前比较,麻醉后5min 4组MAP均下降（P〈0.05）,麻醉后10min差异无显著性（P〉0.05）;与骨水泥灌注前及Ⅰ组和Ⅱ组相同时点的MAP比较,Ⅲ组和Ⅳ组在灌注即刻、灌注后3、5和10minMAP均显著下降（P〈0.01）。②与骨水泥灌注前比较,Ⅲ组和Ⅳ组在灌注即刻、灌注后3、5min HR均加快（P〈0.05）。③与骨水泥灌注前比较,在灌注即刻Ⅲ组和Ⅳ组CVP下降,Ⅳ组CVP比Ⅰ组和Ⅱ组下降（P〈0.05）。④与骨水泥灌注前比较,各组在灌注即刻PaO2均下降,在灌注后5minⅡ组和Ⅳ组PaO2仍下降;与Ⅰ、Ⅲ组比较,Ⅱ、Ⅳ组在灌注即刻、灌注后5min PaO2均下降（P〈0.05或P〈0.01）;与骨水泥灌注前比较,Ⅱ组和Ⅳ组在灌注即刻PaCO2均升高,但都在正常生理范围内（P〈0.05）。结论全髋人工关节置换术中采用轻比重布比卡因单侧腰麻,骨水泥灌注前预防性输注多巴胺和甲泼尼龙琥珀酸钠,并在骨水泥灌注时施行髓腔排气,可降低骨水泥反应对血液动力学和血气参数的影响。     

Effect of acute administration of propranolol and atenolol on baroreflex function in normal man

Summary The acute administration of the -adrenoceptor antagonists propranolol (80 mg) and atenolol (50 mg) on baroreflex function were investigated in healthy volunteers.Two h after administration both propranolol and atenolol significantly prolonged the supine R-R interval (1126, 1128 ms respectively) compared to placebo (1012 ms); systolic arterial pressure also fell (102.9, 102.0 mm Hg respectively) compared to placebo (112.6 mm Hg). Baroreflex function, assessed using glyceryl trinitrate to deactivate the baroreceptors was unchanged by these drugs compared to placebo. Baroreflex sensitivity (slope of the linear regression line relating R-R interval to systolic blood pressure) using phenylephrine to activate the baroreceptors, was also unchanged (17.2, 17.9 ms/mm Hg respectively) compared to placebo (19.9 ms/mm Hg). However both regression lines were shifted (p<0.05) to the left compared to placebo.     

Changes in plasma and urinary 11-dehydrothromboxane B2 in healthy subjects produced by oral CS-518, a novel thromboxane synthase inhibitor

Summary In 18 healthy volunteers, in a double-blind placebo-controlled study, we investigated of whether 14 days treatment with a therapeutic dose of ibopamine (3×100 mg/day p.o.), respectively its active metabolite epinine, would desensitize lymphocyte ₂- or platelet ₂-adrenoceptors, or ₁- and -adrenoceptor mediated (phenylephrine-and isoprenaline infusions, respectively), changes in systolic and diastolic blood pressure and heart rate.Ibopamine-treatment, which resulted in peak plasma epinine concentrations of 4–5 nmol·l^–1, neither affected resting heart rate or blood pressure, nor any of the - or -adrenoceptor parameters measured. Since in man in general long-term administration of - and -adrenoceptor agonists desensitizes - and -adrenoceptors, the lack of any - and -adrenoceptor desensitizing effect of ibopamine suggests that, in the dose employed (3×100 mg per day), ibopamine does not exert - or -adrenoceptor agonistic effect in humans.     

A comparative study of lisinopril and atenolol on low degree urinary albumin excretion,renal function and haemodynamics in uncomplicated,primary hypertension

Summary The presence of slightly increased urinary albumin excretion (UAE), even at levels well below levels detectable by an ordinary dipstick, has been suggested as a predictor of cardiovascular morbidity and as a reflection of the degree of overall vascular permeability.The aim of the present investigation was to study the effects of two different antihypertensive drug regimens, an ACE inhibitor and a-adrenoceptor antagonist, on the low UAE rate observed in subjects with uncomplicated, mild to moderate primary hypertension.After a 4-week placebo run-in period, 49 patients (mean age 54 y) were randomly assigned in a double blind manner either to further 4 weeks on placebo (P,n =15), 8 weeks on lisinopril (L,n = 17; 20 mg/40 mg o. d.) or 8 weeks on atenolol (A,n =17; 50 mg/100 mg o. d.). The 24-h UAE was measured every second week. At entry and after 4 weeks the glomerular filtration rate and the renal plasma flow were measured.Both drugs lowered blood pressure (BP) to a similar extent after 4 and 8 weeks of treatment; the blood pressures were 160/106 (P), 159/104 (L) and 154/103 (A) at entry, and 133/83 (L) and 134/87 (A) at the end of the study after 8 weeks. On entry the 24-h UAE in all patients ranged from 4 to 49 mg (mean 14.1 mg), and it did not differ significantly between groups. After 4 weeks the UAE during 24 h was reduced by approximately one third in the lisinopril-treated group, and by 10 % in the atenolol reated group, whereas it remained unaltered in the group on placebo. After 8 weeks the 24-hour UAE was approximately 20 % lower compared to baseline levels in the lisinopril-treated patients. In the atenolol-treated group the UAE was unaltered compared to baseline. However, none of the changes in the UAE was statistically significant, nor were there any statistically significant differences between the two antihypertensive regimens. Moreover, there were no significant effect of the lisinopril or atenolol treatment on renal function or on renal haemodynamics.It is concluded that in patients with uncomplicated, mild to moderate hypertension both an ACE-inhibitor, such as lisinopril, as well as a ₁-selective adrenoceptor blocking agent, such as ate     

The effect of alinidine (St 567) on emotionally induced tachycardia in man

Summary Experiments were performed in a randomized double blind cross-over study in 6 healthy volunteers to answer the question if alinidine, a new analogue of clonidine with a bradycardic effect directly on the sinus node, would have an effect on an emotionally — induced tachycardia. Alinidine 40 mg orally significantly (1%) reduced the tachycardia and the concomitant rise in diastolic blood pressure during the stress of performing a mental task. Forearm blood flow and the efficiency (total score in the mental task) remained unchanged by alinidine.     

The effect of atrial natriuretic peptide on plasma renin activity,plasma aldosterone,and urinary dopamine in man

Summary The acute natriuretic effect of human atrial natriuretic peptide (ANP) has been well described in man. We have now studied possible hormonal mediators of this effect.We studied six healthy volunteers on two occasions when they received either an infusion of ANP of 1.5 pmol·kg^–1·min^–1 for 30 min followed by 15 pmol·kg^–1·min^–1 for a further 30 min, or matching vehicle infusions in a randomized single-blind fashion.On the placebo day, plasma renin activity (PRA) rose from 1.26±0.08 to 1.57±0.14 ng A1·ml^–1·h^–1, while on the ANP study day PRA fell from 1.45±0.15 to 1.28±0.05 ng A1·ml^–1·h^–1 (p<0.01). No significant changes were found in plasma aldosterone concentrations or in urinary dopamine excretion.These results provide evidence that ANP suppresses renin release in man.     

Effect of one month of lactitol treatment on calcium metabolism in man

Summary The chronic use of lactitol as a food additive or laxative might adversely affect calcium homeostasis. Its effect on calcium metabolism has been examined in an open cross-over study in 12 volunteers given 20–40 g lactitol per day for one month.Compared to a control period without lactitol, the disaccharide did not alter the urinary excretion of calcium, inorganic phosphate or hydroxyproline, nor did it alter the circulating levels of calcium, phosphate, alkaline phosphatase, parathormone and osteocalcin.Chronic treatment with lactitol in laxative doses had no measurable effect on calcium metabolism in man.     

Pizotifen increases 5-HIAA urinary excretion in male healthy volunteers

Summary A single dose of 0.5 mg pizotifen or a placebo was administered to 10 healthy male volunteers in a double blind cross-over trial. 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in hourly urine samples were determined by liquid chromatography with amperometric detection. The 5-HIAA levels were strongly correlated with the HVA levels in control samples (r=0.95, p<0.001). Pizotifen produced a significant increase in the urinary 5-HIAA/HVA ratio over the 3 hours following absorption of the drug (+0.21, +0.18, +0.19, p<0.05). The increase demonstrates an interaction between pizotifen and 5-HT metabolism, which may be involved in its antimigraine effect.