Propranolol serum levels during twenty-four hours

Propranolol serum levels during a 24-hr period were determined every 2 hr in 9 hospitalized patients with angina pectoris after oral administration of 40 mg of propranolol 3 times a day. After the first, second, and third tablets the mean maximum serum propranolol concentrations averaged 118 +/- 71 ng/ml, 134 +/- 97 ng/ml, and 118 +/- 94 ng/ml and the mean minimum concentrations averaged 21 +/- 18 ng/ml, 45 +/- 25 ng/ml, and 54 +/- 34 ng/ml (+/-SD), respectively. These data show a very wide inter- and intraindividual variation in serum propranolol levels. No relationship was found between serum level and blood pressure or dose (related to body weight).     

The effect of minoxidil on blood pressure and plasma renin activity in patients with essential and renal hypertension

The effect of the new vasodilator, minoxidil, on blood pressure and plasma renin activity was studied in 21 hypertensive patients: 12 patients with essential and 9 with renal hypertension. The average maximum dosage of minoxidil was 27.9 +/- 6.0 mg/day (M +/- SD). Average duration of treatment was 84.5 days. During the observation period the average systolic blood pressure fell from 195 +/- 18 to 159 +/- 7 mm Hg (M +/- SD), and the mean diastolic blood pressure fell from 120 +/- 8.3 to 92.5 +/- 8 mm Hg (p less than 0.01). These patients had been treated earlier with other antihypertensive agents, such as reserpine, saluretics, hydralazine, alpha-methyldopa, and clonidine, without any significant reduction in blood pressure. Before treatment, plasma renin activity after resting was 59 +/- 6.4 ng/ml/16 h (M +/- SE) and after saluretics and orthostasis 89 +/- 12.7 ng/ml/16 h. After treatment, the decline in renin value after resting was statistically significant: 42.7 +/- 3.3 ng/ml/16 h (p less than 0.05), and the stimulated renin had fallen to 70 +/- 3.4 ng/ml/16 h (p greater than 0.1). A comparison of the renin stimulation values of patients with renal hypertension also revealed a significant reduction (p less than 0.01). Side effects which appeared at a daily dose of 15 to 30 mg consisted mainly of tachycardia and fluid retention and could be controlled by the administration of propranolol and chlorthalidone. In 5 women and in 1 man was observed a cosmetically disturbing, reversible hypertrichosis. Orthostatic hypotension was observed in one patient. Minoxidil is an effective antihypertensive agent. However, because of its side effects, it generally must be administered with beta-receptor blocking agents and saluretics. It is possible that its blood pressure lowering effect is due, at least in part, to a suppression of the plasma renin activity.     

Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of enalkiren (Abbott-64662, a renin inhibitor). II: A dose-ranging study in patients with congestive heart failure

This study describes the relationship between the measured effects (the acute effects on systemic hemodynamics and cardiac function) and plasma drug levels using a combined pharmacokinetic-pharmacodynamic model after i.v. infusion dosing of enalkiren (A-64662) in patients with congestive heart failure. Ascending doses from 0.003 to 1.0 mg/kg were evaluated. Timed blood samples were obtained to measure enalkiren levels in plasma. The plasma level-effect plots showed little or no hysteresis. A sigmoid Emax model was used to develop the relationship between the predicted plasma enalkiren levels and hemodynamic effects. Although hemodynamic effects were observed for most patients, random noise in the dynamics or modest net effects compared to baseline fluctuations precluded simultaneous modeling of the pharmacokinetics and pharmacodynamics for a few patients. While the sensitivity toward enalkiren's effects varied substantially among this group of patients, the studywide estimates of the EC50 for the blood pressure measures averaged about 3,500 ng/ml. The mean EC50 for systolic blood pressure (SBP, 2,744 ng/ml) was lower than those of diastolic blood pressure (DBP, 3,438 ng/ml) and mean arterial pressure (MAP, 3,371 ng/ml), suggesting that the SBP might be a more sensitive measure than the other two.     

Detection of the change point in oxygen uptake during an incremental exercise test using recursive residuals: relationship to the plasma lactate accumulation and blood acid base balance

BACKGROUND: Lovastatin is oxidized by cytochrome P4503A to active metabolites but pravastatin is active alone and is not metabolized by cytochrome P450. Diltiazem, a substrate and a potent inhibitor of cytochrome P4503A enzymes, is commonly coadministered with cholesterol-lowering agents. METHODS: This was a balanced, randomized, open-label, 4-way crossover study in 10 healthy volunteers, with a 2-week washout period between the phases. Study arms were (1) administration of a single dose of 20 mg lovastatin, (2) administration of a single dose of 20 mg pravastatin, (3) administration of a single dose of lovastatin after administration of 120 mg diltiazem twice a day for 2 weeks, and (4) administration of a single dose of pravastatin after administration of 120 mg diltiazem twice a day for 2 weeks. RESULTS: Diltiazem significantly (P < .05) increased the oral area under the serum concentration-time curve (AUC) of lovastatin from 3607 +/- 1525 ng/ml/min (mean +/- SD) to 12886 +/- 6558 ng/ml/min and maximum serum concentration (Cmax) from 6 +/- 2 to 26 +/- 9 ng/ml but did not influence the elimination half-life. Diltiazem did not affect the oral AUC, Cmax, or half-life of pravastatin. The average steady-state serum concentrations of diltiazem were not significantly different between the lovastatin (130 +/- 58 ng/ml) and pravastatin (110 +/- 30 ng/ml) study arms. CONCLUSION: Diltiazem greatly increased the plasma concentration of lovastatin, but the magnitude of this effect was much greater than that predicted by the systemic serum concentration, suggesting that this interaction is a first-pass rather than a systemic event. The magnitude of this effect and the frequency of coadministration suggest that caution is necessary when administering diltiazem and lovastatin together. Further studies should explore whether this interaction abrogates the efficacy of lovastatin or enhances toxicity and whether it occurs with other cytochrome P4503A4-metabolized 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin.     

Is calcium or ephedrine superior to placebo for emergence from cardiopulmonary bypass?

To determine whether ephedrine or CaCl2 improves hemodynamics in cardiac surgery patients emerging from cardiopulmonary bypass, three sequential doses of either CaCl2 (200 mg/dose; n = 12), ephedrine (5 mg/dose; n = 12), or placebo (n = 12) were administered in a prospective, randomized, double-blind fashion. Thermodilution volumetric catheters were used to calculate right ventricular (RV) volumes and ejection fraction. The first dose of ephedrine improved RV stroke volume from 57 +/- 3 to 63 +/- 4 mL/beat (P < 0.05) and ejection fraction from 44 +/- 2% to 49 +/- 2% (P < 0.05). Subsequent doses maintained this improvement but without further change. In contrast, placebo and CaCl2 had minimal effects on RV end-systolic volume, stroke volume, and ejection fraction. After the third injection of ephedrine, mean arterial pressure had significantly increased from 78 +/- 2 to 93 +/- 4 mmHg (P < 0.05) in contrast to insignificant increments with placebo and CaCl2. Serum ionized calcium increased by 6% to 8% after each CaCl2 bolus but remained stable in the ephedrine and placebo groups. CaCl2 failed to improve RV performance in mildly hypocalcemic patients during separation from cardiopulmonary bypass. In patients with normal preoperative ventricular function, ephedrine more effectively improved RV performance and arterial blood pressure than placebo or CaCl2, and is a suitable short-acting drug to assist separation from cardiopulmonary bypass.     

Cable grafting of the spinal accessory nerve after radical neck dissection

AIMS: To investigate the pharmacokinetic profile of the ACE-inhibitor imidapril in 10 hypertensive patients after a first single dose (10 mg) and after 28 days therapy with imidapril 10 mg once daily. METHODS: Cmax, tmax, t1/2 and AUC of imidapril and imidaprilat were obtained. ACE-activity and arterial blood pressure during imidapril were corrected by a preceding placebo-investigation. RESULTS: The AUC of imidapril was 140 (43 s.d.) ng ml(-1) h after the first dose and 123 (34 s.d.) ng ml(-1) h at steady state. AUC of the active moiety imidaprilat averaged 211 (101 s.d.) ng ml(-1) h after the first dose and 240 (55 s.d.) ng ml(-1) h at the steady state investigation. Maximal ACE-inhibition was 75% after the single dose as well as at steady state. ACE inhibition before drug intake at day 28 (i.e. trough) was 50%. The (placebo-corrected) maximal drop in diastolic blood pressure after imidapril was 22 mm Hg after the first dose and 25 mmHg at steady state. Exploratory analysis of imidaprilat plasma concentration vs effect profiles suggests a hyperbolic concentration effect relationship where data of the single dose contribute to the ascending part of an Emax-curve, whereas the plateau around Emax is maintained at steady state. CONCLUSIONS: In this group of hypertensive patients, the pharmacokinetic profile and the drop in ACE-activity as well as in blood pressure seen after a single dose of imidapril and at steady state were similar. The initial response to a test dose might therefore predict the response during chronic dosing.     

Modification of exercise performance by sharp reduction of blood pressure. A study in patients with uncomplicated hypertension

We evaluated exercise performance in 14 patients with uncomplicated essential hypertension 1 h after the administration of a single dose of placebo, nifedipine (20 mg), captopril (50 mg), and propranolol (80 mg). Drugs were administered at the same time of day following a randomized, double-blind protocol. Mean resting blood pressure (+/- SE) was 135 +/- 3 mm Hg with placebo administration, 118 +/- 4 with captopril, 110 +/- 4 with nifedipine, and 115 +/- 5 with propranolol and increased with exercise to 163 +/- 4, 146 +/- 3, 136 +/- 4, 136 +/- 4, respectively. Oxygen consumption at peak exercise and at ventilatory anaerobic threshold (VAT) was 25.2 +/- 1.1 and 18.1 +/- 1.0 ml/min/kg with placebo. Only propranolol (-2.3 ml/min/kg) decreased peak exercise oxygen consumption. Oxygen consumption at VAT was reduced by nifedipine and propranolol but unaffected by captopril. The effects on exercise capacity of blood pressure reduction in hypertensive patients are dependent on the drug utilized and are not related to the amount of blood pressure reduction. The lowered oxygen consumption at VAT observed with nifedipine and propranolol, and not with captopril, might be due to an excessive downward shift of the muscle perfusion pressure--oxygen consumption relationship which might take place during exercise.     

Altered wound arginine metabolism by corticosterone and retinoic acid

The objective of this study is to study the pharmacokinetics of imipenem-cilastatin in patients with anuria related to multiorgan failure during continuous venovenous hemodialysis (CVVHD) at a fixed blood flow rate of 60 ml/min, fixed dialysate flow rate of 20 ml/min, and drainage flow rate of 1-3 mil/min. A prospective open label study was designed in an intensive care unit in a university hospital. Six patients who required mechanical ventilation and inotropic agents and exhibited acute anuric renal failure were examined. Intravenous imipenem-cilastatin, 500/500 mg, was administered over 30 mins. Blood samples were obtained from the inlet and the outlet of the dialyzer and dialysate samples from the outlet before and at 0.0, 0.5, 1.0, 2.0, 3.0, 6.0, 9.0, and 12.0 hrs after infusion ended. The peak and trough concentrations of imipenem were 32.47 +/- 6.69 micrograms/ml and 1.12 +/- 0.46 micrograms/ml, respectively, whereas those of cilastatin were 50.05 micrograms/ml +/- 14.80 and 9.53 +/- 3.25 micrograms/ml, respectively. The half life was 2.79 +/- 0.3 hr for imipenem, and 6.67 +/- 0.93 hr for cilastatin. Total body clearance of imipenem was 89.4 +/- 17.5 ml/min, including the clearance by CVVHD of 18.7 +/- 1.2 ml/min, and corresponding values for cilastatin were 31.7 +/- 9.0 ml/min and 13.7 +/- 3.4 ml/min. In conclusion, in patients with anuria, the elimination of imipenem-cilastatin was constant during CVVHD. The recommended regimen in patients with anuria who receive CVVHD in this setting was estimated as intravenous imipenem-cilastatin, 500/500 mg, every 12 hrs.     

Region-specific localization of retinoic acid receptor-alpha expression in the rat epididymis

BACKGROUND: Nitric oxide (NO), a recognized cell messenger for activating soluble guanylate cyclase, is produced by the enzyme NO synthase in a wide variety of tissues, including vascular endothelium and the central nervous system. The authors previously reported the possible involvement of the NO pathway in the anesthetic state by showing that a specific NO synthase inhibitor, nitroG-L-arginine methyl ester (L-NAME), dose dependently and reversibly decreases the minimum alveolar concentration (MAC) for halothane anesthesia. The availability of a structurally distinct inhibitor selective for the neuronal isoform of NO synthase, 7-nitro indazole (7-NI), allowed for the possibility of dissociating the central nervous system effects of neuronal NO synthase inhibition from the cardiovascular effects of endothelial NO synthase inhibition. METHODS: The effect of two structurally distinct inhibitors of NO synthase, L-NAME and 7-NI, on the MAC of isoflurane was investigated in Sprague-Dawley rats while concurrently monitoring the animals' arterial blood pressure and heart rate. L-NAME (1 to 30 mg/kg given intravenously, dissolved in 0.9% saline) and 7-NI (20 to 1,000 mg/kg given intraperitoneally, dissolved in arachis oil) were administered after determining control MAC and 30 min before determining MAC in the presence of NO synthase inhibitor. RESULTS: L-NAME and 7-NI caused a dose-dependent decrease from isoflurane control MAC (maximal effect: 35.5 +/- 2.5% and 43.0 +/- 1.7%, respectively) with a ceiling effect observed for both NO synthase inhibitors (above 10 mg/kg and 120 mg/kg, respectively). L-NAME administration significantly increased systolic and diastolic blood pressures (maximal effect: 39.9 +/- 2.2% and 64.3 +/- 4.0%, respectively), which were not accompanied by any changes in heart rate. 7-NI administration resulted in no changes in blood pressure and a small but clinically insignificant decrease in heart rate. CONCLUSIONS: Inhibition of the NO synthase pathway decreased the MAC for isoflurane, which suggests that inhibition of the NO pathway decreases the level of consciousness and augments sedation, analgesia, and anesthesia. The MAC reduction by two structurally distinct NO synthase inhibitors supports that this is a specific effect on NO synthase. Furthermore, the action of the neuronal NO synthase inhibitor 7-NI supports an effect selective for neuronal NO synthase and also avoids the hypertensive response of generalized NO synthase inhibitors.     

Prognostic evaluation of early indicators in fulminant hepatic failure by multivariate analysis

Results of eight multicenter, randomized, placebo-controlled, double-blind, parallel-group studies were pooled to assess the efficacy of the angiotensin II-receptor blocker irbesartan over the dose range of 1 to 900 mg. A total of 2955 adults with a seated diastolic blood pressure of 95 to 110 mm Hg were randomized to treatment with oral irbesartan once daily or placebo for 6 to 8 weeks. Office blood pressure was measured at trough (24+/-3 hours after the last dose) and peak (3+/-1 hours after the last dose) by mercury sphygmomanometry. Demographic characteristics (mean blood pressure; 151/101 mm Hg; mean age, 54 years; 63% male; and 82% white) were similar across all dose groups. After the groups were pooled, antihypertensive efficacy was assessed by therapeutic response (trough seated diastolic blood pressure <90 mm Hg or a reduction from baseline of > or = 10 mm Hg) and by modeling of the maximum reductions in trough and peak seated diastolic and systolic blood pressure. Antihypertensive effects increased with increasing doses and reached a plateau at > or = 300 mg. Irbesartan 150 mg provided placebo-subtracted reductions in trough seated systolic and diastolic blood pressure of approximately 8 and approximately 5 mm Hg, respectively, with 56% of patients displaying a favorable response. In conclusion, irbesartan provides clinically significant blood pressure lowering, with a clear relationship between (log) dose and antihypertensive effect.     

Effect of diaspirin cross-linked hemoglobin on endothelin-1 and blood pressure in acute ischemic stroke in man

OBJECTIVE: For almost 50 years it has been known that hemolysed blood can increase blood pressure. Although preclinical studies suggest that this pressor response is due to an interaction of hemoglobin with endothelium-derived vasoactive substances, its mechanism in humans is unknown. We investigated the involvement of endothelin-1 in the blood pressure response to the oxygen carrier diaspirin cross-linked hemoglobin (DCLHb) in stroke patients. DESIGN: In a randomized phase II study, increasing doses of DCLHb (25, 50 and 100 mg/kg, n=8, 8 and 11, respectively) or placebo (n=26) were infused intravenously every 6 h for 72 h to patients with an acute ischemic stroke. Blood pressure and heart rate were measured every 15 min and plasma concentrations of endothelin-1, catecholamines, renin, vasopressin and atrial natriuretic peptide were measured before and 24 and 66 h after the start of the infusions. RESULTS: In the placebo group, mean arterial pressure (MAP) was 112 (109-115) mmHg (mean and 95% confidence interval) at baseline and decreased spontaneously by 11.4 (5.4-17.5) and 12.5 (5.4-19.5) mmHg after 24 and 66 h, respectively. This decrease in MAP was attenuated in patients treated with DCLHb, reaching statistical significance in the highest dose group. The plasma endothelin-1 concentration decreased slightly in the placebo group, from 4.2 (3.1-5.3) pg/ml (median and range) at baseline to 2.4 (1.9-3.7) pg/ml after 24 h (P=0.0044) and 2.8 (1.9-3.7) pg/ml after 66 h (P=0.0042), but increased dose-dependently in response to DCLHb infusion. With the highest dose of DCLHb, the plasma endothelin-1 concentration rose from 4.8 (0.1-7.8) pg/ml at baseline to 21.2 (13.4-53.2) pg/ml after 24 h (P< 0.001) and to 27.6 (11.9-47.8) pg/ml after 66 h (P< 0.001). The increases in the plasma endothelin-1 concentration and in MAP were correlated (r=0.30, P=0.02). Other vasoactive hormones were not affected by the DCLHb infusion. CONCLUSIONS: Infusion of DCLHb in patients with acute ischemic stroke was associated with a dose-dependent increase in plasma endothelin-1 concentration. This may underlie the attenuation by DCLHb of the natural decrease in blood pressure that we observed in these patients.     

Modelling of the pharmacodynamic interaction of an A1 adenosine receptor agonist and antagonist in vivo: N6-cyclopentyladenosine and 8-cyclopentyltheophylline

1. The purpose of this investigation was to develop a pharmacokinetic-pharmacodynamic model for the interaction between an adenosine A1 receptor agonist and antagonist in vivo. The adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA) and the antagonist, 8-cyclopentyltheophylline (CPT) were used as model drugs. The CPA-induced reduction in mean arterial pressure and heart rate were used as measurements of effect. 2. Four groups of eight rats each received 200 micrograms kg-1 of CPA i.v. in 5 min during a steady-state infusion of CPT at a rate of 0, 57, 114 or 228 micrograms kg-1 h-1. The haemodynamic parameters were continuously measured and frequent blood samples were taken to determine the pharmacokinetics of the drugs. 3. CPT had no influence on the pharmacokinetics of CPA and the baseline values of the haemodynamic variables. Furthermore, no clear antagonism by CPT was observed of the CPA-induced reduction in mean arterial pressure. However, CPT antagonized the effect on heart rate, and with increasing CPT concentrations, a parallel shift of the CPA concentration-effect relationship to the right was observed. 4. An agonist-antagonist interaction model was used to characterize the interaction quantitatively. On the basis of this model, the pharmacodynamic parameters of both CPA and CPT could be estimated. For CPA the values were (mean +/- s.e.): Emax = 198 +/- 11 b.p.m., EC50 = 2.1 +/- 0.7 ng ml-1, Hill factor = 2.3 +/- 0.6 and for CPT: EC50 = 3.7 +/- 0.3 ng ml-1 and Hill factor = 3.1 +/- 0.1. 5. It is concluded that the competitive agonist-antagonist interaction model may be of value to characterize quantitatively the pharmacodynamic interactions between adenosine A1 receptor ligands in vivo.     

Naltrexone: disposition, metabolism, and effects after acute and chronic dosing

The disposition of naltrexone during acute and chronic administration of 100-mg oral dose was studied in 4 subjects. Following an acute dose the mean (X) peak naltrexone plasma level was 43.6 +/- 29.9 ng/ml at 1 hr and for the major biotransformation product, beta-naltrexol, was 87.2 +/- 25.0 ng/ml at 2 hr. Twenty-four hours after the dose the X levels of naltrexone and beta-naltrexol declined to 2.1 +/- 0.47 and 17.6 +/- 5.0 ng/ml, respectively. Following chronic administration and X peak plasma levels of naltrexone and beta-naltrexol rose to 46.4 +/- 18.5 and 158.4 +/- 89.9 ng/ml at 1 hr, but by 24 hr both compounds declined to levels of the same order as in the acute state at 24 hr. Plasma levels of naltrexone and beta-naltrexol measured 24 hr after the daily doses of naltrexone throughout the study indicated that steady-state equilibrium was rapidly attained and that there was no accumulation of naltrexone and beta naltrexol in the plasma after chronic treatment on 100 mg oral doses. Biexponential kinetics were observed for naltrexone and beta-naltrexol in the first 24 hr. The half-life of naltrexone and beta-naltrexol decreased slightly from the acute to thechronic study from 10.3 +/- 3.3 to 9.7 +/- 1.1 hr and from 12.7 +/- 2.6 to 11.4 +/- 2.0 hr. The plasma levels of naltrexone declined slowly from 24 through 72 hr from 2.4 to 1.7 ng/ml, with an apparent half-life of 96 hr. The renal clearance data indicate that naltrexone is partially reabsorbed while beta naltrexol is actively secreted by the kidney. During acute and chronic naltrexone administration the mean fecal excretion was 2.1% and 3.6% while urinary excretion was 38% and 70% of the dose in a 24-hr period. Opiate antagonism to 25 mg heroin challenges was nearly complete through 48 hr after naltrexone. At 72 hr the objective responses reappeared to a greater extent than the subjective ones. Correlation coefficient (r) between naltrexone plasma levels and opiate antagonism was 0.91 and between individual half-life of naltrexone and opiate antagonism it was 0.99.     

Effect of L-arginine on systemic and renal haemodynamics in salt-sensitive patients with essential hypertension

In response to a high sodium (Na+) intake, salt-sensitive patients with hypertension retain more Na+ and manifest a greater rise in arterial pressure than salt-resistant patients. Because there is limited information regarding the role of nitric oxide (NO) in salt-sensitivity we examined the effects of L-arginine (500 mg/kg, i.v. for 30 min) on mean arterial pressure and renal haemodynamics in 21 hypertensive and five normotensive African-Americans. At the end of L-arginine infusion mean arterial pressure fell more in salt-sensitive (-11.5 +/- 2.5) than in salt-resistant (-3.7 +/- 1.5 mm Hg) and control subjects (-3.2 +/- 3.8 mm Hg). At the end of L-arginine infusion effective renal plasma flow (ERPF) increased more (P < 0.05) in controls (+108 +/- 13.9 ml/min/1.73 m2) than in salt-resistant (+55 +/- 16.0 ml/min/1.73 m2) and salt-sensitive patients (+22 +/- 21.5 ml/min/1.73 m2). This study has shown that salt-sensitive African-Americans manifest different systemic and renal haemodynamic responses to L-arginine than salt-resistant patients and controls. The fall in mean blood pressure following L-arginine was greater in salt-sensitive than in salt-resistant patients and controls, whereas the increase in ERPF was reduced in salt-sensitive compared to salt-resistant and normal subjects. The data are in keeping with the notion that a defect in NO production may participate to the genesis of blood pressure sensitivity to salt.     

Trimethoprim resistance and susceptibility genes in Staphylococcus epidermidis

OBJECTIVES: This study was performed to assess the acute effects of the new angiotensin II antagonist, candesartan cilexetil, on systemic and renal haemodynamics in patients with sustained essential hypertension [diastolic blood pressure (DBP) 95-114 mmHg]. METHODS: After 4 weeks of placebo treatment, systemic and renal haemodynamics were investigated in 17 patients with a mean age of 62 years and a mean systolic and diastolic blood pressure of 170/98 mmHg, just before (baseline) and for 4 h after administration of a single oral dose of candesartan cilexetil, 16 mg. Plasma concentrations of candesartan (the active compound formed from the pro-drug candesartan cilexetil), angiotensin II (Ang II), as well as plasma renin activity (PRA), were measured before and after dosing. RESULTS: At 2, 3 h and 4 h after dosing with candesartan cilexetil, systolic blood pressure (SBP) and DBP, as well as mean arterial pressure (MAP), were significantly lower than at baseline. The mean reduction in MAP 4 h after dosing was 8.8 mmHg (-6.5%). This effect was due to a fall in total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and cardiac output (CO) were virtually unchanged. After 4 h there was a marked reduction in renal vascular resistance (RVR) of 0.0273 mmHg x ml(-1) x min (-16%), resulting in an increased renal plasma flow of 64.9 ml x min(-1) (14%). The glomerular filtration rate was increased by 7.75 ml x min(-1) (8%), and the filtration fraction (FF) was not significantly changed. There was no apparent relationship between the changes observed in systemic and renal haemodynamic variables and plasma concentrations of candesartan. Plasma renin activity increased over the study period, but in general the patients had low PRA. Changes in plasma concentrations of angiotensin II were inconsistent between patients. CONCLUSION: A single oral tablet of candesartan cilexetil, 16 mg, induced systemic and renal arterial vasodilatation and blood pressure reduction, without compromising renal perfusion or filtration or affecting cardiac performance. Plasma renin activity which was low in general, increased over the study period, but changes in plasma concentrations of angiotensin II were inconsistent.     

Molecular analysis of the histone gene cluster of Psammechinus miliaris: III. Polarity and asymmetry of the histone-coding sequences

The Ca2+ antagonistic coronary vasodilator, Nifedipine, was sublingually administered by a dose of 30 mg to 19 patients with hypertension. Blood pressure of patients with with essential hypertension (n=14) decreased from 177 +/- 24 to 123 +/- 13 mmHg systolic and from 108 +/- 12 to 80 +/- 11 mmHg diastolic (mean +/- SD) (p less than 0.01). Plasma renin activity (PRA) increased significantly from 0.73 +/- 0.62 to 1.50 +/- 1.02 ng/ml/h (p less than 0.05). The same tendency was observed in malignant and renovascular hypertension. In primary aldosteronism (n = 2), blood pressure decreased but PRA did not increase. Hypotensive action and increased plasma renin activity by Ca2+ antagonist, Nifedipine, were clearly demonstrated in patients with hypertension.     

Hypotensive effect of an inhibitor of cholesterol synthesis (fluvastatin). A pilot study

To investigate whether fluvastatin lowers cholesterol and blood pressure in hypertensives and hypercholesterolemic patients, 23 patients followed by their medical practitioner received 40 mg fluvastatin once a day for 12 weeks. Arterial blood pressure was measured by continuous ambulatory monitoring. Total mean cholesterol (mmol/l) was lowered from 7.98 +/- 1.21 to 6.25 +/- 0.88 and the atherogenic index from 7.26 +/- 2.11 to 5.49 +/- 1.35. Mean arterial systolic and diastolic blood pressure (mm Hg) was reduced from 144.8 +/- 13.7 to 138.6 +/- 18 and from 97.3 +/- 9.1 to 92 +/- 10.8. In responders (n = 12), blood pressure decreased from 142.6 +/- 11 to 126.4 +/- 11.1 and from 99.6 +/- 7.1 to 88.3 +/- 6.5. In conclusion, fluvastatin prescribed in a dose of 40 mg/day for 3 months to 23 hypertensives and hypercholesterolemic patients lowers the cholesterol level and lowers blood pressure. Lowering of blood pressure is independent of lowering of cholesterol.     

Continuous i.v. administration of the angiotensin-converting enzyme inhibitor enalaprilat in the critically ill: effects on regulators of circulatory homeostasis

Several components are responsible for circulatory control at the central, regional, and microcirculatory level. Angiotensin-converting enzyme (ACE) inhibitors are known to act beneficially on circulation by various mechanisms. The influence of continuous i.v. administration of the ACE inhibitor enalaprilat on regulators of circulation was studied in 45 critically ill patients. According to a prospective randomized sequence, either 0.25 mg/h (group 1, n = 15) or 0.5 mg/h (group 2, n = 15) of enalaprilat or saline solution as placebo (control group, n = 15) were continuously given. Infusion was started on the day of admission to the intensive care unit (ICU) and continued for the next 5 days. From arterial blood samples, plasma levels of endothelin-1 (ET), atrial natriuretic peptide (ANP), renin, vasopressin, angiotensin-II, and catecholamines (epinephrine, norepinephrine) were measured. All measurements were carried out before infusion (= baseline values) and during the next 5 days. In both enalaprilat groups, mean arterial blood pressure (MAP) decreased similarly; heart rate (HR) and central venous pressure (CVP) did not change, and were without differences in comparison to the untreated control. Except for ET, plasma levels of all vasoactive substances exceeded normal range at baseline. Angiotensin-II plasma concentrations significantly decreased during enalaprilat infusion (0.25 mg/h: from 53.1 +/- 11.3 to 22.1 +/- 9.3 pg/ml; 0.50 mg/h: 62.1 +/- 14.4 to 17.9 +/- 7.9 pg/ml), but they remained significantly elevated in the untreated control patients. Vasopressin plasma level increased only in the control group (p < 0.01) and decreased in the patients in whom 0.50 mg/h of enalaprilat was infused.(ABSTRACT TRUNCATED AT 250 WORDS)     

The cardiovascular interaction between caffeine and nicotine in humans

In a placebo-controlled, double-blind randomized design, we investigated the cardiovascular interaction between caffeine (250 mg intravenously) and nicotine (4 mg chewing gum) in 10 healthy volunteers, both under baseline conditions and during physical and mental stress (standing up and mental arithmetic). Caffeine alone induced a significant increase in blood pressure associated with a decrease in heart rate, whereas nicotine alone increased both blood pressure and heart rate. The combination of caffeine and nicotine increased systolic and diastolic blood pressure by 10.8 +/- 2.0 and 12.4 +/- 1.9 mm Hg, respectively. This pressor response did not differ significantly from the calculated additive effects of caffeine and nicotine on blood pressure, measuring 12.9 +/- 2.0 and 14.2 +/- 2.1 mm Hg, respectively. Heart rate and forearm blood flow also showed a similar response when the combination of caffeine and nicotine was compared with the calculated sum. During physical stress (standing up), blood pressure, heart rate, and plasma catecholamines increased in the placebo test. The pressor response to standing up was less pronounced after the combination of caffeine and nicotine compared with the sum of the separate effects (combination versus sum: delta diastolic blood pressure, 24.7 +/- 1.9 versus 35.2 +/- 2.6 mm Hg [p < 0.01]; delta mean arterial pressure, 22.1 +/- 2.0 mm Hg versus 28.6 +/- 1.6 mm Hg [p < 0.05]). The plasma catecholamine response did not differ between the combination and the sum of both drugs. During mental arithmetic, blood pressure, heart rate, and forearm blood flow increased in the placebo test. The forearm vasodilator response to mental stress was attenuated by the combination of caffeine and nicotine compared with the sum of both drugs (combination versus sum: delta forearm blood flow, -0.1 +/- 0.3 versus 1.4 +/- 0.5 ml/100 ml/min [p < 0.05]). We conclude that the combined administration of caffeine and nicotine shows additive effects on cardiovascular parameters during baseline conditions but less than additive effects during sympathoadrenal stimulation.     

Concentration-response relationships for fentanyl and sufentanil in patients undergoing coronary artery bypass grafting

BACKGROUND: Concentration-response relationships for sufentanil and fentanyl are undefined in patients undergoing coronary artery bypass grafting. METHODS: Separate studies of sufentanil and fentanyl were performed in lorazepam-premedicated patients undergoing coronary artery bypass grafting. Patients were assigned randomly to groups with different prebypass effect-site opioid concentrations targeted by computer-assisted infusion. The target sufentanil concentrations were 0.4 ng/ml (group LS, n = 11), 0.8 ng/ml (group MS, n = 10), and 1.2 ng/ml (group HS, n = 11); the target fentanyl concentrations were 5 ng/ml (group LF, n = 7), 10 ng/ml (group MF, n = 7), and 15 ng/ml (group HF, n = 6). Propofol at a dose of 1 mg/kg was administered at induction of anesthesia and isoflurane was used for hemodynamic control Hemodynamics, end-tidal isoflurane concentration, and opioid concentration in arterial blood were measured at specific intervals. RESULTS: Intraoperative opioid concentrations were constant, averaging 0.71 +/- 0.13, 1.25 +/- 0.21, and 2.03 +/- 0.46 ng/ml for groups LS, MS, and HS, respectively, and 7.3 +/- 1.1, 13.2 +/- 2.2, and 24.4 +/- 5.8 ng/ml for groups LF, MF, and HF, respectively (all mean +/- SD). Isoflurane requirements were significantly greater in group LS than in groups MS and HS and greater in group LF than in groups MF and HF. The serum opioid and end-tidal isoflurane concentrations were correlated significantly. There were no intergroup differences in hemodynamics. CONCLUSIONS: Serum sufentanil and fentanyl concentrations of 0.71 +/- 0.13 ng/ml and 7.3 +/- 1.3 ng/ml, respectively, are on the steep parts of the concentration-response relationships and facilitate prebypass hemodynamic control in patients undergoing coronary artery bypass grafting with opioid-isoflurane anesthesia. Concentrations of sufentanil > or = 1.25 +/- 0.21 ng/ml and of fentanyl > or = 13.3 +/- 2.2 ng/ml minimize isoflurane requirements but do not improve hemodynamic control.