Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension.

BACKGROUND: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. METHODS: In 569 patients with mild-to-moderate hypertension, blood pressure (BP), plasma renin activity (PRA) and plasma renin concentration (PRC) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren (150, 300 or 600 mg), irbesartan 150 mg or placebo. RESULTS: Aliskiren 150, 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP (SBP) from baseline (p < 0.001 vs. placebo). Aliskiren 150, 300 and 600 mg significantly reduced geometric mean PRA by 69%, 71% and 75% from baseline respectively (p < 0.05 vs. placebo). Irbesartan 150 mg significantly increased PRA by 109% (p < 0.05 vs. placebo). Aliskiren dose-dependently increased PRC from baseline by 157%, 246% and 497%, at 150, 300 and 600 mg respectively, compared with a 9% decrease with placebo (p < 0.05). PRC increased significantly more with aliskiren 300 and 600 mg compared with irbesartan 150 mg (105%; p < 0.05). Regression analysis showed no significant correlations between baseline PRA and changes in SBP in any of the treatment groups, but interestingly, the slopes of the regression lines between changes in SBP and log-transformed baseline PRA were +2.0 for placebo and -1.5, -1.8 and -2.3 for aliskiren 150, 300 and 600 mg respectively. The slope for irbesartan 150 mg (-1.4) was similar to that for aliskiren 150 mg. CONCLUSIONS: Aliskiren reduces SBP and PRA and increases PRC dose-dependently. In contrast, irbesartan reduces SBP but increases both PRC and PRA. As PRA is a measurement of angiotensin I-generating capacity, PRA can be used for measuring the ability of an antihypertensive agent to prevent the generation or action of Ang II, either directly (renin inhibitors, beta-blockers, central alpha(2)-agonists) or indirectly (AT(1)-receptor blockers, ACE inhibitors).

Comparison of plasma and saliva concentrations of levetiracetam following administration orally as a tablet and as a solution in healthy adult volunteers.

OBJECTIVE: Concentrations in saliva, as an alternative to concentrations in blood, can be advantageous for the monitoring of antiepileptic agents. This study assesses the relationship between saliva and plasma concentrations of levetiracetam after administration orally as a solution and as a tablet. The possibility that saliva concentrations of the drug are altered by contamination in the buccal cavity was also examined. METHODS: 4 healthy male subjects received a single 750 mg oral dose of levetiracetam as a 10% solution and 4 subjects received three 250 mg tablets (750 mg). Levetiracetam concentrations in plasma and saliva were monitored for 24 hours post dose. RESULTS: In subjects receiving the levetiracetam solution, maximum saliva concentrations were observed at the first collection point (15 min) after administration and these were 19-74 times higher than corresponding plasma levels. The mean saliva/plasma ratio rapidly decreased thereafter, becoming stable after 4 hours. In subjects receiving tablets, levetiracetam concentration profiles for saliva paralleled the plasma concentration profiles with a fairly constant saliva/plasma concentration ratio throughout the 24-hour sampling period. A significant linear correlation between levetiracetam saliva and plasma concentrations was demonstrated (Pearson r = 0.88; p < 0.001 for tablet (n = 35) and r = 0.87; p < 0.001 for solution at times > or = 4 hours post-dose (n = 20)). The saliva to plasma concentration ratio was 1.11 (95% confidence interval: 0.99 - 1.22) following tablet intake, and 1.55 (95% CI: 1.34 1.77) following oral solution (> or = 4 hours post dose). CONCLUSIONS: Using saliva to monitor therapeutic exposure to levetiracetam is feasible beginning 15 minutes after tablet intake but beginning 4 hours after intake of an oral solution.

Lipid and apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: a placebo-controlled study.

BACKGROUND: Patients with end-stage renal disease commonly present with an atherogenic lipid profile characterized by the accumulation of triglyceride-rich, apoprotein B-containing "remnant" lipoproteins, small dense low-density lipoprotein, and low levels of high-density lipoprotein. They are at increased cardiovascular risk and may benefit from drastic lipid-lowering treatment with atorvastatin, a potent, broadacting lipid regulator. This study aims to assess the effects of atorvastatin on the lipid profile in hemodialysis patients, to determine wether atorvastatin is also effective at lowering lipid levels in this particular high-risk subgroup. METHODS: In this randomized, placebo-controlled, double-blind study in hemodialysis patients with hypercholesterolemia (n = 42, mean total cholesterol 243 +/- 33 mg/dl (6.3 +/- 0.8 mmol/l)), the efficacy of 4-weekly increasing doses of atorvastatin (10 - 40 mg daily) was investigated. Lipids and apoproteins were measured in plasma and isolated lipoprotein fractions. RESULTS: Mean total cholesterol and low-density lipoprotein cholesterol progressively decreased with increasing doses of atorvastatin (total cholesterol -33%, low-density lipoprotein cholesterol -43% after 12 weeks), while high-density lipoprotein cholesterol remained unchanged. Plasma levels of apoprotein B and apoprotein E were also significantly reduced by atorvastatin 10 mg, while up-titration to 20 and 40 mg daily provided additional benefits by lowering triglycerides and apoprotein C-III. At week 12, the fraction of small dense low-density lipoprotein was significantly reduced from 23% - 18%, and apoprotein B-containing intermediate-density lipoproteins were no longer detectable. CONCLUSION: In conclusion, atorvastatin not only treated hypercholesterolemia but also favorably affected the uremic lipid profile in patients on hemodialysis. Atorvastatin 4-weekly dose escalation up to 40 mg daily was well-tolerated. Further prospective studies are needed to evaluate the impact of this improved lipid profile on morbidity and mortality.

Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: an independent multicentre, prospective study.

BACKGROUND: A prognostic scoring system for hospital mortality in acute renal failure (Stuivenberg Hospital Acute Renal Failure, SHARF score) was developed in a single-centre study. The scoring system consists of two scores, for the time of diagnosis of acute renal failure (ARF) and for 48 h later, each originally based on four parameters (age, serum albumin, prothrombin time and heart failure). The scoring system was now tested and adapted in a prospective study. METHODS: The study involved eight intensive care units. We studied 293 consecutive patients with ARF in 6 months. Their mortality was 50.5%. The causes of ARF were medical in 184 (63%) patients and surgical in 108 (37%). In the latter group, 74 (69%) patients underwent cardiac and 19 (18%) vascular surgery. RESULTS: As the performance of the original SHARF scores was much lower in the multicentre study than in the original single-centre study, we re-analysed the multicentre data to customize the original model for the population studied. The independent variables were the score developed in the original study plus all additonal parameters that were significant on univariate analysis. The new multivariate analysis revealed an additional subset of three parameters for inclusion in the model (serum bilirubin, sepsis and hypotension). For the modified SHARF II score, r(2) was 0.27 at 0 and 0.33 at 48 h, respectively, the receiver operating characteristic (ROC) values were 0.82 and 0.83, and the Hosmer-Lemeshow goodness-of-fit P values were 0.19 and 0.05. CONCLUSION: After customizing and by using two scoring moments, this prediction model for hospital mortality in ARF is useful in different settings for comparing groups of patients and centres, quality assessment and clinical trials. We do not recommend its use for individual patient prognosis.

Pharmacokinetics of ertapenem in healthy young volunteers.

Ertapenem (INVANZ) is a new once-a-day parenteral beta-lactam antimicrobial shown to be effective as a single agent for treatment of various community-acquired and mixed infections. The single- and multiple-dose pharmacokinetics of ertapenem at doses up to 3 g were examined in healthy young men and women volunteers. Plasma and urine samples collected were analyzed using reversed-phase high-performance liquid chromatography with UV detection. Ertapenem is highly bound to plasma protein. The protein binding changes from approximately 95% bound at concentrations of <50 micro g/ml to approximately 92% bound at concentrations of 150 micro g/ml (concentration at the end of a 30-min infusion following the 1-g dose). The nonlinear protein binding of ertapenem resulted in a slightly less than dose proportional increase in the area under the curve from 0 h to infinity (AUC(0- infinity )) of total ertapenem. The single-dose AUC(0- infinity ) of unbound ertapenem was nearly dose proportional over the dose range of 0.5 to 2 g. The mean concentration of ertapenem in plasma ranged from approximately 145 to 175 micro g/ml at the end of a 30-min infusion, from approximately 30 to 34 micro g/ml at 6 h, and from approximately 9 to 11 micro g/ml at 12 h. The mean plasma t(1/2) ranged from 3.8 to 4.4 h. About 45% of the plasma clearance (CL(P)) was via renal clearance. The remainder of the CL(P) was primarily via the formation of the beta-lactam ring-opened metabolite that was excreted in urine. There were no clinically significant differences between the pharmacokinetics of ertapenem in men and women. Ertapenem does not accumulate after multiple once-daily dosing.

Nitazoxanide: pharmacokinetics and metabolism in man.

OBJECTIVES: Nitazoxanide (N), a new broad-spectrum parasiticidal agent, is rapidly deacetylated to tizoxanide (T). The objective of the study was to determine if metabolites other than T are present in the plasma and excreted after single dose oral administration of radiocarbon-labelled N in healthy subjects. METHODS: Six healthy volunteers received a single 500 mg oral dose of N labelled with 2.92 MBq radiocarbon. The radioactivity in blood, plasma, urine, feces and expired air was monitored at scheduled intervals for up to 10 days. Selected samples were assayed by HPLC for T and submitted to metabolite identification by mass spectrometry. In vitro experiments were also conducted (incubation with animal and human microsomes, deacetylation kinetics). Plasma and bile samples obtained in a patient treated with N for sporozoal infection were also assayed for T. RESULTS: Elimination of radiocarbon occurred both in the urine (31.5% of the dose on average) and in the feces (66.2% on average). T and T-glucuronide contributed 15% of total urine radioactivity. N was found to deacetylate extremely rapidly to T in plasma (half-life of about 6 minutes at 37 degrees C) as well as in presence of liver microsomes. T was the only species obtained by incubation with human microsomes while rat microsomes yielded hydroxylated T in addition. The main species identified in human plasma, urine and bile was T-glucuronide, the identification of which was confirmed by comparison with an authentic sample. No species other than T was detected in feces, indicating intensive intestinal deconjugation, while radioactivity and absorbance detectors showed largely unresolved clusters.

Effect of antihypertensive treatment on office and self-measured blood pressure: the Autodil study.

OBJECTIVE: To examine prospectively the effects of antihypertensive therapy on office blood pressure (BP) and home BP, in a large-scale hypertensive population followed by their general practitioners. PATIENTS: A total of 760 hypertensive patients either never treated or after a 2-week washout period, aged 18-75 years, with a diastolic office BP between 95 and 110 mm Hg and a systolic office BP below 180 mm Hg. METHODS: Patients measured their BP at home using an automated printer-equipped oscillometric device (OMRON-HEM 705 CP) twice daily for 8 days before the visit to their general practitioner who recorded three office BP. These measurements were performed before and after 8 weeks of antihypertensive therapy with sustained-release diltiazem 300 mg once daily. RESULTS: Diltiazem reduced systolic and diastolic office BP and home BP and heart rate (P < 0.01). Systolic and diastolic office BP were higher than home BP before (P < 0.01) but not during treatment. Correlation coefficients between the two methods before and during therapy were 0.6 and 0.7 for systolic BP and 0.4 and 0.6 for diastolic BP (P < 0. 01). Both methods did not agree equally throughout the range of BP: home BP was higher than office BP for high values and lower for low values. CONCLUSION: The results show that BP measured at home by patients can be higher than office BP in the highest range of BP. Journal of Human Hypertension (2000) 14, 525-529

Prognostic value of a new scoring system for hospital mortality in acute renal failure.

AIM AND METHODS: In order to define a prognostic scoring system for hospital mortality of individual patients with acute renal failure (ARF), data were collected prospectively in a single centre study (Stuivenberg General Hospital, Antwerp, Belgium) on 197 adult patients consecutively admitted to the intensive care unit (ICU) during one year. Mean age was 69.8 (+/- 14.7), male/female ratio was 118/79. RESULTS: Hospital mortality was 53%, 26% of the patients who were treated with renal replacement therapy. For developing the model all parameters showing a significant difference between survivors and non-survivors were entered in the multivariate analysis. Two SHARF scores (= Stuivenberg Hospital Acute Renal Failure scores) were developed, one at the time of diagnosis of ARF (T0) and the other 48 hours later (T48): SHARF T0 (7 x age) + (6 x alb0) + (3 x PTT0) + (39 x vent0) + (9 x heartf0) + 52 SHARF T48 (7 x age) + (6 x alb0) + (3 x PTT0) + (43 x vent48) + (16 x heartf48) + 52 age, albumin (alb0) and prothrombine time (PTT0) at T0 are expressed as categories, respiratory support (vent) and heart failure (heartf) at T0 and T48 are presented as absent (0) or present (1). In the linear regression model, r2 was, respectively, 0.36 and 0.43. The area under the receiver operator characteristic (ROC) curves, judging the discrimination ability between survivors and non-survivors, for T0 and T48 were, respectively, 0.87 and 0.90. The Hosmer-Lemeshow goodness-of-fit C statistic for T0 was C = 8.47; df8; p = 0.3 89 and for T48 C = 11.05; df = 8; p = 0.199. CONCLUSION: We conclude that this scoring system, developed for all types of ARF, compares favorably with published scores and can become useful as a bedside tool for predicting hospital mortality in individual patients. A second measuring point increased the predictive value of the model. The results have to be confirmed in an ongoing prospective multicentre study.

Comparison of different routes of administration of nadroparin in hemodialysis.

AIM: In an open, crossover, randomized study in hemodialysis patients, we investigated possible differences of the effect of the low molecular weight heparin (LMWH) nadroparin/fraxiparine in relation to the route of administration. PATIENTS AND METHODS: The effect of nadroparin, administered by the venous line or by the arterial line after priming of the extracorporeal circuit with a part of the total dose administered, was compared with administration of the same dose by the arterial line as recommended by the manufacturer. Twelve stable, chronic hemodialysis patients were studied during 3 dialysis sessions for each treatment option. Concomitant medication was kept constant. RESULTS: Results obtained after administration of nadroparin by the venous line were comparable to those obtained after administration by the arterial line. When a part of the dose was added to the priming solution, the anti-Xa activity, measured after 2 hours of dialysis, was somewhat lower (p = 0.09). There was also a tendency towards longer manual compression time in this group. There was no difference in hemoglobin, serum urea and creatinine before the study and at the end of each treatment option. CONCLUSION: We therefore conclude that the safety and efficacy of administration of LMWH by the arterial and by the venous route are identical. There is no need for addition of a small dose of LMWH to the priming fluid.

Hypertension and accelerated atherosclerosis in endstage renal disease.

In patients with chronic renal failure cardiovascular morbidity and mortality are higher than in non-uremic controls. Chronic renal failure influences a number of factors that promote atherogenesis: blood pressure, nitric oxide activity, advanced glycosylation, lipid metabolism, oxidant stress, homocysteine levels, glucose metabolism and PTH. How these factors are influenced by chronic renal failure, how they interrelate and how they promote atherogenesis is still debated. Published data are for and against accelerated atherogenesis. The use of only clinical endpoints may be partially responsible for these conflicting data. Measurement of atherosclerosis itself by computerized ultrasound imaging of the common carotid arteries can be used as an outcome variable. We conclude that there is still a need for prospective, controlled, epidemiologic studies to answer the question whether or not atherogenesis is accelerated in chronic renal failure and to clarify the role of hypertension and other risk factors.

Single dose pharmacokinetics of manidipine in hepatic impaired patients and healthy controls.

The pharmacokinetics and safety of a single oral dose of 20 mg manidipine dihydrochloride have been studied in 8 patients with mild to moderate hepatic impairment (grade A or B in Child's classification, or score < or = 7 in Pugh's modification of Child's classification), and in 12 healthy subjects. They received one 20 mg manidipine dihydrochloride tablet with 100 ml of tap water after a standard breakfast. Manidipine was determined using HPLC with electrochemical detection from plasma samples taken up to 24 or 36 h after dosing. The medication was well tolerated. A trend toward higher Cmax, AUC, and MRT was observed in patients with a more severe hepatic impairment, as a consequence of reduction in the liver metabolic function. Patients with grade A hepatic impairment did not exhibit significantly altered pharmacokinetics with respect to healthy subjects, while grade B impairment patients had significantly higher AUC and MRT. Tmax values pointed to reduced absorption rate in patients compared to healthy subjects; the changes were more evident in grade B than grade A patients, although statistical significance was not reached. The reduction in absorption rate in grade B patients is probably related to their higher mean age, since this effect has been reported for manidipine. The pharmacokinetics of manidipine seem only modified in patients with a certain degree of hepatic impairment (at least Pugh grade 6 and Child grade B); therefore, adaptation of the dosing regimen does not seem to be generally recommendable, but should be modulated according to the liver status of the patient.

Importance of volume factors in dialysis related hypertension.

OBJECTIVE: To evaluate the relation between total body water and dialysis related hypertension. PATIENTS AND METHODS: Thirty stable chronic hemodialysis patients were studied. Twenty-four-hour ambulatory blood pressure on the day before dialysis, blood pressure before and after dialysis, weight gain, ultrafiltration and total body water were determined. Total body water was measured by body impedance analysis and expressed as percentage of dry weight (TBW %). Ambulatory blood pressure recordings were defined as hypertensive when the blood pressure load (% of readings above 140/90 mmHg) was more than 40%. RESULTS AND CONCLUSION: Patients, classified as normotensive (n = 11) or hypertensive (n = 19), based on 24-hour blood pressure measurements, had significantly different TBW % (54.7 +/- 5.3 vs. 58.9 +/- 4.6%, p = 0.046). Ambulatory blood pressure and postdialysis blood pressure, but not predialysis blood pressure, were significantly correlated with TBW %. Acute volume changes, as reflected by interdialytic weight gain and ultrafiltration did not correlate with TBW %. These changes correlated weakly with predialysis blood pressure. Multivariate analysis showed that only TBW % and antihypertensive medication had an independent influence on 24-hour blood pressure measurements. We conclude that 24-hour blood pressure and blood pressure after dialysis are better related to total body water than blood pressure before dialysis, which was however weakly related to the acute volume overload, induced by interdialytic weight gain. We hypothesize that this could be the result of a more important chronic volume overload leading to an increase in systemic vascular resistance. On the contrary the acute but less important changes in extracellular volume between dialyses cause no hypertension after dialysis and no sustained hypertension over 24 hours, but only in some cases a temporary increase in the blood pressure just before dialysis. This volume overload can be easily determined by measurement of total body water by bioelectrical impedance analysis.

Population analysis of the non-linear red blood cell partitioning of draflazine following various infusion durations.

OBJECTIVE: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated in 19 healthy male and female subjects (age range 22-55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg.h-1) and variable duration (2-24 h). METHODS: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. RESULTS: The population typical value for the dissociation constant Kd (%CV) was 0.648 (12) ng.ml-1 plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding capacity Bmax (%CV) was 155 (2) ng.ml-1 RBC. The interindividual variability (%CV) was moderate for Kd (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and steady state was reached at about 18 h after the start of the continuous infusion. The t1/2 beta averaged 11.0-30.5 h and the mean CL from the plasma was 327 to 465 ml.min-1. The disposition of draflazine in whole blood was different from that in plasma. The mean t1/2 beta was 30.2 to 42.2 h and the blood CL averaged 17.4-35.6 ml.min-1. CONCLUSION: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg.h-1, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen could be justified in patients.

Treatment of severe thallium intoxication.

CASE REPORT: We report a successfully treated case of severe thallium intoxication. In spite of very high serum thallium (5,240 micrograms/L), symptomatology was minor and recovery complete. Prussian Blue was administered, diuresis was enhanced by intravenous fluids and a prolonged hemodialysis was started early. High blood flows (300 mL/min) and intravenous potassium chloride supplements, to mobilize thallium from the tissues, resulted in good clearances (96 to 150 mL/min). In order to prevent the well known complications, we recommend aggressive treatment of severe thallium intoxication.

Comparative bioavailability of a metoprolol controlled release formulation and a bisoprolol normal release tablet after single oral dose administration in healthy volunteers.

The bioavailability patterns of a 100 mg metoprolol controlled release tablet and a 10 mg bisoprolol normal release tablet were compared in a single dose crossover study in 12 healthy subjects. The plasma drug concentration levels were measured for 36 h post-dose, using HPLC with fluorimetric detection. The 2 formulations were equally well tolerated, headache being the most frequently reported adverse event. Episodes of bradycardia (heart rate < 50 bpm) occurred at a similar rate with both formulations. The plasma metoprolol profile differed significantly (p < 0.05) from the bisoprolol profile regarding time to maximum concentration, mean residence time, the ratio of peak concentration (Cmax) to the area under the curve (AUC) and the plateau time as estimated from the half-value duration. The average drug plasma concentration observed 24 h after administration still accounted for 54% of the Cmax value for the metoprolol controlled release tablet, but only 23% with the bisoprolol normal release tablet. A large inter-individual variability was seen in the bioavailability of metoprolol, with 3 subjects (characterised as CYP2D6 deficient) exhibiting AUC values 8 - 10 times larger than in the other subjects. The controlled release pattern of the formulation was similar in slow and fast metabolizers. No such variability pattern was apparent for bisoprolol. The findings allow to conclude that, after administration of the metoprolol controlled release tablet, the rate of absorption of the active principle is significantly slower, therefore yielding more constant plasma concentration levels over the 24 h post-dose period, than after administration of the bisoprolol normal release tablet.

High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure.

Recently, well performing diagnostic criteria for analgesic nephropathy in end-stage renal failure (ESRF) patients were defined by the demonstration of a bilateral decrease in renal volume combined with either bumpy contours or papillary calcifications. In this study, the diagnostic value of computed tomography (CT) scan was compared to the previously used renal imaging techniques (sonography and conventional tomography). In a first study, a cohort of 40 analgesic abusers (defined as daily use of analgesic mixtures during at least 5 years) and 40 controls, all ESRF patients without a clear renal diagnosis, were investigated with sonography, tomography and CT scan without injection of iodinated contrast material, to search for the imaging signs of analgesic nephropathy. Using CT scan, sonography and tomography, renal size could be evaluated with comparable results while CT scan was superior in the detection of papillary calcifications (sensitivity 87%, specificity 97%). In a second controlled study of 53 analgesic abusers with a serum creatinine between 1.5 to 4 mg/dl in the absence of a clear renal diagnosis, a CT scan was performed and scored for the presence of decreased renal volume, bumpy contours and papillary calcifications. It was found that the renal image of analgesic nephropathy on CT scan in an early stage of renal failure is comparable with the observations made in ESRF patients. Particularly the demonstration of papillary calcifications showed a high sensitivity of 92% with a specificity of 100% for the early diagnosis of analgesic nephropathy.