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.

Acceptability of rilmenidine and long-term surveillance of plasma concentrations in hypertensive patients with renal insufficiency.

Acceptability and plasma concentrations of rilmenidine, a new antihypertensive agent mainly eliminated via the kidney, were evaluated in 17 hypertensive patients (supine diastolic blood pressure, 104 +/- 3 mmHg) with renal insufficiency (creatinine clearance, 35 +/- 4 ml.minute-1/1.73 m2; range, 12 to 58). Patients were treated for six months with rilmenidine at the dose of 1 mg in the morning or 1 mg twice daily as single-drug therapy in untreated patients, or in combination or as substitution in patients already treated. Plasma concentrations of rilmenidine were measured by gas chromatography combined with mass spectrometry at Days 0, 1, 5, 7, 9, and 11, and Months 1.5, 3, 4.5, and 6 before administration. Supine and erect blood pressure (sphygmomanometer) measurements and side effects were noted at the same times. Laboratory and electrocardiographic parameters were evaluated at Days 0 and 11, and Months 1.5 and 6. Blood pressure was effectively controlled during the trial in 12 patients (mean decrease in systolic/diastolic blood pressure of 12/8 mmHg). Five patients were removed from the trial after Month 1.5 because of a rise in blood pressure (three cases) or noncompliance (two cases). Side effects were moderate and transient (dry mouth, constipation, daytime drowsiness, mood disturbances, insomnia) never requiring treatment withdrawal. Surveillance of renal function revealed no significant mean variation. Rilmenidine plasma concentrations reached steady state the fifth day at the latest and were related to the degree of renal insufficiency. When renal function was stable (13 cases), plasma concentrations did not vary until the end of the trial. When renal function was progressive (four cases), plasma concentrations increased in parallel in two patients, without the onset of side effects, and remained stable in the other two patients. In conclusion, this study confirmed the good acceptability of rilmenidine in hypertensive patients with chronic renal insufficiency. It showed stable plasma concentrations of rilmenidine during a six-month treatment in hypertensive patients with renal insufficiency, reflecting the absence of accumulation of the drug.

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

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.

Urinary indices in acute interstitial nephritis.

Nine patients with biopsy-proven acute interstitial nephritis (AIN) were analyzed for their urinary indices, determined on the basis of the first urinary sample upon admission, before any therapeutic intervention. Isosthenuria was present in all patients with a mean urinary osmolality of 283 +/- 48 mOsm/l and a urine/plasma osmolality ratio of 0.9 +/- 0.1. Urinary sodium was more than 40 mEq/l in 8 out of the 9 patients studied. The other urinary indices studied were indicative for both prerenal and intrinsic renal disease.

Acute renal failure due to bilateral lymphomatous infiltrates. Primary extranodal non-Hodgkin's lymphoma (p-EN-NHL) of the kidneys: does it really exist?

Primary extranodal non-Hodgkin's lymphoma (p-EN-NHL) of the kidneys with acute renal failure as the only manifestation is very rare. The origin of neoplastic lymphoid cells in the kidneys, organs normally free of lymphoid tissue, is an unsolved problem. A literature review over the last ten years revealed only 9 adult cases, including ours that match the usual criteria: (1) renal failure as the initial presentation, (2) bilateral enlargement of the kidneys without obstruction and other organ or nodal involvement, (3) diagnosis only made by renal biopsy, (4) absence of other causes of renal failure, and (5) rapid improvement of renal function after radiotherapy or, as in our case, systemic chemotherapy. Autopsy on two patients confirmed that p-EN-NHL of the kidneys without dissemination does exist as a separate entity.

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.

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.

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.

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.

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.

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.

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.

Continuous ambulatory peritoneal dialysis (CAPD) in a patient with glucose-6-phosphatase deficiency.

The metabolic disturbances in glucose-6-phosphatase deficiency (von Gierke's disease) are the consequence of hypoglycemia, occurring mostly during the night. Continuous provision of glucose is the aim of every recently introduced treatment procedure. We studied the influence of continuous ambulatory peritoneal dialysis (CAPD) on the metabolic disturbances in a 42-year-old female patient with von Gierke's disease and end-stage renal disease. During six months of CAPD, there were no dialysis-related complications. The metabolic acidosis didn't worsen: arterial bicarbonate and lactate were not changed. Mean glycemia was 118.6 +/- 14.4 mg%. Total lipemia, cholesterol and triglycerides were not different from those before CAPD, despite the fact that all hypolipidaemic drugs were stopped. Three different exchange procedures were compared during the night: no dialysis, one exchange with a 2 L solution without buffer containing glucose 15 g/L and containing glucose 42.5 g/L. The results show that the 4.25% glucose solution prevents hypoglycaemia, and diminishes the increase in lactate and pyruvate concentration. Intraperitoneal glucose normalizes the plasma free fatty acid concentration. A very important result is the disappearance of hypo-insulinism. We conclude that, from a clinical point of view, CAPD is a well-tolerated treatment in von Gierke's disease. The limited results provide some evidence that the use of a 4.25% glucose solution as an overnight exchange, instead of the usual 1.5% solution, can prevent at least partly the glycogenolysis and consequently the metabolic disturbances of von Gierke's disease.

Campylobacter jejuni peritonitis during chronic ambulatory peritoneal dialysis (CAPD).

A patient treated with chronic ambulatory peritoneal dialysis developed recurrent peritonitis. During a fourth episode, Campylobacter jejuni was cultured from the dialysate. She responded well to streptokinase and imipenem.

Red blood cell function and beta 2 microglobulin kinetics during cuprophan hemodialysis: a hypothesis.

The exact role of beta 2microglobulin (beta 2m) in dialysis amyloidosis is yet not known. Local release of beta 2m from the endothelial cells of the lung and other tissues as a consequence of acute-phase activation due to the contact of blood with membranes has still to be considered a possible pathogenetic factor in this syndrome. beta 2m kinetics and decrease of glutathione content in RBC were studied in 41 chronic hemodialysis patients during cuprophan dialysis. The latter test reflects the RBC scavenger function for free oxygen radicals. Only 30% of patients showed a clinically significant increase in beta 2m. The change in beta 2m in this group between the start and 180 minutes, corrected for plasma volume, was 23.1 +/- 3.6% and the change in gluthathione content between the start and 15 minutes was 4.5 +/- 3.4%. In these patients there was a significant correlation between beta 2m production and decrease of gluthathione (R = -0.61, p = 0.0299). It is possible that the production of free oxygen radicals during bioincompatible dialysis leads to cellular toxicity with release of beta 2m which may be prevented to some extent by the scavenger role of RBC.

Astemizole-D causes less sleep impairment than loratadine-D.

This randomized, double-blind, double-dummy, parallel-group trial was initiated to evaluate and compare the tolerability of once-daily astemizole-D capsules (10 mg astemizole/240 mg pseudoephedrine) and twice-daily loratadine-D tablets (5 mg loratadine/120 mg pseudoephedrine), with particular reference to the impact of treatment on quality of sleep. A total of 240 healthy volunteers participated in this study with a treatment duration of 3 days. Astemizole-D consistently produced less sleep impairment than loratadine-D with statistically significant differences in favour of astemizole-D reported for night-time waking on days 4 and 5 (P = 0.004 and P = 0.006, respectively), as well as for night-time restlessness on day 4 and the total score for all sleep parameters on day 4 (P < 0.05). Global evaluations of overall sleep quality at the end of the trial also revealed some statistically significant differences in favour of astemizole-D. Both drugs were well tolerated and there were no differences in the incidence and type of adverse events reported in the two treatment groups. Slight changes in heart rate and blood-pressure were observed in both treatment groups, but these were small and were not considered to be of clinical significance. In conclusion, once-daily astemizole-D is well tolerated and appears to cause less sleep impairment than twice-daily loratadine-D.

Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure.

OBJECTIVE: To determine whether alfacalcidol--used in management of overt renal bone disease--may safely prevent renal bone disease when used earlier in course of renal failure. DESIGN: Double blind, prospective, randomised, placebo controlled study. SETTING: 17 nephrology centres from Belgium, France, the Netherlands, and the United Kingdom. SUBJECTS: 176 patients aged 18-81 with mild to moderate chronic renal failure (creatinine clearance 15-50 ml/min) and with no clinical, biochemical, or radiographic evidence of bone disease. INTERVENTIONS: Alfacalcidol 0.25 micrograms (titrated according to serum calcium concentration) or placebo given for two years. MAIN OUTCOME MEASURES: Quantitative histology of bone to assess efficacy of treatment and renal function to assess safety. RESULTS: 132 patients had histological evidence of bone disease at start of study. Biochemical, radiographic, and histological indices of bone metabolism were similar for the 89 patients given alfacalcidol and the 87 controls given placebo. After treatment, mean serum alkaline phosphatase activity and intact parathyroid hormone concentration had increased by 13% and 126% respectively in controls but had not changed in patients given alfacalcidol (P < 0.001). Hypercalcaemic episodes occurred in 10 patients given alfacalcidol (but responded to decreases in drug dose) and in three controls. Histological indices of bone turnover significantly improved in patients given alfacalcidol and significantly deteriorated in controls: among patients with abnormal bone histology before treatment, bone disease resolved in 23 (42%) of those given alfacalcidol compared with two (4%) of the controls (P < 0.001). There was no difference in rate of progression of renal failure between the two groups. CONCLUSION: Early administration of alfacalcidol can safely and beneficially alter the natural course of renal bone disease in patients with mild to moderate renal failure.