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Rate-adaptive sensors are designed to restore a physiologic heart rate response to activity, in particular for patients that have chronotropic incompetence (CI). Limited data exist comparing two primary types of sensors; an accelerometer (XL) sensor which detects activity or motion and a minute ventilation (MV) sensor, which detects the product of respiration rate and tidal volume. The APPROPRIATE study will evaluate the MV sensor compared with the XL sensor for superiority in improving functional capacity (peak VO(2)) in pacemaker patients that have CI. This study is a double-blind, randomized, two-arm trial that will enroll approximately 1,000 pacemaker patients. Patients will complete a 6-min walk test at the 2-week visit to screen for potential CI. Those projected to have CI will advance to a 1-month visit. At the 1-month visit, final determination of CI will be done by completing a peak exercise treadmill test while the pacemaker is programmed to DDDR with the device sensors set to passive. Patients failing to meet the study criteria for CI will not continue further in the trial. Patients that demonstrate CI will be randomized to program their rate-adaptive sensors to either MV or XL in a 1:1 ratio. The rate-adaptive sensor will be optimized for each patient using a short walk to determine the appropriate response factor. At a 2-month visit, patients will complete a CPX test with the rate-adaptive sensors in their randomized setting.

Objectives: Grapefruit juice has been reported to increase the bioavailability of several calcium-channel antagonists, i.e. the dihydropyridines and verapamil, which are cytochrome P450 3A4 (CYP3A4) substrates. The objective of the present study was to investigate the effect of grapefruit juice on the pharmacokinetics of diltiazem and the metabolites N-demethyl-diltiazem (MA) and desacetyl-diltiazem (M1)., Methods: Ten healthy male volunteers were included in a randomised, open, crossover study, comparing the effect of a single oral dose of non-retard formulated diltiazem (120 mg) administered with 250 ml grapefruit juice or water. The study was performed on two investigation days separated by 13-38 days (median 28 days). Plasma samples were collected for measurement of diltiazem and the metabolites MA and M1. Blood pressure and heart rate were monitored throughout the study., Results: Grapefruit juice intake resulted in a statistically significant average individual increase in the area under the plasma diltiazem concentration-time curve (AUC(0-24)) of 20+/-25% ( P=0.02) compared with water. The average individual increase in peak plasma concentration (C(max)) of diltiazem after grapefruit juice administration was 22+/-37%, but this effect was not statistically significant ( P=0.14). The time to C(max) (t(max)) or terminal half-life was not affected by grapefruit juice. Considerable interindividual variability in the interaction was observed. There were no statistically significant differences in blood pressure and heart rate between the two treatments., Conclusion: The present study demonstrated that a single intake of grapefruit juice (250 ml) caused a slight but statistically significant increase in the systemic exposure of diltiazem. Inhibition of intestinal metabolism and/or P-glycoprotein efflux transport may be responsible for this effect.

Objective: Patients with renal disease receiving dialysis therapy are susceptible to a deficit in ascorbic acid (AA) caused by loss during dialysis and a restricted dietary AA intake. In previous studies, in such patients, the methods generally used for AA determination are non-specific and insensitive, and control of the easily deteriorating AA in the samples is often disregarded. The purpose of this work was to study the AA plasma levels and dialyser clearances as well as the kinetics of administered AA in a group of dialysis patients, using selective and sensitive methodology and a procedure preserving the AA sample content., Methods: Using an analytical method based on high-performance liquid chromatography and electrochemical detection, we have examined the dialyser clearance of AA as well as the pre- and post dialysis plasma levels of AA in patients on chronic dialysis therapy. The plasma AA levels were further measured after single and multiple dose supplementation of 200 mg p.o. per day., Results: The majority of the patients (16 of 19) had pre-dialysis plasma levels below the normal range. The dialyser clearance of AA was 212 ml/min (median value). Following dialysis, the plasma AA concentrations were reduced by a median of 33%. AA supplementation significantly increased these levels; however, they dropped soon after supplementation was stopped. AA in uraemic whole blood and plasma was, on average, less stable than in samples from healthy subjects., Conclusion: This study, using selective analytical method with adequate stability control, confirms that AA is readily removed by conventional haemodialysis membranes. Patients on chronic haemodialysis have remarkably low plasma AA levels unless given AA supplementation.

Objective: Bilateral cyclosporin A (CsA) and diltiazem pharmacokinetic interactions have previously been investigated, however, not with the new microemulsion preconcentrate formulation of CsA (Sandimmun Neoral). In addition, the pharmacokinetic effects on the pharmacological active metabolites of diltiazem have not previously been investigated. We performed a pharmacokinetic interaction study in renal transplant recipients, measuring both unmetabolised CsA and diltiazem in addition to three of the main metabolites of diltiazem (MA, M1, M2)., Methods: Nine CsA-treated renal transplant patients were treated with diltiazem, 90-120 mg b.i.d., for 4 weeks. Pharmacokinetic investigations were performed both before and at the end of the diltiazem treatment period. Six non-CsA-treated renal transplant patients served as controls of CsA interactions with diltiazem and its metabolites., Results: Diltiazem treatment resulted in a significant mean increase in the area under the concentration time curve (AUC) for CsA of 51(8)% (P < 0.008) and a peak concentration (Cmax) of 34(8)% (P < 0.05), without altering time to peak concentration (tmax). CsA, however, did not significantly influence diltiazem pharmacokinetics, though two of the metabolites (M1 and M2) tended to be increased., Conclusions: Diltiazem interacts significantly with the pharmacokinetics of CsA in the new microemulsion formulation. Microemulsion-formulated CsA, however, did not show significant interaction with diltiazem pharmacokinetics.

101 patients were treated for acute acetylsalicylic acid (ASA) poisoning in the Nephrological Unit Trondheim between 1971-1975. On admission 33 of them had a serum salicylic acid (SA) concentration greater than 400 microgram/ml (mean 588 +/- 40 microgram/ml). This group was compared with a group of 11 children less than 5 years old with ASA poisoning and a mean serum SA on admission of 550 +/- 34 microgram/ml. Blood pH on admission was normal or elevated in all patients more than 12 years old (mean 7.43 +/- 0.01), whereas 7 of the 11 children suffered from metabolic acidosis. The results of forced alkaline diuresis produced by loop diuretics (bumetanide, furosemide) in ASA poisoned patients older than 12 years are reported. The mean T 1/2 of SA was 9.6 h in the treated group as compared to 18-22 h in untreated patients. There was no apparent difference between the diuretic effect of bumetanide and furosemide.

The acute effects of therapeutic doses of acetylsalicylic acid (ASA) on renal water and solute output, and the possible interaction of ASA with the diuretic effects of furosemide, have been studied in a double blind double cross over study in healthy human subjects. There was a significant decrease in 24 h sodium excretion and Na/K ratio in urine in the ASA-treated subjects. The effect of ASA on urinary sodium excretion was most prominent during day time (8 a.m.-10 p.m.) and on days with low sodium intake, as confirmed by control sodium excretion and plasma renin activity. A decrease in urine volume and an increase in tubular reabsorption of free water were caused by ASA, the antidiuretic effect being most marked at night (10 p.m.-8 a.m.). No action of ASA on the effect of furosemide on urinary sodium excretion was found. Creatinine clearance remained unaltered by ASA treatment, and ASA did not interfere with the increase in urinary creatinine excretion after furosemide treatment.

The effect of acetylsalicylic acid (ASA) in patients with renal insufficiency has been examined. In one investigation (A), in patients with a mean GFR of 23.0 ml/min the acute effects of ASA 750 mg i.v. (lysine-ASA 7.5 ml) and 0.9% NaCl 7.5 ml on renal water and solute output and on the clearance of inulin, creatinine and PAH were compared. In another (B) the effects of simultaneous administration of ASA 750 mg or 0.9% NaCl 7.5 ml i.v. with an infusion of furosemide 250 mg were investigated in six patients (mean GFR 12.9 ml/min) in a cross-over study. In study A there was a significant fall in urinary sodium excretion within the first 15 min after ASA administration, with a maximal decrease to 21% of the control period. Urine flow fell to 35%, osmolal clearance to 41%, inulin clearance to 54% and PAH clearance reabsorption of sodium increased. The effect of ASA lasted for 2-6 h. The mean salicylic acid concentration during the first two hours after ASA administration was 60.0 mug/ml, and the mean protein bound salicylic acid (SA) was 70.4%. There was no effect of placebo (0.9% NaCl 7.5 ml) on renal function. Pretreatment with ALA 750 mg i.v. attenuated the diuretic effect of furosemide 250 mg, and reduced creatinine clearance significantly within 0-2 h after drug administration.

The pharmacokinetics and clinical effects of cefuroxime were investigated in 5 patients with severe impairment of renal function (creatinine clearance less than or equal to 23 ml/min), suffering from an urinary tract infection. Bolus i.v. injections of cefuroxime 750 mg b.i.d. or 750 mg once daily were given to the patients depending on the degree of renal impairment. The concentration of drug in serum and urine was measured during treatment, and pharmacokinetic parameters were evaluated on the second and last days; the parameters obtained on the 2 days did not differ significantly. Drug elimination half-life increased from 4.2 h (creatinine clearance 23.0 ml/min) to 22.3 h (creatinine clearance 5.0 ml/min) with decreasing renal function. The apparent volume of distribution ranged from 11.6 to 17.9 l, and showed a substantial increase to 29.6 l in the patient with the poorest renal function. A linear correlation was found between the total and renal clearance of cefuroxime and the creatinine clearance; the extrarenal clearance was 8.24 ml/min. Concomitant treatment with furosemide did not impair renal function and no evidence of nephrotoxicity was found. The clinical efficacy of the drug was good. Symptoms of infection subsided after 3-4 days and the isolated pathogens were eradicated. No relapse or episodes of reinfection were observed in a following-up period of 3 months. The drug was well tolerated and no side effects or changes in haematological or biochemical values were seen.

Sodium azide (6 mg/ml) was used as a positive control for drug-induced lethality in an in vitro clonogenic assay. Petri dishes containing control and sodium azide treated cultures of WiDr cells were placed together in a large Petri dish and incubated at 37 degrees C in an atmosphere of 10% CO2 in air. No growth was observed. Control cells formed colonies only when the dishes were separated from the sodium azide dishes. Using a microtiter plate the toxic effect was inversely related to the distance of the test cultures from the sodium azide treated cultures. These results suggested the formation of a toxic gas or vapour from sodium azide under cell culture conditions, probably an azide. Chemical analysis was based on characteristic reactions, such as the production of a precipitate with silver ions or formation of a red-coloured complex with ferric salts. On a microtiter plate, a gradient of the expected precipitate or red colour was observed, the highest amounts adjacent to the wells containing sodium azide. These results show that sodium azide acts as a positive control of drug-induced lethality for in vitro clonogenic assays. However, the formation of a highly toxic vapour, most likely hydrazaic acid, makes it a less suitable standard.

The effect of bumetanide, a new potent diuretic, was studied in twelve patients with severe chronic renal failure (GFR 2.7 - 10.7 ml/min). Bumetanide 8 mg i.v. caused increased excretion of water and sodium in all patients. In some patients sodium excretion was greater than 50% of filtered load indicating an effect on proximal tubules. Bumetanide 2 mg i.v. was significantly less effective than 8 mg and a greater diuretic effect was produced by bumetanide 16 mg. In a comparative study bumetanide 8 mg was less potent than furosemide 250 mg, a finding in contrast to the potency rate ratio of 1/40 in other conditions. Side effects consisted of mild to moderate muscle pain and stiffness, especially localized in the neck, shoulders and calves. These side effects occurred only in patients with a GFR less than 5.3 ml/min. They were noted in all patients receiving 16 mg and in 3 out of 12 patients who took bumetanide 8 mg. There was no relationship between the occurrence of side effects and plasma bumetanide levels, electrolyte levels or the renal excretion of bumetanide and electrolytes.