Atrial natriuretic peptide and renal adaptation to contralateral nephrectomy in healthy man

Atrial natriuretic peptide (ANP), angiotensin II (AII), aldosterone (Aldo) and arginine vasopression (AVP) in plasma were determined in 12 healthy renal transplant donors before and 5, 12, 26, 54 days after uninephrectomy (N_x) in order to study the possible role of these hormones in functional adaptation to acute reduction in renal mass. Glomerular and tubular function was studied by measurements of the clearances of ⁵¹Cr-EDTA, lithium, sodium, postassium, and albumin. ANP was 7.4±3.1 pmol l^-1 (mean±SD) before N and 8.7±6.1 pmol l^-1 at 5 days after Nx and remained at this level through the observation period. Aldo showed a non-significant transient fall at 5 days after Nx. AII and AVP remained normal after Nx. At 5 days after Nx glomerular filtration rate (GFR) of the remaining kidney had risen from 45±7 ml min-1 before Nx to 57± ml min^-1 (p<0·01), lithium clearance had risen from 13±2 ml min^-1 before Nx to 20±7 ml min^-1 (p<0.01), and sodium and water balance was normal. To conclude, plasma ANP, AII, Aldo and AVP do not appear to be responsible for the hyperfiltration and depression of fractional proximal sodium and water reabsorption observed in recently uninephrectomized man with normal sodium and water balance.     

Changes in glomerular filtration rate, lithium clearance and plasma protein clearances in the early phase after unilateral nephrectomy in living healthy renal transplant donors

1. Glomerular and tubular function was studied before and 2 months after unilateral nephrectomy in 14 healthy kidney donors by measurement of the clearances of 51Cr-labelled ethylenediaminetetra-acetate, lithium, beta 2-microglobulin, albumin and immunoglobulin G. 2. The glomerular filtration rate (GFR) of the kidney that remained in the donor rose from 45 +/- 10 (mean +/- SD) to 59 +/- 10 ml/min (P less than 0.01) 5 days after contralateral nephrectomy and remained at this level through the observation period. 3. The lithium clearance (CLi) of the remaining kidney rose from 11.6 +/- 3.7 to 20.5 +/- 8.2 ml/min (P less than 0.01) and remained significantly elevated throughout the observation period. 4. Absolute proximal fluid reabsorption rate (APR), which was estimated as GFR minus CLi, was unchanged 5 days after contralateral nephrectomy, but then rose gradually to reach significantly elevated levels after 4 weeks. 5. Fractional proximal reabsorption (FPR; APR/GFR) fell from 0.75 +/- 0.06 to 0.66 +/- 0.11 (P less than 0.01) but subsequently rose to levels not significantly decreased from normal. 6. Twenty-four hour fractional clearances of beta 2-microglobulin, albumin and immunoglobulin G rose markedly on the day of nephrectomy, peaked at 2-3 days and subsequently fell to moderately elevated levels. 7. Both the CLi and the plasma protein clearance studies demonstrate that the early response of the remaining kidney to contralateral nephrectomy in man is an increase in GFR, an unchanged APR and a fall in FPR. The proximal tubules thus initially handle the increased filtrate load by passing it on to more distal nephron segments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cisplatin on proximal convoluted and straight segments of the rat kidney

The immediate effect of cisplatin on rat proximal tubular function was investigated by two different methods, the lithium clearance method and the occlusion time-transit time method (TT-OT). Within minutes after administration of cisplatin a significant increase in lithium clearance, fractional lithium clearance (CLi/Cin) and e-TT/OT was observed (from 270 +/- 32 to 387 +/- 60 microliters/min/g kidney weight, 0.202 +/- 0.03 to 0.340 +/- 0.06 and 0.415 +/- 0.02 to 0.497 +/- 0.02, respectively). These increases indicate an increased fluid delivery from both the proximal straight segment and the late proximal convoluted tubule after cisplatin administration. Concomitantly absolute proximal reabsorption rate was significantly decreased. Intervention by saline loading (2% of body weight) did not prevent the increase in e-TT/OT, but the increase in CLi/Cin was significantly less than in the control group. This finding suggests that saline loading protects either the pars recta of the proximal tubule or the juxtamedullary nephrons. Thus, cisplatin-induced nephrotoxicity in the rat is initiated by an acute mainly proximal tubular impairment including both pars convoluta and pars recta of the proximal tubule.     

A randomized, open, parallel group, multicenter trial to investigate analgesic efficacy and safety of a new transdermal fentanyl patch compared to standard opioid treatment in cancer pain

A new 72-hour transdermal fentanyl matrix patch has been designed, which has a 35%–50% reduction of the absolute fentanyl content compared with other currently available transdermal fentanyl patches that are using the matrix technology. The new patch has previously been shown to be pharmacokinetically bioequivalent to the marketed fentanyl patch. To determine noninferiority in efficacy in cancer patients and to compare safety, a clinical trial comparing the new fentanyl patch with standard oral or transdermal opioid treatment was planned. The design was an open, parallel group, multicenter trial, in which 220 patients were randomized to receive either the fentanyl patch or standard opioid treatment for 30 days. The primary efficacy variable, pain intensity (PI) on a 0–10-point numerical rating scale, was recorded once daily. The primary endpoint was the relative area under the curve of PI expressed as a percentage of the maximum possible PI area under the curve. Any adverse events were recorded; four tolerability endpoints, constipation, nausea, daytime drowsiness, and sleeping disturbances, were assessed daily. Noninferiority was shown; the upper 95% confidence interval limits of the mean difference in relative PI area under the curve between the fentanyl patch and standard opioid treatment were less than 10% for both the intention-to-treat and per-protocol populations. Scores for the tolerability endpoints were similar in the treatment groups. The new fentanyl matrix patch with a lower drug load was found noninferior and as safe as established standard oral and transdermal opioid treatment.     

Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers

Aim After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-glucuronide (M3G) and M6G. The aims of this study were to confirm and elucidate the biphasic absorption profile as well as clarify the conversion of M6G to morphine after a single oral administration of M6G in healthy volunteers. Methods The study was conducted accordingly to a nonblinded, randomised, balanced three-way crossover design in eight healthy male subjects. The subjects received 200 mg oral M6G, 50 mg oral M6G and 30 mg oral morphine. Blood samples were collected until 72 h after M6G administration and until 9 h after morphine administration. Paracetamol and sulfasalazine were coadministered with M6G as markers for the gut contents reaching the duodenum and colon, respectively. Results The plasma concentration peaks of M6G were seen at 4.0 (2.0–6.0) and 18 (12.0–24.0) h after 200 mg M6G and at 3.5 (2.0–6.0) and 21.3 (10.0–23.3) h after 50 mg M6G, which was in agreement with previously published results. The K_{M6G_abs}/K_{M6G_M6G} ratio was found to be 10. Conclusion The pharmacokinetic profile of M6G after oral administration was confirmed and with the presence of M3G and morphine in plasma after oral administration of M6G, proof seems to be found of the constant and prolonged absorption of M6G. The K_{M6G_abs}/K_{M6G_M6G} ratio of 10 indicates that the second absorption peak of M6G consists of approximately 10 times more absorbed M6G than reglucuronidated M6G. However, further studies are required to determine the precise kinetics of the second absorption peak.     

Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers

Objective The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only. Methods Twenty-three healthy male volunteers aged 21–40 years received 0.6 mg buprenorphine by means of an i.v. infusion over a 150-min period. The plasma concentration–time profiles up to 24 h post-administration of the infusion were subjected to population pharmacokinetic modelling using NONMEM software. Results A three-compartment model best described the plasma concentration–time course. Body weight was found to be a significant covariate for elimination clearance in a linear fashion. Inter-individual variability (coefficient of variation) was estimable for apparent clearance (CL, 23.5%), central distribution volume (V₁, 81.8%), peripheral distribution volume 1 (V₂, 23.7%) and inter-compartmental clearances between V₁ and V₂ (Q₂, 34.8%). Models using parameters derived from previous published data obtained after an i.v. bolus of buprenorphine were found to overestimate the measured buprenorphine concentrations during the course of the i.v. infusion and to underpredict those following the end of the infusion. Conclusion Most parameters describing the disposition of buprenorphine in the volunteers showed only moderate inter-subject variability. However, the parameters differed from those previously reported for i.v. bolus administration. We conclude that pharmacokinetic parameter estimates obtained from the appropriate study in accordance to the mode of administration should be used in the design of dose regimens of buprenorphine.