Reduction In Renal Clearance Research Articles

EFFECT OF CHRONIC FUROSEMIDE THERAPY ON SERUM FREE LIGHT CHAIN IN CHRONIC KIDNEY DISEASE PATIENTS

Objective: Chronic kidney disease (CKD) is an important cause of morbidity and mortality worldwide. There is a lack of information on the epidemiology and progression of CKD in low-middle-income countries. Chronic use of diuretics is considered to further decrease renal clearance, a pathophysiology not very clearly understood. Free light chains renal deposition is precipitated by loop diuretics. This study attempted to determine whether chronic diuretic usage was associated with increase serum free light chain and a reduction in renal clearance among CKD patients. Design and method: A single-center, record-based study of 84 CKD patients with an established diagnosis of CKD, loop diuretic therapy, between June 2019 and December 2019 was conducted after ethical approval by institutional ethics committee ((RIMS/2018/32). The study included participants with age above 18 years of age, never dialysed, non-neoplastic (specifically plasma cell disorder), non-pregnant, and those on loop diuretic were divided into 3 groups: group 1 with Furosemide exposure more than 6 months; Group 2 with furosemide exposure between 3 months to 6 months but less than 6 months; and Group 3 with furosemide exposure less than 3 months. Results: 46 out of 84 patients were of group 1, 20 belonged to group 2 and 18 were in group 3. In group 1, mean eGFR of 103.6, mean free kappa of 100.98 and mean lambda of 126.65.2 was observed. Group 2 patients had mean eGFR of 125.6 with mean free kappa of 80.98 and mean lambda of 1002.2, whereas group 3 had mean eGFR of 15 5.5, mean free kappa of 79.8 and mean lambda of 96.65.2. It was also observed that 98% patients with stage 5 CKD had high serum free lambda level. Conclusions: This study revealed a strong association of serum free light chain level with stage of CKD in patients on diuretic therapy. Therefore, monitoring of Serum Free Light Chain among CKD patients on diuretic therapy can be an indirect evidence of furosemide induced renal function worsening.

Formulation Design and <i>in vitro-in vivo</i> Evaluation of Sustained Release Aspirin Microparticles Based on PEGylated Lipids

Background: PEGylation is a strategy that on therapeutic molecules such as drugs, proteins and macromolecules, in order to improve their delivery. It has this unique property of increasing the size and molecular weight of biomolecules that are conjugated in nature in order to improve water solubility, reduction in renal clearance and protects the drug from enzymatic degradation. Objectives: The objectives of this work was to formulate sustained release aspirin-loaded solid lipid microparticles based on PEGylated lipid matrix, to evaluate the <i>in-vitro</i> properties of the SLM and to study the anti-inflammatory and ulcerogenic properties of the SLM. Methods: Aspirin-loaded solid lipid microparticles (SLMs) were formulated by cold homogenization method. Furthermore, they were analyzed for the encapsulation efficiency, <i>in-vitro</i> release, particle size, anti-inflammatory and ulcer inhibition properties. Results: Particle size ranged from 9.36±2.63 to 16.77±5.80 µm for batches B₁ to D₁ SLMs loaded with 10% LM, 5% PEG 4000 and 0.25-1% aspirin respectively, while batches B₂ to D₂ formulated with 10% LM, 10% PEG and 0.25 -1% aspirin had particle size range of 9.09±4.03 to 15.71±10.09 µm. Batches D₁ containing 1% of aspirin had the highest encapsulation efficiency of 58%. Maximum <i>in-vitro</i> release of 29.20% and 15.85% were obtained at 6 h for batches D₁ and B₂ respectively. SLMs showed an average of 66.67 – 83.3% oedema inhibition, while the reference had 50%, and ulcer inhibition of 75% for batch D₁. Conclusion: Due to the good properties exhibited by the aspirin-loaded SLMS, they could be used for the treatment of inflammation.

A Multiparametric Assay Platform for Simultaneous In Vivo Assessment of Pronephric Morphology, Renal Function and Heart Rate in Larval Zebrafish.

Automated high-throughput workflows allow for chemical toxicity testing and drug discovery in zebrafish disease models. Due to its conserved structural and functional properties, the zebrafish pronephros offers a unique model to study renal development and disease at larger scale. Ideally, scoring of pronephric phenotypes includes morphological and functional assessments within the same larva. However, to efficiently upscale such assays, refinement of existing methods is required. Here, we describe the development of a multiparametric in vivo screening pipeline for parallel assessment of pronephric morphology, kidney function and heart rate within the same larva on a single imaging platform. To this end, we developed a novel 3D-printed orientation tool enabling multiple consistent orientations of larvae in agarose-filled microplates. Dorsal pronephros imaging was followed by assessing renal clearance and heart rates upon fluorescein isothiocyanate (FITC)-inulin microinjection using automated time-lapse imaging of laterally positioned larvae. The pipeline was benchmarked using a set of drugs known to induce developmental nephrotoxicity in humans and zebrafish. Drug-induced reductions in renal clearance and heart rate alterations were detected even in larvae exhibiting minor pronephric phenotypes. In conclusion, the developed workflow enables rapid and semi-automated in vivo assessment of multiple morphological and functional parameters.

High sensitivity Troponin-I levels in asymptomatic hemodialysis patients

Reduction in renal clearance and removal by hemodialysis adversely affect the level and utility of high-sensitivity troponin I (hsTnI) for diagnosis of acute myocardial infarction (AMI) in hemodialysis (HD) patients. Furthermore, HD process itself might cause undesirable myocardial injury and enhance post HD hsTnI levels. This comparative cross-sectional study was conducted to compare the hsTnI levels between 100 asymptomatic HD patients and their 107 matched non-chronic kidney disease (CKD) population. The hsTnI levels in HD group were higher than non-CKD group [median (IQR): 54.3 (20.6–152.7) vs. 18 (6.2–66.1) ng/L, p < .001)]. The hsTnI levels reduced after HD process from 54.3 (20.6–152.7) ng/L in pre-HD to 27.1 (12.3–91.4) ng/L in post-HD (p = .015). Of interest, 25% of HD patients had increment of hsTnI after HD and might represent HD-induced myocardial injury. The significant risk factors were high hemoglobin level and high blood flow rate. In conclusion, the baseline hsTnI levels in asymptomatic HD patients were higher than non-CKD population. The dynamic change of hsTnI over time would be essential for the diagnosis of AMI. Certain numbers of asymptomatic HD patients had HD-induced silent myocardial injury and should be aggressively investigated to prevent further cardiovascular mortality.

Drug Dosing in Acute Kidney Injury

The prevalence of acute kidney injury (AKI) among hospitalized patients has increased sharply over the past 10 to 20 years. One complicating factor in this population is that many pharmacologic agents that are administered to these patients are handled, to some degree, by the kidneys. These medications may experience altered pharmacokinetic and pharmacodynamic profiles in patients with renal dysfunction, increasing the chances of drug misadventures. Historically, drug dosing in patients with AKI has been approached in the same manner as in patients with chronic renal insufficiency (CRI). The majority of dosing recommendations for AKI have been extrapolated from studies performed in patients with stable CRI. Renal drug clearance, composed of glomerular filtration, tubular secretion, and renal drug metabolism, is affected by renal dysfunction. It is clear that there is a reduction in renal clearance of drugs and toxins in both AKI and CRI. However, the type of renal dysfunction may affect other parameters of drug handling. Thus, dosing stratagems extrapolated from patients with CRI may result in subtherapeutic drug concentrations and ineffective treatment. Achieving a balance between under- and overdosing requires rigorous monitoring and individualized dosing. Key words: acute kidney injury, drug dosing, pharmacokinetics

Drug Dosing in Acute Kidney Injury

The prevalence of acute kidney injury (AKI) among hospitalized patients has increased sharply over the past 10 to 20 years. One complicating factor in this population is that many pharmacologic agents that are administered to these patients are handled, to some degree, by the kidneys. These medications may experience altered pharmacokinetic and pharmacodynamic profiles in patients with renal dysfunction, increasing the chances of drug misadventures. Historically, drug dosing in patients with AKI has been approached in the same manner as in patients with chronic renal insufficiency (CRI). The majority of dosing recommendations for AKI have been extrapolated from studies performed in patients with stable CRI. Renal drug clearance, composed of glomerular filtration, tubular secretion, and renal drug metabolism, is affected by renal dysfunction. It is clear that there is a reduction in renal clearance of drugs and toxins in both AKI and CRI. However, the type of renal dysfunction may affect other parameters of drug handling. Thus, dosing stratagems extrapolated from patients with CRI may result in subtherapeutic drug concentrations and ineffective treatment. Achieving a balance between under- and overdosing requires rigorous monitoring and individualized dosing. Key words: acute kidney injury, drug dosing, pharmacokinetics

Cytogenetic Damage in the Peripheral Blood Lymphocytes of Thyroid Cancer Patients during Pre and Post 131I Therapy

Aim: 131 I therapy is widely used in patients of differentiated thyroid carcinoma for the ablation of remnant thyroid tissue post thyroidectomy as well as metastasis. These patients are in hypothyroid state with consequent reduction in renal clearance of 131 I thereby increasing the extent of whole body exposure. Present study was carried out to assess the DNA damage due to the presence of thyroid carcinoma as well as posttherapeutic 131 I exposure at 72h by measuring micronuclei (MN) frequency in peripheral blood lymphocytes (PBLs) in patients of differentiated thyroid cancer. Methods: The study group consisted of 25 differentiated thyroid carcinoma patients and 35 healthy donors. The blood samples of the patients were collected pre and post 131 I therapy (1.6-9.3 GBq) and processed for PBL MN frequency by cytokinesis-block MN assay. Results: The mean basal MN frequency was significantly high in thyroid cancer patients as compared to the healthy donors (p< 0.001). 131 I exposed patients demonstrated significant increase in the MN frequency at 72h after therapeutic 131 I exposure compared to their basal MN index ( p<0.001 ). However the percent increase in MN frequency post 131 I therapy did not show any correlation with administered dose in thyroid cancer patients. Conclusion: The study has revealed significant DNA damage in PBLs as indicated by increased PBL MN frequency post 131 I therapy. However marked individual variations were observed in the DNA damage response to 131 I therapy.

Pharmacokinetic modeling of tranexamic acid for patients undergoing cardiac surgery with normal renal function and model simulations for patients with renal impairment.

Tranexamic acid (TXA), an effective anti-fibrinolytic agent that is cleared by glomerular filtration, is used widely for cardiopulmonary bypass (CPB) surgery. However, an effective dosing regimen has not been fully developed in patients with renal impairment. The aims of this study were to characterize the inter-patient variability associated with pharmacokinetic parameters and to recommend a new dosing adjustment based on the BART dosing regimen for CPB patients with chronic renal dysfunction (CRD). Recently published data on CPB patients with normal renal function (n = 15) were re-examined with a two-compartment model using the ADAPT5 and NONMEMVII to identify covariates that explain inter-patient variability and to ascertain whether sampling strategies might affect parameter estimation. A series of simulations was performed to adjust the BART dosing regimen for CPB patients with renal impairment. Based on the two-compartmental model, the number of samples obtained after discontinuation of TXA infusion was found not to be critical in parameter estimation (p > 0.05). Both body weight and creatinine clearance were identified as significant covariates (p < 0.005). Simulations showed significantly higher than normal TXA concentrations in CRD patients who received the standard dosing regimen in the BART trial. Adjustment of the maintenance infusion rate based on the percent reduction in renal clearance resulted in predicted plasma TXA concentrations that were safe and therapeutic (~100 mg·L(-1) ). Our proposed dosing regimen, with consideration of renal function, is predicted to maintain effective target plasma concentrations below those associated with toxicity for patients with renal failure for CPB.

Pharmacokinetics of miriplatin in experimental dog models of hepatic or renal impairment

Miriplatin is an anticancer platinum complex for treatment of hepatocellular carcinomas by intra-hepatic arterial injection suspended in an iodinated ethyl ester of fatty acids from poppy seed oil as a carrier. Effects of liver and kidney function on( 14)C-miriplatin pharmacokinetics were assessed using dog models of hepatic and renal impairment introduced by thioacetamide exposure and 7/8 nephrectomy, respectively. Miriplatin was selectively delivered to the liver; platinum and radioactive component were gradually released into systemic circulation and excreted into urine. Microautoradiographic analysis of liver specimens showed( 14)C-miriplatin to be localized in blood vessels and/or macrophage-like cells. These features of miriplatin disposition were not affected by hepatic impairment. Thus, in clinical settings, hepatic impairment would not be expected to affect the intra-hepatic distribution and systemic pharmacokinetics of miriplatin. In dogs with renal impairment, although inconclusive, plasma concentrations of ultrafilterable platinum and radioactivity increased due to reduction in renal clearance.

Leukocytoclastic vasculitis and myocardial infarction as presenting manifestations of infective endocarditis: a case report

In April 2009, a 32-year-old female patient was referred to our hospital with acute chest pain. She was diabetic, nicotine dependent and had a family history of coronary heart disease. The electrocardiogram showed a previously documented complete left bundle branch block. Cardiac troponin T was elevated (1.18 ng/ml, CK and CK-MB normal, LDH 333 U/l), C-reactive protein serum concentration was 157 mg/l (normal \ 5), white blood count was normal. Coronary angiography showed a thrombotic occlusion of the mid-LAD as culprit lesion (Fig. 1a, left panel). Additionally, a smooth lesion in the small PDA of the right coronary artery could be detected (Fig. 1a, right panel). The patient’s past medical history was complex. Aortic valve replacement with a biological prosthesis had been performed in 2006 due to infective endocarditis. Interestingly, 6 months before the acute coronary syndrome, i.e. in November 2008, the patient had been admitted to an external department with diffuse, non-symmetric arthralgia and a recurrent purpuric rash over her distal lower extremities. Hemorrhagic leukocytoclastic vasculitis had been diagnosed by skin biopsy (Fig. 1b). Laboratory tests conducted at that time had revealed a profound reduction in renal clearance (creatinine 2.4 mg/dl, cystatin C 3.3 mg/l, GFR 16-20 ml/min). Urinanalysis had shown proteinuria (0.84 g/24 h) and glomerular hematuria with detection of acanthocytes. These findings suggest that renal impairment had been caused by a glomerulonephritis. Monotherapy with prednisolone had been performed followed by chemotherapy with cyclophosphamid due to recurrence of symptoms after dose reduction of prednisolone. At the current admission to our department with an acute coronary syndrome, revascularization was performed by direct implantation of a bare metal stent in the midLAD. Because of the small vessel diameter there was no indication for a PCI of the PDA. However, the unusual lesion pattern in two distinct coronary vessels in a young patient with no further evidence of coronary heart disease was highly suspicious for coronary embolism, particularly in the light of the patient’s history of valve replacement 2 years earlier. During admission, the patient was recurrently subfebrile (\38 C), serum concentration of C-reactive protein remained elevated. Transesophageal echocardiography was performed twice. No typical endocarditic vegetations could be detected. However, thickening of the cusps of the bioprosthesis only two years after implantation as well as a mild aortic regurgitation were noticed. Immunosuppressant therapy was stopped. Serial blood cultures drawn at consecutive days yielded Granulicatella adiacens which proved to be highly sensitive to penicillin (MIC 0.004 mg/l). In one additional sample a b-lactamase positive, penicillin-resistant Staphylococcus aureus was obtained which was tested to be sensitive to oxacillin (MIC 0.25 mg/l). These positive microbiological results and the assumed embolic coronary event made the diagnosis of prosthetic valve endocarditis very likely and J. Poss M. Bohm H. Kilter (&) Universitatsklinikum des Saarlandes, Klinik fur Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Kirrberger Strase, 66421 Homburg/Saar, Germany e-mail: heiko.kilter@uks.eu

Lithium: Updated Human Knowledge Using an Evidence-Based Approach

After a single dose, lithium, usually given as carbonate, reaches a peak plasma concentration at 1.0-2.0 hours for standard-release dosage forms, and 4-5 hours for sustained-release forms. Its bioavailability is 80-100%, its total clearance 10-40 mL/min and its elimination half-life is 18-36 hours. Use of the sustained-release formulation results in 30-50% reductions in peak plasma concentrations without major changes in the area under the plasma concentration curve. Lithium distribution to the brain, evaluated using 7Li magnetic resonance spectroscopy, showed brain concentrations to be approximately half those in serum, occasionally increasing to 75-80%. Brain concentrations were weakly correlated with serum concentrations. Lithium is almost exclusively excreted via the kidney as a free ion and lithium clearance is considered to decrease with aging. No gender- or race-related differences in kinetics have been demonstrated. Renal insufficiency is associated with a considerable reduction in renal clearance of lithium and is considered a contraindication to its use, especially if a sodium-poor diet is required. During the last months of pregnancy, lithium clearance increases by 30-50% as a result of an increase in glomerular filtration rate. Lithium also passes freely from maternal plasma into breast milk. Numerous kinetic interactions have been described for lithium, usually involving a decrease in the drug's clearance and therefore increasing its potential toxicity. Clinical pharmacology studies performed in healthy volunteers have investigated a possible effect of lithium on cognitive functions. Most of these studies reported a slight, negative effect on vigilance, alertness, learning and short-term memory after long-term administration only. Because of the narrow therapeutic range of lithium, therapeutic monitoring is the basis for optimal use and administration of this drug. Lithium dosages should be adjusted on the basis of the serum concentration drawn (optimally) 12 hours after the last dose. In patients receiving once-daily administration, the serum concentration at 24 hours should serve as the control value. The efficacy of lithium is clearly dose-dependent and reliably correlates with serum concentrations. It is now generally accepted that concentrations should be maintained between 0.6 and 0.8 mmol/L, although some authors still favour 0.8-1.2 mmol/L. With sustained-release preparations, and because of the later peak of serum lithium concentration, it is advised to keep serum concentrations within the upper range (0.8-1 mmol/L), rather than 0.6-0.8 mmol/L for standard formulations. It is controversial whether a reduced concentration is required in elderly people. The usual maintenance daily dose is 25-35 mmol (lithium carbonate 925-1300 mg) for patients aged <40 years; 20-25 mmol (740-925 mg) for those aged 40-60 years; and 15-20 mmol (550-740 mg) for patients aged >60 years. The initial recommended dose is usually 12-24 mmol (450-900 mg) per day, depending on age and bodyweight. The classical administration schedule is two or three times daily, although there is no strong evidence in favour of a three-times-daily schedule, and compliance with the midday dose is questionable. With a modern sustained-release preparation, the twice-daily schedule is well established, although one single evening dose is being recommended by a number of expert panels.

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Pharmacokinetics of single-dose rosiglitazone in chronic ambulatory peritoneal dialysis patients

End-stage renal disease (ESRD) is associated with marked alterations in the pharmacokinetics of many drugs, not only from reduction in renal clearance but also from changes in metabolic activity, bioavailability, volume of distribution and plasma protein binding. To study the pharmacokinetics of a single 8-mg oral dose of rosiglitazone in patients with ESRD and requiring long-term chronic ambulatory peritoneal dialysis (CAPD). The medication was administered just before the first exchange of peritoneal dialysis fluid on the day that blood and peritoneal dialysate collection was performed. In our CAPD patients the mean (+/-SD) T(max) and T(1/2) of rosiglitazone were 1.20 +/- 0.26 and 21.38 +/- 21.96 h respectively. These values were different to those reported for healthy volunteers reported in previous studies. The mean area under the concentration-time curve (AUC((0-infinity))) and an average maximum observed plasma concentration (C(max)) of rosiglitazone in our CAPD patients were 4203.56 +/- 2916.97 ng h/mL and 409.67 +/- 148.89 ng/mL respectively. These appear no different from those reported in healthy volunteers . The apparently significant difference in T(1/2) of rosiglitazone in CAPD patients compared with healthy volunteers suggest that dose adjustment may be necessary in order to avoid toxicity.

Altered intravenous pharmacokinetics of topotecan in rats with acute renal failure (ARF) induced by uranyl nitrate: Do adenosine A1 antagonists (selective/non-selective) normalize the altered topotecan kinetics in ARF?

A series of exploratory investigations with multiple agents was carried out in normal rats and in rats with uranyl nitrate-induced acute renal failure to understand the disposition characteristics of intravenous topotecan (TPT) used as a model substrate. The disposition of TPT was unaltered in normal rats when treated with methotrexate, whereas treatment with probenecid increased the systemic exposure of TPT. In case of uranyl nitrate-induced acute renal failure (UN-ARF) rats, the systemic exposure of TPT was increased when compared with normal rats, whereas in UN-ARF rats treated with probenecid a further reduction in renal clearance of TPT was noted as compared with that of UN-ARF induced rats. Thus, TPT may be involved in the tubular secretory pathway when a passive glomerular filtration pathway for elimination was not possible. The disposition of TPT did not normalize in UN-ARF rats when treated with caffeine, a non-selective adenosine A1 receptor antagonist, whereas the selective adenosine A1 receptor antagonist (1,3-dipropyl-8-phenylxanthine, DPPX) normalized TPT pharmacokinetic disposition by improving renal function. Renal excretion studies demonstrated that CLR improved by almost fivefold following DPPX treatment in ARF rats. In addition, the qualitative stability/metabolism pattern of TPT in liver microsomes prepared from various groups of rats (normal rats, UN-ARF rats, rats treated with DPPX, and UN-ARF rats treated with DPPX) was found to be similar. In summary, using a pharmacokinetic tool as a surrogate, it has been shown that the pharmacokinetic disposition of TPT improved considerably upon treatment with DPPX, a selective adenosine A1 antagonist.

Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics

Fexofenadine is a substrate of P-glycoprotein and organic anion transporting polypeptides. The aim of this study was to compare the inhibitory effects of different transporting inhibitors on fexofenadine pharmacokinetics. Twelve male volunteers took a single oral 120-mg dose of fexofenadine. Thereafter three 6-day courses of either 240 mg verapamil, an inhibitor of P-glycoprotein, 800 mg cimetidine, an inhibitor of organic cation transporters, or 2000 mg probenecid, an inhibitor of organic anion transporting polypeptides, were administered on a daily basis in a randomized fashion with the same dose of fexofenadine on day 6. Plasma and urine concentrations of fexofenadine were monitored up to 48 hours after dosing. Verapamil treatment significantly increased the peak plasma concentration by 2.9-fold (95% confidence interval [CI], 2.4- to 4.0-fold) and the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of fexofenadine by 2.5-fold (95% CI, 2.0- to 3.3-fold). No changes in any plasma pharmacokinetic parameters of fexofenadine were found during cimetidine treatment. AUC(0-infinity) was slightly but significantly increased during probenecid treatment by 1.5-fold (95% CI, 1.1- to 2.4-fold). Renal clearance of fexofenadine was significantly decreased during cimetidine treatment to 61% (95% CI, 50%-98%) and during probenecid treatment to 27% (95% CI, 20%-58%) but not during verapamil treatment. This study suggests that verapamil increases fexofenadine exposure probably because of an increase in bioavailability through P-glycoprotein inhibition and that probenecid slightly increases the area under the plasma concentration-time curve of fexofenadine as a result of a pronounced reduction in renal clearance. However, it may be difficult to explain these interactions by simple inhibitory mechanisms on target transporters.

Renal excretion mechanisms of the antiviral nucleoside analogue AM 188 in the rat isolated perfused kidney.

1. AM 188 is an antiviral guanosine analogue that undergoes extensive renal excretion in humans. The present study was designed to investigate the disposition of AM 188 over a range of concentrations in the rat isolated perfused kidney (IPK) to explore the mechanisms involved in its renal handling. 2. Right kidneys of male Sprague-Dawley rats (n = 23) were isolated and perfused in recirculating mode with Krebs'-Henseleit (pH 7.4) buffer containing 0.65% bovine serum albumin, 3.6% dextran, amino acids and glucose. [14C]-Inulin was added to the perfusate reservoir to permit estimation of glomerular filtration rate (GFR). [3H]-AM 188 and unlabelled AM 188 were added to the perfusate as a bolus initially, followed by a constant rate of infusion at 5, 25, 125, 500 or 1000 microg/min to achieve initial target perfusate concentrations of 1, 5, 25, 100 or 200 microg/mL, respectively. During the 130 min over which AM 188 was infused, urine was collected in 10 min intervals (commencing 10 min after the bolus dose) and perfusate was collected at the mid-point of these intervals to permit calculation of the renal clearance (CLR) of AM 188. Binding of AM 188 in perfusate, measured using ultrafiltration, was negligible. 3. The bolus dose and infusion regimen produced relatively stable AM 188 concentrations in perfusate in the 5, 25 and 125 micro g/min groups and progressively increasing concentrations in the 500 and 1000 microg/min groups. High-pressure liquid chromatography analysis of IPK perfusate and urine suggested that there was no or negligible metabolism of AM 188 in the kidney. The CLR/GFR ratio for AM 188 (mean+/-SD) was 5.76 +/- 1.57, 5.99 +/- 0.52, 6.02 +/- 1.47, 3.38 +/- 0.26 and 1.08 +/- 0.42 in the 5, 25, 125, 500 and 1000 microg/min groups, respectively, showing significant reductions at the two highest infusion rates (P < 0.05). Although there was no difference between the five groups in the distribution of AM 188 between kidney tissue and perfusate (KT/P), at the end of perfusion the corresponding urine-to-tissue concentration ratio declined significantly in the 1000 microg/min group. 4. AM 188 undergoes substantial net renal secretion over a wide range of perfusate concentrations. A reduction in renal clearance at perfusate concentrations above 25 microg/mL could be due to saturation of carrier-mediated transport at the brush border membrane and/or a solubility limitation leading to precipitation of AM 188 in tubular cells and/or tubular urine.

Pharmacokinetics of peginterferons.

Two polyethylene glycol (PEG)-modified interferons are approved for the treatment of chronic hepatitis C. The pharmocokinetic properties of the branched 40 kDa pegylated interferon alfa-2a differ from the linear 12 kDa pegylated interferon alfa-2b. The absorption half-life of standard interferon alfa is 2.3 hours, while absorption half-lives for peginterferon alfa-2a and alfa-2b are 50 hours and 4.6 hours, respectively. The volume of distribution for peginterferon alfa-2a is considerably restricted, while the volume of distribution for peginterferon alfa-2b is only approximately 30% lower than that for conventional interferon. Because of its large size, the 40 kD peginterferon alfa-2a has a more than 100-fold reduction in renal clearance compared with conventional interferon alfa. Clearance of peginterferon alfa-2b is about one-tenth that of unmodified interferon alfa. Although data are limited, both drugs appear to show differences in the initial viral decay pattern in patients with chronic hepatitis C. However, it remains unknown whether these differences in the initial viral decline predict differences in the primary clinical endpoint, sustained virological response.

Plasma concentrations of alpha-melanocyte-stimulating hormone are elevated in patients on chronic haemodialysis.

Clinical and/or laboratory signs of systemic inflammation occur frequently in patients undergoing long-term haemodialysis. It is likely, therefore, that a compensatory release of endogenous anti-inflammatory molecules occurs to limit host reactions. The aim of the present research was to determine if the potent anti-inflammatory peptide alpha-melanocyte-stimulating hormone (alpha-MSH), a pro-opiomelanocortin derivative, is increased in plasma of haemodialysis patients. Because endotoxin and cytokines induce alpha-MSH in vivo and in vitro, we also measured plasma concentrations of endotoxin, interleukin-6 (IL-6), and tumour necrosis factor alpha (TNF-alpha), and the two circulating products of activated monocytes, nitric oxide (NO) and neopterin. Thirty-five chronic haemodialysis patients, 20 patients with chronic renal failure not yet on dialysis, and 35 normal controls were included in the study. In the haemodialysis group, blood samples were obtained before and at the end of a dialysis session. Plasma alpha-MSH was measured using a double antibody radioimmunoassay, and IL-6, TNF-alpha, and neopterin using specific enzyme-linked immunosorbent assays. Plasma nitrites were determined by a colorimetric method, and endotoxin with the quantitative chromogenic LAL (limulus amoebocyte lysate) method. Mean plasma alpha-MSH was higher in haemodialysis patients than in control subjects, with the peptide concentrations being particularly elevated in dialysed patients with detectable endotoxin. High alpha-MSH concentrations were observed in the pre-dialysis samples, with no substantial change at the end of the dialysis session. Plasma concentrations of IL-6, TNF-alpha, neopterin, and NO were generally elevated in chronic haemodialysis patients and there was a negative correlation between circulating alpha-MSH and IL-6. In patients with renal failure not yet on dialysis, mean plasma alpha-MSH was similar to that of normal subjects. alpha-MSH is increased in the circulation of chronic haemodialysis patients and particularly so in case of detectable endotoxaemia. Reduction of renal clearance is unlikely to contribute to the observed rise of the peptide because alpha-MSH concentration is not increased in patients with chronic renal failure who are not yet on dialysis. It is likely that dialysis-associated endotoxaemia, directly and/or through cytokine release, enhances the production of the anti-inflammatory mediator alpha-MSH that limits host reactions.

Renal toxicity of the neuron-blocking and mitochondriotropic agent m-iodobenzylguanidine.

meta-Iodobenzylguanidine (MIBG) is a multipotent drug used in its radiolabeled form as a tumor-seeking radiopharmaceutical in the diagnosis and treatment of pheochromocytoma and neuroblastoma. Nonradiolabeled MIBG has also proved to be effective in the palliation of carcinoid syndromes and, on a predosing schedule, in enhancing the relative tumor uptake of a subsequent [131I]-MIBG dose in tumors of neuroadrenergic origin. In addition, MIBG is under investigation as an inhibitor of mitochondrial respiration and, as such, for its use in tumor-specific acidification. In this report we describe the side effects of nonradiolabeled MIBG on kidney function in mice. High doses of MIBG (40 mg/kg) reduced renal blood perfusion as measured by 86Rb distribution by 50%, which could be antagonized by the bioamine receptor blockers prazosin and cyproheptadine. MIBG also induced reversible renal damage as evidenced from a decrease in [51Cr]-ethylenediaminetetraacetic acid (EDTA) clearance and from histological damage, which was most pronounced in the distal tubuli. These effects were unrelated to reduced perfusion, however, and could not be antagonized by bioamine receptor blockers, Ca2+-channel blockers, or diuretics. Clearance effects of MIBG were mimicked by N-nitro-L-arginine methyl ester (L-NAME), a known inhibitor of nitric oxide synthase (NOS), and MIBG itself (100 microM) also inhibited NOS in vitro, suggesting that NOS inhibition by MIBG may have contributed to the observed reduction in renal clearance. The MIBG analog benzylguanidine (BG), which is equipotent in terms of mitochondrial inhibition, did not affect renal clearance, thus excluding mitochondrial inhibition as the main mechanism of MIBG-induced damage. MIBG, however, was much more cytotoxic than BG to kidney tubular cells in primary cultures. Although the renal effects of high-dose MIBG were reversible, alterations in the pharmacokinetics of concomitant medications by a temporary reduction in renal function should be taken into account in its clinical application.

Plasma and urinary 8-iso-prostane as an indicator of lipid peroxidation in pre-eclampsia and normal pregnancy.

1. This study was designed to seek evidence for excessive lipid peroxidation in pre-eclamptic women using 8-iso-prostane as a novel bioactive marker of lipid peroxidation in vivo. Plasma free, total and urinary 8-iso-prostane were measured in 20 women with proteinuric pre-eclampsia, and compared with 18 age- and gestation-matched pregnant control subjects, before delivery and at 6 weeks post-partum. 2. Plasma free 8-iso-prostane was significantly elevated in the pre-eclamptic women compared with control subjects before delivery, and fell to control levels post-partum. Conversely, levels in women with normal pregnancy rose post-partum. 3. Total plasma 8-iso-prostane levels were not significantly elevated in pre-eclamptic women compared with control subjects during pregnancy, but fell significantly in the pre-eclamptic women post-partum, suggesting that they had relatively higher levels compared with their non-pregnant state. 4. Urinary 8-iso-prostane excretion was significantly lower in the pre-eclamptic women compared with control subjects during pregnancy, suggesting that renal clearance of 8-iso-prostane is impaired in pre-eclampsia. 5. Increased levels of plasma free 8-iso-prostane in pre-eclampsia could be due to an increase in lipid peroxidation, an increase in phospholipase A2 activity or a reduction in renal clearance of 8-iso-prostane, or a combination of all three. The potent direct and indirect vasoconstrictor actions of 8-iso-prostane may contribute to the pathogenesis of pre-eclampsia.