piperidines and Renal-Insufficiency

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of blood glucose-lowering therapy with proven efficacy, tolerability and safety. Four of the five commercially available DPP-4 inhibitors are subject to significant renal clearance, and pharmacokinetic studies in people with renal impairment have led to lower recommended doses based on creatinine clearance in order to prevent drug accumulation. Data from these pharmacokinetic studies and from supratherapeutic doses in healthy individuals and people with uncomplicated diabetes during development suggest, however, that there is a wide therapeutic margin. This should protect against toxicity if people with renal impairment are inadvertently prescribed higher doses than recommended. Doses appropriate to renal function are associated with reductions in HbA1c that are equivalent to those observed in people with type 2 diabetes who do not have renal impairment. Recent large-scale cardiovascular safety trials of saxagliptin and alogliptin have identified heart failure as a potential concern and renal impairment may increase the risk of this complication. Although the incidence of pancreatitis does not appear to be significantly increased by DPP-4 inhibitor therapy, renal impairment is also an independent risk factor. Additional data from other ongoing DPP-4 inhibitor cardiovascular safety trials should provide a more precise assessment of the risks of these uncommon complications, including in people with renal impairment.

Topics: Adamantane; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Glycated Hemoglobin; Humans; Piperidines; Renal Insufficiency; Risk Factors; Treatment Outcome; Uracil

Topics: Adrenal Gland Neoplasms; Bradykinin; Carotid Stenosis; Clinical Trials as Topic; Contrast Media; Endarterectomy, Carotid; Esophageal and Gastric Varices; Female; Heart Failure; Humans; Hyperglycemia; Hypertension; Hyperthyroidism; Internal Medicine; Male; Middle Aged; Osteitis Deformans; Piperidines; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Renal Insufficiency; Rimonabant; Risk Factors; Stents; Stethoscopes; Weight Loss

Repaglinide is a novel, fast-acting prandial oral hypoglycaemic agent developed for the treatment of patients with type 2 diabetes whose disease cannot be controlled by diet and exercise alone. Although repaglinide binds to the sulphonylurea binding sites on pancreatic beta-cells and has a similar mechanism of action, repaglinide exhibits distinct pharmacological properties compared with these agents. Following administration, repaglinide is absorbed rapidly and has a fast onset of dose-dependent blood-glucose lowering effect. The drug is eliminated rapidly via the biliary route, without accumulation in the plasma after multiple doses. Repaglinide is well tolerated in patients with type 2 diabetes, including elderly patients and patients with hepatic or renal impairment. The pharmacokinetic profile of repaglinide and the improvements in post-prandial hyperglycaemia and overall glycaemic control make repaglinide suitable for administration preprandially, with the opportunity for flexible meal arrangements, including skipped meals, without the risk of hypoglycaemia.

Topics: Adult; Aged; Blood Glucose; Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Hypoglycemic Agents; Liver Diseases; Male; Piperidines; Renal Insufficiency; Rifampin

Sinbaglustat (ACT-519276), a brain-penetrating inhibitor of glucosylceramide synthase and nonlysosomal glucosylceramidase, is developed as a new therapy for lysosomal storage disorders. In the first-in-human study, sinbaglustat was primarily excreted unchanged in urine. This study was conducted to evaluate the effect of mild, moderate, and severe renal function impairment on the safety, tolerability, and pharmacokinetics (PK) of sinbaglustat. In this single-center, open-label study, 32 subjects (8 per renal function group, assessed by the Cockcroft-Gault formula, and 8 healthy subjects) received a single oral dose of 200 mg sinbaglustat. Plasma PK parameters of sinbaglustat were derived by noncompartmental analysis. Standard safety and tolerability evaluations were analyzed descriptively. When compared with healthy subjects, C

Topics: Aged; Area Under Curve; Dose-Response Relationship, Drug; Female; Humans; Imino Sugars; Male; Metabolic Clearance Rate; Middle Aged; Patient Acuity; Piperidines; Renal Insufficiency

Bilastine is a novel second-generation H1 antihistamine, which has not shown sedative or cardiotoxic effects in clinical trials and in post-marketing experience so far, developed for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. It has recently been granted marketing authorization for these therapeutic indications in adults and adolescents at a once-daily oral dose of 20 mg in several European countries.. This study was conducted to determine the pharmacokinetics of bilastine at a single oral dose of 20 mg in renally impaired subjects. The need for a dose adjustment in patients with renal insufficiency was assessed by comparing the exposure to bilastine in these subjects with the estimated exposure of a dose corresponding to the safety margin.. The study was an open-label, single-dose, parallel-group study of the pharmacokinetics and safety of a single dose of bilastine. The study was conducted as an in-patient setting at a clinical pharmacology facility. A total of 24 male or female subjects aged 18-80 years were to be enrolled in four groups of six subjects each. The groups were as follows: (1) healthy [glomerular filtration rate (GFR) >80 mL/min/1.73 m(2)]; (2) mild renal insufficiency (GFR 50-80 mL/min/1.73 m(2)); (3) moderate renal insufficiency (GFR 30-50 mL/min/1.73 m(2)); and (4) severe renal insufficiency (GFR ≤30 mL/min/1.73 m(2)). A single 20 mg bilastine tablet was administered in a fasted state. Blood and urine samples were collected from pre-dose up to 72 h post-dose for bilastine pharmacokinetic analysis. Pharmacokinetic results were summarized using appropriate descriptive statistics.. There was a clear trend of increasing area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C(max)) through the groups 1-4. The mean AUC from time zero to infinity (AUC(∞)) ranged from 737.4 to 1708.5 ng·h/mL in healthy subjects and severely impaired subjects, respectively. No significant differences among groups in median time to reach Cmax (tmax) or in the mean terminal disposition rate constants for bilastine were found. Renal and plasma clearance paralleled GFR. In all groups of renally impaired subjects the corresponding 90 % confidence interval of both AUC(∞) and AUC from time zero to time of last measurable plasma concentration (AUC(last)) were not within the 0.8-1.25 interval, indicating that bioequivalence between groups could not be demonstrated. The majority of bilastine was excreted within the first 12 h, and elimination was essentially complete by 72 h.. An oral dose of bilastine (20 mg) was well-tolerated in renal insufficiency, despite the increase in exposure. The oral plasma clearance to renal clearance ratio [(CL(P)/F)/CL(R)] was approximately equal in the different groups, suggesting that renal excretion was the main elimination route for bilastine, and no alternative elimination routes were used even in severe renal insufficiency. Although exposure to bilastine was higher in renally impaired subjects, it remained well within the safety margins, thus allowing the conclusion that a 20-mg daily dose can be safely administered to subjects with different degrees of renal insufficiency without the need for dose adjustments.

Topics: Aged; Aged, 80 and over; Area Under Curve; Benzimidazoles; Drug Evaluation; Female; Glomerular Filtration Rate; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Renal Insufficiency

We compared extubation time following daily interruption of sedation in intensive care unit patients with renal impairment with two sedation regimes remifentanil-midazolam and fentanyl-midazolam.. Prospective, randomized double-blind trial.. Patients with renal impairment needing mechanical ventilation for more than 48 hours. Two groups: remifentanil (R) and fentanyl (F), Infusion rates were titrated to achieve the desired Ramsay score. The two groups received midazolam (2.5 mg then 0.1 mg/kg/h).. Nineteen patients were included. Patient's characteristics, mean sedation time and sedation quality were comparable. Extubation time was significantly shorter in R group (1480+/-980 versus 2880+/-1280 min, P=0.04). Weaning time was also shorter in R group (220+/-164 versus 720+/-480 min). Agitation on weaning was comparable in the two groups. Group R received significantly more morphine than group F after interruption of sedation.. Daily interruption of sedation with remifentanil is associated with shorter weaning and extubation time in patients with renal impairment. However further studies are necessary to determine if this issue is associated with lower rate of ventilation induced complications.

Topics: Anesthetics, Combined; Conscious Sedation; Critical Care; Double-Blind Method; Female; Fentanyl; Humans; Hypnotics and Sedatives; Intensive Care Units; Male; Midazolam; Middle Aged; Piperidines; Prospective Studies; Remifentanil; Renal Insufficiency

This open label, multicentre study was conducted to assess the times to offset of the pharmacodynamic effects and the safety of remifentanil in patients with varying degrees of renal impairment requiring intensive care.. A total of 40 patients, who were aged 18 years or older and had normal/mildly impaired renal function (estimated creatinine clearance >/= 50 ml/min; n = 10) or moderate/severe renal impairment (estimated creatinine clearance <50 ml/min; n = 30), were entered into the study. Remifentanil was infused for up to 72 hours (initial rate 6-9 microgram/kg per hour), with propofol administered if required, to achieve a target Sedation-Agitation Scale score of 2-4, with no or mild pain.. There was no evidence of increased offset time with increased duration of exposure to remifentanil in either group. The time to offset of the effects of remifentanil (at 8, 24, 48 and 72 hours during scheduled down-titrations of the infusion) were more variable and were statistically significantly longer in the moderate/severe group than in the normal/mild group at 24 hours and 72 hours. These observed differences were not clinically significant (the difference in mean offset at 72 hours was only 16.5 min). Propofol consumption was lower with the remifentanil based technique than with hypnotic based sedative techniques. There were no statistically significant differences between the renal function groups in the incidence of adverse events, and no deaths were attributable to remifentanil use.. Remifentanil was well tolerated, and the offset of pharmacodynamic effects was not prolonged either as a result of renal dysfunction or prolonged infusion up to 72 hours.

Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Conscious Sedation; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Infusions, Intravenous; Intensive Care Units; Male; Middle Aged; Piperidines; Propofol; Psychomotor Agitation; Remifentanil; Renal Insufficiency; Safety; Severity of Illness Index; Time Factors

The primary objective of this single-centre, open-label, parallel-group study was to evaluate the pharmacokinetics and safety profile of the prandial glucose regulator repaglinide, following single and multiple dosing, in patients with type 2 diabetes with and without varying degrees of renal impairment.. The study comprised three screening visits, followed by a 7-day inpatient period. Thirty-four patients, with normal renal function (n = 12), mild-to-moderate renal dysfunction (n = 12) or severe renal dysfunction (n = 10), received a single 2-mg dose of repaglinide on day 1, followed by preprandial 2-mg doses with main meals (breakfast, lunch and dinner) on each of days 2-4. A final 2-mg dose of repaglinide was administered on day 5.. Patients with mild-to-moderate renal impairment showed no significant differences in the pharmacokinetics of repaglinide, compared with patients with normal renal function. In the group of patients with severe renal dysfunction, the main pharmacokinetic finding was a longer half-life after multiple dosing. Rates of minor hypoglycaemia were similar in patients with severe, mild-to-moderate and no renal dysfunction. No major hypoglycaemic episodes occurred.. Patients with type 2 diabetes and mild or moderate impairment of renal function may be treated with repaglinide without special precautions. If repaglinide is used in patients with severely impaired renal function, dose adjustment may be necessary if indicated by blood glucose measurements.

Topics: Aged; Analysis of Variance; Area Under Curve; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Hypoglycemic Agents; Male; Metabolic Clearance Rate; Middle Aged; Piperidines; Renal Insufficiency

Limited published real-world data describe adverse events (AEs) among patients treated for mantle-cell lymphoma (MCL). The aim of this retrospective study was to describe treatment patterns, AEs, and associated healthcare costs.. Patients had two or more claims coded for MCL diagnosis, the first claim date (07/01/2012-05/31/2017) was the index date. Patients with pre-index MCL diagnosis or systemic treatment, or hematopoietic stem cell transplantation were excluded. Cohorts by regimen were followed for up to three lines of therapy.. Patients (n=395; median age 72 years; 31% female) were observed over a total of 576 lines of therapy, the most common being bendamustine plus rituximab; rituximab monotherapy; R-CHOP; and ibrutinib. The most frequent AEs were hypertension (40.5%), anemia (37.7%), and infection (36.1%). However, hepatotoxicity ($19,645), stroke ($18,893), and renal failure ($9,037) were associated with the highest medical costs per patient per month.. Among patients receiving common systemic treatments for MCL, AEs occurred frequently; some imposed substantial inpatient care costs.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Chemical and Drug Induced Liver Injury; Cyclophosphamide; Doxorubicin; Female; Health Care Costs; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Prednisone; Renal Insufficiency; Retrospective Studies; Rituximab; Stroke; Vincristine

Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.

Topics: Aged; Blood Glucose; Carbamates; Clopidogrel; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Piperidines; Renal Insufficiency

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Carbazoles; Fasting; Female; Humans; Liver Diseases; Male; Middle Aged; Models, Biological; Neoplasms; Nitriles; Panobinostat; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Renal Insufficiency

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. It is eliminated via multiple pathways including oxidative metabolism (∼70%) and renal excretion (29%). This study aimed to predict the impact of drug-drug interactions and renal or hepatic impairment on tofacitinib pharmacokinetics using a physiologically based pharmacokinetic (PBPK) model. The model was developed using Simcyp based on the physicochemical properties and in vitro and in vivo pharmacokinetics data for tofacitinib. The model was verified by comparing the predicted pharmacokinetic profiles with those observed in available clinical studies after single or multiple doses of tofacitinib, as well as with tofacitinib as a victim of drug-drug interactions (because of inhibition of cytochrome P450 [CYP450] 3A4, CYP450 2C19, or CYP450 induction). In general, good agreement was observed between Simcyp predictions and clinical data. The results from this study provide confidence in using the PBPK modeling and simulation approach to predict the pharmacokinetics of tofacitinib under intrinsic (eg, renal or hepatic impairment) or extrinsic (eg, inhibition of CYP450 enzymes and/or renal transporters) conditions. This approach may also be useful in predicting pharmacokinetics under untested or complex situations (eg, when a combination of intrinsic and extrinsic factors may impact pharmacokinetics) when conducting clinical studies may be difficult, in response to health authority questions regarding dosing in special populations, or for labeling discussions.

Topics: Administration, Oral; Adult; Computer Simulation; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 Enzyme Inhibitors; Drug Administration Schedule; Drug Interactions; Female; Healthy Volunteers; Humans; Infusions, Intravenous; Liver Diseases; Male; Middle Aged; Models, Biological; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Renal Insufficiency; Young Adult

A 74-year-old woman was scheduled for a hepatectomy. Delayed emergence from anesthesia was anticipated because she had renal failure and liver dysfunction. We induced and maintained anesthesia for 478 minutes with propofol and remifentanil. The intraoperative course was uneventful and emergence from anesthesia was not delayed. Spontaneous respiration returned and her trachea was extubated 15 minutes after the surgery. Postoperative analgesia was established by epidural ropivacaine. This case shows that remifentanil is effective in anesthetic management for a patient with renal failure and liver dysfunction undergoing hepatectomy due to its unique mode of metabolism.

Topics: Aged; Anesthesia, General; Female; Hepatectomy; Humans; Liver Cirrhosis; Liver Neoplasms; Piperidines; Remifentanil; Renal Insufficiency

A 52-year-old man with mitochondorial encephalomyopathy was scheduled for renal transplantation from a living donor. He had some characteristic features including muscle weakness, deafness, cerebellar ataxia, diabetes meritus and renal failure. Anesthesia was induced with bolus infusion of propofol 1 mg x kg(-1) and continuous infusion of remifentanil at 0.15 microg x kg(-1) x min(-1) was started. After supporting ventilation for three minutes, the trachea was intubated without any muscle relaxant. Anesthesia was maintained with sevoflurane (0.4-1.0%), air and oxygen (33-50%) and with continuous infusion of 0.1-0.15 microg x kg(-1) x min(-1) of remifentanil without any muscle relaxant. The circulatory status was maintained with 1-5 microg x kg(-1) x min(-1) of dopamine depending on changes of CVP and BP. At the conclusion of the operation, respiratory depression lasted for about 25 minutes. After administration of naloxone 40 microg to antagonize the action of remifentanil, the patient recovered fully from the respiratory depression. The urine output was depressed initially after implantation of donor's kidney, but gradually increased to a usual recovery pattern. This case suggests that careful administration of remifentanil is mandatory in a patient with mitochondorial encephalomyopathy which enhances respiratory depression from opioids.

Topics: Analgesia, Epidural; Anesthesia, General; Humans; Kidney Transplantation; Male; Methyl Ethers; Middle Aged; Mitochondrial Encephalomyopathies; Piperidines; Remifentanil; Renal Insufficiency; Sevoflurane

The aim of this study was to investigate the putative beneficial effect of halofuginone on gentamicin-induced nephrotoxicity in rats. Sprague-Dawley rats were treated with gentamicin sulphate (GEN; 80 mg/kg) or saline intraperitoneally (i.p.) for 7 days. Halofuginone was administered (0.1 mg/kg/day; i.p.) following GEN or saline injections. Blood and urine samples were collected to measure the renal function tests. Kidneys were excised for histological evaluation and for the measurement of malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO) activity, and chemiluminescence (CL). Halofuginone treatment to animals with GEN-induced renal injury caused a significant decrease in serum blood urea nitrogen level and reduced the elevated MDA, GSH content, and MPO activity. It was also effective in reversing the elevated CL values of rats with GEN-induced nephrotoxicity and preserving renal morphology, as examined microscopically. In conclusion, halofuginone was beneficial in GEN-induced acute nephrotoxicity. The mechanism could be attributed, at least in part, to decreased tissue leukocyte infiltration and reactive metabolite production.

Topics: Animals; Antioxidants; Chlorides; Drug Interactions; Female; Gentamicins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Kidney Function Tests; Kidney Tubules; Male; Malondialdehyde; Oxidative Stress; Piperidines; Plant Extracts; Quinazolinones; Rats; Rats, Sprague-Dawley; Renal Insufficiency

To assess the differences in the pharmacokinetics and cardiac safety of ebastine and its active metabolite, carebastine, in patients with normal and impaired renal function.. Twenty-four patients with varying degrees of renal impairment (mild, moderate or severe: n = 8 per group) and 12 healthy subjects participated in an open-label, parallel-group, multicentre study. Ebastine 20mg was administered orally once daily for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours on day 1 and for 72 hours on day 5 by using a validated sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 ng/mL for ebastine and 1.00 ng/mL for carebastine. Renal function was assessed by measuring 24-hour creatinine clearance (CL(CR)) at baseline. Cardiac and general safety parameters were also monitored.. The pharmacokinetics of ebastine were not modified by renal impairment. No correlation between ebastine pharmacokinetics and renal function, as expressed by CL(CR) assessed 2 days prior to dosing, was observed. Comparison of the plasma exposure and the elimination half-life of ebastine and carebastine between groups showed no significant differences. Therefore, no apparent accumulation of ebastine and carebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics for both healthy subjects and patients with renal impairment, even though the variability between the groups was large. In addition, no differences were observed in the safety of ebastine between patients with renal impairment and healthy subjects when assessing adverse events, vital signs, laboratory parameters or ECGs.. Ebastine was generally well tolerated in subjects with impaired renal function. No clinically important pharmacokinetic or safety differences were observed between patients with renal impairment and healthy subjects with normal renal function.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Butyrophenones; Drug Administration Schedule; Drug Monitoring; Electrocardiography; Female; Half-Life; Histamine H1 Antagonists; Humans; Kidney Function Tests; Male; Middle Aged; Piperidines; Renal Insufficiency

Slowly progressive renal injury is the major cause for ESRD. The model of progressive immune complex glomerulonephritis in autoimmune MRL(lpr/lpr) mice was used to evaluate whether chemokine receptor CCR1 blockade late in the disease course can affect progression to renal failure. Mice were treated with subcutaneous injections of either vehicle or BX471, a nonpeptide CCR1 antagonist, three times a day from week 20 to 24 of age [corrected]. BX471 improved blood urea nitrogen levels (BX471, 35.1 +/- 5.3; vehicle, 73.1 +/- 39.6 mg/dl; P < 0.05) and reduced the amount of ERHR-3 macrophages, CD3 lymphocytes, Ki-67 positive proliferating cells, and ssDNA positive apoptotic cells in the interstitium but not in glomeruli. Cell transfer studies with fluorescence-labeled T cells that were pretreated with either vehicle or BX471 showed that BX471 blocks macrophage and T cell recruitment to the renal interstitium of MRL(lpr/lpr) mice. This was associated with reduced renal expression of CC chemokines CCL2, CCL3, CCL4, and CCL5 and the chemokine receptors CCR1, CCR2, and CCR5. Furthermore, BX471 reduced the extent of interstitial fibrosis as evaluated by interstitial smooth muscle actin expression and collagen I deposits, as well as mRNA expression for collagen I and TGF-beta. BX471 did not affect serum DNA autoantibodies, proteinuria, or markers of glomerular injury in MRL(lpr/lpr) mice. This is the first evidence that, in advanced chronic renal injury, blockade of CCR1 can halt disease progression and improve renal function by selective inhibition of interstitial leukocyte recruitment and fibrosis.

Topics: Animals; Autoantibodies; Blood Urea Nitrogen; CD3 Complex; CD8-Positive T-Lymphocytes; Chemokines; Disease Progression; DNA; DNA, Single-Stranded; Fibrosis; Glomerulonephritis; In Situ Hybridization; Ki-67 Antigen; Kidney; Leukocytes; Lupus Nephritis; Lymphocytes; Macrophages; Mice; Mice, Inbred MRL lpr; Microscopy, Fluorescence; Phenylurea Compounds; Piperidines; Receptors, CCR1; Receptors, Chemokine; Renal Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; T-Lymphocytes; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

A 34-h remifentanil infusion was administered for labor analgesia in a patient with thrombocytopenia and renal insufficiency. Compared with other opioids, remifentanil may produce fewer cumulative effects during prolonged infusion because of its unique metabolism.

Topics: Analgesia, Obstetrical; Analgesics, Opioid; Antiphospholipid Syndrome; Female; Fetus; Humans; Infant, Newborn; Infusions, Intravenous; Male; Pain Measurement; Piperidines; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Remifentanil; Renal Insufficiency; Thrombocytopenia

Remifentanil is an opioid analgesic for use in anesthesia. An ester linkage renders it susceptible to rapid metabolism by blood and tissue esterases. Thus it was hypothesized that remifentanil elimination would be independent of renal function. Because its principal metabolite (GR90291) is eliminated renally, it would depend on renal function. This study was designed to evaluate the pharmacokinetics and pharmacodynamics of remifentanil and its metabolite in persons with and without renal failure.. Two groups of volunteers received two-stage infusions of remifentanil: low dose with 0.0125 microg x kg(-1) x min(-1) for 1 h followed by 0.025 microg x kg(-1) x min(-1) for 3 h; and high dose with 0.025 microg x kg(-1) x min(-1) for 1 h followed by 0.05 microg x kg(-1) x min(-1) for 3 h. Blood samples were collected for analysis of remifentanil and GR90291 concentrations. The pharmacokinetics of remifentanil were fit using a one-compartment pharmacokinetic model. Remifentanil's effect was determined intermittently using minute ventilation during a hypercapnic (7.5% CO2) challenge.. Fifteen patients with renal failure and eight control participants were enrolled. The clearance and volume of distribution of remifentanil were not different between those with renal failure and the controls. Patients with renal failure showed a marked reduction in the elimination of GR90291; the half-life of the metabolite increased from 1.5 h in the controls to more than 26 h in patients with renal failure. The steady-state concentration of GR90291 is likely to be more than 25 times higher in persons with renal failure. There were no obvious differences in opioid effects on minute ventilation in the controls and in patients with renal failure.. The pharmacokinetics and pharmacodynamics of remifentanil were not altered in patients with renal disease, but the elimination of its principal metabolite, GR90291, was markedly reduced. Based on simulations, the concentration of GR90291 at the end of a 12-h remifentanil infusion of 2 microg x kg(-1) x min(-1) is not likely to produce significant opioid effects.

Topics: Analgesics, Opioid; Female; Humans; Male; Piperidines; Remifentanil; Renal Dialysis; Renal Insufficiency

Risperidone is rapidly and completely absorbed after oral administration; less than 1% is excreted unchanged in the feces. The principal metabolite was found to be 9-hydroxyrisperidone. Hydroxylation of risperidone is subject to the same genetic polymorphism as debrisoquine and dextromethorphan. In poor metabolizers the half-life of risperidone was about 19 hours compared with about 3 hours in extensive metabolizers. However, becuase the pharmacology of 9-hydroxyrisperidone is very similar to that of risperidone, the half-life for the "active fraction" (risperidone +9-hydroxyrisperidone) was found to be approximately 20 hours in extensive and poor metabolizers. We found that risperidone exhibited linear elimination kinetics and that steady state was reached within 1 day for risperidone and within 5 days for the active fraction.

Topics: Aged; Animals; Antipsychotic Agents; Biotransformation; Dogs; Half-Life; Humans; Isoxazoles; Liver Cirrhosis; Male; Paliperidone Palmitate; Piperidines; Pyrimidines; Rats; Reference Values; Renal Insufficiency; Risperidone; Schizophrenia

Renal patients often complain of vague abdominal symptoms compatible with a gastric motility disorder. Cisapride is a recently available prokinetic agent that improves motility and emptying of the upper gastrointestinal tract in patients on long-term dialysis. The drug is extensively metabolized in the liver producing metabolites with minimal pharmacologic activity. Adverse reactions are primarily gastrointestinal in nature and include abdominal cramps, flatulence, and diarrhea.

Topics: Cisapride; Gastroesophageal Reflux; Humans; Piperidines; Renal Dialysis; Renal Insufficiency