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Hepatic Impairment (hepatic + impairment)
Selected AbstractsPharmacokinetics of dipeptidylpeptidase-4 inhibitorsDIABETES OBESITY & METABOLISM, Issue 8 2010A. J. Scheen Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose-induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase-4 (DPP-4) inhibitors are new oral glucose-lowering agents, so-called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed-dose combined formulations with metformin. Other DPP-4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP-4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle-aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half-life and sustained DPP-4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice-daily administration is recommended because of a shorter half-life. DPP-4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP-4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP-4 inhibitors suggest that these compounds are not exposed to a high risk of drug,drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose-lowering effect without inducing hypoglycaemia or weight gain, DPP-4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice. [source] Clinical Pharmacokinetics of FrovatriptanHEADACHE, Issue 2002P. Buchan PhD Objective.,To review available data on the clinical pharmacokinetics of frovatriptan. Background.,Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from that of the currently available triptans. Methods.,Studies of healthy volunteers, subjects with renal or hepatic impairment, elderly subjects, and patients with migraine during and between attacks were reviewed. Results.,Oral bioavailability of frovatriptan is 22% to 30%, and although the time to maximum concentration is typically 2 to 3 hours, approximately 60% to 70% of plasma maximum concentration is achieved within 1 hour of dosing. Frovatriptan distributes into erythrocytes, with binding reversible and time dependent. The relatively long terminal elimination half-life (about 26 hours) confers good systemic exposure and may produce a long duration of therapeutic action, thus reducing migraine recurrence and the need for redosing. Systemic exposure to frovatriptan generally correlates with dose between 1 and 100 mg. Blood and plasma frovatriptan concentrations are consistently higher in females, but there is no need to adjust dose according to gender. Pharmacokinetics are essentially unaffected by food and were predictable after repeat dosing; steady state is approached in about 4 to 5 days. Pharmacokinetics were changed only slightly in subjects with renal impairment or mild-to-moderate hepatic impairment, elderly individuals, and during migraine attacks. Frovatriptan is principally metabolized by the CYP1A2 isoenzyme of cytochrome P-450 and is cleared by the kidney and liver, each having sufficient capacity to compensate for impairment of the other. Conclusions.,Frovatriptan can be taken without regard for food intake, and because of the large therapeutic margin and shallow dose-response curve, there is no need for dosage adjustment in the elderly, in women taking a combined oral contraceptive, in patients with mild-to-severe renal impairment, mild-to-moderate hepatic impairment, or according to gender. The long duration of exposure may reduce the likelihood of early migraine recurrence. [source] Use of paroxetine for the treatment of depression and anxiety disorders in the elderly: a reviewHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 3 2003*Article first published online: 11 DEC 200, Michel Bourin Abstract Paroxetine is a potent selective serotonin reuptake inhibitor (SSRI) with indications for the treatment of depression, obsessive, compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder and chronic headache. There is wide interindividual variation in the pharmacokinetics of paroxetine in adults as well as in the elderly with higher plasma concentrations and slower elimination noted in the latter. Elimination is also reduced in severe renal and hepatic impairment, however, serious adverse events are extremely rare even in overdose. A Pub Med search was used to collect information on the efficacy and tolerability in elderly patients. There are few studies of depression in the elderly and only one study in the old,old. In anxiety disorders including general anxiety disorder, panic disorder, obsessive,compulsive disorder and social anxiety, there are no studies at all in the elderly. However, the safety of the drug allows its prescription in the elderly. In summary, paroxetine is well tolerated in the treatment of depression in those between the ages of 65 and 75, although few studies have examined its use in those of 75 and older. Copyright © 2002 John Wiley & Sons, Ltd. [source] Nordic guidelines for neuraxial blocks in disturbed haemostasis from the Scandinavian Society of Anaesthesiology and Intensive Care MedicineACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 1 2010H. BREIVIK Background: Central neuraxial blocks (CNBs) for surgery and analgesia are an important part of anaesthesia practice in the Nordic countries. More active thromboprophylaxis with potent antihaemostatic drugs has increased the risk of bleeding into the spinal canal. National guidelines for minimizing this risk in patients who benefit from such blocks vary in their recommendations for safe practice. Methods: The Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) appointed a task force of experts to establish a Nordic consensus on recommendations for best clinical practice in providing effective and safe CNBs in patients with an increased risk of bleeding. We performed a literature search and expert evaluation of evidence for (1) the possible benefits of CNBs on the outcome of anaesthesia and surgery, for (2) risks of spinal bleeding from hereditary and acquired bleeding disorders and antihaemostatic drugs used in surgical patients for thromboprophylaxis, for (3) risk evaluation in published case reports, and for (4) recommendations in published national guidelines. Proposals from the taskforce were available for feedback on the SSAI web-page during the summer of 2008. Results: Neuraxial blocks can improve comfort and reduce morbidity (strong evidence) and mortality (moderate evidence) after surgical procedures. Haemostatic disorders, antihaemostatic drugs, anatomical abnormalities of the spine and spinal blood vessels, elderly patients, and renal and hepatic impairment are risk factors for spinal bleeding (strong evidence). Published national guidelines are mainly based on experts' opinions (weak evidence). The task force reached a consensus on Nordic guidelines, mainly based on our experts' opinions, but we acknowledge different practices in heparinization during vascular surgery and peri-operative administration of non-steroidal anti-inflammatory drugs during neuraxial blocks. Conclusions: Experts from the five Nordic countries offer consensus recommendations for safe clinical practice of neuraxial blocks and how to minimize the risks of serious complications from spinal bleeding. A brief version of the recommendations is available on http://www.ssai.info. [source] Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver diseaseJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2009D. S. Small PhD Summary Background and Objective:, Prasugrel is a thienopyridine antiplatelet agent under investigation for the prevention of atherothrombotic events in patients with acute coronary syndrome who undergo percutaneous coronary intervention. Patients with chronic liver disease are among those in the target population for prasugrel. As hepatic enzymes play a key role in formation of prasugrel's active metabolite, hepatic impairment could affect the safety and/or efficacy of prasugrel in such patients. Methods:, This was a parallel-design, open-label, multiple dose study of 30 subjects, 10 with moderate hepatic impairment (Child-Pugh Class B) and 20 with normal hepatic function. Prasugrel was administered orally as a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MDs) for 5 days. Pharmacokinetic parameters (AUC0,t, Cmax and tmax) and maximal platelet aggregation (MPA) by light transmission aggregometry were assessed after the LD and final MD. Results and Discussion:, Exposure to prasugrel's active metabolite was comparable between healthy subjects and those with moderate hepatic impairment. Point estimates for the ratios of geometric least square means for AUC0,t and Cmax after the LD and last MD ranged from 0·91 to 1·14. MPA to 20 ,m ADP was similar between subjects with moderate hepatic impairment and healthy subjects for both the LD and MD. Prasugrel was well tolerated by all subjects, and adverse events were mild in severity. Conclusion:, Moderate hepatic impairment appears to have no effect on exposure to prasugrel's active metabolite. Furthermore, MPA results suggest that moderate hepatic impairment has little or no effect on platelet aggregation relative to healthy controls. Overall, these results suggest that a dose adjustment would not be required in moderately hepatically impaired patients taking prasugrel. [source] Optimizing outcomes with incretin-based therapies: Practical information for nurse practitioners to share with patientsJOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS, Issue 2009BC-ADM, C-RNP, CDE Nurse Practitioner, Evelyne Fleury-Milfort MSN, Instructor in Clinical Medicine Abstract Purpose: To introduce the role of incretin therapies and suggest strategies for nurse practitioners to implement them in practice. Data sources: PubMed, Medline, summary of product characteristics/package inserts. Conclusions: Incretin-based therapies offer a new alternative to currently available agents. They provide adequate levels of glycemic control and are associated with low incidence of hypoglycemia and weight gain. Dipeptidyl peptidase-4 inhibitors, for example sitagliptin, have a modest effect on A1c levels (,0.7%) as monotherapy; however, they reduce A1c to a greater extent when combined with metformin (,2.0%). Typical starting dose of sitagliptin is 100 mg; dose adjustments are required in subjects with renal complications. Glucagon-like peptide-1 receptor agonists, exenatide and liraglutide, reduce A1c levels (often in excess of 1.5%) and body weight. Exenatide has a starting dose of 5 ,g and is not recommended for patients with hepatic impairment or severe/end-stage renal disease. Liraglutide has been found to benefit from a stepwise dose escalation (i.e., 0.6 mg weekly increments) until a 1.8-mg dose is reached. Unlike exenatide, dose adjustments in patients with renal and hepatic complications are not required. Implications for practice: Incretin-based therapies may help to overcome some of the drawbacks of current therapies used to treat type 2 diabetes. [source] Ebastine in allergic rhinitis and chronic idiopathic urticariaALLERGY, Issue 2008J. Sastre Histamine is a key mediator in the development of allergy symptoms, and oral H1 -antihistamines are among the most widely used treatments for symptomatic relief in conditions such as allergic rhinitis and chronic urticaria. Ebastine is a second-generation antihistamine which has been shown to be an effective treatment for both seasonal and perennial allergic rhinitis. In controlled clinical trials in adult and adolescent patients with allergic rhinitis, ebastine 10 mg once-daily improved symptoms to a significantly greater extent than placebo and to a similar extent as loratadine 10 mg and cetirizine 10 mg (both once-daily), while ebastine 20 mg proved to be more effective than these two comparator antihistamines. In addition, ebastine was significantly more effective than placebo at relieving the symptoms of chronic idiopathic urticaria. Ebastine provides efficacy throughout the 24-h dosing interval with once-daily administration and clinical benefit is seen from the first day of treatment. Small studies have found beneficial effects for ebastine in patients with other disorders, including cold urticaria, dermographic urticaria, atopic asthma, mosquito bites and (in combination with pseudoephedrine) the common cold. In addition to the regular ebastine tablet, a fast-dissolving tablet (FDT) formulation, which disintegrates in the mouth without the aid of a drink, is also available. It has been shown to be bioequivalent to the regular tablet, and to be significantly more effective than desloratadine at reducing histamine-induced cutaneous wheals. A number of patient surveys demonstrated that the majority of individuals who tried the fast-dissolving formulation reported it to be convenient for use, fast-acting and preferred it to their previous antihistamine medication. Perhaps most importantly, a large proportion of patients indicated that they would prefer to use this new formulation in the future. Ebastine has a rapid onset of action and it can be administered once-daily, with or without food. Dose modifications are not needed in elderly patients, or in those with renal or mild to moderate hepatic impairment. Ebastine is generally well-tolerated, and clinical studies showed that at usual therapeutic doses of 10 and 20 mg once-daily, it had no clinically relevant adverse effects on cognitive function and psychomotor performance or on cardiovascular function. In conclusion, ebastine is an effective and generally well-tolerated treatment for allergic rhinitis and chronic idiopathic urticaria. In addition to the regular tablet formulation, ebastine is available as a FDT, providing a treatment option that is particularly convenient for patients. [source] Long-Term Outcomes of Liver Transplantation in Type 1 Gaucher DiseaseAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010R. M. Ayto Gaucher disease (GD) is the most prevalent lysosomal storage disorder. Enzyme replacement therapy (ERT) has demonstrable efficacy in reversing clinical and pathological manifestations of GD. We report four patients with GD and severe hepatic impairment who were successfully treated by orthotopic liver transplantation. Liver failure resulted from GD in two patients and due to a comorbidity in two others (HCV and autoimmune chronic active hepatitis). Following successful liver transplantation, patients received long-term ERT. Liver transplantation is a life-saving treatment for end-stage liver disease in patients with Gaucher disease. All four patients have had excellent outcomes from liver transplantation for up to 10 years postprocedure with no evidence of Gaucher-related pathology in the graft. [source] Comparison of liver hemodynamics according to doppler ultrasonography in alcoholic patients subtyped by Cloninger classification and non-alcoholic healthy subjectsACTA NEUROPSYCHIATRICA, Issue 1 2006Z. Sumru Cosar Background:, The aim of this study was to search for morphological and hemodynamic changes in hepatic and splanchnic vasculature in alcoholic patients without the signs of hepatic damage and subtyped by Cloninger classification by means of sonography, and compare the subtypes among themselves and with nonalcoholic healthy subjects. Methods:, Thirty alcohol dependent patients and 30 healthy subjects with no alcohol problem or hepatic impairment were included in the study. Patients were subtyped by Cloninger classification and all patients were evaluated by gray-scale and spectral Doppler ultrasound. The diameter of the portal vein, portal venous velocity, peak systolic and end diastolic velocities of hepatic and superior mesenteric arteries were assessed. RI, PI and systolic/diastolic velocity ratios were also calculated. Results:, Portal vein diameter (PV diameter), portal vein cross sectional area (PV area), portal vein velocity (PV PSV), hepatic artery peak systolic velocity (HA PSV), hepatic artery end diastolic velocity (HA EDV), hepatic artery resistive index (HA RI), hepatic artery pulsatility index (HA PI), and systolic/diastolic velocity ratios (HA S/D), superior mesenteric artery peak systolic velocity (SMA PSV), superior mesenteric artery end diastolic velocity (SMA EDV), superior mesenteric artery resistive indices (SMA RI), pulsatility index (SMA PI), and systolic/diastolic velocity rates (SMA S/D) showed no significant difference among the groups (P > 0.01). Although there is no significant difference in PV PSV, HA PSV, SMA PSV, SMA EDV values between the groups, mean values of Type II alcoholics is greater than other groups. Portal vein cross-sectional area was greater in alcoholic patients (Type I, II and III) compared to the control group (P = 0.000). Portal vein velocity, hepatic artery peak systolic and end diastolic velocity, superior mesenteric artery peak systolic and end diastolic velocity were significantly greater in alcoholic patients than in the control group (P < 0.001). No statistical difference was detected between other parameters evaluated. Conclusion:, In alcohol dependent patients, some hemodynamic and morphologic changes occur in hepatic and splanchnic circulation, even before the signs of hepatic damage develop, which can be detected by means of Doppler and gray-scale sonography. But as there is no significant difference between the Doppler ultrasonographic findings among alcoholics subtyped by a Cloninger classification, which is a clinical classification, it suggests that psychiatric classification doesn't show any correlation with biological parameters, and because of this Cloninger classification a psychiatric classification cannot be considered as a characteristic determinative factor in the prognosis of hepatic disorder due to alcohol use. However, higher values of Type II alcoholics can be attributed to the longer alcohol intake of this subtype. [source] | ||||||||||