Home About us Contact
|
Home About us Contact | ||
|
|
||
Dose Adjustment (dose + adjustment)
Selected AbstractsDifferential Dose Adjustments of Immunosuppressants after Resuming Boosted versus Unboosted HIV-Protease Inhibitors Postliver TransplantAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009G. Guaraldi Pharmacokinetic (PK) interactions between protease inhibitors (PIs) and immunosuppressive agents (IS) are critical elements in the management of HIV-infected patients who undergo liver transplantation (LTx). The primary objective of this study was to evaluate the decreases in IS dosages necessary to maintain an appropriate therapeutic window (TW) after initiating PI-based antiretroviral therapy regimens post-LTx. Single-center, PK cross-sectional study of consecutive HIV-infected adult patients who underwent LTx was done. Blood trough concentrations (Ct) of IS were obtained using a commercial MEIA test; plasma Ct of PIs were measured using HPLC. Twelve consecutive HIV-infected adult patients (11 males, 1 female) were enrolled. More rapid increases in IS plasma Ct were observed 48 h after initiating ritonavir (RTV)-boosted PI therapy post-LTx than when using unboosted PIs. Seven patients developed acute renal failure. The median fold decrease in IS dosages required to regain IS concentrations that were in the TW was 7.5 (range 6,14) after resuming boosted PIs and 2.9 (range 2,4) after unboosted PIs. The overall median time necessary to reach IS TW after dose adjustment was 3.5 days (range 0,15). Unboosted PIs exhibited lesser PK interactions with IS than did RTV-boosted PIs and were thus more amenable to use in the post-LTx setting. [source] Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2008Furong Qiu What is already known about this subject ,,Danshen extract is widely used for the treatment and prevention of coronary heart disease and other diseases of senility in Asia. ,,Danshen extract and theophylline may be prescribed together to treat patients with asthma. ,,In human, theophylline with low therapeutic index is mainly metabolized by CYP1A2. ,,In vitro findings have shown that human CYP1A2 is inhibited by the ethyl acetate extract of danshen and danshen pharmaceutical product. ,,There may be drug interactions between danshen extract and theophylline (CYP1A2 substrate). What this study adds ,,This study concerned drug interactions between danshen extract and theophylline in Chinese volunteers. ,,Long-term oral intake of danshen extract does not change the basic pharmacokinetic parameters of theophylline. ,,Dose adjustment of theophylline thus may not be necessary in patients receiving concomitant therapy with danshen extract. Aims To examine the potential effect of danshen extract on the pharmacokinetics of theophylline. Methods In a sequential cross-over study with two phases, 12 volunteers took 100 mg theophylline on day 1 and day 15. From day 2 to day 15, volunteers received danshen extract tablets three times daily, four tablets each time for 14 days. On day 15, they received four danshen extract tablets with 100 mg theophylline. Plasma concentrations of theophylline were measured on days 1 and 15 periodically for 24 h. Results The 90% confidence interval of Cmax, t1/2 and CL/F of theophylline with 14-day danshen extract tablets vs. without comedication were (101.42, 121.36) (84.57, 106.72) and (88.82, 105.72), respectively. The time to peak plasma theophylline concentration was unchanged by danshen (P > 0.05). The pharmacokinetics parameter of theophylline was unaffected by danshen extract. Conclusions Danshen extract does not influence the metabolism of theophylline in healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with danshen extract tablets. [source] Clinical benefit of interventions driven by therapeutic drug monitoringHIV MEDICINE, Issue 5 2005AL Rendón Background Adequate plasma concentrations of antiretroviral drugs are key to achieving and maintaining long-term suppression of HIV replication. Multiple factors may influence drug levels, causing increases or reductions that may, respectively, result in toxicity or virological failure. Therapeutic drug monitoring (TDM) might help to detect and correct such abnormalities. Objective To evaluate the usefulness of TDM in the care of HIV-infected patients in an out-patient clinical setting. Methods All the requests for TDM of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients attending our HIV out-patient clinic from October 2000 to August 2003 were analysed. Blood samples were collected before the morning dose. Drug concentrations were measured by high performance liquid chromatography by ultraviolet waves (HPLC-UV). Results A total of 151 requests from 137 patients were assessed. The reasons for requesting TDM were drug toxicity (59%), virological failure (39%) and possible drug interactions (2%). NNRTI levels were more often requested because of toxicity, while PI levels were more often requested because of virological failure. Elevated drug levels were confirmed in 36% of patients with suspected drug toxicity, while subtherapeutic levels were found in 37% of patients failing virologically. Based on the results of TDM, dose modifications were made in 37% of patients, allowing correction of such abnormalities in 80% of cases. Moreover, adequate plasma concentrations were confirmed in 79% of patients whose levels were assessed again. Conclusions Therapeutic drug monitoring may be a useful tool to identify toxic levels of NNRTI and subtherapeutic concentrations of PI. Dose adjustments following TDM may ameliorate drug-related toxicities or improve virological response rates. [source] Pharmacokinetics 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] Training in flexible, intensive insulin management to enable dietary freedom in people with Type 1 diabetes: dose adjustment for normal eating (DAFNE) randomized controlled trialDIABETIC MEDICINE, Issue 2003DAFNE Study Group No abstract is available for this article. [source] Absence of veno-occlussive disease in a cohort of multiple myeloma patients undergoing autologous stem cell transplantation with targeted busulfan dosageEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2006A. Clopés Abstract:,Background:,Plasma concentrations of oral busulfan (BU) were measured in multiple myeloma (MM) patients undergoing autologous peripheral blood stem cell transplantation (ASCT) with a double alkylating conditioning protocol in order to individualise doses of BU based on individual pharmacokinetic parameters and to reduce toxicities related to BU exposure. Patients and methods:,Forty-four consecutive patients with MM participating in the co-operative Spanish protocol were prospectively evaluated. Conditioning regimen prior to autologous infusion consisted of BU followed by melphalan. BU pharmacokinetic parameters were estimated for each patient after the first dose based on measured concentrations and subsequent doses were modified as necessary to achieve target exposure. Results:,Mean BU exposure (AUCss) (±DS) before dosage modification range from 3192 to 12 180 ng h/mL. Twenty-six out of 44 (59%) patients required dose adjustment. None of the patients developed hepatic veno-occlusive disease (VOD). Grade , II oropharyngeal mucositis was observed in the majority of patients (95%) and the severity of mucositis increased with increasing average steady-state BU plasma concentration. There were four treatment-related deaths: two patients died from multiorgan failure and two of respiratory infections. Of the remaining 40 patients, 15 were in complete remission with negative immunofixation, 21 in partial remission and four in stable disease 3 months after ASCT. Conclusions:,The results of the present study show the variability in BU pharmacokinetic parameters and suggest the possible relationship between toxicities and BU exposure. Individualising BU dosage in MM patients undergoing ASCT we observed the absence of VOD. [source] CLINICAL STUDY: Effect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapyADDICTION BIOLOGY, Issue 3 2009Candice Jamois ABSTRACT This study was performed to determine the effect of two protease inhibitors, saquinavir (SQV, oral 1000 mg bid) boosted by ritonavir (RTV, oral 100 mg bid), on pharmacokinetics (PK) of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. This was a two-center, open-label, one-sequence cross-over, multiple-dose study in 13 HIV-negative patients who were on stable methadone therapy (oral, 60,120 mg qd). All patients continued methadone treatment on days 2,15. All patients received SQV/RTV in combination with methadone from days 2,15. PK of methadone was assessed on day 1 (alone) and on day 15 when methadone treatment was combined with SQV/RTV at steady state. Twelve patients completed the study. Median age, body weight and height were 50 years (range: 24,54 years), 80 kg (range: 57,97 kg) and 174 cm (range: 163,189 cm), respectively. All patients were Caucasian, and 11 were smokers. Median methadone dose was 85 mg qd. Geometric mean area under curve of the plasma concentration-time curve over 24 hour dosing interval (AUC0,24 hour) ratio of methadone with and without SQV/RTV was 0.81% (90% confidence interval: 71,91%). There was no significant plasma protein-binding displacement of methadone by SQV/RTV. The combination of SQV/RTV and methadone was well tolerated. There were no clinically significant adverse events or significant changes in laboratory parameters, electrocardiograms or vital signs. The 19% decrease in R-methadone AUC0,24 hour in the presence of SQV/RTV was not clinically relevant. There appears to be no need for methadone dose adjustment when methadone (60,120 mg qd) and SQV/RTV (1000/100 mg bid) are coadministered. [source] Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2002Annick Rousseau Abstract Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin, carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration,time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued. [source] Mirtazapine and paroxetine: a drug-drug interaction study in healthy subjectsHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 6 2001F. J. L. Ruwe Abstract Paroxetine inhibits cytochrome P450 2D6, which is involved in the metabolism of mirtazapine. The possible drug-drug interaction between two pharmacologically distinct antidepressants, mirtazapine and paroxetine, has been investigated in a randomized, three-way crossover study in 24 healthy male and female subjects. After a titration phase of 3 days, each subject received single daily doses of 30,mg mirtazapine, 40,mg paroxetine or the combination for 6 days. Assessments included serial blood sampling for pharmacokinetics at steady state, cognitive testing using the test battery of CDR Ltd, a visual analogue mood rating scale (Bond and Lader) and the Leeds Sleep Evaluation Questionnaire. Paroxetine inhibits the metabolism of mirtazapine, as shown by increases of approximately 17% and 25% of the 24,h AUC's of mirtazapine and its demethyl metabolite, respectively. Mirtazapine did not alter the pharmacokinetics of paroxetine. The combined administration of mirtazapine and paroxetine probably does not alter cognitive functioning or result in major changes on the visual analogue mood rating scale and Sleep Evaluation Questionnaire, compared with the administration of either drug alone. The incidence of adverse events was lower during combined administration of mirtazapine and paroxetine than during administration of either drug alone. Fatigue, dizziness, headache, nausea, anxiety and somnolence were the most common adverse events during combined administration. These data suggest that the combination of mirtazapine and paroxetine is unlikely to lead to clinically relevant drug-drug interactions and can be used without dose adjustment of either drug. The combination may even be better tolerated than either drug alone. Copyright © 2001 John Wiley & Sons, Ltd. [source] Thrombelastometry-guided thrombolytic therapy in massive pulmonary artery embolismACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2010A. PLOPPA We report a case of a patient who suffered a massive pulmonary embolism with cardiac arrest on post-operative day 4 after a Whipple operation. Despite thrombolytic therapy with the recommended maximal bolus of 50 mg recombinant tissue type plasminogen activator (rt-PA), thrombelastometry showed no signs of fibrinolysis and cardiogenic shock persisted, after only a transient hemodynamic improvement. Not until a repeat bolus of 25 mg rt-PA and an infusion of 50 mg/h did thrombelastometry demonstrate complete fibrinolysis. Although only residual emboli were seen on computed tomography, the patient died secondary to refractory right heart failure. This demonstrates that the standard dosing of thrombolytics may fail in a subgroup of patients, and suggests that thrombelastometry may be useful for early dose adjustment when standard dosing regimens fail. [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] Treatment of recurrent hepatitis B infection in liver transplant recipientsLIVER TRANSPLANTATION, Issue 10B 2002Norah A. Terrault MD 1Therapeutic decisions are guided by a patient's clinical status (severity of disease and presence of comorbidities) and previous drug-exposure history. 2Lamivudine is safe and effective in liver transplant recipients with recurrent hepatitis B virus (HBV) infection caused by wild-type virus or failure of hepatitis B immunoglobulin therapy. Lamivudine resistance, developing in approximately 25% after 12 months of therapy, is its main limitation. 3Famciclovir is safe in liver transplant recipients; however, virological and clinical responses are less consistent than with lamivudine. Thus, lamivudine is favored over famciclovir as first-line therapy in transplant recipients with no previous exposure to nucleoside analogues. 4Although limited in availability, adefovir dipivoxil appears safe and effective in treating liver transplant recipients with lamivudine-resistant HBV disease. Close monitoring of renal function is recommended, with dose adjustment in patients with reduced creatinine clearances. 5Limited data suggest that intravenous ganciclovir, tenofovir disoproxil fumarate, and interferon alfa may be useful as rescue therapies for patients with lamivudine- or famciclovir-resistant HBV disease. 6Antiviral therapy with two or more suitable agents may minimize the chance for viral resistance; therefore, future therapeutic strategies likely will use combination therapy in the long-term management of recurrent HBV disease. [source] UNINTENTIONAL OVERDOSE WITH INTRATHECAL ZICONOTIDEPAIN MEDICINE, Issue 2 2002Article first published online: 4 JUL 200 Steven G. Charapata MD, Research Medical Center, Kansas City, MO; David Ellis MD, PhD, Elan Pharmaceuticals, South San Francisco, CA Ziconotide is a novel, N-type, voltage-sensitive calcium channel (VSCC) blocker, with well-documented efficacy as an intrathecal (IT) analgesic. Ziconotide has been administered to over 1000 chronic pain patients in nine clinical trials. Over 350 patients have been on ziconotide IT therapy for more than three months in a long-term safety and tolerability study. Common adverse events for ziconotide include dizziness, nausea, nystagmus, abnormal gait, constipation, urinary retention, somnolence, postural hypotension, vomiting, confusion and abnormal vision. Ziconotide adverse events are recognizable, reversible and manageable, by dose adjustment and slow dose titration. Case reports of unintentional overdose in six chronic pain patients treated with IT ziconotide are presented. These unintentional overdoses were attributable to pump programming or dilution errors; none were lethal. The patient who received the highest overdose was administered 31 mcg/hr over 24 hours, or nearly 750 mcg ziconotide, total. This hourly dose rate is 300-fold the current recommended initial dose rate of 0.1 mcg/hr. This patient was sedated, but arousable; vital signs were stable and patient had no change in blood pressure. His symptoms resolved within 24 hours. His Visual Analog Score of Pain Intensity (VASPI) was reduced from 82 at baseline to 2.5 at the end of the titration period. The patient elected to continue in the long-term IT ziconotide study. The other 5 cases of inadvertent overdose were less severe, with dose rate at 5 mcg/hr or less. Associated adverse events also resolved within 24-hours of discontinuing ziconotide infusion. Unlike an unintentional overdose with IT morphine, which slows respiration and could potentially lead to hypoxia, coma or death; ziconotide does not produce respiratory depression. No tolerance to the analgesic effect of ziconotide, or withdrawal symptoms after discontinuation of the drug have been reported. Ziconotide has a wide margin of safety as an IT analgesic. [source] Improved Cancer Pain Treatment Using Combined Fentanyl-TTS and TramadolPAIN PRACTICE, Issue 4 2007Franco Marinangeli MD ,,Abstract: The aim of the study was to facilitate dose escalation of strong opioids. In this randomized open-label study the influence of tramadol on dose adjustment of transdermal fentanyl in advanced cancer pain control was prospectively evaluated. Seventy patients affected by intractable cancer disease with visual analog scale (VAS) score >3 were enrolled. Thirty-five patients were treated conventionally with increasing transdermal fentanyl dosage as required (group F) and 35 patients received oral tramadol added to their transdermal fentanyl before each increment of the transdermal opioid dosage (group T). Pain control was equally satisfactory in the two groups. VAS scores at baseline (T: 4.36 ± 1.53; F: 4.51 ± 1.36; n.s.) and at the end of the study (T: 1.8 ± 1.6; F: 1.6 ± 1.5; n.s.) did not differ. However, in the tramadol group this level of pain control was achieved with much slower dose escalation of fentanyl. The mean application time of the fentanyl-Transdermal Therapeutic System patch for each dosage (25, 50, 75 ,g/hour) was significantly greater in patients receiving tramadol. No patient in group T escalated to the 100 ,g/hour patch, while in 12 patients of group F the 100 ,g/hour patch was applied after a 75 ,g/hour patch mean application period of 18.6 ± 4.7 days. The number of fentanyl-TTS dosage changes was significantly lower in group T (1.2 ± 0.4 vs. 2.3 ± 0.5; P < 0.05). The mean total duration of treatment in group T, was 37.1 ± 11.6 days. The amount of fentanyl used at study end was 56.6 ± 11.2 ,g/hour plus 141.1 ± 151.9 mg tramadol per day (median: 200 mg/day) in group T patients compared with 84.1 ± 12.2 ,g/hour in group F patients (P < 0.05). The combination of a strong opioid with a weak opioid to treat severe cancer pain allowed a more gradual increase of analgesic delivery than was possible using fentanyl-TTS alone, minimizing periods of under- and overdosing. In addition, it considerably slowed the pace of fentanyl dose escalation. In conclusion, this TTS fentanyl-tramadol analgesic protocol provides a useful alternative to the usual treatment of cancer pain with fentanyl-TTS alone, especially in case of quick progression of disease and pain.,, [source] Single-center experience with mycophenolate mofetil in pediatric renal transplant recipientsPEDIATRIC TRANSPLANTATION, Issue 4 2001Mumtaz Virji Abstract: Mycophenolate mofetil (MMF), a potent and specific inhibitor of guanosine nucleotide synthesis, is a new immunosuppressive drug used to prevent rejection in transplant patients. Extensive data on its utility and efficacy exists in adult patients but there is limited experience in pediatrics. Twenty-four children (14 male, 10 female; 2,19 yr of age), eight of whom had received living-related donor (LRD) transplants and 16 of whom had received cadaveric donor (CD) transplants, have been treated with MMF in our institution since September 1996. MMF was administered for a duration ranging from 13 weeks to 38 months, at an average dose of 600 mg/m2 (range: 200,1,000 mg/dose) every 12 h, for a total experience of 304 patient months. MMF capsules were used in 16 patients and/or pediatric suspension in eight. Five patients were switched to MMF from azathioprine as a result of rejection episodes or inability to taper prednisone, between 5 weeks and 3.5 yr post-transplant. All patients received prednisone, cyclosporin A (CsA), and induction therapy with anti-lymphocyte globulin (19 patients), anti-thymocyte globulin (one patient) or daclizumab (four patients). In 12 patients started on MMF at the time of CD transplant, five (42%) had an acute rejection episode. In seven who received a LRD transplant, one (14%) had an acute rejection episode. No patients who were converted to MMF were treated for acute rejection following conversion to MMF. One LRD graft was lost at 19 days following injury to the donor artery at the time of retrieval. At the last follow-up, the average creatinine level was 93 µmol/L and average urea level was 8.6 mmol/L. One patient developed epigastric distress. Three patients developed diarrhea/abdominal pain requiring dose adjustment. Five episodes of leukopenia and one episode of thrombocytopenia required dose adjustment. Two patients developed symptomatic cytomegalovirus (CMV) infection, one while on acyclovir prophylaxis. No malignancy has been encountered to date. Hence, MMF can be administered safely to children with good effect and with an acceptable side-effect profile. [source] Differential Dose Adjustments of Immunosuppressants after Resuming Boosted versus Unboosted HIV-Protease Inhibitors Postliver TransplantAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009G. Guaraldi Pharmacokinetic (PK) interactions between protease inhibitors (PIs) and immunosuppressive agents (IS) are critical elements in the management of HIV-infected patients who undergo liver transplantation (LTx). The primary objective of this study was to evaluate the decreases in IS dosages necessary to maintain an appropriate therapeutic window (TW) after initiating PI-based antiretroviral therapy regimens post-LTx. Single-center, PK cross-sectional study of consecutive HIV-infected adult patients who underwent LTx was done. Blood trough concentrations (Ct) of IS were obtained using a commercial MEIA test; plasma Ct of PIs were measured using HPLC. Twelve consecutive HIV-infected adult patients (11 males, 1 female) were enrolled. More rapid increases in IS plasma Ct were observed 48 h after initiating ritonavir (RTV)-boosted PI therapy post-LTx than when using unboosted PIs. Seven patients developed acute renal failure. The median fold decrease in IS dosages required to regain IS concentrations that were in the TW was 7.5 (range 6,14) after resuming boosted PIs and 2.9 (range 2,4) after unboosted PIs. The overall median time necessary to reach IS TW after dose adjustment was 3.5 days (range 0,15). Unboosted PIs exhibited lesser PK interactions with IS than did RTV-boosted PIs and were thus more amenable to use in the post-LTx setting. [source] Sugammadex in clinical practiceANAESTHESIA, Issue 2009R. K. Mirakhur Summary The availability of sugammadex allows greater flexibility in the use of rocuronium and vecuronium during anaesthesia and surgery. The neuromuscular block induced by both drugs can be reversed from both superficial and deep levels of block by adjusting the dose of sugammadex. The dose of sugammadex for reversal of shallow block produced by these neuromuscular blocking drugs is approximately 2 mg.kg,1 and for deep block the dose is 4 mg.kg,1. A larger dose of sugammadex (16 mg.kg,1) administered 3 min after the neuromuscular blocking drug allows rapid reversal of a neuromuscular block induced by 1,1.2 mg.kg,1 of rocuronium, thereby raising the possibility of using rocuronium as a replacement for suxamethonium. The use of sugammadex has not been reported to be associated with recurrence of block provided a dose that is adequate for reversal has been used. Sugammadex appears to have an acceptable safety profile. There are no requirements for dose adjustment for age or the use of potent volatile anaesthetic agents. [source] Everolimus drug interactions: application of a classification system for clinical decision makingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2006John M. Kovarik Abstract Introduction. More than half of all drugs used in medical practice are metabolized by cytochrome CYP3A. Coadministration of drugs that share this elimination pathway may lead to pharmacokinetic drug interactions. Efforts are underway by clinical, drug development and regulatory scientists to classify CYP3A-related drug interactions with the ultimate goal of improving guidance for clinical intervention. The CYP3A inhibitory classification system ranks inhibitors according to the fold-increase in area-under-the-curve (AUC) of a probe substrate as: strong (,5-fold), moderate (>2.0- to 4.9-fold), or weak (,2.0-fold). This classification system was applied to characterize everolimus as a CYP3A substrate. Methods. Five open-label crossover drug interaction studies were performed in 12,16 healthy subjects each. Subjects received a single 2 mg dose of everolimus alone and again during single- or multiple-dose treatment with the probe inhibitors ketoconazole, erythromycin, verapamil, cyclosporine and atorvastatin. Results. The fold-increase in everolimus AUC was: 15.0 with the strong inhibitor ketoconazole; 4.4, 3.5 and 2.7 with the moderate inhibitors erythromycin, verapamil and cyclosporine; and no change with the weak inhibitor atorvastatin. Subjects with low baseline AUCs when everolimus was given alone tended to have AUC increases of a higher magnitude (more potent interaction) in the presence of an inhibitor. Conclusions. Strong CYP3A inhibitors should be avoided when possible during everolimus treatment as compensatory everolimus dose reductions could be difficult to manage. Everolimus therapeutic drug monitoring should be used to guide individualized dose adjustments when moderate CYP3A inhibitors are added to or withdrawn from the regimen. Routine everolimus therapeutic drug monitoring should be sufficient to determine whether dose adjustments are needed when weak CYP3A inhibitors are coadministered. This rational and systematic approach to drug interactions on everolimus yielded clinically useful, structured guidelines for dose adjustment. Copyright © 2006 John Wiley & Sons, Ltd. [source] Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug usersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2006Poe-Hirr Hsyu Abstract The effect of nelfinavir 1250 mg twice daily (b.i.d.) on the pharmacokinetics of methadone was determined in 14 HIV-negative methadone users. Design: The methadone dose (20,140 mg/day) was stabilized and fixed for at least 1 month before nelfinavir (1250 mg b.i.d. for 8 days) was added to the regimen. The concentrations of methadone enantiomers were measured before and during nelfinavir treatment, and the concentrations of nelfinavir and its active metabolite, AG1402, were measured during nelfinavir treatment. Adverse events and withdrawal/intoxication symptoms were monitored throughout the study. Results: Nelfinavir reduced the area under the concentration-time curve of R-methadone, and S-methadone by 43% and 51%, respectively. Nelfinavir and AG1402 concentrations were within the normal range of historical data, and no subject experienced withdrawal symptoms during the study or required dose adjustment during or after the study. Conclusions: Although nelfinavir reduced the plasma concentrations of both R- and S-methadone, it seems to have no impact on the maintenance dose of methadone. A routine reduction of methadone dose is not recommended when coadministered with nelfinavir. Copyright © 2005 John Wiley & Sons, Ltd. [source] Rapid determination method of caffeine and application to monitoring of caffeine-assisted chemotherapyBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2004Masami Kawahara Abstract Caffeine-assisted chemotherapy for bone and soft tissue tumours is very effective. However, high serum caffeine concentrations cause severe side effects, so monitoring of the serum level during therapy is important. For this purpose, a rapid determination method was established by high-performance liquid chromatography after solid-phase extraction. This method can measure caffeine and its three major metabolites in serum samples within 8 min. The mean serum caffeine concentrations of patients were 34.6±7.8, 54.5±11.9 and 73.0±12.8 ,g/ml at 24, 48 and 72 h, respectively, after the start of a 1500 mg/m2/day continuous infusion for 72 h. The distribution volume of caffeine was 0.65±0.23 l/kg, and the total body clearance was 0.025±0.011 l/h/kg, which was one-third of the reported low dose clearance. The appropriate infusion rate was calculated to avoid severe side effects in the final phase of the infusion by using a one-compartment constant infusion model based on the serum levels measured at 24 and 48 h. Caffeine clearance did not correlate with the metabolite/caffeine ratio in serum at any time. It is concluded that individual monitoring with this method for the purpose of dose adjustment is useful for avoiding the side effects of caffeine-assisted chemotherapy. Copyright © 2004 John Wiley & Sons, Ltd. [source] Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustmentBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010Stanley Cohen WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , CP-690,550 is a novel JAK inhibitor in development as a therapy for rheumatoid arthritis. , Methotrexate is the cornerstone of combination treatment for rheumatoid arthritis. , The safety and tolerability of co-administration of CP-690,550 with methotrexate have not been addressed to date. WHAT THIS STUDY ADDS , This study in patients with rheumatoid arthritis shows that there are no clinically relevant effects on the pharmacokinetics of either drug following short-term co-administration. , Co-administration of CP-690,550 and methotrexate was safe and well tolerated. AIMS To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX. METHODS This was a fixed-dose drug,drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15,25 mg per week). RESULTS All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC12 ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC12 ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments. CONCLUSIONS Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX. [source] Population pharmacokinetic analysis of varenicline in adult smokersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Patanjali Ravva WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in young adult and elderly smokers and subjects with impaired renal function. , Varenicline pharmacokinetics is linear over the recommended dose range. , Varenicline total clearance is linearly related to its renal clearance. , Both are progressively reduced as renal function declines, which results in a progressive increase in varenicline systemic exposure and prolonged half-life. WHAT THIS STUDY ADDS? , This work provides an integrated model-based analysis of varenicline pharmacokinetics across multiple studies in the target patient population. , The model describes the impact of patient-specific covariates, such as renal function, and provides a rationale for dose adjustment. , The resulting model also provides a means to predict individual-specific drug exposures to clinical responses in subsequent analyses. AIMS To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers. METHODS Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration,time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling. RESULTS A two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h,1 (10.2, 10.6); V2/F, 337 l (309, 364); V3/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h,1 (1.39, 3.79); Ka, 1.69 h,1 (1.27, 2.00); and Alag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for Ka[70% coefficient of variation (CV)], CL/F (25% CV), and V2/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h,1 for a typical subject with normal renal function (CLcr = 100 ml min,1) to 4.4 l h,1 for a typical subject with severe renal impairment (CLcr = 20 ml min,1), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics. CONCLUSIONS Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day,1, which is half the recommended dose, is indicated for subjects with severe renal impairment. [source] The effect of age, gender, and body mass index on the pharmacokinetics and pharmacodynamics of vildagliptin in healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2008Yan-Ling He What is already known about this subject ,,Vildagliptin is a new, potent, and selective inhibitor of DPP-4. ,,The efficacy and safety of vildagliptin in type 2 diabetes has been intensively studied in diverse subject populations. ,,There has been little information published about the pharmacokinetics and pharmacodynamics of vildagliptin. What this study adds ,,No clinically relevant changes in pharmacokinetics or pharmacodynamics were observed between young and elderly, male and female, or high body mass index (BMI) and low BMI subjects. ,,The results suggest that no dose modification is necessary for vildagliptin based on the age, gender, or BMI of a subject. Aims To evaluate the effect of age, gender, and body mass index (BMI) on the pharmacokinetics and pharmacodynamics of vildagliptin. Methods Forty healthy subjects received a single oral dose of 100 mg vildagliptin to assess the effects of age, gender, and BMI on the pharmacokinetics and pharmacodynamics, reflected by the time course of inhibition of DPP-4 activity, of vildagliptin. Results Peak concentration and exposure (AUC(0,,)) of vildagliptin were 17% (90% CI 2, 35%) and 31% (90% CI 18, 45%) higher in elderly vs. young subjects. Renal clearance was reduced by 32% (90% CI 17, 45%) in elderly subjects. The pharmacokinetics of vildagliptin were not significantly influenced by gender or BMI. Inhibition of DPP-4 activity was similar regardless of age, gender, or BMI. Conclusions The pharmacokinetics of a single oral 100 mg dose of vildagliptin were not affected by gender and BMI. Exposure to vildagliptin was higher in elderly patients, but this was not associated with any difference in the effect of DPP-4 inhibition. Based on these results, no vildagliptin dose adjustment is necessary for age, gender, or BMI. [source] Toxicity in standard melphalan,prednisone therapy among myeloma patients with renal failure , a retrospective analysis and recommendations for dose adjustmentBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2005Kristina Carlson Summary Haematological and infectious toxicity was correlated to renal function in 272 newly diagnosed myeloma patients given standard dose melphalan,prednisone (MP) as initial treatment without dose adjustment for renal impairment. The glomerular filtration rate (GFR) was estimated by calculated creatinine clearance. Haematological toxicity was found to be significantly related to renal dysfunction. Haematological toxicity World Health Organization (WHO) grades 3,4 after the first MP course was seen in 18%, 28% and 36% of patients with a creatinine clearance of >50, 30,50 and <30 ml/min respectively. WHO grades 3,4 infections occurred in 6% and were not significantly related to renal function. We conclude that MP therapy can be used for initial therapy in myeloma patients with renal impairment but suggest that reduction of the melphalan dose should be considered in patients with a GFR of <30 ml/min. As only 2% of our patients had a clearance of ,10 ml/min no conclusions can be drawn for this subgroup. [source] Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomitingCANCER, Issue 9 2003Sant P. Chawla M.D. Abstract BACKGROUND The neurokinin-1 antagonist aprepitant (EMENDÔ; Merck Research Laboratories, West Point, PA) has been shown to reduce chemotherapy-induced nausea and vomiting when it is given with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The current study sought to define the most appropriate dose regimen of oral aprepitant. METHODS This multicenter, randomized, double-blind, placebo-controlled study was conducted in patients with cancer who were receiving initial cisplatin (, 70mg/m2) and standard antiemetic therapy (intravenous ondansetron plus oral dexamethasone). Patients were randomized to receive standard therapy plus either aprepitant 375 mg on Day 1 and 250 mg on Days 2,5, aprepitant 125 mg on Day 1 and 80 mg on Days 2,5, or placebo. Due to an apparent interaction with dexamethasone suggested by pharmacokinetic data obtained while the study was ongoing, the aprepitant 375/250 mg dose was discontinued and replaced with aprepitant 40 mg on Day 1 and 25 mg on Days 2,5, and a new randomization schedule was generated. Patients recorded nausea and emesis in a diary. The primary endpoint was complete response (no emesis and no rescue therapy), which was analyzed using an intent-to-treat approach with data obtained after the dose adjustment. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments, and included all available data. RESULTS The percentages of patients who achieved a complete response in the overall study period were 71.0% for the aprepitant 125/80-mg group (n = 131 patients), 58.8% for the aprepitant 40/25-mg group (n = 119 patients), and 43.7% for the standard therapy group (n = 126 patients; P < 0.05 for either aprepitant regimen vs. standard therapy). Rates for Day 1 were 83.2% for the aprepitant 125/80-mg group, 75.6% for aprepitant 40/25-mg group, and 71.4% for the standard therapy group (P < 0.05 for aprepitant 125/80 mg vs. standard therapy), and rates on Days 2,5 were 72.7% for the aprepitant 125/80-mg group, 63.9% for the aprepitant 40/25-mg group, and 45.2% for the standard therapy group (P < 0.01 for either aprepitant group vs. standard therapy). The efficacy of the aprepitant 375/250-mg regimen was similar to that of the aprepitant 125/80-mg regimen. The overall incidence of adverse events was generally similar across treatment groups: 85% in the aprepitant 375/250-mg group (n = 34 patients), 76% in the aprepitant 125/80-mg group (n = 214 patients), 71% in the aprepitant 40/25-mg group (n = 120 patients), and 72% in the standard therapy group (n = 212 patients), with the exception of a higher incidence of infection in the aprepitant 125/80-mg group (13%) compared with the standard therapy group (4%). CONCLUSIONS When it was added to a standard regimen of intravenous ondansetron and oral dexamethasone in the current study, aprepitant reduced chemotherapy-induced nausea and vomiting and was generally well tolerated, although increases in infection were noted that were assumed to be due to elevated dexamethasone levels as a result of the pharmacokinetic interaction. The aprepitant 125/80-mg regimen had the most favorable benefit:risk profile. Cancer 2003;97:2290,300. © 2003 American Cancer Society. DOI 10.1002/cncr.11320 [source] A novel therapeutic paradigm to treat congenital hypothyroidismCLINICAL ENDOCRINOLOGY, Issue 1 2008Sarah Mathai Summary Objective, To determine the effectiveness of a novel therapeutic paradigm to treat congenital hypothyroidism (CH) incorporating variable initial doses of L-T4 based on the underlying aetiology and frequent monitoring, up to 2 years of age. Design, Retrospective cohort study. Patients, Infants with primary CH diagnosed by newborn screening. Measurements, Treatment with L-T4 suspension initiated at 10, 12 and 15 µg/kg/day for dyshormonogenesis, ectopia and athyreosis, respectively. Serum TSH and free T4 (FT4) levels monitored weekly during the first 4 weeks, at 6 weeks, thereafter monthly during the first 2 years. Dose changes were made to keep FT4 level in upper half of the normal range. Results, Sixty-nine infants; 17 had dyshormonogenesis, 35 ectopia and 17 athyreosis. Seventy-eight percent of subjects normalized FT4 levels within 7 days of treatment and 100% within 14 days. TSH levels normalized in 26% of infants within 7 days and in 92% by 21 days. Supraphysiological levels of FT4 were noted in 28% of infants, for a maximum of 2 weeks. 48% infants needed one dose adjustment and 30% needed at least two in the first month. In 52 infants over the first 2 years, mean FT4 levels were consistently in the upper half of the normal range. Two or more dose adjustments every 3 months were made 57 times in the first year as compared to 19 times in the second year. Conclusions, A variable initial dose paradigm based on aetiology with frequent testing and using T4 suspension rapidly normalizes FT4 levels without producing persistent hyperthyroxinaemia. [source] Optimal prophylactic dosage and disposition of micafungin in living donor liver recipientsCLINICAL TRANSPLANTATION, Issue 6 2004Satoshi Kishino Abstract:, Micafungin, a new candin antifungal drug, has a good safety profile and a significant therapeutic effect against Candida and Aspergillus. Little is known, however, about the optimal prophylactic dosage and the disposition of micafungin in liver transplant recipients, or about the effect of continuous venovenous hemodialysis (CVVH) on the pharmacokinetics of micafungin. Six living donor liver transplant patients were enrolled in this study. The mean Cmax and Cmin (trough) values of micafungin in plasma were 6.31 ± 1.08 and 1.65 ± 0.54 ,g/mL, respectively. The mean elimination half-life (t1/2) and mean area under the curve up to 12 h post-dosing (AUC 0,12 h) were 13.63 ± 2.77 h and 50.04 ± 6.48 ,g·h/mL, respectively. The concentrations of micafungin at the inlet and outlet of the dialyzer were very similar. The mean (±SD) ratio of micafungin concentrations at the inlet and outlet of the dialyzer (coutlet/cinlet) and the clearance of micafungin were 0.96 ± 0.04 and 0.054 ± 0.04 mL/min/kg, respectively. The amount in the ultrafiltrate was 1.0 mg. Micafungin effectively prevents systemic fungal infection in patients who have undergone liver transplantation. No significant differences were observed in the disposition of micafungin in recipients, and the therapeutic drug level can be achieved by administration of micafungin at a dosage of 40,50 mg/d. The CVVH had little effect on micafungin kinetics, and no dose adjustment or modification of dosing interval was needed during CVVH. [source] The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes , results of the randomized, controlled PREDICTIVEÔ 303 studyDIABETES OBESITY & METABOLISM, Issue 6 2007L. Meneghini The Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation 303 (PREDICTIVEÔ 303) Study (n = 5604) evaluated the effectiveness of insulin detemir, a long-acting basal insulin analogue, using a simplified patient self-adjusted dosing algorithm (303 Algorithm group) compared with standard-of-care physician-driven adjustments (Standard-of-care group) in a predominantly primary care setting, over a period of 6 months. Insulin detemir was to be started once-daily as add-on therapy to any other glucose-lowering regimens or as a replacement of prestudy basal insulin in patients with type 2 diabetes. Investigator sites rather than individual patients were randomized to either the 303 Algorithm group or the Standard-of-care group. Patients from the 303 Algorithm group sites were instructed to adjust their insulin detemir dose every 3 days based on the mean of three ,adjusted' fasting plasma glucose (aFPG) values (capillary blood glucose calibrated to equivalent plasma glucose values) using a simple algorithm: mean aFPG < 80 mg/dl (<4.4 mmol/l), reduce dose by 3 U; aFPG between 80 and 110 mg/dl (4.4,6.1 mmol/l), no change; and aFPG > 110 mg/dl (>1.1 mmol/l), increase dose by 3 U. The insulin detemir dose for patients in the Standard-of-care group was adjusted by the investigator according to the standard of care. Mean A1C decreased from 8.5% at baseline to 7.9% at 26 weeks for the 303 Algorithm group and from 8.5 to 8.0% for the Standard-of-care group (p = 0.0106 for difference in A1C reduction between the two groups). Mean FPG values decreased from 175 mg/dl (9.7 mmol/l) at baseline to 141 mg/dl (7.8 mmol/l) for the 303 Algorithm group and decreased from 174 mg/dl (9.7 mmol/l) to 152 mg/dl (8.4 mmol/l) for the Standard-of-care group (p < 0.0001 for difference in FPG reduction between the two groups). Mean body weight remained the same at 26 weeks in both groups (change from baseline 0.1 and ,0.2 kg for the 303 Algorithm group and the Standard-of-care group respectively). At 26 weeks, 91% of the patients in the 303 Algorithm group and 85% of the patients in the Standard-of-care group remained on once-daily insulin detemir administration. The rates of overall hypoglycaemia (events/patient/year) decreased significantly from baseline in both groups [from 9.05 to 6.44 for the 303 Algorithm group (p = 0.0039) and from 9.53 to 4.95 for the Standard-of-care group (p < 0.0001)]. Major hypoglycaemic events were rare in both groups (0.26 events/patient/year for the 303 Algorithm group and 0.20 events/patient/year for the Standard-of-care group; p = 0.2395). In conclusion, patients in the 303 Algorithm group achieved comparable glycaemic control with higher rate of hypoglycaemia as compared with patients in the Standard-of-care group, possibly because of more aggressive insulin dose adjustments. The vast majority of the patients in both groups were effectively treated with once-daily insulin detemir therapy. The use of insulin detemir in this predominantly primary care setting achieved significant improvements in glycaemic control with minimal risk of hypoglycaemia and no weight gain. [source] High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C,HEPATOLOGY, Issue 2 2005Karin Lindahl Improved treatment regimens for patients with chronic hepatitis C, genotype 1 and high viral load are needed. Increasing the dose of ribavirin has increased the response rate, but experience with doses of more than 1,200 mg/day is limited. The aim of this study was to investigate the safety and tolerance to treatment with a high and individualized dose of ribavirin in combination with peginterferon. Ten patients with chronic hepatitis C, genotype 1 and high viral load were treated with peginterferon alfa-2a and ribavirin for 48 weeks in a prospective trial. The initial ribavirin dose was individualized and calculated from a pharmacokinetic formula based mainly on renal function. Ribavirin plasma concentrations were monitored, and the dose was adjusted to reach the target concentration. Hemoglobin was monitored, and patients were treated with erythropoietin and blood transfusions when indicated. After dose adjustments, the mean dose of ribavirin was 2,540 mg/day (range, 1,600-3,600) at week 24. The main side effect was anemia, which was controlled with erythropoietin. Two patients required blood transfusions. One patient was withdrawn at week 24 because of a lack of viral response, and one patient at week 39 because of side effects, primarily interferon associated. At follow-up (,24 weeks posttreatment), nine of ten patients had undetectable HCV RNA and thus were cured by standard definitions. In conclusion, a high dose of ribavirin according to an individualized schedule is feasible but associated with more frequent and serious side effects such as anemia. The viral response merits further evaluation. (HEPATOLOGY 2005;41:275,279.) [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] | |||||||||||||||||||||||||||||||