(drugs [ta] OR clin pharmacol ther [ta] OR pharmacol ther [ta] OR j clin psychopharmacol [ta] OR clin pharmacokinet [ta] OR psychopharmacology [ta] OR br j clin pharmacol [ta] OR ther drug monit [ta] ) AND ( human [mesh] ) (only with abstract)

28434 articles - 08.09.10

1: Clin Pharmacol Ther. 2010 Aug;88(2):161-3.

Experiences with learning and confirming in drug and biological development.

Patterson SD.

Pfizer Vaccine Research, Philadelphia, Pennsylvania, USA. patters4@wyeth.com

Since the 1997 landmark article by Dr. Lewis Sheiner in Clinical Pharmacology & Therapeutics, biopharmaceutical development in phases I-IIA has become more targeted toward learning (i.e., establishing proof of concept), then subsequently confirming that regulated standards are met. The purpose and importance of the learning-proof-of-concept phase is subjective but typically uses traditional statistics (which were developed for use in confirming). Two examples from development are presented to illustrate learning in practice. Suggestions for how to improve and embed the learn-confirm concept and how to enhance the contributions of clinical pharmacology and statistics are considered.

Publication Types: Comment Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20648033&dopt=ExternalLink

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2: Clin Pharmacol Ther. 2010 Aug;88(2):183-90. Epub 2010 Jul 14.

Biological and hemodynamic effects of low doses of fludrocortisone and hydrocortisone, alone or in combination, in healthy volunteers with hypoaldosteronism.

Laviolle B, Le Maguet P, Verdier MC, Massart C, Donal E, Laine F, Lavenu A, Pape D, Bellissant E.

Department of Clinical Pharmacology, University Hospital, Rennes 1 University, Rennes, France.

Low doses of hydrocortisone (HC) and fludrocortisone (FC) administered together improve the prognosis after septic shock; however, there continues to be disagreement about the utility of FC for this indication. The biological and hemodynamic effects of HC (50 mg intravenously) and FC (50 microg orally) were assessed in 12 healthy male volunteers with saline-induced hypoaldosteronism in a placebo-controlled, randomized, double-blind, crossover study performed according to a 2 x 2 factorial design. HC and FC significantly decreased urinary sodium and potassium levels (from -58% at 4 h to -28% at 10 h and from -35% at 8 h to -24% at 12 h, respectively) with additive effects. At 4 h after administration, HC significantly increased cardiac output (+14%), decreased systemic vascular resistances (-14%), and slightly increased heart rate (+4 beats/min), whereas FC had no hemodynamic effect. At doses used in septic shock, HC induced greater mineralocorticoid effect than FC did. HC also induced transient systemic hemodynamic effects, whereas FC did not. New studies are required to better define the optimal dose of FC in septic shock.

Publication Types: Randomized Controlled Trial Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20631694&dopt=ExternalLink

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3: Clin Pharmacol Ther. 2010 Aug;88(2):166-82. Epub 2010 Jul 7.

Clinical trial simulation: a review.

Holford N, Ma SC, Ploeger BA.

Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand. n.holford@auckland.ac.nz

Modeling and simulation in general, and specifically clinical trial simulation (CTS), have been recognized by the (larger) pharmaceutical companies and regulatory authorities as being pivotal to improving the efficiency of the drug development process. This includes the use of CTS to learn about drug effectiveness and safety and to optimize trial designs at the various stages of development. By reviewing papers published during the period January 2000-January 2010, this paper discusses recent developments with respect to methodology, applications, and lessons learned in the use of CTS in the development and clinical use of specific drugs. It is expected that future CTS experiments will be aided by the hybridization of optimal design methods with computationally intensive stochastic simulations. This will take advantage of optimizing the experimental design and leave the task of evaluating the probable real-world performance of a limited number of candidate trial designs and analysis procedures.

Publication Types: Research Support, Non-U.S. Gov't Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20613720&dopt=ExternalLink

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4: Clin Pharmacol Ther. 2010 Aug;88(2):191-6. Epub 2010 Jun 30.

Genetic variations in GRIA1 on chromosome 5q33 related to asparaginase hypersensitivity.

Chen SH, Pei D, Yang W, Cheng C, Jeha S, Cox NJ, Evans WE, Pui CH, Relling MV.

Department of Pharmaceutical Sciences, St Jude Children's Research Hospital,Memphis, Tennessee, USA.

The genetic variations that result in allergy to asparaginase are as yet undetermined. We interrogated more than 500,000 single-nucleotide polymorphisms (SNPs) in 485 children with acute lymphoblastic leukemia (ALL), 322 in a discovery cohort, and 163 in a validation cohort. In the top 100 SNPs associated with allergy in the discovery cohort, chromosome 5 was overrepresented as compared with other chromosomes (P = 0.00032), hosting 10 SNPs annotated to genes. Among these 10 SNPs, one SNP (rs4958381), in GRIA1 on chromosome 5q33, was replicated in the validation cohort (P = 1.8 x 10(-5), 2.9 x 10(-3), and 3.5 x 10(-7) in the discovery, validation, and combined cohorts, respectively). Four additional SNPs annotated to GRIA1 were also significantly associated with allergy (P < 0.05) in both cohorts. Chromosome 5q33 has previously been associated with asthma and atopy. These data contribute to the growing body of evidence that there is an inherited component to predisposition to drug allergy.

Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20592726&dopt=ExternalLink

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5: Clin Pharmacol Ther. 2010 Aug;88(2):237-42. Epub 2010 Jun 30.

Plasma pharmacokinetics of two consecutive doses of ferumoxytol in healthy subjects.

Pai AB, Nielsen JC, Kausz A, Miller P, Owen JS.

Albany Nephrology Pharmacy Group, Albany College of Pharmacy and Health Sciences, Albany, New York, USA. Amy.BartonPai@acphs.edu

Intravenous (IV) iron is used to treat iron-deficiency anemia in patients with chronic kidney disease (CKD). Ferumoxytol is a novel iron formulation administered rapidly as two IV boluses of 510 mg each. In this placebo-controlled, double-blind, parallel-group study, 58 healthy volunteers received ferumoxytol in two 510 mg doses administered 24 h apart. Population pharmacokinetics (PK) analysis was conducted, and a two-compartment open model with zero-order input and Michaelis-Menten elimination was found to best describe the data. The population mean estimates for volume of distribution of the central compartment (V(1)), maximal elimination rate (V(max)), and ferumoxytol concentration at which rate of metabolism would be one-half of V(max) (K(m)) were 2.71 l, 14.3 mg/h, and 77.5 mg/l, respectively. When the effect of body weight on V(1) was added in the analysis, interindividual variability was found to be reduced. A noncompartmental analysis of two simulated 510-mg ferumoxytol doses was also performed to provide clinically interpretable data on half life and exposure. Ferumoxytol given as two consecutive 510-mg doses was well tolerated.

Publication Types: Randomized Controlled Trial

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20592725&dopt=ExternalLink

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6: Clin Pharmacol Ther. 2010 Aug;88(2):223-30. Epub 2010 Jun 30.

Gemfibrozil markedly increases the plasma concentrations of montelukast: a previously unrecognized role for CYP2C8 in the metabolism of montelukast.

Karonen T, Filppula A, Laitila J, Niemi M, Neuvonen PJ, Backman JT.

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

According to available information, montelukast is metabolized by cytochrome P450 (CYP) 3A4 and 2C9. In order to study the significance of CYP2C8 in the pharmacokinetics of montelukast, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 3 days, and 10 mg montelukast on day 3, in a randomized, crossover study. Gemfibrozil increased the mean area under the plasma concentration-time curve (AUC)(0-infinity), peak plasma concentration (C(max)), and elimination half-life (t(1/2)) of montelukast 4.5-fold, 1.5-fold, and 3.0-fold, respectively (P < 0.001). After administration of gemfibrozil, the time to reach C(max) (t(max)) of the montelukast metabolite M6 was prolonged threefold (P = 0.005), its AUC(0-7) was reduced by 40% (P = 0.027), and the AUC(0-24) of the secondary metabolite M4 was reduced by >90% (P < 0.001). In human liver microsomes, gemfibrozil 1-O-beta glucuronide inhibited the formation of M6 (but not of M5) from montelukast 35-fold more potently than did gemfibrozil (half-maximal inhibitory concentration (IC(50)) 3.0 and 107 micromol/l, respectively). In conclusion, gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.

Publication Types: Randomized Controlled Trial Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20592724&dopt=ExternalLink

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7: Clin Pharmacol Ther. 2010 Aug;88(2):214-22. Epub 2010 Jun 30.

Anti-infectives and the risk of severe hypoglycemia in users of glipizide or glyburide.

Schelleman H, Bilker WB, Brensinger CM, Wan F, Hennessy S.

Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Center for Clinical Epidemiology and Biostatistics, Philadelphia, Pennsylvania, USA.

The objective of this study was to evaluate whether orally administered anti-infectives increase the risk of severe hypoglycemia in users of glipizide or glyburide. We performed two case-control studies and two case-crossover studies using US Medicaid data. All the anti-infectives examined were associated with an elevated risk of severe hypoglycemia. Using cephalexin as the reference category, in glipizide users, statistically significant associations were found with co-trimoxazole (odds ratio (OR) = 3.14; 95% confidence interval (CI): 1.83-5.37); clarithromycin (OR = 2.90; 95% CI: 1.69-4.98); fluconazole (OR = 2.53; 95% CI: 1.23-5.23); and levofloxacin (OR = 2.09; 95% CI: 1.35-3.25). In glyburide users, with cephalexin as the reference, statistically significant associations were found with clarithromycin (OR = 5.02; 95% CI: 3.35-7.54); levofloxacin (OR = 2.83; 95% CI: 1.73-4.62); co-trimoxazole (OR = 2.68; 95% CI: 1.59-4.52); fluconazole (OR = 2.20; 95% CI: 1.04-4.68); and ciprofloxacin (OR = 2.08; 95% CI: 1.23-3.52). In conclusion, exposure to all studied anti-infective agents were associated with subsequent severe hypoglycemia. Using cephalexin as the reference, drug-drug interactions were evident with ciprofloxacin (in glyburide users only), clarithromycin, co-trimoxazole, fluconazole, and levofloxacin.

Publication Types: Research Support, N.I.H., Extramural

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20592722&dopt=ExternalLink

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8: Clin Pharmacol Ther. 2010 Aug;88(2):243-50. Epub 2010 Jun 30.

Pharmacokinetics and pharmacodynamics of inhaled GLP-1 (MKC253): proof-of-concept studies in healthy normal volunteers and in patients with type 2 diabetes.

Marino MT, Costello D, Baughman R, Boss A, Cassidy J, Damico C, van Marle S, van Vliet A, Richardson PC.

MannKind Corporation, Paramus, New Jersey, USA. mmarino@mannkindcorp.com

MKC253 is glucagon-like peptide 1 (GLP-1, 7-36 amide) adsorbed onto Technosphere microparticles for oral inhalation. The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5 min, and levels returned to baseline within 30 min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose excursions in subjects with type 2 diabetes. An E(max) (maximum effect) model described the relationship between GLP-1 concentration and insulin release. The variability in the E(max) may be due to differences in baseline glucose levels, differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.

Publication Types: Clinical Trial, Phase I

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20592721&dopt=ExternalLink

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9: Clin Pharmacol Ther. 2010 Aug;88(2):231-6. Epub 2010 Jun 23.

Quality of methods for assessing and reporting serious adverse events in clinical trials of cancer drugs.

Belknap SM, Georgopoulos CH, West DP, Yarnold PR, Kelly WN.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. sbelknap@northwestern.edu

The validity of information regarding drug toxicity in humans depends on the quality of the methods and instruments used to assess adverse drug events (ADEs). This study evaluates the quality of instruments used to assess and report ADEs to institutional review boards (IRBs) at US cancer centers. Forms from all 49 National Cancer Institute (NCI)-designated centers were assessed for utility in abstracting event type, severity, and causality; patient demographics; safety monitoring; and consequent changes in the conduct of the relevant study. Of the 55 items considered essential for ADE reporting, one item (event description) was present on all the forms. Seventy-eight percent of the instruments prompted for global introspection of the investigator, a method known to be unreliable. Of the 34 items that our panel of experts considered essential for event description, the median number of items present was four (domain = 1-11). The use of a validated tool to describe and assess event type, severity, and causality may lead to more timely, accurate identification of safety signals in cancer treatment.

Publication Types: Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20571489&dopt=ExternalLink

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10: Clin Pharmacol Ther. 2010 Jul;88(1):25-33. Epub 2010 Jun 9.

Systems biology: an approach.

Kohl P, Crampin EJ, Quinn TA, Noble D.

Department of Physiology, University of Oxford, Oxford, UK. peter.kohl@dpag.ox.ac.uk

In just over a decade, Systems Biology has moved from being an idea, or rather a disparate set of ideas, to a mainstream feature of research and funding priorities. Institutes, departments, and centers of various flavors of Systems Biology have sprung up all over the world. An Internet search now produces more than 2 million hits. Of the 2,800 entries in PubMed with "Systems Biology" in either the title or the abstract, only two papers were published before 2000, and >90% were published in the past five years. In this article, we interpret Systems Biology as an approach rather than as a field or a destination of research. We illustrate that this approach is productive for the exploration of systems behavior, or "phenotypes," at all levels of structural and functional complexity, explicitly including the supracellular domain, and suggest how this may be related conceptually to genomes and biochemical networks. We discuss the role of models in Systems Biology and conclude with a consideration of their utility in biomedical research and development.

Publication Types: Research Support, Non-U.S. Gov't Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20531468&dopt=ExternalLink

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11: Clin Pharmacol Ther. 2010 Jul;88(1):135-7. Epub 2010 Jun 9.

Next-generation model-based drug discovery and development: quantitative and systems pharmacology.

Allerheiligen SR.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. sandra.allerheiligen@merck.com

Pharmaceutical researchers have undertaken many initiatives and technologies to stem the rising costs of drug discovery and development. Biomarkers, adaptive trial designs, modeling, trial simulations, predictive metabolism, data mining, and disease models have reshaped the way in which researchers approach discovery and development. Quantitative pharmacology (QP), which leverages model-based approaches, operates at both cultural and technical levels to integrate data and scientific disciplines so as to utilize existing knowledge while concomitantly enhancing the ability to make predictions about future experiments and results.

Publication Types: Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20531467&dopt=ExternalLink

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12: Clin Pharmacol Ther. 2010 Jul;88(1):130-4. Epub 2010 Jun 2.

The systems biology approach to drug development: application to toxicity assessment of cardiac drugs.

Rodriguez B, Burrage K, Gavaghan D, Grau V, Kohl P, Noble D.

Oxford University Computing Laboratory, University of Oxford, Oxford, UK.

Side effects account for most of the instances of failure of candidate drugs at late stages of development. These development failures contribute to the exorbitant cost of bringing new compounds to market: a single withdrawal can represent a loss of more than $1 billion. Many unwanted actions of drugs affect the heart, resulting in potentially proarrhythmic alteration of ion channel function. Because these can be fatal, potential electrophysiological cardiotoxicity is among the most stringent exclusion criteria in the licensing process.

Publication Types: Research Support, Non-U.S. Gov't Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20520607&dopt=ExternalLink

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13: Clin Pharmacol Ther. 2010 Jul;88(1):34-8. Epub 2010 Jun 2.

Dissecting variability in responses to cancer chemotherapy through systems pharmacology.

Yang R, Niepel M, Mitchison TK, Sorger PK.

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.

Variability in patient responses to even the most potent and targeted therapeutics is now the primary challenge facing drug discovery and patient care, particularly in oncology and immune therapy. Variability with respect to mechanisms of induced resistance is observed both in drug-naive patients and among those who are initially responsive. Genomics has developed powerful tools for systematic interrogation of disease genotype and transcriptional states (particularly in cancer) and for correlation of these measures with parameters of disease such as histological diagnosis and outcome. In contrast, mechanistic preclinical studies remain relatively narrowly focused, leading to many apparent contradictions and poor understanding of the determinants of response. We describe the emergence of a systems pharmacology approach that is mechanistic, quantitative, probabilistic, and postgenomic and promises to do for mechanistic pharmacology what genomics is doing for correlative studies. We focus on studies in cell lines (which currently dominate mechanism-oriented analysis), but our arguments are equally valid for real tumors studied in short-term culture as xenografts and, perhaps some time in the future, in humans.

Publication Types: Research Support, N.I.H., Extramural Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20520606&dopt=ExternalLink

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14: Clin Pharmacol Ther. 2010 Jul;88(1):79-87. Epub 2010 Jun 2.

Dose selection of corifollitropin alfa by modeling and simulation in controlled ovarian stimulation.

de Greef R, Zandvliet AS, de Haan AF, Ijzerman-Boon PC, Marintcheva-Petrova M, Mannaerts BM.

Global Drug Metabolism & Pharmacokinetics, Merck Research Labs, Merck Sharp & Dohme, Oss, The Netherlands.

In controlled ovarian stimulation (COS), a single subcutaneous dose of corifollitropin alfa is used to initiate and sustain multifollicular growth for 7 days. The objective of this study was to determine the optimal dose of corifollitropin alfa. A pharmacokinetic model was developed to describe the time profile of corifollitropin alfa concentrations. Multiple parameters reflecting ovarian response were included in a pharmacokinetic-pharmacodynamic (PK-PD) model framework. An early decline in serum inhibin B was shown to be a sensitive marker for COS failure. Simulations were performed to select the lowest corifollitropin alfa dose that would result in a minimal cancellation rate: 100 microg for a group of women weighing <or=60 kg and 150 microg for a group of women weighing >60 kg. With these doses, the predicted mean number of oocytes per started COS cycle was similar in the two groups, i.e., 12.1 and 13.2, respectively. The selected doses were tested in prospective clinical trials and were proven to be adequate.

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20520605&dopt=ExternalLink

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15: Clin Pharmacol Ther. 2010 Jul;88(1):39-44. Epub 2010 Jun 2.

Acute effects of ephedra on autonomic nervous modulation in healthy young adults.

Chen WL, Tsai TH, Yang CC, Kuo TB.

Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.

The aim of this study was to assess the acute effects of ephedra on autonomic nervous modulation by means of heart rate variability (HRV) analysis, using a randomized, double-blind, placebo-controlled, crossover design. On three separate days, 20 healthy subjects took capsules containing either 1 or 2 g of ephedra dry extract or a placebo, and the sequential percentage changes in HRV measures were compared. After the subjects took ephedra, the normalized low-frequency component (LF) and the ratio of LF to high-frequency component (HF) increased significantly in a dose-dependent manner, whereas the normalized HF (HF%) decreased significantly. We conclude that ingestion of ephedra tilts the sympathovagal balance dose-dependently toward increased sympathetic activity and impairs parasympathetic activity.

Publication Types: Randomized Controlled Trial Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20520603&dopt=ExternalLink

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16: Clin Pharmacol Ther. 2010 Jul;88(1):69-78. Epub 2010 Jun 2.

Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users.

Schoedel KA, Meier D, Chakraborty B, Manniche PM, Sellers EM.

Kendle Early Stage-Toronto, Ontario, Canada. schoedel.kerri@kendle.com

Tesofensine is a (triple) reuptake inhibitor of noradrenaline, dopamine, and serotonin that is in development for the treatment of obesity. The abuse potential of triple reuptake inhibitors is not yet known, and so this study was undertaken to evaluate the potential abuse-related effects of tesofensine in humans. It was designed as a single-dose, randomized, double-blind, crossover study involving tesofensine vs. placebo, D-amphetamine (positive control for dopaminergic/stimulant effects), bupropion, and atomoxetine (negative/unscheduled controls) in recreational stimulant users (N = 52). Subjective and objective measures were assessed for 48 h after drug administration. The study results show that the effects of D-amphetamine were significantly greater than those of placebo on all primary and secondary subjective measures. The effects of tesofensine were not significantly different from those of placebo and were lower than those of D-amphetamine 30 mg on all primary and most secondary measures. The effects of tesofensine were either lower than or not different from those of bupropion or atomoxetine. These results demonstrate that the abuse potential for tesofensine is no greater than that of bupropion or atomoxetine, and tesofensine is therefore unlikely to be recreationally abused.

Publication Types: Comparative Study Randomized Controlled Trial Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20520602&dopt=ExternalLink

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17: Drugs. 2010 Jun 18;70(9):1189-213.

Maraviroc: a review of its use in the management of CCR5-tropic HIV-1 infection.

Perry CM.

Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz

Maraviroc (Celsentri; Selzentry) is a CCR5 coreceptor antagonist used in the treatment of CCR5-tropic HIV-1 infection. Administered orally twice daily, maraviroc, in combination with optimized background therapy regimens, showed good virological and immunological efficacy over 48 weeks in antiretroviral treatment-experienced patients aged > or = 16 years with CCR5-tropic HIV-1 infection, in the randomized, double-blind, placebo-controlled, multicentre, MOTIVATE 1 and MOTIVATE 2 studies. Initial data indicate that the efficacy of maraviroc in this patient population is sustained for up to 96 weeks. In the MERIT study in antiretroviral therapy-naive patients aged > or = 16 years with CCR5-tropic HIV-1 infection, maraviroc was noninferior to efavirenz (each in combination with zidovudine/lamivudine) for one primary virological endpoint (HIV-1-RNA levels < 400 copies/mL), but not for the other primary endpoint (HIV-1 RNA levels < 50 copies/mL) in the primary analysis at 48 weeks. However, in a subsequent analysis, which used a more sensitive tropism testing assay than the one originally used and retrospectively excluded patients with non CCR5-tropic HIV-1 infection who were ineligible for inclusion in the study, maraviroc demonstrated noninferiority to efavirenz on both primary virological endpoints. Maraviroc showed sustained virological efficacy in this patient population and improved immunological markers for up to 96 weeks. Maraviroc was generally well tolerated by both treatment-experienced and treatment-naive patients with CCR5-tropic HIV-1 infection. Thus, maraviroc, as a component of antiretroviral combination therapy regimens, is an important option for use in treatment-experienced adults with CCR5-tropic HIV-1 infection. Available data indicate that maraviroc may also have a role in treatment-naive adults with CCR5-tropic HIV-1 infection, a population in whom CCR5-tropic HIV-1 is often the major quasispecies.

Publication Types: Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20518583&dopt=ExternalLink

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18: Drugs. 2010 Jun 18;70(9):1165-88.

Pentavalent rotavirus vaccine (RotaTeq): a review of its use in the prevention of rotavirus gastroenteritis in Europe.

Plosker GL.

Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz

In Europe, rotavirus gastroenteritis is associated with a significant health, economic and social burden, as it is responsible for large numbers of hospitalizations and other healthcare encounters among infants and children, as well as numerous days of work lost by parents and caregivers. RotaTeq is a three-dose, orally administered, live, pentavalent human-bovine reassortant rotavirus vaccine used for the active immunization of infants for prevention of rotavirus gastroenteritis. The protective efficacy of RotaTeq has been evaluated in terms of its effects on the incidence of rotavirus gastroenteritis and on healthcare resource use. Clinical trial data from REST (a randomized, double-blind, placebo-controlled, multinational study in approximately 70,000 healthy infants aged 6-12 weeks) and various subgroup analyses, including a large European cohort, have shown that RotaTeq may be administered at the same time as various other routine vaccines, has high and sustained efficacy covering the main period of risk for rotavirus gastroenteritis, has early protective efficacy after the first and second doses, reduces rotavirus gastroenteritis-associated hospitalization and emergency department and physician visits, and is generally well tolerated. Moreover, RotaTeq has demonstrated efficacy against the five most prevalent serotypes of rotavirus in Europe (G1-G4, G9), in terms of reductions in associated healthcare resource use. There is also evidence that the widespread use of RotaTeq may provide herd immunity, as it appears to have indirect benefits in older, unvaccinated children. Reports on the 'real world' effectiveness of RotaTeq in Europe are just emerging, but data from the US have shown a rapid and marked reduction in rotavirus burden nationwide during the approximately 2-year period following the introduction of RotaTeq and the subsequent availability of official recommendations advocating universal use of the vaccine as part of routine childhood immunization. Similar benefits have also been demonstrated in Australia after the introduction of a publicly funded rotavirus vaccination programme. Postmarketing surveillance data from the US have not identified any concerns, such as an association with intussusception or Kawasaki disease, related to the safety of RotaTeq. In conclusion, RotaTeq is a generally well tolerated vaccine that has efficacy against the five most prevalent serotypes of rotavirus in Europe and provides sustained efficacy over the main risk period for rotavirus gastroenteritis in infants and children, reducing hospitalizations and emergency department visits by decreasing the incidence and severity of illness.

Publication Types: Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20518582&dopt=ExternalLink

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19: Drugs. 2010 Jun 18;70(9):1149-63.

Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: a systematic review of randomized controlled trials.

McCarthy GC, Megalla SA, Habib AS.

Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA. habib001@mc.duke

Postoperative pain continues to be inadequately managed. While opioids remain the mainstay for postoperative analgesia, their use can be associated with adverse effects, including ileus, which can prolong hospital stay. A number of studies have investigated the use of perioperative intravenous lidocaine infusion for improving postoperative analgesia and enhancing recovery of bowel function. This systematic review was performed to determine the overall efficacy of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery in patients undergoing various surgical procedures. We searched the databases of MEDLINE, CINAHL and the Cochrane Library from 1966 to December 2009. We searched for randomized controlled comparisons of lidocaine infusion with placebo in the surgical setting and reporting on postoperative analgesia and other aspects of patient recovery from surgery. The quality of all included studies was assessed using the Modified Oxford Scale. Information on postoperative pain intensity and analgesic requirements was extracted from the trials and compared qualitatively. Other relevant data such as return of bowel function, length of hospital stay, intraoperative anaesthetic requirement and adverse effects were also compared. Sixteen trials were included. A total of 395 patients received intravenous lidocaine with 369 controls. In open and laparoscopic abdominal surgery, as well as in ambulatory surgery patients, intravenous perioperative infusion of lidocaine resulted in significant reductions in postoperative pain intensity and opioid consumption. Pain scores were reduced at rest and with cough or movement for up to 48 hours postoperatively. Opioid consumption was reduced by up to 85% in lidocaine-treated patients when compared with controls. Infusion of lidocaine also resulted in earlier return of bowel function, allowing for earlier rehabilitation and shorter duration of hospital stay. First flatus occurred up to 23 hours earlier, while first bowel movement occurred up to 28 hours earlier in the lidocaine-treated patients. Duration of hospital stay was reduced by an average of 1.1 days in the lidocaine-treated patients. Administration of intravenous lidocaine infusion did not result in toxicity or clinically significant adverse events. Lidocaine had no impact on postoperative analgesia in patients undergoing tonsillectomy, total hip arthroplasty or coronary artery bypass surgery. In conclusion, intravenous lidocaine infusion in the perioperative period is safe and has clear advantages in patients undergoing abdominal surgery. Patients receiving lidocaine infusion had lower pain scores, reduced postoperative analgesic requirements and decreased intraoperative anaesthetic requirements, as well as faster return of bowel function and decreased length of hospital stay. Further studies are needed to assess whether lidocaine has a beneficial effect in patients undergoing other types of surgery and to determine the optimum dose, timing and duration of infusion of lidocaine in this setting.

Publication Types: Meta-Analysis Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20518581&dopt=ExternalLink

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20: Drugs. 2010 Jun 18;70(9):1131-48.

Pharmacotherapy for hepatic encephalopathy.

Phongsamran PV, Kim JW, Cupo Abbott J, Rosenblatt A.

Department of Clinical Pharmacy, University of Southern California School of Pharmacy, USC University Hospital Department of Pharmacy, Los Angeles, California, USA. phongsam@usc.edu

Hepatic encephalopathy (HE) is a challenging clinical complication of liver dysfunction with a wide spectrum of neuropsychiatric abnormalities that range from mild disturbances in cognitive function and consciousness to coma and death. The pathogenesis of HE in cirrhosis is complex and multifactorial, but a key role is thought to be played by circulating gut-derived toxins of the nitrogenous compounds, most notably ammonia. Therapeutic treatment options for HE are currently limited and have appreciable risks and benefits associated with their use. Management of HE primarily involves avoidance of precipitating factors, limitation of dietary protein intake, and administration of various ammonia-lowering therapies such as non-absorbable disaccharides and select antimicrobial agents. Non-absorbable disaccharides, such as lactulose, have traditionally been regarded as first-line pharmacotherapy for patients with HE. However, multiple adverse events have been associated with their use. In addition, recent literature has questioned the true efficacy of the disaccharides for this indication. Neomycin, metronidazole and vancomycin may be used as alternative treatments for patients intolerant or unresponsive to non-absorbable disaccharides. Antimicrobials reduce bacterial production of ammonia and other bacteria-derived toxins through suppression of intestinal flora. Neomycin has been reported to be as effective as lactulose, and similar efficacy has been reported with vancomycin and metronidazole for the management of HE. However, the adverse effects frequently associated with these antimicrobials limit their use as first-line pharmacological agents. Neomycin is the most commonly used antimicrobial for HE and, although poorly absorbed, systemic exposure to the drug in sufficient amounts causes hearing loss and renal toxicity. Long-term neomycin therapy requires annual auditory testing and continuous monitoring of renal function. Long-term use of metronidazole has been associated with neurotoxicity in patients with cirrhosis, including dose-dependent peripheral neuropathy. Vancomycin may be a safer option for HE in patients with chronic liver disease; however, limited experience, possible bacterial overgrowth and risk for enteric bacteria resistance preclude the routine use of vancomycin for HE. Rifaximin is a novel antimicrobial agent with a wide spectrum of activity that has shown promise as an alternative antimicrobial treatment option for HE. Several clinical trials have compared rifaximin to the disaccharides, lactulose and lactitol, and the antimicrobial neomycin. Rifaximin appears to be at least as effective as conventional drug therapy and has been associated with fewer adverse effects due to its limited systemic absorption. The available clinical data appear to support a favourable benefit-risk ratio for rifaximin, which has shown efficacy with an improved tolerability profile. Future studies are needed in order to truly characterize its cost effectiveness in today's healthcare environment. Other less frequently utilized alternative treatment options include administration of benzodiazepine receptor antagonists, branched-chain amino acids, ornithine aspartate, zinc supplementation, sodium benzoate, dopamine receptor agonists, acarbose and probiotics. Presently, there is relatively limited clinical data supporting their routine use in HE.

Publication Types: Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20518580&dopt=ExternalLink

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