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Neonatal pharmacology: rational therapeutics for the most vulnerable.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19915596 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - November 19, 2009 Category: Drugs & Pharmacology Authors: James L, Ito S Tags: Clin Pharmacol Ther Source Type: journals

Clinical trials in neonates: a therapeutic imperative.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The lack of study of medications in pediatric patients has been recognized since the 1960s, when Shirkey described children as "therapeutic orphans." In 1968, only 25% of approved drugs included adequate pediatric prescribing information on the label. This did not begin to improve until the 1990s, with the 1997 US Food and Drug Administration (FDA) Modernization Act, the Best Pharmaceuticals for Children Acts, and the Pediatric Research Equity Acts. By 2009, more than 300 labeling changes improved pediatric prescribing information, but newborns were seldom included. PMID: 19915600 [PubMed - in process] (Source: Cli...
Source: Clinical Pharmacology and Therapeutics - November 19, 2009 Category: Drugs & Pharmacology Authors: Ward RM, Kern SE Tags: Clin Pharmacol Ther Source Type: journals

Can we afford it?: ethical consideration of expensive drug treatment for neonates and infants.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
When considering expensive drug treatment for neonates and infants, how should we decide what we can and cannot afford? Accountably allocating health-care resources can be achieved using a framework that reflects the values a society considers so reflective of the collective will that they have been formally entrenched in law. The values and procedural mechanisms entrenched in the Canadian Charter of Rights and Freedoms are particularly helpful for those faced with these difficult spending decisions. PMID: 19915601 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - November 19, 2009 Category: Drugs & Pharmacology Authors: Zlotnik Shaul R, Vitale D Tags: Clin Pharmacol Ther Source Type: journals

Clinical trial design in neonatal pharmacology: effect of center differences, with lessons from the pediatric oncology cooperative research experience.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Survival for premature neonates has improved dramatically over the past 20 years; however, there has been minimal improvement in prematurity-associated morbidities. Morbidity rates and assessment of outcomes vary across neonatology intensive care units (NICUs). Here, we address the reasons underlying these differences, note the impact that this center variation has on trial design and interpretation, and highlight the success of the efforts in pediatric oncology to develop standards of care through the conduct of multicenter clinical trials. PMID: 19915602 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - November 19, 2009 Category: Drugs & Pharmacology Authors: Moran C, Smith PB, Cohen-Wolkowiez M, Benjamin DK Tags: Clin Pharmacol Ther Source Type: journals

The road from discovery to clinic: adiponectin as a biomarker of metabolic status.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Biomarkers are globally used to monitor clinical responses to therapeutic and lifestyle interventions. The adipocyte-derived hormone adiponectin is recognized as a promising new biomarker owing to its many associations with components of the metabolic syndrome. The study described by Wagner and colleagues in this issue offers a first example of how a large-scale effort in the context of a cross-company collaborative study in the pharmaceutical industry can offer a powerful tool for the further validation of a new biomarker in the context of pharmacological intervention with peroxisome proliferator-activated receptor-ga...
Source: Clinical Pharmacology and Therapeutics - November 19, 2009 Category: Drugs & Pharmacology Authors: Kusminski CM, Scherer PE Tags: Clin Pharmacol Ther Source Type: journals

Current understanding of the pharmacogenomics of metformin.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The identification of transporters for organic cations involved in the distribution and elimination of the antidiabetic compound metformin marks a milestone in the study of metformin's pharmacokinetics. This was followed by the urgent question of whether genetic variations in these transporters can affect efficacy and risk of adverse events associated with metformin use. After a brief historical review of the discovery of the transporters for cationic drugs, the pharmacogenetics of metformin is discussed here in the light of recent literature. PMID: 19915604 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - November 19, 2009 Category: Drugs & Pharmacology Authors: Zolk O Tags: Clin Pharmacol Ther Source Type: journals

Selective Antagonism of Opioid-Induced Ventilatory Depression by an Ampakine Molecule in Humans Without Loss of Opioid Analgesia.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ventilatory depression is a significant risk associated with the use of opioids. We assessed whether opioid-induced ventilatory depression can be selectively antagonized by an ampakine without reduction of analgesia. In 16 healthy men, after a single oral dose of 1,500 mg of the ampakine CX717, a target concentration of 100 ng/ml alfentanil decreased the respiratory frequency by only 2.9 +/- 33.4% as compared with 25.6 +/- 27.9% during placebo coadministration (P < 0.01).Blood oxygenation and the ventilatory response to hypercapnic challenge also showed significantly smaller decreases with CX717 than with placebo. I...
Source: Clinical Pharmacology and Therapeutics - November 11, 2009 Category: Drugs & Pharmacology Authors: Oertel BG, Felden L, Tran PV, Bradshaw MH, Angst MS, Schmidt H, Johnson S, Greer JJ, Geisslinger G, Varney MA, Lötsch J Tags: Clin Pharmacol Ther Source Type: journals

High Frequency of Occurrence of CYP2D6 Gene Duplication/Multiduplication Indicating Ultrarapid Metabolism Among Suicide Cases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In Sweden, about 550 individuals die every year of drug intoxication. Many of these drugs are metabolized by CYP enzymes such as CYP2D6 and CYP2C19. A lack of these enzymes, resulting in poor metabolism, can lead to adverse reactions and even to fatality. On the other hand, an ultrarapid metabolism can lead to insufficient drug plasma concentration, resulting in failure of treatment, or it can lead to high concentrations of active/toxic metabolites. The aim of this project was to study the genetic profile of individuals with regard to the presence of CYP2D6 and CYP2C19 genes, in cases of fatal intoxication (242), suici...
Source: Clinical Pharmacology and Therapeutics - November 11, 2009 Category: Drugs & Pharmacology Authors: Zackrisson AL, Lindblom B, Ahlner J Tags: Clin Pharmacol Ther Source Type: journals

Transporters as Drug Targets: Discovery and Development of NPC1L1 Inhibitors.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The potent cholesterol absorption inhibitor ezetimibe was developed as a first-in-class drug for treating hypercholesterolemia even before its molecular target, Niemann-Pick C1-like 1 (NPC1L1), had been identified. The NPC1L1 protein mediates sterol transport across the enterocyte brush border membrane and is essential for intestinal cholesterol absorption, a major pathway controlling whole-body cholesterol homeostasis. An elucidation of the mechanism underlying NPC1L1-dependent cholesterol absorption would greatly facilitate the discovery and development of new cholesterol-lowering agents for treating hypercholesterol...
Source: Clinical Pharmacology and Therapeutics - November 11, 2009 Category: Drugs & Pharmacology Authors: Betters JL, Yu L Tags: Clin Pharmacol Ther Source Type: journals

The Role of Organic Anion-Transporting Polypeptides and Their Common Genetic Variants in Mycophenolic Acid Pharmacokinetics.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The goal of this study was to determine the roles of the organic anion-transporting polypeptides (OATPs) OATP1A2, OATP1B1, and OATP1B3 and their genetic variants in the pharmacokinetics of the immunosuppressive drug mycophenolate mofetil (MMF). Using OATP-transfected human embryonic kidney (HEK) cells, we measured the uptake of mycophenolic acid (MPA) and its glucuronide (MPAG). MPAG, but not MPA, significantly accumulated in cells expressing OATP1B3 or OATP1B1 (P < 0.05). The pharmacokinetics of both MPA and MPAG were significantly influenced by the OATP1B3 polymorphism 334T>G/699G>A in 70 renal transplant pa...
Source: Clinical Pharmacology and Therapeutics - November 4, 2009 Category: Drugs & Pharmacology Authors: Picard N, Yee SW, Woillard JB, Lebranchu Y, Le Meur Y, Giacomini KM, Marquet P Tags: Clin Pharmacol Ther Source Type: journals

Ocular Hemodynamic Effects of Nitrovasodilators in Healthy Subjects.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Nitric oxide (NO) plays a key role in the regulation of ocular blood flow and may be an interesting therapeutic target in ocular ischemic disease. In the present study, we hypothesized that NO-releasing drugs may increase blood flow to the head of the optic nerve and also in the choroid. The study employed a randomized, placebo-controlled, double blind, four-way crossover design. On separate study days, 12 healthy subjects received infusions of nitroglycerin, isosorbide dinitrate, sodium nitroprusside, or placebo. All three study drugs reduced the mean arterial pressure (MAP) and ocular perfusion pressure (OPP) (P <...
Source: Clinical Pharmacology and Therapeutics - November 4, 2009 Category: Drugs & Pharmacology Authors: Schmidl D, Polska E, Kiss B, Sacu S, Garhofer G, Schmetterer L Tags: Clin Pharmacol Ther Source Type: journals

Safety and Pharmacokinetics of Repeat-Dose Micafungin in Young Infants.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Given the risk of central nervous system infection, relatively high weight-based echinocandin dosages may be required for the successful treatment of invasive candidiasis and candidemia in young infants. This open-label study assessed the safety and pharmacokinetics (PK) of micafungin in 13 young infants (>48 h and <120 days of life) with suspected candidemia or invasive candidiasis. Infants of body weight >/=1,000 and <1,000 g received 7 and 10 mg/kg/day, respectively, for a minimum of 4-5 days. In the 7-mg/kg/day group, the mean baseline weight and gestational age were 2,101 g and 30 weeks, respectively; ...
Source: Clinical Pharmacology and Therapeutics - November 4, 2009 Category: Drugs & Pharmacology Authors: Benjamin DK, Smith PB, Arrieta A, Castro L, Sánchez PJ, Kaufman D, Arnold LJ, Kovanda LL, Sawamoto T, Buell DN, Hope WW, Walsh TJ Tags: Clin Pharmacol Ther Source Type: journals

Comparison of Critical Drug-Drug Interaction Listings: The Department of Veterans Affairs Medical System and Standard Reference Compendia.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The objective of this study was to evaluate the agreement among the US Department of Veterans Affairs (VA) listing of "critical" drug-drug interactions (DDIs) and two standard drug-interaction compendia. A list of critical DDIs, as defined by the VA, was compared with two standard commercially available compendia (Micromedex DRUG-REAX and Drug Interactions: Analysis and Management (DIAM)) in order to determine the level of agreement among the systems. Of 982 DDIs classified as critical by the VA, only 136 DDIs (13.7%) were considered critical in all three systems. Our conclusion was that, overall, there is poor agreement a...
Source: Clinical Pharmacology and Therapeutics - November 4, 2009 Category: Drugs & Pharmacology Authors: Olvey EL, Clauschee S, Malone DC Tags: Clin Pharmacol Ther Source Type: journals

Transporter Pharmacogenetics and Statin Toxicity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Polymorphisms in transporter genes can have profound effects on statin pharmacokinetics. In particular, a common genetic variant of organic anion-transporting polypeptide 1B1 reduces the hepatic uptake of many statins, increasing the risk of statin-induced myopathy. Similarly, genetically impaired adenosine triphosphate (ATP)-binding cassette G2 transporter efflux activity results in a marked increase in systemic exposure to various statins. Importantly, the effects of these genetic polymorphisms differ depending on the specific statin that is used. This provides a rational basis for the individualization of lipid-lowe...
Source: Clinical Pharmacology and Therapeutics - November 4, 2009 Category: Drugs & Pharmacology Authors: Niemi M Tags: Clin Pharmacol Ther Source Type: journals

A Pharmacovigilance Program From Laboratory Signals for the Detection and Reporting of Serious Adverse Drug Reactions in Hospitalized Patients.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We present the implementation of a prospective pharmacovigilance program based on automatic laboratory signals (ALSs) at a hospital. We also report the general findings after the first year of operation of the program, which involved ALSs that indicate various SADRs: agranulocytosis, aplastic anemia, liver injury, thrombocytopenia, hyponatremia, and rhabdomyolysis. The number of hospitalizations during the year was 54,525, and 1,732 patients experienced at least one ALS. The review of electronic medical records (EMRs) showed that no alternative cause (i.e., no non-SADR explanation) for the ALS was identified in 520 (30%) o...
Source: Clinical Pharmacology and Therapeutics - November 4, 2009 Category: Drugs & Pharmacology Authors: Ramirez E, Carcas AJ, Borobia AM, Lei SH, Piñana E, Fudio S, Frias J Tags: Clin Pharmacol Ther Source Type: journals

Sustained Neurobehavioral Effects of Exposure to SSRI Antidepressants During Development: Molecular to Clinical Evidence.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Selective serotonin reuptake inhibitor (SSRI) antidepressants are frequently used in the management of antenatal maternal mood disturbances. SSRIs readily cross the placenta and increase central serotonergic tone in the fetus. Given serotonin's key neurodevelopmental role, such prenatal exposure raises concerns about its impact on child development. Preclinical studies report enduring molecular, physiological, and behavioral consequences of developmental SSRI exposure. In humans, sustained developmental outcomes remain largely unstudied, and distinguishing between the effects of prenatal SSRI exposure and the impact of...
Source: Clinical Pharmacology and Therapeutics - November 4, 2009 Category: Drugs & Pharmacology Authors: Oberlander TF, Gingrich JA, Ansorge MS Tags: Clin Pharmacol Ther Source Type: journals

Drug dosing in patients with impaired renal function.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Renal function can affect disposition and response to drugs in a variety of ways. This review discusses the principles underlying such responses, with particular emphasis on how changes in disposition parameters affect dosing decisions. PMID: 19626002 [PubMed - indexed for MEDLINE] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - November 1, 2009 Category: Drugs & Pharmacology Authors: Brater DC Tags: Clin Pharmacol Ther Source Type: journals

Public health consequences of chronic kidney disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
With its rising incidence and prevalence, chronic kidney disease (CKD) is a major public health concern, both in the United States and worldwide. Recent worldwide initiatives have attempted to garner attention for CKD by emphasizing that the condition is "common, harmful, and treatable." In the United States, as many as 26 million adults may have CKD, an increase from approximately 10% of the US adult population between 1988 and 1994 to >13% just one decade later. Similar rates have been seen worldwide, with a CKD prevalence of 13% in Beijing, China and 16% in Australia. In the United States, the dramatic rise in th...
Source: Clinical Pharmacology and Therapeutics - November 1, 2009 Category: Drugs & Pharmacology Authors: Weiner DE Tags: Clin Pharmacol Ther Source Type: journals

Effects of selective serotonin reuptake inhibitor therapy on endothelial function and inflammatory markers in patients with coronary heart disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We investigated the effect of sertraline on inflammation and endothelial function in patients with coronary heart disease (CHD) and symptoms of depression. One hundred patients with CHD and depression were randomized in a double-blind fashion to receive sertraline or a placebo. We measured symptoms of depression (Beck Depression Inventory (BDI) score), levels of inflammatory markers (C-reactive protein (CRP) and interleukin-6 (IL-6)), and flow-dependent endothelium-mediated dilation (FMD) before and after 20 weeks of treatment. Sertraline treatment significantly reduced the BDI score as compared with both baseline and ...
Source: Clinical Pharmacology and Therapeutics - November 1, 2009 Category: Drugs & Pharmacology Authors: Pizzi C, Mancini S, Angeloni L, Fontana F, Manzoli L, Costa GM Tags: Clin Pharmacol Ther Source Type: journals

Novel biomarkers of acute kidney toxicity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Novel biomarkers of kidney toxicity are powerful tools not only with respect to their clinical applications but also because of their impact on drug development. These biomarkers can influence the assessment of efficacy of new drugs for kidney diseases as well as the risk management for new drugs. The science behind these novel biomarkers reflects the evolution over the past decade of genomic and proteomic platforms that have transformed the discovery and development of new biomarkers for preclinical and clinical applications in drug development. Several of these biomarkers are in use as transcriptomic biomarkers in an...
Source: Clinical Pharmacology and Therapeutics - November 1, 2009 Category: Drugs & Pharmacology Authors: Goodsaid FM, Blank M, Dieterle F, Harlow P, Hausner E, Sistare F, Thompson A, Vonderscher J Tags: Clin Pharmacol Ther Source Type: journals

The influence of chronic renal failure on drug metabolism and transport.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chronic renal failure (CRF) has been shown, in animal models and clinical studies, to significantly reduce nonrenal clearance and to alter the bioavailability of predominantly metabolized drugs. Phase II reactions and drug transporters such as P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) are also affected. High levels of parathyroid hormone (PTH), cytokines, and uremic toxins are implicated in some of these effects, which have a clinically significant impact on drug disposition and increase the risk of adverse drug reaction. PMID: 19776735 [PubMed - indexed for MEDLINE] (Source: Clinical ...
Source: Clinical Pharmacology and Therapeutics - November 1, 2009 Category: Drugs & Pharmacology Authors: Dreisbach AW Tags: Clin Pharmacol Ther Source Type: journals

Drug development perspective on pharmacokinetic studies of new drugs in patients with renal impairment.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Severe renal impairment can, through diverse mechanisms, alter the pharmacokinetics (PK) of drugs that are renally eliminated and even of some drugs that are nonrenally eliminated. Consequently, dose adjustment for new molecular entities in patients with renal insufficiency is a critical issue in drug development. Clinical pharmacology studies undertaken in patients with renal impairment are generally quite small. We therefore recommend that all pertinent pharmacokinetic data relating to subjects with different degrees of renal impairment and from different clinical trials, including population pharmacokinetic evaluati...
Source: Clinical Pharmacology and Therapeutics - November 1, 2009 Category: Drugs & Pharmacology Authors: Lalonde RL, Wagner JA Tags: Clin Pharmacol Ther Source Type: journals

Nephropharmacology: drugs and the kidney.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19844216 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - October 24, 2009 Category: Drugs & Pharmacology Authors: Atkinson AJ, Huang SM Tags: Clin Pharmacol Ther Source Type: journals

Use of the MDRD study equation to estimate kidney function for drug dosing.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19844220 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - October 24, 2009 Category: Drugs & Pharmacology Authors: Stevens LA, Levey AS Tags: Clin Pharmacol Ther Source Type: journals

Continuing the use of the Cockcroft-Gault equation for drug dosing in patients with impaired renal function.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19844221 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - October 24, 2009 Category: Drugs & Pharmacology Authors: Spruill WJ, Wade WE, Cobb HH Tags: Clin Pharmacol Ther Source Type: journals

How a US regulator can encourage new science.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA) is developing a process to qualify biomarkers for use under particular conditions. As part of this effort, Goodsaid et al. have carried out work, described in this issue, on the formal qualification of novel biomarkers of acute renal toxicity in animals. The authors' experiences highlight the importance of collaboration and the role of regulators. PMID: 19844222 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - October 24, 2009 Category: Drugs & Pharmacology Authors: Throckmorton DC Tags: Clin Pharmacol Ther Source Type: journals

How will GINA influence participation in pharmacogenomics research and clinical testing?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
After a 13-year battle in Congress--longer than it took to map the human genome--the Genetic Information Nondiscrimination Act (GINA) was passed into law on 21 May 2008. Before its passing, Francis Collins, then director of the National Human Genome Research Institute, testified before the 110th Congress that the success of personalized medicine hinged on the passing of the legislation. How will GINA, which takes effect in 2009, influence participation in pharmacogenomic research and clinical testing? PMID: 19844223 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - October 24, 2009 Category: Drugs & Pharmacology Authors: Dressler LG, Terry SF Tags: Clin Pharmacol Ther Source Type: journals

When to conduct a renal impairment study during drug development: US Food and Drug Administration perspective.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
To optimize drug therapy for individuals, it is critical to understand how various intrinsic (e.g., age, gender, race, genetics, organ impairment) and extrinsic factors (e.g., diet, smoking, concomitantly administered drugs) affect drug exposure and response.(1) Up to now, it has been far easier to discover effects on exposure caused by these factors, and the US Food and Drug Administration (FDA) has published several guidance documents with recommendations on how to evaluate these factors during drug development. PMID: 19844224 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - October 24, 2009 Category: Drugs & Pharmacology Authors: Huang SM, Temple R, Xiao S, Zhang L, Lesko LJ Tags: Clin Pharmacol Ther Source Type: journals

Challenges in developing evidence-based drug dosing guidelines for adults and children receiving renal replacement therapy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The challenges of appropriate drug dosing in patients with renal failure requiring renal replacement therapy (RRT) have been exacerbated by recent trends in both RRT technology and practices. Nearly all these changes have resulted in augmented drug clearance, making most existing RRT drug dosing recommendations obsolete. Many barriers exist to conducting research to update our knowledge of appropriate drug dosing in the context of contemporary RRT. Recommendations on how this research could be conducted, including the use of in vitro techniques, are offered here. PMID: 19844225 [PubMed - in process] (Source: Clinic...
Source: Clinical Pharmacology and Therapeutics - October 24, 2009 Category: Drugs & Pharmacology Authors: Mueller BA, Smoyer WE Tags: Clin Pharmacol Ther Source Type: journals

Clinical Trial Simulations in Pediatric Patients Using Realistic Covariates: Application to Teduglutide, a Glucagon-Like Peptide-2 Analog in Neonates and Infants With Short-Bowel Syndrome.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect. PMID: 19847163 [PubMed - as supplied by publisher] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - October 20, 2009 Category: Drugs & Pharmacology Authors: Mouksassi MS, Marier JF, Cyran J, Vinks AA Tags: Clin Pharmacol Ther Source Type: journals

Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
P-glycoprotein (P-gp), an efflux transporter, controls the pharmacokinetics of various compounds under physiological conditions. P-gp-mediated drug efflux has been suggested as playing a role in various disorders, including multidrug-resistant cancer and medication-refractory epilepsy. However, P-gp inhibition has had, to date, little or no clinically significant effect in multidrug-resistant cancer. To enhance our understanding of its in vivo function under pathophysiological conditions, substrates of P-gp have been radiolabeled and imaged using single-photon emission computed tomography (SPECT) and positron emission ...
Source: Clinical Pharmacology and Therapeutics - September 30, 2009 Category: Drugs & Pharmacology Authors: Kannan P, John C, Zoghbi SS, Halldin C, Gottesman MM, Innis RB, Hall MD Tags: Clin Pharmacol Ther Source Type: journals

Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cisplatin is one of the most widely used anticancer agents for the treatment of solid tumors. The clinical use of cisplatin is associated with dose-limiting nephrotoxicity, which occurs in one-third of patients despite intensive prophylactic measures. Organic cation transporter 2 (OCT2) has been implicated in the cellular uptake of cisplatin, but its role in cisplatin-induced nephrotoxicity remains unknown. In mice, deletion of Oct1 and Oct2 resulted in significantly impaired urinary excretion of cisplatin without an apparent influence on plasma levels. Furthermore, the Oct1/Oct2-deficient mice were protected from seve...
Source: Clinical Pharmacology and Therapeutics - September 30, 2009 Category: Drugs & Pharmacology Authors: Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A Tags: Clin Pharmacol Ther Source Type: journals

Clozapine, GABA(B), and the treatment of resistant schizophrenia.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19626000 [PubMed - indexed for MEDLINE] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 30, 2009 Category: Drugs & Pharmacology Authors: Daskalakis ZJ, George TP Tags: Clin Pharmacol Ther Source Type: journals

A pharmacodynamic Markov mixed-effects model for determining the effect of exposure to certolizumab pegol on the ACR20 score in patients with rheumatoid arthritis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The objectives of this analysis were to develop an exposure-response model of ACR20 in subjects receiving treatment with certolizumab pegol and to predict clinical outcomes following various treatment schedules. At each visit, subjects were classified as being ACR20 responders or ACR20 nonresponders or as having dropped out. A Markov mixed-effects model was developed to investigate the effects of the drug on the transitions between the three defined states. Increasing certolizumab pegol exposure predicted an increasing probability of becoming a responder and remaining a responder, as well as a reduced probability of droppi...
Source: Clinical Pharmacology and Therapeutics - September 30, 2009 Category: Drugs & Pharmacology Authors: Lacroix BD, Lovern MR, Stockis A, Sargentini-Maier ML, Karlsson MO, Friberg LE Tags: Clin Pharmacol Ther Source Type: journals

Imaging and biomarkers in early Alzheimer's disease and mild cognitive impairment.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A major focus of research on aging and dementia pertains to the prediction of future cognitive decline. Toward this end, several longitudinal studies are under way that are designed to explore early predictors of cognitive impairment. Neuroimaging techniques and biomarkers have shown promise in this application. Ultimately, it is likely that the use of a combination of neuroimaging and chemical biomarkers will be involved in predicting the development of dementia and Alzheimer's disease (AD). PMID: 19710641 [PubMed - indexed for MEDLINE] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 30, 2009 Category: Drugs & Pharmacology Authors: Petersen RC, Jack CR Tags: Clin Pharmacol Ther Source Type: journals

Benefits exceed risks of newer antidepressant medications in youth--maybe.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19763113 [PubMed - indexed for MEDLINE] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 30, 2009 Category: Drugs & Pharmacology Authors: March JS, Vitiello B Tags: Clin Pharmacol Ther Source Type: journals

Brain and disease: the long path to discovery and treatment.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19763109 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 20, 2009 Category: Drugs & Pharmacology Authors: Miksys SL, Tyndale RF Tags: Clin Pharmacol Ther Source Type: journals

Neuroimaging placebo effects: new tools generate new questions.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19763112 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 20, 2009 Category: Drugs & Pharmacology Authors: Jarcho JM, Mayer EA, London ED Tags: Clin Pharmacol Ther Source Type: journals

Benefits exceed risks of newer antidepressant medications in youth-maybe.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19763113 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 20, 2009 Category: Drugs & Pharmacology Authors: March JS, Vitiello B Tags: Clin Pharmacol Ther Source Type: journals

Benefits exceed risks of newer antidepressant medications in youth--maybe not.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19763114 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 20, 2009 Category: Drugs & Pharmacology Authors: Potter WZ Tags: Clin Pharmacol Ther Source Type: journals

Predicting age-specific dosing of antipsychotics.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Antipsychotic medications are the standard of care for both acute and maintenance treatment of schizophrenia, the latter requiring an indefinite treatment across a patient's life span. However, dosing and tolerability of antipsychotics have been studied primarily in younger patients, and very limited data are available for age- and phase-specific dosing. This leaves the clinician with no guidance on dose adjustment as patients grow older-an issue of critical importance, especially in light of recent concerns about increased morbidity and mortality associated with antipsychotics. PMID: 19763115 [PubMed - in process]...
Source: Clinical Pharmacology and Therapeutics - September 20, 2009 Category: Drugs & Pharmacology Authors: Uchida H, Pollock BG, Bies RR, Mamo DC Tags: Clin Pharmacol Ther Source Type: journals

Pharmacotherapy for depressed pregnant women: overcoming obstacles to gathering essential data.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Approximately 3% of pregnant women take antidepressant medications. Information on the impact of antidepressants on short- and long-term maternal and offspring outcomes is highly desirable but neglected. The position that the dearth of treatment information is of greater concern than the risks to pregnant subjects involved in medical research is gaining support. Mandating the collection of reproductive outcome data in exposed childbearing women is an overdue step toward societal responsibility to our most vulnerable members. PMID: 19763116 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 20, 2009 Category: Drugs & Pharmacology Authors: Wisner KL, Appelbaum PS, Uhl K, Goldkind SF Tags: Clin Pharmacol Ther Source Type: journals

The Coalition Against Major Diseases: developing tools for an integrated drug development process for Alzheimer's and Parkinson's diseases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aiming to emulate the successful accelerated development of HIV/AIDS drugs, the Critical Path Institute (C-Path), in collaboration with the Engelberg Center for Health Care Reform at the Brookings Institution, has formed the Coalition Against Major Diseases (CAMD). Members include 6 nonprofit groups representing patients' interests, 15 leading pharmaceutical companies, the US Food and Drug Administration (FDA), the European Medicines Agency (EMEA), 2 institutes of the National Institutes of Health (NIH)-the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS)-and rep...
Source: Clinical Pharmacology and Therapeutics - September 20, 2009 Category: Drugs & Pharmacology Authors: Romero K, de Mars M, Frank D, Anthony M, Neville J, Kirby L, Smith K, Woosley RL Tags: Clin Pharmacol Ther Source Type: journals

Potent and Selective Agonism of the Melanocortin Receptor 4 With MK-0493 Does Not Induce Weight Loss in Obese Human Subjects: Energy Intake Predicts Lack of Weight Loss Efficacy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
MK-0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best-validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy-intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK-0493 showed a small and marginally significant effect on 24-h energy intake, whereas 30 mg of sibu...
Source: Clinical Pharmacology and Therapeutics - September 8, 2009 Category: Drugs & Pharmacology Authors: Krishna R, Gumbiner B, Stevens C, Musser B, Mallick M, Suryawanshi S, Maganti L, Zhu H, Han TH, Scherer L, Simpson B, Cosgrove D, Gottesdiener K, Amatruda J, Rolls BJ, Blundell J, Bray GA, Fujioka K, Heymsfield SB, Wagner JA, Herman GA Tags: Clin Pharmacol Ther Source Type: journals

Comparison of Native E. coli and PEG Asparaginase Pharmacokinetics and Pharmacodynamics in Pediatric Acute Lymphoblastic Leukemia.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Asparaginase (ASP) is used routinely in frontline clinical trials for the treatment of childhood acute lymphoblastic leukemia (ALL). The goals of this study were to assess the pharmacokinetics and pharmacodynamics of ASP and to mathematically model the dynamics between ASP and asparagine (ASN) in relapsed ALL. Forty children were randomized to receive either native or polyethylene glycolated (PEG) Escherichia coli ASP during reinduction therapy. Serial plasma ASP and ASN, cerebrospinal fluid (CSF) ASN, and serum anti-ASP antibody samples were collected. The ASP clearance was higher (P = 0.001) for native vs. PEG ASP. P...
Source: Clinical Pharmacology and Therapeutics - September 8, 2009 Category: Drugs & Pharmacology Authors: Panetta JC, Gajjar A, Hijiya N, Hak LJ, Cheng C, Liu W, Pui CH, Relling MV Tags: Clin Pharmacol Ther Source Type: journals

The Impact of Continuous Renal Replacement Therapy on Drug Therapy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Critically ill patients with multisystem organ failure often require daily administration of large volumes of fluid to provide electrolyte and nutrition support, medications, and blood products. This often results in fluid overload, which has historically been managed with intermittent hemodialysis (IHD). Unfortunately, IHD entails a high rate of fluid and solute removal that often exacerbates hemodynamic instability. Accordingly, continuous renal replacement therapy (CRRT), involving slow and continuous removal of water and solutes from the plasma, is currently preferred for managing these patients. PMID: 19727069...
Source: Clinical Pharmacology and Therapeutics - September 1, 2009 Category: Drugs & Pharmacology Authors: Susla GM Tags: Clin Pharmacol Ther Source Type: journals

Rupatadine and Heart Rhythm Disturbances.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19727070 [PubMed - as supplied by publisher] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 1, 2009 Category: Drugs & Pharmacology Authors: Fité R, Borja J Tags: Clin Pharmacol Ther Source Type: journals

Orally Administered Glucagon-Like Peptide-1 Affects Glucose Homeostasis Following an Oral Glucose Tolerance Test in Healthy Male Subjects.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Glucagon-like peptide-1 (GLP-1) exerts several effects on glucose homeostasis and reduces food intake. After its release from intestinal L cells, GLP-1 is subject to (i) rapid breakdown by dipeptidyl peptidase IV and (ii) high liver extraction. The highest concentrations of GLP-1 are found in the splanchnic blood rather than in the systemic circulation. An oral delivery system would mimic endogenous secretion. Here we investigated the pharmacokinetic/pharmacodynamic (PK/PD) effects of a single dose (2 mg) of oral GLP-1 administered prior to an oral glucose tolerance test (OGTT) in 16 healthy males. GLP-1 was rapidly ab...
Source: Clinical Pharmacology and Therapeutics - September 1, 2009 Category: Drugs & Pharmacology Authors: Steinert RE, Poller B, Castelli MC, Friedman K, Huber AR, Drewe J, Beglinger C Tags: Clin Pharmacol Ther Source Type: journals

Response to "Rupatadine and Heart Rhythm Disturbances"Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19727072 [PubMed - as supplied by publisher] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - September 1, 2009 Category: Drugs & Pharmacology Authors: Carvajal A, Macías D, Salado I, Sáinz M, Ortega S, Campo C, García Del Pozo J, Martín Arias LH, Velasco A, Gonçalves S, Pombal R, Carmona R Tags: Clin Pharmacol Ther Source Type: journals

Drug development for emerging infections.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19707209 [PubMed - in process] (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - August 27, 2009 Category: Drugs & Pharmacology Authors: Reynolds KS Tags: Clin Pharmacol Ther Source Type: journals