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Pharmacokinetics pharmacodynamics

Jiang-Tao Tang, Brenda C de Winter, Dennis A Hesselink, Ferdi Sombogaard, Lan-Lan Wang, Teun van Gelder
AIM: Elderly transplant recipients have a lower incidence of acute rejection, and a higher risk to die from infectious complications. Potentially this may be caused by differences in the pharmacokinetics (PK) or pharmacodynamics (PD) of the immunosuppressive drugs they are taking. This study was designed to comprehensively evaluate the influence of age on the PK and PD of mycophenolic acid (MPA). METHODS: In this study the PK and PD of MPA was studied in 26 elderly and 54 younger renal transplant recipients treated with mycophenolate mofetil and tacrolimus...
October 18, 2016: British Journal of Clinical Pharmacology
Bishoy Kamel, Garry G Graham, Kenneth M Williams, Kevin D Pile, Richard O Day
Febuxostat is a xanthine oxidoreductase inhibitor that has been developed to treat chronic gout. In healthy subjects, the pharmacokinetic parameters of febuxostat after multiple oral dose administration include an oral availability of about 85 %, an apparent oral clearance (CL/F) of 10.5 ± 3.4 L/h and an apparent volume of distribution at steady state (V ss/F) of 48 ± 23 L. The time course of plasma concentrations follows a two-compartment model. The initial half-life (t ½) is approximately 2 h and the terminal t ½ determined at daily doses of 40 mg or more is 9...
October 17, 2016: Clinical Pharmacokinetics
Iris K Minichmayr, André Schaeftlein, Joseph L Kuti, Markus Zeitlinger, Charlotte Kloft
OBJECTIVES: We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients. METHODS: Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid...
October 17, 2016: Clinical Pharmacokinetics
Rodrigo Cristofoletti, Jennifer B Dressman
In vitro-in vivo extrapolation techniques combined with physiologically based pharmacokinetic models represent a feasible approach to establishing links between critical quality attributes and the time course of drug concentrations in vivo. By further integrating the results with pharmacodynamic (PD) models, scientists can also explore the time course of drug effect. The aim of this study was to assess whether differences in dissolution rates would affect the onset, magnitude, and duration of the time course of ibuprofen-mediating pain relief...
October 14, 2016: Journal of Pharmaceutical Sciences
Christina Binder, Caroline Zotter-Tufaro, Diana Bonderman
The development of pulmonary hypertension (PH) has multifactorial underlying pathophysiological causes and can be classified into five groups. While three different classes of therapeutic drugs are licensed for the treatment of pulmonary arterial hypertension (PAH, WHO group 1), specific medical therapies are lacking for other forms of PH, such as PH due to left heart disease. In 2013 riociguat, a first-in class soluble guanylate cyclase stimulator, has also become available for the treatment of PAH. Riociguat was further introduced as the first approved pharmacotherapy for the treatment of patients with chronic thromboembolic PH (WHO group 4, CTEPH)...
October 18, 2016: Expert Opinion on Drug Safety
Keren Turjeman, Yechezkel Barenholz
BACKGROUND: Steroids are the most efficacious anti-inflammatory agents. However, their toxicities and side-effects compromise their clinical application. Various strategies and major efforts were dedicated for formulating viable liposomal glucocorticosteroids (GCs), so far none of these were approved. OBJECTIVES: To evaluate these approaches for formulating GC-delivery systems, especially liposomes, and with focus on the Barenholz Lab experience. METHODS: We developed PEGylated nano-liposomes (NSSL) remotely loaded with water-soluble amphipathic weak acid GC-prodrugs...
October 18, 2016: Journal of Drug Targeting
Susanne Hafner, Sabine Haubensak, Tanusree Paul, Oliver Zolk
Background | Differences (polymorphisms) in genes encoding drug targets, drug transport proteins, or drug metabolizing enzymes may be responsible, among other factors, for the observed variation in patients' responses to medications. The field of pharmacogenetics aims to identify patients at higher genetically-determined risk of adverse effects or poor response to medication. This information would allow for modification of dosage or substitution with alternative therapy. However, there is a lack of awareness of pharmacogenetic clinical practise guidelines...
October 2016: Deutsche Medizinische Wochenschrift
Shouwen Zhang, Jie Wang, Jin Pan
CONTEXT: Baicalin has many pharmacological activities, including protective function against myocardial ischemia by antioxidant effects and free radical scavenging activity. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy. OBJECTIVE: Novel baicalin-loaded PEGylated nanostructured lipid carriers (BN-PEG-NLC) were developed to improve bioavailability of BN, to prolong retention time in vivo and to enhance its protective effect...
October 17, 2016: Drug Delivery
Maxime Luu, Marc Bardou, Philippe Bonniaud, Françoise Goirand
Omalizumab is a subcutaneously administrated monoclonal anti-IgE antibody indicated in adults, adolescents and children 6 years of age and older with moderate to severe allergic asthma uncontrolled by conventional pharmacological treatments and sensitization to at least one perennial allergen. Area covered: This drug evaluation summarizes published data on pharmacokinetic and pharmacodynamic properties of omalizumab, on clinical efficacy and safety, including real-world evidence, and provides a medico-economic evaluation of the drug...
October 17, 2016: Expert Opinion on Drug Metabolism & Toxicology
Guillermo Gervasini, Carlos Jara, Clara Olier, Nuria Romero, Ruth Martínez, Juan Antonio Carrillo
AIMS: Anastrozole, an aromatase inhibitor widely used in breast cancer, has recently been pointed out as a P-glycoprotein (ABCB1) substrate. We have aimed to determine whether ABCB1 single-nucleotide polymorphisms (SNPs) can affect anastrozole plasma concentrations in these patients. In addition, we assessed the impact of SNPs in CYP19A1 and TCL1A on the development of arthralgia and cancer recurrence in our series. METHODS: One-hundred-and-ten postmenopausal women with hormone receptor-positive breast cancer were included...
October 17, 2016: British Journal of Clinical Pharmacology
Meghan K Mattos, Susan M Sereika, Jennifer G Naples, Steven M Albert
BACKGROUND: Older adults are especially susceptible to adverse consequences of potentially inappropriate medications (PIMs), such as benzodiazepine receptor agonists (BZDRAs), due to age-related pharmacokinetic and pharmacodynamic changes. Although some risk factors for BZDRA use in older adults have been identified, the role of rural versus urban residence is less clear. OBJECTIVE: To describe BZDRA use in rural versus urban older adults using pharmaceutical claims from Pennsylvania's Pharmaceutical Assistance Contract for the Elderly (PACE) program...
September 2016: Drugs—Real World Outcomes
Ciara M Kelly, Yelena Y Janjigian
Gastric cancer is a biologically heterogeneous tumor. The identification of human epidermal growth factor receptor-2 (HER2) biomarker overexpression in gastric cancer represented a significant step towards unraveling the molecular complexity of this disease. Trastuzumab in combination with chemotherapy, in the first-line setting of patients with metastatic, HER2-positive gastric and gastroesophageal, represents the first targeted therapeutic to demonstrate improvement in response rate and survival in gastric cancer...
October 2016: Journal of Gastrointestinal Oncology
Hidehito Horinouchi
The mutation or expression of HER family members serves as a therapeutic target for tyrosine kinase inhibitors or monoclonal antibodies in diverse cancers, such as non-small cell lung cancer, breast cancer, gastric cancer, head and neck cancer, colorectal cancer, pancreatic cancer and glioblastoma. HER3, which heterodimerizes with HER1 and HER2, has received much attention as a potential target for anti-EGFR treatment. Patritumab is a novel, fully human monoclonal antibody directed against HER3. Areas covered: In this review article, an overview of the market, chemistry, pharmacodynamics, pharmacokinetics, efficacy, and safety of patritumab is provided based on data from phase I studies, a combination phase I trial, and a randomized phase II trial comparing two doses of patritumab...
October 17, 2016: Expert Opinion on Biological Therapy
Kyoji Tsuchikama, Zhiqiang An
The antibody-drug conjugate (ADC), a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules (payloads) through chemical linkers, is a novel therapeutic format and has great potential to make a paradigm shift in cancer chemotherapy. This new antibody-based molecular platform enables selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics (PK)/pharmacodynamics (PD) and biodistribution compared to traditional chemotherapy...
October 14, 2016: Protein & Cell
Shashikant Srivastava, Devyani Deshpande, Jotam G Pasipanodya, Tania Thomas, Soumya Swaminathan, Eric Nuermberger, Tawanda Gumbo
Children with tuberculosis are treated with drug regimens copied from adults despite significant differences in antibiotic pharmacokinetics, pathology, and the microbial burden between childhood and adult tuberculosis. We sought to develop a new and effective oral treatment regimen specific to children of different ages. We investigated and validated the concept that target drug concentrations associated with therapy failure and death in children are different from those of adults. On that basis, we proposed a 4-step program to rapidly develop treatment regimens for children...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Abrar K Thabit, Jared L Crandon, David P Nicolau
Increasing antimicrobial resistance in community-acquired pneumonia (CAP) pathogens has contributed to infection-related morbidity and mortality. Delafloxacin is a novel fluoroquinolone with broad-spectrum activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to define the pharmacodynamic profile of delafloxacin against CAP pathogens using a neutropenic murine lung infection model. Five S. pneumoniae, 2 methicillin-susceptible S...
September 29, 2016: International Journal of Antimicrobial Agents
Jennifer Greene Naples, Walid F Gellad, Joseph T Hanlon
When possible, chronic noncancer pain (CNCP) in older adults should be managed by nonpharmacologic modalities in conjunction with nonopioid analgesics. If moderate-to-severe pain persists despite these approaches, however, nonparenteral opioids may be considered as adjunctive therapy. This article reviews the epidemiology of opioid use and their effectiveness for CNCP in older adults and summarizes important age-related changes in opioid pharmacokinetics and pharmacodynamics that increase the risks of adverse effects in the elderly...
November 2016: Clinics in Geriatric Medicine
Per Bäckman, Ulrika Tehler, Bo Olsson
BACKGROUND: Exposure following oral inhalation depends on the deposition pattern of the inhaled aerosol, the extent and rate of oral and pulmonary absorption, as well as systemic distribution and clearance. For lipophilic inhaled compounds with low water solubility and high permeability, the extent and rate of pulmonary absorption can be assumed dependent on deposition pattern as well as dissolution rate. MATERIALS AND METHODS: A mechanistic model of airway deposition, mucociliary clearance, dissolution, absorption, and dissipation was applied to simulate systemic exposure of the novel selective glucocorticoid receptor modulator, AZD5423, when dosed to healthy volunteers using two different nebulizers and two different dry powder inhalers in combination with two different primary particle size distributions...
October 14, 2016: Journal of Aerosol Medicine and Pulmonary Drug Delivery
Thomas Schluep, Jason Lickliter, James Hamilton, David L Lewis, Ching-Lung Lai, Johnson Yn Lau, Stephen A Locarnini, Robert G Gish, Bruce D Given
ARC-520 Injection, an RNA interference drug for the treatment of hepatitis B that targets cccDNA-derived viral mRNA transcripts with high specificity, effectively reduces the production of viral proteins and HBV DNA. In this phase I, randomized, double-blind, placebo-controlled study, 54 healthy volunteers (half male, half female) received a single, intravenous dose of 0.01-4.0 mg/kg ARC-520 Injection (N = 36) or placebo (N = 18). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (cytokines and complement)...
October 14, 2016: Clinical Pharmacology in Drug Development
Janine Stucke-Ring, Julian Ronnacker, Caroline Brand, Carsten Höltke, Christoph Schliemann, Torsten Kessler, Lars Henning Schmidt, Saliha Harrach, Verena Mantke, Heike Hintelmann, Wolfgang Hartmann, Eva Wardelmann, Georg Lenz, Bernhard Wünsch, Carsten Müller-Tidow, Rolf M Mesters, Christian Schwöppe, Wolfgang E Berdel
Truncated tissue factor (tTF), retargeted to tumor vasculature by GNGRAHA peptide (tTF-NGR), and doxorubicin have therapeutic activity against a variety of tumors. We report on combination experiments of both drugs using different schedules. We have tested fluorescence- and HPLC-based intratumoral pharmacokinetics of doxorubicin, flow cytometry for cellular phosphatidylserine (PS) expression, and tumor xenograft studies for showing in vivo apoptosis, proliferation decrease, and tumor shrinkage upon combination therapy with doxorubicin and induced tumor vascular infarction...
October 11, 2016: Oncotarget
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