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Sample records for acceptable pharmacokinetic properties

  1. Pharmacokinetic Properties of Netilmicin in Newborn Infants

    PubMed Central

    Siegel, Jane D.; McCracken, George H.; Thomas, Marion L.; Threlkeld, Norma

    1979-01-01

    Netilmicin and gentamicin susceptibilities of 258 gram-negative organisms and 25 strains of Staphylococcus aureus were nearly identical. The pharmacokinetic properties of netilmicin were evaluated in 101 newborn infants and related to birth weight, gestational age, chronological age, and route of administration. Mean peak serum concentrations of 5.6 to 6.9 and 7.8 to 8.4 μg/ml were observed 30 min after 3- and 4-mg/kg doses, respectively, were given intramuscularly. The peak concentrations were directly related to gestational age. The average serum half-life values varied from 3.4 to 4.7 h and in general were inversely related to birth weight, gestational age, and postnatal age. The pharmacokinetics of netilmicin in 10 infants were similar after intramuscular and intravenous administration. A comparative study of netilmicin and gentamicin in seven neonates revealed greater variability in serum concentrations of gentamicin and a shorter half-life for netilmicin. There was evidence of accumulation of netilmicin in 12 low-birth weight, premature infants who received 4-mg/kg doses for an average of 6.4 days. Serum and urine levels of netilmicin were measured up to 11 days after discontinuation of the drug. These data are well characterized by a two-compartment model. Additional studies of efficacy and long-term toxicity of netilmicin in neonates are necessary. PMID:426516

  2. Pharmacokinetic properties and in silico ADME modeling in drug discovery.

    PubMed

    Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D

    2013-03-01

    The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry. PMID:23016542

  3. Second-Generation Phenylthiazole Antibiotics with Enhanced Pharmacokinetic Properties.

    PubMed

    Seleem, Mohammed A; Disouky, Ahmed M; Mohammad, Haroon; Abdelghany, Tamer M; Mancy, Ahmed S; Bayoumi, Sammar A; Elshafeey, Ahmed; El-Morsy, Ahmed; Seleem, Mohamed N; Mayhoub, Abdelrahman S

    2016-05-26

    A series of second-generation analogues for 2-(1-(2-(4-butylphenyl)-4-methylthiazol-5-yl)ethylidene)aminoguanidine (1) have been synthesized and tested against methicillin-resistant Staphylococcus aureus (MRSA). The compounds were designed with the objective of improving pharmacokinetic properties. This main aim has been accomplished by replacing the rapidly hydrolyzable Schiff-base moiety of first-generation members with a cyclic, unhydrolyzable pyrimidine ring. The hydrazide-containing analogue 17 was identified as the most potent analogue constructed thus far. The corresponding amine 8 was 8 times less active. Finally, incorporating the nitrogenous side chain within an aromatic system completely abolished the antibacterial character. Replacement of the n-butyl group with cyclic bioisosteres revealed cyclohexenyl analogue 29, which showed significant improvement in in vitro anti-MRSA potency. Increasing or decreasing the ring size deteriorated the antibacterial activity. Compound 17 demonstrated a superior in vitro and in vivo pharmacokinetic profile, providing compelling evidence that this particular analogue is a good drug candidate worthy of further analysis. PMID:27187739

  4. 48 CFR 28.203-3 - Acceptance of real property.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Acceptance of real property. 28.203-3 Section 28.203-3 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... Acceptance of real property. (a) Whenever a bond with a security interest in real property is submitted,...

  5. 48 CFR 28.203-3 - Acceptance of real property.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Acceptance of real property. 28.203-3 Section 28.203-3 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... Acceptance of real property. (a) Whenever a bond with a security interest in real property is submitted,...

  6. 10 CFR 603.550 - Acceptability of intellectual property.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Acceptability of intellectual property. 603.550 Section 603.550 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Pre-Award Business Evaluation Cost Sharing § 603.550 Acceptability of intellectual property. (a) In most instances, the contracting officer...

  7. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures

    PubMed Central

    2015-01-01

    Drug development has a high attrition rate, with poor pharmacokinetic and safety properties a significant hurdle. Computational approaches may help minimize these risks. We have developed a novel approach (pkCSM) which uses graph-based signatures to develop predictive models of central ADMET properties for drug development. pkCSM performs as well or better than current methods. A freely accessible web server (http://structure.bioc.cam.ac.uk/pkcsm), which retains no information submitted to it, provides an integrated platform to rapidly evaluate pharmacokinetic and toxicity properties. PMID:25860834

  8. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures.

    PubMed

    Pires, Douglas E V; Blundell, Tom L; Ascher, David B

    2015-05-14

    Drug development has a high attrition rate, with poor pharmacokinetic and safety properties a significant hurdle. Computational approaches may help minimize these risks. We have developed a novel approach (pkCSM) which uses graph-based signatures to develop predictive models of central ADMET properties for drug development. pkCSM performs as well or better than current methods. A freely accessible web server (http://structure.bioc.cam.ac.uk/pkcsm), which retains no information submitted to it, provides an integrated platform to rapidly evaluate pharmacokinetic and toxicity properties. PMID:25860834

  9. Pharmacokinetic properties of tandem d-peptides designed for treatment of Alzheimer's disease.

    PubMed

    Leithold, Leonie H E; Jiang, Nan; Post, Julia; Niemietz, Nicole; Schartmann, Elena; Ziehm, Tamar; Kutzsche, Janine; Shah, N Jon; Breitkreutz, Jörg; Langen, Karl-Josef; Willuweit, Antje; Willbold, Dieter

    2016-06-30

    Peptides are more and more considered for the development of drug candidates. However, they frequently exhibit severe disadvantages such as instability and unfavourable pharmacokinetic properties. Many peptides are rapidly cleared from the organism and oral bioavailabilities as well as in vivo half-lives often remain low. In contrast, some peptides consisting solely of d-enantiomeric amino acid residues were shown to combine promising therapeutic properties with high proteolytic stability and enhanced pharmacokinetic parameters. Recently, we have shown that D3 and RD2 have highly advantageous pharmacokinetic properties. Especially D3 has already proven promising properties suitable for treatment of Alzheimer's disease. Here, we analyse the pharmacokinetic profiles of D3D3 and RD2D3, which are head-to-tail tandem d-peptides built of D3 and its derivative RD2. Both D3D3 and RD2D3 show proteolytic stability in mouse plasma and organ homogenates for at least 24h and in murine and human liver microsomes for 4h. Notwithstanding their high affinity to plasma proteins, both peptides are taken up into the brain following i.v. as well as i.p. administration. Although both peptides contain identical d-amino acid residues, they are arranged in a different sequence order and the peptides show differences in pharmacokinetic properties. After i.p. administration RD2D3 exhibits lower plasma clearance and higher bioavailability than D3D3. We therefore concluded that the amino acid sequence of RD2 leads to more favourable pharmacokinetic properties within the tandem peptide, which underlines the importance of particular sequence motifs, even in short peptides, for the design of further therapeutic d-peptides. PMID:27086111

  10. Pharmacokinetic and pharmacodynamic properties of oral anticoagulants, especially phenprocoumon.

    PubMed

    Haustein, K O

    1999-01-01

    Anticoagulants of the cumarin-type (warfarin, phenprocoumon, and acenocoumarol) are drugs for the long-term treatment and prevention of thromboembolic disorders. Because of their narrow therapeutic range, many patients have bleedings of variable severity or have recurrent thrombotic events. For this reason, the study of the pharmacokinetic parameters of phenprocoumon (PPC), considering its influence on blood clotting factors, is of high interest. The elimination kinetics of PPC, its interaction with phytomenadion (vitamin K), and the pharmacokinetic behavior of the anticoagulant under steady-state conditions have been investigated in studies with healthy volunteers and patients taking anticoagulants. The maintenance dose and the plasma levels of PPC were correlated with prothrombin time (PT) in 89 patients treated with PPC. Varying parameters in each patient (e.g., elimination kinetics of PPC, activity of the cumarin-dependent blood-clotting factors, endogenous phytomenadion stores), render it impossible to use a different means of monitoring than that of PT determination. PMID:10327214

  11. 42 CFR 35.65 - Acceptable personal property.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Acceptable personal property. 35.65 Section 35.65 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Contributions for the Benefit of Patients § 35.65...

  12. 42 CFR 35.65 - Acceptable personal property.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Acceptable personal property. 35.65 Section 35.65 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Contributions for the Benefit of Patients § 35.65...

  13. 42 CFR 35.65 - Acceptable personal property.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Acceptable personal property. 35.65 Section 35.65 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Contributions for the Benefit of Patients § 35.65...

  14. Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation

    PubMed Central

    2015-01-01

    A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated. PMID:26191360

  15. Toxicity, pharmacokinetics, and photodynamic properties of chlorin e6

    NASA Astrophysics Data System (ADS)

    Kostenich, Gennady; Zhuravkin, Ivan N.; Gurinovich, G. P.; Zhavrid, Edvard A.

    1993-03-01

    Toxicity, pharmacokinetics, and the tumor damage effect of chlorin e6 after light irradiation were studied. The results show that chlorin e6 LD50 value in C57Bl mice was 189 +/- 10 mg/kg, in non-inbred white rats it was 99 +/- 14 mg/kg 14 days after the agent iv injection. The concentration of chlorin e6 in blood, liver, kidney, spleen, and tumors (sarcoma M-1 and sarcoma 45) of the rats was determined by the fluorescence method 3, 6, 12, 18, 24, 48, and 72 hours after the agent iv injection at the dose of 10 mg/kg. For this purpose chlorin e6 was extracted from tissues by detergent triton X-100. The depth of necrosis spreading in tumor tissue was evaluated after chlorin e6 injection at the doses of 1 - 10 mg/kg and subsequent irradiation by a krypton laser with light energy density of 90 J/cm2, using the method of vital staining with Evans blue. It was found that depending on the agent dose and time interval between chlorin e6 injection and photoradiation, the depth of tumor necrosis varied from 4.0 to 16.6 mm in sarcoma M-1 and from 5.0 to 15.0 in sarcoma 45.

  16. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update.

    PubMed

    Schachter, Michael

    2005-02-01

    Statins are the treatment of choice for the management of hypercholesterolaemia because of their proven efficacy and safety profile. They also have an increasing role in managing cardiovascular risk in patients with relatively normal levels of plasma cholesterol. Although all statins share a common mechanism of action, they differ in terms of their chemical structures, pharmacokinetic profiles, and lipid-modifying efficacy. The chemical structures of statins govern their water solubility, which in turn influences their absorption, distribution, metabolism and excretion. Lovastatin, pravastatin and simvastatin are derived from fungal metabolites and have elimination half-lives of 1-3 h. Atorvastatin, cerivastatin (withdrawn from clinical use in 2001), fluvastatin, pitavastatin and rosuvastatin are fully synthetic compounds, with elimination half-lives ranging from 1 h for fluvastatin to 19 h for rosuvastatin. Atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and pitavastatin are relatively lipophilic compounds. Lipophilic statins are more susceptible to metabolism by the cytochrome P(450) system, except for pitavastatin, which undergoes limited metabolism via this pathway. Pravastatin and rosuvastatin are relatively hydrophilic and not significantly metabolized by cytochrome P(450) enzymes. All statins are selective for effect in the liver, largely because of efficient first-pass uptake; passive diffusion through hepatocyte cell membranes is primarily responsible for hepatic uptake of lipophilic statins, while hydrophilic agents are taken up by active carrier-mediated processes. Pravastatin and rosuvastatin show greater hepatoselectivity than lipophilic agents, as well as a reduced potential for uptake by peripheral cells. The bioavailability of the statins differs greatly, from 5% for lovastatin and simvastatin to 60% or greater for cerivastatin and pitavastatin. Clinical studies have demonstrated rosuvastatin to be the most effective for reducing

  17. Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method.

    PubMed

    Solymosi, Tamás; Angi, Réka; Basa-Dénes, Orsolya; Ránky, Soma; Ötvös, Zsolt; Glavinas, Hristos; Filipcsei, Genovéva; Heltovics, Gábor

    2015-08-01

    The oral bioavailability of Sirolimus is limited by poor dissolution of the compound in the gastrointestinal tract resulting in a low bioavailability and large inter-individual differences in blood levels. Several different formulation approaches were applied to overcome these disadvantageous pharmacokinetic properties including the marketed oral solution and a tablet form containing wet milled nanocrystals. These approaches deliver improved pharmacokinetics, yet, they share the characteristics of complex production method and composition. We have developed a nanostructured Sirolimus formulation prepared by the controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. We have shown that contrary to the batch production the process could be easily intensified and scaled up; apparently the uniformity of the precipitation is heavily dependent on the production parameters, most likely the mixing of the solvent and antisolvent. We compared the physicochemical and pharmacokinetic properties of the nanostructured formula with the marketed nanoformula. We found that our method produces particles in the size range of less than 100nm. The solid form redispersed instantaneously in water and in biorelevant media. Both the solid form and the redispersed colloid solution showed excellent stability even in accelerated test conditions. The oral administration of the nanostructured formula resulted in faster absorption, higher exposure and higher trough concentrations when compared to the marked form. These advantageous properties could allow the development of solid oral Sirolimus formulae with lower strength and gel based topical delivery systems. PMID:26003815

  18. Pharmacokinetic and pharmacodynamic properties of the new AEDs: A review article

    PubMed Central

    Pakdaman, Hossein; Harirchian, Mohammad Hossein; Omrani, Hossein-Ali Ghelichnia; Ghabaee, Mojdeh; Zamani, Babak; Bahrami, Parviz; Siroos, Bahaadin

    2013-01-01

    The new-AEDs, whose developments were motivated following the discovery of the valproate and its marketing in the U.S in 1978, have presented more therapeutic options. There are approximately twenty four FDA-approved antiepileptic drugs for use in patients with epilepsy, five of which were identified and have come on to the market between 2009 and 2012. The new-AEDs are of interest, not due to their efficacy, but rather owing to better tolerance, favorable pharmacokinetic profile, fewer interactions, and in some instances, lesser protein binding. No standard AED or those in developing have all properties of an ideal antiepileptic drug, thus to achieve desirable outcome, physicians should be aware of pharmacokinetics (PKs) and pharmacodynamics (PDs) of drugs. This review describes briefly the major features of the new AEDs. PMID:24250926

  19. Comparative Pharmacokinetic Properties and Antitumor Activity of the Marine HDACi Largazole and Largazole Peptide Isostere

    PubMed Central

    Pilon, John L.; Clausen, Dane J.; Hansen, Ryan J.; Lunghofer, Paul J.; Charles, Brad; Rose, Barbara J.; Thamm, Douglas H.; Gustafson, Daniel L.; Bradner, James E.; Williams, Robert M.

    2015-01-01

    Purpose Largazole is a potent class I selective HDACi natural product isolated from the marine cyanobacteria Symploca sp. The purpose of this study was to test synthetic analogs of Largazole to identify potential scaffold structural modifications that would improve the drug-like properties of this clinically relevant natural product. Methods The impact of Largazole scaffold replacements on in vitro growth inhibition, cell cycle arrest, induction of apoptosis, pharmacokinetic properties, and in vivo activity using a xenograft model were investigated. Results In vitro studies in colon, lung, and pancreatic cancer cell lines showed that pyridyl substituted Largazole analogs had low nanomolar/high-picomolar activity on cell proliferation, and induced apoptosis and cell cycle arrest at concentrations equivalent to or lower than the parent compound Largazole. Using IV bolus delivery at 5mg/kg, two compartmental pharmacokinetic modeling on the peptide isostere analog of Largazole indicated improved pharmacokinetics including AUC, CL, and Vss. In the A549 non-small cell lung carcinoma xenograft model using a dosage of 5 mg/kg administered intraperitoneally every other day, Largazole, Largazole thiol, and Largazole peptide isostere demonstrated tumor growth inhibition (TGI%) of 32, 44, and 66 percent respectively. Moreover, the decreased tumor growth rate for Largazole peptide isostere was statistically significant compared to control (p=0.002) and superior to Largazole (p=0.006). Surprisingly tumor growth inhibition in this system and treatment regimen was not observed with the potent pyridyl-based analogs. Conclusions Our results establish that replacing the depsipepitde linkage in Largazole with an amide may impart pharmacokinetic advantage and that alternative prodrug forms of largazole are feasible. PMID:25616967

  20. A Phase 1 Randomized, Open Label, Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Three Formulations of Tenofovir 1% Gel (the CHARM-01 Study)

    PubMed Central

    Mcgowan, Ian; Cranston, Ross D.; Duffill, Kathryn; Siegel, Aaron; Engstrom, Jarret C.; Nikiforov, Alexyi; Jacobson, Cindy; Rehman, Khaja K.; Elliott, Julie; Khanukhova, Elena; Abebe, Kaleab; Mauck, Christine; Spiegel, Hans M. L.; Dezzutti, Charlene S.; Rohan, Lisa C.; Marzinke, Mark A.; Hiruy, Hiwot; Hendrix, Craig W.; Richardson-Harman, Nicola; Anton, Peter A.

    2015-01-01

    Objectives The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three tenofovir (TFV) gels for rectal application. The vaginal formulation (VF) gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF) gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF) gel was also evaluated in the CHARM-01 study. Methods Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial. Results All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC) TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/106 cells respectively). Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection. Conclusions All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection. Trial Registration ClinicalTrials.gov NCT01575405 PMID:25942472

  1. A novel approach to investigate the effect of methionine oxidation on pharmacokinetic properties of therapeutic antibodies

    PubMed Central

    Stracke, Jan; Emrich, Thomas; Rueger, Petra; Schlothauer, Tilman; Kling, Lothar; Knaupp, Alexander; Hertenberger, Hubert; Wolfert, Andreas; Spick, Christian; Lau, Wilma; Drabner, Georg; Reiff, Ulrike; Koll, Hans; Papadimitriou, Apollon

    2014-01-01

    Preserving the chemical and structural integrity of therapeutic antibodies during manufacturing and storage is a major challenge during pharmaceutical development. Oxidation of Fc methionines Met252 and Met428 is frequently observed, which leads to reduced affinity to FcRn and faster plasma clearance if present at high levels. Because oxidation occurs in both positions simultaneously, their individual contribution to the concomitant changes in pharmacokinetic properties has not been clearly established. A novel pH-gradient FcRn affinity chromatography method was applied to isolate three antibody oxidation variants from an oxidized IgG1 preparation based on their FcRn binding properties. Physico-chemical characterization revealed that the three oxidation variants differed predominantly in the number of oxMet252 per IgG (0, 1, or 2), but not significantly in the content of oxMet428. Corresponding to the increase in oxMet252 content, stepwise reduction of FcRn affinity in vitro, as well as faster clearance and shorter terminal half-life, in huFcRn-transgenic mice were observed. A single Met252 oxidation per antibody had no significant effect on pharmacokinetics (PK) compared with unmodified IgG. Importantly, only molecules with both heavy chains oxidized at Met252 exhibited significantly faster clearance. In contrast, Met428 oxidation had no apparent negative effect on PK and even led to somewhat improved FcRn binding and slower clearance. This minor effect, however, seemed to be abrogated by the dominant effect of Met252 oxidation. The novel approach of functional chromatographic separation of IgG oxidation variants followed by physico-chemical and biological characterization has yielded the first experimentally-backed explanation for the unaltered PK properties of antibody preparations containing relatively high Met252 and Met428 oxidation levels. PMID:25517308

  2. Discovery of a potent class I selective ketone histone deacetylase inhibitor with antitumor activity in vivo and optimized pharmacokinetic properties.

    PubMed

    Kinzel, Olaf; Llauger-Bufi, Laura; Pescatore, Giovanna; Rowley, Michael; Schultz-Fademrecht, Carsten; Monteagudo, Edith; Fonsi, Massimiliano; Gonzalez Paz, Odalys; Fiore, Fabrizio; Steinkühler, Christian; Jones, Philip

    2009-06-11

    The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclinical species, has a clean off-target profile, and is negative in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose. PMID:19441846

  3. Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine1-receptor agonist, in hypertensive patients.

    PubMed Central

    Weber, R R; McCoy, C E; Ziemniak, J A; Frederickson, E D; Goldberg, L I; Murphy, M B

    1988-01-01

    1 The pharmacokinetic properties of intravenous fenoldopam, a selective dopamine1-receptor agonist, were studied in 10 patients with essential hypertension. 2 Reduction in blood pressure was linearly related to the log fenoldopam plasma concentration (r = 0.69) and the log fenoldopam infusion rate (r = 0.71). 3 The mean elimination half-life (+/- s. e. mean) was 9.8 +/- 1.0 min. The total body clearance was 30.3 +/- 2.3 ml kg-1 min-1 and the volume of distribution was 582 +/- 62 ml kg-1. 4 The rapid onset of action, short elimination half-life, linear dose-response relationship, and ease of administration suggest that fenoldopam may have a role where parenteral treatment of hypertension is required. PMID:2897206

  4. RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

    PubMed Central

    Cranston, Ross D.; Kashuba, Angela; Hendrix, Craig W.; Bumpus, Namandjé N.; Richardson-Harman, Nicola; Elliott, Julie; Janocko, Laura; Khanukhova, Elena; Dennis, Robert; Cumberland, William G.; Ju, Chuan; Carballo-Diéguez, Alex; Mauck, Christine; McGowan, Ian

    2012-01-01

    Abstract This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs (p=0.002). Only 25% of participants liked the TFV gel. Likelihood of use “if somewhat protective” was ∼75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) Cmax 30 min after single rectal exposure was 6–10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p=0.12, analysis of covariance (ANCOVA) p=0.006; 7-day rectal: p=0.02, ANCOVA p=0.005]. Tissue PK–PD was significantly correlated (p=0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK–PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations. PMID:22943559

  5. 41 CFR 102-75.1155 - May an acceptable gift of property be converted to money?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... of property be converted to money? 102-75.1155 Section 102-75.1155 Public Contracts and Property...-75.1155 May an acceptable gift of property be converted to money? GSA can determine whether or not a gift of property can and should be converted to money. After conversion, GSA must deposit the...

  6. Production, characterization, and pharmacokinetic properties of antibodies with N-linked mannose-5 glycans.

    PubMed

    Yu, Marcella; Brown, Darren; Reed, Chae; Chung, Shan; Lutman, Jeff; Stefanich, Eric; Wong, Anne; Stephan, Jean-Philippe; Bayer, Robert

    2012-01-01

    The effector functions of therapeutic antibodies are strongly affected by the specific glycans added to the Fc domain during post-translational processing. Antibodies bearing high levels of N-linked mannose-5 glycan (Man5) have been reported to exhibit enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) compared with antibodies with fucosylated complex or hybrid glycans. To better understand the relationship between antibodies with high levels of Man5 and their biological activity in vivo, we developed an approach to generate substantially homogeneous antibodies bearing the Man5 glycoform. A mannosidase inhibitor, kifunensine, was first incorporated in the cell culture process to generate antibodies with a distribution of high mannose glycoforms. Antibodies were then purified and treated with a mannosidase for trimming to Man5 in vitro. This 2-step approach can consistently generate antibodies with > 99% Man5 glycan. Antibodies bearing varying levels of Man5 were studied to compare ADCC and Fcγ receptor binding, and they showed enhanced ADCC activity and increased binding affinity to the FcγRIIIA. In addition, the clearance rate of antibodies bearing Man8/9 and Man5 glycans was determined in a pharmacokinetics study in mice. When compared with historical data, the antibodies bearing the high mannose glycoform exhibited faster clearance rate compared with antibodies bearing the fucosylated complex glycoform, while the pharmacokinetic properties of antibodies with Man8/9 and Man5 glycoforms appeared similar. In addition, we identified the presence of a mannosidase in mouse serum that converted most Man8/9 to Man6 after 24 h. PMID:22699308

  7. 49 CFR 1546.201 - Acceptance and screening of individuals and accessible property.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Acceptance and screening of individuals and... FOREIGN AIR CARRIER SECURITY Operations § 1546.201 Acceptance and screening of individuals and accessible... or accessible property before boarding an aircraft or entering a sterile area. (b) Screening...

  8. Further Evaluation of the Psychometric Properties of the Acceptance and Action Questionnaire-II

    ERIC Educational Resources Information Center

    Fledderus, Martine; Oude Voshaar, Martijn A. H.; ten Klooster, Peter M.; Bohlmeijer, Ernst T.

    2012-01-01

    The Acceptance and Action Questionnaire-II (AAQ-II) is a self-report measure designed to assess experiential avoidance as conceptualized in acceptance and commitment therapy (ACT). The current study is the first to evaluate the psychometric properties of the AAQ-II in a large sample of adults (N = 376) with mild to moderate levels of depression…

  9. 10 CFR 603.540 - Acceptability of fully depreciated real property or equipment.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Acceptability of fully depreciated real property or equipment. 603.540 Section 603.540 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Pre-Award Business Evaluation Cost Sharing § 603.540 Acceptability of fully...

  10. 10 CFR 603.550 - Acceptability of intellectual property.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... property (e.g., copyrighted material, including software) as cost sharing because: (1) It is difficult to... the contribution. For example, a for-profit firm may offer the use of commercially available software for which there is an established license fee for use of the product. The costs of the development...

  11. 10 CFR 603.550 - Acceptability of intellectual property.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... property (e.g., copyrighted material, including software) as cost sharing because: (1) It is difficult to... the contribution. For example, a for-profit firm may offer the use of commercially available software... the software would not be a reasonable basis for valuing its use....

  12. 10 CFR 603.550 - Acceptability of intellectual property.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... property (e.g., copyrighted material, including software) as cost sharing because: (1) It is difficult to... the contribution. For example, a for-profit firm may offer the use of commercially available software... the software would not be a reasonable basis for valuing its use....

  13. 10 CFR 603.550 - Acceptability of intellectual property.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... property (e.g., copyrighted material, including software) as cost sharing because: (1) It is difficult to... the contribution. For example, a for-profit firm may offer the use of commercially available software... the software would not be a reasonable basis for valuing its use....

  14. Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia.

    PubMed

    Moree, Wilna J; Li, Bin-Feng; Zamani-Kord, Said; Yu, Jinghua; Coon, Timothy; Huang, Charles; Marinkovic, Dragan; Tucci, Fabio C; Malany, Siobhan; Bradbury, Margaret J; Hernandez, Lisa M; Wen, Jianyun; Wang, Hua; Hoare, Samuel R J; Petroski, Robert E; Jalali, Kayvon; Yang, Chun; Sacaan, Aida; Madan, Ajay; Crowe, Paul D; Beaton, Graham

    2010-10-01

    Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study. PMID:20800486

  15. [Physico-chemical profiling of centrally acting molecules for prediction of pharmacokinetic properties].

    PubMed

    Deák, Katalin

    2008-01-01

    Physico-chemical profiling is a fundamental tool at the early stage of drug discovery in screening drug-like candidates. Complex physico-chemical profiling, including molecular properties such as solubility, ionization, lipophilicity and permeability, has been found to be of predictive power in ADME (absorption, distribution, metabolism, elimination). In the present thesis work, the physico-chemical properties of centrally acting compounds were investigated. We determined the protonation constants (K), the partition coeffitient in octanol/water (Poct) and cyclohexane/water (Pch) systems of antidepressive sertraline and 15 antipsychotic piperidine and piperazine derivatives and calculated the delta logP (logPoct-logPch) values of the molecules. Due to the poor water solubility of the compounds potentiometry using the "co-solvent" technique was applied for the determination of the protonation constants. The logP values were measured by the dual-phase potentiometric titration in octanol/water system and the traditional shake-flask method was used in cyclohexane/water system. Highly precise physico-chemical data were obtained by these validated methods. The relationship between the structure of the molecules and the physico-chemical data was investigated. The pharmacokinetic properties of the compounds were predicted by the physico-chemical parameters. Linear relationship has been found between the brain penetration characterized by the logBB values and the delta logP values. The validity of the equation was controlled by the delta logP and the logBB values of sertraline. PMID:18986088

  16. Improvement of pyrazolo[3,4-d]pyrimidines pharmacokinetic properties: nanosystem approaches for drug delivery

    PubMed Central

    Vignaroli, Giulia; Calandro, Pierpaolo; Zamperini, Claudio; Coniglio, Federica; Iovenitti, Giulia; Tavanti, Matteo; Colecchia, David; Dreassi, Elena; Valoti, Massimo; Schenone, Silvia; Chiariello, Mario; Botta, Maurizio

    2016-01-01

    Pyrazolo[3,4-d]pyrimidines are a class of compounds with a good activity against several cancer cell lines. Despite the promising anticancer activity, these molecules showed a poor aqueous solubility. This issue could threat the future development of pyrazolo[3,4-d]pyrimidines as clinical drug candidates. With the aim of improving their solubility profile and consequently their pharmacokinetic properties, we have chosen four compounds (1–4) on the base of their anti-neuroblastoma activity and we have developed albumin nanoparticles and liposomes for the selected candidates. Albumin nanoparticles and liposomes were prepared and characterized regarding size and ζ-potential distribution, polidispersity index, entrapment efficiency and activity against SH-SY5Y human neuroblastoma cell line. The most promising nanosystem, namely LP-2, was chosen to perform further studies: confocal microscopy, stability and drug release in physiological conditions, and biodistribution. Altogether, the obtained data strongly indicate that the encapsulation of pyrazolo[3,4-d]pyrimidines in liposomes represent an effective method to overcome the poor water solubility. PMID:26898318

  17. Improvement of pyrazolo[3,4-d]pyrimidines pharmacokinetic properties: nanosystem approaches for drug delivery.

    PubMed

    Vignaroli, Giulia; Calandro, Pierpaolo; Zamperini, Claudio; Coniglio, Federica; Iovenitti, Giulia; Tavanti, Matteo; Colecchia, David; Dreassi, Elena; Valoti, Massimo; Schenone, Silvia; Chiariello, Mario; Botta, Maurizio

    2016-01-01

    Pyrazolo[3,4-d]pyrimidines are a class of compounds with a good activity against several cancer cell lines. Despite the promising anticancer activity, these molecules showed a poor aqueous solubility. This issue could threat the future development of pyrazolo[3,4-d]pyrimidines as clinical drug candidates. With the aim of improving their solubility profile and consequently their pharmacokinetic properties, we have chosen four compounds (1-4) on the base of their anti-neuroblastoma activity and we have developed albumin nanoparticles and liposomes for the selected candidates. Albumin nanoparticles and liposomes were prepared and characterized regarding size and ζ-potential distribution, polidispersity index, entrapment efficiency and activity against SH-SY5Y human neuroblastoma cell line. The most promising nanosystem, namely LP-2, was chosen to perform further studies: confocal microscopy, stability and drug release in physiological conditions, and biodistribution. Altogether, the obtained data strongly indicate that the encapsulation of pyrazolo[3,4-d]pyrimidines in liposomes represent an effective method to overcome the poor water solubility. PMID:26898318

  18. 10 CFR 603.540 - Acceptability of fully depreciated real property or equipment.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Acceptability of fully depreciated real property or... real property or equipment. The contracting officer should limit the value of any contribution of a... time of the negotiations; (c) The effect of any increased maintenance charges or decreased...

  19. 49 CFR 1544.201 - Acceptance and screening of individuals and accessible property.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Acceptance and screening of individuals and... screening of individuals and accessible property. (a) Preventing or deterring the carriage of any explosive...) Screening of individuals and accessible property. Except as provided in its security program, each...

  20. Artificial Neural Network Analysis of Pharmacokinetic and Toxicity Properties of Lead Molecules for Dengue Fever, Tuberculosis and Malaria.

    PubMed

    Nilar, Shahul H; Lakshminarayana, Suresh B; Ma, Ngai Ling; Keller, Thomas H; Blasco, Francesca; Smith, Paul W

    2016-01-01

    Poor pharmacokinetic and toxicity profiles are major reasons for the low rate of advancing lead drug candidates into efficacy studies. The In-silico prediction of primary pharmacokinetic and toxicity properties in the drug discovery and development process can be used as guidance in the design of candidates. In-silico parameters can also be used to choose suitable compounds for in-vivo testing thereby reducing the number of animals used in experiments. At the Novartis Institute for Tropical Diseases, a data set has been curated from in-house measurements in the disease areas of Dengue, Tuberculosis and Malaria. Volume of distribution, half-life, total in-vivo clearance, in-vitro human plasma protein binding and in-vivo oral bioavailability have been measured for molecules in the lead optimization stage in each of these three disease areas. Data for the inhibition of the hERG channel using the radio ligand binding dofetilide assay was determined for a set of 300 molecules in these therapeutic areas. Based on this data, Artificial Neural Networks were used to construct In-silico models for each of the properties listed above that can be used to prioritize candidates for lead optimization and to assist in selecting promising molecules for in-vivo pharmacokinetic studies. PMID:26777113

  1. Pharmacokinetic Properties of Artemether, Dihydroartemisinin, Lumefantrine, and Quinine in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria in Uganda

    PubMed Central

    Kloprogge, Frank; Dhorda, Mehul; Jullien, Vincent; Nosten, Francois; White, Nicholas J.; Guerin, Philippe J.; Piola, Patrice

    2013-01-01

    Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens. PMID:23917320

  2. A novel stearic acid-modified hirudin peptidomimetic with improved pharmacokinetic properties and anticoagulant activity

    PubMed Central

    Liu, Zhuguo; Yu, Zheng; Huang, Yuanyuan; Zhang, Yan; Han, Guozhu; Li, Xian; Dong, Mingxin; Yu, Shuo; Wang, Yu; Hu, Jie; Guo, Huiqin; Cheng, Yuanguo; Lv, Li; Dai, Qiuyun

    2015-01-01

    A novel hirudin isoform 3 mimetic peptide, named peptide S2, has been prepared by introduction of a stearic acid modification. Peptide S2 exhibited superior inhibitory activity to hirulog-1 (Bivariludin) and showed significantly higher anticoagulant potency in vivo. Peptide S2 elevated the thrombin time, prothrombin time and activated partial thromboplastin time of rat and human plasma more efficiently than hirulog-1 and the unmodified form of peptide S2 (peptide 1). Furthermore, peptide S2 inhibited arterial thrombosis and inferior vena cava in rat model 8 h after administration, and was 10-fold more potent than hirulog-1 300 min after administration of 0.1 μmol/kg peptide. The enhanced antithrombotic activity could be attributed to its long half-life (T1/2 = 212.2 ± 58.4 min), which was 13.1 and 14.7-fold longer than those of hirulog-1 (T1/2 = 15.1 ± 1.3 min) and peptide 1 (T1/2 = 13.5 ± 2.6 min), respectively. Further enzymatic degradation and binding assay with human serum albumin (HSA) demonstrated that the longer duration time should be originated from the slowing of trypsin or thrombin–mediated degradation, as well as its binding to HSA. The improved pharmacokinetic properties observed for peptide S2 has made it a promising therapeutic agent for the treatment of thrombi-related diseases. PMID:26400022

  3. Pharmacokinetic properties of γ-hydroxybutyrate (GHB) in whole blood, serum, and urine.

    PubMed

    Brailsford, Alan D; Cowan, David A; Kicman, Andrew T

    2012-03-01

    Over the last 10-15 years, γ-hydroxybutyrate (GHB) and γ-butyrolactone have become increasingly popular "club drugs", but they have also gained attention as potential agents of drug-facilitated sexual assault (DFSA). Several studies have attempted to characterize GHB's pharmacokinetic properties in humans, and the aim of this paper is to build on this research with an emphasis on DFSA cases. A 25 mg/kg dose of GHB was given to 12 GHB-naïve volunteers (6 men and 6 women). Urine and blood samples (serum and whole blood) were collected and analyzed by gas chromatography-mass spectrometry following liquid-liquid extraction. The urinary T(max) was 1 h in 11 volunteers with a mean C(max) of 67.6 mg/L (32.6-161.3 mg/L). Urinary concentrations rapidly decreased to < 10 mg/L (interpretive limit) for 11 volunteers after just 4 h. Data derived from whole blood (mean C(max) = 48.0 mg/L, T(max) = 24.6 min) closely matched that from serum (mean C(max) = 59.4 mg/L, T(max) = 23.3 min), suggesting GHB is distributed into erythrocytes. All 12 volunteers had GHB concentrations of less than 5 mg/L in both whole blood and serum after 3 h. Results verify the rapid elimination of GHB and the limited retrospective power of a concentration-based approach to prove GHB administration in blood and urine and confirm that, in DFSA cases, samples should be collected as soon as possible. PMID:22337777

  4. ANATOMIC AND PHARMACOKINETIC PROPERTIES OF INTRAVITREAL BEVACIZUMAB AND RANIBIZUMAB AFTER VITRECTOMY AND LENSECTOMY

    PubMed Central

    CHRISTOFORIDIS, JOHN B.; CARLTON, MICHELLE M.; WANG, JILLIAN; JIANG, ANGELA; PRATT, CEDRIC; ABDEL-RASOUL, MAHMOUD; HINKLE, GEORGE H.; KNOPP, MICHAEL V.

    2014-01-01

    Purpose To determine the anatomic characteristics and pharmacokinetic properties of intravitreally placed bevacizumab and ranibizumab after pars plana lensectomy or pars plana vitrectomy and to compare these with nonoperated control eyes in a rabbit model. Methods Three groups of six Dutch-belted rabbits each underwent pars plana vitrectomy, pars plana lensectomy, or served as nonsurgical controls. Twelve days after surgery, 3 rabbits from each group underwent intravitreal injection in one eye with 1.25 mg/0.05 mL I-124–bevacizumab or 0.5 mg/0.05 mL I-124-ranibizumab. Serial imaging with PET/CT were obtained on Days 0, 2, 5, 7, 14, 21, 28, and 35. Measured radioactivity emission in becquerels/milliliter was used to calculate the half-lives for each agent. Results The intravitreally placed radiolabeled agents were contained within the vitreous cavity for the duration of the study. The average clearance half-lives with standard error for bevacizumab and ranibizumab after correction for radioactive decay were, respectively, 4.22 ± 0.07 days and 2.81 ± 0.05 days in unoperated eyes, 2.30 ± 0.09 days (P < 0.0001) and 2.13 ± 0.05 days (P < 0.0001) after vitrectomy, and 2.08 ± 0.07 days (P = 0.0001) and 1.79 ± 0.05 days (P < 0.0001) after lensectomy. Conclusion Intravitreal retention was longer for bevacizumab than ranibizumab within all study groups and was significantly reduced after vitrectomy and lensectomy for both agents. Consideration for more frequent intravitreal anti–vascular endothelial growth factor dosing regimens may be made for patients whose treated eyes have undergone previous vitrectomy or who are aphakic. PMID:23407351

  5. Improving the pharmacokinetic properties of biologics by fusion to an anti-HSA shark VNAR domain

    PubMed Central

    Müller, Mischa R.; Saunders, Kenneth; Grace, Christopher; Jin, Macy; Piche-Nicholas, Nicole; Steven, John; O’Dwyer, Ronan; Wu, Leeying; Khetemenee, Lam; Vugmeyster, Yulia; Hickling, Timothy P.; Tchistiakova, Lioudmila; Olland, Stephane; Gill, Davinder; Jensen, Allan; Barelle, Caroline J.

    2012-01-01

    Advances in recombinant antibody technology and protein engineering have provided the opportunity to reduce antibodies to their smallest binding domain components and have concomitantly driven the requirement for devising strategies to increase serum half-life to optimise drug exposure, thereby increasing therapeutic efficacy. In this study, we adopted an immunization route to raise picomolar affinity shark immunoglobulin new antigen receptors (IgNARs) to target human serum albumin (HSA). From our model shark species, Squalus acanthias, a phage display library encompassing the variable binding domain of IgNAR (VNAR) was constructed, screened against target, and positive clones were characterized for affinity and specificity. N-terminal and C-terminal molecular fusions of our lead hit in complex with a naïve VNAR domain were expressed, purified and exhibited the retention of high affinity binding to HSA, but also cross-selectivity to mouse, rat and monkey serum albumin both in vitro and in vivo. Furthermore, the naïve VNAR had enhanced pharmacokinetic (PK) characteristics in both N- and C-terminal orientations and when tested as a three domain construct with naïve VNAR flanking the HSA binding domain at both the N and C termini. Molecules derived from this platform technology also demonstrated the potential for clinical utility by being available via the subcutaneous route of delivery. This study thus demonstrates the first in vivo functional efficacy of a VNAR binding domain with the ability to enhance PK properties and support delivery of multifunctional therapies. PMID:23676205

  6. Medicinal properties of mangiferin, structural features, derivative synthesis, pharmacokinetics and biological activities.

    PubMed

    Benard, Outhiriaradjou; Chi, Yuling

    2015-01-01

    The identification of biologically active and potentially therapeutically useful pharmacophores from natural products has been a long-term focus in the pharmaceutical industry. The recent emergence of a worldwide obesity and Type II diabetes epidemic has increased focus upon small molecules that can modulate energy metabolism, insulin sensitivity and fat biology. Interesting preliminary work done on mangiferin (MGF), the predominant constituent of extracts of the mango plant Mangifera indica L., portends potential for this pharmacophore as a novel parent compound for treating metabolic disorders. MGF is comprised of a C-glucosylated xanthone. Owing to the xanthone chemical structure, MGF has a redox active aromatic system and has antioxidant properties. MGF exerts varied and impressive metabolic effects in animals, improving metabolic disorders. For example we have discovered that MGF is a novel activator of the mammalian pyruvate dehydrogenase complex, leading to enhancement of carbohydrate utilization in oxidative metabolism, and leading to increased insulin sensitivity in animal models of obesity and insulin resistance. In addition, recent unbiased proteomics studies revealed that MGF upregulates proteins pivotal for mitochondrial bioenergetics and downregulates proteins controlling de novo lipogenesis in liver, helping to explain protective effects of MGF in prevention of liver steatosis. Several chemical studies have achieved synthesis of MGF, suggesting possible synthetic strategies to alter its chemical structure for development of structure-activity relationship (SAR) information. Ultimately, chemical derivatization studies could lead to the eventual development of novel therapeutics based upon the parent pharmacophore structure. Here we provide comprehensive review on chemical features of MGF, synthesis of its derivatives, its pharmacokinetics and biological activities. PMID:25827900

  7. Pharmacokinetic properties of low-dose SoluMatrix meloxicam in healthy adults.

    PubMed

    Hussaini, Azra; Solorio, Daniel; Young, Clarence

    2016-04-01

    SoluMatrix® meloxicam has been developed using SoluMatrix Fine Particle Technology™ to produce a meloxicam drug product with enhanced absorption properties to enable treatment at lower doses than available oral meloxicam drug products. This follows recognition of serious dose-dependent adverse events (AEs) associated with nonsteroidal anti-inflammatory drugs, including meloxicam. This study investigated the pharmacokinetic (PK) properties of SoluMatrix meloxicam 5-mg (fasting conditions) and 10-mg capsules (fasting and fed conditions) and compared SoluMatrix meloxicam 10-mg capsules with meloxicam 15-mg tablets under fasting conditions. This four-period crossover study randomized 28 healthy adult participants to receive single doses of SoluMatrix meloxicam 5-mg capsules (fasting) and 10-mg capsules (fasting or fed) and meloxicam tablets 15 mg (fasting). Meloxicam plasma concentrations were assessed through 96 h postdose. Safety was assessed. Twenty-five participants (89.3 %) completed the study. Under fasting conditions, SoluMatrix meloxicam 10 mg [1252.8 (254.22) ng/mL] produced similar meloxicam mean (standard deviation (SD)) maximum plasma concentrations vs meloxicam 15-mg tablets [1288.8 (424.40) ng/mL]. The overall mean (SD) systemic meloxicam exposure was 33 % lower for SoluMatrix meloxicam 10 mg [29,173.01 (11,042.09) ng*h/mL] vs meloxicam 15-mg tablets [40,875.6 (11,733.47) ng*h/mL]. The median time to maximum plasma meloxicam levels occurred earlier following SoluMatrix meloxicam 5 mg (2.0 h) and 10 mg (2.0 h) administration vs meloxicam 15-mg tablets (4.0 h). Few study-medication-related AEs were reported. SoluMatrix meloxicam 10 mg was more rapidly absorbed and associated with a lower overall exposure compared with meloxicam 15-mg tablets in this study in healthy adults under fasting conditions. PMID:26638161

  8. 49 CFR 1544.201 - Acceptance and screening of individuals and accessible property.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 9 2012-10-01 2012-10-01 false Acceptance and screening of individuals and accessible property. 1544.201 Section 1544.201 Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION...

  9. 49 CFR 1546.201 - Acceptance and screening of individuals and accessible property.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 9 2014-10-01 2014-10-01 false Acceptance and screening of individuals and accessible property. 1546.201 Section 1546.201 Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION SECURITY FOREIGN AIR CARRIER SECURITY Operations...

  10. 49 CFR 1544.201 - Acceptance and screening of individuals and accessible property.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 9 2014-10-01 2014-10-01 false Acceptance and screening of individuals and accessible property. 1544.201 Section 1544.201 Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION SECURITY AIRCRAFT OPERATOR SECURITY: AIR...

  11. 49 CFR 1544.201 - Acceptance and screening of individuals and accessible property.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 9 2011-10-01 2011-10-01 false Acceptance and screening of individuals and accessible property. 1544.201 Section 1544.201 Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION...

  12. 49 CFR 1546.201 - Acceptance and screening of individuals and accessible property.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 9 2011-10-01 2011-10-01 false Acceptance and screening of individuals and accessible property. 1546.201 Section 1546.201 Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION...

  13. 49 CFR 1544.201 - Acceptance and screening of individuals and accessible property.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 9 2013-10-01 2013-10-01 false Acceptance and screening of individuals and accessible property. 1544.201 Section 1544.201 Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION...

  14. 10 CFR 603.540 - Acceptability of fully depreciated real property or equipment.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Acceptability of fully depreciated real property or equipment. 603.540 Section 603.540 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY... officer must consider: (a) The original cost of the asset; (b) Its estimated remaining useful life at...

  15. Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat.

    PubMed

    Roda, Aldo; Pellicciari, Roberto; Gioiello, Antimo; Neri, Flavia; Camborata, Cecilia; Passeri, Daniela; De Franco, Francesca; Spinozzi, Silvia; Colliva, Carolina; Adorini, Luciano; Montagnani, Marco; Aldini, Rita

    2014-07-01

    We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7α-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6α-Ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6

  16. Physico-chemical properties and acceptability of yam flour substituted with soy flour.

    PubMed

    Akingbala, J O; Oguntimein, G B; Sobande, A O

    1995-07-01

    Yam flour was substituted 10, 20 and 40% with defatted and full fat soy flour. The effect of the substitution on the proximate composition, swelling power, solubility, water binding capacity and Brabender visco amylograph cooking properties of the yam flour and acceptability of the cooked paste (amala), were evaluated. Protein contents of the mixtures were 23.0 and 25.5% on substituting 40% full-and defatted soy flours for yam flour, ash and crude fibre contents increased while carbohydrate content, swelling power, Brabender paste viscosities decreased with increase in soy flour substitution of yam flour. Colour, texture, taste and overall acceptability of pastes (amala) from the mixed flours were rated lower than that of yam flour. Up to 10% defatted and 20% full fat soy flour substitution for yam flour was acceptable for amala. PMID:8719741

  17. Lisdexamfetamine: A pharmacokinetic review.

    PubMed

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. PMID:27125257

  18. Regression methods for developing QSAR and QSPR models to predict compounds of specific pharmacodynamic, pharmacokinetic and toxicological properties.

    PubMed

    Yap, C W; Li, H; Ji, Z L; Chen, Y Z

    2007-11-01

    Quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) models have been extensively used for predicting compounds of specific pharmacodynamic, pharmacokinetic, or toxicological property from structure-derived physicochemical and structural features. These models can be developed by using various regression methods including conventional approaches (multiple linear regression and partial least squares) and more recently explored genetic (genetic function approximation) and machine learning (k-nearest neighbour, neural networks, and support vector regression) approaches. This article describes the algorithms of these methods, evaluates their advantages and disadvantages, and discusses the application potential of the recently explored methods. Freely available online and commercial software for these regression methods and the areas of their applications are also presented. PMID:18045213

  19. Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties

    SciTech Connect

    Liu Aiming; Xie Shuilin; Sun He; Gonzalez, Frank J.; Wei Xiaoxiong; Dai Renke

    2009-03-15

    Fibrate drugs are PPAR{alpha} agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPAR{alpha} agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey no. 2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly, they exhibited a much higher incidence of myotoxicity than that of humans. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity.

  20. Pharmacokinetics and stability properties of catalase modified with water-soluble polysaccharides.

    PubMed

    Valdivia, Aymara; Pérez, Yunel; Gómez, Leissy; Ramírez, Hector L; Schacht, Etienne H; Villalonga, Reynaldo

    2006-07-01

    Bovine liver catalase (EC 1.11.1.6) was chemically modified with mannan, carboxymethylcellulose, and carboxymethylchitin. The enzyme retained about 48-97% of the initial specific activity after glycosidation with the polysaccharides. The prepared neoglycoenzyme was 1.9-5.7 fold more stable against the thermal inactivation processes at 55 degrees C, in comparison with the native counterpart. Also, the modified enzyme was more resistant to proteolytic degradation with trypsin. Pharmacokinetics studies revealed higher plasma half-life time for all the enzyme-polymer preparations, but better results were achieved for the enzyme modified with the anionic macromolecules. PMID:16838281

  1. Effect of flaxseed flour incorporation on the physical properties and consumer acceptability of cereal bars.

    PubMed

    Khouryieh, H; Aramouni, F

    2013-12-01

    Extensive research has revealed numerous nutritional and health benefits of flaxseed due primarily to its nutrients content. The objective of this study was to evaluate the effect of flaxseed flour addition on the physical and sensory characteristics of cereal bars. Four formulations of the flaxseed cereal bars were prepared by partially replacing oats with flaxseed flour added at levels of 0 (control), 6%, 12% and 18%. There were no significant differences (p > 0.05) in water activity, moisture and firmness values between the flaxseed bars and control. Flaxseed addition significantly (p < 0.05) decreased lightness and increased redness of the bars. There were no significant differences (p > 0.05) between the 12% flax cereal bars and the control with respect to sensory attributes and overall acceptability. The overall acceptability for both 12% flax bars and the control was in between 'like moderately' and 'like slightly' on the 9-point hedonic scale. The overall acceptability was most highly correlated with flavor acceptability for both control (r = 0.80) and 12% flax (r = 0.82) cereal bars. Flaxseed bars provided 12% dietary fiber of the daily recommended value. These results indicated that flaxseed flour incorporation up to 12% substantially enhanced the nutritional qualities of the cereal bars without affecting their sensory and quality properties. PMID:23733813

  2. PHARMACOKINETIC PROPERTIES OF A SINGLE ADMINISTRATION OF ORAL GABAPENTIN IN THE GREAT HORNED OWL (BUBO VIRGINIANUS).

    PubMed

    Yaw, Taylor J; Zaffarano, Bianca A; Gall, Andrew; Olds, June E; Wulf, Larry; Papastavros, Efthimia; Coetzee, Johann F

    2015-09-01

    Gabapentin (1-[aminomethyl] cyclohexane acetic acid) is a γ-aminobutyric acid analogue that has been shown to be efficacious for neuropathic pain control in humans. Plasma gabapentin concentrations >2 μg/ml are considered effective in treating epilepsy in humans and are suggested to provide analgesia for neuropathic pain. This study investigated the pharmacokinetics of a single oral dose of gabapentin suspension (11 mg/kg) in great horned owls ( Bubo virginianus ). Plasma gabapentin concentrations were determined in six healthy birds for 48 hr using high-performance liquid chromatography with mass spectrometric detection. Plasma gabapentin concentrations were estimated by noncompartmental pharmacokinetic analysis. The harmonic mean (±SD) maximum concentration (Cmax), time to maximum concentration (Tmax), and elimination half-life (tv2λZ) for gabapentin (11 mg/kg) were 6.17±0.83 μg/ml, 51.43±5.66 min, and 264.60±69.35 min, respectively. In this study, plasma gabapentin concentrations were maintained above 2 μg/ml for 528 min (8.8 hr), suggesting that gabapentin administered orally every 8 hr may be appropriate in great horned owls. PMID:26352959

  3. Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties.

    PubMed

    Cheng, Shuihong; Wang, Yan; Zhang, Zhenxing; Lv, Xun; Gao, George F; Shao, Yiming; Ma, Liying; Li, Xuebing

    2016-10-01

    Enfuvirtide (ENF) is a clinically used peptide drug for the treatment of HIV infections, but its poor pharmacokinetic profile (T1/2 = 1.5 h in rats) and low aqueous solubility make the therapy expensive and inconvenience. In this study, we present a simple and practical strategy to address these problems by conjugating ENF with polyethylene glycol (PEG). Site-specific attachment of a 2 kDa PEG at the N-terminus of ENF resulted in an ENF-PEG (EP) conjugate with high solubility (≥3 mg/mL) and long half-life in rats (T1/2 = 16.1 h). This conjugate showed similar antiviral activity to ENF against various primary HIV-1 isolates (EC50 = 6-91 nM). Mechanistic studies suggested the sources of the antiviral potency. The conjugate bound to a functional domain of the HIV gp41 protein in a helical conformation with high affinity (Kd = 307 nM), thereby inhibiting the gp41-mediated fusion of viral and host-cell membranes. As PEG conjugation has advanced many bioactive proteins and peptides into clinical applications, the EP conjugate described here represents a potential new treatment for HIV infections that may address the unmet medical needs associated with the current ENF therapy. PMID:27240277

  4. Pharmacokinetic properties of N-nitrosofenfluramine after its administration to rats.

    PubMed

    Kaddoumi, Amal; Wada, Mitsuhiro; Nakashima, Kenichiro

    2011-05-01

    N-nitrosofenfluramine (N-Fen), a synthetic adulterant in Chinese herbal diet products, is believed to cause hepatotoxicity in people who use these products. N-Fen is a relatively new compound, and thus pharmacological and toxicological studies are insufficient. The aim of this work was to (1) define N-Fen's plasma pharmacokinetics and tissue distribution after single intraperitoneal (i.p.) administration of 25 mg/kg to rats; (2) define its bioavailability; and (3) identify fenfluramine (Fen) and norfenfluramine (Norf) as N-Fen metabolites. N-Fen rapidly appeared in the circulation and was distributed to all tissues. Norf was found to be the primary metabolite and not Fen. Plasma and tissue levels of N-Fen and Norf were low with bioavailability of N-Fen after i.p. administration was <3%. The AUC(0) (-t) of N-Fen in the liver and kidney were 6.6 and 12.1 times, respectively, greater than the brain, and 17.8 and 32.6 times, respectively, greater than the plasma. In conclusion, N-Fen did not show local accumulation in the liver, the site of toxicity, with concentrations represented as percentage of the total dose ranging from 0.008 to 0.122%; hence the cause of hepatotoxicity could be related to the mechanisms other than toxicity consequences accumulation. PMID:20857399

  5. Use of solubilizers in preclinical formulations: Effect of Cremophor EL on the pharmacokinetic properties on early discovery compounds.

    PubMed

    Liu, Bo; Gordon, William Perry; Richmond, Wendy; Groessl, Todd; Tuntland, Tove

    2016-05-25

    The aim of the present study was to determine whether Cremophor EL is a suitable surfactant that can be routinely applied to pharmacokinetic (PK) studies in early drug discovery without influencing the intrinsic PK characteristics of the new chemical entities (NCEs). Cremophor EL, a polyoxyl 35 castor oil, has been used as a solubilization aid for water-insoluble compounds in pre-clinical drug discovery. The effect of Cremophor EL on the PK properties of NCEs was examined in seven structurally diverse discovery compounds after intravenous administration. Significant effects of Cremophor EL on plasma volume of distribution (Vss) and plasma clearance (CL) were observed in compounds with moderate to high Vss or CL. The plasma Vss decreased more than 2-fold and the Vss binning category decreased by one unit (e.g. from moderate to low Vss) in 6 of 7 test compounds. Two to five-fold reduction of CL was observed with these 6 compounds. Effect on the terminal half-life (T1/2) was minimal. Using one of these 7 NCEs, concentration dependent effect of Cremophor EL in the vehicle was also determined. Higher percentage of Cremophor EL in vehicle resulted in progressively increased alterations on the plasma CL and Vss. Taken together, these findings indicated that Cremophor EL altered the intrinsic PK properties of these discovery compounds in a concentration dependent manner. PMID:26499309

  6. Relating sensory and chemical properties of sour cream to consumer acceptance.

    PubMed

    Shepard, L; Miracle, R E; Leksrisompong, P; Drake, M A

    2013-09-01

    Sour cream is a widely popular acidified dairy product. Volatile compounds and organic acids and their specific contributions to flavor or acceptance have not been established, nor has a comprehensive study been conducted to characterize drivers of liking for sour cream. The objective of this study was to characterize chemical and sensory properties of sour cream and to determine the drivers of liking for sour cream. Descriptive sensory and instrumental analyses followed by consumer testing were conducted. Flavor and texture attributes of 32 (22 full-fat, 6 reduced-fat, and 4 fat-free) commercial sour creams were evaluated by a trained descriptive sensory panel. Percent solids, percent fat, pH, titratable acidity, and colorimetric measurements were conducted to characterize physical properties of sour creams. Organic acids were evaluated by HPLC and volatile aroma active compounds were evaluated by gas chromatography-mass spectrometry with gas chromatography-olfactometry. Consumer acceptance testing (n=201) was conducted on selected sour creams, followed by external preference mapping. Full-fat sour creams were characterized by the lack of surface gloss and chalky textural attributes, whereas reduced-fat and fat-free samples displayed high intensities of these attributes. Full-fat sour creams were higher in cooked/milky and milk fat flavors than the reduced-fat and fat-free samples. Reduced-fat and fat-free sour creams were characterized by cardboard, acetaldehyde/green, and potato flavors, bitter taste, and astringency. Lactic acid was the prominent organic acid in all sour creams, followed by acetic and citric acids. High aroma-impact volatile compounds in sour creams were 2,3-butanedione, acetic acid, butyric acid, octanal, 2-methyl-3-furanthiol, 1-octene-3-one, and acetaldehyde. Positive drivers of liking for sour cream were milk fat, cooked/milky and sweet aromatic flavors, opacity, color intensity, and adhesiveness. This comprehensive study established

  7. Pharmacokinetic/Toxicity Properties of the New Anti-Staphylococcal Lead Compound SK-03-92

    PubMed Central

    Schwan, William R.; Kolesar, Jill M.; Kabir, M. Shahjahan; Elder, Edmund J.; Williams, Jeffrey B.; Minerath, Rachel; Cook, James M.; Witzigmann, Christopher M.; Monte, Aaron; Flaherty, Tricia

    2015-01-01

    Because of the potential of a new anti-staphylococcal lead compound SK-03-92 as a topical antibiotic, a patch, or an orally active drug, we sought to determine its safety profile and oral bioavailability. SK-03-92 had a high IC50 (125 μg/mL) in vitro against several mammalian cell lines, and mice injected intraperiteonally at the highest dose did not exhibit gross toxicity (e.g., altered gait, ungroomed, significant weight loss). Single dose (100 μg/g) pharmacokinetic (PK) analysis with formulated SK-03-92 showed that peak plasma concentration (1.64 μg/mL) was achieved at 20–30 min. Oral relative bioavailability was 8%, and the drug half-life was 20–30 min, demonstrating that SK-03-92 is likely not a candidate for oral delivery. Five-day and two-week PK analyses demonstrated that SK-03-92 plasma levels were low. Multi-dose analysis showed no gross adverse effects to the mice and a SK-03-92 peak plasma concentration of 2.12 μg/mL with the presence of significant concentrations of breakdown products 15 min after dosing. SK-03-92 appeared to be very safe based on tissue culture and mouse gross toxicity determinations, but the peak plasma concentration suggests that a pro-drug of SK-03-92 or preparation of analogs of SK-03-92 with greater bioavailability and longer half-lives are warranted. PMID:26877886

  8. 24 CFR 1710.558 - Previously accepted state filings-notice of revocation rights on property report cover page.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...-notice of revocation rights on property report cover page. 1710.558 Section 1710.558 Housing and Urban....558 Previously accepted state filings—notice of revocation rights on property report cover page. (a)(1... after 15 percent of the purchase price, exclusive of interest, has been paid, the seller shall refund...

  9. 24 CFR 1710.558 - Previously accepted state filings-notice of revocation rights on property report cover page.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...-notice of revocation rights on property report cover page. 1710.558 Section 1710.558 Housing and Urban....558 Previously accepted state filings—notice of revocation rights on property report cover page. (a)(1... after 15 percent of the purchase price, exclusive of interest, has been paid, the seller shall refund...

  10. 24 CFR 1710.558 - Previously accepted state filings-notice of revocation rights on property report cover page.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...-notice of revocation rights on property report cover page. 1710.558 Section 1710.558 Housing and Urban....558 Previously accepted state filings—notice of revocation rights on property report cover page. (a)(1... after 15 percent of the purchase price, exclusive of interest, has been paid, the seller shall refund...

  11. 24 CFR 1710.558 - Previously accepted state filings-notice of revocation rights on property report cover page.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...-notice of revocation rights on property report cover page. 1710.558 Section 1710.558 Housing and Urban....558 Previously accepted state filings—notice of revocation rights on property report cover page. (a)(1... after 15 percent of the purchase price, exclusive of interest, has been paid, the seller shall refund...

  12. 12 CFR 1010.558 - Previously accepted state filings-notice of revocation rights on property report cover page.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... revocation rights on property report cover page. 1010.558 Section 1010.558 Banks and Banking BUREAU OF... State Law § 1010.558 Previously accepted state filings—notice of revocation rights on property report... purchaser's default or breach of contract after 15 percent of the purchase price, exclusive of interest,...

  13. Thymoquinone-loaded nanostructured lipid carriers: preparation, gastroprotection, in vitro toxicity, and pharmacokinetic properties after extravascular administration

    PubMed Central

    Abdelwahab, Siddig Ibrahim; Sheikh, Bassem Yousef; Taha, Manal Mohamed Elhassan; How, Chee Wun; Abdullah, Rasedee; Yagoub, Umar; El-Sunousi, Rashad; Eid, Eltayeb EM

    2013-01-01

    Background Nanostructured lipid carriers (NLCs), composed of solid and liquid lipids, and surfactants are potentially good colloidal drug carriers. Thymoquinone is the main bioactive compound of Nigella sativa. In this study, the preparation, gastroprotective effects, and pharmacokinetic (PK) properties of thymoquinone (TQ)-loaded NLCs (TQNLCs) were evaluated. Method TQNLCs were prepared using hydrogenated palm oil (Softisan® 154), olive oil, and phosphatidylcholine for the lipid phase and sorbitol, polysorbate 80, thimerosal, and double distilled water for the liquid lipid material. A morphological assessment of TQNLCs was performed using various methods. Analysis of the ulcer index, hydrogen concentration, mucus content, and biochemical and histochemical studies confirmed that the loading of TQ into the NLCs significantly improved the gastroprotective activity of this natural compound against the formation of ethanol-induced ulcers. The safety of TQNLC was tested on WRL68 liver normal cells with cisplatin as a positive control. Results The average diameter of the TQNLCs was 75 ± 2.4 nm. The particles had negative zeta potential values of −31 ± 0.1 mV and a single melting peak of 55.85°C. Immunohistochemical methods revealed that TQNLCs inhibited the formation of ethanol-induced ulcers through the modulation of heat shock protein-70 (Hsp70). Acute hepatotoxic effects of the TQNLCs were not observed in rats or normal human liver cells (WRL-68). After validation, PK studies in rabbits showed that the PK properties of TQ were improved and indicated that the drug behaves linearly. The Tmax, Cmax, and elimination half-life of TQ were found to be 3.96 ± 0.19 hours, 4811.33 ± 55.52 ng/mL, and 4.4933 ± 0.015 hours, respectively, indicating that TQ is suitable for extravascular administration. Conclusion NLCs could be a promising vehicle for the oral delivery of TQ and improve its gastroprotective properties. PMID:23818776

  14. An Updated Review on Drug-Induced Cholestasis: Mechanisms and Investigation of Physicochemical Properties and Pharmacokinetic Parameters

    PubMed Central

    YANG, KYUNGHEE; KÖCK, KATHLEEN; SEDYKH, ALEXANDER; TROPSHA, ALEXANDER; BROUWER, KIM L.R.

    2014-01-01

    Drug-induced cholestasis is an important form of acquired liver disease and is associated with significant morbidity and mortality. Bile acids are key signaling molecules, but they can exert toxic responses when they accumulate in hepatocytes. This review focuses on the physiological mechanisms of drug-induced cholestasis associated with altered bile acid homeostasis due to direct (e.g. bile acid transporter inhibition) or indirect (e.g. activation of nuclear receptors, altered function/expression of bile acid transporters) processes. Mechanistic information about the effects of a drug on bile acid homeostasis is important when evaluating the cholestatic potential of a compound, but experimental data often are not available. The relationship between physicochemical properties, pharmacokinetic parameters, and inhibition of the bile salt export pump (BSEP) among seventy-seven cholestatic drugs with different pathophysiological mechanisms of cholestasis (i.e. impaired formation of bile vs. physical obstruction of bile flow) was investigated. The utility of in silico models to obtain mechanistic information about the impact of compounds on bile acid homeostasis to aid in predicting the cholestatic potential of drugs is highlighted. PMID:23653385

  15. CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.

    PubMed

    Boulenc, Xavier; Nicolas, Olivier; Hermabessière, Stéphanie; Zobouyan, Isabelle; Martin, Valérie; Donazzolo, Yves; Ollier, Céline

    2016-02-01

    The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect. PMID:25374256

  16. Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors.

    PubMed

    Benešová, Martina; Bauder-Wüst, Ulrike; Schäfer, Martin; Klika, Karel D; Mier, Walter; Haberkorn, Uwe; Kopka, Klaus; Eder, Matthias

    2016-03-10

    Since prostate-specific membrane antigen (PSMA) is up-regulated in nearly all stages of prostate cancer (PCa), PSMA can be considered as a viable diagnostic biomarker and treatment target in PCa. This project is focused on the development and evaluation of a series of compounds directed against PSMA. The modifications to the linker are designed to improve the binding potential and pharmacokinetics for theranostic application. In addition, the results help to further elucidate the structure-activity relationships (SAR) of the resulting PSMA inhibitors. Both in vitro and in vivo experiments of 18 synthesized PSMA inhibitor variants showed that systematic chemical modification of the linker has a significant impact on the tumor-targeting and pharmacokinetic properties. This approach can lead to an improved management of patients suffering from recurrent prostate cancer by the use of one radiolabeling precursor, which can be radiolabeled either with (68)Ga for diagnosis or with (177)Lu or (225)Ac for therapy. PMID:26878194

  17. Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.

    PubMed

    Ellsworth, Bruce A; Sher, Philip M; Wu, Ximao; Wu, Gang; Sulsky, Richard B; Gu, Zhengxiang; Murugesan, Natesan; Zhu, Yeheng; Yu, Guixue; Sitkoff, Doree F; Carlson, Kenneth E; Kang, Liya; Yang, Yifan; Lee, Ning; Baska, Rose A; Keim, William J; Cullen, Mary Jane; Azzara, Anthony V; Zuvich, Eva; Thomas, Michael A; Rohrbach, Kenneth W; Devenny, James J; Godonis, Helen E; Harvey, Susan J; Murphy, Brian J; Everlof, Gerry G; Stetsko, Paul I; Gudmundsson, Olafur; Johnghar, Susan; Ranasinghe, Asoka; Behnia, Kamelia; Pelleymounter, Mary Ann; Ewing, William R

    2013-12-12

    Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile. PMID:24182233

  18. 41 CFR 102-75.1140 - What is the policy governing the acceptance or rejection of a conditional gift of real property...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... governing the acceptance or rejection of a conditional gift of real property for a particular defense... governing the acceptance or rejection of a conditional gift of real property for a particular defense... action taken with respect to acceptance or rejection of the conditional gift and of its final disposition....

  19. 41 CFR 102-75.1140 - What is the policy governing the acceptance or rejection of a conditional gift of real property...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... governing the acceptance or rejection of a conditional gift of real property for a particular defense... governing the acceptance or rejection of a conditional gift of real property for a particular defense... action taken with respect to acceptance or rejection of the conditional gift and of its final disposition....

  20. 41 CFR 102-75.1140 - What is the policy governing the acceptance or rejection of a conditional gift of real property...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... governing the acceptance or rejection of a conditional gift of real property for a particular defense... governing the acceptance or rejection of a conditional gift of real property for a particular defense... action taken with respect to acceptance or rejection of the conditional gift and of its final disposition....

  1. 41 CFR 102-75.1140 - What is the policy governing the acceptance or rejection of a conditional gift of real property...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... governing the acceptance or rejection of a conditional gift of real property for a particular defense... governing the acceptance or rejection of a conditional gift of real property for a particular defense... action taken with respect to acceptance or rejection of the conditional gift and of its final disposition....

  2. 41 CFR 102-75.1140 - What is the policy governing the acceptance or rejection of a conditional gift of real property...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... governing the acceptance or rejection of a conditional gift of real property for a particular defense... governing the acceptance or rejection of a conditional gift of real property for a particular defense... action taken with respect to acceptance or rejection of the conditional gift and of its final disposition....

  3. Characterization of in Vitro Pharmacokinetic Properties of Hoodigogenin A from Hoodia gordonii

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was aimed to determine ADME properties of Hoodigogenin A, which is aglycone of oxypregnane steroidal glycoside P57AS3 (P57) isolated from Hoodia gordonii. A series of in vitro assays were used to predict its gastric, intestinal and metabolic stability, intestinal and blood brain barrier (...

  4. Pharmacokinetic properties of IB1001, an investigational recombinant factor IX, in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis.

    PubMed

    Martinowitz, U; Shapiro, A; Quon, D V; Escobar, M; Kempton, C; Collins, P W; Chowdary, P; Makris, M; Mannucci, P M; Morfini, M; Valentino, L A; Gomperts, E; Lee, M

    2012-11-01

    IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double-blind, non-inferiority, cross-over study conducted in participants aged ≥ 12 years weighing ≥ 40 kg, with severe or moderately severe haemophilia B (FIX activity ≤ 2 IU dL (-1) ). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4-18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8-59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg(-1) or nonacog alfa. The lower limit of the one-sided 95% confidence interval for the ratio of AUC(0-t) and AUC(0-∞) (IB1001/nonacog alfa) was 0.90, establishing non-inferiority. Terminal phase half-lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non-inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B. PMID:22764744

  5. Impact of physicochemical and structural properties on the pharmacokinetics of a series of alpha1L-adrenoceptor antagonists.

    PubMed

    Betts, Alison; Atkinson, Fidelma; Gardner, Iain; Fox, David; Webster, Rob; Beaumont, Kevin; Morgan, Paul

    2007-08-01

    A rational drug discovery process was initiated to design a potent and prostate-selective alpha1(L)-adrenoceptor antagonist with pharmacokinetic properties suitable for once a day administration after oral dosing, for the treatment of benign prostatic hyperplasia. Two series of compounds based on a quinoline or quinazoline template were identified with appropriate pharmacology. A series of high molecular weight cations with high hydrogen-bonding potential had extensive in vivo clearance, despite demonstrating metabolic stability. Studies in the isolated perfused rat liver and fresh rat hepatocytes indicated that active transport protein-mediated hepatobiliary elimination is an efficient clearance process for these compounds. A reduction in molecular weight and hydrogen-bonding potential resulted in a second series of compounds with in vivo hepatic clearance predictable from in vitro metabolic clearance. Initially, lipophilicity was reduced within this second series to reduce metabolic clearance and increase elimination half-life. However, this strategy also resulted in a concomitant reduction in volume of distribution and a negligible effect on prolonging half-life. An alternative strategy was to increase the intrinsic metabolic stability of the molecule by careful structural modifications while maintaining lipophilicity. Replacement of the metabolically vulnerable morpholine side chain resulted in identification of UK-338,003, (N-[2-(4-amino-6,7-dimethoxy-5-pyridin-2-yl-quinazolin-2-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-methanesulfonamide), which fulfilled the objectives of the discovery program with suitable pharmacology (human prostate alpha1(L) pA(2) of 9.2 with 25-fold selectivity over rat aorta alpha1(D)) and sufficiently long elimination half-life in human volunteers (11-17 h) for once a day administration. PMID:17502340

  6. Pharmacokinetics & Neurophysiology

    ERIC Educational Resources Information Center

    Davis, Andrew S.; Salpekar, Jay A.

    2009-01-01

    Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

  7. Charge Variants of an Avastin Biosimilar Isolation, Characterization, In Vitro Properties and Pharmacokinetics in Rat.

    PubMed

    Zhao, Yan-Yan; Wang, Ning; Liu, Wan-Hui; Tao, Wen-Jie; Liu, Li-Li; Shen, Zhen-Duo

    2016-01-01

    The similarity between a proposed biosimilar product and the reference product can be affected by many factors. This study is designed to examine whether any subtle difference in the distribution of the charge variants of an Avastin biosimilar can affect its in vitro potency and in vivo PK. Here, the acidic, basic and main peak fractions of a biosimilar product were isolated using high-performance cation-exchange chromatography and were subjected to various studies to compare their in vitro properties and in vivo PK profile. A serial of analytical methods, including size exclusion chromatography (SEC), imaged capillary isoelectric focusing (icIEF) capillary zone electrophoresis (CZE) and cation-exchange chromatography (CEX-HPLC) were also used to characterize the isolated charge variants. The kinetics constant was measured using a Biacore X100 system. The study indicates the biosimilar product has a high similarity with avastin in physicochemical properties. The potency in vitro and PK profile in rat of charge variants and biosimilar product are consistent with avastin. PMID:26987122

  8. Charge Variants of an Avastin Biosimilar Isolation, Characterization, In Vitro Properties and Pharmacokinetics in Rat

    PubMed Central

    Liu, Wan-Hui; Tao, Wen-Jie; Liu, Li-Li; Shen, Zhen-Duo

    2016-01-01

    The similarity between a proposed biosimilar product and the reference product can be affected by many factors. This study is designed to examine whether any subtle difference in the distribution of the charge variants of an Avastin biosimilar can affect its in vitro potency and in vivo PK. Here, the acidic, basic and main peak fractions of a biosimilar product were isolated using high-performance cation-exchange chromatography and were subjected to various studies to compare their in vitro properties and in vivo PK profile. A serial of analytical methods, including size exclusion chromatography (SEC), imaged capillary isoelectric focusing (icIEF) capillary zone electrophoresis (CZE) and cation-exchange chromatography (CEX-HPLC) were also used to characterize the isolated charge variants. The kinetics constant was measured using a Biacore X100 system. The study indicates the biosimilar product has a high similarity with avastin in physicochemical properties. The potency in vitro and PK profile in rat of charge variants and biosimilar product are consistent with avastin. PMID:26987122

  9. Cardioprotective effects and pharmacokinetic properties of a controlled release formulation of a novel hydrogen sulfide donor in rats with acute myocardial infarction

    PubMed Central

    Tran, Ba Hieu; Huang, Chengrong; Zhang, Qiuyan; Liu, Xu; Lin, Shizhou; Liu, Hongrui; Wang, Shujun; Zhu, Yi Zhun

    2015-01-01

    We previously reported that S-propargyl-cysteine (SPRC) exerts cardioprotective effects by elevating H2S levels via the CSE/H2S pathway. In the present study, we investigated the cardioprotective effects and pharmacokinetic properties of a controlled release formulation of SPRC (CR-SPRC) in an in vivo rat model of myocardial infarction (MI). Rats were randomly assigned to seven groups that were pre-treated with CR-SPRC daily for 7 days prior to ligation of the left anterior descending coronary artery to induce MI. Cardiac function and infarct size were determined after MI, and we examined the activity of antioxidant enzymes, expression of anti-inflammation proteins and hydrogen sulfide levels. Mixed-mode, reversed-phase and cation-exchange HPLC–MS/MS were used to compare the pharmacokinetic properties of CR-SPRC and SPRC. CR-SPRC significantly reduced infarct size and creatine kinase (CK) and lactate dehydrogenase (LDH) leakage and it preserved cardiac function during MI. CR-SPRC displayed antioxidant properties, preserving glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) levels whereas reducing malondialdehyde (MDA) levels. Moreover, CR-SPRC significantly reduced the protein levels of inflammatory biomarkers (phospho-NF-κB p65/NF-κB p65, TNF-α) and increased cystathionine-γ-lyase (CSE) and Iκ-Bα protein levels. CR-SPRC had better pharmacokinetic properties than SPRC, with a reduced concentration peak (Cmax), prolonged time to reach peak concentration (Tmax), prolonged mean residence time (MRTinf) and increased AUC0–t. CR-SPRC showed protective effects against MI via the CSE/H2S pathway and demonstrated better cardioprotective effects than SPRC by prolonging the release of endogenous H2S. PMID:26182378

  10. Nanodrugs: pharmacokinetics and safety.

    PubMed

    Onoue, Satomi; Yamada, Shizuo; Chan, Hak-Kim

    2014-01-01

    To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. PMID:24591825

  11. Psychometric Properties of the Acceptance and Action Questionnaire-II for Chinese College Students and Elite Chinese Athletes

    ERIC Educational Resources Information Center

    Zhang, Chun-Qing; Chung, Pak-Kwong; Si, Gangyan; Liu, Jing Dong

    2014-01-01

    The purpose of the present study was to examine the psychometric properties of the Chinese version of the Acceptance and Action Questionnaire-II (AAQ-II) across two samples of Chinese college students (n = 183 and n = 366) and a sample of elite Chinese athletes (n = 330). Exploratory and confirmatory factor analyses supported the existence of a…

  12. 12 CFR 1010.558 - Previously accepted state filings-notice of revocation rights on property report cover page.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 8 2014-01-01 2014-01-01 false Previously accepted state filings-notice of revocation rights on property report cover page. 1010.558 Section 1010.558 Banks and Banking BUREAU OF CONSUMER FINANCIAL PROTECTION LAND REGISTRATION (REGULATION J) Certification of Substantially Equivalent State Law § 1010.558 Previously...

  13. 12 CFR 1010.558 - Previously accepted state filings-notice of revocation rights on property report cover page.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 8 2013-01-01 2013-01-01 false Previously accepted state filings-notice of revocation rights on property report cover page. 1010.558 Section 1010.558 Banks and Banking BUREAU OF CONSUMER FINANCIAL PROTECTION LAND REGISTRATION (REGULATION J) Certification of Substantially Equivalent State Law § 1010.558 Previously...

  14. 24 CFR 1710.558 - Previously accepted state filings-notice of revocation rights on property report cover page.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Previously accepted state filings-notice of revocation rights on property report cover page. 1710.558 Section 1710.558 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR HOUSING-FEDERAL HOUSING...

  15. 32 CFR 37.540 - May I accept fully depreciated real property or equipment as cost sharing?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false May I accept fully depreciated real property or equipment as cost sharing? 37.540 Section 37.540 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DoD GRANT AND AGREEMENT REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Pre-Award...

  16. Pharmacokinetic Properties of Single-Dose Primaquine in Papua New Guinean Children: Feasibility of Abbreviated High-Dose Regimens for Radical Cure of Vivax Malaria

    PubMed Central

    Moore, Brioni R.; Salman, Sam; Benjamin, John; Page-Sharp, Madhu; Robinson, Leanne J.; Waita, Elizabeth; Batty, Kevin T.; Siba, Peter; Mueller, Ivo; Betuela, Inoni

    2014-01-01

    Since conventional 14-day primaquine (PMQ) radical cure of vivax malaria is associated with poor compliance, and as total dose, not therapy duration, determines efficacy, a preliminary pharmacokinetic study of two doses (0.5 and 1.0 mg/kg of body weight) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children, aged 5 to 12 years, to facilitate development of abbreviated high-dose regimens. Dosing was with food and was directly observed, and venous blood samples were drawn during a 168-h postdose period. Detailed safety monitoring was performed for hepatorenal function and hemoglobin and methemoglobin concentrations. Plasma concentrations of PMQ and its metabolite carboxyprimaquine (CPMQ) were determined by liquid chromatography-mass spectrometry and analyzed using population pharmacokinetic methods. The derived models were used in simulations. Both single-dose regimens were well tolerated with no changes in safety parameters. The mean PMQ central volume of distribution and clearance relative to bioavailability (200 liters/70 kg and 24.6 liters/h/70 kg) were within published ranges for adults. The median predicted maximal concentrations (Cmax) for both PMQ and CPMQ after the last dose of a 1.0 mg/kg 7-day PMQ regimen were approximately double those at the end of 14 days of 0.5 mg/kg daily, while a regimen of 1.0 mg/kg twice daily resulted in a 2.38 and 3.33 times higher Cmax for PMQ and CPMQ, respectively. All predicted median Cmax concentrations were within ranges for adult high-dose studies that also showed acceptable safety and tolerability. The present pharmacokinetic data, the first for PMQ in children, show that further studies of abbreviated high-dose regimens are feasible in this age group. PMID:24189254

  17. Effects of chitosan coating on physical properties and pharmacokinetic behavior of mitoxantrone liposomes.

    PubMed

    Zhuang, Jie; Ping, Qineng; Song, Yunmei; Qi, Jianping; Cui, Zheng

    2010-01-01

    The objective of this work was to evaluate the physical properties and in vivo circulation of chitosan (CH)-coated liposomes of mitoxantrone (MTO). Changes in particle size and zeta potential confirmed the existence of a coating layer on the surface of liposomes. The in vitro release of adsorbed CH from the liposomes was significantly slower than CH solution, indicating the stable interaction between CH and liposomes. The physical stability of the CH-coated liposomes was evaluated by measuring the change in particle size before and after freeze-drying and rehydration. The smallest change was observed when saturated adsorption of CH occurred (0.3%). The sustained release in vitro of MTO from CH-coated liposomes confirmed the increased stability of liposomes. Systemic circulation of CH-coated MTO liposomes was examined. The 0.3% CH-coated liposomes showed the longest circulation time. It could be concluded that the prolonged retention time of the liposomes was closely related with CH coating and its stability effect. PMID:20957162

  18. Comparative fasting bioavailability and pharmacokinetic properties of 2 formulations of glucosamine hydrochloride in healthy Chinese adult male volunteers.

    PubMed

    Wu, H; Liu, M; Wang, S; Zhao, H; Yao, W; Feng, W; Yan, M; Tang, Y; Wei, M

    2012-08-01

    Glucosamine (CAS 66-84-2) hydrochloride is an amino monosaccharide indicated for the treatment of arthrosis, especially osteoarthritis of the knee joint. This study was conducted to assess and compare the pharmacokinetic (PK) properties, bioavailability of a newly developed dispersible tablet formulation (test) of glucosamine hydrochloride with those of an established branded capsule formulation (reference) in healthy Chinese adult male volunteers.This single-dose, randomized, open-label, 2-period crossover study was conducted in 18 healthy Chinese adult male volunteers under fasting condition. Plasma samples were collected at pre-specified times over a 12-h period following administration in each period and analyzed the plasma glucosamine concentrations by Liquid Chromatography coupled with Tandem Mass Spectrometry (LC/MS/MS) method. The mean (SD) PK parameters of Cmax, Tmax, AUC0-12, and AUC0-∞ after administration of the test and reference formulations were, respectively, as follows: Cmax, 907.01 (444.22) vs. 944.40 (429.89) ng/mL, Tmax, 3.03 (0.95) vs. 3.30 (0.99) hours, AUC0-12, 2891.41 (1352.30) vs. 2889.69 (925.48) ng/mL/h, and AUC0-∞, 3029.90 (1321.36) vs. 3091.87 (870.36) ng/mL/h. The mean (SD) t1/2 was 1.10 (0.52) hours for the test formulation and 1.50 (1.17) hours for the reference formulation. On ANOVA, neither period nor sequence effects were observed for any PK properties. The relative bioavailability of the test formulation was 98.3% assessed by AUC0-12. The 90% CIs of glucosamine for the log-transformed ratios of Cmax, AUC0-12, and AUC0-∞ were 78.4-113.9%, 80.8-108.5% and 80.8-105.8%, respectively, meeting the predetermined criteria for bioequivalence of SFDA. PMID:22791244

  19. Pharmacokinetic and Pharmacodynamic Properties of Anti-VEGF Drugs After Intravitreal Injection.

    PubMed

    Semeraro, Francesco; Morescalchi, Francesco; Duse, Sarah; Gambicorti, Elena; Cancarini, Anna; Costagliola, Ciro

    2015-01-01

    Subretinal neovascularization and pathologic ocular angiogenesis are common causes of progressive, irreversible impairment of central vision, and dramatically affect quality of life. Anti-vascular endothelial growth factor (anti-VEGF) therapy has improved the quality of life for many patients with age-related macular degeneration, diabetic retinopathy, and other ocular diseases involving neovascularization and edema. In these pathologies, the inhibition of intraocular VEGF is the only therapy that can preserve vision. Four anti-VEGF drugs are currently used to treat ocular neovascularization; pegaptanib, ranibizumab, and aflibercept have been approved for this condition, while bevacizumab can be used off-label. Anti-VEGF therapy is administered regularly for many months or years because its suspension or discontinuation may cause recurrence of neovascularization. On the other hand, VEGF is necessary for the survival of retinal and choroidal endothelial cells. Experimental studies in animal models have shown that local inhibition of VEGF causes thinning and atrophy of the choriocapillaris and degeneration of photoreceptors, primarily cones. These studies combined with clinical experience indicated that prolonged VEGF inhibition could impair retinal function. Moreover, anti-VEGF compounds can cross the blood-retina barrier, enter the systemic circulation, and inhibit serum VEGF. Since circulating VEGF protects blood vessel integrity, prolonged anti-VEGF treatment could induce thromboembolic adverse events from vascular causes such as heart attack and stroke, and even death. The ocular dosing regimen and systemic toxicity of anti-VEGF compounds are therefore central concerns. A better understanding of this topic requires knowledge of the metabolism, tissue distribution, and clearance of anti-VEGF compounds. This manuscript reviews the properties of anti-VEGF compounds following intravitreal administration. PMID:26424177

  20. An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome.

    PubMed

    Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Mathy, Francois-Xavier; Braun, Marina

    2015-04-01

    This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D₃/D₂/D₁ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile

  1. [Cephalexin pharmacokinetics].

    PubMed

    Koroleva, V G; Vasil'ev, V K; Danilova, V I; Firsov, A A

    1981-03-01

    The pharmacokinetics of cephalexin monohydrate after its oral administration in a single dose was studied on rats and dogs. The analysis of the pharmacokinetic data obtained with the one-compartmental model showed that the rate of the antibiotic absorption in the rats was higher than that in the dogs. The periods of the cephalexin half-absorption and maximum concentration were 0.2 and 1.1 hour in the rats and 0.64 and 1.9 hours in the dogs respectively. The period of the antibiotic half-life was almost the same in both animal species. Selective localization of cephalexin in the kidney and liver tissues was noted. The antibiotic was mainly excreted by the kidneys (98.8 per cent for 24 hours). PMID:7235651

  2. Modeling Pharmacokinetics.

    PubMed

    Bois, Frederic Y; Brochot, Céline

    2016-01-01

    Pharmacokinetics is the study of the fate of xenobiotics in a living organism. Physiologically based pharmacokinetic (PBPK) models provide realistic descriptions of xenobiotics' absorption, distribution, metabolism, and excretion processes. They model the body as a set of homogeneous compartments representing organs, and their parameters refer to anatomical, physiological, biochemical, and physicochemical entities. They offer a quantitative mechanistic framework to understand and simulate the time-course of the concentration of a substance in various organs and body fluids. These models are well suited for performing extrapolations inherent to toxicology and pharmacology (e.g., between species or doses) and for integrating data obtained from various sources (e.g., in vitro or in vivo experiments, structure-activity models). In this chapter, we describe the practical development and basic use of a PBPK model from model building to model simulations, through implementation with an easily accessible free software. PMID:27311461

  3. Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor

    PubMed Central

    Lavreysen, Hilde; Ahnaou, Abdellah; Drinkenburg, Wilhelmus; Langlois, Xavier; Mackie, Claire; Pype, Stefan; Lütjens, Robert; Le Poul, Emmanuel; Trabanco, Andrés A; Nuñez, José María Cid

    2015-01-01

    Compounds modulating metabotropic glutamate type 2 (mGlu2) receptor activity may have therapeutic benefits in treating psychiatric disorders like schizophrenia and anxiety. The pharmacological and pharmacokinetic properties of a novel mGlu2 receptor-positive allosteric modulator (PAM), 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-2(1H)-pyridinone (JNJ-40411813/ADX71149) are described here. JNJ-40411813 acts as a PAM at the cloned mGlu2 receptor: EC50 = 147 ± 42 nmol/L in a [35S]GTPγS binding assay with human metabotropic glutamate type 2 (hmGlu2) CHO cells and EC50 = 64 ± 29 nmol/L in a Ca2+ mobilization assay with hmGlu2 Gα16 cotransfected HEK293 cells. [35S]GTPγS autoradiography on rat brain slices confirmed PAM activity of JNJ-40411813 on native mGlu2 receptor. JNJ-40411813 displaced [3H]JNJ-40068782 and [3H]JNJ-46281222 (mGlu2 receptor PAMs), while it failed to displace [3H]LY341495 (a competitive mGlu2/3 receptor antagonist). In rats, JNJ-40411813 showed ex vivo mGlu2 receptor occupancy using [3H]JNJ-46281222 with ED50 of 16 mg/kg (p.o.). PK-PD modeling using the same radioligand resulted in an EC50 of 1032 ng/mL. While JNJ-40411813 demonstrated moderate affinity for human 5HT2A receptor in vitro (Kb = 1.1 μmol/L), higher than expected 5HT2A occupancy was observed in vivo (in rats, ED50 = 17 mg/kg p.o.) due to a metabolite. JNJ-40411813 dose dependently suppressed REM sleep (LAD, 3 mg/kg p.o.), and promoted and consolidated deep sleep. In fed rats, JNJ-40411813 (10 mg/kg p.o.) was rapidly absorbed (Cmax 938 ng/mL at 0.5 h) with an absolute oral bioavailability of 31%. Collectively, our data show that JNJ-40411813 is an interesting candidate to explore the therapeutic potential of mGlu2 PAMs, in in vivo rodents experiments as well as in clinical studies. PMID:25692015

  4. Pharmacokinetics of Cannabis in Cancer Cachexia-Anorexia Syndrome.

    PubMed

    Reuter, Stephanie E; Martin, Jennifer H

    2016-07-01

    Anorexia can affect up to 90 % of people with advanced cancer. It is a complex symptom associated with changes in taste, lack of hunger at mealtimes and lack of food enjoyment. Associated weight loss is part of the physical decline that occurs as cancer worsens. Weight loss can also occur from cachexia, the increased metabolism of energy due to raised inflammatory cytokines, liver metastases and other factors seen in several advanced cancers. Independent of anorexia, although frequently associated (where it is referred to as the cachexia-anorexia syndrome), it accounts for a significant amount of morbidity and deaths in people with cancer. In particular, quality of life for the patient and the family is significantly affected with this syndrome as it causes anxiety and distress. Therefore, it is important that research into therapies is undertaken, particularly focusing on an understanding of the pharmacokinetic properties of compounds in this cachexic population. Cannabinoids are one such group of therapies that have received a large amount of media focus recently. However, there appears to be a lack on rigorous pharmacokinetic data of these complex and varied compounds in the cachexic population. Similarly, there is a lack of pharmacokinetic data in any population group for the non- tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabinoids (often due to the lack of analytical standards for quantification). This review will thus examine the pharmacokinetics of major cannabinoids i.e. THC and CBD in a cancer population. Overall, based on the current literature, evidence for the use of cannabinoids for the treatment of cancer-related cachexia-anorexia syndrome remains equivocal. A high-quality, rigorous, phase I/II study to elicit pharmacokinetic dose-concentration and concentration-response data, with a clinically acceptable mode of delivery to reduce intrapatient variability and enable more consistent bioavailability is needed in this population. PMID

  5. 76 FR 35213 - AJT Mining Properties, Inc.; Notice of Preliminary Permit Application Accepted for Filing and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-16

    ... Energy Regulatory Commission AJT Mining Properties, Inc.; Notice of Preliminary Permit Application..., 2011, AJT Mining Properties, Inc., filed an application for a preliminary permit, pursuant to section 4...: Mr. Scott Willis, AJT Mining Properties, Inc., 5601 Tonsgard Court, Juneau, Alaska 99801; phone:...

  6. Pharmacokinetic properties of lansoprazole (30-mg enteric-coated capsules) and its metabolites: A single-dose, open-label study in healthy Chinese male subjects

    PubMed Central

    Song, Min; Gao, Xuan; Hang, Tai-Jun; Wen, Ai-Dong

    2009-01-01

    Background: Lansoprazole, a benzimidazole derivative, is indicated for the treatment of various peptic diseases. It is metabolized mainly in the liver, and its primary active metabolites present in plasma are 5′-hydroxy lansoprazole and lansoprazole sulfone. Few data are available on the pharmacokinetic properties of lansoprazole, 5′-hydroxy lansoprazole, and lansoprazole sulfone, which can be used to measure cytochrome P450 (CYP) 2C19 activity. Objectives: The aims of this study were to investigate the clinical plasma pharmacokinetic properties of lansoprazole and its metabolites in healthy Chinese male volunteers, and to assess the influences of CYP2C19 on the pharmacokinetics of lansoprazole. Methods: Healthy adult Chinese male volunteers were enrolled in this single-dose, open-label study. All patients received a single oral enteric capsule containing 30 mg of lansoprazole after a 12-hour overnight fast. Serial blood samples were collected immediately before (0 hour) and at 20, 40, 60, 90, 120, and 150 minutes and 3, 4, 6, 8, 10, 12, 15, and 24 hours after study drug administration. The plasma concentrations of lansoprazole, 5′-hydroxy lansoprazole, and lansoprazole sulfone were determined using a validated internal standard high-performance liquid chromatography—tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic properties (including Cmax, Tmax, elimination t½ [t½z], mean residence time [MRT], AUC0–24, AUC0−∞, apparent oral clearance [CLz/F], and apparent volume of distribution [Vz/F]) were determined using the noncompartmental method. Results: Twenty volunteers (mean [SD] age, 34.9 [2.9] years; weight, 64.6 [2.2] kg; height, 171.3 [3.3] cm) were enrolled in and completed the study. The mean (SD) pharmacokinetic properties of lansoprazole were as follows: Cmax, 1047 (344) ng/mL; Tmax, 2.0 (0.7) hours; t½z, 2.24 (1.43) hours; MRT, 3.62 (0.87) hours; AUC0−24, 3388 (1484) ng/mL/h; AUC0-∞, 3496 (1693) ng/mL/h; CLz/F, 9.96 (3.74) L

  7. Effect of addition of thermally modified cowpea protein on sensory acceptability and textural properties of wheat bread and sponge cake.

    PubMed

    Campbell, Lydia; Euston, Stephen R; Ahmed, Mohamed A

    2016-03-01

    This paper investigates the sensory acceptability and textural properties of leavened wheat bread and sponge cake fortified with cow protein isolates that had been denatured and glycated by thermal treatment. Defatted cowpea flour was prepared from cow pea beans and the protein isolate was prepared (CPI) and thermally denatured (DCPI). To prepare glycated cowpea protein isolate (GCPI) the cowpea flour slurry was heat treated before isolation of the protein. CPI was more susceptible to thermal denaturation than GCPI as determined by turbidity and sulphydryl groups resulting in greater loss of solubility. This is attributed to the higher glycation degree and higher carbohydrate content of GCPI as demonstrated by glycoprotein staining of SDS PAGE gels. Water absorption of bread dough was significantly enhanced by DCPI and to a larger extent GCPI compared to the control, resulting in softer texture. CPI resulted in significantly increased crumb hardness in baked bread than the control whereas DCPI or GCPI resulted in significantly softer crumb. Bread fortified with 4% DCPI or GCPI was similar to control as regards sensory and textural properties whereas 4% CPI was significantly different, limiting its inclusion level to 2%. There was a trend for higher sensory acceptability scores for GCPI containing bread compared DCPI. Whole egg was replaced by 20% by GCPI (3.5%) in sponge cake without affecting the sensory acceptability, whereas CPI and DCPI supplemented cakes were significantly different than the control. PMID:26471676

  8. The human and rat recombinant receptors for advanced glycation end products have a high degree of homology but different pharmacokinetic properties in rats.

    PubMed

    Renard, C; Chappey, O; Wautier, M P; Nagashima, M; Morser, J; Scherrmann, J M; Wautier, J L

    1999-09-01

    The accelerated formation of advanced glycation end products (AGEs) is implicated in diabetic microvascular and macrovascular complications. The binding of AGEs to their cellular surface receptor (RAGE) induces vascular dysfunction and in particular an increase in vascular permeability. We previously demonstrated that rat recombinant RAGE (rR-RAGE) produced in insect cells corrected the hyperpermeability due to RAGE-AGE interaction and that pharmacokinetic properties of rR-RAGE after i.v. administration in rats were compatible with a potential therapeutic use. In the present study, we showed that recombinant human RAGE (rH-RAGE) had a similar efficacy in inhibiting AGE-induced endothelial alteration and in reducing the hyperpermeability observed in streptozotocin-induced diabetic rats. (125)I-rH-RAGE elimination half-life after i.v. administration was similar in diabetic and normal rats (53.7 +/- 7.6 and 45.3 +/- 4.0 h, respectively). The presence of AGEs is responsible for a higher distribution volume in diabetic rats compared with normal rats (15.3 +/- 2.7 and 7.7 +/- 0. 7 l/kg, respectively). Immunoreactive (125)I-rH-RAGE decreased more rapidly than did immunoreactive (125)I-rR-RAGE. The differences between (125)I-rH-RAGE and (125)I-rR-RAGE pharmacokinetics in rat may be related to differences in potential O-glycosylation and protease cleavage sites between the two RAGE molecules. PMID:10454525

  9. In vivo toxicity, metabolism and pharmacokinetic properties of FAK inhibitor 14 or Y15 (1, 2, 4, 5-benzenetetramine tetrahydrochloride).

    PubMed

    Golubovskaya, Vita; Curtin, Leslie; Groman, Adrienne; Sexton, Sandra; Cance, William G

    2015-07-01

    Y15 or inhibitor 14 (1,2,4,5-benzenetetramine tetrahydrochloride) is a potent and specific inhibitor of focal adhesion kinase that inhibits its autophosphorylation activity, decreases the viability of cancer cells, and blocks tumor growth. In this preclinical study, we analyzed the pharmacokinetics of Y15 in mice plasma, its metabolic stability in mouse and human liver microsomes and toxicity in mice. The pharmacokinetics study in mice demonstrated that, following intraperitoneal administration at 30 mg/kg dose, Y15 was very rapidly absorbed in mice, reaching maximum plasma concentration in 4.8 min. Y15 rapidly metabolized in mouse and human liver microsomes with half-life t1/2 of 6.9 and 11.6 min, respectively. The maximal tolerated dose of single-dose administration of Y15 by oral administration was 200 mg/kg, and the multiple maximum tolerated dose of Y15 was 100 mg/kg by PO during 7 day study. Y15 did not cause any mortality or statistically significant differences in the body weight at 30 mg/kg by IP during 28-day study, and at 100 mg/kg by PO during the 7-day study. There were no clinical chemical, hematological, or histopathological changes in different mice organs at 30 mg/kg by IP during 28 days and at 100 mg/kg dose by PO during 7 days. Thus, this is the first preclinical toxicity, pharmacokinetics, and metabolic stability study of Y15 inhibitor. Further development of Y15 will provide a basis for new therapeutic and future clinical studies. PMID:24915938

  10. The Coding Properties of Lysine-accepting Transfer Ribonucleic Acids from Black-eyed Peas 1

    PubMed Central

    Hague, Donald R.; Kofoid, Eric C.

    1971-01-01

    Lysine-accepting transfer RNA from ungerminated and germinated embryo axes of black-eyed peas (Vigna sinensis L. Savi) was fractionated on benzoylated diethylaminoethyl cellulose and reverse phase Freon columns. Cochromatography indicated the presence of two similar lysyl transfer RNA fractions in each tissue. Ribosome binding studies revealed that the larger of the two fractions in each case is specific for the AAG codon, while the smaller one recognizes AAA and AAG. Possible implications of this difference in quantities of isoacceptors in translation of genetic information are discussed. PMID:16657787

  11. Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials.

    PubMed

    Madelain, Vincent; Nguyen, Thi Huyen Tram; Olivo, Anaelle; de Lamballerie, Xavier; Guedj, Jérémie; Taburet, Anne-Marie; Mentré, France

    2016-08-01

    The 2014-2015 outbreak of Ebola virus disease is the largest epidemic to date in terms of the number of cases, deaths, and affected areas. In October 2015, no antiviral agents had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried and has since regularly updated a list of potential drug candidates with demonstrated antiviral efficacy in in vitro or animal models. This includes agents belonging to various therapeutic classes, namely direct antiviral agents (favipiravir and BCX4430), a combination of antibodies (ZMapp), type I interferons, RNA interference-based drugs (TKM-Ebola and AVI-7537), and anticoagulant drugs (rNAPc2). Here, we review the pharmacokinetic and pharmacodynamic information presently available for these drugs, using data obtained in healthy volunteers for pharmacokinetics and data obtained in human clinical trials or animal models for pharmacodynamics. Future studies evaluating these drugs in clinical trials are critical to confirm their efficacy in humans, propose appropriate doses, and evaluate the possibility of treatment combinations. PMID:26798032

  12. Peripheral substitution as a tool for tuning electron-accepting properties of phthalocyanine analogs in intramolecular charge transfer.

    PubMed

    Cidlina, Antonin; Novakova, Veronika; Miletin, Miroslav; Zimcik, Petr

    2015-04-21

    The intramolecular charge transfer (ICT), which is a pathway for excited state relaxation, was studied on the newly synthesized zinc(ii) complexes of tetrapyrazinoporphyrazines bearing one fixed donor (i.e., a dialkylamino substituent). The rest of the peripheral substituents on the core was designed with respect to their different electronic effects (OBu, neopentyl, StBu, COOBu). The photophysical (singlet oxygen and fluorescence quantum yields) and electrochemical (reduction potentials) properties were determined and compared within the series and with compounds that did not contain a donor moiety. The ICT efficiency correlated well with both the electron-deficient character of the core and the Hammett substituent constants σp. The most efficient ICT was observed for the core with the most electron-accepting substituent (COOBu), and the lowest ICT efficiency was detected for the least electron-deficient core (substituted by OBu). Titration of DMSO solutions of target compounds with H2SO4 indicated that basicity of the azomethine bridges was largely influenced by the character of the peripheral substituents while the dialkylamino donor center remained nearly unaffected. Furthermore, protonation of the donor nitrogen caused partial restoration of the fluorescence quantum yield (increase up to 90 times) due to blocking of ICT. The results implied that the ICT efficiency was strongly dependent on the electron-accepting properties of the core whose properties can be readily affected by suitable selection of peripheral substituents. PMID:25782137

  13. Physical properties and sixth graders' acceptance of an extruded ready-to-eat sweetpotato breakfast cereal

    NASA Technical Reports Server (NTRS)

    Dansby, M. Y.; Bovell-Benjamin, A. C.

    2003-01-01

    Extruded ready-to-eat breakfast cereals (RTEBCs) were made from varying levels of sweetpotato flour (SPF), whole-wheat bran (WWB), and extrusion cooking. Moisture, protein, and ash contents were lower in the 100% SPF than the 100% WWB. Carbohydrate, beta-carotene, and ascorbic acid contents were higher in the 100% SPF. Fat, thiamin, riboflavin contents, bulk densities, and the water absorption index were similar for the cereals. However, the expansion ratio was highest in the 100% SPF cereal. The 100% WWB had the lightest color and most fibrous morphology. Extruded RTEBC containing 100% SPF and 75%/25% SPF/WWB were well-liked and acceptable to sixth graders attending an elementary school in Auburn, Alabama, but the 100% WWB was unacceptable.

  14. Consumer acceptability and sensory profile of cooked broccoli with mustard seeds added to improve chemoprotective properties.

    PubMed

    Ghawi, Sameer Khalil; Shen, Yuchi; Niranjan, Keshavan; Methven, Lisa

    2014-09-01

    Broccoli, a rich source of glucosinolates, is a commonly consumed vegetable of the Brassica family. Hydrolysis products of glucosinolates, isothiocyanates, have been associated with health benefits and contribute to the flavor of Brassica. However, boiling broccoli causes the myrosinase enzyme needed for hydrolysis to denature. In order to ensure hydrolysis, broccoli must either be mildly cooked or active sources of myrosinase, such as mustard seed powder, can be added postcooking. In this study, samples of broccoli were prepared in 6 different ways; standard boiling, standard boiling followed by the addition of mustard seeds, sous vide cooking at low temperature (70 °C) and sous vide cooking at higher temperature (100 °C) and sous vide cooking at higher temperature followed by the addition of mustard seeds at 2 different concentrations. The majority of consumers disliked the mildly cooked broccoli samples (70 °C, 12 min, sous vide) which had a hard and stringy texture. The highest mean consumer liking was for standard boiled samples (100 °C, 7 min). Addition of 1% mustard seed powder developed sensory attributes, such as pungency, burning sensation, mustard odor, and flavor. One cluster of consumers (32%) found mustard seeds to be a good complement to cooked broccoli; however, the majority disliked the mustard-derived sensory attributes. Where the mustard seeds were partially processed, doubling the addition to 2% led to only the same level of mustard and pungent flavors as 1% unprocessed seeds, and mean consumer liking remained unaltered. This suggests that optimization of the addition level of partially processed mustard seeds may be a route to enhance bioactivity of cooked broccoli without compromising consumer acceptability. PMID:25156799

  15. Influence of oak maturation regimen on composition, sensory properties, quality, and consumer acceptability of cabernet sauvignon wines.

    PubMed

    Crump, Anna M; Johnson, Trent E; Wilkinson, Kerry L; Bastian, Susan E P

    2015-02-11

    Oak barrels have long been the preferred method for oak maturation of wine, but barrels contribute significantly to production costs, so alternate oak maturation regimens have been introduced, particularly for wines at lower price points. To date, few studies have investigated consumers' acceptance of wines made using non-traditional oak treatments. In this study, two Cabernet Sauvignon wines were aged using traditional (i.e., barrel) and/or alternative (i.e., stainless steel or plastic tanks and vats, with oak wood added) maturation regimens. Chemical and sensory analyses were subsequently performed to determine the influence on wine composition and sensory properties, that is, the presence of key oak-derived volatile compounds and perceptible oak aromas and flavor. The quality of a subset of wines was rated by a panel of 10 wine experts using a 20-point scoring system, with all wines considered technically sound. Consumer acceptance of wines was also determined. Hedonic ratings ranged from 5.7 to 5.9 (on a 9-point scale), indicating there was no significant difference in consumers' overall liking of each wine. However, segmentation based on individual liking scores identified three distinct clusters comprising consumers with considerably different wine preferences. These results justify wine producers' use of alternative oak maturation regimens to achieve wine styles that appeal to different segments of their target market. PMID:25584640

  16. Hypothesis for the Mechanism of Ascorbic Acid Activity in Living Cells Related to Its Electron-Accepting Properties.

    PubMed

    Pshenichnyuk, Stanislav A; Modelli, Alberto; Lazneva, Eleonora F; Komolov, Alexei S

    2016-05-01

    Electron-accepting properties, and in particular resonance dissociative electron attachment (DEA) to ascorbic acid (AA), are investigated by means of DEA spectroscopy in vacuo. The experimental features are assigned in silico and discussed in relation to expected dissociative electron transfer processes in vivo with the support of density functional theory calculations and the polarizable continuum model. It is shown that formation of the two most abundant AA metabolites in living cells, namely monodehydroascorbic acid and dehydroascorbic acid, can be stimulated by cellular electron transfer to AA under reductive conditions. Prooxidant effects caused by AA are suggested to be mediated by hydroxyl radicals formation via the DEA mechanism. The involvement of excited electronic states under UV-irradiation in plants could open additional DEA channels leading to specific AA activity forbidden under dark state conditions. PMID:27074645

  17. Implementing and maintaining a private pharmacokinetics practice.

    PubMed

    Murphy, J E; Ward, E S; Job, M L

    1990-03-01

    The development and maintenance of a private-practice pharmacokinetics service is described. A contracted pharmacokinetics service has been in place at Georgia Baptist Medical Center, a 525-bed hospital, for the past eight years. Physician support, inhouse study results, and literature documentation of the benefits of scheduling drug concentration determinations were used to convince hospital administrators of the value of a pharmacokinetics service. Services were reimbursed by increasing the fee charged for each drug concentration determination, with payment made to the pharmacokinetics service on a monthly basis. The service is associated with the pathology department for administrative purposes. Each member of the pharmacokinetics service is credentialed by the medical staff. The group trains part-time personnel to provide services when needed. Services provided by the group but not required by the contract include collecting quality assurance data, conducting research, serving on hospital committees, writing newsletter articles, conducting inservice-education programs, and providing clinical interventions for nonconsultation patients. This private-practice pharmacokinetics service provides high-quality services and is well accepted within the institution. PMID:2316544

  18. MR 714, a new aryloxypropionic non-steroidal antiinflammatory agent. Chemical and pharmacokinetic properties and preliminary pharmacotoxicological data.

    PubMed

    Marzo, A; Quadro, G; Bruno, G; Treffner, E; Reali, F L; Borrelli, G; Stradi, R

    1983-01-01

    2-(4-(2',4'-Difluorophenyl)-phenoxy)propionic acid (MR 714) is endowed with an interesting analgesic and antiinflammatory activity, while any remarkable gastro-ulcerogenic action is virtually absent. From a toxicological point of view, MR 714 orally administered to mice showed a LD50 of 848 mg/kg; an observation of general behaviour proved that the drug is free of any remarkable effect on general behaviour, food and water intake, or diuresis after single or repeated administration. An autoptic examination after single oral doses (25, 50, 100 and 200 mg/kg) or repeated oral doses (100 mg/kg/day over 5 days) did not show any adverse modification and also the Ames test didn't allow any mutagenic action to be detected. From a pharmacokinetic point of view, MR 714 given p.o. to rats was absorbed excellently and plasma levels showed a peak after 4-6 h, followed by a plateau lasting 24-36 h at a dose of 50 or 100 mg/kg and considerably less at a dosage of 25 mg/kg. This lower dose allowed a dominant half-life (t1/2) of plasma levels of 13 h to be determined. Excretion occurred only via the bile in conjugated form (acylglucuronide) which reverted easily into the parent drug. The resultant enterohepatic circulation contributes to a substantial maintenance of plasma levels and hence long-lasting activity. Among the organs examined, the uterus showed the highest ratio of organ/plasma concentration; this evidence points to a possible clinical application of MR 714 in the treatment of dysmenorrhoea. From a chemical point of view, the aryloxypropionic structure may be regarded as an interesting novelty in the field of structure-activity relationship studies on non-steroidal antiinflammatory agents. PMID:6342626

  19. New Photosafety Assessment Strategy Based on the Photochemical and Pharmacokinetic Properties of Both Parent Chemicals and Metabolites.

    PubMed

    Kato, Masashi; Suzuki, Gen; Ohtake, Hiroto; Seto, Yoshiki; Onoue, Satomi

    2015-11-01

    Photoreactivity and dermal/ocular deposition of compounds have been recognized as key considerations for evaluating the phototoxic risk of compounds. Because some drugs are known to cause phototoxic reactions via generation of potent phototoxic metabolites, photosafety assessments on parent drugs alone may lead to false predictions about their photosafety. This study aimed to establish a new photosafety assessment strategy for evaluating the in vivo phototoxic potential of both a parent substance and its metabolites. The in vivo phototoxic risk of fenofibrate (FF) and its metabolites, fenofibric acid (FA) and reduced fenofibric acid, were evaluated based on photochemical and pharmacokinetic analyses. FF and FA exhibited intensive UV absorption, with molar extinction coefficient values of 17,000 (290 nm) and 14,000 M(-1)cm(-1) (295 nm), respectively. Superoxide generation from FA was significantly higher than from FF, and a marked increase in superoxide generation from FF was observed after incubation with rat hepatic S9 fractions, suggesting enhanced photoreactivity of FF after metabolism. FA showed high dermal/ocular deposition after oral administration (5 mg/kg, p.o.) although the concentration of FF was negligible, suggesting high exposure risk from FA. On the basis of these findings, FA was deduced to be a major contributor to phototoxicity induced by FF taken orally, and this prediction was in accordance with the results from in vitro/in vivo phototoxicity tests. Results from this study suggest that this new screening strategy for parent substances and their metabolites provides reliable photosafety information on drug candidates and would be useful for drug development with wide safety margins. PMID:26296710

  20. Quantitative and qualitative variation of fat in model vanilla custard desserts: effects on sensory properties and consumer acceptance.

    PubMed

    Tomaschunas, Maja; Köhn, Ehrhard; Bennwitz, Petra; Hinrichs, Jörg; Busch-Stockfisch, Mechthild

    2013-06-01

    The effects of variation in fat content (0.1% to 15.8%) and type of fat, using different types of milk, dairy cream, or vegetable fat cream, on sensory characteristics and consumer acceptance of starch-based vanilla model custards were studied. Descriptive analysis with trained panelists and consumer testing with untrained assessors were applied. Descriptive data were related to hedonic data using principal component analysis to determine drivers of liking and disliking. Results demonstrated an increasing effect of fat concerning visual and oral thickness, creamy flavor, and fat-related texture properties, as well as a decreasing effect concerning yellow color and surface shine. A lack of fat caused moderate intensities in pudding-like flavor attributes and an intensive jelly texture. Adding a vegetable fat cream led to lower intensities in attributes yellow color, cooked flavor, thick, and jelly texture, whereas intensities in vegetable fat flavor and fat-related texture properties increased. All consumers favored custards with medium fat contents, being high in pudding-like and vegetable fat flavor as well as in fat-related texture attributes. Nonfat custards were rejected due to jelly texture and moderate intensities in pudding-flavor attributes. High-fat samples were liked by some consumers, but their high intensities in thickness, white color, and creamy flavor also drove disliking for others. PMID:23772708

  1. Pharmacokinetic properties of a 40 kDa branched polyethylene glycol-modified form of consensus interferon-alpha (PEG-CIFN) in rhesus monkeys.

    PubMed

    Du, Yu; Tian, Hong; Gao, Xiang-Dong; Yao, Wen-Bing

    2008-11-01

    The pharmacokinetic properties of a branched 40 kDa polyethylene glycol (PEG) conjugate formulation of consensus interferon-alpha (CIFN) was evaluated in rhesus monkeys following subcutaneous administration. Four groups of rhesus monkeys (n=6 per group) received 1250, 300 and 150 microg/kg of PEG-CIFN and 150 microg/kg CIFN, respectively. Serum concentrations of the interferons were measured with an antiviral activity assay at various time points after administration. The PK profiles of the pooled data were described by a noncompartmental method. Peak concentration of PEG-CIFN was observed at 27-31 h, followed by a prolonged decay in comparison with the unmodified CIFN, the PEG-CIFN had a 4-5-fold longer terminal half-life. The apparent clearance (dose(sc)/AUC) decreased from 150 mL/h/kg for CIFN to 19.0-45.5 mL/h/kg for PEG-CIFNs. The AUC was lower for PEG-CIFN than that for CIFN at the 150 microg/kg. PMID:18985796

  2. Pharmacokinetics and tumor and neural tissue penetrating properties of SR-2508 and SR-2555 in the dog-hydrophilic radiosensitizers potentially less toxic than misonidazole

    SciTech Connect

    White, R.A.S.; Workman, P.; Brown, J.M.

    1980-12-01

    The behavior of three 2-nitroimidazole drugs of similar electron affinity to misonidazole but with varying octanol: water partition coefficients has been compared in normal and tumor-bearing dogs. In particular the pharmacokinetic behavior, urinary excretion, and tumor and neural tissue penetrating properties of the three drugs have been studied. Peak plasma concentrations and plasma clearance rates increased with decreasing lipophilicity. Penetration into both the central and peripheral nervous system was significantly slower for the more polar drugs, and as a result of this and the increased plasma clearance rates, the drug exposure to these sites of potential neurotoxicity was reduced. Peak tumor concentrations increased with decreasing lipophilicity, and those for the two SR drugs were more than twice those for equimolar iv doses of misonidazole. It would seem on the basis of the increased plasma clearance rates, improved peak tumor concentrations, and reduced drug exposure to neural tissue that lowering lipophilicity may be an important means of designing radiosensitizing drugs which are less toxic than and superior to misonidazole.

  3. Glycoluril-tetrathiafulvalene molecular clips: on the influence of electronic and spatial properties for binding neutral accepting guests.

    PubMed

    Cotelle, Yoann; Hardouin-Lerouge, Marie; Legoupy, Stéphanie; Alévêque, Olivier; Levillain, Eric; Hudhomme, Piétrick

    2015-01-01

    Glycoluril-based molecular clips incorporating tetrathiafulvalene (TTF) sidewalls have been synthesized through different strategies with the aim of investigating the effect of electrochemical and spatial properties for binding neutral accepting guests. We have in particular focused our study on the spacer extension in order to tune the intramolecular TTF···TTF distance within the clip and, consequently, the redox behavior of the receptor. Carried out at different concentrations in solution, electrochemical and spectroelectrochemical experiments provide evidence of mixed-valence and/or π-dimer intermolecular interactions between TTF units from two closed clips. The stepwise oxidation of each molecular clip involves an electrochemical mechanism with three one-electron processes and two charge-coupled chemical reactions, a scheme which is supported by electrochemical simulations. The fine-tunable π-donating ability of the TTF units and the cavity size allow to control binding interaction towards a strong electron acceptor such as tetrafluorotetracyanoquinodimethane (F4-TCNQ) or a weaker electron acceptor such as 1,3-dinitrobenzene (m-DNB). PMID:26199657

  4. Glycoluril–tetrathiafulvalene molecular clips: on the influence of electronic and spatial properties for binding neutral accepting guests

    PubMed Central

    Cotelle, Yoann; Hardouin-Lerouge, Marie; Legoupy, Stéphanie; Alévêque, Olivier

    2015-01-01

    Summary Glycoluril-based molecular clips incorporating tetrathiafulvalene (TTF) sidewalls have been synthesized through different strategies with the aim of investigating the effect of electrochemical and spatial properties for binding neutral accepting guests. We have in particular focused our study on the spacer extension in order to tune the intramolecular TTF···TTF distance within the clip and, consequently, the redox behavior of the receptor. Carried out at different concentrations in solution, electrochemical and spectroelectrochemical experiments provide evidence of mixed-valence and/or π-dimer intermolecular interactions between TTF units from two closed clips. The stepwise oxidation of each molecular clip involves an electrochemical mechanism with three one-electron processes and two charge-coupled chemical reactions, a scheme which is supported by electrochemical simulations. The fine-tunable π-donating ability of the TTF units and the cavity size allow to control binding interaction towards a strong electron acceptor such as tetrafluorotetracyanoquinodimethane (F4-TCNQ) or a weaker electron acceptor such as 1,3-dinitrobenzene (m-DNB). PMID:26199657

  5. Potentially acceptable substitutes for the chlorofluorocarbons: properties and performance features of HFC-134a, HCFC-123, and HCFC-141b

    NASA Astrophysics Data System (ADS)

    Sukornick, B.

    1989-05-01

    Potentially acceptable substitutes are known for CFC-11 and CFC-12-the most important Chlorofluorocarbons. HFC-134a could replace CFC-12 in airconditioning and refrigeration and both HCFC-123 and HCFC-141b show promise as CFC-11 substitutes. The replacement molecules all have significantly reduced greenhouse and ozone depletion potentials compared to their fully halogenated counterparts. HCFC-123 is theoretically a less efficient blowing agent than CFC-11, but 141b is more efficient. Results from experimental foaming tests confirm these relationships and show that initial insulating values are slightly lower for 141b and 123 than 11. Both substitutes are nonflammable liquids. Based on its physical properties, HFC-134a is an excellent replacement candidate for CFC-12. In addition, it is more thermally stable than CFC-12. A new family of HFC-134a compatible lubricant oils will be required. The estimated coefficient of performance (COP) of 134a is 96 98% that of CFC-12. Subacute toxicity tests show HFC-134a to have a low order of toxicity. HCFC-123 reveals no serious side effects at a concentration of 0.1% in subchronic tests and the inhalation toxicity of 141b is lower than that of CFC-11 based on a 6-h exposure. Chronic tests on all the new candidates will have to be completed for large-scale commercial use. Allied-Signal is conducting process development at a highly accelerated pace, and we plan to begin commercialization of substitutes within 5 years.

  6. Potentially acceptable substitutes for the chlorofluorocarbons: Properties and performance features of HFC-134a, HCFC-123, and HCFC-141b

    SciTech Connect

    Sukornick, B. )

    1989-05-01

    Potentially acceptable substitutes are known for CFC-11 and CFC-12 - the most important chlorofluorocarbons. HFC-134a could replace CFC-12 in air-conditioning and refrigeration and both HCFC-123 and HCFC-141b show promise as CFC-11 substitutes. The replacement molecules all have significantly reduced greenhouse and ozone depletion potentials compared to their fully halogenated counterparts. HCFC-123 is theoretically a less efficient blowing agent than CFC-11, but 141b is more efficient. Results from experimental foaming tests confirm these relationships and show that initial insulating values are slightly lower for 141 b and 123 than 11. Both substitutes are nonflammable liquids. Based on its physical properties, HFC-134a is an excellent replacement candidate for CFC-12. In addition, it is more thermally stable than CFC-12. A new family of HFC-134a compatible lubricant oils will be required. The estimated coefficient of performance (COP) of 134a is 96-98% that of CFC-12. Subacute toxicity tests show HFC-134a to have a low order of toxicity. HCFC-123 reveals no serious side effects at a concentration of 0.1% in subchronic tests and the inhalation toxicity of 141b is lower than that of CFC-11 based on a 6-h exposure. Chronic tests on all the new candidates will have to be completed for large-scale commercial use. Allied-Signal is conducting process development at a highly accelerated pace, and they plan to begin commercialization of substitutes within 5 years.

  7. In vitro and in vivo antileishmanial properties of a 2-n-propylquinoline hydroxypropyl β-cyclodextrin formulation and pharmacokinetics via intravenous route.

    PubMed

    Balaraman, Kaluvu; Vieira, Nashira Campos; Moussa, Fathi; Vacus, Joël; Cojean, Sandrine; Pomel, Sébastien; Bories, Christian; Figadère, Bruno; Kesavan, Ventikasamy; Loiseau, Philippe M

    2015-12-01

    2-n-propylquinoline (2-n-PQ) had shown interesting in vivo antileishmanial activities after administration by oral route on leishmaniasis animal models. However, the lipophilic properties of this compound avoid its use by intravenous route, this route being indicated in cases of severe visceral leishmaniasis with vomiting. Thus, a 2-n-propylquinoline hydroxypropyl beta-cyclodextrin (2-n-PQ-HPC) formulation was set up in this aim. The formulation was active in vitro both on Leishmania donovani axenic and intramacrophage amastigotes with IC50 values at 6.22±0.82μM and 20.01±0.52μM, respectively, without any toxicity on macrophages. 2-n-PQ-HPC exhibited similar activity on WT and drug-resistant parasites. Its in vitro interactions with antimonials, amphotericin B and miltefosine were found as additive both in axenic amastigotes and intramacrophage amastigotes. 2-n-PQ-HPC was not able to generate drug resistance after in vitro drug pressure since the resistance index was less than 4. 2-n-PQ-HPC was also active on the L. donovani/Balb/c mice model with an intravenous treatment regimen at 10mgkg(-1)day(-1) on 10 consecutive days without hepatic, renal and blood toxicity. The pharmacokinetics of 2-n-PQ in rats showed that after an intravenous treatment of the formulation at 10mgkg(-1), the plasma drug concentrations rapidly declined bi-exponentially with a half-life of 58.7min and a total clearance of 18.63lh(-1)kg(-1). The apparent volume of distribution was higher than the blood volume in rats, indicating that 2-n-PQ was well distributed in tissues, allowing parasite elimination. Such a formulation is worth of further antiparasitic and toxicological evaluations. PMID:26653559

  8. 41 CFR 102-75.1290 - What happens if the landholding agency requesting the property does not promptly accept custody...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... System (Continued) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 75-REAL PROPERTY DISPOSAL Screening of Federal Real Property § 102-75.1290 What happens if the landholding agency requesting the property...

  9. Physicochemical and Pharmacokinetic Characterization of Amorphous Solid Dispersion of Meloxicam with Enhanced Dissolution Property and Storage Stability.

    PubMed

    Ochi, Masanori; Kimura, Keisuke; Kanda, Atsushi; Kawachi, Takaki; Matsuda, Akitoshi; Yuminoki, Kayo; Hashimoto, Naofumi

    2016-08-01

    The aim of the present study was to develop amorphous solid dispersion (ASD) of meloxicam (MEL) for providing rapid onset of action. ASDs of MEL with polyvinylpyrrolidone (PVP) K-30 (MEL/PVP), HPC-SSL (MEL/HPC), and Eudragit EPO (MEL/EPO) were prepared. The physicochemical properties were characterized by focusing on morphology, crystallinity, dissolution properties, stability, and the interaction of MEL with coexisting polymers. MEL/EPO was physicochemically stable after storage at 40°C/75% RH for 30 days. In contrast, recrystallization of MEL was observed in MEL/PVP and MEL/HPC at 40°C/50% RH for 30 days. Infrared spectroscopic studies and (1)H NMR analyses of MEL/EPO revealed that Eudragit EPO interacted with MEL and reduced intermolecular binding between MEL molecules. Intermolecular interaction of drug molecules is necessary for the formation of crystalline. Thus, the interaction of MEL with Eudragit EPO and interruption of the formation of supramolecular interaction between MEL molecules might lead to the inhibition of crystal growth of MEL. Of all the MEL solid dispersions prepared, MEL/EPO showed the largest improvement in dissolution behavior. Oral administration of MEL/EPO to rats showed rapid and enhanced MEL exposure with a 2.4-fold increase in bioavailability compared with crystalline MEL. Based on these findings, MEL/EPO was physicochemically stable and provided a rapid onset of action and enhanced bioavailability after oral administration. PMID:27435198

  10. Pharmacokinetics of drugs in pregnancy

    PubMed Central

    Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve

    2016-01-01

    Pregnancy is a complex state where changes in maternal physiology have evolved to favor the development and growth of the placenta and the fetus. These adaptations may affect preexisting disease or result in pregnancy-specific disorders. Similarly, variations in physiology may alter the pharmacokinetics or pharmacodynamics that determines drug dosing and effect. It follows that detailed pharmacologic information is required to adjust therapeutic treatment strategies during pregnancy. Understanding both pregnancy physiology and the gestation-specific pharmacology of different agents is necessary to achieve effective treatment and limit maternal and fetal risk. Unfortunately, most drug studies have excluded pregnant women based on often-mistaken concerns regarding fetal risk. Furthermore, over two-thirds of women receive prescription drugs while pregnant, with treatment and dosing strategies based on data from healthy male volunteers and non-pregnant women, and with little adjustment for the complex physiology of pregnancy and its unique disease states. This review will describe basic concepts in pharmacokinetics and their clinical relevance and highlight the variations in pregnancy that may impact the pharmacokinetic properties of medications. PMID:26452316

  11. Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles

    NASA Astrophysics Data System (ADS)

    Kang, Homan; Mintri, Shrutika; Menon, Archita Venugopal; Lee, Hea Yeon; Choi, Hak Soo; Kim, Jonghan

    2015-11-01

    Nanoparticles (NPs) are considered a promising tool in both diagnosis and therapeutics. Theranostic NPs possess the combined properties of targeted imaging and drug delivery within a single entity. While the categorization of theranostic NPs is based on their structure and composition, the pharmacokinetics of NPs are significantly influenced by the physicochemical properties of theranostic NPs as well as the routes of administration. Consequently, altered pharmacokinetics modify the pharmacodynamic efficacy and toxicity of NPs. Although theranostic NPs hold great promise in nanomedicine and biomedical applications, a lack of understanding persists on the mechanisms of the biodistribution and adverse effects of NPs. To better understand the diagnostic and therapeutic functions of NPs, this review discusses the factors that influence the pharmacokinetics, pharmacodynamics and toxicology of theranostic NPs, along with several strategies for developing novel diagnostic and therapeutic modalities.

  12. Biochemical, thrombolytic and pharmacokinetic properties of rt-PA P47G, K49N, a substitution variant of human tissue-type plasminogen activator.

    PubMed

    Nelles, L; Li, X K; Vanlinthout, I; De Cock, F; Lijnen, H R; Collen, D

    1992-04-01

    rt-PA P47G, K49N, a substitution variant of recombinant human tissue-type plasminogen activator (rt-PA), in which proline at position 47 and lysine at position 49 were replaced by glycine and asparagine respectively, was previously described by Ahern et al. (J Biol Chem 1990; 265:5540-5) to have an extended in vivo half-life with unaltered in vitro fibrinolytic properties. Because this variant might possess an increased in vivo thrombolytic potency, we have constructed its cDNA, expressed it in Chinese hamster ovary cells and determined its biochemical, thrombolytic and pharmacokinetic properties relative to those of home-made rt-PA and of alteplase (Actilyse). The specific fibrinolytic activities on fibrin plates were 160,000 +/- 17,000, 210,000 +/- 88,000 and 460,000 +/- 72,000 IU/mg (mean +/- SEM) for rt-PA P47G, K49N, rt-PA and alteplase, respectively, while the catalytic efficiencies for plasminogen activation (k2/Km) in the absence of fibrin were comparable (1.1 to 1.7 x 10(-3) microM-1s-1). Fibrin enhanced the rate of plasminogen activation by rt-PA P47G, K49N 100-fold and by both wild-type molecules 390-fold. Binding of the variant rt-PA to fibrin was significantly reduced, but its affinity for lysine-Sepharose was unaltered. In an in vitro clot lysis system, consisting of a radiolabeled human plasma clot submersed in plasma, 50% clot lysis in 2 h required 0.67 +/- 0.14 micrograms/ml rt-PA P47G, K49N, 0.36 +/- 0.01 micrograms/ml rt-PA and 0.17 +/- 0.01 micrograms/ml alteplase, respectively (mean +/- SEM; n = 3 or 4). At these doses residual fibrinogen levels at 2 h were in excess of 80%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1631793

  13. Buflomedil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in peripheral and cerebral vascular diseases.

    PubMed

    Clissold, S P; Lynch, S; Sorkin, E M

    1987-05-01

    Buflomedil hydrochloride is a vasoactive drug with a variety of pharmacodynamic properties. Importantly, it seems to improve nutritional blood flow in ischaemic tissue of patients with peripheral and/or cerebral vascular disease by a combination of pharmacological effects: inhibition of alpha-adrenoceptors, inhibition of platelet aggregation, improved erythrocyte deformability, nonspecific and weak calcium antagonistic effects, and oxygen sparing activity. Therapeutic trials with buflomedil in patients with peripheral vascular diseases have shown that it increases walking distances in those with intermittent claudication and heals trophic lesions and reduces rest pain in many patients with more severe vasculopathies. In open clinical trials a good to very good clinical response was achieved in 57 to 87% of those treated. In comparative studies buflomedil 600 mg/day orally was shown to be significantly superior to placebo and comparable in efficacy to pentoxifylline (oxpentifylline) and naftidrofuryl. In patients with symptoms presumed to be due to cerebrovascular insufficiencies and elderly patients with senile dementia, buflomedil 450 to 600 mg/day alleviated symptoms associated with impairment of cognitive and psychometric function and was significantly superior to placebo and slightly more effective than drugs such as cinnarizine, flunarizine and co-dergocrine mesylate. Overall, buflomedil at dosages of up to 600 mg/day has been very well tolerated and discontinuation of therapy has rarely been necessary. Thus, buflomedil would seem to be a useful adjunct to conservative treatment in patients with mild-to-moderate peripheral vascular disease and/or cerebrovascular insufficiency, and well worth a try in patients with more severe peripheral disease unable to undergo surgery. However, a few well-designed long term studies are needed to fully define its overall place in therapy. PMID:3297620

  14. Pharmacokinetic Modeling of Perfluoroalkyl Acids in Rodents

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) has pharmacokinetic properties that appear consistent with a number of processes that are currently not well understood. Studies in mice exposed orally at lower doses (1 and 10 mg/kg) demonstrated blood, liver, and kidney concentration time courses ...

  15. Organophosphorus Insecticide Pharmacokinetics

    SciTech Connect

    Timchalk, Charles

    2010-01-01

    This chapter highlights a number of current and future applications of pharmacokinetics to assess organophosphate (OP) insecticide dosimetry, biological response and risk in humans exposed to these agents. Organophosphates represent a large family of pesticides where insecticidal as well as toxicological mode of action is associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetics entails the quantitative integration of physiological and metabolic processes associated with the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics. Pharmacokinetic studies provide important data on the amount of toxicant delivered to a target site as well as species-, age-, gender-specific and dose-dependent differences in biological response. These studies have been conducted with organophosphorus insecticides in multiple species, at various dose levels, and across different routes of exposure to understand their in vivo pharmacokinetics and how they contribute to the observed toxicological response. To access human exposure to organophosphorus insecticides, human pharmacokinetic studies have been conducted and used to develop biological monitoring strategies based on the quantitation of key metabolites in biological fluids. Pharmacokinetic studies with these insecticides are also useful to facilitate extrapolation of dosimetry and biological response from animals to humans and for the assessment of human health risk. In this regard, physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models are being utilized to assess risk and understand the toxicological implications of known or suspected exposures to various insecticides. In this chapter a number of examples are presented that illustrate the utility and limitation of pharmacokinetic studies to address human health concerns associated with organophosphorus insecticides.

  16. Clinical pharmacokinetics of camptothecin topoisomerase I inhibitors.

    PubMed

    Herben, V M; Ten Bokkel Huinink, W W; Schellens, J H; Beijnen, J H

    1998-08-01

    In this review the clinical pharmacokinetics of camptothecin topoisomerase I inhibitors, an important new class of anticancer drugs, is discussed. Two prototypes, topotecan and irinotecan, are currently marketed in many European countries and the USA for the treatment of patients with ovarian and colorectal cancer, respectively. Other camptothecin derivatives, including lurtotecan, 9-aminocamptothecin (9-AC) and 9-nitrocamptothecin (9-NC), are at different stages of clinical development. The common property of camptothecin analogues is their action against DNA topoisomerase I, but beyond this similarity the compounds differ widely in terms of antitumour efficacy, pharmacology, pharmacokinetics and metabolism. We review chemistry, mechanism of action, stability and bioanalysis of the camptothecins. Dosage and administration, status of clinical application, pharmacokinetics, pharmacodynamics and drug interactions are discussed. PMID:9762728

  17. The factor structure and psychometric properties of the Italian version of the Acceptance of Cosmetic Surgery Scale.

    PubMed

    Stefanile, Cristina; Nerini, Amanda; Matera, Camilla

    2014-09-01

    The current study examined the validity of the Italian version of the Acceptance of Cosmetic Surgery Scale (ACSS; Henderson-King & Henderson-King, 2005) in a sample of 378 Italian adult women. A series of confirmatory factor analyses were conducted. A three-factor solution provided the best fit to the data and confirmed the Intrapersonal, Social, and Consider dimensions. The three factors were strongly inter-correlated. Cronbach's alphas were high (all alphas>.86). The scale showed good convergent and discriminant validity (estimated by Composite Reliability and the Average Variance Extracted). The nomological validity of the Italian version of the ACSS was confirmed by its significant correlations with participants' body dissatisfaction and sociocultural influences (internalization of thin ideals and perceived media pressure). The ACSS seems to be a useful measure of acceptance of cosmetic surgery in the Italian context. This instrument can be used with Italian speakers for research, health promotion, and preventive interventions. PMID:24997285

  18. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling

    PubMed Central

    Moss, Darren Michael; Siccardi, Marco

    2014-01-01

    The delivery of therapeutic agents is characterized by numerous challenges including poor absorption, low penetration in target tissues and non-specific dissemination in organs, leading to toxicity or poor drug exposure. Several nanomedicine strategies have emerged as an advanced approach to enhance drug delivery and improve the treatment of several diseases. Numerous processes mediate the pharmacokinetics of nanoformulations, with the absorption, distribution, metabolism and elimination (ADME) being poorly understood and often differing substantially from traditional formulations. Understanding how nanoformulation composition and physicochemical properties influence drug distribution in the human body is of central importance when developing future treatment strategies. A helpful pharmacological tool to simulate the distribution of nanoformulations is represented by physiologically based pharmacokinetics (PBPK) modelling, which integrates system data describing a population of interest with drug/nanoparticle in vitro data through a mathematical description of ADME. The application of PBPK models for nanomedicine is in its infancy and characterized by several challenges. The integration of property–distribution relationships in PBPK models may benefit nanomedicine research, giving opportunities for innovative development of nanotechnologies. PBPK modelling has the potential to improve our understanding of the mechanisms underpinning nanoformulation disposition and allow for more rapid and accurate determination of their kinetics. This review provides an overview of the current knowledge of nanomedicine distribution and the use of PBPK modelling in the characterization of nanoformulations with optimal pharmacokinetics. Linked Articles This article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-17 PMID:24467481

  19. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    EPA Science Inventory

    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  20. PET Pharmacokinetic Modelling

    NASA Astrophysics Data System (ADS)

    Müller-Schauenburg, Wolfgang; Reimold, Matthias

    Positron Emission Tomography is a well-established technique that allows imaging and quantification of tissue properties in-vivo. The goal of pharmacokinetic modelling is to estimate physiological parameters, e.g. perfusion or receptor density from the measured time course of a radiotracer. After a brief overview of clinical application of PET, we summarize the fundamentals of modelling: distribution volume, Fick's principle of local balancing, extraction and perfusion, and how to calculate equilibrium data from measurements after bolus injection. Three fundamental models are considered: (i) the 1-tissue compartment model, e.g. for regional cerebral blood flow (rCBF) with the short-lived tracer [15O]water, (ii) the 2-tissue compartment model accounting for trapping (one exponential + constant), e.g. for glucose metabolism with [18F]FDG, (iii) the reversible 2-tissue compartment model (two exponentials), e.g. for receptor binding. Arterial blood sampling is required for classical PET modelling, but can often be avoided by comparing regions with specific binding with so called reference regions with negligible specific uptake, e.g. in receptor imaging. To estimate the model parameters, non-linear least square fits are the standard. Various linearizations have been proposed for rapid parameter estimation, e.g. on a pixel-by-pixel basis, for the prize of a bias. Such linear approaches exist for all three models; e.g. the PATLAK-plot for trapping substances like FDG, and the LOGAN-plot to obtain distribution volumes for reversibly binding tracers. The description of receptor modelling is dedicated to the approaches of the subsequent lecture (chapter) of Millet, who works in the tradition of Delforge with multiple-injection investigations.

  1. Pharmacokinetic evaluation of fosaprepitant dimeglumine

    PubMed Central

    Colon-Gonzalez, Francheska; Kraft, Walter K.

    2011-01-01

    Importance of the field Chemotherapy induced nausea and vomiting (CINV) is a common complication in the treatment of patients with cancer. The introduction of the first in class neurokinin-1 receptor antagonist aprepitant provided additive control on CINV in combination to existing antiemetics. Due to formulation issues, aprepitant is only available for oral administration. Fosaprepitant, a prodrug of aprepitant, was introduced to the market in 2008 as an intravenous bioequivalent to aprepitant. Areas covered in this review This review examines the chemical development of fosaprepitant, its pharmacokinetic properties, approved uses, and potential applications. What the reader will gain The reader will get up-to-date information on the pharmacology and clinical uses of fosaprepitant. Clinical studies have demonstrated pharmacokinetic bioequivalence of aprepitant 125-mg to fosaprepitant 115-mg, as well as comparable efficacy in prevention of acute and delayed emesis following the first day of chemotherapy regimens. Take home message Fosaprepitant is an IV pro-drug of aprepitant that offers a new alternative to patients with CINV. Currently, fosaprepitant can substitute oral aprepitant in the first day of a 3-day regimen. Current studies show that a single-day fosaprepitant regimen is also bioequivalent to the 3-day aprepitant regimen, this could significantly simplify the care for CINV patients in the future. PMID:20795794

  2. Pharmacokinetic Profile and Acute Toxicological Properties of a Novel Radiosensitizer Cytosine-Phosphate-Guanosine Oligodeoxynucleotide 107 in Mice Following Intravenous and Orthotopic Administration.

    PubMed

    Cen, Yanyan; Li, Xiaoli; Yin, Zhiwei; Yan, Zifei; Liu, Dan; Peng, Wei; Pan, Feng; Zhou, Hong

    2015-10-01

    The synthetic cytosine-phosphate-guanosine oligodeoxynucleotide 107 (CpG ODN107) is a novel radiosensitizer for glioma treatment. However, the information related to its pharmacokinetics and toxicity remains unclear. Therefore, the plasma pharmacokinetics, distribution, elimination, and acute toxicity of CpG ODN107 in mice were investigated in the present experiments. The results from the liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay showed that the plasma elimination half-life (t1/2β) of CpG ODN107 in BALB/c mice varied slightly with the dose, and it was 0.65, 0.49, and 0.50 h at the intravenous doses of 2.5, 5, and 10 mg/kg, respectively. CpG ODN107 rapidly and widely distributed in organs/tissues, except the brain and testes. The highest concentrations were found in the liver (28.6% of the administered dose after 0.5 h) and the kidneys (5.7% of the administered dose after 1 h). CpG ODN107 (0.3, 3, and 30 μg/mL) could highly bind to human and mouse plasma proteins in vitro. CpG ODN107 in the forms of prototype was excreted in urine (1.79%) and feces (0.91%), and its shortened metabolites were excreted in urine (2.1%) and feces (2.2%) within the first 24 h. The mice in vivo optical image showed CpG ODN107 labeled with Alexa Fluor 680 fluorochrome (AF680) accumulated in the brain after orthotopic injection, eliminated very slowly, and excreted in urine compared with poly T labeled with AF680. The median lethal dose (LD50) of CpG ODN107 was 75.7 mg/kg for mice; this dose only could produce apparent spleen and liver damage, in line with the distribution features of CpG ODN. In conclusion, our present pharmacokinetic and toxicity investigation will provide helpful information to further pharmacodynamic and pharmacokinetic research of CpG ODN107 and other oligodeoxynucleotide drugs in the future. PMID:26213852

  3. In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral Leishmaniasis.

    PubMed

    Mukkavilli, Rao; Pinjari, Jakir; Patel, Bhavesh; Sengottuvelan, Shankar; Mondal, Subodh; Gadekar, Ajit; Verma, Manas; Patel, Jignesh; Pothuri, Lavanya; Chandrashekar, Gopu; Koiram, Prabhakar; Harisudhan, Tanukrishnan; Moinuddin, Ansari; Launay, Delphine; Vachharajani, Nimish; Ramanathan, Vikram; Martin, Denis

    2014-12-18

    The in vitro metabolism and in vivo pharmacokinetic (PK) properties of DNDI-VL-2098, a potential oral agent for Visceral Leishmaniasis (VL) were studied and used to predict its human pharmacokinetics. DNDI-VL-2098 showed a low solubility (10μM) and was highly permeable (>200nm/s) in the Caco-2 model. It was stable in vitro in liver microsomes and hepatocytes and no metabolite was detectable in circulating plasma from dosed animals suggesting very slow, if any, metabolism of the compound. DNDI-VL-2098 was moderate to highly bound to plasma proteins across the species tested (94-98%). DNDI-VL-2098 showed satisfactory PK properties in mouse, hamster, rat and dog with a low blood clearance (<15% of hepatic blood flow except hamster), a volume of distribution of about 3 times total body water, acceptable half-life (1-6h across the species) and good oral bioavailability (37-100%). Allometric scaling of the preclinical PK data to human gave a blood half-life of approximately 20h suggesting that the compound could be a once-a-day drug. Based on the above assumptions, the minimum efficacious dose predicted for a 50kg human was 150mg and 300mg, using efficacy results in the mouse and hamster, respectively. PMID:25261338

  4. Development of a Performance and Processing Property Acceptance Region for Cementitious Low-Level Waste Forms at Savannah River Site - 13174

    SciTech Connect

    Staub, Aaron V.; Reigel, Marissa M.

    2013-07-01

    The Saltstone Production and Disposal Facilities (SPF and SDF) at the Savannah River Site (SRS) have been treating decontaminated salt solution, a low-level aqueous waste stream (LLW) since facility commissioning in 1990. In 2012, the Saltstone Facilities implemented a new Performance Assessment (PA) that incorporates an alternate design for the disposal facility to ensure that the performance objectives of DOE Order 435.1 and the National Defense Authorization Act (NDAA) of Fiscal Year 2005 Section 3116 are met. The PA performs long term modeling of the waste form, disposal facility, and disposal site hydrogeology to determine the transport history of radionuclides disposed in the LLW. Saltstone has been successfully used to dispose of LLW in a grout waste form for 15 years. Numerous waste form property assumptions directly impact the fate and transport modeling performed in the PA. The extent of process variability and consequence on performance properties are critical to meeting the assumptions of the PA. The SPF has ensured performance property acceptability by way of implementing control strategies that ensure the process operates within the analyzed limits of variability, but efforts continue to improve the understanding of facility performance in relation to the PA analysis. A similar understanding of the impact of variability on processing parameters is important from the standpoint of the operability of the production facility. The fresh grout slurry properties (particularly slurry rheology and the rate of hydration and structure formation) of the waste form directly impact the pressure and flow rates that can be reliably processed. It is thus equally important to quantify the impact of variability on processing parameters to ensure that the design basis assumptions for the production facility are maintained. Savannah River Remediation (SRR) has been pursuing a process that will ultimately establish a property acceptance region (PAR) to incorporate

  5. Effect of variety and processing method on functional properties of traditional sweet potato flour (“elubo”) and sensory acceptability of cooked paste (“amala”)

    PubMed Central

    Fetuga, Ganiyat; Tomlins, Keith; Henshaw, Folake; Idowu, Michael

    2014-01-01

    “Amala” is a generic term in Nigeria, used to describe a thick paste prepared by stirring flour (“elubo”) from yam, cassava or unripe plantain, in hot water, to form a smooth consistency. In order to overcome its high perishability and increase the utilization of sweet potato roots, three varieties of sweet potato roots were processed into flour using two methods. The interactive effect of variety and the processing method had a significant effect (P < 0.05) on all the functional properties of the flour except yellowness, setback viscosity, and peak time. Acceptable sweet potato “amala” with average sensory acceptability score of 7.5 were obtained from yellow-fleshed varieties irrespective of the processing method. Flour that produced acceptable “amala” were characterized by lower values of protein (2.20–3.94%), fiber (1.30–1.65%), total sugar (12.41–38.83 μg/mg), water absorption capacity (168–215 g/100 g), water solubility (8.29–14.65%), swelling power (0.52–0.82 g/g), and higher peak time (6.9–8.7 min). PMID:25493186

  6. Axitinib plasma pharmacokinetics and ethnic differences.

    PubMed

    Chen, Ying; Suzuki, Akiyuki; Tortorici, Michael A; Garrett, May; LaBadie, Robert R; Umeyama, Yoshiko; Pithavala, Yazdi K

    2015-04-01

    Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians. Upon review, the data demonstrated that axitinib can be characterized as not sensitive to ethnic factors based on its pharmacokinetic and pharmacodynamic properties. Axitinib exhibited similar pharmacokinetics in Asian and non-Asian subjects. A pooled population pharmacokinetic analysis indicated lack of a clinically meaningful effect of ethnicity on axitinib disposition. Therefore, dose adjustment for axitinib on the basis of ethnicity is not currently warranted. PMID:25663295

  7. How do the Properties of Allan Hills 84001 Compare With Accepted Criteria for Evidence of Ancient Life?

    NASA Technical Reports Server (NTRS)

    Gibson, E. K., Jr.; McKay, D. S.; Thomas-Keprta, K.; Westall, F.; Romanek, C. A.

    1998-01-01

    Criteria for Past Life: To be confident that any sample contains evidence of past life or biogenic activity, one must determine beyond a shadow of a doubt that certain well-established features or biomarker signatures are present in the sample. In the case of martian samples, the criteria for past life have not been established because if life existed on the planet, we have no way of knowing its detailed characteristics. Lacking independent evidence about the nature of possible past life on Mars, the scientific community must use, for the time being, the criteria established for ancient samples from the Earth: (1) Do we know the geologic context of the sample? Is it compatible with past life? (2) Do we know the age of the sample and its stratigraphic location? Are they understood enough to relate possible life to geologic history? (3) Does the sample contain evidence of cellular morphology? (4) What structural remains of colonies or communities exist within the samples? (5) Is there any evidence of biominerals showing chemical or mineral disequilibria? (6) Is there any evidence of stable isotope patterns unique to biology? (7) Are there any organic biomarkers present? (8) Are the features indigenous to the sample? For acceptance of past life in a geologic sample, essentially all of these criteria must he met.

  8. Relationship of quantitative structure and pharmacokinetics in fluoroquinolone antibacterials

    PubMed Central

    Cheng, Die; Xu, Wei-Ren; Liu, Chang-Xiao

    2007-01-01

    AIM: To study the relationship between quantitative structure and pharmacokinetics (QSPkR) of fluoroquinolone antibacterials. METHODS: The pharmacokinetic (PK) parameters of oral fluoroquinolones were collected from the litera-ture. These pharmacokinetic data were averaged, 19 compounds were used as the training set, and 3 served as the test set. Genetic function approximation (GFA) module of Cerius2 software was used in QSPkR analysis. RESULTS: A small volume and large polarizability and surface area of substituents at C-7 contribute to a large area under the curve (AUC) for fluoroquinolones. Large polarizability and small volume of substituents at N-1 contribute to a long half life elimination. CONCLUSION: QSPkR models can contribute to some fluoroquinolones antibacterials with excellent pharmacokinetic properties. PMID:17552035

  9. Pharmacokinetics and Drug Dosing in Obese Children

    PubMed Central

    Kendrick, Jennifer G.; Carr, Roxane R.; Ensom, Mary H.H.

    2010-01-01

    , comorbidities, organ function, and side effects and physiochemical properties of the drug. Extrapolating from available adult data is possible, as long as practitioners consider the effects of growth and development on the pharmacokinetics relevant to the child's age. PMID:22477800

  10. Pharmacokinetic consequences of spaceflight

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Cintron, N. M.

    1991-01-01

    Spaceflight induces a wide range of physiological and biochemical changes, including disruption of gastrointestinal (GI) function, fluid and electrolyte balance, circulatory dynamics, and organ blood flow, as well as hormonal and metabolic perturbations. Any of these changes can influence the pharmacokinetics and pharmacodynamics of in-flight medication. That spaceflight may alter bioavailability was proposed when drugs prescribed to alleviate space motion sickness (SMS) had little therapeutic effect. Characterization of the pharmacokinetic and/or pharmacodynamic behavior of operationally critical medications is crucial for their effective use in flight; as a first step, we sought to determine whether drugs administered in space actually reach the site of action at concentrations sufficient to elicit the therapeutic response.

  11. Changes in sensory properties and consumer acceptance of reduced fat pork Lyon-style and liver sausages containing inulin and citrus fiber as fat replacers.

    PubMed

    Tomaschunas, Maja; Zörb, Rebecca; Fischer, Jürgen; Köhn, Ehrhard; Hinrichs, Jörg; Busch-Stockfisch, Mechthild

    2013-11-01

    The effects of fat reduction in Lyon-style (25% fat) and liver sausages (30% fat) using inulin, citrus fiber and partially rice starch were studied in terms of sensory properties and consumer acceptance. Fat reduced Lyon-style sausages (3 to 17% fat) and liver sausages (3 to 20% fat) were respectively compared to the full-fat controls. Reducing fat in Lyon-style sausages decreased meat flavor, aftertaste meat flavor, greasiness and juiciness, and enhanced color intensity, spiciness, spicy aftertaste, raspy throat, coarseness and firmness scores. But adding inulin and citrus fiber led to sensory characteristics similar to the full-fat reference. Regarding liver sausages, attribute scores in greasiness, creaminess, lumpiness and foamy were decreased with fat reduction and simultaneous addition of fibers. Color intensity, spiciness, firmness and attribute furred tongue were increased. Consumer tests revealed acceptable fat reduced (32 to 90% less than control) and fiber enriched (1.0 to 5.6%) sausages. Drivers of liking were found to relate not only to high-fat but also to low-fat samples. PMID:23811098

  12. Acceptance speech.

    PubMed

    Carpenter, M

    1994-01-01

    In Bangladesh, the assistant administrator of USAID gave an acceptance speech at an awards ceremony on the occasion of the 25th anniversary of oral rehydration solution (ORS). The ceremony celebrated the key role of the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) in the discovery of ORS. Its research activities over the last 25 years have brought ORS to every village in the world, preventing more than a million deaths each year. ORS is the most important medical advance of the 20th century. It is affordable and client-oriented, a true appropriate technology. USAID has provided more than US$ 40 million to ICDDR,B for diarrheal disease and measles research, urban and rural applied family planning and maternal and child health research, and vaccine development. ICDDR,B began as the relatively small Cholera Research Laboratory and has grown into an acclaimed international center for health, family planning, and population research. It leads the world in diarrheal disease research. ICDDR,B is the leading center for applied health research in South Asia. It trains public health specialists from around the world. The government of Bangladesh and the international donor community have actively joined in support of ICDDR,B. The government applies the results of ICDDR,B research to its programs to improve the health and well-being of Bangladeshis. ICDDR,B now also studies acute respiratory diseases and measles. Population and health comprise 1 of USAID's 4 strategic priorities, the others being economic growth, environment, and democracy, USAID promotes people's participation in these 4 areas and in the design and implementation of development projects. USAID is committed to the use and improvement of ORS and to complementary strategies that further reduce diarrhea-related deaths. Continued collaboration with a strong user perspective and integrated services will lead to sustainable development. PMID:12345470

  13. Acceptance speech.

    PubMed

    Yusuf, C K

    1994-01-01

    I am proud and honored to accept this award on behalf of the Government of Bangladesh, and the millions of Bangladeshi children saved by oral rehydration solution. The Government of Bangladesh is grateful for this recognition of its commitment to international health and population research and cost-effective health care for all. The Government of Bangladesh has already made remarkable strides forward in the health and population sector, and this was recognized in UNICEF's 1993 "State of the World's Children". The national contraceptive prevalence rate, at 40%, is higher than that of many developed countries. It is appropriate that Bangladesh, where ORS was discovered, has the largest ORS production capacity in the world. It was remarkable that after the devastating cyclone in 1991, the country was able to produce enough ORS to meet the needs and remain self-sufficient. Similarly, Bangladesh has one of the most effective, flexible and efficient control of diarrheal disease and epidemic response program in the world. Through the country, doctors have been trained in diarrheal disease management, and stores of ORS are maintained ready for any outbreak. Despite grim predictions after the 1991 cyclone and the 1993 floods, relatively few people died from diarrheal disease. This is indicative of the strength of the national program. I want to take this opportunity to acknowledge the contribution of ICDDR, B and the important role it plays in supporting the Government's efforts in the health and population sector. The partnership between the Government of Bangladesh and ICDDR, B has already borne great fruit, and I hope and believe that it will continue to do so for many years in the future. Thank you. PMID:12345479

  14. Data sharing for pharmacokinetic studies.

    PubMed

    Anderson, Brian J; Merry, Alan F

    2009-10-01

    Pooling data from different pediatric studies can provide a single robust pharmacokinetic analysis that allows covariate analysis and hypothesis testing. Data sharing should be driven by the altruistic purpose of improving drug understanding to the clinical benefit of children. Electronic communications have rendered the sharing of data relatively easy, and data sharing within the wider scientific community has become commonplace. Data sharing allows verification of results, save costs and time, allows new interpretation of old data, and can fulfill teaching benefits. It may stimulate cooperative competition between researchers and allow individual researchers to concentrate on unique aspects of the scientific puzzle. However, there is occasionally a reluctance to share, in part because of fear of others stealing the hard work of a research group, which may not be recognized in subsequent publications that reuse data. Providing data may require additional effort for presentation in a suitable format. Data may be abused or used for purposes other than those for which they were collected. Propriety claims may limit access to industry-sponsored drug research. The question of who has ownership of data is contentious. Investigators often consider data they have collected to be their own property. Reputations and grants may be hinge on ownership of a data set. However, other team members, institutions, funding agencies, and the public also have a stake. The difficulties identified in the general scientific community also apply to data sharing for pediatric pharmacokinetic studies. There are few clearly established rules at present, and consideration of the issues hinges on ethical and philosophical arguments. The development of databases will depend on collaboration and cooperation and greater clarity and consensus over appropriate processes and procedures. PMID:19558615

  15. Effect of Coadministered Fat on the Tolerability, Safety, and Pharmacokinetic Properties of Dihydroartemisinin-Piperaquine in Papua New Guinean Children with Uncomplicated Malaria

    PubMed Central

    Moore, B. R.; Benjamin, J. M.; Salman, S.; Griffin, S.; Ginny, E.; Page-Sharp, M.; Robinson, L. J.; Siba, P.; Batty, K. T.; Mueller, I.

    2014-01-01

    Coadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/kg doses were given with water (n = 14, group A) or milk (n = 16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was generally well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC0–∞) for PQ (median, 41,906 versus 36,752 μg · h/liter in groups A and B, respectively; P = 0.24) or DHA (4,047 versus 4,190 μg · h/liter; P = 0.67). There were also no significant between-group differences in prolongation of the corrected electrocardiographic QT interval (QTc) initially during follow-up, but the QTc tended to be higher in group B children at 24 h (mean ± standard deviation [SD], 15 ± 10 versus 6 ± 15 ms0.5 in group A, P = 0.067) and 168 h (10 ± 18 versus 1 ± 23 ms0.5, P = 0.24) when plasma PQ concentrations were relatively low. A small amount of fat does not change the bioavailability of DHA-PQ in children, but a delayed persistent effect on ventricular repolarization cannot be excluded. PMID:25049242

  16. Antiviral Properties, Metabolism, and Pharmacokinetics of a Novel Azolo-1,2,4-Triazine-Derived Inhibitor of Influenza A and B Virus Replication▿

    PubMed Central

    Karpenko, Inna; Deev, Sergey; Kiselev, Oleg; Charushin, Valerey; Rusinov, Vladimir; Ulomsky, Eugeney; Deeva, Ella; Yanvarev, Dmitry; Ivanov, Alexander; Smirnova, Olga; Kochetkov, Sergey; Chupakhin, Oleg; Kukhanova, Marina

    2010-01-01

    Influenza viruses of types A and B cause periodic pandemics in the human population. The antiviral drugs approved to combat influenza virus infections are currently limited. We have investigated an effective novel inhibitor of human influenza A and B viruses, triazavirine {2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7(4Í)-one} (TZV). TZV suppressed the replication of influenza virus in cell culture and in chicken chorioallantoic membranes, and it protected mice from death caused by type A and B influenza viruses. TZV was also effective against a rimantadine-resistant influenza virus strain and against avian influenza A virus H5N1 strains. The pharmacokinetic parameters and bioavailability of TZV were calculated after the administration of TZV to rabbits. The TZV metabolite AMTZV {2-methylthio-6-amino-1,2,4-triazolo[5,1-s]-1,2,4-triazin(e)-7(4Í)-one} was discovered in ÍÅK 293T and Huh7 cell cultures, a liver homogenate, and rabbit blood after intragastric administration of TZV. AMTZV was nontoxic and inactive as an inhibitor of influenza virus in cell culture. Most likely, this metabolite is a product of TZV elimination. PMID:20194696

  17. Clinical pharmacokinetics of molsidomine.

    PubMed

    Rosenkranz, B; Winkelmann, B R; Parnham, M J

    1996-05-01

    Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with

  18. Pharmacokinetics of ketoprofen syrup in small children.

    PubMed

    Kokki, H; Le Liboux, A; Jekunen, A; Montay, G; Heikkinen, M

    2000-04-01

    Ketoprofen is a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties. Its pharmacokinetics has not been determined in small children. The objective here was to determine the pharmacokinetics of ketoprofen syrup, 0.5 mg/kg, in two groups of 10 children. Group 1 was from ages 6 months up to 2 years (7/10 younger than 1 year), and Group 2 was from ages 2 to 7 years. Venous blood samples were collected before drug administration and 0.5, 1, 2, 4, 6, 8, and 12 hours after. A validated HPLC method was used to determine plasma levels of ketoprofen. The lower limit of quantification was 0.02 microgram/ml of plasma. Ketoprofen syrup was absorbed rapidly, the plasma level reaching its maximum at 0.5 hours, with C0.5 hours = 3 micrograms/ml. The pharmacokinetics was similar between the two groups of children. The elimination half-life, 2.0 hours in Group 1 or 1.9 hours in Group 2, was similar to that reported in adults. PMID:10761162

  19. Effect of Small Molecule Modification on Single Cell Pharmacokinetics of PARP Inhibitors

    PubMed Central

    Thurber, Greg M.; Reiner, Thomas; Yang, Katherine S; Kohler, Rainer; Weissleder, Ralph

    2014-01-01

    The heterogeneous delivery of drugs in tumors is an established process contributing to variability in treatment outcome. Despite the general acceptance of variable delivery, the study of the underlying causes is challenging given the complex tumor microenvironment including intra- and inter-tumor heterogeneity. The difficulty in studying this distribution is even more significant for small molecule drugs where radiolabeled compounds or mass spectrometry detection lack the spatial and temporal resolution required to quantify the kinetics of drug distribution in vivo. In this work, we take advantage of the synthesis of fluorescent drug conjugates that retain their target binding but are designed with different physiochemical and thus pharmacokinetic properties. Using these probes, we followed the drug distribution in cell culture and tumor xenografts with temporal resolution of seconds and subcellular spatial resolution. These measurements, including in vivo permeability of small molecule drugs, can be used directly in predictive pharmacokinetic models for the design of therapeutics and companion imaging agents as demonstrated by a finite element model. PMID:24552776

  20. Clinical pharmacokinetics of vasodilators. Part II.

    PubMed

    Kirsten, R; Nelson, K; Kirsten, D; Heintz, B

    1998-07-01

    Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast

  1. Pharmacokinetics of pivmecillinam.

    PubMed

    Parsons, R L; Hossack, G A; Paddock, G M

    1977-06-01

    1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition. PMID:197981

  2. Pharmacokinetics of pivmecillinam.

    PubMed Central

    Parsons, R L; Hossack, G A; Paddock, G M

    1977-01-01

    1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition. PMID:197981

  3. Safety, Tolerability, and Pharmacokinetics of Intravenous Nemonoxacin in Healthy Chinese Volunteers

    PubMed Central

    Cao, Guo-ying; Zhang, Ying-yuan; Guo, Bei-ning; Yu, Ji-cheng; Wu, Xiao-jie; Chen, Yuan-cheng; Wu, Ju-Fang; Shi, Yao-guo

    2014-01-01

    Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (Cmax) values were 4.826 μg/ml, 7.152 μg/ml, and 11.029 μg/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC0–72 h) were 17.05 μg · h/ml, 39.30 μg · h/ml, and 61.98 μg · h/ml. The mean elimination half-life (t1/2) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. Volunteers treated with 250 to 750 mg nemonoxacin exhibited a linear dose-response relationship between the AUC0–72 h and AUC0–∞. These findings provide further support for the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.) PMID:25092690

  4. Formulation, pharmacokinetics and pharmacodynamics of topical microbicides

    PubMed Central

    Adams, Jessica L.; Kashuba, Angela D.M.

    2013-01-01

    The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency virus pandemic. A number of past failures resulting from mucosal toxicity or lack of efficacy have informed the field. Products that caused toxicity to the female genital tract mucosa, and thereby increased the likelihood of HIV acquisition, included nonoxynol 9, cellulose sulfate, and C31 G vaginal gel Savvy®. Topical products that were ineffective in preventing HIV infection include BufferGel®, Carraguard®, and PRO 2000®. Antiretroviral drugs such as tenofovir and dapivirine formulated into microbicide products have shown promise, but there is much to learn about ideal product formulation and acceptability, and drug distribution and disposition (pharmacokinetics). Current formulations for water-soluble molecules include vaginally or rectally applied gels, vaginal rings, films and tablets. Dosing strategies (e.g. coitally dependent or independent) will be based on the pharmacokinetics of the active ingredient and the tolerance for less than perfect adherence. PMID:22306523

  5. Formulation, pharmacokinetics and pharmacodynamics of topical microbicides.

    PubMed

    Adams, Jessica L; Kashuba, Angela D M

    2012-08-01

    The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency virus pandemic. A number of past failures resulting from mucosal toxicity or lack of efficacy have informed the field. Products that caused toxicity to the female genital tract mucosa, and thereby increased the likelihood of HIV acquisition, included nonoxynol 9, cellulose sulfate, and C31 G vaginal gel Savvy. Topical products that were ineffective in preventing HIV infection include BufferGel, Carraguard, and PRO 2000. Antiretroviral drugs such as tenofovir and dapivirine formulated into microbicide products have shown promise, but there is much to learn about ideal product formulation and acceptability, and drug distribution and disposition (pharmacokinetics). Current formulations for water-soluble molecules include vaginally or rectally applied gels, vaginal rings, films and tablets. Dosing strategies (e.g. coitally dependent or independent) will be based on the pharmacokinetics of the active ingredient and the tolerance for less than perfect adherence. PMID:22306523

  6. Pharmacokinetics of cefixime

    SciTech Connect

    Tonelli, A.P.

    1987-01-01

    The serum protein binding of cefixime, was concentration-dependent. Below 30 mcg/mL, free-fractions (fu) of cefixime in dog serum were approximately 8%. As cefixime concentrations increased, concomitant increases in free-fraction were observed. At 328 mcg/mL almost half of the cefixime in serum was not bound. To examine the effect of this concentration-dependent binding on cefixime's pharmacokinetics, four dogs were administered 50 mg/kg of the carbon 14-labeled drug by the oral and intravenous routes. The absolute bioavailability of cefixime was 48.0 +/- 17% (mean +/- SD). Absorption of radioactivity was 51.9 +/- 18%. Cefixime's elimination was a function of its free-fraction in serum and reabsorption of filtered drug by the kidney.

  7. Clinical pharmacokinetics of anticonvulsants.

    PubMed

    Hvidberg, E F; Dam, M

    1976-01-01

    Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration. Phenytoin (diphenylhydantoin) is stil the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug. Carbamazepine is probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide. Phenobarbitone is still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half

  8. Cocrystals and alloys of nitazoxanide: enhanced pharmacokinetics.

    PubMed

    Suresh, Kuthuru; Mannava, M K Chaitanya; Nangia, Ashwini

    2016-03-01

    Two isomorphous cocrystals of nitazoxanide (NTZ) with p-aminosalicylic acid (PASA) and p-aminobenzoic acid (PABA) as well as their alloys were prepared by slurry and grinding techniques. The cocrystals exhibit faster dissolution rates and higher pharmacokinetic properties compared to the reference drug, and surprisingly the cocrystal alloy NTZ-PABA : NTZ-PASA (0.75 : 0.25) exhibited 4 fold higher bioavailability of NTZ in Sprague Dawley rats. This study opens the opportunity for cocrystal alloys as improved medicines. PMID:26911515

  9. Steady-State Pharmacokinetics of Bupropion SR in Juvenile Patients

    ERIC Educational Resources Information Center

    Daviss, W. Burleson; Perel, James M.; Rudolph, George R.; Axelson, David A.; Gilchrist, Richard; Nuss, Sharon; Birmaher, Boris; Brent, David A.

    2005-01-01

    Objective: To examine the steady-state pharmacokinetic properties of bupropion sustained release (SR) and their potential developmental differences in youths. Method: Eleven boys and eight girls aged 11 to 17 years old were prescribed bupropion SR monotherapy for attention-deficit/hyperactivity disorder (n = 16) and/or depressive disorders (n =…

  10. Comparative Pharmacokinetics of Perfluorononanoic acid in Rats and Mice

    EPA Science Inventory

    Perfluorononanoic acid (PFNA) is a fluorinated organic chemical found at low levels in the environment, but is detectable in humans and wildlife. This study compared the pharmacokinetic properties of PFNA in two laboratory rodent species. Male and female Sprague-Dawley rats (n ...

  11. Comparative pharmacokinetics of perfluorononanoic acid in rat and mouse

    EPA Science Inventory

    Perfluorononanoic acid (PFNA) is a fluorinated organic chemical found at low levels in the environment, but is detectable in humans and wildlife. The present study compared the pharmacokinetic properties of PFNA in two laboratory rodent species. Male and female Sprague-Dawley rat...

  12. SUBCELLULAR PHARMACOKINETICS AND ITS POTENTIAL FOR LIBRARY FOCUSING (R826652)

    EPA Science Inventory

    Abstract

    Subcellular pharmacokinetics (SP) optimizes biology-related factors in the design of libraries for high throughput screening by defining comparatively narrow ranges of properties (lipophilicity, amphiphilicity, acidity, reactivity, 3D-structural features) of t...

  13. Pharmacokinetics of macrolides in foals.

    PubMed

    Villarino, N; Martín-Jiménez, T

    2013-02-01

    Macrolides are used for treatment of pneumonia and extrapulmonary conditions caused by Rhodococcus equi. In foals, macrolides have an extraordinary capacity to accumulate in different lung tissue compartments. These drugs show unique pharmacokinetic features such as rapid and extensive distribution and long persistence in pulmonary epithelial lining fluid (PELF) and bronchoalveolar lavage (BAL) cells from foals. This article reviews the pharmacokinetic characteristics of erythromycin, azithromycin, clarithromycin, tulathromycin, telithromycin, gamithromycin, and tilmicosin in foals, with emphasis on PELF and BAL cell concentrations. PMID:23082900

  14. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    SciTech Connect

    Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

    1992-01-01

    Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug's effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed.

  15. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    SciTech Connect

    Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

    1992-12-31

    Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug`s effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed.

  16. Physiologic and pharmacokinetic changes in pregnancy.

    PubMed

    Costantine, Maged M

    2014-01-01

    Physiologic changes in pregnancy induce profound alterations to the pharmacokinetic properties of many medications. These changes affect distribution, absorption, metabolism, and excretion of drugs, and thus may impact their pharmacodynamic properties during pregnancy. Pregnant women undergo several adaptations in many organ systems. Some adaptations are secondary to hormonal changes in pregnancy, while others occur to support the gravid woman and her developing fetus. Some of the changes in maternal physiology during pregnancy include, for example, increased maternal fat and total body water, decreased plasma protein concentrations, especially albumin, increased maternal blood volume, cardiac output, and blood flow to the kidneys and uteroplacental unit, and decreased blood pressure. The maternal blood volume expansion occurs at a larger proportion than the increase in red blood cell mass, which results in physiologic anemia and hemodilution. Other physiologic changes include increased tidal volume, partially compensated respiratory alkalosis, delayed gastric emptying and gastrointestinal motility, and altered activity of hepatic drug metabolizing enzymes. Understating these changes and their profound impact on the pharmacokinetic properties of drugs in pregnancy is essential to optimize maternal and fetal health. PMID:24772083

  17. Estimation of pharmacokinetic model parameters.

    PubMed

    Timcenko, A; Reich, D L; Trunfio, G

    1995-01-01

    This paper addresses the problem of estimating the depth of anesthesia in clinical practice where many drugs are used in combination. The aim of the project is to use pharmacokinetically-derived data to predict episodes of light anesthesia. The weighted linear combination of anesthetic drug concentrations was computed using a stochastic pharmacokinetic model. The clinical definition of light anesthesia was based on the hemodynamic consequences of autonomic nervous system responses to surgical stimuli. A rule-based expert system was used to review anesthesia records to determine instances of light anesthesia using hemodynamic criteria. It was assumed that light anesthesia was a direct consequence of the weighted linear combination of drug concentrations in the patient's body that decreased below a certain threshold. We augmented traditional two-compartment models with a stochastic component of anesthetics' concentrations to compensate for interpatient pharmacokinetic and pharmacodynamic variability. A cohort of 532 clinical anesthesia cases was examined and parameters of two compartment pharmacokinetic models for 6 intravenously administered anesthetic drugs (fentanyl, thiopenthal, morphine, propofol, midazolam, ketamine) were estimated, as well as the parameters for 2 inhalational anesthetics (N2O and isoflurane). These parameters were then prospectively applied to 22 cases that were not used for parameter estimation, and the predictive ability of the pharmacokinetic model was determined. The goal of the study is the development of a pharmacokinetic model that will be useful in predicting light anesthesia in the clinically relevant circumstance where many drugs are used concurrently. PMID:8563327

  18. Discovery of substituted lactams as novel dual orexin receptor antagonists. Synthesis, preliminary structure-activity relationship studies and efforts towards improved metabolic stability and pharmacokinetic properties. Part 1.

    PubMed

    Sifferlen, Thierry; Boller, Amandine; Chardonneau, Audrey; Cottreel, Emmanuelle; Hoecker, Johannes; Aissaoui, Hamed; Williams, Jodi T; Brotschi, Christine; Heidmann, Bibia; Siegrist, Romain; Gatfield, John; Treiber, Alexander; Brisbare-Roch, Catherine; Jenck, Francois; Boss, Christoph

    2014-02-15

    Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization. PMID:24447850

  19. 48 CFR 570.111 - Inspection and acceptance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 4 2011-10-01 2011-10-01 false Inspection and acceptance... CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY General 570.111 Inspection and acceptance... acceptance document must contain the square footage accepted and the acceptance date. Include the...

  20. Pharmacokinetics and Pharmacodynamics in Space

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi; Cintron, Nitza M.

    1990-01-01

    The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic

  1. Pharmacokinetic drug interactions with phenytoin (Part I).

    PubMed

    Nation, R L; Evans, A M; Milne, R W

    1990-01-01

    Phenytoin, which is used primarily as an anticonvulsant agent, has a relatively low therapeutic index, and monitoring of plasma phenytoin concentration is often used to help guide therapy. It has properties which predispose it to an involvement in pharmacokinetic interactions, a large number of which have been reported. These properties include: low aqueous solubility and slow rate of gastrointestinal absorption; a relatively high degree of plasma protein binding; a clearance that is non-linear due to saturable oxidative biotransformation; and the ability to induce hepatic microsomal enzymes. Because of its narrow therapeutic range, drug interactions leading to alterations in plasma phenytoin concentration may be clinically important. Such interactions have often been reported initially as either cases of phenytoin intoxication or of decreased effectiveness. Drugs may modify the pharmacokinetics of phenytoin by altering its absorption, plasma protein binding, or hepatic biotransformation; alterations in the absorption and/or biotransformation may lead to changes in both the unbound plasma phenytoin concentration and, as a result, the clinical effect. Preparations which may decrease the gastrointestinal absorption of phenytoin include nutritional formulae and charcoal. There are many reports of drugs which may increase (e.g. folic acid, dexamethasone and rifampicin) or decrease (e.g. valproic acid, sulthiame, isoniazid, cimetidine, phenylbutazone, chloramphenicol and some sulphonamides) the metabolism of phenytoin. It is important to bear in mind that, as a result of its non-linear clearance, changes in phenytoin absorption and/or biotransformation will lead to more than proportionate changes in plasma drug concentration. Drugs which may displace phenytoin from plasma albumin include valproic acid, salicylic acid, phenylbutazone and some sulphonamides. Although an alteration in the unbound fraction of phenytoin in plasma would not, in itself, be expected to alter

  2. Pharmacokinetic study of sulbactomax.

    PubMed

    Payasi, Anurag; Chaudhary, Manu; Gupta, Ankush; Dwivedi, Vivek Kumar; Bhatnagar, Anuj

    2010-08-01

    We have evaluated pharmacokinetics of a fixed dose combination (FDC) of ceftriaxone and sulbactam (2:1) or sulbactomax in eight healthy volunteers. A 1.5 g dose of sulbactomax, 1 g dose of ceftriaxone and 0.5 g sulbactam were given intravenously in a balanced two-ways cross-over study. Serially collected plasma sample was analyzed for ceftriaxone and sulbactam by high performance liquid chromatography (HPLC). The mean peaks of ceftriaxone and sulbactam concentrations in plasma were 152.06+/-6.65 microg/ml and 21.32+/-1.80 microg/ml, respectively and plasma half-lives for ceftriaxone and sulbactam were 5.2+/-0.35 hr and 0.94+/-0.038 hr, respectively. The AUC0-24 for ceftriaxone and sulbactam was 760.16+/-27.68 microg.hr/ml and 20.74+/-2.34 microg.hr/ml, respectively, with elimination rate constant of 0.133+/-0.009 hr(-1) and 0.732+/-0.029 hr(-1), respectively. The kinetics of ceftriaxone and sulbactum did not change in combination as compared to the alone treatment. Also, concentration of the ceftriaxone after 24 hr is higher than the minimum inhibitory concentration (MIC) of the most of the gram positive and gram negative bacteria indicating that one dose in a day is sufficient to treat the disease caused by these organisms. PMID:20686332

  3. Thrombolytic and pharmacokinetic properties of human tissue-type plasminogen activator variants, obtained by deletion and/or duplication of structural/functional domains, in a hamster pulmonary embolism model.

    PubMed

    Collen, D; Lijnen, H R; Vanlinthout, I; Kieckens, L; Nelles, L; Stassen, J M

    1991-02-12

    A pulmonary embolism model in hamsters was used for the quantitative evaluation of the thrombolytic and pharmacokinetic properties of variants of tissue-type plasminogen activator (t-PA). A 25 microliters 125I-fibrin labeled human plasma clot was made in vitro and injected into the jugular vein of heparinized hamsters. The extent of thrombolysis within 90 min was determined as the difference between the radioactivity injected in the jugular vein and that recovered in the heart and lungs. Recombinant t-PA (home-made rt-PA or Activase) infused intravenously over 60 min caused dose-dependent progressive thrombolysis. The results of thrombolytic potency (clot lysis in percent versus dose administered in mg/kg) and of specific thrombolytic activity (clot lysis in percent versus steady state plasma level in microgram/ml) were fitted with an exponentially transformed sigmoidal function y = 100 c/(1 + e-a(ax-eh] and the maximal percent lysis (c), the dose or plasma level at which maximal rate of lysis is achieved (b) and the maximal rate of lysis (z = 1/4 ac.eb) were determined. With rt-PA, these parameters were c = 72 +/- 6% (mean +/- SEM), b = 0.19 +/- 0.08 mg/kg, z = 68 +/- 25% lysis per mg/kg, with corresponding values of 87 +/- 5%, 0.07 +/- 0.03 mg/kg and 150 +/- 38% lysis per mg/kg for Activase (p = NS). Deletion of the finger and growth factor domains in rt-PA (rt-PA-delta FE) was not associated with marked alteration of the thrombolytic potency (c = 90 +/- 30%, b = 0.34 +/- 0.35 mg/kg, and z = 54 +/- 14% per mg/kg), but was associated with a significant reduction of the specific thrombolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1905070

  4. 36 CFR 251.62 - Acceptance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 2 2011-07-01 2011-07-01 false Acceptance. 251.62 Section 251.62 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LAND USES Special Uses § 251.62 Acceptance. Except for an easement, a special use authorization shall become...

  5. 36 CFR 251.62 - Acceptance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 2 2010-07-01 2010-07-01 false Acceptance. 251.62 Section 251.62 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LAND USES Special Uses § 251.62 Acceptance. Except for an easement, a special use authorization shall become...

  6. Applied Pharmacokinetics: Course Description and Retrospective Evaluation.

    ERIC Educational Resources Information Center

    Beck, Diane E.

    1984-01-01

    An applied course designed to allow students to formulate pharmacokinetic recommendations individually for actual patient data and compare their recommendations to those of a pharmacokinetic consulting service is described and evaluated, and an objective student evaluation method is outlined. (MSE)

  7. Bioavailability and Pharmacokinetics of Genistein: Mechanistic Studies on its ADME

    PubMed Central

    Yang, Zhen; Kulkarni, Kaustubh; Zhu, Wei; Hu, Ming

    2014-01-01

    Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More than 30 clinical trials of genistein with various disease indications have been conducted to evaluate its clinical efficacy. Based on many animals and human pharmacokinetic studies, it is well known that the most challenge issue for developing genistein as a chemoprevention agent is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large interindividual variations in clinical trials. In order to better correlate pharmacokinetic to pharmacodynamics results in animals and clinical studies, an in-depth understanding of pharmacokinetic behavior of genistein and its ADME properties are needed. Numerous in vitro/in vivo ADME studies had been conducted to reveal the main factors contributing to the low oral bioavailability of genistein. Therefore, this review focuses on summarizing the most recent progress on mechanistic studies of genistein ADME and provides a systemic view of these processes to explain genistein pharmacokinetic behaviors in vivo. The better understanding of genistein ADME property may lead to development of proper strategy to improve genistein oral bioavailability via mechanism-based approaches. PMID:22583407

  8. Pirbenicillin: Pharmacokinetic Parameters in Mice

    PubMed Central

    English, Arthur R.; Girard, Dennis; Retsema, James A.

    1976-01-01

    The rapid intravenous administration to mice of pirbenicillin, carbenicillin, and ampicillin produced biexponential blood concentration-time curves when assessed by frequent blood samplings at short intervals. The pharmacokinetic behavior of pirbenicillin and the other penicillins was analyzed by the two-compartment open model. This is thought to be the first study giving detailed pharmacokinetic values of penicillins in mice. Some significant differences were noted between the pharmacokinetic values of pirbenicillin, ampicillin, and carbenicillin. These values suggest that the interchange of pirbenicillin between the central and peripheral body compartments of the mouse was slower than that of either carbenicillin or ampicillin and indicated that a greater fraction of the pirbenicillin than the ampicillin dose reached the peripheral compartment. PMID:984791

  9. Clinical pharmacokinetics of metformin.

    PubMed

    Graham, Garry G; Punt, Jeroen; Arora, Manit; Day, Richard O; Doogue, Matthew P; Duong, Janna K; Furlong, Timothy J; Greenfield, Jerry R; Greenup, Louise C; Kirkpatrick, Carl M; Ray, John E; Timmins, Peter; Williams, Kenneth M

    2011-02-01

    Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t(½)) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CL(R)) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CL(R) and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural

  10. Pharmacokinetics of mitragynine in man

    PubMed Central

    Trakulsrichai, Satariya; Sathirakul, Korbtham; Auparakkitanon, Saranya; Krongvorakul, Jatupon; Sueajai, Jetjamnong; Noumjad, Nantida; Sukasem, Chonlaphat; Wananukul, Winai

    2015-01-01

    Background Kratom, known botanically as Mitragyna speciosa (Korth.), is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users. Methods Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. Results Ten male subjects completed the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour), terminal half-life (23.24±16.07 hours), and the apparent volume of distribution (38.04±24.32 L/kg). The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. Conclusion This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half

  11. Fasudil and SOD packaged in peptide-studded-liposomes: Properties, pharmacokinetics and ex-vivo targeting to isolated perfused rat lungs.

    PubMed

    Gupta, Nilesh; Al-Saikhan, Fahad I; Patel, Brijeshkumar; Rashid, Jahidur; Ahsan, Fakhrul

    2015-07-01

    The present study investigated the feasibility of encapsulating two drugs, fasudil and superoxide dismutase (SOD), into liposomes for targeted and inhalational delivery to the pulmonary vasculature to treat pulmonary arterial hypertension (PAH). Nanosized liposomes were prepared by a thin-film formation and extrusion method, and the drugs were encapsulated by a modified freeze-thaw technique. The peptide CARSKNKDC (CAR), a pulmonary-specific targeting sequence, was conjugated on the surface of liposomes. Formulations were optimized for various physicochemical properties, tested for their ex-vivo and in-vivo drug absorption after intratracheal administration, and evaluated for short-term safety in healthy rats. The homogenous nanosized liposomes contained both SOD (~55% entrapment) and fasudil (~40% entrapment), and were stable at 4°C and after nebulization. Liposomes released the drugs in a controlled-release fashion. Compared with plain liposomes, CAR-liposomes increased the uptake by pulmonary endothelial and smooth muscle cells by ~2-fold. CAR-liposomes extended the biological half-lives of SOD and fasudil by ~3-fold. Ex-vivo studies demonstrated that CAR-liposomes were better retained in the lungs than plain liposomes. Bronchoalveolar lavage studies indicated the safety of peptide-equipped liposomes as pulmonary delivery carriers. Overall, this study demonstrates that CAR-liposomes may be used as inhalational carriers for SOD plus fasudil-based combination therapy for PAH. PMID:25888802

  12. 41 CFR 105-8.170-10 - Acceptance of appeals.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Acceptance of appeals. 105-8.170-10 Section 105-8.170-10 Public Contracts and Property Management Federal Property Management... Acceptance of appeals. The Special Counsel shall accept and process any timely appeal. A party may appeal...

  13. 41 CFR 105-8.170-10 - Acceptance of appeals.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 41 Public Contracts and Property Management 3 2011-01-01 2011-01-01 false Acceptance of appeals. 105-8.170-10 Section 105-8.170-10 Public Contracts and Property Management Federal Property Management... Acceptance of appeals. The Special Counsel shall accept and process any timely appeal. A party may appeal...

  14. Pharmacokinetics of Chloroquine and Monodesethylchloroquine in Pregnancy▿

    PubMed Central

    Karunajeewa, Harin A.; Salman, Sam; Mueller, Ivo; Baiwog, Francisca; Gomorrai, Servina; Law, Irwin; Page-Sharp, Madhu; Rogerson, Stephen; Siba, Peter; Ilett, Kenneth F.; Davis, Timothy M. E.

    2010-01-01

    In order to determine the pharmacokinetic disposition of chloroquine (CQ) and its active metabolite, desethylchloroquine (DECQ), when administered as intermittent presumptive treatment in pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were administered three daily doses of 450 mg CQ (8.5 mg/kg of body weight/day) in addition to a single dose of sulfadoxine-pyrimethamine. For all women, blood was taken at baseline; at 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h posttreatment; and at 7, 10, 14, 28, and 42 days posttreatment. Plasma was subsequently assayed for CQ and DECQ by high-performance liquid chromatography, and population pharmacokinetic modeling was performed. Pregnant subjects had significantly lower area under the plasma concentration-time curve for both CQ (35,750 versus 47,892 μg·h/liter, P < 0.001) and DECQ (23,073 versus 41,584 μg·h/liter, P < 0.001), reflecting significant differences in elimination half-lives and in volumes of distribution and clearances relative to bioavailability. Reduced plasma concentrations of both CQ and DECQ could compromise both curative efficacy and posttreatment prophylactic properties in pregnant patients. Higher IPTp CQ doses may be desirable but could increase the risk of adverse hemodynamic effects. PMID:20086162

  15. Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery?

    PubMed

    Smith, Dennis; Schmid, Esther; Jones, Barry

    2002-01-01

    The alignment of drug metabolism and pharmacokinetic departments with drug discovery has not produced a radical improvement in the pharmacokinetic properties of new chemical entities. The reason for this is complex, reflecting in part the difficulty of combining potency, selectivity, water solubility, metabolic stability and membrane permeability into a single molecule. This combination becomes increasingly problematic as the drug targets become more distant from aminergic seven-transmembrane-spanning receptors (7-TMs). The leads available for aminergic 7-TMs, like the natural agonists, are invariably small molecular weight, water soluble and potent. Even moving to 7-TMs for which the agonist is a peptide invariably produces lead matter that is less drug-like (higher molecular weight and lipophilic). The role of drug metabolism departments, therefore, has been to guide chemistry to obtaining adequate, rather than optimal, pharmacokinetic properties for these 'difficult' drug targets. A consistent belief of many researchers is that a high value is placed on optimal, rather than adequate, pharmacokinetic properties. One measure of value is market sales, and when these are examined no clear pattern emerges. Part of the success of amlodipine in the calcium channel antagonist sector must be due to its excellent pharmacokinetic profile, but the best-selling drugs among the angiotensin antagonists and beta-blockers have a much greater market share than other agents with better pharmacokinetic properties. Clearly, many other factors are important in the successful launch of a medicine, some reflected in the manner the compound is developed and the subsequent structure of the labelling. Overall, therefore the presence of drug metabolism in drug discovery has probably contributed most by allowing 'difficult' drug targets to be prosecuted, rather than by guiding medicinal chemists to optimal pharmacokinetics. These 'difficult' target candidates become successful drugs when

  16. Clinical pharmacokinetics of dapsone.

    PubMed

    Zuidema, J; Hilbers-Modderman, E S; Merkus, F W

    1986-01-01

    Dapsone (DDS) has for about 4 decades been the most important antileprosy drug. Concentrations of dapsone and its monoacetyl metabolite, MADDS, can be determined in biological media by high-performance liquid chromatography. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. However, the extent of absorption has not been adequately determined. The elimination half-life of dapsone is about 30 hours. The drug shows linear pharmacokinetics within the therapeutic range and the time-course after oral administration fits a 2-compartment model. The concentration-time profile of dapsone after parenteral administration is reviewed. Of clinical importance is the development of a new long acting injection, which permits monthly supervised administration as recommended by the World Health Organization. Following dapsone injection in gluteal subcutaneous adipose tissue, a sufficiently sustained absorption for this purpose has been reported. Dapsone is about 70 to 90% protein bound and its monoacetylated metabolite (MADDS) is almost completely protein bound. The volume of distribution of dapsone is estimated to be 1.5 L/kg. It is distributed in most tissues, but M. leprae living in the Schwann cells of the nerves might be unaffected. Dapsone crosses the placenta and is excreted in breast milk and saliva. Dapsone is extensively metabolised. Dapsone, some MADDS and their hydroxylated metabolites are found in urine, partly conjugated as N-glucuronides and N-sulphates. The acetylation ratio (MADDS:dapsone) shows a genetically determined bimodal distribution and allows the definition of 'slow' and 'rapid' acetylators. As enterohepatic circulation occurs, the elimination half-life of dapsone is markedly decreased after oral administration of activated charcoal. This permits successful treatment in cases of intoxication. The daily dose of dapsone in leprosy is 50 to

  17. PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING

    EPA Science Inventory

    Physiologically-based pharmacokinetic (PB-PK) models attempt to provide both a realistic anatomic description of the animal to which a drug or toxic chemical has been administered and a biologically accurate representation of the physiological pathways for chemical storage, metab...

  18. Clinical pharmacokinetics of ibuprofen arginine.

    PubMed

    Cattaneo, Dario; Clementi, Emilio

    2010-11-01

    Currently, several ibuprofen compounds are available on the market, mainly differing in terms of pharmaceutical composition that influence the pharmacokinetic profile and eventually the onset of drug action. This review will mainly deal with the clinical pharmacokinetics of ibuprofen arginine, an alternative formulation specifically designed to improve the absorption of ibuprofen. Indeed, available data from studies in healthy volunteers have consistently shown that the formulation of ibuprofen arginine is characterized by prompt absorption of ibuprofen as compared to the conventional formulation at all tested doses with higher peak plasma concentration and lower Tmax values. This trend has been confirmed also in studies dealing with chiral ibuprofen pharmacokinetics. Most importantly, the shortening in the absorption time observed either with racemic mixture or with the S(+)-enantiomer of ibuprofen arginine did not imply a faster drug elimination eventually leading to inadequate daily drug exposure, as documented by T1/2 and AUC values being comparable to those measured with the free acid form. Taken together, the pharmacokinetic/dynamic characteristics of ibuprofen arginine can be considered particularly favorable for several clinical conditions, such as moderate/severe pain, in which a rapid pharmacologic effect is required. PMID:20925647

  19. Aztreonam pharmacokinetics in burn patients.

    PubMed Central

    Friedrich, L V; White, R L; Kays, M B; Brundage, D M; Yarbrough, D

    1991-01-01

    The pharmacokinetics of aztreonam in eight adult patients with severe burn injuries (total body surface area burn, 49% +/- 21% [mean +/- standard deviation]) were studied. The time of initiation of study following burn injury was 7.0 +/- 1.4 days. Four patients at first dose and at steady state were studied. Aztreonam concentrations were measured by high-performance liquid chromatography, and a two-compartment model was used to fit the data. No significant differences in any pharmacokinetic parameters between first dose and steady state were observed. Volume of distribution of the central compartment after first dose (0.14 liters/kg) and volume of distribution at steady state (0.31 liters/kg) were approximately 30% higher than those reported for other patient populations. Total drug clearance and renal drug clearance when normalized to creatinine clearance (CLCR) were similar to those previously reported for other critically ill patients. CLCR was strongly correlated with renal drug clearance (r = 0.94) and total drug clearance (r = 0.95). The extent and degree of burn (percent second or third degree burn) were poorly correlated with all pharmacokinetic parameters with the exception of the volume of distribution at steady state, which was correlated with both total body surface area burn (r = 0.95) and percent second degree burn (r = 0.83). Aztreonam pharmacokinetics are altered as a result of thermal injury; however, CLCR can be used to assess the clearance of aztreonam in burn patients. PMID:2014982

  20. Pharmacokinetics of ricobendazole in calves.

    PubMed

    Formentini, E A; Mestorino, O N; Mariño, E L; Errecalde, J O

    2001-06-01

    The pharmacokinetics of ricobendazole (RBZ) and its major metabolite albendazole sulphone (ABZSO2) were studied in six calves, after administration of RBZ (7.5 mg/kg), using a 10% experimental solution by the intravenous (i.v.) route, a 10% commercial solution by the subcutaneous (s.c.) route, and a 10% experimental suspension by the intraruminal (i.r.) route. Blood samples were drawn during a 60-h period. Plasma drug and metabolite concentrations were determined by HPLC. The pharmacokinetic evaluation in each case was prepared by weighted least-squares nonlinear regression analysis. Ricobendazole i.v. data were best fitted by a two-compartment model. The best pharmacokinetic exponents and coefficients were estimated, and the pharmacokinetic variables for RBZ and ABZSO2 were calculated from them. Similar patterns of plasma disposition were found for RBZ after i.r. and s.c. administration, suggesting delayed release from the s.c. site resembling the slow release of the drug from the rumen. PMID:11442798

  1. BioDMET: a physiologically based pharmacokinetic simulation tool for assessing proposed solutions to complex biological problems.

    PubMed

    Graf, John F; Scholz, Bernhard J; Zavodszky, Maria I

    2012-02-01

    We developed a detailed, whole-body physiologically based pharmacokinetic (PBPK) modeling tool for calculating the distribution of pharmaceutical agents in the various tissues and organs of a human or animal as a function of time. Ordinary differential equations (ODEs) represent the circulation of body fluids through organs and tissues at the macroscopic level, and the biological transport mechanisms and biotransformations within cells and their organelles at the molecular scale. Each major organ in the body is modeled as composed of one or more tissues. Tissues are made up of cells and fluid spaces. The model accounts for the circulation of arterial and venous blood as well as lymph. Since its development was fueled by the need to accurately predict the pharmacokinetic properties of imaging agents, BioDMET is more complex than most PBPK models. The anatomical details of the model are important for the imaging simulation endpoints. Model complexity has also been crucial for quickly adapting the tool to different problems without the need to generate a new model for every problem. When simpler models are preferred, the non-critical compartments can be dynamically collapsed to reduce unnecessary complexity. BioDMET has been used for imaging feasibility calculations in oncology, neurology, cardiology, and diabetes. For this purpose, the time concentration data generated by the model is inputted into a physics-based image simulator to establish imageability criteria. These are then used to define agent and physiology property ranges required for successful imaging. BioDMET has lately been adapted to aid the development of antimicrobial therapeutics. Given a range of built-in features and its inherent flexibility to customization, the model can be used to study a variety of pharmacokinetic and pharmacodynamic problems such as the effects of inter-individual differences and disease-states on drug pharmacokinetics and pharmacodynamics, dosing optimization, and inter

  2. [Pharmacokinetics and pharmacodynamics of ceftaroline].

    PubMed

    Grau, Santiago; Sorlí, Luisa; Luque, Sonia

    2014-03-01

    Ceftaroline is administered intravenously in the form of a prodrug, ceftaroline fosamil, which is rapidly hydrolyzed by plasma phosphatases to its active form, ceftaroline. In general, the pharmacokinetics of ceftaroline differ little from those of other cephalosporins. A proportional increase in both the peak plasma concentration (Cmax) and the area under the curve (AUC) have been observed when the drug is administered in increasing doses, which demonstrates its linear pharmacokinetics. Half the dose of ceftaroline is excreted actively through the kidneys. The pharmacokinetic parameters of ceftaroline administered through the intramuscular route in diverse animal species were similar to those observed when the drug was administered intravenously and consequently clinical research into ceftaroline administered through this alternative route would be appropriate. Patients with moderate-severe alterations of renal function and those undergoing hemodialysis require dose adjustments. There is limited experience of the pharmacokinetics of ceftaroline in children, which has given rise to several schedules stratified by age groups. The pharmacodynamics of the drug have been studied in models of animal infection and in in vitro infections caused mainly by Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA], strains with intermediate vancomycin sensitivity [hVISA or hGISA]) and by Streptococcus pneumoniae strains with distinct sensitivities to penicillin. Because ceftaroline is a time-dependent antibiotic, the most widely studied pharmacokinetic/pharmacodynamic (PK/PD) indicator is the time interval during which drug concentrations are maintained above the minimum inhibitory concentration (MIC), calculated both as total drug (T > MIC) and as free fraction of the drug (fT > MIC). The PK/PD simulations carried out in these models, developed on the basis of the concentrations obtained with routine doses in humans, have shown that ceftaroline has a good PK

  3. Emodin: A Review of its Pharmacology, Toxicity and Pharmacokinetics.

    PubMed

    Dong, Xiaoxv; Fu, Jing; Yin, Xingbin; Cao, Sali; Li, Xuechun; Lin, Longfei; Ni, Jian

    2016-08-01

    Emodin is a natural anthraquinone derivative that occurs in many widely used Chinese medicinal herbs, such as Rheum palmatum, Polygonum cuspidatum and Polygonum multiflorum. Emodin has been used as a traditional Chinese medicine for over 2000 years and is still present in various herbal preparations. Emerging evidence indicates that emodin possesses a wide spectrum of pharmacological properties, including anticancer, hepatoprotective, antiinflammatory, antioxidant and antimicrobial activities. However, emodin could also lead to hepatotoxicity, kidney toxicity and reproductive toxicity, particularly in high doses and with long-term use. Pharmacokinetic studies have demonstrated that emodin has poor oral bioavailability in rats because of its extensive glucuronidation. This review aims to comprehensively summarize the pharmacology, toxicity and pharmacokinetics of emodin reported to date with an emphasis on its biological properties and mechanisms of action. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27188216

  4. Pharmacokinetics and pharmacodynamics of cannabinoids.

    PubMed

    Grotenhermen, Franjo

    2003-01-01

    Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial

  5. Development and Characterization of Pharmacokinetic Parameters of Fast-Dissolving Films Containing Levocetirizine

    PubMed Central

    Choudhary, Dhagla R.; Patel, Vishnu A.; Chhalotiya, Usmangani K.; Patel, Harsha V.; Kundawala, Aliasgar J.

    2012-01-01

    A fast-dissolving film containing levocetirizine, a non-sedative antihistamine drug, was developed using pullulan, xanthan gum, propylene glycol, and tween 80 as the base materials. The drug content of the prepared films was within an acceptable limit as prescribed by the USP. The film exhibited excellent stability for four months when stored at 40 °C and 75% humidity. In vitro dissolution studies suggested a rapid disintegration, in which most of levocetirizine (93.54 ± 3.9%) dissolved within 90 seconds after insertion into the medium. Subsequently, Sprague–Dawley rats were used to compare the pharmacokinetic properties of the film preparation administered to the oral cavity, to those with oral administration of the pure drug solution. The pharmacokinetic parameters were similar between the two groups in which AUC0–t (ng h/ml), AUC0–∞ (ng h/ml) Cmax (ng/ml), Tmax (min), Kel (h−1), and t1/2 (h) of the reference were 452.033 ± 43.68, 465.78 ± 48.16, 237.16 ± 19.87, 30, 0.453 ± 0.051, and 1.536 ± 0.118, respectively, for the film formulation 447.233 ± 46.24, 458.22 ± 46.74, 233.32 ± 17.19, 30, 0.464 ± 0.060, and 1.496 ± 0.293, respectively. These results suggest that the present levocetirizine containing fast-dissolving film is likely to become one of the choices to treat different allergic conditions. PMID:23008821

  6. Development and characterization of pharmacokinetic parameters of fast-dissolving films containing levocetirizine.

    PubMed

    Choudhary, Dhagla R; Patel, Vishnu A; Chhalotiya, Usmangani K; Patel, Harsha V; Kundawala, Aliasgar J

    2012-09-01

    A fast-dissolving film containing levocetirizine, a non-sedative antihistamine drug, was developed using pullulan, xanthan gum, propylene glycol, and tween 80 as the base materials. The drug content of the prepared films was within an acceptable limit as prescribed by the USP. The film exhibited excellent stability for four months when stored at 40 °C and 75% humidity. In vitro dissolution studies suggested a rapid disintegration, in which most of levocetirizine (93.54 ± 3.9%) dissolved within 90 seconds after insertion into the medium. Subsequently, Sprague-Dawley rats were used to compare the pharmacokinetic properties of the film preparation administered to the oral cavity, to those with oral administration of the pure drug solution. The pharmacokinetic parameters were similar between the two groups in which AUC(0-t) (ng h/ml), AUC(0-∞) (ng h/ml) C(max) (ng/ml), T(max) (min), K(el) (h(-1)), and t(1/2) (h) of the reference were 452.033 ± 43.68, 465.78 ± 48.16, 237.16 ± 19.87, 30, 0.453 ± 0.051, and 1.536 ± 0.118, respectively, for the film formulation 447.233 ± 46.24, 458.22 ± 46.74, 233.32 ± 17.19, 30, 0.464 ± 0.060, and 1.496 ± 0.293, respectively. These results suggest that the present levocetirizine containing fast-dissolving film is likely to become one of the choices to treat different allergic conditions. PMID:23008821

  7. [Pharmacokinetic interactions of telaprevir with other drugs].

    PubMed

    Berenguer Berenguer, Juan; González-García, Juan

    2013-07-01

    Telaprevir is a new direct-acting antiviral drug for the treatment of hepatitis C virus (HCV) infection and is both a substrate and an inhibitor of cytochrome P450 (CYP450) isoenzymes. With the introduction of this new drug, assessment of drug-drug interactions has become a key factor in the evaluation of patients under treatment for HCV infection. During the treatment of this infection, many patients require other drugs to mitigate the adverse effects of anti-HCV drugs and to control other comorbidities. Moreover, most patients coinfected with HIV and HCV require antiretroviral therapy during treatment for HCV. Physicians should therefore be familiar with the pharmacokinetic properties of direct-acting antivirals for HCV treatment and their potential drug-drug interactions. The present article reviews the available information to date on the interactions of telaprevir with other drugs and provides recommendations for daily clinical practice. PMID:24063902

  8. 41 CFR 105-8.170-6 - Acceptance of complaint.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Acceptance of complaint... Acceptance of complaint. (a) The Official shall accept a complete complaint that is filed in accordance with... the respondent of receipt and acceptance of the complaint. (b) If the Official receives a...

  9. 41 CFR 105-8.170-6 - Acceptance of complaint.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 41 Public Contracts and Property Management 3 2011-01-01 2011-01-01 false Acceptance of complaint... Acceptance of complaint. (a) The Official shall accept a complete complaint that is filed in accordance with... the respondent of receipt and acceptance of the complaint. (b) If the Official receives a...

  10. Predicting neonatal pharmacokinetics from prior data using population pharmacokinetic modeling.

    PubMed

    Wang, Jian; Edginton, Andrea N; Avant, Debbie; Burckart, Gilbert J

    2015-10-01

    Selection of the first dose for neonates in clinical trials is very challenging. The objective of this analysis was to assess if a population pharmacokinetic (PK) model developed with data from infants to adults is predictive of neonatal clearance and to evaluate what age range of prior PK data is needed for informative modeling to predict neonate exposure. Two sources of pharmacokinetic data from 8 drugs were used to develop population models: (1) data from all patients > 2 years of age, and (2) data from all nonneonatal patients aged > 28 days. The prediction error based on the models using data from subjects > 2 years of age showed bias toward overprediction, with median average fold error (AFE) for CL predicted/CLobserved greater than 1.5. The bias for predicting neonatal PK was improved when using all prior PK data including infants as opposed to an assessment without infant PK data, with the median AFE 0.91. As an increased number of pediatric trials are conducted in neonates under the Food and Drug Administration Safety and Innovation Act, dose selection should be based on the best estimates of neonatal pharmacokinetics and pharmacodynamics prior to conducting efficacy and safety studies in neonates. PMID:25907280

  11. Stochastic Control of Pharmacokinetic Systems

    PubMed Central

    Schumitzky, Alan; Milman, Mark; Katz, Darryl; D'Argenio, David Z.; Jelliffe, Roger W.

    1983-01-01

    The application of stochastic control theory to the clinical problem of designing a dosage regimen for a pharmacokinetic system is considered. This involves defining a patient-dependent pharmacokinetic model and a clinically appropriate therapeutic goal. Most investigators have attacked the dosage regimen problem by first estimating the values of the patient's unknown model parameters and then controlling the system as if those parameter estimates were in fact the true values. We have developed an alternative approach utilizing stochastic control theory in which the estimation and control phases of the problem are not separated. Mathematical results are given which show that this approach yields significant potential improvement in attaining, for example, therapeutic serum level goals over methods in which estimation and control are separated. Finally, a computer simulation is given for the optimal stochastic control of an aminoglycoside regimen which shows that this approach is feasible for practical applications.

  12. [Interspecies differences of noopept pharmacokinetics].

    PubMed

    Boĭko, S S; Korotkov, S A; Zherdev, V P; Gudasheva, T A; Ostrovskaia, R U; Voronina, T A

    2004-01-01

    Significant interspecific differences in the pharmacokinetics of noopept are manifested by a decrease in the drug elimination rate on the passage from rats to rabbits and humans. Very intensive metabolism of noopept was observed upon intravenous administration in rats. In these animals, presystemic elimination mechanisms lead to the formation of a specific metabolite representing a product of drug biotransformation hydroxylated at the phenyl ring. In rabbits, unchanged noopept circulates in the blood for a longer time upon both intravenous and peroral introduction, biotransformation proceeds at a much slower rate, and no metabolites analogous to that found in rats are detected. The noopept pharmacokinetics in humans differs from that in animals by still slower elimination and considerable individual variability. No drug metabolites are found in the human blood plasma, probably because of a relatively small dose and low concentration. PMID:15079908

  13. Population Pharmacokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  14. Pregnancy-related pharmacokinetic changes.

    PubMed

    Tasnif, Y; Morado, J; Hebert, M F

    2016-07-01

    The pharmacokinetics of many drugs are altered by pregnancy. Drug distribution and protein binding are changed by pregnancy. While some drug metabolizing enzymes have an apparent increase in activity, others have an apparent decrease in activity. Not only is drug metabolism affected by pregnancy, but renal filtration is also increased. In addition, pregnancy alters the apparent activities of multiple drug transporters resulting in changes in the net renal secretion of drugs. PMID:27082931

  15. Pharmacokinetic study of harmane and its 10 metabolites in rat after intravenous and oral administration by UPLC-ESI-MS/MS.

    PubMed

    Li, Shuping; Teng, Liang; Liu, Wei; Cheng, Xuemei; Jiang, Bo; Wang, Zhengtao; Wang, Chang-Hong

    2016-09-01

    Context The β-carboline alkaloid harmane is widely distributed in common foods, beverages and hallucinogenic plants. Harmane exerts potential in therapies for Alzheimer's and depression diseases. However, little information on its dynamic metabolic profiles and pharmacokinetics in vivo is currently available. Objective This study investigates the dynamic metabolic profiles and pharmacokinetic properties of harmane and its metabolites in rats in vivo. Materials and methods A highly selective, sensitive and rapid ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and well-validated for simultaneous quantitative determination of harmane and its uncertain endogenous metabolite harmine, as well as for semiquantitative determination of 10 harmane metabolites in rats after intravenous injection and oral administration of harmane at 1.0 and 30.0 mg/kg, respectively. Results The calibration curves of harmane and harmine showed excellent linearity within the concentration range of 1-2000 ng/mL with acceptable accuracy, precision, selectivity, recovery, matrix effect and stability. Ten metabolites, including harmane but not harmine, were detected and identified after intravenous and oral administration of harmane. The absolute bioavailability of harmane following an oral dose was 19.41 ± 3.97%. According to the AUC0-t values of all the metabolites, the metabolic levels of phase II metabolites were higher than those of phase I metabolites, and the sulphation pathways were the dominant metabolic routes for harmane in both routes of administration. Discussion and conclusion The pharmacokinetic properties of harmane and its 10 metabolites in rats were determined. Sulphate conjugation was the predominant metabolic process of harmane in rats. PMID:26730489

  16. Pharmacokinetic study of the structural components of adenosine diphosphate-encapsulated liposomes coated with fibrinogen γ-chain dodecapeptide as a synthetic platelet substitute.

    PubMed

    Taguchi, Kazuaki; Ujihira, Hayato; Ogaki, Shigeru; Watanabe, Hiroshi; Fujiyama, Atsushi; Doi, Mami; Okamura, Yosuke; Takeoka, Shinji; Ikeda, Yasuo; Handa, Makoto; Otagiri, Masaki; Maruyama, Toru

    2013-08-01

    Fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV, H12)-coated, ADP-encapsulated liposomes [H12-(ADP)-liposomes] were developed as a synthetic platelet alternative that specifically accumulates at bleeding sites as the result of interactions with activated platelets via glycoprotein IIb/IIIa and augments platelet aggregation by releasing ADP. The aim of this study is to characterize the pharmacokinetic properties of H12-(ADP)-liposomes and structural components in rats, and to predict the blood retention of H12-(ADP)-liposomes in humans. With use of H12-(ADP)-liposomes in which the encapsulated ADP and liposomal membrane cholesterol were radiolabeled with (14)C and (3)H, respectively, it was found that the time courses for the plasma concentration curves of (14)C and (3)H radioactivity showed that the H12-(ADP)-liposomes remained intact in the blood circulation for up to 24 hours after injection, and were mainly distributed to the liver and spleen. However, the (14)C and (3)H radioactivity of H12-(ADP)-liposomes disappeared from organs within 7 days after injection. The encapsulated ADP was metabolized to allantoin, which is the final metabolite of ADP in rodents, and was mainly eliminated in the urine, whereas the cholesterol was mainly eliminated in feces. In addition, the half-life of the H12-(ADP)-liposomes in humans was predicted to be approximately 96 hours from pharmacokinetic data obtained for mice, rats, and rabbits using an allometric equation. These results suggest that the H12-(ADP)-liposome has potential with proper pharmacokinetic and acceptable biodegradable properties as a synthetic platelet substitute. PMID:23735758

  17. Multiple-dose acetaminophen pharmacokinetics.

    PubMed

    Sahajwalla, C G; Ayres, J W

    1991-09-01

    Four different treatments of acetaminophen (Tylenol) were administered in multiple doses to eight healthy volunteers. Each treatment (325, 650, 825, and 1000 mg) was administered five times at 6-h intervals. Saliva acetaminophen concentration versus time profiles were determined. Noncompartmental pharmacokinetic parameters were calculated and compared to determine whether acetaminophen exhibited linear or dose-dependent pharmacokinetics. For doses less than or equal to 18 mg/kg, area under the curve (AUC), half-life (t1/2), mean residence time (MRT), and ratio of AUC to dose for the first dose were compared with the last dose. No statistically significant differences were observed in dose-corrected AUC for the first or last dose among subjects or treatments. Half-lives and MRT were not significantly different among treatments for the first or the last dose. Statistically significant differences in t1/2 and MRT were noted (p less than 0.05) among subjects for the last dose. A plot of AUC versus dose for the first and the last doses exhibited a linear relationship. Dose-corrected saliva concentration versus time curves for the treatments were superimposable. Thus, acetaminophen exhibits linear pharmacokinetics for doses of 18 mg/kg or less. Plots of AUC versus dose for one subject who received doses higher than 18 mg/kg were curved, suggesting nonlinear behavior of acetaminophen in this subject. PMID:1800709

  18. Pharmacokinetic drug interactions with oral contraceptives.

    PubMed

    Back, D J; Orme, M L

    1990-06-01

    Oral contraceptive steroids are used by an estimated 60 to 70 million women world-wide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs. A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol. Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability

  19. Pharmacokinetic interactions of cimetidine 1987.

    PubMed

    Somogyi, A; Muirhead, M

    1987-05-01

    The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but

  20. Azithromycin pharmacokinetics and penetration to lymph.

    PubMed

    Bergan, T; Jørgensen, N P; Olszewski, W; Zhang, Y

    1992-01-01

    The study of pharmacokinetics of azithromycin and penetration to peripheral human lymph was carried out in 14 healthy male volunteers taking 1 g orally after overnight fasting. Samples were analyzed by microbiological assay. The mean peak concentrations were 0.82 +/- 0.23 mg/l after 1.7 +/- 0.5 h in serum and 0.22 +/- 0.07 mg/l after 3.1 h in lymph. Nine of the 14 subjects showed a second and lower serum peak indicating the existence of enterohepatic circulation. The total areas under the serum concentrations curves (AUCs) till infinity were 7.9 +/- 3.1 mg. h/l compared to 4.4 +/- 1.2 mg.h/l in lymph. The mean lymph AUC was 68.1 +/- 20.7% of the serum AUC indicating a penetration ratio of 0.68. However, the actual amounts penetrating the tissues were much higher than this ratio suggests. Thus, after 6 h 81% of the drug was within the tissue compartment and after 120 h, 63% of the azithromycin was still present in the tissue compartment. The urinary recovery of azithromycin was 14.7 +/- 7.7% during the first 48 h. The serum curves and lymph curves displayed a distinctly slower phase of elimination after 12 h. The mean serum half-life was 5.4 +/- 3.4 h during the first 12 h (after the peak), whereas the value was 44.2 +/- 10.1 h during the interval 12-120 h. The corresponding half-life values for the peripheral lymph were 5.4 +/- 2.2 h and 50.8 +/- 11.6 h. Azithromycin possesses key pharmacokinetic properties that are prerequisites for a convenient once-daily dosage schedule which may improve patient compliance. PMID:1336891

  1. ATLAS ACCEPTANCE TEST

    SciTech Connect

    J.C. COCHRANE; J.V. PARKER; ET AL

    2001-06-01

    The acceptance test program for Atlas, a 23 MJ pulsed power facility for use in the Los Alamos High Energy Density Hydrodynamics program, has been completed. Completion of this program officially releases Atlas from the construction phase and readies it for experiments. Details of the acceptance test program results and of machine capabilities for experiments will be presented.

  2. An integrated pharmacokinetics ontology and corpus for text mining

    PubMed Central

    2013-01-01

    Background Drug pharmacokinetics parameters, drug interaction parameters, and pharmacogenetics data have been unevenly collected in different databases and published extensively in the literature. Without appropriate pharmacokinetics ontology and a well annotated pharmacokinetics corpus, it will be difficult to develop text mining tools for pharmacokinetics data collection from the literature and pharmacokinetics data integration from multiple databases. Description A comprehensive pharmacokinetics ontology was constructed. It can annotate all aspects of in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. It covers all drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK-corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK-corpus was demonstrated by a drug interaction extraction text mining analysis. Conclusions The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK-corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions. PMID:23374886

  3. Self-assembly properties of semiconducting donor-acceptor-donor bithienyl derivatives of tetrazine and thiadiazole-effect of the electron accepting central ring.

    PubMed

    Zapala, Joanna; Knor, Marek; Jaroch, Tomasz; Maranda-Niedbala, Agnieszka; Kurach, Ewa; Kotwica, Kamil; Nowakowski, Robert; Djurado, David; Pecaut, Jacques; Zagorska, Malgorzata; Pron, Adam

    2013-11-26

    Scanning tunneling microscopy was used to study the effect of the electron-accepting unit and the alkyl substituent's position on the type and extent of 2D supramolecular organization of penta-ring donor-acceptor-donor (DAD) semiconductors, consisting of either tetrazine or thiadiazole central acceptor ring symmetrically attached to two bithienyl groups. Microscopic observations of monomolecular layers on HOPG of four alkyl derivatives of the studied adsorbates indicate significant differences in their 2D organizations. Ordered monolayers of thiadiazole derivatives are relatively loose and, independent of the position of alkyl substituents, characterized by large intermolecular separation of acceptor units in the adjacent molecules located in the face-to-face configuration. The 2D supramolecular architecture in both derivatives of thiadiazole is very sensitive to the alkyl substituent's position. Significantly different behavior is observed for derivatives of tetrazine (which is a stronger electron acceptor). Stronger intermolecular DA interactions in these adsorbates generate an intermolecular shift in the monolayer, which is a dominant factor determining the 2D structural organization. As a consequence of this molecular arrangement, tetrazine groups (A segments) face thiophene rings (D segments) of the neighboring molecules. Monolayers of tetrazine derivatives are therefore much more densely packed and characterized by similar π-stacking of molecules independently of the position of alkyl substituents. Moreover, a comparative study of 3D supramolecular organization, deduced from the X-ray diffraction patterns, is also presented clearly confirming the polymorphism of the studied adsorbates. PMID:24228736

  4. Psychometric Properties and Validity of a Multi-dimensional Risk Perception Scale Developed in the Context of a Microbicide Acceptability Study.

    PubMed

    Vargas, Sara E; Fava, Joseph L; Severy, Lawrence; Rosen, Rochelle K; Salomon, Liz; Shulman, Lawrence; Guthrie, Kate Morrow

    2016-02-01

    Currently available risk perception scales tend to focus on risk behaviors and overall risk (vs partner-specific risk). While these types of assessments may be useful in clinical contexts, they may be inadequate for understanding the relationship between sexual risk and motivations to engage in safer sex or one's willingness to use prevention products during a specific sexual encounter. We present the psychometric evaluation and validation of a scale that includes both general and specific dimensions of sexual risk perception. A one-time, audio computer-assisted self-interview was administered to 531 women aged 18-55 years. Items assessing sexual risk perceptions, both in general and in regards to a specific partner, were examined in the context of a larger study of willingness to use HIV/STD prevention products and preferences for specific product characteristics. Exploratory and confirmatory factor analyses yielded two subscales: general perceived risk and partner-specific perceived risk. Validity analyses demonstrated that the two subscales were related to many sociodemographic and relationship factors. We suggest that this risk perception scale may be useful in research settings where the outcomes of interest are related to motivations to use HIV and STD prevention products and/or product acceptability. Further, we provide specific guidance on how this risk perception scale might be utilized to understand such motivations with one or more specific partners. PMID:26621151

  5. COMPUTATIONAL PHARMACOKINETICS DURING DEVELOPMENTAL WINDOWS OF SUSPECTIBILITY

    EPA Science Inventory

    ABSTRACT

    Computational modeling has an increasing role in analyses of biological effects including how the body handles chemicals (i.e. pharmacokinetics or toxicokinetics) and how the body responds to chemicals (i.e. pharmacodynamics or toxicodynamics). Pharmacokinetic mo...

  6. Drug Transport and Pharmacokinetics for Chemical Engineers

    ERIC Educational Resources Information Center

    Simon, Laurent; Kanneganti, Kumud; Kim, Kwang Seok

    2010-01-01

    Experiments in continuous-stirred vessels were proposed to introduce methods in pharmacokinetics and drug transport to chemical engineering students. The activities can be incorporated into the curriculum to illustrate fundamentals learned in the classroom. An appreciation for the role of pharmacokinetics in drug discovery will also be gained…

  7. Population Pharmacokinetics of Abacavir in Pregnant Women

    PubMed Central

    Treluyer, Jean-Marc; Préta, Laure-Helene; Valade, Elodie; Pannier, Emmanuelle; Urien, Saik; Hirt, Déborah

    2014-01-01

    For the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy. PMID:25070097

  8. Pharmacokinetics of peginterferons.

    PubMed

    Zeuzem, Stefan; Welsch, Christoph; Herrmann, Eva

    2003-01-01

    Two polyethylene glycol (PEG)-modified interferons are approved for the treatment of chronic hepatitis C. The pharmocokinetic properties of the branched 40 kDa pegylated interferon alfa-2a differ from the linear 12 kDa pegylated interferon alfa-2b. The absorption half-life of standard interferon alfa is 2.3 hours, while absorption half-lives for peginterferon alfa-2a and alfa-2b are 50 hours and 4.6 hours, respectively. The volume of distribution for peginterferon alfa-2a is considerably restricted, while the volume of distribution for peginterferon alfa-2b is only approximately 30% lower than that for conventional interferon. Because of its large size, the 40 kD peginterferon alfa-2a has a more than 100-fold reduction in renal clearance compared with conventional interferon alfa. Clearance of peginterferon alfa-2b is about one-tenth that of unmodified interferon alfa. Although data are limited, both drugs appear to show differences in the initial viral decay pattern in patients with chronic hepatitis C. However, it remains unknown whether these differences in the initial viral decline predict differences in the primary clinical endpoint, sustained virological response. PMID:12934165

  9. The pharmacokinetics in mice and dogs of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole

    SciTech Connect

    White, R.; Workman, P.; Owen, L.

    1982-03-01

    The pharmacokinetic properties of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole (MISO) were examined. In dogs, 2 analogues showed comparable peak plasma concentrations with considerable shorter half-lives (t1/2) and reduced areas under curves (AUC). Benznidazole (R0 07-1051) had a much longer t1/2, a higher AUC, and somewhat higher peak concentrations. In mice tumor/plasma, brain/plasma, and tumor/brain ratios were generally similar to MISO, as was penetration of brain and peripheral nerve by benznidazole in dogs. Selection of lipophilic analogues with appropriate pharmacokinetic properties may facilitate accommodation of the potentially different requirements for improved radiosensitization or chemosensitization.

  10. [Quantum-chemical basics of pharmacokinetics (literary review and own investigations)].

    PubMed

    Chekman, I S; Horchakova, N O; Nebesna, T Iu; Kazakova, O O; Luk"ianchuk, V D; Bielienichev, I F; Zviagintseva, T V; Syrova, H O; Zagorodnyĭ, M I; Kravets', D S

    2012-01-01

    The work is devoted to the use of quantum-pharmacological approaches in pharmacokinetic investigations. The main objective of the pharmacological researches is to find new, more active and less toxic drugs. To date, such a search is carried out empirically. The current approach can not fully meet the needs of medicine in the new drugs, requires considerable time and financial costs and does not meet modern standards of bioethics. Quantum pharmacology leads to the synthesis of drugs with desired properties is much faster and more efficient. Computer prediction of pharmacokinetic and biopharmaceutical properties of biologically active substances can make 50-70% more effective development of original drugs. PMID:23356130

  11. Acceptance, values, and probability.

    PubMed

    Steel, Daniel

    2015-10-01

    This essay makes a case for regarding personal probabilities used in Bayesian analyses of confirmation as objects of acceptance and rejection. That in turn entails that personal probabilities are subject to the argument from inductive risk, which aims to show non-epistemic values can legitimately influence scientific decisions about which hypotheses to accept. In a Bayesian context, the argument from inductive risk suggests that value judgments can influence decisions about which probability models to accept for likelihoods and priors. As a consequence, if the argument from inductive risk is sound, then non-epistemic values can affect not only the level of evidence deemed necessary to accept a hypothesis but also degrees of confirmation themselves. PMID:26386533

  12. Newbery Medal Acceptance.

    ERIC Educational Resources Information Center

    Freedman, Russell

    1988-01-01

    Presents the Newbery Medal acceptance speech of Russell Freedman, writer of children's nonfiction. Discusses the place of nonfiction in the world of children's literature, the evolution of children's biographies, and the author's work on "Lincoln." (ARH)

  13. Newbery Medal Acceptance.

    ERIC Educational Resources Information Center

    Cleary, Beverly

    1984-01-01

    Reprints the text of Ms. Cleary's Newbery medal acceptance speech in which she gives personal history concerning her development as a writer and her response to the letters she receives from children. (CRH)

  14. Caldecott Medal Acceptance.

    ERIC Educational Resources Information Center

    Provensen, Alice; Provensen, Martin

    1984-01-01

    Reprints the text of the Provensens' Caldecott medal acceptance speech in which they describe their early interest in libraries and literature, the collaborative aspect of their work, and their current interest in aviation. (CRH)

  15. Self nanoemulsifying drug delivery system (SNEDDS) of rosuvastatin calcium: design, formulation, bioavailability and pharmacokinetic evaluation.

    PubMed

    Balakumar, Krishnamoorthy; Raghavan, Chellan Vijaya; selvan, Natarajan Tamil; prasad, Ranganathan Hari; Abdu, Siyad

    2013-12-01

    The aim of the present study is to improve solubility and bioavailability of Rosuvastatin calcium using self nanoemulsifying drug delivery system (SNEDDS). Self emulsifying property of various oils including essential oils was evaluated with suitable surfactants and co-surfactants. Ternary phase diagrams were constructed based on Rosuvastatin calcium solubility analysis for optimizing the system. The prepared formulations were evaluated for self emulsifying time, robustness to dilution, droplet size determination and zeta potential analysis. The system was found to be robust in different pH media and dilution volume. The globule size of the optimized system was less than 200nm which could be an acceptable nanoemulsion size range. The zeta potential of the selected CN 7 SNEDDS formulation (cinnamon oil 30%; labrasol 60%; Capmul MCM C8 10%) was -29.5±0.63 with an average particle size distribution of 122nm. In vitro drug release studies showed remarkable increase in dissolution of CN7 SNEDDS compared to marketed formulation. In house developed HPLC method for determination of Rosuvastatin calcium in rat plasma was used in the bioavailability and pharmacokinetic evaluation. The relative bioavailability of self nanoemulsified formulation showed an enhanced bioavailability of 2.45 times greater than that of drug in suspension. The obtained plasma drug concentration data was processed with PKSolver 2.0 and it was best fit into the one compartment model. PMID:24012665

  16. Roles of the scalar and vector components of the solvation effects on the vibrational properties of hydrogen- or halogen-bond accepting stretching modes.

    PubMed

    Torii, Hajime; Noge, Saori

    2016-04-21

    Solvation-induced vibrational frequency shifts and infrared (IR) intensity changes of the hydrogen- or halogen-bond accepting stretching modes, especially their dependence on the angular position of the hydrogen- or halogen-bond donating molecule, are examined theoretically. Calculations are carried out for some modes of hydrogen- or halogen-bonding molecular complexes, including the S[double bond, length as m-dash]O stretch of dimethyl sulfoxide-(13)C2H2O, the C[triple bond, length as m-dash]N stretch of acetonitrileH2O, and the amide I' mode of the N-methylacetamide-d1BrNC 1 : 1 complex. It is shown that, in all the example cases dealt with in this study, the frequency shift depends rather strongly on the hydrogen- or halogen-bond angle (e.g., S[double bond, length as m-dash]OH angle), with a larger low-frequency shift as the hydrogen or halogen bond becomes more bent, indicating the generality of the results obtained for the amide I' mode of the N-methylacetamide-d1(2)H2O 1 : 1 complex in a previous study. Contrary to our vague expectation, the frequency shift is not well correlated to the hydrogen- or halogen-bond distance or strength, but nevertheless, it is well reproduced by an electrostatic interaction model if it is carefully constructed by considering the scalar and vector components separately in a reasonable way. On the basis of this electrostatic interaction model, the reason why our vague expectation is not realized is clarified, and a unified understanding is achieved on the hydration-induced high-frequency shift of the C[triple bond, length as m-dash]N stretch and the low-frequency shifts of the S[double bond, length as m-dash]O stretch and amide I'. With regard to the IR intensity, it is shown that, in some of the example cases, it also has rather strong angular position dependence. The mechanism of the IR intensity changes is estimated by analyzing the dipole derivative vector, especially its angular relation with the hydrogen or halogen

  17. The pharmacokinetics of long-acting antipsychotic medications.

    PubMed

    Spanarello, Stefano; La Ferla, Teresa

    2014-01-01

    The depot antipsychotics are synthesized by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil, with the exception of some molecules of new generation characterized by microcrystalline technologies. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate. The pharmacokinetics of depot antipsychotic medications are such that an intramuscular injection given at intervals from 1 to 4 weeks will produce adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot formulations of antipsychotic drugs have been extensively studied. The clinical pharmacokinetics of the depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, bromperidol decanoate, clopenthixol decanoate, flupenthixol decanoate, perphenazine onanthat, pipotiazine undecylenate, pipotiazine palmitate, fluspirilene, long-acting injectable risperidone, olanzapine pamoate, paliperidone palmitate, long-acting iloperidone, long-acting injectable aripiprazole) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed. PMID:23343447

  18. Development of a computer-based instructional system in pharmacokinetics: efficacy in clinical pharmacology teaching for senior medical students.

    PubMed

    Feldman, R D; Schoenwald, R; Kane, J

    1989-02-01

    The teaching of pharmacokinetics is acknowledged to be a key aspect of the core curriculum in clinical pharmacology and therapeutics, but is also widely acknowledged to be a very difficult part of the curriculum to teach. In order to assess the potential efficacy of interactive computer instruction in clinical pharmacokinetics we have developed a prototype computer-based instructional package. The courseware contains a comprehensive learning system including tutorial, simulation, and problem solving components. To determine the efficacy of this approach we randomly assigned senior medical student volunteers enrolled in the fourth year clinical pharmacology and therapeutics course to receive conventional teaching in clinical pharmacokinetics and/or adjuctive teaching using the computer-based instructional system. There was a high degree of acceptance of the program and over the short term of the trial those students using the computer program scored significantly higher [35%, P less than 0.05] on the mid-term pharmacokinetics quiz. The data suggests that a computerized instructional system in pharmacokinetics may significantly improve the teaching of clinical pharmacokinetics to medical students. PMID:2654201

  19. Simultaneous determination of four secoiridoid and iridoid glycosides in rat plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application to a comparative pharmacokinetic study.

    PubMed

    Wu, Yun; Ai, Yu; Wang, Fenrong; Ma, Wen; Bian, Qiaoxia; Lee, David Y-W; Dai, Ronghua

    2016-02-01

    A simple, reliable and rapid ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of four secoiridoid (gentiopicroside, swertiamarin, sweroside) and iridoid glycosides (loganic acid), the bio-active ingredients in rat plasma. After liquid-liquid extraction, chromatographic separation was accomplished on a Shim-pack XR-ODS column with a mobile phase consisting of methanol and 0.1% formic acid in water. A triple quadrupole tandem mass spectrometry equipped with an electrospray ionization source was used as detector operating both in positive and negative ionization mode and operated by multiple-reaction monitoring scanning. The lower limits of quantitation were 0.25-30 ng/mL for all the analytes. Both intra-day and inter-day precision and accuracy of analytes were well within acceptance criteria (±15%). The mean extraction recoveries of analytes and internal standard (amygdalin) from rat plasma were all >71.4%. The validated method was successfully applied to a comparative pharmacokinetic study of four analytes in rat plasma between normal and arthritic rats after oral administration of Huo Luo Xiao Ling Dan and Gentiana macrophylla extract, respectively. Results showed significant differences in pharmacokinetic properties of the analytes among the different groups. PMID:26014753

  20. Pharmacology in space. Part 1. Influence of adaptive changes on pharmacokinetics

    NASA Technical Reports Server (NTRS)

    Lathers, C. M.; Charles, J. B.; Bungo, M. W.

    1989-01-01

    The topic of pharmacology in space, i.e. the administration of drugs during space flight and the subsequent pharmacokinetic handling of the pharmaceuticals, is a new field about which little is known. In a two-part series, Claire Lathers and colleagues highlight some of the current questions in this field. In this first article the physiological and biochemical changes associated with weightlessness in space are discussed. These changes induce adaptive alterations which may influence the pharmacokinetic properties of drugs. The cardiovascular system is of particular relevance here. Also discussed are the classes of pharmacological agent that are most likely to be used during space flight for medical problems and thus, by necessity, will become drugs to be examined in space to determine whether their pharmacokinetic and pharmacodynamic properties are altered. Therapy of the most common spaceflight ailment-motion sickness-will be considered next month in Part 2.

  1. Pharmacokinetics of Indomethacin in Pregnancy

    PubMed Central

    Rytting, Erik; Nanovskaya, Tatiana N.; Wang, Xiaoming; Vernikovskaya, Daria I.; Clark, Shannon M.; Cochran, Marlo; Abdel-Rahman, Susan M.; Venkataramanan, Raman; Caritis, Steve N.; Hankins, Gary D. V.; Ahmed, Mahmoud S.

    2014-01-01

    Background and objectives Although indomethacin has been widely used for the treatment of preterm labor over the past 40 years, there are few reports regarding its pharmacokinetics in pregnant women. Methods This opportunistic study assessed the steady-state pharmacokinetics of indomethacin in pregnant subjects to whom an oral dose of 25 mg every 6 h was prescribed. Indomethacin concentrations in plasma and urine were analyzed by a validated high-performance liquid chromatography method with mass spectrometric detection. Results The mean area under the plasma concentration versus time curve at steady state (AUCss) was 1.91 ± 0.53 lg h/mL, mean peak plasma concentration (Cmax) was 1.02 ± 0.49 lg/mL, and mean time to reach Cmax (tmax) was 1.3 ± 0.7 h. The mean apparent clearance at steady state was 14.5 ± 5.5 L/h, which is higher than the apparent clearance reported in the literature for non-pregnant subjects. Indomethacin crosses the placenta; the mean fetal/maternal ratio from five sets of cord blood samples collected at delivery was 4.0 ± 1.1. Conclusions Further studies are needed to determine whether any dose adjustments are necessary as a result of the increased clearance of indomethacin during pregnancy. PMID:24493205

  2. Pharmacokinetics of ciprofloxacin in ponies.

    PubMed

    Dowling, P M; Wilson, R C; Tyler, J W; Duran, S H

    1995-02-01

    The pharmacokinetics of ciprofloxacin was investigated in healthy, mature ponies. Ciprofloxacin was administered intravenously to six ponies at a dose of 5 mg per kg body weight. Seven days later, ciprofloxacin was administered orally to each pony at the same dose. Intravenous ciprofloxacin concentration vs. time data best fit a two-compartment open model with first-order elimination from the central compartment. Mean plasma half-life, based on the terminal phase, was 157.89 min (harmonic mean). Total body clearance of ciprofloxacin was 18.12 +/- 3.99 mL/min/kg. Volume of distribution at steady-state was 3.45 +/- 0.72 L/kg. From the pharmacokinetic data and reported minimum inhibitory concentrations for equine gram-negative pathogens, the appropriate dosage of ciprofloxacin was determined to be 5.32 mg per kg body weight at 12 h intervals. Bioavailability of oral ciprofloxacin in ponies was 6.8 +/- 5.33%. Owing to the poor bioavailability, a dosage regimen could not be proposed for oral ciprofloxacin administration in horses. Ciprofloxacin concentrations were determined in tissues and body fluids at 1, 2 and 4 h after intravenous administration. At all times, tissue concentrations exceeded plasma concentrations of ciprofloxacin. Highest concentrations were achieved in kidneys and urine. Potentially therapeutic concentrations were obtained in cerebrospinal and joint fluid, but low concentrations were achieved in aqueous humour. PMID:7752310

  3. Pharmacokinetic enhancers in HIV therapeutics.

    PubMed

    Larson, Kajal B; Wang, Kun; Delille, Cecile; Otofokun, Igho; Acosta, Edward P

    2014-10-01

    Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed. PMID:25164142

  4. In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs

    PubMed Central

    Restrepo Valencia, Piedad

    2015-01-01

    Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance. PMID:26600625

  5. Divalproex-ER pharmacokinetics in older children and adolescents.

    PubMed

    Dutta, Sandeep; Zhang, Yiming; Conway, Jeannine M; Sallee, Floyd R; Biton, Victor; Reed, Michael D; Kearns, Gregory L

    2004-05-01

    Valproic acid pharmacokinetic profile and tolerability after administration of divalproex sodium extended-release tablets was characterized in older children and adolescents. In this multiple-dose, open-label, pharmacokinetic study, the patients were divided into two age groups, 8-11 years (older children; n = 15) and 12-17 years (adolescents; n = 14). Once-daily administration of divalproex sodium extended-release tablets (doses ranged from 250 to 1750 mg) in older children and adolescents produced relatively flat plasma valproic acid concentration-time profiles over the entire 24-hour dosing interval, similar to the pharmacokinetic performance of this formulation in adults. The mean (standard deviation) oral clearance values for unbound valproic acid were 94.3 (51.8) and 82.3 (28.2) mL/h/kg and for total valproic acid were 11.2 (3.77) and 9.06 (2.03) mL/h/kg in older children and adolescents, respectively. Two patients discontinued for administrative reasons, whereas one discontinued for an adverse event (flulike syndrome). Adverse events reported by three or more patients were flu syndrome (5 patients, 17.2%) and headache (3 patients, 10.3%). Reported adverse events were generally mild to moderate in severity and similar to those reported in previous divalproex studies. This study demonstrates that in older children and adolescents, once-daily administration of divalproex sodium extended-release tablets may potentially be used to sustain plasma valproic acid concentrations within the usually accepted therapeutic ranges for various indications. PMID:15165635

  6. Population pharmacokinetics of pyrazinamide in elephants.

    PubMed

    Zhu, M; Maslow, J N; Mikota, S K; Isaza, R; Dunker, F; Riddle, H; Peloquin, C A

    2005-10-01

    This study was undertaken to characterize the population pharmacokinetics (PK), therapeutic dose, and preferred route of administration for pyrazinamide (PZA) in elephants. Twenty-three African (Loxodonta africana) and Asian (Elephas maximus) elephants infected with or in contact with others culture positive for Mycobacterium tuberculosis were dosed under treatment conditions. PZA was dosed daily at 20-30 mg/kg via oral (fasting or nonfasting state) or rectal (enema or suppository) administration. Blood samples were collected 0-24 h postdose. Population PK was estimated using nonlinear mixed effect modeling. Drug absorption was rapid with T(max) at or before 2 h regardless of the method of drug administration. C(max) at a mean dose of 25.6 (+/-4.6) mg/kg was 19.6 (+/-9.5 microg/mL) for PZA given orally under fasting conditions. Under nonfasting conditions at a mean dose of 26.1 +/- 4.2 mg/kg, C(max) was 25% (4.87 +/- 4.89 microg/mL) and area under concentration curve (AUC) was 30% of the values observed under fasting conditions. Mean rectal dose of 32.6 +/- 15.2 mg/kg yielded C(max) of 12.3 +/- 6.3 microg/mL, but comparable AUC to PZA administered orally while fasting. Both oral and rectal administration of PZA appeared to be acceptable and oral dosing is preferred because of the higher C(max) and lower inter-subject variability. A starting dose of 30 mg/kg is recommended with drug monitoring between 1 and 2 h postdose. Higher doses may be required if the achieved C(max) values are below the recommended 20-50 microg/mL range. PMID:16207301

  7. Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis.

    PubMed

    Ternant, David; Bejan-Angoulvant, Theodora; Passot, Christophe; Mulleman, Denis; Paintaud, Gilles

    2015-11-01

    Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity. PMID:26123705

  8. Population pharmacokinetics of oseltamivir and oseltamivir carboxylate in obese and non‐obese volunteers

    PubMed Central

    Chairat, Kalayanee; Jittamala, Podjanee; Hanpithakpong, Warunee; Day, Nicholas P. J.; White, Nicholas J.; Pukrittayakamee, Sasithon

    2016-01-01

    Aims The aims of the present study were to compare the pharmacokinetics of oseltamivir and its active antiviral metabolite oseltamivir carboxylate in obese and non‐obese individuals and to determine the effect of obesity on the pharmacokinetic properties of oseltamivir and oseltamivir carboxylate. Methods The population pharmacokinetic properties of oseltamivir and oseltamivir carboxylate were evaluated in 12 obese [body mass index (BMI) ≥30 kg m−2) and 12 non‐obese (BMI <30 kg m−2) Thai adult volunteers receiving a standard dose of 75 mg and a double dose of 150 mg in a randomized sequence. Concentration–time data were collected and analysed using nonlinear mixed‐effects modelling. Results The pharmacokinetics of oseltamivir and oseltamivir carboxylate were described simultaneously by first‐order absorption, with a one‐compartment disposition model for oseltamivir, followed by a metabolism compartment and a one‐compartment disposition model for oseltamivir carboxylate. Creatinine clearance was a significant predictor of oseltamivir carboxylate clearance {3.84% increase for each 10 ml min−1 increase in creatinine clearance [95% confidence interval (CI) 0.178%, 8.02%]}. Obese individuals had an approximately 25% (95% CI 24%, 28%) higher oseltamivir clearance, 20% higher oseltamivir volume of distribution (95% CI 19%, 23%) and 10% higher oseltamivir carboxylate clearance (95% CI 9%, 11%) compared with non‐obese individuals. However, these altered pharmacokinetic properties were small and did not change the overall exposure to oseltamivir carboxylate. Conclusions The results confirmed that a dose adjustment for oseltamivir in obese individuals is not necessary on the basis of its pharmacokinetics. PMID:26810861

  9. Pattern Recognition in Pharmacokinetic Data Analysis.

    PubMed

    Gabrielsson, Johan; Meibohm, Bernd; Weiner, Daniel

    2016-01-01

    Pattern recognition is a key element in pharmacokinetic data analyses when first selecting a model to be regressed to data. We call this process going from data to insight and it is an important aspect of exploratory data analysis (EDA). But there are very few formal ways or strategies that scientists typically use when the experiment has been done and data collected. This report deals with identifying the properties of a kinetic model by dissecting the pattern that concentration-time data reveal. Pattern recognition is a pivotal activity when modeling kinetic data, because a rigorous strategy is essential for dissecting the determinants behind concentration-time courses. First, we extend a commonly used relationship for calculation of the number of potential model parameters by simultaneously utilizing all concentration-time courses. Then, a set of points to consider are proposed that specifically addresses exploratory data analyses, number of phases in the concentration-time course, baseline behavior, time delays, peak shifts with increasing doses, flip-flop phenomena, saturation, and other potential nonlinearities that an experienced eye catches in the data. Finally, we set up a series of equations related to the patterns. In other words, we look at what causes the shapes that make up the concentration-time course and propose a strategy to construct a model. By practicing pattern recognition, one can significantly improve the quality and timeliness of data analysis and model building. A consequence of this is a better understanding of the complete concentration-time profile. PMID:26338231

  10. A pharmacokinetic simulation tool for inhaled corticosteroids.

    PubMed

    Weber, Benjamin; Hochhaus, Guenther

    2013-01-01

    The pharmacokinetic (PK) behavior of inhaled drugs is more complicated than that of other forms of administration. In particular, the effects of certain physiological (mucociliary clearance and differences in membrane properties in central and peripheral (C/P) areas of the lung), formulation (as it relates to drug deposition and particle dissolution rate), and patient-related factors (lung function; effects on C/P deposition ratio) affect the systemic PKs of inhaled drugs. The objectives of this project were (1) to describe a compartmental model that adequately describes the fate of inhaled corticosteroids (ICS) after administration while incorporating variability between and within subjects and (2) based upon the model, to provide a freely available tool for simulation of PK trials after ICS administration. This compartment model allows for mucociliary removal of undissolved particles from the lung, distinguishes between central and peripheral regions of the lung, and models drug entering the systemic circulation via the lung and the gastrointestinal tract. The PK simulation tool is provided as an extension package to the statistical software R ('ICSpkTS'). It allows simulation of PK trials for hypothetical ICS and of four commercially available ICS (budesonide, flunisolide, fluticasone propionate, and triamcinolone acetonide) in a parallel study design. Simulated PK data and parameters agreed well with literature data for all four ICS. The ICSpkTS package is especially suitable to explore the effect of changes in model parameters on PK behavior and can be easily adjusted for other inhaled drugs. PMID:23139018

  11. Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers

    PubMed Central

    Fischer, Andreas; Hjelmström, Peter

    2015-01-01

    Abstract Context Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery. Objective To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability. Methods Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4 mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2 mg). Results Buprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively. Conclusions A sublingual tablet formulation with an improved acceptability has been successfully developed. PMID:24099551

  12. Pharmacokinetics of cannabidiol in dogs.

    PubMed

    Samara, E; Bialer, M; Mechoulam, R

    1988-01-01

    Cannabidiol (CBD) is one of the major nonpsychoactive cannabinoids produced by Cannabis sativa L. Recent studies have shown that CBD has a high protective index, comparable to that of phenobarbital and phenytoin. Because CBD has been reported to possess both anticonvulsant and antiepileptic activity, its pharmacokinetics were studied in dogs after the administration of two iv doses (45 and 90 mg) and one oral dose (180 mg) to dogs. After iv administration, CBD was rapidly distributed, followed by a prolonged elimination. It has a terminal half-life of 9 hr. CBD plasma levels declined in a triphasic fashion. The total body clearance of CBD was 17 liters/hr (after the 45-mg dose) and 16 liters/hr (after the 90-mg dose). This clearance value, after its normalization to blood clearance using mathematical equations, approaches the value of the hepatic blood flow; the extraction ratio in the liver is 0.74. CBD was observed to have a large volume of distribution, approximately 100 liters. In the dose range of 45 to 90 mg, the increase in the AUC was proportional to the dose, a fact that indicates that the pharmacokinetic profile of CBD in this dose range was not dose dependent. In three of the six dogs studied, CBD could not be detected in the plasma after oral administration. In the other three, the oral bioavailability ranged from 13 to 19%. The results of this study show that CBD is barely absorbed after oral administration to dogs. This low bioavailability may be due to a first pass effect. PMID:2900742

  13. Accept or divert?

    PubMed

    Angelucci, P A

    1999-09-01

    Stretching scarce resources is more than a managerial issue. Should you accept the patient to an understaffed ICU or divert him to another facility? The intense "medical utility" controversy focuses on a situation that critical care nurses now face every day. PMID:10614370

  14. Approaches to acceptable risk

    SciTech Connect

    Whipple, C.

    1997-04-30

    Several alternative approaches to address the question {open_quotes}How safe is safe enough?{close_quotes} are reviewed and an attempt is made to apply the reasoning behind these approaches to the issue of acceptability of radiation exposures received in space. The approaches to the issue of the acceptability of technological risk described here are primarily analytical, and are drawn from examples in the management of environmental health risks. These include risk-based approaches, in which specific quantitative risk targets determine the acceptability of an activity, and cost-benefit and decision analysis, which generally focus on the estimation and evaluation of risks, benefits and costs, in a framework that balances these factors against each other. These analytical methods tend by their quantitative nature to emphasize the magnitude of risks, costs and alternatives, and to downplay other factors, especially those that are not easily expressed in quantitative terms, that affect acceptance or rejection of risk. Such other factors include the issues of risk perceptions and how and by whom risk decisions are made.

  15. 1984 Newbery Acceptance Speech.

    ERIC Educational Resources Information Center

    Cleary, Beverly

    1984-01-01

    This acceptance speech for an award honoring "Dear Mr. Henshaw," a book about feelings of a lonely child of divorce intended for eight-, nine-, and ten-year-olds, highlights children's letters to author. Changes in society that affect children, the inception of "Dear Mr. Henshaw," and children's reactions to books are highlighted. (EJS)

  16. Why was Relativity Accepted?

    NASA Astrophysics Data System (ADS)

    Brush, S. G.

    Historians of science have published many studies of the reception of Einstein's special and general theories of relativity. Based on a review of these studies, and my own research on the role of the light-bending prediction in the reception of general relativity, I discuss the role of three kinds of reasons for accepting relativity (1) empirical predictions and explanations; (2) social-psychological factors; and (3) aesthetic-mathematical factors. According to the historical studies, acceptance was a three-stage process. First, a few leading scientists adopted the special theory for aesthetic-mathematical reasons. In the second stage, their enthusiastic advocacy persuaded other scientists to work on the theory and apply it to problems currently of interest in atomic physics. The special theory was accepted by many German physicists by 1910 and had begun to attract some interest in other countries. In the third stage, the confirmation of Einstein's light-bending prediction attracted much public attention and forced all physicists to take the general theory of relativity seriously. In addition to light-bending, the explanation of the advance of Mercury's perihelion was considered strong evidence by theoretical physicists. The American astronomers who conducted successful tests of general relativity became defenders of the theory. There is little evidence that relativity was `socially constructed' but its initial acceptance was facilitated by the prestige and resources of its advocates.

  17. UGV acceptance testing

    NASA Astrophysics Data System (ADS)

    Kramer, Jeffrey A.; Murphy, Robin R.

    2006-05-01

    With over 100 models of unmanned vehicles now available for military and civilian safety, security or rescue applications, it is important to for agencies to establish acceptance testing. However, there appears to be no general guidelines for what constitutes a reasonable acceptance test. This paper describes i) a preliminary method for acceptance testing by a customer of the mechanical and electrical components of an unmanned ground vehicle system, ii) how it has been applied to a man-packable micro-robot, and iii) discusses the value of testing both to ensure that the customer has a workable system and to improve design. The test method automated the operation of the robot to repeatedly exercise all aspects and combinations of components on the robot for 6 hours. The acceptance testing process uncovered many failures consistent with those shown to occur in the field, showing that testing by the user does predict failures. The process also demonstrated that the testing by the manufacturer can provide important design data that can be used to identify, diagnose, and prevent long-term problems. Also, the structured testing environment showed that sensor systems can be used to predict errors and changes in performance, as well as uncovering unmodeled behavior in subsystems.

  18. Chiral Pesticide Pharmacokinetics: A Range of Values

    EPA Science Inventory

    Approximately 30% of pesticides are chiral and used as mixtures of two or more stereoisomers. In biological systems, these stereoisomers can exhibit significantly different pharmacokinetics (absorption, distribution, metabolism, and elimination). In spite of these differences, th...

  19. A PHARMACOKINETIC PROGRAM (PKFIT) FOR R

    EPA Science Inventory

    The purpose of this study was to create a nonlinear regression (including a genetic algorithm) program (R script) to deal with data fitting for pharmacokinetics (PK) in R environment using its available packages. We call this tool as PKfit.

  20. Molecular pharmacokinetics of catharanthus (vinca) alkaloids.

    PubMed

    Levêque, Dominique; Jehl, François

    2007-05-01

    This review focuses on the published data regarding the molecular determinants (enzymes, transporters, orphan nuclear receptors) of Catharanthus (vinca) alkaloids pharmacokinetics in humans. The clinical impact of these determinants (drug disposition, drug-drug interactions) is also discussed. PMID:17442684

  1. Development of quantitative structure-pharmacokinetic relationships.

    PubMed Central

    Mayer, J M; van de Waterbeemd, H

    1985-01-01

    Quantitative structure-activity relationships (QSAR) relating biological activity to physiochemical descriptors have been successfully used for a number of years. It is also long recognized that pharmacokinetic parameters may play an important and even determinant role in drug action. This prompted several researchers to focus attention to pharmacokinetic parameters as potential descriptors in quantitative drug design. A number of examples of quantitative structure-pharmacokinetic relationships (QSPR) have appeared in the literature. The present contribution reviews some developments in this field. In particular, a number of concepts and problems are critically discussed, rather than compilations of examples already published in recent reviews. Attention will be paid to the main processes of the pharmacokinetic or toxicokinetic phase in drug action, including absorption, distribution and elimination (biotransformation and excretion). It is clear that quantitative approaches are of considerable interest to toxicologists, since these methods may contribute to the development of real predictive toxicology. PMID:3905378

  2. Effectiveness, Safety, and Pharmacokinetics of Quetiapine in Aggressive Children with Conduct Disorder

    ERIC Educational Resources Information Center

    Findling, Robert L.; Reed, Michael D.; O'Riordan, Mary Ann; Demeter, Christine A.; Stansbrey, Robert J.; McNamara, Nora K.

    2006-01-01

    Objective: To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). Method: This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale…

  3. Pharmacokinetics and dosimetry of the anti-androgen vinclozolin after oral administration inthe rat

    EPA Science Inventory

    Vinclozolin (V) is a fungicide with antiandrogenic properties. To determine the pharmacokinetics and dosimetry of V, adult male rats were administered an oral dose of V (100 mg/kg) in corn oil and sacrificed over time after dosing. V and its metabolites were analyzed in serum and...

  4. On the assessment of effects of food on the pharmacokinetics of drugs in early development.

    PubMed

    Li, Zhihong; Vachharajani, Nimish N; Krishna, Rajesh

    2002-05-01

    The impact of food on the pharmacokinetics of a drug has important implications in drug development. This commentary is aimed at addressing two key challenges, developability of drugs whose pharmacokinetics are severely influenced by food, and the need for addressing the effects of fruit juice ingredients which modulate metabolic/efflux properties of a compound. Perspectives on the value in predicting food-drug interactions during preclinical development, timing of clinical food-drug interaction studies, and implications of food effects are presented herein. PMID:12015791

  5. Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

    PubMed Central

    Ostiguy, Valerie; Cadieux, Cordelia; Malouin, Mireille; Belanger, Odette; Far, Adel Rafai; Parr, Thomas R.

    2015-01-01

    The pharmacokinetics and bone concentrations of oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of oritavancin for the treatment of infections in bone tissues is warranted. PMID:26239977

  6. Clinical Pharmacokinetics: A Simplified Approach, Part 2

    PubMed Central

    Perlin, Elliott; Taylor, Robert E.; Peck, Carl C.

    1986-01-01

    Part 1 of this two-part series in clinical pharmacokinetics (J Natl Med Assoc 1985; 77:475-482) introduced the clinician to the basic principles required for rational therapeutic drug management at the bedside. Practical problems were included that demonstrated how these principles could be put to clinical use. In Part 2 the clinical pharmacology of three commonly used drugs (theophylline, digoxin and gentamicin) are discussed, and practical problems are presented to illustrate the use of their pharmacokinetic profiles. PMID:3783759

  7. Pharmacokinetics of oral amantadine in greyhound dogs.

    PubMed

    Norkus, C; Rankin, D; Warner, M; KuKanich, B

    2015-06-01

    This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine CMAX was 275 ng/mL (225-351 ng/mL) at 2.6 h (1-4 h) with a terminal half-life of 4.96 h (4.11-6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed-specific differences in the pharmacokinetics of amantadine in dogs. PMID:25427541

  8. Nanoparticle Drug Loading as a Design Parameter to Improve Docetaxel Pharmacokinetics and Efficacy

    PubMed Central

    Chu, Kevin S.; Schorzman, Allison N.; Finniss, Mathew C.; Bowerman, Charles J.; Peng, Lei; Luft, J. Christopher; Madden, Andrew; Wang, Andrew Z.; Zamboni, William C.; DeSimone, Joseph M.

    2013-01-01

    Nanoparticle (NP) drug loading is one of the key defining characteristics of a NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT®), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel. PMID:23899444

  9. Acceptability of human risk.

    PubMed Central

    Kasperson, R E

    1983-01-01

    This paper has three objectives: to explore the nature of the problem implicit in the term "risk acceptability," to examine the possible contributions of scientific information to risk standard-setting, and to argue that societal response is best guided by considerations of process rather than formal methods of analysis. Most technological risks are not accepted but are imposed. There is also little reason to expect consensus among individuals on their tolerance of risk. Moreover, debates about risk levels are often at base debates over the adequacy of the institutions which manage the risks. Scientific information can contribute three broad types of analyses to risk-setting deliberations: contextual analysis, equity assessment, and public preference analysis. More effective risk-setting decisions will involve attention to the process used, particularly in regard to the requirements of procedural justice and democratic responsibility. PMID:6418541

  10. Age and Acceptance of Euthanasia.

    ERIC Educational Resources Information Center

    Ward, Russell A.

    1980-01-01

    Study explores relationship between age (and sex and race) and acceptance of euthanasia. Women and non-Whites were less accepting because of religiosity. Among older people less acceptance was attributable to their lesser education and greater religiosity. Results suggest that quality of life in old age affects acceptability of euthanasia. (Author)

  11. Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated Plasmodium falciparum Malaria in Uganda

    PubMed Central

    Kloprogge, F; Piola, P; Dhorda, M; Muwanga, S; Turyakira, E; Apinan, S; Lindegårdh, N; Nosten, F; Day, N P J; White, N J; Guerin, P J; Tarning, J

    2013-01-01

    Pregnancy alters the pharmacokinetic properties of many antimalarial compounds. The objective of this study was to evaluate the pharmacokinetic properties of lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Uganda after a standard fixed oral artemether–lumefantrine treatment. Dense venous (n = 26) and sparse capillary (n = 90) lumefantrine samples were drawn from pregnant patients. A total of 17 nonpregnant women contributed with dense venous lumefantrine samples. Lumefantrine pharmacokinetics was best described by a flexible absorption model with multiphasic disposition. Pregnancy and body temperature had a significant impact on the pharmacokinetic properties of lumefantrine. Simulations from the final model indicated 27% lower day 7 concentrations in pregnant women compared with nonpregnant women and a decreased median time of 0.92 and 0.42 days above previously defined critical concentration cutoff values (280 and 175 ng/ml, respectively). The standard artemether–lumefantrine dose regimen in P. falciparum malaria may need reevaluation in nonimmune pregnant women. PMID:24226803

  12. Pharmacokinetic drug interactions of macrolides.

    PubMed

    Periti, P; Mazzei, T; Mini, E; Novelli, A

    1992-08-01

    The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline

  13. Pharmacokinetics of pantoprazole in man.

    PubMed

    Huber, R; Hartmann, M; Bliesath, H; Lühmann, R; Steinijans, V W; Zech, K

    1996-05-01

    The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(0,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2

  14. Pharmacokinetics of pantoprazole in man.

    PubMed

    Huber, R; Hartmann, M; Bliesath, H; Lühmann, R; Steinijans, V W; Zech, K

    1996-05-01

    The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(O,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination halflife of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2

  15. Clinical pharmacokinetics of the salicylates.

    PubMed

    Needs, C J; Brooks, P M

    1985-01-01

    -order kinetics. The serum half-life of salicylic acid is dose-dependent; thus, the larger the dose employed, the longer it will take to reach steady-state. There is also evidence that enzyme induction of salicyluric acid formation occurs. No significant differences exist between the pharmacokinetics of the salicylates in the elderly or in children when compared with young adults. Apart from differences in free versus albumin-bound salicylate in various disease states and physiological conditions associated with low serum albumin, pharmacokinetic parameters in patients with rheumatoid arthritis, osteoarthritis, chronic renal failure or liver disease are essentially the same.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3888490

  16. Enhanced Pharmacokinetics of Factor VIIa as a Monomeric Fc Fusion.

    PubMed

    Salas, Joe; Liu, Tongyao; Lu, Qi; Kulman, John D; Ashworth, Tamera; Kistanova, Elena; Moore, Nancy; Pierce, Glenn F; Jiang, Haiyan; Peters, Robert

    2015-05-01

    Recombinant Factor VIIa (rFVIIa) is utilized for on-demand treatment of bleeding episodes in hemophilia patients with neutralizing antibodies (inhibitors) against Factor VIII or Factor IX, but a short half-life in the circulation (~2.5hrs) limits its use in a prophylactic setting. Recombinant FVIIa variants with improved pharmacokinetic properties may enable improved treatment and prevention of bleeding episodes in the inhibitor population. In this study we describe recombinant FVIIaFc (rFVIIaFc), a recombinant Fc-fusion protein generated to utilize the neonatal Fc receptor (FcRn)-mediated recycling pathway that protects immunoglobulin G from catabolism. On the basis of activity, rFVIIaFc exhibited a 5.5-fold extension in terminal half-life in hemophilia A mice compared to rFVIIa. The potency of rFVIIaFc was comparable to that of rFVIIa in thrombin generation assay and ROTEM. In agreement with these data, rFVIIaFc and rFVIIa showed similar acute efficacy at comparable molar doses in the tail clip bleeding model in hemophilia A mice. Taken together, these studies demonstrate enhanced pharmacokinetics and similar hemostatic properties for rFVIIaFc compared to rFVIIa. PMID:25721936

  17. Tools to evaluate pharmacokinetics data for establishing maximum residue limits for approved veterinary drugs: examples from JECFA's work.

    PubMed

    Sanders, P; Henri, J; Laurentie, M

    2016-05-01

    Maximum residue limits (MRLs) for residues of veterinary drugs are the maximum concentrations of residues permitted in or on a food by national or regional legislation. In the process of MRLs recommendations by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), analysis of pharmacokinetic data describing the ADME process (absorption, distribution, metabolism and excretion) is a crucial step and requires the use of different pharmacokinetic tools. The results of animal metabolism studies are the prime determinants of the residue definition in food commodities. Substances labelled with radioactive isotopes are used so that the disposition of the residue can be followed as total residue and main metabolites concentrations. Residue depletion studies with radiolabelled parent drug will lead to the estimate of the time course of the total residue and to determine a marker residue. Depletion studies with an unlabelled drug provide more information on the time course of the marker residue in raw commodities after administration under approved practical conditions of use. By use of this information and after conversion with the total/residue marker ratio, MRLs are derived by comparison of the acceptable daily intake with the daily intakes calculated with different scenarios of dietary exposure. Progress in pharmacokinetic model such as physiologically based pharmacokinetics and population pharmacokinetics will drive the future research in this field to improved veterinary drug development. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27443212

  18. Baby-Crying Acceptance

    NASA Astrophysics Data System (ADS)

    Martins, Tiago; de Magalhães, Sérgio Tenreiro

    The baby's crying is his most important mean of communication. The crying monitoring performed by devices that have been developed doesn't ensure the complete safety of the child. It is necessary to join, to these technological resources, means of communicating the results to the responsible, which would involve the digital processing of information available from crying. The survey carried out, enabled to understand the level of adoption, in the continental territory of Portugal, of a technology that will be able to do such a digital processing. It was used the TAM as the theoretical referential. The statistical analysis showed that there is a good probability of acceptance of such a system.

  19. High acceptance recoil polarimeter

    SciTech Connect

    The HARP Collaboration

    1992-12-05

    In order to detect neutrons and protons in the 50 to 600 MeV energy range and measure their polarization, an efficient, low-noise, self-calibrating device is being designed. This detector, known as the High Acceptance Recoil Polarimeter (HARP), is based on the recoil principle of proton detection from np[r arrow]n[prime]p[prime] or pp[r arrow]p[prime]p[prime] scattering (detected particles are underlined) which intrinsically yields polarization information on the incoming particle. HARP will be commissioned to carry out experiments in 1994.

  20. Pharmacokinetic and pharmacodynamic assessment of bioavailability for two prodrugs of methylprednisolone

    PubMed Central

    Daley-Yates, P. T.; Gregory, A. J.; Brooks, C. D.

    1997-01-01

    Aims The aim of this study was to establish whether pharmacokinetic differences between two pro-drugs of methylprednisolone (MP) are likely to be of clinical significance. Methods This study was a single-blind, randomized, crossover design comparing the bioequivalence of MP released from the pro-drugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) after a single 250 mg (MP equivalent) intramuscular injection to 20 healthy male volunteers. Bioequivalence was assessed by conventional pharmacokinetic analysis, by measuring pharmacodynamic responses plus a novel approach using pharmacokinetic/pharmacodynamic modeling. The main measure of pharmacodynamic response was whole blood histamine (WBH), a measure of basophil numbers. Results The MP Cmax was less for MP suleptanate due to a longer absorption half-life of the prodrug from the intramuscular injection site. The bioavailability of MP was equivalent when based on AUC with a MP suleptanate median 108% of the MP succinate value (90% CI: 102–114%). For Cmax the MP suleptanate median was 81% of the MP succinate value (90% CI: 75–88%). The tmax for MP from MP suleptanate was delayed relative to MP succinate. The median difference was 200% (90% non-parametric CI: 141–283%). The area under the WBH effect-time curve (AUEC) and the maximum response (Emax ) were found to be equivalent (90% CI: 98–113% and 93–109% respectively). The maximum changes in other white blood cell counts, blood glucose concentration and the parameters of the pharmacodynamic sigmoid Emax model (EC50, Emax and γ) were also not significantly different between prodrugs. Conclusions MP suleptanate is an acceptable pharmaceutical alternative to MP succinate. The use of both pharmacokinetic and pharmacodynamic response data together gives greater confidence in the conclusions compared with those based only on conventional pharmacokinetic bioequivalence analysis. PMID:9205819

  1. Euthanasia Method for Mice in Rapid Time-Course Pulmonary Pharmacokinetic Studies

    PubMed Central

    Schoell, Adam R; Heyde, Bruce R; Weir, Dana E; Chiang, Po-Chang; Hu, Yiding; Tung, David K

    2009-01-01

    To develop a means of euthanasia to support rapid time-course pharmacokinetic studies in mice, we compared retroorbital and intravenous lateral tail vein injection of ketamine–xylazine with regard to preparation time, utility, tissue distribution, and time to onset of euthanasia. Tissue distribution and time to onset of euthanasia did not differ between administration methods. However, retroorbital injection could be performed more rapidly than intravenous injection and was considered to be a technically simple and superior alternative for mouse euthanasia. Retroorbital ketamine–xylazine, CO2 gas, and intraperitoneal pentobarbital then were compared as euthanasia agents in a rapid time-point pharmacokinetic study. Retroorbital ketamine–xylazine was the most efficient and consistent of the 3 methods, with an average time to death of approximately 5 s after injection. In addition, euthanasia by retroorbital ketamine–xylazine enabled accurate sample collection at closely spaced time points and satisfied established criteria for acceptable euthanasia technique. PMID:19807971

  2. Euthanasia method for mice in rapid time-course pulmonary pharmacokinetic studies.

    PubMed

    Schoell, Adam R; Heyde, Bruce R; Weir, Dana E; Chiang, Po-Chang; Hu, Yiding; Tung, David K

    2009-09-01

    To develop a means of euthanasia to support rapid time-course pharmacokinetic studies in mice, we compared retroorbital and intravenous lateral tail vein injection of ketamine-xylazine with regard to preparation time, utility, tissue distribution, and time to onset of euthanasia. Tissue distribution and time to onset of euthanasia did not differ between administration methods. However, retroorbital injection could be performed more rapidly than intravenous injection and was considered to be a technically simple and superior alternative for mouse euthanasia. Retroorbital ketamine-xylazine, CO(2) gas, and intraperitoneal pentobarbital then were compared as euthanasia agents in a rapid time-point pharmacokinetic study. Retroorbital ketamine-xylazine was the most efficient and consistent of the 3 methods, with an average time to death of approximately 5 s after injection. In addition, euthanasia by retroorbital ketamine-xylazine enabled accurate sample collection at closely spaced time points and satisfied established criteria for acceptable euthanasia technique. PMID:19807971

  3. Integration of Physiologically-Based Pharmacokinetic Modeling into Early Clinical Development: An Investigation of the Pharmacokinetic Nonlinearity

    PubMed Central

    Zhou, L; Gan, J; Yoshitsugu, H; Gu, X; Lutz, JD; Masson, E; Humphreys, WG

    2015-01-01

    BMS-911543, a promising anticancer agent, exhibited time-dependent and dose-dependent nonlinear pharmacokinetics (PKs) in its first-in-human (FIH) study. Initial physiologically based pharmacokinetic (PBPK) modeling efforts using CYP1A2-mediated clearance kinetics were unsuccessful; however, further model analysis revealed that CYP1A2 time-dependent inhibition (TDI) and perhaps other factors could be keys to the nonlinearity. Subsequent experiments in human liver microsomes showed that the compound was a time-dependent inhibitor of CYP1A2 and were used to determine the enzyme inactivation parameter values. In addition, a rat tissue distribution study was conducted and human plasma samples were profiled to support the refinement of the PBPK model. It was concluded that the interplay between four BMS-911543 properties, namely, low solubility, saturation of the metabolizing enzyme CYP1A2, CYP1A2 TDI, and CYP1A2 induction likely resulted in the time-dependent and dose-dependent nonlinear PKs. The methodology of PBPK model-guided unmasking of compound properties can serve as a general practice for mechanistic understanding of a new compound's disposition. PMID:26225254

  4. Pharmacokinetic modeling in aquatic animals. 1. Models and concepts

    USGS Publications Warehouse

    Barron, M.G.; Stehly, Guy R.; Hayton, W.L.

    1990-01-01

    While clinical and toxicological applications of pharmacokinetics have continued to evolve both conceptually and experimentally, pharmacokinetics modeling in aquatic animals has not progressed accordingly. In this paper we present methods and concepts of pharmacokinetic modeling in aquatic animals using multicompartmental, clearance-based, non-compartmental and physiologically-based pharmacokinetic models. These models should be considered as alternatives to traditional approaches, which assume that the animal acts as a single homogeneous compartment based on apparent monoexponential elimination.

  5. 41 CFR 102-38.205 - Must we accept all bids?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Must we accept all bids? 102-38.205 Section 102-38.205 Public Contracts and Property Management Federal Property Management... Bids Acceptance of Bids § 102-38.205 Must we accept all bids? No, the Government reserves the right...

  6. Special endpoint and product specific considerations in pharmaceutical acceptable daily exposure derivation.

    PubMed

    Gould, Janet; Callis, Courtney M; Dolan, David G; Stanard, Brad; Weideman, Patricia A

    2016-08-01

    Recently, a guideline has been published by the European Medicines Agency (EMA) on setting safe limits, permitted daily exposures (PDE) [also called acceptable daily exposures (ADE)], for medicines manufactured in multi-product facilities. The ADE provides a safe exposure limit for inadvertent exposure of a drug due to cross-contamination in manufacturing. The ADE determination encompasses a standard risk assessment, requiring an understanding of the toxicological and pharmacological effects, the mechanism of action, drug compound class, and the dose-response as well as the pharmacokinetic properties of the compound. While the ADE concept has broad application in pharmaceutical safety there are also nuances and specific challenges associated with some toxicological endpoints or drug product categories. In this manuscript we discuss considerations for setting ADEs when the following specific adverse health endpoints may constitute the critical effect: genotoxicity, developmental and reproductive toxicity (DART), and immune system modulation (immunostimulation or immunosuppression), and for specific drug classes, including antibody drug conjugates (ADCs), emerging medicinal therapeutic compounds, and compounds with limited datasets. These are challenging toxicological scenarios that require a careful evaluation of all of the available information in order to establish a health-based safe level. PMID:27233924

  7. Pharmacokinetics of intravenous and subcutaneous cefovecin in alpacas.

    PubMed

    Cox, S; Sommardahl, C; Seddighi, R; Videla, R; Hayes, J; Pistole, N; Hamill, M; Doherty, T

    2015-08-01

    The purpose of this study was to determine the pharmacokinetics of cefovecin after intravenous and subcutaneous dose of 8 mg/kg to alpacas. Bacterial infections requiring long-term antibiotic therapy such as neonatal bacteremia, pneumonia, peritonitis, dental, and uterine infections are a significant cause of morbidity and mortality in this species. However, few antimicrobials have been evaluated and proven to have favorable pharmacokinetics for therapeutic use. Most antimicrobials that are currently used require daily injections for many days. Cefovecin is a long-acting cephalosporin that is formulated for subcutaneous administration, and its long-elimination half-life allows for 14-day dosing intervals in dogs and cats. The properties of cefovecin may be advantageous for medical treatment of camelids due to its broad spectrum, route of administration, and long duration of activity. Pharmacokinetic evaluation of antimicrobial drugs in camelids is essential for the proper treatment and prevention of bacterial disease, and to minimize development of antibiotic resistant bacterial strains due to inadequate antibiotic concentrations. Cefovecin mean half-life, volume of distribution at steady-state, and clearance after intravenous administration were 10.3 h, 86 mL/kg, and 7.07 mL·h/kg. The bioavailability was 143%, while half-life, C(max), and T(max) were 16.9 h, 108 μg/mL, and 2.8 h following subcutaneous administration. In the absence of additional microbial susceptibility data for alpaca pathogens, the current cefovecin dosage regimen prescribed for dogs (8 mg/kg SC every 14 days) may need to be optimized for the treatment of infections in this species. PMID:25407784

  8. Preclinical Pharmacokinetic Analysis of NOV-002, a Glutathione Disulfide Mimetic

    PubMed Central

    Uys, Joachim D.; Manevich, Yefim; DeVane, Lindsay C.; He, Lin; Garret, Tracy E.; Pazoles, Christopher J.; Tew, Kenneth D.; Townsend, Danyelle M.

    2010-01-01

    Summary NOV-002 is a glutathione disulfide (GSSG) mimetic that is in Phase III clinical trials for the treatment of advanced non-small cell lung cancer and other oncology indications. GSSG is reduced by glutathione reductase (GR) to form glutathione (GSH), thereby maintaining redox homeostasis. The purpose of the study was to report the pharmacokinetic properties of NOV-002 and evaluate the effect that NOV-002 elicits in redox homeostasis. The pharmacokinetic analysis and tissue distribution of NOV-002 and GSH was evaluated in mice following a dose of 250 mg/kg, i.p. The redox potential and total protein thiol status was calculated. Here we show that NOV-002 is a substrate for GR and that GSH is a primary metabolite. Nonlinear pharmacokinetic modeling predicted that the estimated absorption and elimination rate constants correspond to a half-life of ~13 mins with an AUC of 1.18 μg.h/ml, a Cmax of 2.16 μg/ml and a volume of distribution of 42.61 L/kg. In addition, measurement of the redox potential and total protein thiol status indicated the generation of a transient oxidative signal in the plasma compartment after administration of NOV-002. These results indicate that NOV-002 exerts kinetic and dynamic effects in mice consistent with the GSSG component as the active pharmacological constituent of the drug. A longer-lasting decrease in total plasma free thiol content was also seen, suggesting that the oxidative effect of the GSSG from NOV-002 was impacting redox homeostasis. PMID:20359856

  9. Preclinical pharmacokinetic analysis of NOV-002, a glutathione disulfide mimetic.

    PubMed

    Uys, J D; Manevich, Y; Devane, L C; He, L; Garret, T E; Pazoles, C J; Tew, K D; Townsend, D M

    2010-09-01

    NOV-002 is a glutathione disulfide (GSSG) mimetic that is the subject of clinical investigation in oncology indications. GSSG is reduced by glutathione reductase (GR) to form glutathione (GSH), thereby maintaining redox homeostasis. The purpose of the study was to report the pharmacokinetic properties of NOV-002 and evaluate the effect that NOV-002 elicits in redox homeostasis. The pharmacokinetic analysis and tissue distribution of NOV-002 and GSH was evaluated in mice following a dose of 250 mg/kg, i.p. The redox potential and total protein thiol status was calculated. Here we show that NOV-002 is a substrate for GR and that GSH is a primary metabolite. Non-linear pharmacokinetic modeling predicted that the estimated absorption and elimination rate constants correspond to a half-life of approximately 13 min with an AUC of 1.18 μgh/mL, a C(max) of 2.16 μg/ml and a volume of distribution of 42.61 L/kg. In addition, measurement of the redox potential and total protein thiol status indicated the generation of a transient oxidative signal in the plasma compartment after administration of NOV-002. These results indicate that NOV-002 exerts kinetic and dynamic effects in mice consistent with the GSSG component as the active pharmacological constituent of the drug. A longer-lasting decrease in total plasma free thiol content was also seen, suggesting that the oxidative effect of the GSSG from NOV-002 was impacting redox homeostasis. PMID:20359856

  10. Pharmacokinetics of Cefovecin in Cynomolgus Macaques (Macaca fascicularis), Olive Baboons (Papio anubis), and Rhesus Macaques (Macaca mulatto)

    SciTech Connect

    Raabe, Brigitte M.; Lovaglio, Jamie A.; Grover, GScott; Brown, Scott A.; Boucher, Joseph F.; Yuan, Yang; Civil, Jacqueline R.; Gillhouse, Kimberly A.; Stubbs, Makeida N.; Hoggatt, Amber F.; Halliday, Lisa C.; Fortman, Jeffrey D.

    2011-05-01

    Cefovecin sodium is a long-acting, third-generation, cephalosporin antibiotic approved for the treatment of skin infections in dogs and cats. The pharmacokinetic properties of cefovecin were evaluated in cynomolgus macaques (Macaca fascicularis), olive baboons (Papio anubis), and rhesus macaques (Macaca mulatto) by using a single-dose (8 mg/kg SC) dosing regimen. Plasma cefovecin concentrations were determined by using ultra-performance liquid chromatography with tandem mass spectrometry, and a noncompartmental model was used to determine pharmacokinetic parameters. The half-life of cefovecin was 4.95 {+-} 1.47 h in cynomolgus macaques, 9.17 {+-} 1.84 h in olive baboons, and 8.40 {+-} 2.53 h in rhesus macaques. These values are considerably lower than the half-lives previously published for dogs (133 h) and cats (166 h). The extended half-life of cefovecin in dogs and cats is speculated to be due to active reabsorption of drug in the kidney tubules because plasma clearance is well below the normal glomerular filtration rate. In nonhuman primates, renal clearance rates approximated plasma clearance rates, suggesting that active renal reabsorption of cefovecin does not occur in these species. The pharmacokinetic properties of cefovecin in nonhuman primates are vastly different from the pharmacokinetic properties in dogs and cats, precluding its use as a long-acting antibiotic in nonhuman primates. This study highlights the importance of performing pharmacokinetic studies prior to extralabel drug usage.

  11. Simultaneous Characterization of Intravenous and Oral Pharmacokinetics of Lychnopholide in Rats by Transit Compartment Model.

    PubMed

    Lachi-Silva, Larissa; Sy, Sherwin K B; Voelkner, Alexander; de Sousa, João Paulo Barreto; Lopes, João Luis C; Silva, Denise B; Lopes, Norberto P; Kimura, Elza; Derendorf, Hartmut; Diniz, Andrea

    2015-08-01

    The pharmacokinetic properties of a new molecular entity are important aspects in evaluating the viability of the compound as a pharmacological agent. The sesquiterpene lactone lychnopholide exhibits important biological activities. The objective of this study was to characterize the pharmacokinetics of lychnopholide after intravenous administration of 1.65 mg/kg (n = 5) and oral administration of 3.3 mg/kg (n = 3) lychnopholide in rats (0.2 ± 0.02 kg in weight) through nonlinear mixed effects modeling and non-compartmental pharmacokinetic analysis. A highly sensitive analytical method was used to quantify the plasma lychnopholide concentrations in rats. Plasma protein binding of this compound was over 99 % as determined by a filtration method. A two-compartment body model plus three transit compartments to characterize the absorption process best described the disposition of lychnopholide after both routes of administration. The oral bioavailability was approximately 68 %. The clearance was 0.131 l/min and intercompartmental clearance was 0.171 l/min; steady-state volume of distribution was 4.83 l. The mean transit time for the absorption process was 9.15 minutes. No flip-flop phenomenon was observed after oral administration. The pharmacokinetic properties are favorable for further development of lychnopholide as a potential oral pharmacological agent. PMID:26218336

  12. Steady-state pharmacokinetics of lithium carbonate in healthy subjects.

    PubMed Central

    Hunter, R

    1988-01-01

    1. The pharmacokinetics of lithium in six healthy volunteers stabilised on lithium were investigated and appropriate pharmacokinetic parameters calculated. 2. The results illustrate important differences in single and multiple dose lithium pharmacokinetics; the implications for minimising lithium-induced renal damage are discussed. PMID:3129009

  13. Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi-mechanistic pharmacokinetic modeling.

    PubMed

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

    2014-11-01

    Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 ± 3.4 nmol/min/mg, 204 ± 22 μM, and 233 ± 9 μl/min/mg with intestinal microsomes and 2.92 ± 0.07 nmol/min/mg, 22.7 ± 1.2 μM, and 129 ± 4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses. PMID:25274606

  14. Pharmacokinetic and Pharmacodynamic Properties of Calaspargase Pegol Escherichia coli L-Asparaginase in the Treatment of Patients With Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Study AALL07P4

    PubMed Central

    Angiolillo, Anne L.; Schore, Reuven J.; Devidas, Meenakshi; Borowitz, Michael J.; Carroll, Andrew J.; Gastier-Foster, Julie M.; Heerema, Nyla A.; Keilani, Taha; Lane, Ashley R.; Loh, Mignon L.; Reaman, Gregory H.; Adamson, Peter C.; Wood, Brent; Wood, Charlotte; Zheng, Hao W.; Raetz, Elizabeth A.; Winick, Naomi J.; Carroll, William L.; Hunger, Stephen P.

    2014-01-01

    Purpose Asparaginase is a critical agent used to treat acute lymphoblastic leukemia (ALL). Pegaspargase (SS-PEG), a pegylated form of Escherichia coli L-asparaginase with a succinimidyl succinate (SS) linker, is the first-line asparaginase product used in Children's Oncology Group (COG) ALL trials. Calaspargase pegol (SC-PEG) replaces the SS linker in SS-PEG with a succinimidyl carbamate linker, creating a more stable molecule. COG AALL07P4 was designed to determine the pharmacokinetic and pharmacodynamic comparability of SC-PEG to SS-PEG in patients with newly diagnosed high-risk (HR) B-cell ALL. Patients and Methods A total of 165 evaluable patients were randomly assigned at a 2:1 ratio to receive SC-PEG at 2,100 (SC-PEG2100; n = 69) or 2,500 IU/m2 (SC-PEG2500; n = 42) versus SS-PEG 2,500 IU/m2 (SS-PEG2500; n = 54) as part of an otherwise identical chemotherapy regimen. The groups were similar demographically, except more female patients received SC-PEG2500. Results The mean half-life of plasma asparaginase activity for both SC-PEG doses was approximately 2.5× longer than that of SS-PEG2500. The total systemic exposure, as defined by induction area under the curve from time 0 to 25 days, was greater with SC-PEG2500 than with SS-PEG2500 or SC-PEG2100. The proportion of patients with plasma asparaginase activity ≥ 100 mIU/mL and ≥ 400 mIU/mL was higher in patients who received SC-PEG as compared with SS-PEG2500. After one dose of pegylated asparaginase on induction day 4, plasma asparagine was undetectable for 11 days for SS-PEG2500 and 18 days for both SC-PEG groups. Conclusion SC-PEG2500 achieves a significantly longer period of asparaginase activity above defined thresholds and asparagine depletion compared with SS-PEG2500 and has a comparable toxicity profile in children with HR B-cell ALL. PMID:25348002

  15. Developing reimbursable clinical pharmacy programs: pharmacokinetic dosing service.

    PubMed

    Moore, T D; Schneider, P J; Nold, E G

    1979-11-01

    The development, operation and evaluation of a pharmacy-conducted pharmacokinetic dosing service is described. Pharmacists recommend individualized drug dosing regimens based on pharmacokinetic models and equations clinically tested for accuracy by the pharmacy department. Pharmacokinetic values are determined with the aid of online computer programs developed by the department. Drug assays are provided by the hospital's laboratory. All of the department's pharmacists were trained to provide the 24-hour service. The pharmacy department's $20 pharmacokinetic dosing service fee is reimbursed by Blue Cross. The pharmacokinetic dosing service is the first nonteaching, nonproduct-oriented pharmaceutical service whose cost-effectiveness has been recognized by a third-party payer. PMID:517538

  16. New insight into the clinical pharmacokinetics of cefaclor: tissue penetration.

    PubMed

    Mazzei, T; Novelli, A; Esposito, S; Periti, P

    2000-02-01

    The serum pharmacokinetic data presented are generally in agreement with those obtained by other authors with both the cefaclor IR (immediate release) and AF (advanced formulation) or MR (modified release) formulations. With the new sustained-release formulation, the time of peak (Tmax) and mean residence time (MRT) values are significantly longer than those observed with the standard cefaclor IR. For the first time the penetration of the MR formulation of cefaclor was determined both in suction blister fluid (SBF) and alveolar epithelial lining fluid (ELF). Cefaclor demonstrated a high tissue distribution, with a high penetration index (PI) into blister fluid, which is at least representative of a relatively large volume of fluid-filled spaces and in part of highly vascularized tissues. SBF and ELF concentrations were higher than blood levels starting at the 4th-6th hour after dose, with longer elimination half-lives from the extravascular compartment than from serum. Cefaclor has a favorable pharmacokinetic profile, especially the new sustained-release formulation, which maintains effective concentrations for a longer time than the IR preparation. The MR formulation improves the kinetic properties of the cefaclor molecule with a prolonged MRT which allows a daily dosage of 750 mg every 12 h. PMID:10768516

  17. Moxidectin: a review of chemistry, pharmacokinetics and use in horses

    PubMed Central

    Cobb, Rami; Boeckh, Albert

    2009-01-01

    This article reviews the current knowledge of the use of moxidectin (MOX) in horses, including its mode of action, pharmacokinetic and pharmacodynamic properties, efficacy, safety and resistance profile. Moxidectin is a second generation macrocyclic lactone (ML) with potent endectocide activity. It is used for parasite control in horses in an oral gel formulation. The principal mode of action of MOX and of other MLs is binding to gamma-aminobutyric (GABA) and glutamate-gated chloride channels. Moxidectin is different from other MLs in that it is a poor substrate for P-glycoproteins (P-gps) and therefore less susceptible to elimination from parasite cells through this mechanism. Due to its unique physicochemical and pharmacokinetic characteristics, MOX provides broad distribution into tissues, long half-life, significant residual antiparasitic activity, and high efficacy against encysted cyathostomin larvae. These characteristics allow for high efficacy and longer treatment interval against all important nematodes, when compared to other equine anthelmintics. A combination of MOX with praziquantel provides expanded spectrum of activity by adding activity against cestodes. Appropriate use of MOX allows for the development of strategic anthelmintic programmes that are different from those with conventional anthelmintics. Fewer treatments are required over a period of time, and therefore impose less frequent selection pressure for resistance. PMID:19778466

  18. Pharmacokinetic study of adenosine diphosphate-encapsulated liposomes coated with fibrinogen γ-chain dodecapeptide as a synthetic platelet substitute in an anticancer drug-induced thrombocytopenia rat model.

    PubMed

    Taguchi, Kazuaki; Ujihira, Hayato; Watanabe, Hiroshi; Fujiyama, Atsushi; Doi, Mami; Takeoka, Shinji; Ikeda, Yasuo; Handa, Makoto; Otagiri, Masaki; Maruyama, Toru

    2013-10-01

    A fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV, H12)-coated, adenosine diphosphate (ADP)-encapsulated liposome [H12-(ADP)-liposome] was designed to achieve optimal performance as a homeostatic agent and expected as a synthetic platelet alternative. For the purpose of efficient function as platelet substitute, H12-(ADP)-liposomes should potentially have both acceptable pharmacokinetic and biodegradable properties under conditions of an adaptation disease including thrombocytopenia induced by anticancer drugs. The aim of this study was to characterize the pharmacokinetics of H12-(ADP)-liposomes in busulphan-induced thrombocytopenic rats using (14) C, (3) H double radiolabeled H12-(ADP)-liposomes, in which the encapsulated ADP and liposomal membrane (cholesterol) were labeled with (14) C and (3) H, respectively. After the administration of H12-(ADP)-liposomes, they were determined to be mainly distributed to the liver and spleen and disappeared from organs within 7 days after injection. The encapsulated ADP was mainly eliminated in the urine, whereas the outer membrane (cholesterol) was mainly eliminated in feces. The successive dispositions of the H12-(ADP)-liposomes were similar in both normal and thrombocytopenic rats. However, the kinetics of H12-(ADP)-liposomes in thrombocytopenic rats was more rapid, compared with the corresponding values for normal rats. These findings, which well reflect the clinical features of patients with anticancer drug-induced thrombocytopenia, provide useful information for the development of the H12-(ADP)-liposomes for future clinical use. PMID:23918456

  19. Ethnic and genetic factors in methadone pharmacokinetics: A population pharmacokinetic study☆

    PubMed Central

    Bart, Gavin; Lenz, Scott; Straka, Robert J.; Brundage, Richard C.

    2014-01-01

    Background Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population. Methods Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of racmethadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics. Results In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G > T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G > T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone. Conclusion This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability. PMID:25456329

  20. A Qualitative Review on the Pharmacokinetics of Antibiotics in Saliva: Implications on Clinical Pharmacokinetic Monitoring in Humans.

    PubMed

    Kiang, Tony K L; Ensom, Mary H H

    2016-03-01

    We conducted a systematic search to describe the current state of knowledge regarding the utility of saliva for clinical pharmacokinetic monitoring (CPM) of antibiotics. Although the majority of identified studies lacked sufficient pharmacokinetic data needed to assign an appropriate suitability classification, most aminoglycosides, fluoroquinolones, macrolides, penicillins/cephalosporins, and tetracyclines are likely not suitable for CPM in saliva. No clear pattern of correlation was observed between physiochemical properties that favor drug distribution into saliva and the likelihood of the antibiotic being classified as suitable for CPM in saliva (and vice versa). Insufficient data were available to determine if pathophysiological conditions affected salivary distribution of antibiotics. Additional confirmatory data are required for drugs (especially in patients) that are deemed likely suitable for CPM in saliva because only a few studies were available and many focused only on healthy subjects. All studies identified had relatively small sample sizes and exhibited large variability. Very few studies reported salivary collection parameters (e.g., salivary flow, pH) that could potentially have some impact on drug distribution into saliva. The available data are heavily weighted on healthy subjects, and insufficient data were available to determine if pathophysiology had effects on saliva drug distribution. Some studies also lacked assay sensitivity for detecting antibiotics in saliva. Overall, this review can be useful to clinicians who desire an overview on the suitability of saliva for conducting CPM of specific antibiotics, or for researchers who wish to fill the identified knowledge gaps to move the science of salivary CPM further. PMID:26346776

  1. Sonic boom acceptability studies

    NASA Astrophysics Data System (ADS)

    Shepherd, Kevin P.; Sullivan, Brenda M.; Leatherwood, Jack D.; McCurdy, David A.

    1992-04-01

    The determination of the magnitude of sonic boom exposure which would be acceptable to the general population requires, as a starting point, a method to assess and compare individual sonic booms. There is no consensus within the scientific and regulatory communities regarding an appropriate sonic boom assessment metric. Loudness, being a fundamental and well-understood attribute of human hearing was chosen as a means of comparing sonic booms of differing shapes and amplitudes. The figure illustrates the basic steps which yield a calculated value of loudness. Based upon the aircraft configuration and its operating conditions, the sonic boom pressure signature which reaches the ground is calculated. This pressure-time history is transformed to the frequency domain and converted into a one-third octave band spectrum. The essence of the loudness method is to account for the frequency response and integration characteristics of the auditory system. The result of the calculation procedure is a numerical description (perceived level, dB) which represents the loudness of the sonic boom waveform.

  2. Sonic boom acceptability studies

    NASA Technical Reports Server (NTRS)

    Shepherd, Kevin P.; Sullivan, Brenda M.; Leatherwood, Jack D.; Mccurdy, David A.

    1992-01-01

    The determination of the magnitude of sonic boom exposure which would be acceptable to the general population requires, as a starting point, a method to assess and compare individual sonic booms. There is no consensus within the scientific and regulatory communities regarding an appropriate sonic boom assessment metric. Loudness, being a fundamental and well-understood attribute of human hearing was chosen as a means of comparing sonic booms of differing shapes and amplitudes. The figure illustrates the basic steps which yield a calculated value of loudness. Based upon the aircraft configuration and its operating conditions, the sonic boom pressure signature which reaches the ground is calculated. This pressure-time history is transformed to the frequency domain and converted into a one-third octave band spectrum. The essence of the loudness method is to account for the frequency response and integration characteristics of the auditory system. The result of the calculation procedure is a numerical description (perceived level, dB) which represents the loudness of the sonic boom waveform.

  3. Microcomputer-Based Programs for Pharmacokinetic Simulations.

    ERIC Educational Resources Information Center

    Li, Ronald C.; And Others

    1995-01-01

    Microcomputer software that simulates drug-concentration time profiles based on user-assigned pharmacokinetic parameters such as central volume of distribution, elimination rate constant, absorption rate constant, dosing regimens, and compartmental transfer rate constants is described. The software is recommended for use in undergraduate…

  4. A Terminal Pharmaceutics Course in Clinical Pharmacokinetics.

    ERIC Educational Resources Information Center

    Reuning, Richard H.; Krautheim, Daniel

    1978-01-01

    At Ohio State University, an undergraduate course extends the course sequence in biopharmaceutics and pharmacokinetics to application to problems in optimizing drug therapy. Course content, structure, instructional methods, and student term projects are described, and a course outline, typical projects, and some behavioral objectives are appended.…

  5. Pharmacokinetics of Drug Entry into Cochlear Fluids

    ERIC Educational Resources Information Center

    Salt, Alec N.

    2005-01-01

    The inner ear is exposed to aminoglycosides or other drugs either intentionally or as a side effect of clinical treatments directed at other regions of the body. An understanding of the effects of drugs on the inner ear requires knowledge of the pharmacokinetics of the drug once it reaches the cochlear fluids, specifically how much of it reaches…

  6. Pharmacokinetics of Peptide-Fc fusion proteins.

    PubMed

    Wu, Benjamin; Sun, Yu-Nien

    2014-01-01

    Peptide-Fc fusion proteins (or peptibodies) are chimeric proteins generated by fusing a biologically active peptide with the Fc-domain of immunoglobulin G. In this review, we describe recent studies that have evaluated the absorption, distribution, metabolism, and excretion characteristics of peptibodies. Key features of the pharmacokinetics of peptibodies include their extended half-life due to recycling by the neonatal Fc receptor (FcRn), a substantial contribution by renal excretion to total clearance and, for certain peptibodies, target-mediated drug disposition. The prolonged half-life of peptibodies permits less-frequent dose administration compared with small therapeutic peptides, thereby supporting patient convenience and compliance. Hence, a considerable number of peptibodies are currently in preclinical and clinical development. Investigation of the metabolism (biotransformation) of biologics is an evolving area of research: ligand-binding mass spectrometry techniques have been employed for the characterization of the peptibody romiplostim, providing a new approach to evaluation of the degradation products of biologics. Pharmacokinetic/pharmacodynamic modeling and simulation techniques have been used to predict the pharmacokinetics of peptibodies which can inform clinical decision-making, particularly selection of dosing regimens. This integrated review highlights the distinct pharmacokinetic characteristics of peptibodies and their influence on the drug development process for this emerging family of therapeutics. PMID:24285510

  7. Pharmacokinetics of melatonin in preterm infants

    PubMed Central

    Merchant, Nazakat M; Azzopardi, Denis V; Hawwa, Ahmed F; McElnay, James C; Middleton, Benita; Arendt, J; Arichi, Tomoki; Gressens, Pierre; Edwards, A David

    2013-01-01

    Aims Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. Methods Melatonin was administered to 18 preterm infants in doses ranging from 0.04–0.6 μg kg−1 over 0.5–6 h. Pharmacokinetic profiles were analyzed individually and by population methods. Results Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 μg kg−1 h−1 for 2 h showed a median half-life of 15.82 h and median maximum plasma concentration of 203.3 pg ml−1. On population pharmacokinetics, clearance was 0.045 l h−1, volume of distribution 1.098 l and elimination half-life 16.91 h with gender (P = 0.047) and race (P < 0.0001) as significant covariates. Conclusions A 2 h infusion of 0.1 μg kg−1 h−1 increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants. PMID:23432339

  8. FIRST REPORTS OF CLINICAL PHARMACOKINETICS IN NIGERIA

    PubMed Central

    Michael, O.S.

    2015-01-01

    The German Friedrich Hartmut Dost (1910-1985) introduced the word Pharmacokinetics. Clinical pharmacokinetics is the direct application of knowledge regarding a drug's pharmacokinetics to a therapeutic situation in an individual or a population. It is the basis of therapeutic drug monitoring with the ultimate goal of keeping drugs safe. This branch of pharmacology has become the most relevant to the sub-specialty of clinical pharmacology. First reports of Clinical Pharmacokinetics in Nigeria can be credited to two gifted Nigerians, Prof Ayodele O. Iyun and Prof Lateef A. Salako, both of whom were affiliated to the great institutions- University of Ibadan (UI) and the Teaching Hospital, University College Hospital (UCH). Prof A.O Iyun was Nigeria's first home-trained Clinical Pharmacologist, while Prof L.A. Salako played a most significant role in the creation of the Department of Clinical Pharmacology, UCH. This edition of the Chronicles highlights a few of the first reports of this exciting branch of pharmacology in Nigeria. This historical review is based on publications listed on the United States National Library of Medicine database (PUBMED). PMID:26807087

  9. FIRST REPORTS OF CLINICAL PHARMACOKINETICS IN NIGERIA.

    PubMed

    Michael, O S

    2015-06-01

    The German Friedrich Hartmut Dost (1910-1985) introduced the word Pharmacokinetics. Clinical pharmacokinetics is the direct application of knowledge regarding a drug's pharmacokinetics to a therapeutic situation in an individual or a population. It is the basis of therapeutic drug monitoring with the ultimate goal of keeping drugs safe. This branch of pharmacology has become the most relevant to the sub-specialty of clinical pharmacology. First reports of Clinical Pharmacokinetics in Nigeria can be credited to two gifted Nigerians, Prof Ayodele O. Iyun and Prof Lateef A. Salako, both of whom were affiliated to the great institutions- University of Ibadan (UI) and the Teaching Hospital, University College Hospital (UCH). Prof A.O Iyun was Nigeria's first home-trained Clinical Pharmacologist, while Prof L.A. Salako played a most significant role in the creation of the Department of Clinical Pharmacology, UCH. This edition of the Chronicles highlights a few of the first reports of this exciting branch of pharmacology in Nigeria. This historical review is based on publications listed on the United States National Library of Medicine database (PUBMED). PMID:26807087

  10. Heritability of metoprolol and torsemide pharmacokinetics.

    PubMed

    Matthaei, J; Brockmöller, J; Tzvetkov, M V; Sehrt, D; Sachse-Seeboth, C; Hjelmborg, J B; Möller, S; Halekoh, U; Hofmann, U; Schwab, M; Kerb, R

    2015-12-01

    Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated. PMID:26344676

  11. 45 CFR 2544.150 - How will accepted donations be recorded and used?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 4 2013-10-01 2013-10-01 false How will accepted donations be recorded and used... FOR NATIONAL AND COMMUNITY SERVICE SOLICITATION AND ACCEPTANCE OF DONATIONS § 2544.150 How will accepted donations be recorded and used? (a) All accepted donations of money and other property will...

  12. 45 CFR 2544.150 - How will accepted donations be recorded and used?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 4 2012-10-01 2012-10-01 false How will accepted donations be recorded and used... FOR NATIONAL AND COMMUNITY SERVICE SOLICITATION AND ACCEPTANCE OF DONATIONS § 2544.150 How will accepted donations be recorded and used? (a) All accepted donations of money and other property will...

  13. 45 CFR 2544.150 - How will accepted donations be recorded and used?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 4 2011-10-01 2011-10-01 false How will accepted donations be recorded and used... FOR NATIONAL AND COMMUNITY SERVICE SOLICITATION AND ACCEPTANCE OF DONATIONS § 2544.150 How will accepted donations be recorded and used? (a) All accepted donations of money and other property will...

  14. 45 CFR 2544.150 - How will accepted donations be recorded and used?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 4 2014-10-01 2014-10-01 false How will accepted donations be recorded and used... FOR NATIONAL AND COMMUNITY SERVICE SOLICITATION AND ACCEPTANCE OF DONATIONS § 2544.150 How will accepted donations be recorded and used? (a) All accepted donations of money and other property will...

  15. Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review.

    PubMed

    Jhee, S S; Shiovitz, T; Crawford, A W; Cutler, N R

    2001-01-01

    The current approach to antimigraine therapy comprises potent serotonin 5-HT1B/1D receptor agonists collectively termed triptans. Sumatriptan was the first of these compounds to be developed, and offered improved efficacy and tolerability over ergot-derived compounds. The development of sumatriptan was quickly followed by a number of 'second generation' triptan compounds, characterised by improved pharmacokinetic properties and/or tolerability profiles. Triptans are believed to effect migraine relief by binding to serotonin (5-hydroxy-tryptamine) receptors in the brain, where they act to induce vasoconstriction of extracerebral blood vessels and also reduce neurogenic inflammation. Although the pharmacological mechanism of the triptans is similar, their pharmacokinetic properties are distinct. For example, bioavailability of oral formulations ranges between 14% (sumatriptan) and 74% (naratriptan), and their elimination half-life ranges from 2 hours (sumatriptan and rizatriptan) to 25 hours (frovatriptan). Clearly, such diverse pharmacokinetic properties will influence the effectiveness of the compounds and favour the prescription of one over another in different patient populations. This article reviews the pharmacological properties of the triptans (time to peak plasma concentration, half-life, bioavailability and receptor binding) and relates these properties to efficacy and time of onset. It also considers the effects of concomitant medication, food, age and disease on the pharmacokinetics of the compounds. In addition, the relative merits, such as headache recurrence, tolerability and route of administration, are discussed. Finally, the performance of the triptans is considered in the context of direct head-to-head comparative trials that have assessed the efficacy profile of the compounds. PMID:11327198

  16. Pharmacokinetics of hederacoside C, an active ingredient in AG NPP709, in rats.

    PubMed

    Kim, Ju Myung; Yoon, Ji Na; Jung, Ji Won; Choi, Hye Duck; Shin, Young June; Han, Chang Kyun; Lee, Hye Suk; Kang, Hee Eun

    2013-11-01

    1. Hederacoside C (HDC) is one of the active ingredients in Hedera helix leaf extract (Ivy Ex.) and AG NPP709, a new botanical drug to treat acute respiratory infection and chronic inflammatory bronchitis. However, information regarding its pharmacokinetic properties remains limited. 2. Here, we report the pharmacokinetics of HDC in rats after intravenous administration of HDC (3, 12.5, and 25 mg/kg) and after oral administration of HDC, Ivy Ex., and AG NPP709 (equivalent to 12.5, 25, and 50 mg/kg HDC). 3. Linear pharmacokinetics of HDC were identified upon its intravenous administration at doses of 3-25 mg/kg. Intravenous administration of HDC results in relatively slow clearance (1.46-2.08 mL/min/kg) and a small volume of distribution at steady state (138-222 mL/kg), while oral administration results in a low absolute oral bioavailability (F) of 0.118-0.250%. The extremely low F of HDC may be due to poor absorption of HDC from the gastrointestinal (GI) tract and/or its decomposition therein. 4. The oral pharmacokinetics of HDC did not differ significantly among pure HDC, Ivy Ex., and AG NPP709. PMID:23607546

  17. Influence of two commercial fibers in the pharmacokinetics of ethinylestradiol in rabbits.

    PubMed

    Fernández, N; Diez, M J; Terán, M T; García, J J; Calle, A P; Sierra, M

    1998-08-01

    Fiber formulations are used in human nutrition owing to their beneficial properties for health. It is probable that ingestion of fiber coincides with the oral administration of drugs, and a modification of its oral absorption, and therefore of its pharmacokinetics, can appear. In the present study, the compartmental and noncompartmental pharmacokinetic parameters of ethinylestradiol (EE) in rabbits after oral administration were determined. It was also studied whether the presence of two different fiber formulations [A, wheat bran (76.5%), fruit fiber (12%) and guar gum (2%) and B, Plantago ovata seeds (65%) and P. ovata seed cuticles (2.2%)] in the gastrointestinal tract modified the pharmacokinetics of EE when administered at the same time. Three groups of rabbits were used: control, fiber A and fiber B. The animals in all three groups received 1 mg/kg b. wt. EE. The estrogen was administered alone in the control group and in the presence of 4 g of fiber A and fiber B, respectively, in the other two groups. After compartmental (two-compartment open model) and noncompartmental analyses of plasma concentrations, statistical analysis revealed that the presence of fiber (both A and B) decreased between 29% and 35% the extent of EE absorbed (represented by the pharmacokinetic parameters area under the curve and the maximum plasma concentration) without affecting the rate of the absorption process (represented by the time to reach maximum concentration and the absorption rate constant). PMID:9694944

  18. Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy greyhound dogs.

    PubMed

    KuKanich, B; Allen, P

    2014-12-01

    The purpose of this study was to compare the pharmacokinetics of two highly protein-bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL·min/kg) was faster than buprenorphine (10.3 mL·min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including octanol-water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. PMID:24684621

  19. 39 CFR 777.51 - Acceptance of donations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 39 Postal Service 1 2011-07-01 2011-07-01 false Acceptance of donations. 777.51 Section 777.51 Postal Service UNITED STATES POSTAL SERVICE SPECIAL REGULATIONS RELOCATION ASSISTANCE AND REAL PROPERTY ACQUISITION POLICIES Donations § 777.51 Acceptance of donations. Nothing in these regulations shall prevent...

  20. 39 CFR 777.51 - Acceptance of donations.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 39 Postal Service 1 2013-07-01 2013-07-01 false Acceptance of donations. 777.51 Section 777.51... ACQUISITION POLICIES Donations § 777.51 Acceptance of donations. Nothing in these regulations shall prevent a person from making a gift or donation of real property or any part thereof, or any interest therein,...

  1. 39 CFR 777.51 - Acceptance of donations.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 39 Postal Service 1 2014-07-01 2014-07-01 false Acceptance of donations. 777.51 Section 777.51... ACQUISITION POLICIES Donations § 777.51 Acceptance of donations. Nothing in these regulations shall prevent a person from making a gift or donation of real property or any part thereof, or any interest therein,...

  2. 39 CFR 777.51 - Acceptance of donations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 39 Postal Service 1 2010-07-01 2010-07-01 false Acceptance of donations. 777.51 Section 777.51... ACQUISITION POLICIES Donations § 777.51 Acceptance of donations. Nothing in these regulations shall prevent a person from making a gift or donation of real property or any part thereof, or any interest therein,...

  3. 39 CFR 777.51 - Acceptance of donations.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 39 Postal Service 1 2012-07-01 2012-07-01 false Acceptance of donations. 777.51 Section 777.51 Postal Service UNITED STATES POSTAL SERVICE SPECIAL REGULATIONS RELOCATION ASSISTANCE AND REAL PROPERTY ACQUISITION POLICIES Donations § 777.51 Acceptance of donations. Nothing in these regulations shall prevent...

  4. Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: impact of human pharmacokinetics.

    PubMed

    Tenor, Hermann; Hatzelmann, Armin; Beume, Rolf; Lahu, Gezim; Zech, Karl; Bethke, Thomas D

    2011-01-01

    Since more than two decades anti-inflammatory effects of inhibitors of phosphodiesterase-4 have been described in numerous cellular and animal studies and were finally confirmed in clinical trials. The path from an early, pioneering study with Ro20-1724 showing reduction of psoriatric plaque size in 1979 to modern PDE4 inhibitors such as oral apremilast in development for psoriasis, the inhaled PDE4 inhibitor GSK256066 in development for asthma and COPD and finally roflumilast, the first PDE4 inhibitor approved and currently marketed as an oral, once-daily remedy for severe COPD was marked by large progress in chemical optimization based on improved understanding of PDE4 biology and drug-like properties determining the appropriate pharmacokinetic profile. In this chapter aspects of the pharmacology and clinical efficacy of PDE4 inhibitors, which have been in clinical development over the years are summarized with specific emphasis on their clinical pharmacokinetic properties. PMID:21695636

  5. Specific pharmacokinetic aspects of the urinary tract.

    PubMed

    Korstanje, Cees; Krauwinkel, Walter

    2011-01-01

    This chapter reviews the evidence for "specific" pharmacokinetics playing a role in currently marketed drugs intended to treat lower urinary tract (LUT) symptoms. Principles of drug targeting include intrinsic properties of drugs or organs as well as drug formulations to modify drug release or to create confinement of drug presence. Prodrugs and specific formulations to deliver high drug concentrations at the site(s) of action as well as other ways to manipulate drug distribution to achieve enrichment in target tissues are considered. In overactive bladder (OAB), specific formulations for oxybutynin have been introduced to reduce the level of side effects of the active drug. Extended release tablet formulations and a topical gel formulation have been introduced, with efficacy similar to immediate release (IR) tablets, but with a reduction in anticholinergic adverse effects. However, these modifications have not led to outstanding performance parameters compared to other anticholinergic drugs marketed as IR formulations. Urinary excretion is discussed as potential mechanism for targeting LUT symptoms, but no strong indications appear to exist that this mechanism would contribute for currently available drugs. Intravesical administration of drugs is not a preferred option and only considered for drugs like botulinum toxin, where the inconvenient application compensates for a reasonable degree of long-term efficacy in severe refractory OAB. Alpha acid glycoprotein binding is discussed as a potential factor to influence drug tissue distribution, and it is concluded that there is reasonable evidence that for tamsulosin this mechanism is responsible for the difference in free fraction of the drug observed in plasma and prostate, which could contribute to its relative absence of blood pressure effects in patients with LUT symptoms related to benign prostate hyperplasia (LUTS-BPH). The principle of irreversible inhibition of type II 5α-reductase as a tool to develop drugs

  6. 48 CFR 28.203-2 - Acceptability of assets.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... assets will be accepted at 100 percent of the most current tax assessment value (exclusive of encumbrances) or 75 percent of the properties' unencumbered market value provided a current appraisal...

  7. 48 CFR 28.203-2 - Acceptability of assets.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... assets will be accepted at 100 percent of the most current tax assessment value (exclusive of encumbrances) or 75 percent of the properties' unencumbered market value provided a current appraisal...

  8. Pharmacokinetics in risk assessment: drinking water and health. Volume 8

    SciTech Connect

    Not Available

    1987-01-01

    Contents include: risk assessment: historical perspectives; tissue dosimetry in risk assessment; modeling: an introduction; physiologically based pharmacokinetic modeling; allometry: body-size constraints in animal design; prediction of in vivo parameters of drug metabolism and distribution from in-vitro studies; dose, species, and route extrapolation; uncertainty in pharmacokinetic models using SIMUSOLV; interspecies and dose-route extrapolations; carcinogen DNA adducts as a measure of biological dose for risk analysis of carcinogenic data; resources available for simulation in toxicology; route-to-route extrapolation of dichloromethane exposure using a physiological pharmacokinetic model; sensitivity analysis in pharmacokinetic modeling; mutation accumulation: chronic cytotoxicant exposure; model for ethylene chloride and its application in risk assessment; mathematical modeling of ozone absorption in the lower respiratory tract; development of a physiologically based pharmacokinetic model for multiday inhalation of carbon tetrachloride; the delivered/administered dose relationship and its impact on formaldehyde risk estimates; pharmacokinetic simulation in risk assessment; hazard assessment: ozone; role of pharmacokinetic modeling in risk assessment; development of multispecies, multiroute pharmacokinetic models for methylene chloride and 1,1,1-trichloroethane (methyl chloroform); methotrexate: pharmacokinetics and assessment of toxicity; prospective predictions and validations in anticancer therapy; the application of pharmacokinetic data in carcinogenic risk assessment.

  9. Pharmacokinetics of meptazinol after parenteral administration in the elderly.

    PubMed

    Murray, G R; Franklin, R A; Graham, D F; Lewis, R R; Bolland, M E

    1987-01-01

    We have determined the pharmacokinetics of meptazinol after its intravenous and intramuscular administration in a crossover study in 7 elderly hospital in-patients (greater than 70 years), and have compared with the results from 14 healthy, young volunteers (ages 20-40 years). The systemic availability after i.m. administration was comparable to that after i.v. administration, a result consistent with the physicochemical properties of the drug. There was a slight, but statistically significant (p less than 0.01) prolongation in t1/2Z in the elderly (mean 2.93 h) compared with the young (mean 2.06 h). This was associated with a 25% lower clearance in the elderly rather than with any alteration in volume of distribution. However, these changes would not appear to be substantial enough to require a revised dosage recommendation for meptazinol for this age group. PMID:3556381

  10. Asparaginase pharmacokinetics and implications of therapeutic drug monitoring

    PubMed Central

    Asselin, Barbara; Rizzari, Carmelo

    2015-01-01

    Asparaginase is widely used in chemotherapeutic regimens for the treatment of acute lymphoblastic leukemia (ALL) and has led to a substantial improvement in cure rates, especially in children. Optimal therapeutic effects depend on a complete and sustained depletion of serum asparagine. However, pronounced interpatient variability, differences in pharmacokinetic properties between asparaginases and the formation of asparaginase antibodies make it difficult to predict the degree of asparagine depletion that will result from a given dose of asparaginase. The pharmacological principles underlying asparaginase therapy in the treatment of ALL are summarized in this article. A better understanding of the many factors that influence asparaginase activity and subsequent asparagine depletion may allow physicians to tailor treatment to the individual, maximizing therapeutic effect and minimizing treatment-related toxicity. Therapeutic drug monitoring provides a means of assessing a patient's current depletion status and can be used to better evaluate the potential benefit of treatment adjustments. PMID:25586605

  11. The product label: how pharmacokinetics and pharmacodynamics reach the prescriber.

    PubMed

    Marroum, Patrick J; Gobburu, Jogarao

    2002-01-01

    The product label, or package insert, is the 'manual' for the safe and effective use of a drug. Important pharmacokinetic and pharmacodynamic properties of a drug product should appear in the label under specific sections, as required in the Code of Federal Regulations (CFR), using a format and language recommended by the Food and Drug Administration (FDA) in various guidances to the industry. The relevant regulations and guidance documents impacting on how this information is conveyed to the healthcare professional are discussed, with special emphasis on how the new proposed rule will impact upon how information is to be conveyed. With the availability of new clinical pharmacology information not available at the time of approval, package inserts for older drugs should be updated to reflect the new data and recommend the proper dosage regimen, enabling prescribers to optimise drug therapy and minimise possible adverse events. PMID:11929317

  12. Pharmacokinetic study of medicinal polymers: models based on dextrans

    SciTech Connect

    Kulakov, V.N.; Pimenova, G.N.; Matveev, V.A.; Sedov, V.V.; Vasil'ev, A.E.

    1986-09-01

    The authors study the pharmacokinetics of dextrans with various molecular masses modified by fluorescein isothiocyanate (FITC) using a radioisotope method. The radionuclide /sup 125/I was selectively bound to a FITC residue attached to the polysaccharide by electrochemical iodination under potentiostatic conditions. In the experiments, dextrans modified by FITC were labeled with /sup 125/I (DF-/sup 125/I) by electrochemical iodination. The separation of DF-/sup 125/I and FITC from ionic forms of the radionuclide not bound to the polymer was carried out. The properties of the samples obtained are presented. The radioactivity accumulated in the rate organs and urine studied are shown. The features of DF-/sup 125/I behavior in the blood and liver are examined.

  13. Pharmacokinetics of new nootropic acylprolyldipeptide and its penetration across the blood-brain barrier after oral administration.

    PubMed

    Boiko, S S; Ostrovskaya, R U; Zherdev, V P; Korotkov, S A; Gudasheva, T A; Voronina, T A; Seredenin, S B

    2000-04-01

    Pharmacokinetics of GVS-111, a new acylprolyldipeptide with nootropic properties and its penetration across the blood-brain barrier were studied in rats using HPLC. It was found that the dipeptide is absorbed in the gastrointestinal tract, enters the circulation, and penetrates through the blood-brain barrier in an unmodified state. PMID:10977920

  14. Liraglutide in Type 2 Diabetes Mellitus: Clinical Pharmacokinetics and Pharmacodynamics.

    PubMed

    Jacobsen, Lisbeth V; Flint, Anne; Olsen, Anette K; Ingwersen, Steen H

    2016-06-01

    Liraglutide is an acylated glucagon-like peptide-1 analogue with 97 % amino acid homology with native glucagon-like peptide-1 and greatly protracted action. It is widely used for the treatment of type 2 diabetes mellitus, and administered by subcutaneous injection once daily. The pharmacokinetic properties of liraglutide enable 24-h exposure coverage, a requirement for 24-h glycaemic control with once-daily dosing. The mechanism of protraction relates to slowed release from the injection site, and a reduced elimination rate owing to metabolic stabilisation and reduced renal filtration. Drug exposure is largely independent of injection site, as well as age, race and ethnicity. Increasing body weight and male sex are associated with reduced concentrations, but there is substantial overlap between subgroups; therefore, dose escalation should be based on individual treatment outcome. Exposure is reduced with mild, moderate or severe renal or hepatic impairment. There are no clinically relevant changes in overall concentrations of various drugs (e.g. paracetamol, atorvastatin, griseofulvin, digoxin, lisinopril and oral combination contraceptives) when co-administered with liraglutide. Pharmacodynamic studies show multiple beneficial actions with liraglutide, including improved fasting and postprandial glycaemic control (mediated by increased insulin and reduced glucagon levels and minor delays in gastric emptying), reduced appetite and energy intake, and effects on postprandial lipid profiles. The counter-regulatory hormone response to hypoglycaemia is largely unaltered. The effects of liraglutide on insulin and glucagon secretion are glucose dependent, and hence the risk of hypoglycaemia is low. The pharmacokinetic and pharmacodynamic properties of liraglutide make it an important treatment option for many patients with type 2 diabetes. PMID:26597252

  15. Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: optimization of kinase selectivity and pharmacokinetics.

    PubMed

    Hornberger, Keith R; Chen, Xin; Crew, Andrew P; Kleinberg, Andrew; Ma, Lifu; Mulvihill, Mark J; Wang, Jing; Wilde, Victoria L; Albertella, Mark; Bittner, Mark; Cooke, Andrew; Kadhim, Salam; Kahler, Jennifer; Maresca, Paul; May, Earl; Meyn, Peter; Romashko, Darlene; Tokar, Brianna; Turton, Roy

    2013-08-15

    The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer. PMID:23856049

  16. Understanding the pharmacokinetics of Coartem®

    PubMed Central

    Djimdé, Abdoulaye; Lefèvre, Gilbert

    2009-01-01

    Artemether and lumefantrine (AL), the active constituents of Coartem® exhibit complementary pharmacokinetic profiles. Artemether is absorbed quickly; peak concentrations of artemether and its main active metabolite, dihydroartemisinin (DHA) occur at approximately two hours post-dose, leading to a rapid reduction in asexual parasite mass and a prompt resolution of symptoms. Lumefantrine is absorbed and cleared more slowly (terminal elimination half-life 3-4 days in malaria patients), and accumulates with successive doses, acting to prevent recrudescence by destroying any residual parasites that remain after artemether and DHA have been cleared from the body. Food intake significantly enhances the bioavailability of both artemether and lumefantrine, an effect which is more apparent for the highly lipophilic lumefantrine. However, a meal with only a small amount of fat (1.6 g) is considered sufficient to achieve adequate exposure to lumefantrine. The pharmacokinetics of artemether or lumefantrine are similar in children, when dosed according to their body weight, compared with adults. No randomized study has compared the pharmacokinetics of either agent in pregnant versus non-pregnant women. Studies in healthy volunteers and in children with malaria have confirmed that the pharmacokinetic characteristics of crushed standard AL tablets and the newly-developed Coartem® Dispersible tablet formulation are similar. Studies to date in healthy volunteers have not identified any clinically relevant drug-drug interactions; data relating to concomitant administration of HIV therapies are limited. While dose-response analyses are difficult to undertake because of the low rate of treatment failures under AL, it appears that artemether and DHA exposure impact on parasite clearance time while lumefantrine exposure is associated with cure rate, consistent with their respective modes of action. In conclusion, knowledge of the pharmacokinetic profiles of artemether and lumefantrine

  17. Validation and application of pharmacokinetic models for interspecies extrapolations in toxicity risk assessments of volatile organics. Annual report No. 2, 1 July 1988-30 June 1989

    SciTech Connect

    Dallas, C.E.; Bruckner, J.V.; Gallo, J.; Ramanathan, R.; Muralidhara, S.

    1989-07-21

    In pursuit of the goal of establishing a scientific basis for the interspecies extrapolation of pharmacokinetic data in health-risk assessments, a series of studies were conducted involving pharmacokinetic determinations in rats to several aliphatic halocarbons (with parallel studies initiated in the dog). Direct measurements of the uptake and elimination of halocarbon in rats were completed during the following inhalation exposures and following oral administration of dichloroethylene (DCE) and perchloroethylene (PCE). An assay for the measurement of halocarbons in the tissues of exposed animals has been successfully developed, and tissue-concentration profiles in the liver, kidney, lung, fat, brain, muscle, and heart were completed for oral and intraarterial administrations of PCE. The utility of the physiologically-based pharmacokinetic model for the accurate computer simulations of the pharmacokinetics of three halocarbons with wide variation in physicochemical properties (TRI, TCE, and PCE) has been demonstrated.

  18. Drug Dosing in Obese Children: A Systematic Review of Current Pharmacokinetic Data

    PubMed Central

    Harskamp-van Ginkel, Margreet W.; Hill, Kevin D.; Becker, Kristian; Testoni, Daniela; Cohen-Wolkowiez, Michael; Gonzalez, Daniel; Barrett, Jeffrey S.; Benjamin, Daniel K.; Siegel, David A.; Banks, Patricia; Watt, Kevin M.

    2015-01-01

    IMPORTANCE Obesity affects nearly one sixth of U.S. children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxicity. The depth of available literature regarding obesity’s effect on drug safety, pharmacokinetics (PK) and dosing in obese children is unknown. OBJECTIVE To perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children. EVIDENCE REVIEW We searched the Medline, Cochrane, and Embase databases (January 1970–December 2012) and included studies if they contained clearance, volume of distribution, or drug concentration data in obese children (age ≤18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and non-obese children. We explored the relationship between drug physicochemical properties and clearance and volume of distribution. FINDINGS Twenty studies met inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range 1–112), ages ranged from 0–29 years. Dosing schema varied and were based on a fixed dose (n=6, 29%), body weight (n=10, 48%), and body surface area (n=4, 19%). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11/17) of studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and non-obese children for 38% (5/13) of drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity. CONCLUSIONS AND RELEVANCE Consensus is lacking on the most appropriate weight-based dosing strategy. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety. PMID:25961828

  19. Prediction of pharmacokinetic parameters using a genetic algorithm combined with an artificial neural network for a series of alkaloid drugs.

    PubMed

    Zandkarimi, Majid; Shafiei, Mohammad; Hadizadeh, Farzin; Darbandi, Mohammad Ali; Tabrizian, Kaveh

    2014-03-01

    An important goal for drug development within the pharmaceutical industry is the application of simple methods to determine human pharmacokinetic parameters. Effective computing tools are able to increase scientists' ability to make precise selections of chemical compounds in accordance with desired pharmacokinetic and safety profiles. This work presents a method for making predictions of the clearance, plasma protein binding, and volume of distribution for alkaloid drugs. The tools used in this method were genetic algorithms (GAs) combined with artificial neural networks (ANNs) and these were applied to select the most relevant molecular descriptors and to develop quantitative structure-pharmacokinetic relationship (QSPkR) models. Results showed that three-dimensional structural descriptors had more influence on QSPkR models. The models developed in this study were able to predict systemic clearance, volume of distribution, and plasma protein binding with normalized root mean square error (NRMSE) values of 0.151, 0.263, and 0.423, respectively. These results demonstrate an acceptable level of efficiency of the developed models for the prediction of pharmacokinetic parameters. PMID:24634842

  20. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update.

    PubMed

    Italiano, Domenico; Perucca, Emilio

    2013-08-01

    Epilepsies occur across the entire age range, and their incidence peaks in the first years of life and in the elderly. Therefore, antiepileptic drugs (AEDs) are commonly used at the extremes of age. Rational prescribing in these age groups requires not only an understanding of the drugs' pharmacodynamic properties, but also careful consideration of potential age-related changes in their pharmacokinetic profile. The present article, which updates a review published in 2006 in this journal, focuses on recent findings on the pharmacokinetics of new-generation AEDs in neonates, infants, children, and the elderly. Significant new information on the pharmacokinetics of new AEDs in the perinatal period has been acquired, particularly for lamotrigine and levetiracetam. As a result of slow maturation of the enzymes involved in glucuronide conjugation, lamotrigine elimination occurs at a particularly slow rate in neonates, and becomes gradually more efficient during the first months of life. In the case of levetiracetam, elimination occurs primarily by renal excretion and is also slow at birth, but drug clearance increases rapidly thereafter and can even double within 1 week. In general, infants older than 2-3 months and children show higher drug clearance (normalized for body weight) than adults. This pattern was confirmed in recent studies that investigated the pediatric pharmacokinetics of several new AEDs, including levetiracetam, rufinamide, stiripentol, and eslicarbazepine acetate. At the other extreme of age, in the elderly, drug clearance is generally reduced compared with younger adults because of less efficient drug-metabolizing activity, decreased renal function, or both. This general pattern, described previously for several AEDs, was confirmed in recent studies on the effect of old age on the clearance of felbamate, levetiracetam, pregabalin, lacosamide, and retigabine. For those drugs which are predominantly eliminated by renal excretion, aging

  1. Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis.

    PubMed

    Zuurmond, Anne-Marie; Koudijs, Angela; van El, Benno; Doornbos, Robert P; van Manen-Vernooij, Babs C T; Bastiaans, Jacqueline H M W; Penninks, André H; van Bilsen, Jolanda H M; Cnubben, Nicole H P; Degroot, Jeroen

    2011-04-01

    Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure. PMID:21300126

  2. Population pharmacokinetics of artesunate and amodiaquine in African children

    PubMed Central

    2009-01-01

    Background Pharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC) of artesunate and amodiaquine. Methods A prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm) to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC). Results The two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138) for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range) elimination half-life of 9 (7 to 12) days. Efficacy was similar in the two treatments groups, with cure rates of 0.946 (95% CI: 0.840

  3. Accepters and Rejecters of Counseling.

    ERIC Educational Resources Information Center

    Rose, Harriett A.; Elton, Charles F.

    Personality differences between students who accept or reject proffered counseling assistance were investigated by comparing personality traits of 116 male students at the University of Kentucky who accepted or rejected letters of invitation to group counseling. Factor analysis of Omnibus Personality Inventory (OPI) scores to two groups of 60 and…

  4. Cone penetrometer acceptance test report

    SciTech Connect

    Boechler, G.N.

    1996-09-19

    This Acceptance Test Report (ATR) documents the results of acceptance test procedure WHC-SD-WM-ATR-151. Included in this report is a summary of the tests, the results and issues, the signature and sign- off ATP pages, and a summarized table of the specification vs. ATP section that satisfied the specification.

  5. Development and validation of an UFLC-MS/MS assay for the absolute quantitation of nine notoginsenosides in rat plasma: Application to the pharmacokinetic study of Panax Notoginseng Extract.

    PubMed

    Zhou, Lijun; Xing, Rong; Xie, Lin; Rao, Tai; Wang, Qian; Ye, Wei; Fu, Hanxu; Xiao, Jingcheng; Shao, Yuhao; Kang, Dian; Wang, Guangji; Liang, Yan

    2015-07-15

    Notoginsenosides, the main active gradients of Chinese traditional medicine Panax notoginseng, possesses a variety of biological activities including antioxidant property, anti-hyperglycemic, anti-obese, etc. However, pharmacokinetic evaluation for notoginsenosides is still a formidable task due to their low concentrations and complex components in vivo. The summation of this work generated a rapid and sensitive method for quantitative analysis of multi-notoginsenoside in rat plasma based on ultra fast liquid chromatographic-tandem mass spectrometric. After liquid-liquid extraction by n-butanol, notoginsenoside R1, Rg3, Rd, Rg2, Rb2, Rf, Rg1, Rb1 and Re were simultaneously monitored in negative ionization mode after separating on a Thermo ODS C18 column (5mm 50mm×2.1mm) by a binary gradient elution, and all compounds were analyzed within 9min. Multiple reaction monitoring (MRM) was performed as follows: R1 (m/z 967.7→637.4), Rg3 (m/z 819.6→621.4), Rd (m/z 981.6→783.5), Rg2 (m/z 819.6→475.4), Rb2 (m/z 1113.4→783.4), Rf (m/z 835.6→475.4), Rg1 (m/z 835.6→637.6), Rb1 (m/z 1143.7→945.6), Re (m/z 981.6→637.4), internal standard (digoxin, m/z 815.5→779.4). Validation parameters (linearity, sensitivity, intra-and inter-assay precision and accuracy, recovery and matrix effect) were within acceptable ranges and biological extracts were stable during the entire storing and preparing process. This UFLC-MS/MS approach was further validated by being applied to the pharmacokinetic study for P. Notoginseng extract in rats, and the pharmacokinetic parameters were calculated by Winolin software. Thus, the presently developed methodology was simple, robust, accurate, precise, and would be useful for the pharmacokinetic studies for all kinds of notoginsenosides and other herbal saponins. PMID:26021851

  6. What is meant by the term acceptance of technology and locating the acceptance of the CCS Technology?

    NASA Astrophysics Data System (ADS)

    Harz, Mario; Vesper, Anton

    2013-04-01

    abstract: The formal language of logic expresses concepts and statements exactly. The logic of relations can serve as an important ressource for the philosophical analysis of technology and the construction of philosophical propositions about acceptance of technology. The theory of logical relations is used to investigate the theoretical structure of how acceptance of technologies can be revealed. The term "ordered tuple" helps to define the basis of the concept of logical relations. The term "acceptance of technology" refers to neither a thing nor a property; but to a complex relationship. The research refers to the study of the properties of this complex relationship. It examines the properties of reflexivity, total reflexivity, symmetry, transitivity, irreflexivity and asymmetry. Using these properties and the rules for forming converses-relations and partial-relations the question is analyzed: What, in general, is meant by the term "acceptance of technology?" These properties have been observed empirically at a discussion forum for the key players in the Brandenburg discourse on the acceptance of CCS technology. The meeting was held on the 8th of May 2012 in St. Nicholas Church, Cottbus (GER). The pragma-dialectical theory of argumentation is used to locate the acceptance of the CCS technology. With the ideal model of critical discussion as the methodological starting point the term "acceptance" can be defined in terms of the four meta-theoretical principles of the theory. That boils down to the findings that acceptance is the externalization of a positive commitment towards a proposition, acceptance is expressed by the speech act "to accept" and acceptance occurs in the dialogical, interactional setting of a critical discussion with the aim of resolving a difference of opinion. In the study differences of opinion about (descriptive, normative, evaluative) standpoints about the CCS technology from everyday problem-solving discussions are investigated. The

  7. Pharmacokinetics of melatonin in human sexual maturation.

    PubMed

    Cavallo, A; Ritschel, W A

    1996-05-01

    To determine whether melatonin pharmacokinetics change during puberty, we infused melatonin iv in 9 prepubertal, 8 pubertal, and 16 adult subjects and measured melatonin in serum and saliva, and 6-hydroxymelatonin sulfate in urine. A pilot study of 3 adult males showed dose linearity, absence of saturation kinetics, and unaltered metabolism and urinary excretion for doses of 0.1, 0.5, and 5.0 micrograms/kg. All other subjects received 0.5 microgram/kg melatonin. The results of pharmacokinetic parameters calculated from serum melatonin showed no significant gender differences in adults. However, developmental differences were significant between prepubertal children and adults for terminal elimination rate constant (1.08 +/- 0.25 vs. 0.89 +/- 0.11 h-1), elimination half-life (0.67 +/- 0.12 vs. 0.79 +/- 0.10 h), and area under the concentration-time curve (250.9 +/- 91.8 vs. 376.9 +/- 154.3 (pg/mL).h, respectively). At all time points melatonin levels were higher in serum than in saliva, and the ratio between serum and salivary melatonin varied up to 55-fold within and between individuals. Results based on salivary melatonin showed significant differences between prepubertal children and adults for the terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 h-1). The described group differences in pharmacokinetic parameters suggest that prepubertal children metabolize melatonin faster than adults. The inconsistent ratio between serum and salivary melatonin calls for caution in the use of salivary melatonin for pharmacokinetic studies or to infer pineal function. The present findings, suggestive of faster melatonin metabolism in prepubertal children, combined with the known decline of serum melatonin with age and higher excretion rate of the metabolite in prepubertal children lead us to conclude that the prepubertal pineal gland has a higher melatonin secretion rate than the adult gland. PMID:8626852

  8. Pharmacokinetics of Tenofovir During Pregnancy and Postpartum

    PubMed Central

    Best, Brookie M.; Burchett, Sandra; Li, Hong; Stek, Alice; Hu, Chengcheng; Wang, Jiajia; Hawkins, Elizabeth; Byroads, Mark; Watts, D. Heather; Smith, Elizabeth; Fletcher, Courtney V.; Capparelli, Edmund V.; Mirochnick, Mark

    2016-01-01

    Objectives Tenofovir disoproxol fumarate (TDF) is increasingly used in HAART regimens of pregnant women, but limited data exist on pregnancy pharmacokinetics of chronically-dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. Methods IMPAACT P1026s is a prospective, non-blinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at 2nd and 3rd trimester and postpartum, with maternal and umbilical cord samples at delivery. Tenofovir was measured by LC-MS. The target AUC was ≥ 1.99 mcg•hr/mL (non-pregnant historical control 10th percentile). Results Median tenofovir AUC was decreased during the 2nd (1.9 mcg•hr/mL) and 3rd (2.4 mcg•hr/mL, p=0.005) trimesters versus postpartum (3.0 mcg•hr/mL). Tenofovir AUC exceeded the target for 2/4 (50%) 2nd trimester; 27/37 (73%; 95% CI: 56%, 86%) 3rd trimester; and 27/32 (84%; 95% CI: 67%, 95%) postpartum women (p>0.05). Median 2nd/3rd trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median 3rd trimester weight was heavier for subjects below target AUC versus those above target (97.9 vs. 74.2 kg, p = 0.006). Median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. Conclusions This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90kg) or inadequate HIV RNA response. PMID:25959631

  9. Pharmacokinetic Profile of Spectinomycin in Rats

    PubMed Central

    Madhura, Dora Babu; Lee, Richard; Meibohm, Bernd

    2014-01-01

    Short Summary Following intravenous (IV) administration, the pharmacokinetics of spectinomycin in rats was found to be on par with its profile in other mammalian species including humans with respect to its overall excretion and half-life at effective concentrations. This study, however, indicates that a small fraction of the spectinomycin dose is retained in peripheral tissues for a prolonged period of time at low concentrations. PMID:24020122

  10. [Pharmacokinetics--pharmacodynamics of modafinil in mice].

    PubMed

    Ma, Zhang-Qing; Hong, Zong-Yuan; Wang, Wu-San; Tao, Fang

    2012-01-01

    To guide the reasonable clinical application of modafinil (MOD), pharmacokinetics and pharmacodynamics of MOD in mice and the correlation between them were investigated. Male mice (Kunming strain) were given a single oral dose of MOD (120 mg x kg(-1)). The plasma concentration of MOD was measured by HPLC and the pharmacokinetic parameters were calculated with DAS 3.0 software. For another batch of male Kunming strain mice, their locomotor activities were recorded by an infrared ray passive sensor after a same oral dose of MOD, and the synchronization and correlation between the changes of MOD plasma concentration and the locomotor activity induced by MOD were compared and analyzed. The results showed that the plasma concentration-time curve of MOD was fitted to two-compartment open model with a first order absorption. The main pharmacokinetic parameters t1/2alpha, t1/2beta, t(max), C(max) and AUC(0-inifinity) were 0.42 h, 3.10 h, 1.00 h, 41.34 mg x L(-1) and 142.22 mg x L(-1) x h, respectively. MOD significantly increased locomotor activity and the effect lasted for about 4 h. The changes of MOD plasma concentration and the locomotor activity induced by MOD were synchronous. In conclusion, there is a significant correlation between the effect of MOD and its plasma concentration after administration of 120 mg x kg(-1) in mice. PMID:22493813

  11. Pharmacokinetics of Hoasca alkaloids in healthy humans.

    PubMed

    Callaway, J C; McKenna, D J; Grob, C S; Brito, G S; Raymon, L P; Poland, R E; Andrade, E N; Andrade, E O; Mash, D C

    1999-06-01

    N,N-Dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine (THH) are the characteristic alkaloids found in Amazonian sacraments known as hoasca, ayahuasca, and yajè. Such beverages are characterized by the presence of these three harmala alkaloids, where harmine and harmaline reversibly inhibit monoamine oxidase A (MAO-A) while tetrahydroharmine weakly inhibits the uptake of serotonin. Together, both actions increase central and peripheral serotonergic activity while facilitating the psychoactivity of DMT. Though the use of such 'teas' has be known to western science for over 100 years, little is known of their pharmacokinetics. In this study, hoasca was prepared and administered in a ceremonial context. All four alkaloids were measured in the tea and in the plasma of 15 volunteers, subsequent to the ingestion of 2 ml hoasca/kg body weight, using gas (GC) and high pressure liquid chromatographic (HPLC) methods. Pharmacokinetic parameters were calculated and peak times of psychoactivity coincided with high alkaloid concentrations, particularly DMT which had an average Tmax of 107.5 +/- 32.5 min. While DMT parameters correlated with those of harmine, THH showed a pharmacokinetic profile relatively independent of harmine's. PMID:10404423

  12. Pharmacokinetics of intravitreal antibiotics in endophthalmitis

    PubMed Central

    2014-01-01

    Intravitreal antibiotics are the mainstay of treatment in the management of infectious endophthalmitis. Basic knowledge of the commonly used intravitreal antibiotics, which includes their pharmacokinetics, half-life, duration of action and clearance, is essential for elimination of intraocular infection without any iatrogenic adverse effect to the ocular tissue. Various drugs have been studied over the past century to achieve this goal. We performed a comprehensive review of the antibiotics which have been used for intravitreal route and the pharmacokinetic factors influencing the drug delivery and safety profile of these antibiotics. Using online resources like PubMed and Google Scholar, articles were reviewed. The articles were confined to the English language only. We present a broad overview of pharmacokinetic concepts fundamental for use of intravitreal antibiotics in endophthalmitis along with a tabulated compendium of the intravitreal antibiotics using available literature. Recent advances for increasing bioavailability of antibiotics to the posterior segment with the development of controlled drug delivery devices are also described. PMID:25667683

  13. Clinical pharmacokinetics in infants and children.

    PubMed

    Rane, A; Wilson, J T

    1976-01-01

    Wide variations in drug dose recommendations for children of the same or different ages reflect the inadequacy of data on pharmacokinetics and pharmacodynamics in children. Selected aspects of available literature on pharmacokinetics of drugs used in older infants and children has been reviewed with special attention to calculation of an age-appropriate dose. During the neonatal period and early infancy the elimination of many drugs that are excreted in the urine in unchanged form is restricted by the immaturity of glomerular filtration and renal tubular secretion. On the other hand, in late infancy and/or in childhood, a similar or greater rate of elimination from plasma than in adults has been observed for many drugs, notably digoxin, phenobarbitone, phenytoin, carbamazepine, ethosuximide, diazoxide, clindamycin and propoxyphene. Consistent with this, it has been shown that some drugs exhibit a lower plasma level/dose ratio in infancy and early childhood as compared with the adult. This is true for phenobarbitone, phenytoin and ethosuximide. Some age groups of children remain uninvestigated with regard to pharmacokinetics, even for the drugs reviewed. Therefore, pediatric therapy remains empirically based for many drugs. PMID:1017153

  14. Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution.

    PubMed

    Tolman, Justin A; Nelson, Nicole A; Son, Yoen Ju; Bosselmann, Stephanie; Wiederhold, Nathan P; Peters, Jay I; McConville, Jason T; Williams, Robert O

    2009-05-01

    Invasive fungal infections in immunocompromised patients have high mortality rates despite current treatment modalities. This study was designed to evaluate the suitability of an aqueous solution of voriconazole solubilized with sulfobutyl ether-beta-cyclodextrin for targeted drug delivery to the lungs via nebulization. A solution was prepared such that the inspired aerosol dose was isotonic with an acceptable mass median aerodynamic diameter of 2.98 microm and a fine particle fraction of 71.7%. Following single and multiple inhaled doses, high voriconazole concentrations were observed within 30 min in the lung tissue and plasma. Drug solubilization with sulfobutyl ether-beta-cyclodextrin contributed to the rapid and high drug concentrations in plasma following inhalation. Maximal concentrations in the lung and plasma were 11.0 +/- 1.6 microg/g wet lung weight and 7.9 +/- 0.68 microg/mL, respectively, following a single inhaled dose with a corresponding tissue/plasma concentration ratio of 1.4 to 1. Following multiple inhaled doses, peak concentrations in lung tissue and plasma were 6.73 +/- 3.64 microg/g wet lung weight and 2.32 +/- 1.52 microg/mL, respectively. AUC values in lung tissue and plasma were also high. The clinically relevant observed pharmacokinetic parameters of inhaled aqueous solutions of voriconazole suggest that therapeutic outcomes could be benefitted through the use of inhaled voriconazole. PMID:19348016

  15. A PC-based graphical simulator for physiological pharmacokinetic models.

    PubMed

    Wada, D R; Stanski, D R; Ebling, W F

    1995-04-01

    Since many intravenous anesthetic drugs alter blood flows, physiologically-based pharmacokinetic models describing drug disposition may be time-varying. Using the commercially available programming software MATLAB, a platform to simulate time-varying physiological pharmacokinetic models was developed. The platform is based upon a library of pharmacokinetic blocks which mimic physiological structure. The blocks can be linked together flexibly to form models for different drugs. Because of MATLAB's additional numerical capabilities (e.g. non-linear optimization), the platform provides a complete graphical microcomputer-based tool for physiologic pharmacokinetic modeling. PMID:7656558

  16. Pre-formulation characterization and pharmacokinetic evaluation of resveratrol

    NASA Astrophysics Data System (ADS)

    Robinson-Barnes, Keila Delores

    Resveratrol, a natural compound found in grapes has potential chemotherapy effects but very low oral bioavailability in humans. The objectives of this study are to quantitatively characterized and understand the physiochemical properties and the pharmacokinetic evaluation of resveratrol. Solubility of resveratrol was measured in 10 common solvents at 25°C using HPLC. The solution state pH stability of resveratrol was assessed in various USP buffers ranging from pH 2-10 for 24 hours at 37 °C. Human plasma protein binding was determined using ultracentrifugation technique. Stability of resveratrol in human and rat plasma was also assessed at 37°C. Aliquots of blank plasma were spiked with a standard drug concentration to yield final plasma concentration of 50 mug/mL. Samples were analyzed for resveratrol concentration up to 96 hours. A group (n=8) of jugular vein-cannulated adult male Sprague-Dawley rats were evaluated and received intravenous dose of 20 mg/kg resveratrol. Serial blood samples were collected up to 8 hours after the dose. Plasma concentrations of resveratrol were measured by an established LC-MS/MS method. Pharmacokinetic parameters were assessed using noncompartmental methods. Resveratrol is more soluble in alcohol and PEG-400, and stable in acidic pH. It binds highly to plasma proteins, and degrades slower in human then rat plasma. Resveratrol exhibits bioexponential disposition after intravenous administration and has a short elimination half-life. Resveratrol displays bioexponential disposition following intravenous administration. The estimated mean maximum concentration was 1045.5 ng/mL and rapidly dropped below 100 ng/mL within 30 minutes. The area under the concentration time curve (AUC) for resveratrol was 13888.7 min*ng/mL The mean terminal elimination half-life was 50.9 minutes. The mean total body clearance (Cl) and volume of distribution of trans-resveratrol were 1711.9mL/min/kg and 91087.8 mL/kg, respectively. Pre

  17. Pharmacokinetics of cabozantinib tablet and capsule formulations in healthy adults.

    PubMed

    Nguyen, Linh; Benrimoh, Natacha; Xie, Yuli; Offman, Elliot; Lacy, Steven

    2016-08-01

    Cabozantinib capsules (COMETRIQ) are approved for the treatment of patients with progressive metastatic medullary thyroid cancer. Cabozantinib tablets are investigational drug products considered to be potentially preferred pharmaceutical dosing forms. Two phase I open-label single-dose studies in healthy individuals were carried out to characterize the plasma pharmacokinetics of cabozantinib capsule and tablet formulations: a two-way crossover bioequivalence study (n=77) comparing the tablet formulation and the marketed capsule formulation at the approved 140 mg dose and a dose-proportionality study (n=21 per treatment arm) evaluating the 20, 40, and 60 mg tablet strengths. In the bioequivalence study, plasma exposure [area under the plasma concentration-time curve (AUC0-t and AUC0-inf)] values were similar (<10% difference) for both formulations and the 90% confidence intervals (CIs) around the ratio of geometric least-squares means (GLSM) were within the accepted bioequivalence limits of 80-125%. However, the GLSM for Cmax was 19% higher for the tablet formulation and the upper 90% CI for the ratio of GLSM (131.65%) was beyond the 80-125% range. Thus, the tablet and capsule formulations failed to fulfill the bioequivalence study acceptance criteria. In the dose-proportionality study, single doses of the 20, 40, and 60 mg cabozantinib tablet strengths showed dose-proportional increases where the 95% CIs for the slopes of the ln-transformed Cmax, AUC0-t, and AUC0-inf values versus ln-transformed cabozantinib dose included the value of 1. These findings indicate that cabozantinib plasma exposures increased proportionally with increasing cabozantinib dose over the 20-60 mg tablet strength dose range. PMID:27139820

  18. Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest.

    PubMed

    Lees, P; Landoni, M F; Giraudel, J; Toutain, P L

    2004-12-01

    This review summarises selected aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of nonsteroidal anti-inflammatory drugs (NSAIDs). It is not intended to be comprehensive, in that it covers neither minor species nor several important aspects of NSAID PD. The limited objective of the review is to summarise those aspects of NSAID PK and PD, which are important to an understanding of PK-PD integration and PK-PD modelling (the subject of the next review in this issue). The general features of NSAID PK are: usually good bioavailability from oral, intramuscular and subcutaneous administration routes (but with delayed absorption in horses and ruminants after oral dosing), a high degree of binding to plasma protein, low volumes of distribution, limited excretion of administered dose as parent drug in urine, marked inter-species differences in clearance and elimination half-life and ready penetration into and slow clearance from acute inflammatory exudate. The therapeutic effects of NSAIDs are exerted both locally (at peripheral inflammatory sites) and centrally. There is widespread acceptance that the principal mechanism of action (both PD and toxicodynamics) of NSAIDs at the molecular level comprises inhibition of cyclooxygenase (COX), an enzyme in the arachidonic acid cascade, which generates inflammatory mediators of the prostaglandin group. However, NSAIDs possess also many other actions at the molecular level. Two isoforms of COX have been identified. Inhibition of COX-1 is likely to account for most of the side-effects of NSAIDs (gastrointestinal irritation, renotoxicity and inhibition of blood clotting) but a minor contribution also to some of the therapeutic effects (analgesic and anti-inflammatory actions) cannot be excluded. Inhibition of COX-2 accounts for most and possibly all of the therapeutic effects of NSAIDs. Consequently, there has been an intensive search to identify and develop drugs with selectivity for inhibition of COX-2. Whole blood in

  19. The pharmacokinetics of anthocyanins and their metabolites in humans

    PubMed Central

    de Ferrars, R M; Czank, C; Zhang, Q; Botting, N P; Kroon, P A; Cassidy, A; Kay, C D

    2014-01-01

    BACKGROUND AND PURPOSE Anthocyanins are phytochemicals with reported vasoactive bioactivity. However, given their instability at neutral pH, they are presumed to undergo significant degradation and subsequent biotransformation. The aim of the present study was to establish the pharmacokinetics of the metabolites of cyanidin-3-glucoside (C3G), a widely consumed dietary phytochemical with potential cardioprotective properties. EXPERIMENTAL APPROACH A 500 mg oral bolus dose of 6,8,10,3′,5′-13C5-C3G was fed to eight healthy male participants, followed by a 48 h collection (0, 0.5, 1, 2, 4, 6, 24, 48 h) of blood, urine and faecal samples. Samples were analysed by HPLC-ESI-MS/MS with elimination kinetics established using non-compartmental pharmacokinetic modelling. KEY RESULTS Seventeen 13C-labelled compounds were identified in the serum, including 13C5-C3G, its degradation products, protocatechuic acid (PCA) and phloroglucinaldehyde (PGA), 13 metabolites of PCA and 1 metabolite derived from PGA. The maximal concentrations of the phenolic metabolites (Cmax) ranged from 10 to 2000 nM, between 2 and 30 h (tmax) post-consumption, with half-lives of elimination observed between 0.5 and 96 h. The major phenolic metabolites identified were hippuric acid and ferulic acid, which peaked in the serum at approximately 16 and 8 h respectively. CONCLUSIONS AND IMPLICATIONS Anthocyanins are metabolized to a structurally diverse range of metabolites that exhibit dynamic kinetic profiles. Understanding the elimination kinetics of these metabolites is key to the design of future studies examining their utility in dietary interventions or as therapeutics for disease risk reduction. PMID:24602005

  20. Influence of oxytetracycline on carprofen pharmacodynamics and pharmacokinetics in calves.

    PubMed

    Brentnall, C; Cheng, Z; McKellar, Q A; Lees, P

    2013-08-01

    A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four-period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(-) and S(+) carprofen enantiomers, except for a lower maximum concentration (Cmax ) of S(+) carprofen in serum after co-administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration-time curve (AUC0-96 h were 136.9 and 128.3 μg·h/mL and means for the terminal half-life (T(1/2) k10 ) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC0-96 h in both carprofen treatments and T(1/2) k10 for carprofen alone were lower (P < 0.05) than R(-) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B2 ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E2 synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE2 correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(-) and S(+) enantiomers, respectively. Carprofen reduction of zymosan-induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co-administered. PMID:22913421

  1. Pharmacokinetics of three sulphonamides in ruminant and preruminant kids.

    PubMed

    Watson, A D; van Gogh, H; van Deurzen, E J; van Duin, C T; van Miert, A S

    1987-09-01

    The pharmacokinetic properties of three sulphonamides were determined in ruminant and preruminant kids after oral and intravenous administration. First, sulphisomidine (SIM, 50 mg kg-1) and sulphadoxine (SDX, 30 mg kg-1) were given to seven kids, 10 to 12 weeks old, while on a milk replacer diet and again at 15 to 18 weeks when fed roughage. Secondly, SIM (100 mg kg-1) and sulphadimidine (SDD, 100 mg kg-1) were given at six to nine, 12 to 15 and 18 to 21 weeks old to eight kids, of which four were fed milk replacer and four were with their mothers (with access to roughage) until 15 weeks, after which all were fed roughage only. SDX and SDD exhibited non-linear (or capacity limited) absorption after oral dosage, suggesting possible active absorption mechanisms, and both drugs also showed non-linear elimination. Intravenous curves for SDD and SIM indicated that recycling occurred. With SDX, ruminant kids showed poorer systemic availability after oral dosage, shorter t1/2(el) and higher B than did preruminants. For SDD, ruminant kids had lower Vd and higher B than preruminants. SIM's t1/2(el) tended to shorten and beta to increase in both groups throughout the experiment. Not all differences between ruminants and preruminants in sulphonamide pharmacokinetics could be explained by the accumulation of acidic forestomach contents and the change of urine pH from acid to alkaline in the maturing ruminant. Other potential contributing factors require investigation, including possible alterations in hepatic drug metabolism. Of the three drugs tested, SDX might be the most satisfactory for therapeutic use in preruminant animals, because it has good bioavailability after oral administration and long t1/2(el). PMID:3685634

  2. Pharmacokinetics of non-intravenous formulations of fentanyl.

    PubMed

    Lötsch, Jörn; Walter, Carmen; Parnham, Michael J; Oertel, Bruno G; Geisslinger, Gerd

    2013-01-01

    Fentanyl was structurally designed by Paul Janssen in the early 1960s as a potent opioid analgesic (100-fold more potent than morphine). It is a full agonist at μ-opioid receptors and possesses physicochemical properties, in particular a high lipophilicity (octanol:water partition coefficient >700), which allow it to cross quickly between plasma and central nervous target sites (transfer half-life of 4.7-6.6 min). It undergoes first-pass metabolism via cytochrome P450 3A (bioavailability ~30 % after rapid swallowing), which can be circumvented by non-intravenous formulations (bioavailability 50-90 % for oral transmucosal or intranasal formulations). Non-intravenous preparations deliver fentanyl orally-transmucosally, intranasally or transdermally. Passive transdermal patches release fentanyl at a constant zero-order rate for 2-3 days, making them suitable for chronic pain management, as are iontophoretic transdermal systems. Oral transmucosal and intranasal routes provide fast delivery (time to reach maximum fentanyl plasma concentrations 20 min [range 20-180 min] and 12 min [range 12-21 min], respectively) suitable for rapid onset of analgesia in acute pain conditions with time to onset of analgesia of 5 or 2 min, respectively. Intranasal formulations partly bypass the blood-brain barrier and deliver a fraction of the dose directly to relevant brain target sites, providing ultra-fast analgesia for breakthrough pain. Thanks to the development of non-intravenous pharmaceutical formulations, fentanyl has become one of the most successful opioid analgesics, and can be regarded as an example of a successful reformulation strategy of an existing drug based on pharmacokinetic research and pharmaceutical technology. This development broadened the indications for fentanyl beyond the initial restriction to intra- or perioperative clinical uses. The clinical utility of fentanyl could be expanded further by more comprehensive mathematical characterizations of its parametric

  3. Pharmacokinetic profile of phytoconstituent(s) isolated from medicinal plants—A comprehensive review

    PubMed Central

    Mehta, Piyush; Shah, Rishi; Lohidasan, Sathiyanarayanan; Mahadik, K.R.

    2015-01-01

    Herbal medicine, the backbone of traditional medicine, has played an important role in human health and welfare for a long period. Traditional therapeutic approaches of regional significance are found in Africa, South and Central America, China, India, Tibet, Indonesia, and the Pacific Islands. The considerable scientific significance and commercial potential of traditional medicines have resulted in increased international attention and global market demands for herbal medicines, especially Chinese herbal medicines. Herbal medicines currently are the primary form of health care for the poor in the developing countries, and also are widely used as a supplement or substitute for conventional drugs in developed countries. These traditional medicines have a pivotal role in the treatment of various ailments and more than 50% of drugs used in Western pharmacopoeia are isolated from herbs or derived from modifications of chemicals found in plants. Herbal medicines usually contain a complex mixture of various bioactive molecules, which make its standardization complicated, and there is little information about all compounds responsible for pharmacological activity. Several research papers have been published that claim pharmacological activity of herbal medicines but few are discussing the role of the exact phytoconstituent. Understanding the pharmacokinetic profile of such phytoconstituents is essential. Although there are research papers that deal with pharmacokinetic properties of phytoconstituents, there are a number of phytoconstituents yet to be explored for their kinetic properties. This article reviews the pharmacokinetic profile of 50 different therapeutically effective traditional medicinal plants from the year 2003 onward. PMID:26587392

  4. Pharmacokinetic profile of phytoconstituent(s) isolated from medicinal plants-A comprehensive review.

    PubMed

    Mehta, Piyush; Shah, Rishi; Lohidasan, Sathiyanarayanan; Mahadik, K R

    2015-10-01

    Herbal medicine, the backbone of traditional medicine, has played an important role in human health and welfare for a long period. Traditional therapeutic approaches of regional significance are found in Africa, South and Central America, China, India, Tibet, Indonesia, and the Pacific Islands. The considerable scientific significance and commercial potential of traditional medicines have resulted in increased international attention and global market demands for herbal medicines, especially Chinese herbal medicines. Herbal medicines currently are the primary form of health care for the poor in the developing countries, and also are widely used as a supplement or substitute for conventional drugs in developed countries. These traditional medicines have a pivotal role in the treatment of various ailments and more than 50% of drugs used in Western pharmacopoeia are isolated from herbs or derived from modifications of chemicals found in plants. Herbal medicines usually contain a complex mixture of various bioactive molecules, which make its standardization complicated, and there is little information about all compounds responsible for pharmacological activity. Several research papers have been published that claim pharmacological activity of herbal medicines but few are discussing the role of the exact phytoconstituent. Understanding the pharmacokinetic profile of such phytoconstituents is essential. Although there are research papers that deal with pharmacokinetic properties of phytoconstituents, there are a number of phytoconstituents yet to be explored for their kinetic properties. This article reviews the pharmacokinetic profile of 50 different therapeutically effective traditional medicinal plants from the year 2003 onward. PMID:26587392

  5. Preclinical pharmacokinetics of a novel HIV-1 attachment inhibitor BMS-378806 and prediction of its human pharmacokinetics.

    PubMed

    Yang, Zheng; Zadjura, Lisa; D'Arienzo, Celia; Marino, Anthony; Santone, Kenneth; Klunk, Lewis; Greene, Douglas; Lin, Pin-Fang; Colonno, Richard; Wang, Tao; Meanwell, Nicholas; Hansel, Steven

    2005-12-01

    to improving absorption and half-life of future compounds in the series. The current studies also demonstrate the value and approaches of understanding pharmacokinetic properties in the early stage of drug discovery. PMID:16142720

  6. Pharmacokinetics of quercetin-loaded nanodroplets with ultrasound activation and their use for bioimaging

    PubMed Central

    Chang, Li-Wen; Hou, Mei-Ling; Hung, Shuo-Hui; Lin, Lie-Chwen; Tsai, Tung-Hu

    2015-01-01

    Bubble formulations have both diagnostic and therapeutic applications. However, research on nanobubbles/nanodroplets remains in the initial stages. In this study, a nanodroplet formulation was prepared and loaded with a novel class of chemotherapeutic drug, ie, quercetin, to observe its pharmacokinetic properties and ultrasonic bioimaging of specific sites, namely the abdominal vein and bladder. Four parallel groups were designed to investigate the effects of ultrasound and nanodroplets on the pharmacokinetics of quercetin. These groups were quercetin alone, quercetin triggered with ultrasound, quercetin-encapsulated in nanodroplets, and quercetin encapsulated in nanodroplets triggered with ultrasound. Spherical vesicles with a mean diameter of 280 nm were formed, and quercetin was completely encapsulated within. In vivo ultrasonic imaging confirmed that the nanodroplets could be treated by ultrasound. The results indicate that the initial 5-minute serum concentration, area under the concentration–time curve, elimination half-life, and clearance of quercetin were significantly enhanced by nanodroplets with or without ultrasound. PMID:25945049

  7. Development of a human physiologically based pharmacokinetic (PBPK) model for dermal permeability for lindane.

    PubMed

    Sawyer, Megan E; Evans, Marina V; Wilson, Charles A; Beesley, Lauren J; Leon, Lider S; Eklund, Chris R; Croom, Edward L; Pegram, Rex A

    2016-03-14

    Lindane is a neurotoxicant used for the treatment of lice and scabies present on human skin. Due to its pharmaceutical application, an extensive pharmacokinetic database exists in humans. Mathematical diffusion models allow for calculation of lindane skin permeability coefficients using human kinetic data obtained from in vitro and in vivo experimentation as well as a default compound-specific calculation based on physicochemical characteristics used in the absence of kinetic data. A dermal model was developed to describe lindane diffusion into the skin, where the skin compartment consisted of homogeneous dermal tissue. This study utilized Fick's law of diffusion along with chemical binding to protein and lipids to determine appropriate dermal absorption parameters which were then incorporated into a physiologically based pharmacokinetic (PBPK) model to describe in vivo kinetics. The estimation of permeability coefficients using chemical binding in combination with in vivo data demonstrates the advantages of combining physiochemical properties with a PBPK model to predict dermal absorption. PMID:26794662

  8. Pharmacokinetics of quercetin-loaded nanodroplets with ultrasound activation and their use for bioimaging.

    PubMed

    Chang, Li-Wen; Hou, Mei-Ling; Hung, Shuo-Hui; Lin, Lie-Chwen; Tsai, Tung-Hu

    2015-01-01

    Bubble formulations have both diagnostic and therapeutic applications. However, research on nanobubbles/nanodroplets remains in the initial stages. In this study, a nanodroplet formulation was prepared and loaded with a novel class of chemotherapeutic drug, ie, quercetin, to observe its pharmacokinetic properties and ultrasonic bioimaging of specific sites, namely the abdominal vein and bladder. Four parallel groups were designed to investigate the effects of ultrasound and nanodroplets on the pharmacokinetics of quercetin. These groups were quercetin alone, quercetin triggered with ultrasound, quercetin-encapsulated in nanodroplets, and quercetin encapsulated in nanodroplets triggered with ultrasound. Spherical vesicles with a mean diameter of 280 nm were formed, and quercetin was completely encapsulated within. In vivo ultrasonic imaging confirmed that the nanodroplets could be treated by ultrasound. The results indicate that the initial 5-minute serum concentration, area under the concentration-time curve, elimination half-life, and clearance of quercetin were significantly enhanced by nanodroplets with or without ultrasound. PMID:25945049

  9. Accepted scientific research works (abstracts).

    PubMed

    2014-01-01

    These are the 39 accepted abstracts for IAYT's Symposium on Yoga Research (SYR) September 24-24, 2014 at the Kripalu Center for Yoga & Health and published in the Final Program Guide and Abstracts. PMID:25645134

  10. L-286 Acceptance Test Record

    SciTech Connect

    HARMON, B.C.

    2000-01-14

    This document provides a detailed account of how the acceptance testing was conducted for Project L-286, ''200E Area Sanitary Water Plant Effluent Stream Reduction''. The testing of the L-286 instrumentation system was conducted under the direct supervision

  11. Quantitative determination of sirolimus in dog blood using liquid chromatography-tandem mass spectrometry, and its applications to pharmacokinetic studies.

    PubMed

    Lee, Jong-Hwa; Cha, Kwang-Ho; Cho, Wonkyung; Park, Junsung; Park, Hee Jun; Cho, Youngseok; Hwang, Sung-Joo

    2010-12-01

    A rapid, sensitive method of detecting sirolimus in blood was developed and applied in pharmacokinetic studies employing deionized water for hemolysis and a weakly basic mobile phase to enhance chromatographic peak intensity. Dog blood samples were processed via liquid-liquid extraction and the amounts of sirolimus and tacrolimus, an internal standard, were quantified by LC-MS/MS. Specificity, the lower limit of quantification, linearity, accuracy, precision, dilution, recovery, matrix effects, robustness and stability were within the acceptable range for assay validation. The concentration of sirolimus was quantifiable in blood samples for up to 36 h after the dog had received a 3 mg/kg dose of sirolimus. These observations suggest that sirolimus can be detected at low levels in dog blood using a basic mobile phase and metal-free hemolysis. This method is therefore applicable to pharmacokinetic studies in dogs. PMID:20674213

  12. Population Pharmacokinetics of Benznidazole in Adult Patients with Chagas Disease

    PubMed Central

    Aldasoro, E.; Guerrero, L.; Posada, E.; Serret, N.; Mejía, T.; Urbina, J. A.; Gascón, J.

    2015-01-01

    The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h−1). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011

  13. Property.

    ERIC Educational Resources Information Center

    Goldblatt, Steven M.

    In this chapter on decisions made by federal and state courts during 1983 concerning school property it is noted that no new trends emerged during the year. Among the topics addressed are the extent of school board authority over property use and other property matters; the attachment and detachment of land from school district holdings; school…

  14. Property.

    ERIC Educational Resources Information Center

    Piele, Philip K.

    Several court cases involving acquisition, use, and disposal of property by institutions of higher education are briefly summarized in this chapter. Cases discussed touch on such topics as municipal annexation of university property; repurchase of properties temporarily allocated to faculty members; implications of zoning laws and zoning board…

  15. Multiple-Dose Pharmacokinetics of Fluvoxamine in Children and Adolescents.

    ERIC Educational Resources Information Center

    Labellarte, Michael; Biederman, Joseph; Emslie, Graham; Ferguson, James; Khan, Arifulla; Ruckle, Jon; Sallee, Randy; Riddle, Mark

    2004-01-01

    Objective: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. Method: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder…

  16. PHARMACOKINETIC MODELING FOR PERFLUORINATED CHEMICALS USED IN HOUSEHOLD CONSUMER PRODUCTS

    EPA Science Inventory

    PHARMACOKINETIC MODELING FOR PERFLUORONATED CHEMICALS USED IN HOUSEHOLD CONSUMER PRODUCTS
    Leona H. Clark and Hugh A. Barton
    US Environmental Protection Agency, ORD, NHEERL, ETD, Research Triangle Park, NC

    The physiologically-based pharmacokinetic model to be presente...

  17. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... addition to the reporting requirements as specified in 40 CFR part 792, the following specific information... pharmacokinetics and metabolism of a chemical substance or mixture (“test substance”) are similar after oral and... administration. (3) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the...

  18. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... requirements as specified in the EPA Good Laboratory Practice Standards (40 CFR 792.185), the following... whether the pharmacokinetics and metabolism of the “test substance” are similar after oral and inhalation...) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the test substance....

  19. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... addition to the reporting requirements as specified in 40 CFR part 792, the following specific information... pharmacokinetics and metabolism of a chemical substance or mixture (“test substance”) are similar after oral and... administration. (3) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the...

  20. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... requirements as specified in the EPA Good Laboratory Practice Standards (40 CFR 792.185), the following... whether the pharmacokinetics and metabolism of the “test substance” are similar after oral and inhalation...) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the test substance....

  1. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... requirements as specified in the EPA Good Laboratory Practice Standards (40 CFR 792.185), the following... whether the pharmacokinetics and metabolism of the “test substance” are similar after oral and inhalation...) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the test substance....

  2. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... requirements as specified in the EPA Good Laboratory Practice Standards (40 CFR 792.185), the following... whether the pharmacokinetics and metabolism of the “test substance” are similar after oral and inhalation...) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the test substance....

  3. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... addition to the reporting requirements as specified in 40 CFR part 792, the following specific information... pharmacokinetics and metabolism of a chemical substance or mixture (“test substance”) are similar after oral and... administration. (3) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the...

  4. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... addition to the reporting requirements as specified in 40 CFR part 792, the following specific information... pharmacokinetics and metabolism of a chemical substance or mixture (“test substance”) are similar after oral and... administration. (3) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the...

  5. PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF PERMETHRIN IN THE RAT

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model was used to describe pharmacokinetics of permethrin and calibrated using experimental data on the concentration time-course of cis- and trans-permethrin in rat blood and brain tissues following oral administration...

  6. KINPLOT: An Interactive Pharmacokinetics Graphics Program for Digital Computers.

    ERIC Educational Resources Information Center

    Wilson, Robert C.; And Others

    1982-01-01

    Inability to see the relevance of mathematics to understanding the time course of drugs in the body may discourage interest in pharmacokinetics. A UNC-developed computer graphics simulation program helps visualize the nature of pharmacokinetic-patient interactions, generates classroom handouts, and is used in the pharmaceuticals industry to…

  7. [Research progress on current pharmacokinetic evaluation of Chinese herbal medicines].

    PubMed

    Li, Guofu; Zhao, Haoru; Yang, Jin

    2011-03-01

    In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction. PMID:21657088

  8. Ocular pharmacokinetics of cephalosporins using microdialysis.

    PubMed

    Macha, S; Mitra, A K

    2001-10-01

    The purpose of this study was to delineate the ocular pharmacokinetics of cephalosporins and investigate the presence of peptide transporters in the retina. New Zealand albino rabbits were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous chamber and linear probe across the cornea in the aqueous humor. Isotonic phosphate buffer saline was perfused through the probes, and samples were collected every 20 min over a period of 10 hr. A 500 microg dose of cephalexin, cephazolin, and cephalothin was administered intravitreally. Inhibition experiments were carried out in vivo, using gly-pro and gly-sar. The vitreal half-lives of cephalexin, cefazolin, and cephalothin were 185.38 +/- 27.25 min, 111.40 +/- 17.17 min, and 146.68 +/- 47.52 min, respectively. Cephalexin generated higher aqueous humor concentrations compared to cefazolin. The pharmacokinetic parameters of cephalexin in the presence of gly-pro, i.e., AUC (44452.06 +/- 3326.55 microg x min/ml), clearance (0.0013 +/- 0.0004 ml/min) and vitreal half-life (825.12 +/- 499.95 min) were different from that of the control (14612.83 +/- 4036.47 microg x min/ml, 0.0036 +/- 0.0011 ml/min, and 187.96 +/- 65.12 min, respectively). Gly-pro did not inhibit cefazolin, and gly-sar showed no effect on the pharmacokinetics of both drugs. These studies indicate the involvement of a peptide carrier in the transport of cephalosporins across the retina. Although gly-pro inhibited the elimination of cephalexin from the vitreous, the effect of an alpha-amino group on peptide carriers was not clearly evident. PMID:11765153

  9. The pharmacokinetics of meloxicam in vultures.

    PubMed

    Naidoo, V; Wolter, K; Cromarty, A D; Bartels, P; Bekker, L; McGaw, L; Taggart, M A; Cuthbert, R; Swan, G E

    2008-04-01

    Vulture populations across the Asian subcontinent have declined dramatically in the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian, Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based on extensive acute safety studies in the African White-backed vulture (Gyps africanus), which evaluated worst case scenarios of maximum intake based on a once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further support for the safety of meloxicam in this animal species. This article discusses the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combination with a short duration of effect in the studied species Gyps vultures shown in this study makes it unlikely that the drug could accumulate. This confirms the safety of repeated exposure to meloxicam in vultures of this genus. PMID:18307504

  10. Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications.

    PubMed

    Stockmann, Chris; Constance, Jonathan E; Roberts, Jessica K; Olson, Jared; Doby, Elizabeth H; Ampofo, Krow; Stiers, Justin; Spigarelli, Michael G; Sherwin, Catherine M T

    2014-05-01

    Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected

  11. Chemical contaminants, pharmacokinetics, and the lactating mother.

    PubMed Central

    Rogan, W J; Ragan, N B

    1994-01-01

    We review the commonly occurring persistent pesticides and industrial chemicals in breast milk. These chemicals are dichlorodiphenyl trichloroethane as dichlorodiphenyl dichloroethene dieldrin, chlordane as oxychlordane, heptachlor, polychlorinated biphenyls, polychlorinated dibenzofurans, and polychlorinated dibenzodioxins. We present a worked example of the kinds of pharmacokinetic assumptions and calculations necessary for setting regulatory limits of contaminants in the food supply, calculating dose of chemical contaminants to the nursed infant, converting risks from lifetime exposure in laboratory animals to risks for short-term exposure in humans, and estimating the excess cancer risk to the nursed infant. PMID:7737048

  12. Pharmacokinetics of prednisolone in children with nephrosis.

    PubMed Central

    Miller, P F; Bowmer, C J; Wheeldon, J; Brocklebank, J T

    1990-01-01

    The pharmacokinetics of prednisolone given intravenously were studied in 11 children with relapsed steroid responsive nephrotic syndrome, and four control subjects. The clearance of both total and unbound drug was decreased in these children and the unbound fraction of the drug in plasma was significantly correlated with the degree of hypoalbuminaemia. We conclude that changes in the clearance of prednisolone and altered protein binding might account for some of the variability in both therapeutic responses and the incidence of toxicity in patients treated with standard dosage regimens. PMID:2317067

  13. Duloxetine: clinical pharmacokinetics and drug interactions.

    PubMed

    Knadler, Mary Pat; Lobo, Evelyn; Chappell, Jill; Bergstrom, Richard

    2011-05-01

    Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C(max)) of approximately 47 ng/mL (40 mg twice-daily dosing) to 110 ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10-12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C(max) of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate

  14. Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.

    PubMed

    Zhang, Minli; Zhou, Diansong; Wang, Yi; Maier, Donna L; Widzowski, Daniel V; Sobotka-Briner, Cynthia D; Brockel, Becky J; Potts, William M; Shenvi, Ashok B; Bernstein, Peter R; Pierson, M Edward

    2011-11-01

    The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients. PMID:21825000

  15. Freeze-drying of polycaprolactone and poly(D,L-lactic-glycolic) nanoparticles induce minor particle size changes affecting the oral pharmacokinetics of loaded drugs.

    PubMed

    Saez, A; Guzmán, M; Molpeceres, J; Aberturas, M R

    2000-11-01

    The present study was geared at identifying the conditions to stabilize poly (D,L-lactic-glycolic) (PLGA) and polycaprolactone (PCL) nanoparticles (NP) by freeze-drying with several cryoprotective agents. Differential scanning calorimetry and freeze-thawing studies were used to optimize the lyophilization process. These studies showed that all samples were totally frozen at -45 degrees C and evidenced the necessity of adding sucrose, glucose, trehalose or gelatine to preserve the properties of NP regardless of the freezing procedure. However, only 20% sucrose and 20% glucose exerted an acceptable lyoprotective effect on PLGA and PCL NP, respectively. Nonetheless, the final to initial size ratios ( approximately 1.5) indicated that particle size was slightly affected in both cases. In vivo studies with CyA-loaded PCL NP whose sizes matched those obtained after NP preparation (100 nm) and after being lyophilized (160 nm) showed that the changes of particle size might have some relevance on drug pharmacokinetics. The MRT was significantly (P<0.05) modified after an oral CyA dose of 5 mg/kg and the treatment with 160-nm sized CyA-loaded NP produced a higher drug partition into the liver of Wistar rats potentially affecting the toxic and immunosuppressive profile of the drug. Therefore, although the particle size changes induced by NP lyophilization were slight, they need to be carefully evaluated and cannot be neglected. PMID:11072195

  16. Defining acceptable conditions in wilderness

    NASA Astrophysics Data System (ADS)

    Roggenbuck, J. W.; Williams, D. R.; Watson, A. E.

    1993-03-01

    The limits of acceptable change (LAC) planning framework recognizes that forest managers must decide what indicators of wilderness conditions best represent resource naturalness and high-quality visitor experiences and how much change from the pristine is acceptable for each indicator. Visitor opinions on the aspects of the wilderness that have great impact on their experience can provide valuable input to selection of indicators. Cohutta, Georgia; Caney Creek, Arkansas; Upland Island, Texas; and Rattlesnake, Montana, wilderness visitors have high shared agreement that littering and damage to trees in campsites, noise, and seeing wildlife are very important influences on wilderness experiences. Camping within sight or sound of other people influences experience quality more than do encounters on the trails. Visitors’ standards of acceptable conditions within wilderness vary considerably, suggesting a potential need to manage different zones within wilderness for different clientele groups and experiences. Standards across wildernesses, however, are remarkably similar.

  17. From requirements to acceptance tests

    NASA Technical Reports Server (NTRS)

    Baize, Lionel; Pasquier, Helene

    1993-01-01

    From user requirements definition to accepted software system, the software project management wants to be sure that the system will meet the requirements. For the development of a telecommunication satellites Control Centre, C.N.E.S. has used new rules to make the use of tracing matrix easier. From Requirements to Acceptance Tests, each item of a document must have an identifier. A unique matrix traces the system and allows the tracking of the consequences of a change in the requirements. A tool has been developed, to import documents into a relational data base. Each record of the data base corresponds to an item of a document, the access key is the item identifier. Tracing matrix is also processed, providing automatically links between the different documents. It enables the reading on the same screen of traced items. For example one can read simultaneously the User Requirements items, the corresponding Software Requirements items and the Acceptance Tests.

  18. Pharmacokinetics and physiologic effects of alprazolam after a single oral dose in healthy mares.

    PubMed

    Wong, D M; Davis, J L; Alcott, C J; Hepworth-Warren, K L; Galow-Kersh, N L; Rice, S; Coetzee, J F

    2015-06-01

    The objective of this study was to evaluate the pharmacokinetic properties and physiologic effects of a single oral dose of alprazolam in horses. Seven adult female horses received an oral administration of alprazolam at a dosage of 0.04 mg/kg body weight. Blood samples were collected at various time points and assayed for alprazolam and its metabolite, α-hydroxyalprazolam, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of alprazolam was analyzed by a one-compartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single-dose administration of alprazolam were as follows: Cmax 14.76 ± 3.72 ng/mL and area under the curve (AUC0-∞ ) 358.77 ± 76.26 ng·h/mL. Median (range) Tmax was 3 h (1-12 h). Alpha-hydroxyalprazolam concentrations were detected in each horse, although concentrations were low (Cmax 1.36 ± 0.28 ng/mL). Repeat physical examinations and assessment of the degree of sedation and ataxia were performed every 12 h to evaluate for adverse effects. Oral alprazolam tablets were absorbed in adult horses and no clinically relevant adverse events were observed. Further evaluation of repeated dosing and safety of administration of alprazolam to horses is warranted. PMID:25427652

  19. Pharmacokinetics of enrofloxacin and marbofloxacin in Japanese quails and common pheasants.

    PubMed

    Lashev, L D; Dimitrova, D J; Milanova, A; Moutafchieva, R G

    2015-04-01

    The pharmacokinetics of enrofloxacin and marbofloxacin was studied in Japanese quails and common pheasants. Healthy mature birds from both species and both genders were treated intravenously and orally with enrofloxacin (10 mg/kg) and marbofloxacin (5 mg/kg). After intravenous administration enrofloxacin was extensively metabolised to ciprofloxacin. Metabolites of marbofloxacin were not detected. Values of volume of distribution were respectively 4.63 l/kg and 3.67 l/kg for enrofloxacin and 1.56 l/kg and 1.43 l/kg for marbofloxacin. In quails, total body clearance values were higher than those in pheasants and other avian species. After oral application enrofloxacin was rapidly absorbed in quails, more rapidly than marbofloxacin. Pheasants absorbed both antimicrobials at a lower rate. Higher bioavailability was observed for marbofloxacin (118%). Relatively low bioavailability was established in quails for enrofloxacin (26.4%), accompanied by extensive conversion to ciprofloxacin. Generally, quails absorbed and eliminated both fluoroquinolones more rapidly than pheasants; the latter showed pharmacokinetics similar to poultry. Because of favourable pharmacokinetic properties, marbofloxacin should be preferred for oral administration in Japanese quails and pheasants for treatment of infections caused by equally susceptible pathogens. PMID:25567298

  20. Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

    PubMed Central

    Badhan, Raj K. Singh; Chenel, Marylore; Penny, Jeffrey I.

    2014-01-01

    Central nervous system (CNS) drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB), blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF), choroidal epithelial and total cerebrospinal fluid (CSF) compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain) and CSF:plasma ratio (CSF:Plasmau) using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways. PMID:24647103

  1. Effect of piperine on the bioavailability and pharmacokinetics of emodin in rats.

    PubMed

    Di, Xin; Wang, Xin; Di, Xin; Liu, Youping

    2015-11-10

    Emodin (1,3,8-trihydroxy-6-methylanthraquinone) has been widely used as a traditional medicine and was shown to possess a multitude of health-promoting properties in pre-clinical studies, but its bioavailability was low due to the extensive glucuronidation in liver and intestine, hindering the development of emodin as a feasible chemopreventive agent. In this study, piperine, as a bioenhancer, was used to enhance the bioavailability of emodin by inhibiting its glucuronidation. The pharmacokinetic profiles of emodin after oral administration of emodin (20mg/kg) alone and in combination with piperine (20mg/kg) to rats were investigated via a validated LC/MS/MS method. As the in vivo pharmacokinetic studies had indicated, the AUC and Cmax of emodin were increased significantly after piperine treatment, and the glucuronidation of emodin was markedly inhibited. Our study demonstrated that piperine significantly improved the in vivo bioavailability of emodin and the influence of piperine on the pharmacokinetics of emodin may be attributed to the inhibition of glucuronidation of emodin. Further research is needed to investigate the detailed mechanism of improved bioavailability of emodin via its combination with piperine. PMID:26201645

  2. Development of a Physiologically-Based Pharmacokinetic Model for Preterm Neonates: Evaluation with In Vivo Data.

    PubMed

    Claassen, Karina; Thelen, Kirstin; Coboeken, Katrin; Gaub, Thomas; Lippert, Jorg; Allegaert, Karel; Willmann, Stefan

    2015-01-01

    Among pediatric patients, preterm neonates and newborns are the most vulnerable subpopulation. Rapid developmental changes of physiological factors affecting the pharmacokinetics of drug substances in newborns require extreme care in dose and dose regimen decisions. These decisions could be supported by in silico methods such as physiologically-based pharmacokinetic (PBPK) modeling. In a comprehensive literature search, the physiological information of preterm neonates that is required to establish a PBPK model has been summarized and implemented into the database of a generic PBPK software. Physiological parameters include the organ weights and blood flow rates, tissue composition, as well as ontogeny information about metabolic and elimination processes in the liver and kidney. The aim of this work is to evaluate the model's accuracy in predicting the pharmacokinetics following intravenous administration of two model drugs with distinct physicochemical properties and elimination pathways based on earlier reported in vivo data. To this end, PBPK models of amikacin and paracetamol have been set up to predict their plasma levels in preterm neonates. Predicted plasma concentration-time profiles were compared to experimentally obtained in vivo data. For both drugs, plasma concentration time profiles following single and multiple dosing were appropriately predicted for a large range gestational and postnatal ages. In summary, PBPK simulations in preterm neonates appear feasible and might become a useful tool in the future to support dosing decisions in this special patient population. PMID:26323410

  3. In vivo gastroprotective effect along with pharmacokinetics, tissue distribution and metabolism of isoliquiritigenin in mice.

    PubMed

    Choi, Young Hee; Kim, You-Jin; Chae, Hee-Sung; Chin, Young-Won

    2015-05-01

    As numerous herbal products have been used as dietary supplements or functional foods, the demands of the pharmacokinetic and pharmacodynamic characteristics of active compounds are increasing in order to secure a consistent outcome (i.e., efficiency and safety). In this study, the pharmacokinetics including tissue distribution, metabolism, and protein binding of isoliquiritigenin, a chalcone found in Glycyrrhiza glabra, and its metabolite, liquiritigenin, at various doses in mice are reported. Also, correlations between the preferential tissue distribution and pharmacological effect of isoliquiritigenin in certain organs were investigated using the in vivo gastroprotective effect of isoliquiritigenin in mice with indomethacin-induced ulcer. The absorbed fraction of isoliquiritigenin was high, but the absolute bioavailability was low mainly due to its metabolism. In spite of the low bioavailability, the gastroprotective effect of isoliquiritigenin was attributed to its high distribution in the stomach. Isoliquiritigenin prevented the occurrence of gastric ulcers by indomethacin, which is associated with increased gastric mucous secretion because the pretreatment with isoliquiritigenin presumably counteracted the decreased cyclooxygenase 2 by indomethacin. This may suggest that the pharmacokinetic properties of isoliquiritigenin are useful to predict its efficacy as a gastroprotective agent in a target organ such as the stomach. PMID:25875506

  4. Property.

    ERIC Educational Resources Information Center

    Piele, Philip K.; Johnson, Margaret M.

    This chapter deals with 1981 cases involving disputes over property. Cases involving the detachment and attachment of land continue to dominate the property chapter with 11 cases reported, the same number summarized in last year's chapter. One case involving school board referenda raised the interesting question of whether or not a state could…

  5. Property.

    ERIC Educational Resources Information Center

    Bickel, Robert D.; Zeller, Trisha A.

    A number of cases related to property issues involving institutions of higher education are examined in this chapter. Cases discussed touch on such topics as funding for property and equipment acquisition; opposition to building construction or demolition; zoning issues; building construction and equipment contracts; and lease agreements. Current…

  6. Property.

    ERIC Educational Resources Information Center

    Goldblatt, Steven M.; Piele, Philip K.

    This chapter reviews 1982 cases related to school property. Cases involving citizen efforts to overturn school board decisions to close schools dominate the property chapter, and courts continue to uphold school board authority to close schools, transfer students, and sell or lease the buildings. Ten cases involving detachment and attachment of…

  7. Property.

    ERIC Educational Resources Information Center

    Piele, Philip K.

    Chapter 7 of a book on school law, this chapter deals with 1979 cases involving disputes over property. Cases involving taxpayer attempts to prevent the construction of school buildings dominate this year's property chapter, as they did last year's. Yet, paradoxically, there is also a significant increase in cases in which taxpayers tried to…

  8. The MAGNEX large acceptance spectrometer

    SciTech Connect

    Cavallaro, M.; Cappuzzello, F.; Cunsolo, A.; Carbone, D.; Foti, A.

    2010-03-01

    The main features of the MAGNEX large acceptance magnetic spectrometer are described. It has a quadrupole + dipole layout and a hybrid detector located at the focal plane. The aberrations due to the large angular (50 msr) and momentum (+- 13%) acceptance are reduced by an accurate hardware design and then compensated by an innovative software ray-reconstruction technique. The obtained resolution in energy, angle and mass are presented in the paper. MAGNEX has been used up to now for different experiments in nuclear physics and astrophysics confirming to be a multipurpose device.

  9. Comparative pharmacokinetics of apalcillin and piperacillin.

    PubMed Central

    Lode, H; Elvers, A; Koeppe, P; Borner, K

    1984-01-01

    The pharmacokinetics of apalcillin and piperacillin, each administered intravenously as a single 2-g dose, were compared in 10 volunteers in a randomized study of crossover design using bioassay and high-pressure liquid chromatographic procedures. The concentrations of both penicillins in serum were determined over a period of 12 h and in urine over 24 h. Concentrations of apalcillin and piperacillin at the end of the 15-min infusion were similar; however, at 8 h, concentrations of piperacillin were below measurable levels, whereas concentrations of apalcillin were still measurable at 10 h. Pharmacokinetic parameters were calculated according to a two-compartment open model. The area under the curve and the half-life for apalcillin were larger than for piperacillin. On the other hand, renal clearance of piperacillin was substantially greater than that of apalcillin. Of the apalcillin excreted via the kidneys, approximately one-fifth was eliminated as two microbiologically inactive penicilloic acid derivatives. The nonrenal clearance of apalcillin was 79% of total clearance. Binding of apalcillin to serum protein was almost twice that of piperacillin. PMID:6703672

  10. Pharmacokinetics of subcutaneous fentanyl in Greyhounds.

    PubMed

    KuKanich, Butch

    2011-11-01

    The purpose of the study was to describe the pharmacokinetics of subcutaneous fentanyl (15μg/kg) in six healthy Greyhound dogs. Fentanyl plasma concentrations were determined by a liquid chromatography with mass spectrometry method. Non-compartmental pharmacokinetic analysis was used. Fentanyl was rapidly absorbed with a mean peak concentration (C(MAX)) of 3.56ng/mL at 0.24h. The mean terminal half-life, volume of distribution per bioavailability, and clearance per bioavailability were 2.97h, 7.09L/kg, 27.60mL/min/kg, respectively. Pain occurred on injection in all six dogs, but addition of 8.4% sodium bicarbonate (1mL per 20mL fentanyl) resulted in no pain on injection in 3/3 dogs but similar C(MAX) values. The subcutaneous route may be an alternative route of fentanyl administration if intravenous administration is not practical. PMID:21388844

  11. Salicylate pharmacokinetics in patients with rheumatoid arthritis.

    PubMed Central

    Owen, S G; Roberts, M S; Friesen, W T; Francis, H W

    1989-01-01

    1. The pharmacokinetics of salicylic acid (SA) and its major metabolite salicyluric acid (SU) were studied in nine patients with rheumatoid arthritis following a 900 mg oral dose of acetylsalicylic acid and during 6 weeks of chronic administration of enteric coated aspirin (3,900 mg day). Response to therapy was also monitored. 2. The various pharmacokinetic parameters determined in the study were similar to those observed in other single dose salicylate studies amongst healthy volunteers but were not predictive of salicylate concentration in the chronic dose study. 3. Plasma concentrations of SA (total and unbound) were found to decline significantly over the 6 weeks and plasma SU concentrations increased. 4. During the chronic dosing study, there was a significant increase in the Vmax (total and unbound) for the formation of SU, whilst the Km and SU clearance remained constant. Also, the elimination rate constant (k) for salicylate was not significantly affected. 5. Therapeutic response to salicylate therapy was not significantly affected by the decline in SA concentrations. PMID:2590603

  12. Pharmacokinetic study of copper (II) acetylsalicylate.

    PubMed

    Iqbal, Mohammad S; Sher, Muhammad; Pervez, Humayun; Saeed, Maryiam

    2008-09-01

    This study was aimed at determination of pharmacokinetic parameters of copper (II) acetylsalicylate (CAS). Ten volunteers received a 60-mg dose of CAS. Blood samples were collected just before and after 0.25, 0.5, 0.75, 1.0, 1.5, 2.5, 3.0, 3.5, 4.0, 4.5, 5.5, 7.0, 10, and 12.0 h of administration of the drug. The plasma samples were analyzed for CAS and its metabolites by a validated high-performance liquid chromatography method having a suitable lower limit of quantification. The dose of 60 mg was well tolerated without any adverse effect. The maximum plasma concentration of CAS was found to be 0.38 mg L(-1) with t (max) of 0.72 h. The plasma half-life, clearance, and volume of distribution of CAS were 8.67 h, 66.30 L h(-1) and 829 L kg(-1), respectively. The elimination of CAS, acetylsalicylic acid, copper salicylate, and salicylic acid follows the first order kinetics with r (2) 0.979, 0.880, 0.991, and 0.998, respectively. The study provided for the first time the pharmacokinetic data for CAS after oral administration of CAS. The data were found to be useful in understanding the claimed enhanced anti-inflammatory activity of the drug as compared with that of acetylsalicylic acid. PMID:18478192

  13. Gender differences in ondansetron pharmacokinetics in rats.

    PubMed

    Yang, Si H; Yang, Kyung H; Lee, Myung G

    2008-10-01

    It has been reported that ondansetron is primarily metabolized via hepatic CYP2D and 3A1/2 in male Sprague-Dawley rats, and CYP2D1 and 3A2 are male dominant and male specific isozymes, respectively, in rats. Thus, it could be expected that the pharmacokinetics of ondansetron would be changed in male rats compared with those in female rats. Thus, gender-different ondansetron pharmacokinetics were evaluated after its intravenous or oral administration at a dose of 8 mg/kg to male and female Sprague-Dawley rats. After intravenous administration of ondansetron to male rats, the AUC and time-averaged non-renal clearance (Clnr) of the drug were significantly smaller (22.6% decrease) and faster (27.3% increase), respectively, than those in female rats. This probably could be due to faster hepatic blood flow rate in male rats. After oral administration of ondansetron to male rats, the AUC of the drug was also significantly smaller (58.8% decrease) than that in female rats, and this could have been due mainly to increased intestinal metabolism of ondansetron in addition to increased hepatic metabolism of the drug in male rats. PMID:18696412

  14. Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans

    PubMed Central

    Huestis, M.A.; Cone, E.J.; Pirnay, S.O.; Umbricht, A.; Preston, K.L.

    2013-01-01

    Background Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine. Methods Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography tandem mass spectrometry with limits of quantitation of 0.1 μg/L. Results Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3±1.0, 44.5±4.8, 85.2±7.7, 124.6±16.6, and 137.7±18.8 μg/L, respectively. Maximum norbuprenorphine concentrations occurred 10–15 min (3.7±0.7 μg/L) after 16 mg IV administration. Conclusions Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2–16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg. PMID:23246635

  15. Pharmacokinetics of cefoperazone in healthy volunteers.

    PubMed

    Saudek, F; Morávek, J; Modr, Z

    1986-01-01

    Pharmacokinetics of cefoperazone was studied in 10 healthy volunteers following 15 min intravenous infusion of 2 g. Cefoperazone levels in the blood serum and in the urine were determined microbiologically. At the end of the infusion, mean serum concentrations of the antibiotic were 340.4 (+/- 81.5) mg/l, at the 4th hour after the infusion 38.4 (+/- 10.3) mg/l, and 12 hours after the infusion all subjects had detectable concentrations with the mean value 2.2 (+/- 0.7) mg/l. Within 12 hours, 33.3 (+/- 6.1) % of the total dose of cefoperazone had been eliminated in the urine. The fitting of the individual serum concentration curves and the determination of pharmacokinetic constants were done according to a two-compartment model with the aid of nonlinear least-squares regression analysis on a programmable calculator TI 59. The mean value of the biological half-life (beta phase) of cefoperazone was 1.77 (+/- 0.25) h, mean serum clearance was 61.7 (+/- 12.1) ml/min and the mean distribution volume (Vd area) was 9.44 (+/- 2.2) 1. Our data are in agreement with those previously reported in the literature. The only exception is the distribution volume, which we found to be smaller. PMID:3095076

  16. Pharmacokinetics of Antiretrovirals in Mucosal Tissue

    PubMed Central

    Cottrell, M.L.; Srinivas, N.; Kashuba, A.D.M.

    2015-01-01

    Introduction In the absence of an HIV vaccine or cure, antiretroviral (ARV) based prevention strategies are being investigated to reduce HIV incidence. These prevention strategies depend on achieving effective drug concentrations at the site HIV exposure which is most commonly the mucosal tissues of the lower gastrointestinal tract and the female genital tract. Areas covered This article collates all known data regarding drug exposure in these vulnerable mucosal tissues, and reviews important mechanisms of ARV drug distribution. Research papers and abstracts describing antiretroviral pharmacokinetics in the female genital tract and lower gastrointestinal mucosal tissues available in MEDLINE® or presented at scientific conferences prior to December 2014 are reviewed in detail. Important influences on ARV mucosal tissue distribution, including protein binding, active drug transport, and endogenous hormones, are also reviewed. Expert opinion ARVs exhibit highly variable pharmacokinetics in mucosal tissues. In general, antiretroviral exposure is higher in the lower gastrointestinal tract compared to the female genital tract, but concentrations required for protective efficacy are largely unknown. The expected site of HIV exposure represents an important consideration when designing and optimizing antiretroviral based prevention strategies. PMID:25797064

  17. 41 CFR 102-75.1150 - What happens to the gift if GSA determines it to be acceptable?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... if GSA determines it to be acceptable? 102-75.1150 Section 102-75.1150 Public Contracts and Property...-75.1150 What happens to the gift if GSA determines it to be acceptable? When GSA determines that the gift is acceptable and can be accepted and used in the form in which it was offered, GSA must...

  18. Pharmacokinetics and immunogenicity of a recombinant human butyrylcholinesterase bioscavenger in macaques following intravenous and pulmonary delivery.

    PubMed

    Rosenberg, Yvonne J; Adams, Robert J; Hernandez-Abanto, Segundo; Jiang, Xiaoming; Sun, Wei; Mao, Lingjun; Lee, K David

    2015-12-01

    Recombinant (r) and native butyrylcholinesterse (BChE) are potent bioscavengers of organophosphates (OPs) such as nerve agents and pesticides and are undergoing development as antidotal treatments for OP-induced toxicity. Because of the lethal properties of such agents, regulatory approval will require extensive testing under the Animal Rule. However, human (Hu) glycoprotein biologicals, such as BChE, present a challenge for assessing immunogenicity and efficacy in heterologous animal models since any immune responses to the small species differences in amino acids or glycans between the host and biologic may alter pharmacodynamics and preclude accurate efficacy testing; possibly underestimating their potential protective value in humans. To establish accurate pharmacokinetic and efficacy data, an homologous animal model has been developed in which native and PEGylated forms of CHO-derived rMaBChE were multiply injected into homologous macaques with no induction of antibody. These now serve as controls for assessing the pharmacokinetics and immunogenicity in macaques of multiple administrations of PEGylated and unmodified human rBChE (rHuBChE) by both intravenous (IV) and pulmonary routes. The results indicate that, except for maximal concentration (Cmax), the pharmacokinetic parameters following IV injection with heterologous PEG-rHuBChE were greatly reduced even after the first injection compared with homologous PEG-rMaBChE. Anti-HuBChE antibody responses were induced in all monkeys after the second and third administrations regardless of the route of delivery; impacting rates of clearance and usually resulting in reduced endogenous MaBChE activity. These data highlight the difficulties inherent in assessing pharmacokinetics and immunogenicity in animal models, but bode well for the efficacy and safety of rHuBChE pretreatments in homologous humans. PMID:26415620

  19. Physiologically-based pharmacokinetic modeling to predict the clinical pharmacokinetics of monoclonal antibodies.

    PubMed

    Glassman, Patrick M; Balthasar, Joseph P

    2016-08-01

    Accurate prediction of the clinical pharmacokinetics of new therapeutic entities facilitates decision making during drug discovery, and increases the probability of success for early clinical trials. Standard strategies employed for predicting the pharmacokinetics of small-molecule drugs (e.g., allometric scaling) are often not useful for predicting the disposition monoclonal antibodies (mAbs), as mAbs frequently demonstrate species-specific non-linear pharmacokinetics that is related to mAb-target binding (i.e., target-mediated drug disposition, TMDD). The saturable kinetics of TMDD are known to be influenced by a variety of factors, including the sites of target expression (which determines the accessibility of target to mAb), the extent of target expression, the rate of target turnover, and the fate of mAb-target complexes. In most cases, quantitative information on the determinants of TMDD is not available during early phases of drug discovery, and this has complicated attempts to employ mechanistic mathematical models to predict the clinical pharmacokinetics of mAbs. In this report, we introduce a simple strategy, employing physiologically-based modeling, to predict mAb disposition in humans. The approach employs estimates of inter-antibody variability in rate processes of extravasation in tissues and fluid-phase endocytosis, estimates for target concentrations in tissues derived through use of categorical immunohistochemical scores, and in vitro measures of the turnover of target and target-mAb complexes. Monte Carlo simulations were performed for four mAbs (cetuximab, figitumumab, dalotuzumab, trastuzumab) directed against three targets (epidermal growth factor receptor, insulin-like growth factor receptor 1, human epidermal growth factor receptor 2). The proposed modeling strategy was able to predict well the pharmacokinetics of cetuximab, dalotuzumab, and trastuzumab at a range of doses, but trended towards underprediction of figitumumab concentrations

  20. Nitrogen trailer acceptance test report

    SciTech Connect

    Kostelnik, A.J.

    1996-02-12

    This Acceptance Test Report documents compliance with the requirements of specification WHC-S-0249. The equipment was tested according to WHC-SD-WM-ATP-108 Rev.0. The equipment being tested is a portable contained nitrogen supply. The test was conducted at Norco`s facility.

  1. Helping Our Children Accept Themselves.

    ERIC Educational Resources Information Center

    Gamble, Mae

    1984-01-01

    Parents of a child with muscular dystrophy recount their reactions to learning of the diagnosis, their gradual acceptance, and their son's resistance, which was gradually lessened when he was provided with more information and treated more normally as a member of the family. (CL)

  2. Acceptability of Treatments for Plagiarism

    ERIC Educational Resources Information Center

    Carter, Stacy L.; Punyanunt-Carter, Narissra Maria

    2007-01-01

    This study focused on various treatments for addressing incidents of plagiarism by college students. College students rated the acceptability of different responses by college faculty to a case description of a college student who engaged in plagiarism. The findings revealed that students found some methods of addressing this problem behavior by…

  3. Euthanasia Acceptance: An Attitudinal Inquiry.

    ERIC Educational Resources Information Center

    Klopfer, Fredrick J.; Price, William F.

    The study presented was conducted to examine potential relationships between attitudes regarding the dying process, including acceptance of euthanasia, and other attitudinal or demographic attributes. The data of the survey was comprised of responses given by 331 respondents to a door-to-door interview. Results are discussed in terms of preferred…

  4. [Discussion about traditional Chinese medicine pharmacokinetics study based on first botanical drug approved by FDA].

    PubMed

    Huang, Fanghua

    2010-04-01

    Pharmacokinetics study is one of main components of pharmaceuticals development. Food and Drug Administration (FDA) approved Veregen as the first botanical drug in 2006. This article introduced FDA's requirement on pharmacokinetics study of botanical drug and pharmacokinetics studies of Veregen, summarized current requirement and status quo of pharmacokinetics study on traditional Chinese medicine (TCM) and natural medicine in China, and discussed about pharmacokinetics study strategy for TCM and natural medicine. PMID:20575403

  5. Nonlinear pharmacokinetics of 5-methoxy-N,N-dimethyltryptamine in mice.

    PubMed

    Shen, Hong-Wu; Jiang, Xi-Ling; Yu, Ai-Ming

    2011-07-01

    5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, was placed into Schedule I controlled substance status in the United States as of January 19, 2011. In previous studies, we have shown the impact of monoamine oxidase A and cytochrome P450 2D6 enzymes on 5-MeO-DMT metabolism and pharmacokinetics. The aim of this study was to investigate 5-MeO-DMT pharmacokinetic properties after intravenous or intraperitoneal administration of three different doses (2, 10, and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. Systemic exposure [area under the curve (AUC)] to 5-MeO-DMT was increased nonproportionally with the increase in dose. The existence of nonlinearity in serum 5-MeO-DMT pharmacokinetics was clearly manifested by dose-normalized AUC values, which were approximately 1.5- to 2.0-fold (intravenous) and 1.8- to 2.7-fold (intraperitoneal) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination, and CYP2D6-dependent linear elimination from the central compartment was developed to characterize the intravenous and intraperitoneal pharmacokinetic data for 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain after drug treatment, and brain 5-MeO-DMT concentrations were also increased nonproportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that the risk of 5-MeO-DMT intoxication may be increased nonproportionally at higher doses. PMID:21464174

  6. Nonlinear Pharmacokinetics of 5-Methoxy-N,N-dimethyltryptamine in MiceS⃞

    PubMed Central

    Shen, Hong-Wu; Jiang, Xi-Ling

    2011-01-01

    5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, was placed into Schedule I controlled substance status in the United States as of January 19, 2011. In previous studies, we have shown the impact of monoamine oxidase A and cytochrome P450 2D6 enzymes on 5-MeO-DMT metabolism and pharmacokinetics. The aim of this study was to investigate 5-MeO-DMT pharmacokinetic properties after intravenous or intraperitoneal administration of three different doses (2, 10, and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. Systemic exposure [area under the curve (AUC)] to 5-MeO-DMT was increased nonproportionally with the increase in dose. The existence of nonlinearity in serum 5-MeO-DMT pharmacokinetics was clearly manifested by dose-normalized AUC values, which were approximately 1.5- to 2.0-fold (intravenous) and 1.8- to 2.7-fold (intraperitoneal) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination, and CYP2D6-dependent linear elimination from the central compartment was developed to characterize the intravenous and intraperitoneal pharmacokinetic data for 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain after drug treatment, and brain 5-MeO-DMT concentrations were also increased nonproportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that the risk of 5-MeO-DMT intoxication may be increased nonproportionally at higher doses. PMID:21464174

  7. Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling

    PubMed Central

    Størset, Elisabet; Holford, Nick; Hennig, Stefanie; Bergmann, Troels K; Bergan, Stein; Bremer, Sara; Åsberg, Anders; Midtvedt, Karsten; Staatz, Christine E

    2014-01-01

    Aims The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models. Methods Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting. Results Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h−1 [95% CI 12.6, 18.0 l h−1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range. Conclusion A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation. PMID:25279405

  8. Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development.

    PubMed

    Rioux, Nathalie; Waters, Nigel J

    2016-07-01

    Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field. PMID:26936973

  9. Pharmacokinetic Profile of µSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats.

    PubMed

    Russo, Rosario; Mancinelli, Angelo; Ciccone, Michele; Terruzzi, Fabio; Pisano, Claudio; Severino, Lorella

    2015-09-01

    Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (µSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t½), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with µSMIN Plus™ compared with animals treated with micronized diosmin. In particular, µSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for µSMIN Plus™, which may represent a new tool for CVI management. PMID:26594761

  10. Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs.

    PubMed

    Fader, Lee D; Bailey, Murray; Beaulieu, Eric; Bilodeau, François; Bonneau, Pierre; Bousquet, Yves; Carson, Rebekah J; Chabot, Catherine; Coulombe, René; Duan, Jianmin; Fenwick, Craig; Garneau, Michel; Halmos, Ted; Jakalian, Araz; James, Clint; Kawai, Stephen H; Landry, Serge; LaPlante, Steven R; Mason, Stephen W; Morin, Sebastien; Rioux, Nathalie; Simoneau, Bruno; Surprenant, Simon; Thavonekham, Bounkham; Thibeault, Carl; Trinh, Thao; Tsantrizos, Youla; Tsoung, Jennifer; Yoakim, Christiane; Wernic, Dominik

    2016-08-11

    Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV. PMID:27563405

  11. Cyclosporine pharmacokinetics in pancreas transplant recipients.

    PubMed

    Munda, R; Schroeder, T J; Pedersen, S A; Clardy, C W; Wadhwa, N K; Myre, S A; Stephens, G W; Pesce, A J; Alexander, J W; First, M R

    1988-04-01

    Ten CsA pharmacokinetic studies were performed on five pancreas transplant recipients to determine proper doses and dosing intervals. These cadaver pancreas transplants were performed with exocrine ductal drainage into the urinary tract through a bladder anastomosis in four cases and into the bowel in one case. Four CsA pharmacokinetic studies were performed on diabetic renal transplant recipients and an additional six studies were performed while with pancreas transplant patients taking metoclopramide in an effort to enhance absorption of CsA. Mean CsA dose was 3.7 mg/kg/dose (range 2.1 to 7.5 mg/kg/dose). All patients but one were on twice daily dosing intervals yielding an average daily dose of 7.4 mg/kg/d. Noncompartmental pharmacokinetic analyses were used. The adequacy of a 1-, 2-, or 3-exponential model was determined by breakpoint analysis of the log concentration v time curve using the F statistic. The terminal rate constant was calculated by nonlinear regression analysis. The AUC and AUMC were calculated by the trapezoidal method with exponential extrapolation and these were used to calculate the MRT and Vdss. The unknown fractional absorption, F, was used to correct the oral data. The average CsA concentration maximum (Cmax) was 528 ng/mL with an average time to maximum concentration (Tmax) of 4.7 hours, a mean residence time of 7.75 hours, with a Vdss/%F of 9.61 L/kg in the pancreas transplant recipients. Additional studies of six patients receiving metoclopramide with CsA revealed an average Cmax of 723 ng/mL, an average Tmax of 2.3 hours, an average MRT of 6.08 hours, and an average Vdss/%F of 5.7% L/kg. These results indicate that coexistent gastroparesis in diabetic recipients of either pancreatic or renal transplants may result in reduced bioavailability of CsA. PMID:3284095

  12. Covariates of intravenous paracetamol pharmacokinetics in adults

    PubMed Central

    2014-01-01

    Background Pharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled. Methods This pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models. Results Paracetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (FPREG = 1.14) and decreased during abdominal surgery (FABDCL = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (FORTHOV = 0.649), while those in intensive care had increased V2 (FICV = 1.51). Conclusions Size and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored. PMID:25342929

  13. Clinical Pharmacokinetic and Pharmacodynamic Profile of Idelalisib.

    PubMed

    Ramanathan, Srinivasan; Jin, Feng; Sharma, Shringi; Kearney, Brian P

    2016-01-01

    Idelalisib is a potent and selective phosphatidylinositol 3-kinase-δ inhibitor, which is a first-in-class agent to be approved for the treatment of relapsed chronic lymphocytic leukaemia, follicular B cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. In dose-ranging studies, idelalisib exposure increased in a less than dose-proportional manner, likely because of solubility-limited absorption. The approved starting dose of 150 mg twice daily was supported by extensive exposure-response evaluations, with dose reduction to 100 mg twice daily being allowed for specific toxicities. Idelalisib may be administered without regard to food on the basis of the absence of clinically relevant food effects, and was accordingly dosed in primary efficacy/safety studies. Idelalisib is metabolized primarily via aldehyde oxidase (AO) and, to a lesser extent, via cytochrome P450 (CYP) 3A. Coadministration with the strong CYP3A inhibitor ketoconazole 400 mg once daily resulted in a ~79 % increase in the idelalisib area under the plasma concentration-time curve (AUC). Administration with the potent inducer rifampin resulted in a 75 % decrease in idelalisib exposure (AUC) and, as such, coadministration with strong inducers should be avoided. GS-563117 is an inactive primary circulating metabolite of idelalisib formed mainly via AO. Unlike idelalisib, GS-563117 is a mechanism-based inhibitor of CYP3A. Accordingly, idelalisib 150 mg twice-daily dosing increases the midazolam AUC 5.4-fold. Clinically, idelalisib is not an inhibitor of the transporters P-glycoprotein, breast cancer resistance protein, organic anion-transporting polypeptide (OATP) 1B1 or OAPT1B3. In a population pharmacokinetic model, no meaningful impact on idelalisib pharmacokinetics was noted for any of the covariates tested. Idelalisib exposure was ~60 % higher with moderate/severe hepatic impairment; no relevant changes were observed with severe renal impairment. This article reviews a comprehensive

  14. Pharmacokinetics and interactions of headache medications, part I: introduction, pharmacokinetics, metabolism and acute treatments.

    PubMed

    Sternieri, Emilio; Coccia, Ciro Pio Rosario; Pinetti, Diego; Ferrari, Anna

    2006-12-01

    Recent progress in the treatment of primary headaches has made available specific, effective and safe medications for these disorders, which are widely spread among the general population. One of the negative consequences of this undoubtedly positive progress is the risk of drug-drug interactions. This review is the first in a two-part series on pharmacokinetic drug-drug interactions of headache medications. Part I addresses acute treatments. Part II focuses on prophylactic treatments. The overall aim of this series is to increase the awareness of physicians, either primary care providers or specialists, regarding this topic. Pharmacokinetic drug-drug interactions of major severity involving acute medications are a minority among those reported in literature. The main drug combinations to avoid are: i) NSAIDs plus drugs with a narrow therapeutic range (i.e., digoxin, methotrexate, etc.); ii) sumatriptan, rizatriptan or zolmitriptan plus monoamine oxidase inhibitors; iii) substrates and inhibitors of CYP2D6 (i.e., chlorpromazine, metoclopramide, etc.) and -3A4 (i.e., ergot derivatives, eletriptan, etc.), as well as other substrates or inhibitors of the same CYP isoenzymes. The risk of having clinically significant pharmacokinetic drug-drug interactions seems to be limited in patients with low frequency headaches, but could be higher in chronic headache sufferers with medication overuse. PMID:17125411

  15. The pharmacokinetic effect of coadministration of apremilast and methotrexate in individuals with rheumatoid arthritis and psoriatic arthritis

    PubMed Central

    Liu, Yong; Zhou, Simon; Nissel, James; Wu, Anfan; Lau, Henry; Palmisano, Maria

    2014-01-01

    Apremilast is a novel agent for the treatment of inflammatory based autoimmune disorders. The objective of this study was to assess the pharmacokinetic effects of co administration of apremilast and methotrexate on both agents. This was an open-label, multi-center, 3-treatment period, sequential study conducted in otherwise healthy subjects with psoriatic arthritis or rheumatoid arthritis who were receiving a stable oral dose of methotrexate between 7.5 to 20 mg once weekly. Subjects received their dose of methotrexate on Days 1 and 8 of the study in addition to Apremilast 30 mg oral every 12 hours on Days 3–8. Pharmacokinectic profiles of methotrexate and 7-OH methotrexate were characterized after methotrexate alone (Day 1) and after co-administration of methotrexate and Apremilast (on Day 8). The pharmacokinetic profile of Apremilast was characterized after Apremilast alone (on Day 7) and after co-administration of methotrexate and Apremilast (on Day 8). The 90% confidence interval of the ratio of the geometric means for the Cmax and AUC parameters for methotrexate, 7-OH methotrexate, and Apremilast alone and after co-adminstration are all within the FDA acceptance range for equivalency (80–125%). This study showed that methotrexate and apremilast can be co-administered without any effect on the pharmacokinetic exposure of either agent. PMID:26097790

  16. Preclinical pharmacokinetics, tissue distribution and excretion studies of a novel anti-candidal agent-thiosemicarbazide derivative of isoniazid (TSC-INH) by validated UPLC-MS/MS assay.

    PubMed

    Iqbal, Muzaffar; Ezzeldin, Essam; Bhat, Mashooq A; Raish, Mohammad; Al-Rashood, Khalid A

    2016-01-01

    A simple and sensitive UPLC-MS/MS assay was developed and validated for rapid determination of thiosemicarbazide derivative of isoniazid (TSC-INH), a potent anti-candidal agent in rat plasma, tissues, urine and feces. All biological samples were prepared by protein precipitation method using celecoxib as an internal standard (IS). Chromatographic separation was achieved on Acquity BEH™ C18 (50×2.1 mm, 1.7 μm) column using gradient mobile phase of acetonitrile and water (containing 0.1% formic acid) at flow rate of 0.3 mL/min. The MRM transitions were monitored at m/z 305.00→135.89 for TSC-INH and m/z 380.08→316.03 for IS in ESI negative mode. All validation parameter results were within the acceptable range described in guideline for bioanalytical method validation. The pharmacokinetic study showed that the compound TSC-INH was orally active with 66% absolute bioavailability in rats. It was rapidly absorbed with peak plasma concentration of 1985.92 ng/mL achieved within 1 h after single oral dose (10 mg/kg) administration. TSC-INH exhibited rapid distribution across the body with highest levels in liver and lungs. Penetration in brain tissues suggests that TSC-INH crossed the blood brain barrier. Only 5.23% of the orally administered drug was excreted as unconverted form in urine and feces implying that TSC-INH was metabolized extensively before excretion. With the preliminary knowledge of in vivo pharmacokinetics and disposition properties, this study will be beneficial for further development of compound TSC-INH in future studies. PMID:26355768

  17. Simultaneous multi-component quantitation of Chinese herbal injection Yin-zhi-huang in rat plasma by using a single-tube extraction procedure for mass spectrometry-based pharmacokinetic measurement.

    PubMed

    Zeng, Le; Wang, Meiling; Yuan, Yu; Guo, Bin; Zhou, Jing; Tan, Zhen; Ye, Meiling; Ding, Li; Chen, Bo

    2014-09-15

    Ying-zhi-huang injection (YZH-I) is an injectable multi-herbal prescription derived from the ancient Chinese remedy "Yin-chen-hao-tang", which is widely used in the clinic for the treatment of jaundice and chronic liver diseases. To date, little information is available on the pharmacokinetic properties of this poly-herbal formulation. Herein, we reported a simple, rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantitative multiple reaction monitoring (MRM) of eight major ingredients of YZH-I (including baicalin, baicalein, wogonoside, geniposide, geniposidic acid, chlorogenic acid, neochlorogenic acid, and caffeic acid) in rat plasma. A fast single-tube multi-impurity precipitation extraction ("SMIPE") procedure was introduced for straightforward plasma preparation, based on one-pot deproteinization precipitation with acidified methanol extraction and in-situ multifunction impurity removal by a solid sorbent mixture (anh. magnesium sulfate plus octadecylsilane). Particularly, the addition of ascorbic acid in methanol (10 mg/mL) was found to exhibit a pronounced protective effect and significantly increase extraction effectiveness of the herbal phenolic components. Some pretreatment variables (protein precipitating solvent, acidifying agent and sorbent) were optimized with acceptable matrix effect (-18 to 7.7%), extraction recovery (65-88%) and process efficiency (62-91%) for the SMIPE-based LC-MRM multi-analyte quantitation using matrix-matched calibration (5-1000 ng/mL) without using internal standard. Mean accuracies were obtained in the range of 83-114% at three different fortification levels, with intra- and inter-day variations within 13%. This validated method was successfully applied to the simultaneous measurement and pharmacokinetic investigation of the chemical constituents in rats following an intravenous administration of YZH-I. PMID:25129410

  18. The pharmacokinetics of cefadroxil associated with probenecid.

    PubMed

    Mariño, E L; Dominguez-Gil, A

    1981-11-01

    The effects of probenecid on the pharmacokinetic parameters of cefadroxil administered in a single dose of 500 mg are studied. The serum and urine levels of the antibiotic were determined by a microbiologic plate diffusion method. The antibiotic follows a single-compartment model. The half-life of cefadroxil in serum has an average value of 1.13 h, rising to 1.63 h when the antibiotic is associated with probenecid. The apparent distribution volume remains unmodified with a value close to 23 liters. The lag time is 0.25 h in the absence of probenecid, rising to 1.029 h in the presence of the uricosuric agent. PMID:6795136

  19. Pharmacokinetic/Pharmacodynamic-Driven Drug Development

    PubMed Central

    Gallo, James M.

    2010-01-01

    The drug discovery and development enterprise, traditionally an industrial juggernaut, has spanned into the academic arena that is partially motivated by the National Institutes of Health Roadmap highlighting translational science and medicine. Since drug discovery and development represents a pipeline of basic to clinical investigations it meshes well with the prime “bench to the bedside” directive of translational medicine. The renewed interest in drug discovery and develpoment in academia provides an opportunity to rethink the hiearchary of studies with the hope to improve the staid approaches that have been critizied for lacking innovation. One area that has received limited attention concerns the use of pharmacokinetic [PK] and pharmacodynamic [PD] studies in the drug development process. Using anticancer drug development as a focus, this review will address past and current deficencies in how PK/PD studies are conducted and offer new strategies that might bridge the gap between preclinical and clinical trials. PMID:20687184

  20. Pharmacokinetics of oral dichloroacetate in dogs.

    PubMed

    Maisenbacher, Herbert W; Shroads, Albert L; Zhong, Guo; Daigle, Adam D; Abdelmalak, Monica M; Samper, Ivan Sosa; Mincey, Brandy D; James, Margaret O; Stacpoole, Peter W

    2013-12-01

    We characterized the pharmacokinetics and dynamics of dichloroacetate (DCA), an investigational drug for mitochondrial diseases, pulmonary arterial hypertension, and cancer. Adult Beagle dogs were orally administered 6.25 mg/kg q12h DCA for 4 weeks. Plasma kinetics was determined after 1, 14, and 28 days. The activity and expression of glutathione transferase zeta 1 (GSTZ1), which biotransforms DCA to glyoxylate, were determined from liver biopsies at baseline and after 27 days. Dogs demonstrate much slower clearance and greater inhibition of DCA metabolism and GSTZ1 activity and expression than rodents and most humans. Indeed, the plasma kinetics of DCA in dogs is similar to humans with GSTZ1 polymorphisms that confer exceptionally slow plasma clearance. Dogs may be a useful model to further investigate the toxicokinetics and therapeutic potential of DCA. PMID:24038869

  1. [Mechanism of action and pharmacokinetics of rilpivirine].

    PubMed

    Portilla, Joaquín; Estrada, Vicente

    2013-06-01

    Rilpivirine is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) with high efficacy in the treatment of HIV infection in treatment-naïve patients. This drug is active against both wild-type HIV-1 and a wide variety of first-generation NNRTI. Rilpivirine has a highly favorable pharmacokinetics profile, but, because its absorption depends on gastric pH, it should be administered with food to ensure correct absorption. Rilpivirine is metabolized by cytochrome P450 (CYP) 3A and consequently potential interactions should be considered when it is administered with P450 (CYP) 3A inducers or inhibitors. Although higher doses can behave as enzyme inducers, at a dose of 25mg/day, rilpivirine is unlikely to alter the concentrations of other drugs metabolized through this pathway. Because of its prolonged half-life, rilpivirine can be administered orally once daily. PMID:24252527

  2. Pharmacokinetics and metabolism of brotizolam in humans

    PubMed Central

    Bechtel, W. D.

    1983-01-01

    1 Pharmacokinetic studies were performed in healthy young volunteers and in elderly patients after oral administration of single doses (0.5 mg), increasing doses (0.5-1.5 mg), and multiple doses (1.0 mg) of brotizolam. 2 Brotizolam was absorbed quickly from the gastro-intestinal tract. Elimination half-lives were in the range of 3.6-7.9 h. 3 In healthy young volunteers as well as in elderly patients, there was neither a tendency for brotizolam to accumulate nor was there any indication of enzyme induction. 4 Brotizolam was metabolized almost completely into hydroxylated compounds which were conjugated prior to renal excretion. 5 After oral administration of [14C]-brotizolam, two-thirds of excretion of radioactivity was renal and was completed within 4 days. PMID:6661373

  3. Factors Controlling the Pharmacokinetics, Biodistribution and Intratumoral Penetration of Nanoparticles

    PubMed Central

    Ernsting, Mark J.; Murakami, Mami; Roy, Aniruddha; Li, Shyh-Dar

    2014-01-01

    Nanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided. PMID:24075927

  4. Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk.

    PubMed Central

    Oo, C Y; Kuhn, R J; Desai, N; Wright, C E; McNamara, P J

    1995-01-01

    1. Alprazolam, a triazolobenzodiazepine, is extensively prescribed for the treatment of anxiety disorders, which predominantly affect women of child-bearing age. The purpose of the present study was to assess the pharmacokinetics of alprazolam and its two hydroxylated metabolites: 4-hydroxy-alprazolam and alpha-hydroxy-alprazolam in lactating human volunteers and to test the predictability of four recently reported models for drug transfer into milk based on physicochemical properties. 2. Multiple milk and serum samples in eight lactating subjects were collected up to 36 h following single oral doses of 0.5 mg alprazolam; suckling of the infant was discontinued after drug administration. 4-Hydroxy-alprazolam was the predominant metabolite in serum samples while alpha-hydroxy-alprazolam was not detected. 3. The mean oral clearance of alprazolam was 1.15 +/- 0.32 ml min-1 kg-1. The time course of alprazolam in milk roughly paralleled the perspective plasma time profile (mean serum residence time = 16.42 +/- 4.69 h; mean milk residence time = 18.93 +/- 7.03 h). The mean terminal half-life in serum was 12.52 +/- 3.53 h. 4. Observed milk/serum concentration ratios were determined in vivo as AUCmilk/AUCserum (mean M/S(obs) = 0.36 +/- 0.11).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8527284

  5. Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities

    PubMed Central

    Zhang, Yong; Jiang, Peixin; Ye, Min; Kim, Sung-Hoon; Jiang, Cheng; Lü, Junxuan

    2012-01-01

    Tanshinones are a class of abietane diterpene compound isolated from Salvia miltiorrhiza (Danshen or Tanshen in Chinese), a well-known herb in Traditional Chinese Medicine (TCM). Since they were first identified in the 1930s, more than 40 lipophilic tanshinones and structurally related compounds have been isolated from Danshen. In recent decades, numerous studies have been conducted to investigate the isolation, identification, synthesis and pharmacology of tanshinones. In addition to the well-studied cardiovascular activities, tanshinones have been investigated more recently for their anti-cancer activities in vitro and in vivo. In this review, we update the herbal and alternative sources of tanshinones, and the pharmacokinetics of selected tanshinones. We discuss anti-cancer properties and identify critical issues for future research. Whereas previous studies have suggested anti-cancer potential of tanshinones affecting multiple cellular processes and molecular targets in cell culture models, data from in vivo potency assessment experiments in preclinical models vary greatly due to lack of uniformity of solvent vehicles and routes of administration. Chemical modifications and novel formulations had been made to address the poor oral bioavailability of tanshinones. So far, human clinical trials have been far from ideal in their design and execution for the purpose of supporting an anti-cancer indication of tanshinones. PMID:23202971

  6. A Review: Pharmaceutical and Pharmacokinetic Aspect of Nanocrystalline Suspensions.

    PubMed

    Shah, Dhaval A; Murdande, Sharad B; Dave, Rutesh H

    2016-01-01

    Nanocrystals have emerged as a potential formulation strategy to eliminate the bioavailability-related problems by enhancing the initial dissolution rate and moderately super-saturating the thermodynamic solubility. This review contains an in-depth knowledge of, the processing method for formulation, an accurate quantitative assessment of the solubility and dissolution rates and their correlation to observe pharmacokinetic data. Poor aqueous solubility is considered the major hurdle in the development of pharmaceutical compounds. Because of a lack of understanding with regard to the change in the thermodynamic and kinetic properties (i.e., solubility and dissolution rate) upon nanosizing, we critically reviewed the literatures for solubility determination to understand the significance and accuracy of the implemented analytical method. In the latter part, we reviewed reports that have quantitatively studied the effect of the particle size and the surface area change on the initial dissolution rate enhancement using alternative approaches besides the sink condition dissolution. The lack of an apparent relationship between the dissolution rate enhancement and the observed bioavailability are discussed by reviewing the reported in vivo data on animal models along with the particle size and food effect. The review will provide comprehensive information to the pharmaceutical scientist in the area of nanoparticulate drug delivery. PMID:26580860

  7. 41 CFR 102-38.290 - What types of payment may we accept?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... are not acceptable. (b) Irrevocable commercial letters of credit issued by a United States bank... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false What types of payment... PROPERTY Completion of Sale Payments § 102-38.290 What types of payment may we accept? You must adopt...

  8. Clinical pharmacokinetics of transdermal opioids: focus on transdermal fentanyl.

    PubMed

    Grond, S; Radbruch, L; Lehmann, K A

    2000-01-01

    Transdermal delivery allows continuous systemic application of opioids through the intact skin. This review analyses the pharmacokinetic properties of transdermal opioid administration in the context of clinical experience, with a focus on fentanyl. A transdermal therapeutic system (TTS) for fentanyl has been developed. The amount of fentanyl released is proportional to the surface area of the TTS, which is available in different sizes. After the first application of a TTS, a fentanyl depot concentrates in the upper skin layers and it takes several hours until clinical effects are observed. The time from application to minimal effective and maximum serum concentrations is 1.2 to 40 hours and 12 to 48 hours, respectively. Steady state is reached on the third day, and can be maintained as long as patches are renewed. Within each 72-hour period, serum concentrations decrease gradually over the second and third days. When a TTS is removed, fentanyl continues to be absorbed into the systemic circulation from the cutaneous depot. The terminal half-life for TTS fentanyl is approximately 13 to 25 hours. The interindividual variability of serum concentrations, partly caused by different clearance rates, is markedly larger than the intraindividual variability. The effectiveness of TTS fentanyl was first demonstrated in acute postoperative pain. However, the slow pharmacokinetics and large variability of TTS fentanyl, together with the relatively short duration of postoperative pain, precluded adequate dose finding and led to inadequate pain relief or, especially, a high incidence of respiratory depression; such use is now contraindicated. Conversely, in cancer pain, TTS fentanyl offers an interesting alternative to oral morphine, and its effectiveness and tolerability in this indication has been demonstrated by a number of trials. Its usefulness in chronic pain of nonmalignant origin remains to be confirmed in controlled trials. In general, TTS fentanyl produces the same

  9. Pharmacokinetics and pharmacodynamics of beta blockers in heart failure.

    PubMed

    Talbert, Robert L

    2004-04-01

    Although beta-blockers have been used for nearly three decades in the management of heart failure, only recent randomized clinical trials have demonstrated substantial benefit in reducing morbidity and mortality. Carvedilol, metoprolol succinate and bisprolol have evidence supporting their use in heart failure while other beta blockers either lack evidence supporting their use or have not been shown to be useful in heart failure. The only currently approved beta-blockers in the U.S. for heart failure are metoprolol succinate and carvedilol.Beta-blockers differ in their pharmacokinetic and pharmacodynamic properties. It should not be assumed that potential benefit in heart failure is a class effect since differences in the half-life, volume of distribution, protein binding, and route of elimination may give rise to differences in duration of beta blockade and potential drug interactions. Furthermore, pharmacodynamic differences exist because of selectivity for beta(1), beta(2) or alpha(1) adrenoreceptor blockade among the beta-blockers. Receptor kinetics also differ among the beta-blockers and this may influence the extent and duration of beta and alpha blockade across the category. Carvedilol is an inherently long-acting beta-blocker while the duration of beta blockade for metoprolol is dependent on the salt and formulation, which is used. Metoprolol tartrate is a short-acting form of metoprolol while metoprolol succinate is a longer acting salt and the commercially available product is designed as a once daily formulation. A recently published trial, the Carvedilol or Metoprolol European Trial (COMET) tested carvedilol given twice daily versus metoprolol tartrate given twice daily in patients with chronic heart failure. Although carvedilol reduced all cause mortality when compared with metoprolol tartrate, extrapolation to similar findings with metoprolol succinate are not possible since the pharmacokinetic and pharmacodynamic effects of these two formulations are

  10. Pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion

    PubMed Central

    Fidler, Meredith C; Barshop, Bruce A; Gangoiti, Jon A; Deutsch, Reena; Martin, Michael; Schneider, Jerry A; Dohil, Ranjan

    2007-01-01

    Aims Although cysteamine was first used in the treatment of cystinosis in 1976 and approved by the FDA as cysteamine bitartrate (Cystagon™) in 1994, surprisingly little pharmacological data are available for this compound. Cysteamine and its related drugs are currently being evaluated for the treatment of Huntington’s and Parkinson’s disease. The aim of te study was to understand the pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion. Method Cysteamine bitartrate was delivered through a naso-enteric catheter into the stomach (n = 8), small intestine (n = 8) and caecum (n = 4) of normal subjects. Plasma cysteamine concentrations were determined using LC-MS/MS. Results The rate and extent of drug absorption were assessed by comparing AUC(0, ∞), Cmax and tmax, among the gastrointestinal infusion sites. Total cysteamine exposure, expressed as area under the curve (AUC(0, ∞)) was greatest when the drug was infused into the small intestine (4331.3 ± 1907.6 min × µm) followed by stomach (3901.9 ± 1591.9 min × µm) and caecum (3141.4 ± 1627.6 min × µm). Cysteamine infusion into the small intestine resulted in the most rapid rise to maximal plasma concentrations (tmax = 21 ± 0.56 min); tmax was delayed to 50 ± 26 min and 64 ± 26 min after gastric and caecal infusion, respectively. The maximum cysteamine plasma concentration (Cmax) was reached after infusion of the drug into the small intestine (51 ± 21 µm), which was higher than plasma Cmax concentrations after gastric (39 ± 16 µm) and caecal infusion (23 ± 15 µm). Conclusions The pharmacokinetic data generated help extend our understanding of cysteamine. PMID:17229040

  11. Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

    PubMed Central

    Boak, Lauren M.; Rayner, Craig R.; Grayson, M. Lindsay; Paterson, David L.; Spelman, Denis; Khumra, Sharmila; Capitano, Blair; Forrest, Alan; Li, Jian

    2014-01-01

    Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of <100 ×109/liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h. PMID:24514086

  12. PREDICTIVE PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE FLOATING TABLETS.

    PubMed

    Wang, Jianming; Zhang, Yanzhen; Guo, Zhiling; Tao, Qingwen; Wang, Yongjun; Zhou, Wei; Ma, Xiao; Li, Zhihong

    2016-01-01

    The purpose of this study was to propose the effectiveness of convolution approach to predict pharmacokinetics of tramadol hydrochloride floating tablets, prepared by using various ratios of carbopol, HPMC K100M, and Hibiscus rosa Sinensis as excipient. The in vitro dissolution test was conducted using paddle method in 900 mL of HCl buffer with pH 1.2 to simulate the gastric condition. The stirring speed of paddles was set at 70 rpm. Temperature of dissolution medium was adjusted at 37 ± 5 °C. At predetermined time points, 5 mL of dissolution samples were taken with a replacement of same volume using fresh medium. The obtained samples were analyzed at 271 nm using UV visible spectrophotometer. The values of predicted pharmacokinetic parameters like Cmax (maximum blood drug level), Tmax (time required to attain maximum blood drug level), and AUC (area under blood drug concentration curve) ranged between 80.8 ± 3.2-119.6 ± 4.7 ng/mL, 11.4 ± 0.2-12.2 ± 0.2 h, and 1430.5 ± 209.5-1970.6 ± 287.4 ng.h/mL, respectively. This certainly is a desired feature required at the formulation development step, where the formulator requires the development of a formulation using desired in vivo features on the basis of only accessible in vitro data. It can be concluded from the results that convolution method is a practical method for the prediction of drug concentration in blood and for quality control. PMID:27476294

  13. Reporting guidelines for population pharmacokinetic analyses.

    PubMed

    Dykstra, Kevin; Mehrotra, Nitin; Tornøe, Christoffer Wenzel; Kastrissios, Helen; Patel, Bela; Al-Huniti, Nidal; Jadhav, Pravin; Wang, Yaning; Byon, Wonkyung

    2015-08-01

    The purpose of this work was to develop a consolidated set of guiding principles for the reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting, and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (in which population PK frequently serves as preparatory analysis for exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider 2 main purposes of population PK reports: (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified 2 main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results; and (2) a scientifically literate but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with 6 questions that need to be addressed throughout the report. We recommend 8 sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step toward industrialization of the field of pharmacometrics such that a nontechnical audience also understands the role of pharmacometric analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports

  14. Pharmacokinetics of Intranasal Scopolamine Gel Formulation (Inscop)

    NASA Technical Reports Server (NTRS)

    Boyd, Jason L.; Du, Brian; Daniels, Vernie; Simmons, Rita; Buckey, Jay; Putcha, Lakshmi

    2009-01-01

    Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during early flight days of space missions. Orally administered scopolamine is commonly used by astronauts to prevent SMS. Bioavailability of oral (PO) SMS medications is often low and highly variable. Intranasal (IN) administration of medications achieves higher and more reliable bioavailability than from an equivalent PO dose. Methods: To test the safety and reliability of INSCOP, two clinical studies were performed, a dose escalation study and a comparison study administering INSCOP during normal ambulation and head down tilt bedrest. Efficacy was evaluated by testing INSCOP with two, different motion sickness inducing paradigms. Results: Preliminary results indicate that INSCOP demonstrates linear pharmacokinetics and a low side effect profile. In head down tilt bedrest, relative bioavailability of INSCOP was increased for females at both doses (0.2 and 0.4 mg) and for males at the higher dose (0.4 mg) but is reduced at the lower dose (0.2 mg) compared to normal ambulation. INSCOP displays gender specific differences during ABR. One of the treatment efficacy trials conducted at Dartmouth Hitchcock Medical Center demonstrated that INSCOP is efficacious at both doses (0.2 and 0.4 mg) in suppressing motion sickness symptoms as indicated by longer chair ride times with INSCOP administration than with placebo, and efficacy increases with dose. Similar results were seen using another motion sickness simulator, the motion simulator dome, at the Naval Aerospace Medical Research Laboratory, with significantly increased time in the dome in motion-susceptible subjects when using INSCOP compared to untreated controls. Conclusion: Higher bioavailability, linear pharmacokinetics, a low incidence of side effects, and a favorable efficacy profile make INSCOP a desirable formulation for prophylactic and rescue treatment of astronauts in space and military personnel on

  15. Pharmacokinetics of metoprolol during pregnancy and lactation.

    PubMed

    Ryu, Rachel J; Eyal, Sara; Easterling, Thomas R; Caritis, Steve N; Venkataraman, Raman; Hankins, Gary; Rytting, Erik; Thummel, Kenneth; Kelly, Edward J; Risler, Linda; Phillips, Brian; Honaker, Matthew T; Shen, Danny D; Hebert, Mary F

    2016-05-01

    The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25-750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n = 3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker. PMID:26461463

  16. Pharmacokinetics of procaterol in thoroughbred horses.

    PubMed

    Kusano, K; Nomura, M; Toju, K; Ishikawa, Y; Minamijima, Y; Yamashita, S; Nagata, S

    2016-06-01

    Procaterol (PCR) is a beta-2-adrenergic bronchodilator widely used in Japanese racehorses for treating lower respiratory disease. The pharmacokinetics of PCR following single intravenous (0.5 μg/kg) and oral (2.0 μg/kg) administrations were investigated in six thoroughbred horses. Plasma and urine concentrations of PCR were measured using liquid chromatography-mass spectrometry. Plasma PCR concentration following intravenous administration showed a biphasic elimination pattern. The systemic clearance was 0.47 ± 0.16 L/h/kg, the steady-state volume of the distribution was 1.21 ± 0.23 L/kg, and the elimination half-life was 2.85 ± 1.35 h. Heart rate rapidly increased after intravenous administration and gradually decreased thereafter. A strong correlation between heart rate and plasma concentration of PCR was observed. Plasma concentrations of PCR after oral administration were not quantifiable in all horses. Urine concentrations of PCR following intravenous and oral administrations were quantified in all horses until 32 h after administration. Urine PCR concentrations were not significantly different on and after 24 h between intravenous and oral administrations. These results suggest that the bioavailability of orally administrated PCR in horses is very poor, and the drug was eliminated from the body slowly based on urinary concentrations. This report is the first study to demonstrate the pharmacokinetic character of PCR in thoroughbred horses. PMID:26538319

  17. Acceptability of reactors in space

    SciTech Connect

    Buden, D.

    1981-04-01

    Reactors are the key to our future expansion into space. However, there has been some confusion in the public as to whether they are a safe and acceptable technology for use in space. The answer to these questions is explored. The US position is that when reactors are the preferred technical choice, that they can be used safely. In fact, it dies not appear that reactors add measurably to the risk associated with the Space Transportation System.

  18. Acceptability of reactors in space

    SciTech Connect

    Buden, D.

    1981-01-01

    Reactors are the key to our future expansion into space. However, there has been some confusion in the public as to whether they are a safe and acceptable technology for use in space. The answer to these questions is explored. The US position is that when reactors are the preferred technical choice, that they can be used safely. In fact, it does not appear that reactors add measurably to the risk associated with the Space Transportation System.

  19. Application of a novel liquid chromatography/tandem mass spectrometry method for the determination of antazoline in human plasma: Result of ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study.

    PubMed

    Giebułtowicz, Joanna; Piotrowski, Roman; Baran, Jakub; Kułakowski, Piotr; Wroczyński, Piotr

    2016-05-10

    Antazoline is a first-generation antihistaminic agent with antiarrhythmic quinidine-like properties. In some countries, it is widely used for termination of cardiac arrhythmias, especially atrial fibrillation (AF). However, no human pharmacokinetic studies have been conducted with intravenous antazoline. The aim of our study was to develop and validate a novel liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the determination of antazoline in human plasma: the ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study. Antazoline was extracted from plasma using liquid-liquid extraction. The concentration of the analyte was measured by LC-MS/MS with xylometazoline as an internal standard. The method was validated for linearity, precision, accuracy, stability (freeze/thaw stability, stability in autosampler, short and long term stability), dilution integrity and matrix effect. The analyzed validation criteria were fulfilled. The method was applied to a pharmacokinetic study involving 10 healthy volunteers. Following a single intravenous dose of antazoline mesylate (100 mg), the plasma concentration profile showed a relative fast elimination with a terminal elimination half-life of 2.29 h. A relatively high volume of distribution was observed (Vss=315 L). The values of mean residence time (MRT∞), area under the curve (AUC∞) and clearance were 3.45 h, 0.91 mg h L(-1) and 80.5 L h(-1), respectively. One volunteer showed significant differences in pharmacokinetic parameters. In conclusion, the proposed new LC-MS/MS method was successfully used for the first time for the determination of antazoline in human plasma. PMID:26895496

  20. Reactor tank UT acceptance criteria

    SciTech Connect

    Daugherty, W.L.

    1990-01-30

    The SRS reactor tanks are constructed of type 304 stainless steel, with 0.5 inch thick walls. An ultrasonic (UT) in-service inspection program has been developed for examination of these tanks, in accordance with the ISI Plan for the Savannah River Production Reactors Process Water System (DPSTM-88-100-1). Prior to initiation of these inspections, criteria for the disposition of any indications that might be found are required. A working group has been formed to review available information on the SRS reactor tanks and develop acceptance criteria. This working group includes nationally recognized experts in the nuclear industry. The working group has met three times and produced three documents describing the proposed acceptance criteria, the technical basis for the criteria and a proposed initial sampling plan. This report transmits these three documents, which were prepared in accordance with the technical task plan and quality assurance plan for this task, task 88-001-A- 1. In addition, this report summarizes the acceptance criteria and proposed sampling plan, and provides further interpretation of the intent of these three documents where necessary.

  1. Applications of a Pharmacokinetic Simulation Program in Pharmacy Courses.

    ERIC Educational Resources Information Center

    Ingram, D.; And Others

    1979-01-01

    Presents a multicompartment model which illustrates aspects of drug absorption, distribution, and elimination in the human body for a course in pharmacokinetics. The course work consists of the interpretation of computer generated simulated data. (Author/CMV)

  2. Enhancing the Modeling of PFOA Pharmacokinetics with Bayesian Analysis

    EPA Science Inventory

    The detail sufficient to describe the pharmacokinetics (PK) for perfluorooctanoic acid (PFOA) and the methods necessary to combine information from multiple data sets are both subjects of ongoing investigation. Bayesian analysis provides tools to accommodate these goals. We exa...

  3. Explicit Pharmacokinetic Modeling: Tools for Documentation, Verification, and Portability

    EPA Science Inventory

    Quantitative estimates of tissue dosimetry of environmental chemicals due to multiple exposure pathways require the use of complex mathematical models, such as physiologically-based pharmacokinetic (PBPK) models. The process of translating the abstract mathematics of a PBPK mode...

  4. 12 CFR 7.1007 - Acceptances.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 1 2010-01-01 2010-01-01 false Acceptances. 7.1007 Section 7.1007 Banks and... § 7.1007 Acceptances. A national bank is not limited in the character of acceptances it may make in financing credit transactions. Bankers' acceptances may be used for such purpose, since the making...

  5. 12 CFR 7.1007 - Acceptances.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 1 2011-01-01 2011-01-01 false Acceptances. 7.1007 Section 7.1007 Banks and... § 7.1007 Acceptances. A national bank is not limited in the character of acceptances it may make in financing credit transactions. Bankers' acceptances may be used for such purpose, since the making...

  6. 21 CFR 820.86 - Acceptance status.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Acceptance status. 820.86 Section 820.86 Food and... QUALITY SYSTEM REGULATION Acceptance Activities § 820.86 Acceptance status. Each manufacturer shall identify by suitable means the acceptance status of product, to indicate the conformance or...

  7. 12 CFR 615.5550 - Bankers' acceptances.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 6 2011-01-01 2011-01-01 false Bankers' acceptances. 615.5550 Section 615.5550... POLICIES AND OPERATIONS, AND FUNDING OPERATIONS Bankers' Acceptances § 615.5550 Bankers' acceptances. Banks for cooperatives may rediscount with other purchasers the acceptances they have created. The bank...

  8. 48 CFR 245.606-3 - Acceptance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Acceptance. 245.606-3... Contractor Inventory 245.606-3 Acceptance. (a) If the schedules are acceptable, the plant clearance officer shall, within 15 days, complete and send the contractor a DD Form 1637, Notice of Acceptance...

  9. 48 CFR 12.402 - Acceptance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Acceptance. 12.402 Section... Acceptance. (a) The acceptance paragraph in 52.212-4 is based upon the assumption that the Government will rely on the contractor's assurances that the commercial item tendered for acceptance conforms to...

  10. 21 CFR 820.86 - Acceptance status.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Acceptance status. 820.86 Section 820.86 Food and... QUALITY SYSTEM REGULATION Acceptance Activities § 820.86 Acceptance status. Each manufacturer shall identify by suitable means the acceptance status of product, to indicate the conformance or...

  11. 12 CFR 615.5550 - Bankers' acceptances.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Bankers' acceptances. 615.5550 Section 615.5550... POLICIES AND OPERATIONS, AND FUNDING OPERATIONS Bankers' Acceptances § 615.5550 Bankers' acceptances. Banks for cooperatives may rediscount with other purchasers the acceptances they have created. The bank...

  12. 48 CFR 12.402 - Acceptance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Acceptance. 12.402 Section... Acceptance. (a) The acceptance paragraph in 52.212-4 is based upon the assumption that the Government will rely on the contractor's assurances that the commercial item tendered for acceptance conforms to...

  13. Property.

    ERIC Educational Resources Information Center

    Piele, Philip K.

    Reflecting widespread unhappiness with the growing tax burdens in this country, the most active area of litigation reported in the property chapter this year involves various attempts by taxpayers to prevent the construction or remodeling of public school facilities. While some taxpayers fought to keep schools from being built, others in New York…

  14. Calculator programs to deal with non-steady state, multiple dosage regimen clinical pharmacokinetics.

    PubMed

    Ensom, R J; Nakagawa, R S

    1983-07-01

    Serum drug levels have become a useful tool in the optimization of dosage requirements for several therapeutically important drugs. In the acute care situation the interpretation of these levels is complicated by multiple dosage regimens and inadequate time to achieve steady-state serum drug levels. Mathematical equations describing first order single compartment pharmacokinetics have been compiled. An alpha-numeric programmable calculator has been programmed to accept information regarding up to seven different serial dosage regimens. The calculator is also programmed to predict concentrations at any time during a complex set of dosage regimens or peak, trough, and average concentrations given a maintenance dosage regimen. Examples are given to demonstrate the usefulness of the programs in the clinical setting. PMID:6688607

  15. Selection between Michaelis-Menten and target-mediated drug disposition pharmacokinetic models.

    PubMed

    Yan, Xiaoyu; Mager, Donald E; Krzyzanski, Wojciech

    2010-02-01

    Target-mediated drug disposition (TMDD) models have been applied to describe the pharmacokinetics of drugs whose distribution and/or clearance are affected by its target due to high binding affinity and limited capacity. The Michaelis-Menten (M-M) model has also been frequently used to describe the pharmacokinetics of such drugs. The purpose of this study is to investigate conditions for equivalence between M-M and TMDD pharmacokinetic models and provide guidelines for selection between these two approaches. Theoretical derivations were used to determine conditions under which M-M and TMDD pharmacokinetic models are equivalent. Computer simulations and model fitting were conducted to demonstrate these conditions. Typical M-M and TMDD profiles were simulated based on literature data for an anti-CD4 monoclonal antibody (TRX1) and phenytoin administered intravenously. Both models were fitted to data and goodness of fit criteria were evaluated for model selection. A case study of recombinant human erythropoietin was conducted to qualify results. A rapid binding TMDD model is equivalent to the M-M model if total target density R ( tot ) is constant, and R ( tot ) K ( D ) /(K ( D ) + C) ( 2 ) < 1 where K ( D ) represents the dissociation constant and C is the free drug concentration. Under these conditions, M-M parameters are defined as: V ( max ) = k ( int ) R ( tot ) V ( c ) and K ( m ) = K ( D ) where k ( int ) represents an internalization rate constant, and V ( c ) is the volume of the central compartment. R ( tot ) is constant if and only if k ( int ) = k ( deg,) where k ( deg ) is a degradation rate constant. If the TMDD model predictions are not sensitive to k ( int ) or k ( deg ) parameters, the condition of R ( tot ) K ( D ) /(K ( D ) + C) ( 2 ) < 1 alone can preserve the equivalence between rapid binding TMDD and M-M models. The model selection process for drugs that exhibit TMDD should involve a full mechanistic model as well as reduced models. The best model

  16. [Mecanisms of pharmacokinetic interactions involving oral anticancer agents].

    PubMed

    Levêque, Dominique; Duval, Céline; Poulat, Charlotte; Palas, Benjamin; El Aatmani, Anne; Dory, Anne; Becker, Guillaume; Gourieux, Bénédicte

    2015-01-01

    Oral anticancer agents and particularly kinase inhibitors are subject to pharmacokinetic drug interactions in relation to absorption and elimination phases. Interacting factors are food, fruit juices, cigarette smoke, acid-reducing agents and inducers/inhibitors. Some anticancer agents are inducers and/or inhibitors and can also perpetrate drug interactions. This review emphasizes the mechanisms of pharmacokinetic drug interactions involving oral anticancer agents. PMID:25609481

  17. Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J

    2016-05-01

    Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic haematopoietic cell transplantation (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared with solid organ transplantation, alloHCT is unique because of the potential for bidirectional reactions (i.e. host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning, or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATGs) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants' pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressants deserves to be explored in depth. Development of

  18. Impact of release characteristics of sinomenine hydrochloride dosage forms on its pharmacokinetics in beagle dogs

    PubMed Central

    Sun, Jin; Shi, Jie-Ming; Zhang, Tian-Hong; Gao, Kun; Mao, Jing-Jing; Li, Bing; Sun, Ying-Hua; He, Zhong-Gui

    2005-01-01

    AIM: To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride (SM•HCl) on its pharmacokinetics in beagle dogs. METHODS: The in vitro release behavior of two SM•HCl dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo SM•HCl pharmacokinetics was investigated and compared. RESULTS: The optimal SM•HCl sustained-release formulation was achieved by mixing slow- and rapid-release pellets (9:1, w/w). The SM•HCl release profiles of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs 68.7%. From a pharmacokinetic standpoint, the 24-h SM•HCl sustained-release pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67×0.52 h vs 9.83×0.98 h and the Cmax being 1 334.45±368.76 ng/mL vs 893.12±292.55 ng/mL, respectively. However, the AUC0-tn of two SM•HCl dosage forms was comparable and both preparations were statistically bioequivalent. Furthermore, the two preparations had good correlations between SM•HCl percentage absorption in vivo and the cumulative percentage release in vitro. CONCLUSION: The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves. PMID:16052686

  19. Computational approaches and metrics required for formulating biologically realistic nanomaterial pharmacokinetic models

    NASA Astrophysics Data System (ADS)

    Riviere, Jim E.; Scoglio, Caterina; Sahneh, Faryad D.; Monteiro-Riviere, Nancy A.

    2013-01-01

    The field of nanomaterial pharmacokinetics is in its infancy, with major advances largely restricted by a lack of biologically relevant metrics, fundamental differences between particles and small molecules of organic chemicals and drugs relative to biological processes involved in disposition, a scarcity of sufficiently rich and characterized in vivo data and a lack of computational approaches to integrating nanomaterial properties to biological endpoints. A central concept that links nanomaterial properties to biological disposition, in addition to their colloidal properties, is the tendency to form a biocorona which modulates biological interactions including cellular uptake and biodistribution. Pharmacokinetic models must take this crucial process into consideration to accurately predict in vivo disposition, especially when extrapolating from laboratory animals to humans since allometric principles may not be applicable. The dynamics of corona formation, which modulates biological interactions including cellular uptake and biodistribution, is thereby a crucial process involved in the rate and extent of biodisposition. The challenge will be to develop a quantitative metric that characterizes a nanoparticle's surface adsorption forces that are important for predicting biocorona dynamics. These types of integrative quantitative approaches discussed in this paper for the dynamics of corona formation must be developed before realistic engineered nanomaterial risk assessment can be accomplished.

  20. Abuse-Deterrent Opioid Formulations: Pharmacokinetic and Pharmacodynamic Considerations.

    PubMed

    Walter, Carmen; Knothe, Claudia; Lötsch, Jörn

    2016-07-01

    Abuse-deterrent formulations (ADFs) are technologically sophisticated pharmaceutical formulations that impede manipulation and extraction of opioids and/or provoke unpleasant effects when they are taken in excessive quantity. This is implemented by creating physical barriers, inseparably combining the opioid with an opioid antagonist or adding aversive agents to the formulation. These pharmaceutical changes may potentially alter the pharmacokinetics and consequently the pharmacodynamics of the opioid. In this review, comparative evidence on pharmacokinetic differences between abuse-deterrent and classical formulations of the same opioids is summarized; furthermore, pharmacodynamic differences, with a focus on analgesia and abuse-related symptoms, are addressed. Most of the 12 studies comparing opioid pharmacokinetics have judged the physically intact ADF as being bioequivalent to the corresponding classical formulation. Pharmacokinetic differences have, however, been reported with physically manipulated ADFs and have ranged from moderate deviations from bioequivalence to complete changes in the pharmacokinetic profile (e.g. from a sustained-release formulation to a fast-release formulation). Pharmacodynamic effects were assessed in 14 comparative studies, which reported that intact ADFs usually provided clinically equivalent analgesia and clear advantages with respect to their addiction potential. However, withdrawal symptoms could be induced by the ADFs, although rarely and, in particular, when the ADFs had been physically altered. This evidence suggests that opioid ADFs are a working concept resulting in mostly minor pharmacokinetic and pharmacodynamic differences in comparison with classical formulations; however, they may deviate from this equivalence when physically altered. PMID:26719075

  1. Developing a New Instrument for Assessing Acceptance of Change

    PubMed Central

    Di Fabio, Annamaria; Gori, Alessio

    2016-01-01

    This article focuses on the usefulness of going beyond the concept of resistance to change and capitalizing on the use of a model that includes positivity and acceptance of change. We first discuss the theoretical background of this new construct in the work and organizational fields and then evaluate the psychometric properties of a new measure for assessing acceptance of change. The results of exploratory factor analysis indicated a factor structure with five principal dimensions; besides confirmatory factor analysis (CFA) goodness of fit indices indicated a good fit of the model to the data. All the dimensions showed good values of internal consistency. The results of the present study indicate that the Acceptance of Change Scale (ACS) is a brief and easily administered instrument with good psychometric properties that can promote the development of clients' strengths and the growth of a sense of Self, thereby helping them choose their own way without losing any opportunities in their lives and their work. PMID:27303356

  2. Developing a New Instrument for Assessing Acceptance of Change.

    PubMed

    Di Fabio, Annamaria; Gori, Alessio

    2016-01-01

    This article focuses on the usefulness of going beyond the concept of resistance to change and capitalizing on the use of a model that includes positivity and acceptance of change. We first discuss the theoretical background of this new construct in the work and organizational fields and then evaluate the psychometric properties of a new measure for assessing acceptance of change. The results of exploratory factor analysis indicated a factor structure with five principal dimensions; besides confirmatory factor analysis (CFA) goodness of fit indices indicated a good fit of the model to the data. All the dimensions showed good values of internal consistency. The results of the present study indicate that the Acceptance of Change Scale (ACS) is a brief and easily administered instrument with good psychometric properties that can promote the development of clients' strengths and the growth of a sense of Self, thereby helping them choose their own way without losing any opportunities in their lives and their work. PMID:27303356

  3. Opposite malaria and pregnancy effect on oral bioavailability of artesunate – a population pharmacokinetic evaluation

    PubMed Central

    Kloprogge, Frank; McGready, Rose; Phyo, Aung Pyae; Rijken, Marcus J; Hanpithakpon, Warunee; Than, Hla Hla; Hlaing, Nathar; Zin, Naw Thida; Day, Nicholas P J; White, Nicholas J; Nosten, François; Tarning, Joel

    2015-01-01

    Aim The aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7. Methods Non-linear mixed-effects modelling was used to compare plasma concentration–time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously. Results Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%. Conclusions The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy. PMID:25877779

  4. Measuring Attitudes toward Acceptable and Unacceptable Parenting Practices

    ERIC Educational Resources Information Center

    Budd, Karen S.; Behling, Steven; Li, Yan; Parikshak, Sangeeta; Gershenson, Rachel A.; Feuer, Rachel; Danko, Christina M.

    2012-01-01

    This study investigated the properties of a new rating instrument, the Parenting Questionnaire (PQ), designed to measure attitudes about acceptable and unacceptable parenting practices. In Study 1, subject matter experts representing culturally diverse psychologists, parents, and college students were consulted to identify 110 items receiving high…

  5. 48 CFR 570.402-5 - Potential acceptable locations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 4 2011-10-01 2011-10-01 false Potential acceptable locations. 570.402-5 Section 570.402-5 Federal Acquisition Regulations System GENERAL SERVICES ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects...

  6. 48 CFR 570.402-5 - Potential acceptable locations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 4 2013-10-01 2013-10-01 false Potential acceptable locations. 570.402-5 Section 570.402-5 Federal Acquisition Regulations System GENERAL SERVICES ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects...

  7. 48 CFR 570.402-4 - No potential acceptable locations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false No potential acceptable locations. 570.402-4 Section 570.402-4 Federal Acquisition Regulations System GENERAL SERVICES ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects...

  8. 48 CFR 570.402-4 - No potential acceptable locations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 4 2012-10-01 2012-10-01 false No potential acceptable locations. 570.402-4 Section 570.402-4 Federal Acquisition Regulations System GENERAL SERVICES ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects...

  9. 48 CFR 570.402-4 - No potential acceptable locations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 4 2014-10-01 2014-10-01 false No potential acceptable locations. 570.402-4 Section 570.402-4 Federal Acquisition Regulations System GENERAL SERVICES ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects...

  10. 48 CFR 570.402-4 - No potential acceptable locations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 4 2013-10-01 2013-10-01 false No potential acceptable locations. 570.402-4 Section 570.402-4 Federal Acquisition Regulations System GENERAL SERVICES ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects...

  11. 48 CFR 570.402-4 - No potential acceptable locations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 4 2011-10-01 2011-10-01 false No potential acceptable locations. 570.402-4 Section 570.402-4 Federal Acquisition Regulations System GENERAL SERVICES ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects...

  12. 48 CFR 570.402-5 - Potential acceptable locations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 4 2014-10-01 2014-10-01 false Potential acceptable locations. 570.402-5 Section 570.402-5 Federal Acquisition Regulations System GENERAL SERVICES ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects...

  13. 48 CFR 570.402-5 - Potential acceptable locations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 4 2012-10-01 2012-10-01 false Potential acceptable locations. 570.402-5 Section 570.402-5 Federal Acquisition Regulations System GENERAL SERVICES ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects...

  14. Population pharmacokinetic analysis of voriconazole from a pharmacokinetic study with immunocompromised Japanese pediatric subjects.

    PubMed

    Muto, Chieko; Shoji, Satoshi; Tomono, Yoshiro; Liu, Ping

    2015-01-01

    A population pharmacokinetic (PK) analysis was conducted to characterize the voriconazole pharmacokinetic profiles in immunocompromised Japanese pediatric subjects and to compare them to those in immunocompromised non-Japanese pediatric subjects. A previously developed two-compartment pharmacokinetic model with first-order absorption and mixed linear and nonlinear elimination adequately described the voriconazole intravenous and oral data from Japanese pediatric subjects with few modifications. Bayesian priors were applied to this analysis by using the NONMEM routine NWPRI, which allowed priors for the fixed-effect parameter vector and variance matrix of the random-effect parameters to be a normal distribution and an inverse Wishart distribution, respectively. Large intersubject variabilities in oral bioavailability and voriconazole exposure were observed in these pediatric subjects. The mean oral bioavailability estimated in Japanese pediatric subjects was 73% (range, 17% to 99%), which is consistent with the reported estimates of 64% in the previous model and less than what was originally estimated for healthy adults-96%. Voriconazole exposures in Japanese pediatric subjects were generally comparable to those in non-Japanese pediatric subjects receiving the same dosing regimens, given the large intersubject variability. Consistent with the previous findings, the CYP2C19 genotyping status did not have a clinically relevant effect on voriconazole exposure in Japanese pediatric subjects, although it was identified as a covariate in the model to help explain the intersubject variability in voriconazole exposure. The CYP2C19 genotyping status alone does not warrant dose adjustment of voriconazole. No other factors besides age and weight were identified to explain the PK variability of voriconazole. PMID:25801557

  15. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials.

    PubMed

    Lamp, K C; Freeman, C D; Klutman, N E; Lacy, M K

    1999-05-01

    Metronidazole, the prototype nitroimidazole antimicrobial, was originally introduced to treat Trichomonas vaginalis, but is now used for the treatment of anaerobic and protozoal infections. The nitroimidazoles are bactericidal through toxic metabolites which cause DNA strand breakage. Resistance, both clinical and microbiological, has been described only rarely. Metronidazole given orally is absorbed almost completely, with bioavailability > 90% for tablets; absorption is unaffected by infection. Rectal and intravaginal absorption are 67 to 82%, and 20 to 56%, of the dose, respectively. Metronidazole is distributed widely and has low protein binding (< 20%). The volume of distribution at steady state in adults is 0.51 to 1.1 L/kg. Metronidazole reaches 60 to 100% of plasma concentrations in most tissues studied, including the central nervous system, but does not reach high concentrations in placental tissue. Metronidazole is extensively metabolised by the liver to 5 metabolites. The hydroxy metabolite has biological activity of 30 to 65% and a longer elimination half-life than the parent compound. The majority of metronidazole and its metabolites are excreted in urine and faeces, with less than 12% excreted unchanged in urine. The pharmacokinetics of metronidazole are unaffected by acute or chronic renal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age, pregnancy or enteric disease. Renal dysfunction reduces the elimination of metronidazole metabolites; however, no toxicity has been documented and dosage alterations are unnecessary. Liver disease leads to a decreased clearance of metronidazole and dosage reduction is recommended. Recent pharmacodynamic studies of metronidazole have demonstrated activity for 12 to 24 hours after administration of metronidazole 1 g. The post-antibiotic effect of metronidazole extends beyond 3 hours after the concentration falls below the minimum inhibitory concentration (MIC). The concentration

  16. Pharmacokinetics of Ethanol - Issues of Forensic Importance.

    PubMed

    Jones, A W

    2011-07-01

    A reliable method for the quantitative analysis of ethanol in microvolumes (50-100 μL) of blood became available in 1922, making it possible to investigate the absorption, distribution, metabolism, and excretion (ADME) of ethanol in healthy volunteers. The basic principles of ethanol pharmacokinetics were established in the 1930s, including the notion of zero-order elimination kinetics from blood and distribution of the absorbed dose into the total body water. The hepatic enzyme alcohol dehydrogenase (ADH) is primarily responsible for the oxidative metabolism of ethanol. This enzyme was purified and characterized in the early 1950s and shown to have a low Michaelis constant (km), being about ~0.1 g/L. Liver ADH is therefore saturated with substrate after the first couple of drinks and for all practical purposes the concentration-time (C-T) profiles of ethanol are a good approximation to zero-order kinetics. However, because of dose-dependent saturation kinetics, the entire postabsorptive declining part of the blood-alcohol concentration (BAC) curve looks more like a hockey stick rather than a straight line. A faster rate of ethanol elimination from blood in habituated individuals (alcoholics) is explained by participation of a high km microsomal enzyme (CYP2E1), which is inducible after a period of chronic heavy drinking. Owing to the combined influences of genetic and environmental factors, one expects a roughly threefold difference in elimination rates of ethanol from blood (0.1-0.3 g/L/h) between individuals. The volume of distribution (Vd) of ethanol, which depends on a person's age, gender, and proportion of fat to lean body mass, shows a twofold variation between individuals (0.4-0.8 L/kg). This forensic science review traces the development of forensic pharmacokinetics of ethanol from a historical perspective, followed by a discussion of important issues related to the disposition and fate of ethanol in the body, including (a) quantitative evaluation of

  17. Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects.

    PubMed

    Tahara, Atsuo; Takasu, Toshiyuki; Yokono, Masanori; Imamura, Masakazu; Kurosaki, Eiji

    2016-03-01

    The sodium-glucose cotransporter (SGLT) 2 offer a novel approach to treating type 2 diabetes by reducing hyperglycaemia via increased urinary glucose excretion. In the present study, the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six SGLT2 inhibitors commercially available in Japan were investigated and compared. Based on findings in normal and diabetic mice, the six drugs were classified into two categories, long-acting: ipragliflozin and dapagliflozin, and intermediate-acting: tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. Long-acting SGLT2 inhibitors exerted an antihyperglycemic effect with lower variability of blood glucose level via a long-lasting increase in urinary glucose excretion. In addition, ipragliflozin and luseogliflozin exhibited superiority over the others with respect to fast onset of pharmacological effect. Duration and onset of the pharmacologic effects seemed to be closely correlated with the pharmacokinetic properties of each SGLT2 inhibitor, particularly with respect to high distribution and long retention in the target organ, the kidney. While all six SGLT2 inhibitors were significantly effective in increasing urinary glucose excretion and reducing hyperglycemia, our findings suggest that variation in the quality of daily blood glucose control associated with duration and onset of pharmacologic effects of each SGLT2 inhibitor might cause slight differences in rates of improvement in type 2 diabetes. PMID:26970780

  18. Sensitivity Analysis of a Pharmacokinetic Model of Vaginal Anti-HIV Microbicide Drug Delivery.

    PubMed

    Jarrett, Angela M; Gao, Yajing; Hussaini, M Yousuff; Cogan, Nicholas G; Katz, David F

    2016-05-01

    Uncertainties in parameter values in microbicide pharmacokinetics (PK) models confound the models' use in understanding the determinants of drug delivery and in designing and interpreting dosing and sampling in PK studies. A global sensitivity analysis (Sobol' indices) was performed for a compartmental model of the pharmacokinetics of gel delivery of tenofovir to the vaginal mucosa. The model's parameter space was explored to quantify model output sensitivities to parameters characterizing properties for the gel-drug product (volume, drug transport, initial loading) and host environment (thicknesses of the mucosal epithelium and stroma and the role of ambient vaginal fluid in diluting gel). Greatest sensitivities overall were to the initial drug concentration in gel, gel-epithelium partition coefficient for drug, and rate constant for gel dilution by vaginal fluid. Sensitivities for 3 PK measures of drug concentration values were somewhat different than those for the kinetic PK measure. Sensitivities in the stromal compartment (where tenofovir acts against host cells) and a simulated biopsy also depended on thicknesses of epithelium and stroma. This methodology and results here contribute an approach to help interpret uncertainties in measures of vaginal microbicide gel properties and their host environment. In turn, this will inform rational gel design and optimization. PMID:27012224

  19. The effect of quinidine, a strong P-glycoprotein inhibitor, on the pharmacokinetics and central nervous system distribution of naloxegol.

    PubMed

    Bui, Khanh; She, Fahua; Zhou, Diansong; Butler, Kathleen; Al-Huniti, Nidal; Sostek, Mark

    2016-04-01

    Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol's AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics was unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor. PMID:26248047

  20. Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys.

    PubMed

    Datta-Mannan, Amita; Croy, Johnny E; Schirtzinger, Linda; Torgerson, Stacy; Breyer, Matthew; Wroblewski, Victor J

    2016-07-01

    Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5 mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgG-scFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures. PMID:27111637