Pharmacokinetics of retinyl palmitate and retinol after intramuscular retinyl palmitate administration in severe malaria

2000 ◽  
Vol 99 (5) ◽  
pp. 433-441 ◽  
Author(s):  
Timothy M. E. DAVIS ◽  
Tran Quang BINH ◽  
Le The Anh THU ◽  
Ric ROSSI ◽  
Phan Thi DANH ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Half Life ◽  
Supportive Therapy ◽  
Indirect Evidence ◽  
Retinyl Palmitate ◽  
Adjunctive Treatment ◽  
Severe Illness ◽  
Serum Retinol ◽  
Elimination Half

Retinol (vitamin A alcohol) is an accepted adjunctive treatment in infections such as measles. There is also indirect evidence from in vitro, animal and human studies that retinol supplementation may be beneficial in severe malaria. There have, however, been no studies that have examined the pharmacokinetics of acute retinol supplementation in severe illness. To establish whether mobilization of intramuscular retinyl palmitate (RP) and its availability as retinol are adequate in complicated falciparum malaria, we administered a single dose of 400000 i.u. of RP to six Vietnamese adults with severe malaria. Another 28 patients were not given RP. All patients had blood samples taken over 96 h for RP and retinol assay using HPLC, and received conventional anti-malarial and supportive therapy. Admission serum retinol concentrations were below the lower limit of the reference range (< 1.0 µmol/l) in 74% of the 34 patients. In supplemented patients, analysis of serum RP between 0 and 96 h using a multi-compartmental model revealed a median (range) delay in mobilization of 6.9 h (0.7–15.1 h), a bioavailability of 55% (19–100%) and an elimination half-life of 13.5 h (4.2–23.7 h). The area under the serum retinol curve expressed as an absolute or percentage change from baseline was greater in supplemented than in unsupplemented patients (P < 0.05). The separation in median serum retinol concentrations in the two groups was maximal at 48 h. The model-derived retinol half-life [1.5 (0.7–15.8) h] suggested rapid uptake, metabolism and/or excretion. In conclusion, there is variable RP bioavailability in severe malaria, but a significant if delayed increase in serum retinol over that associated with recovery from the infection. In severe infections, RP supplementation appears simple, well tolerated and of potential benefit once anti-microbial and supportive therapy have been established.

scholarly journals Characterization and pharmacokinetic parameters of recombinant soluble interleukin-4 receptor

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2396-2403 ◽  
Author(s):  
CA Jacobs ◽  
DH Lynch ◽  
ER Roux ◽  
R Miller ◽  
B Davis ◽  
...  
Keyword(s):  
Half Life ◽  
Integral Membrane Protein ◽  
Interleukin 4 ◽  
Soluble Form ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Cdna Clones ◽  
Elimination Half ◽  
Interleukin 4 Receptor

Abstract The interleukin-4 receptor (IL-4R) is expressed as a 140-Kd membrane glycoprotein that binds IL-4 with high affinity. Recently, cDNA clones for the murine IL-4R have been isolated. One clone encodes an integral membrane protein, while another encodes a protein in which translation is terminated before the transmembrane region, thus producing a soluble form of the IL-4R (sIL-4R). HeLa cell clones overexpressing sIL-4R were isolated using a novel filter-overlay and 125I-IL-4 ligand binding technique. Quantitative analysis demonstrated that the kinetics and affinity of IL-4 binding to the recombinant sIL-4R were similar to the native membrane-bound IL-4R. As low doses of sIL-4R specifically inhibited IL-4-induced proliferative responses in vitro, sIL-4R biodistribution and elimination parameters were evaluated to assess the pharmacokinetic potential of sIL-4R as a therapeutic agent. Pharmacokinetic studies demonstrated that radiolabeled sIL-4R had a distribution half-life of 9 minutes and an elimination half-life of 2.3 hours following intravenous (IV) administration. When administered by intraperitoneal or subcutaneous (SC) injection, the elimination half- lives were prolonged to 4.2 hours and 6.2 hours, respectively. Although the initial blood level of sIL-4R was reduced if administered by SC injection, the bioavailability was comparable with IV administration. The main sites of sIL-4R elimination were the liver and kidney.

scholarly journals Pharmacokinetics, tissue residues of tilmicosin phosphate (tilmicor-al®) and its in vitro and in vivo evaluation for the control of Mycoplas-ma gallisepticum infection in broiler chickens

2017 ◽  
Vol 5 (1) ◽  
pp. 11 ◽  
Author(s):  
Mohamed Elbadawy ◽  
Mohamed Aboubakr
Keyword(s):  
Half Life ◽  
Broiler Chickens ◽  
Peak Plasma ◽  
Clinical Signs ◽  
In Vivo Evaluation ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Residue Study

The aim of present study was to determine the pharmacokinetics and tissue residues of tilmicosin phosphate (tilmicoral®) as well as its in vitro and in vivo evaluation for control of Mycoplasma gallisepticum (MG) infection in broiler chickens. Pharmacokinetics (single oral dose) and tissues residues (daily for five days) of tilmicosin (25 mg/kg b.wt) in broilers were investigated. Peak plasma concentration of tilmicosin was 1.25±0.0.09 μg/mL and achieved at 3.15±0.34 h. Elimination half-life was long (44.3±7.22 h) and Vdarea was large (1.25±0.082 L/kg). Residue study revealed a good distribution and penetration of tilmicosine in lung, liver, kidney and muscles. Tilmicosin could not be detected in all tested tissues (except in lung) at 6 days after last administration. The MIC of tilmicosin and tylosin against MG were 0.054 and 0.319 μg/mL, respectively. MG infected chickens and treated by tilmicosin or tylosin showed a significant (p<0.05) improvement in mean body weights gain and a significant (p<0.05) decline in mean clinical signs score, air sac lesion score and mortality rate, however tilmicosin was a superior drug. In conclusion, timicoral® was a very effective medication for controlling MG infection in broiler chickens due to its rapid absorption, long elimination half-life, rapid and extensive penetration from blood into tissues especially lungs and air sacs. Additionally, tilmicoral® had a short withdrawal time. Moreover, its superior efficacy (in vitro and in vivo) against MG.

scholarly journals JPC-2997, a New Aminomethylphenol with HighIn VitroandIn VivoAntimalarial Activities against Blood Stages of Plasmodium

2014 ◽  
Vol 59 (1) ◽  
pp. 170-177 ◽  
Author(s):  
Geoffrey W. Birrell ◽  
Marina Chavchich ◽  
Arba L. Ager ◽  
Hong-Ming Shieh ◽  
Gavin D. Heffernan ◽  
...  
Keyword(s):  
Half Life ◽  
Multidrug Resistant ◽  
Volume Of Distribution ◽  
Parasite Line ◽  
Content Type ◽  
Elimination Half Life ◽  
Highly Active ◽  
Elimination Half

ABSTRACT4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly activein vitroagainst the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2BPlasmodium falciparumlines, with 50% inhibitory concentrations (IC50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC50s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more activein vitroagainstP. falciparumlines and 3-fold less cytotoxic. The compound possesses potentin vivosuppression activity againstPlasmodium berghei, with a 50% effective dose (ED50) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing threeAotusmonkeys infected with a chloroquine- and pyrimethamine-resistant strain ofPlasmodium vivaxat a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The highin vivopotency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug.

scholarly journals Activity and Diffusion of Tigecycline (GAR-936) in Experimental Enterococcal Endocarditis

2003 ◽  
Vol 47 (1) ◽  
pp. 216-222 ◽  
Author(s):  
Agnès Lefort ◽  
Matthieu Lafaurie ◽  
Laurent Massias ◽  
Yolande Petegnief ◽  
Azzam Saleh-Mghir ◽  
...  
Keyword(s):  
Body Weight ◽  
Half Life ◽  
Type Strain ◽  
Postantibiotic Effect ◽  
Bacteriostatic Effect ◽  
Elimination Half ◽  
Resistant Mutants ◽  
And Diffusion

ABSTRACT The activity of tigecycline (GAR-936), a novel glycylcycline, was investigated in vitro and in experimental endocarditis due to the susceptible Enterococcus faecalis JH2-2 strain, its VanA type transconjugant BM4316, and a clinical VanA type strain, E. faecium HB217 resistant to tetracycline. MICs of GAR-936 were 0.06 μg/ml for the three strains. In vitro pharmacodynamic studies demonstrated a bacteriostatic effect of GAR-936 that was not enhanced by increasing concentrations to more than 1 μg/ml and a postantibiotic effect ranging from 1 to 4.5 h for concentrations of 1- to 20-fold the MIC. Intravenous injection of [14C]GAR-936 to five rabbits with enterococcal endocarditis sacrificed 30 min, 4 h, or 12 h after the end of the infusion evidenced a lower clearance of GAR-936 from aortic vegetations than from serum and a homogeneous diffusion of GAR-936 into the vegetations. In rabbits with endocarditis, GAR-936 (14 mg/kg of body weight twice a day [b.i.d.]) given intravenously for 5 days was bacteriostatic against both strains of E. faecalis. Against E. faecium HB217, bacterial counts in vegetations significantly decreased during therapy (P < 0.01), and the effect was similar with GAR-936 at 14 mg/kg b.i.d., 14 mg/kg once a day (o.d.), and 7 mg/kg o.d., which provided concentrations in serum constantly above the MIC. Mean serum elimination half-life ranged from 3.3 to 3.6 h. No GAR-936-resistant mutants were selected in vivo with any regimen. We concluded that the combination of prolonged half-life, significant postantibiotic effect, and good and homogeneous diffusion into the vegetations may account for the in vivo activity of GAR-936 against enterococci susceptible or resistant to glycopeptides and tetracyclines, even when using a o.d. regimen in rabbits.

scholarly journals The Dynamics of Circulating Heparin-Binding Protein: Implications for Its Use as a Biomarker

2021 ◽  
pp. 1-14
Author(s):  
Jane Fisher ◽  
Fredrik Kahn ◽  
Elena Wiebe ◽  
Pontus Gustafsson ◽  
Thomas Kander ◽  
...  
Keyword(s):  
Half Life ◽  
Binding Protein ◽  
Hematologic Malignancies ◽  
Heparin Binding ◽  
Monocytic Cell ◽  
Negative Results ◽  
Heparin Binding Protein ◽  
Elimination Half ◽  
The Impact

Heparin-binding protein (HBP) is a promising biomarker for the development and severity of sepsis. To guide its use, it is important to understand the factors that could lead to false-positive or negative results, such as inappropriate release and inadequate clearance of HBP. HBP is presumably released only by neutrophils, and the organs responsible for its elimination are unknown. In this study, we aimed to determine whether non-neutrophil cells can be a source of circulating HBP and which organs are responsible for its removal. We found that in two cohorts of neutropenic patients, 12% and 19% of patients in each cohort, respectively, had detectable plasma HBP levels. In vitro, three leukemia-derived monocytic cell lines and healthy CD14+ monocytes constitutively released detectable levels of HBP. When HBP was injected intravenously in rats, we found that plasma levels of HBP decreased rapidly, with a distribution half-life below 10 min and an elimination half-life of 1–2 h. We measured HBP levels in the liver, spleen, kidneys, lungs, and urine using both ELISA and immunofluorescence quantitation, and found that the majority of HBP was present in the liver, and a small amount was present in the spleen. Immunofluorescence imaging indicated that HBP is associated mainly with hepatocytes in the liver and monocytes/macrophages in the spleen. The impact of hematologic malignancies and liver diseases on plasma HBP levels should be explored further in clinical studies.

scholarly journals Optimisation of a Microfluidic Method for the Delivery of a Small Peptide

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1505
Author(s):  
Felicity Y. Han ◽  
Weizhi Xu ◽  
Vinod Kumar ◽  
Cedric S. Cui ◽  
Xaria Li ◽  
...  
Keyword(s):  
Half Life ◽  
Drug Loading ◽  
In Vitro Release ◽  
Aqueous Solubility ◽  
The Body ◽  
Related Factors ◽  
Elimination Half ◽  
Therapeutic Peptides

Peptides hold promise as therapeutics, as they have high bioactivity and specificity, good aqueous solubility, and low toxicity. However, they typically suffer from short circulation half-lives in the body. To address this issue, here, we have developed a method for encapsulation of an innate-immune targeted hexapeptide into nanoparticles using safe non-toxic FDA-approved materials. Peptide-loaded nanoparticles were formulated using a two-stage microfluidic chip. Microfluidic-related factors (i.e., flow rate, organic solvent, theoretical drug loading, PLGA type, and concentration) that may potentially influence the nanoparticle properties were systematically investigated using dynamic light scattering and transmission electron microscopy. The pharmacokinetic (PK) profile and biodistribution of the optimised nanoparticles were assessed in mice. Peptide-loaded lipid shell-PLGA core nanoparticles with designated size (~400 nm) and a sustained in vitro release profile were further characterized in vivo. In the form of nanoparticles, the elimination half-life of the encapsulated peptide was extended significantly compared with the peptide alone and resulted in a much higher distribution into the lung. These novel nanoparticles with lipid shells have considerable potential for increasing the circulation half-life and improving the biodistribution of therapeutic peptides to improve their clinical utility, including peptides aimed at treating lung-related diseases.

scholarly journals Activities of Dalbavancin In Vitro and in a Rabbit Model of Experimental Endocarditis Due to Staphylococcus aureus with or without Reduced Susceptibility to Vancomycin and Teicoplanin

2004 ◽  
Vol 48 (3) ◽  
pp. 1061-1064 ◽  
Author(s):  
Agnès Lefort ◽  
Juliette Pavie ◽  
Louis Garry ◽  
Françoise Chau ◽  
Bruno Fantin
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Half Life ◽  
Rabbit Model ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Once Daily ◽  
Elimination Half Life ◽  
Elimination Half

ABSTRACT For the treatment of rabbit endocarditis, dalbavancin given once daily (10 mg/kg of body weight for 4 days) or as a single 40-mg/kg dose was active against Staphylococcus aureus with or without reduced susceptibility to glycopeptides, as expected from its good in vitro activity, even in broth supplemented with 90% serum and given its prolonged elimination half-life.

Alteration of the pharmacokinetics of high-dose ara-C by its metabolite, high ara-U in patients with acute leukemia.

1983 ◽  
Vol 1 (12) ◽  
pp. 763-771 ◽  
Author(s):  
R L Capizzi ◽  
J L Yang ◽  
E Cheng ◽  
T Bjornsson ◽  
D Sahasrabudhe ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cytosine Arabinoside ◽  
Half Life ◽  
Disease Status ◽  
Inhibitory Effect ◽  
High Dose ◽  
Elimination Half ◽  
Kinetics Of ◽  
Time Of Administration

The pharmacokinetics of high-dose cytosine arabinoside (HiDAC) given as a three-hour intravenous infusion at 3 g/m2 were studied in five patients with acute leukemia during relapse and/or remission of their disease. Apparent steady state plasma levels of ara-C during 13 infusions averaged 115 +/- 32 microM. Upon cessation of the infusion, cytosine arabinoside (ara-C) was rapidly cleared from the plasma. The apparent postinfusion kinetics of ara-C were triexponential with a distribution half-life of 16 minutes and elimination half-lives of 1.8 hours and six hours. Total clearance averaged 86 L per hour and mean residence time averaged 0.47 hours. Disease status (relapse or remission) had no apparent effect on the pharmacokinetic characteristics of ara-C. Peak levels of ara-U averaged 310 microM and the metabolite had an average apparent elimination half-life of 3.75 hours. Despite the persistence of ara-U at about 100 microM at the time of administration of subsequent infusions of ara-C, there was no further accumulation of ara-U in the plasma with repetitive infusions of HiDAC. In vitro studies indicate that ara-U can exert an inhibitory effect on deoxycytidine (dCyd) deaminase activity. The ratio of the Ki of ara-U to the Km of ara-C for cytidine (Cyd)-dCyd deaminase is 40:1; however, during the gamma phase of ara-C elimination, the ratio of ara-U:ara-C in plasma is at least 100:1. Thus, a retardation of systemic catabolism of ara-C by ara-U is possible. Two to three hours after the termination of the HiDAC infusion, the ara-C cerebrospinal fluid: plasma ratio is 1-3:1, a feature of potential therapeutic significance. The slower elimination of ara-C from the CSF may also contribute to the plasma gamma half-life.

scholarly journals Formulation And In-Vitro Evaluation Of Cocrystals Of Pantoprazole Sodium For Immediate Release

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Shiwangi Jain ◽  
Mayank Bansal ◽  
Ashutosh Sharma
Keyword(s):  
Half Life ◽  
Serum Proteins ◽  
Immediate Release ◽  
Volume Of Distribution ◽  
Current Approach ◽  
Total Serum ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Acid Labile

Pantoprazole is extensively metabolized in the liver and 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. 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 clearance of pantoprazole is only slightly affected by age, with its half-life being approximately 1.25 h in the elderly. Pantoprazole is an acid labile drug that requires protection from degradation in acidic media. Hence, co-crystallization of pantoprazole sodium with appropriate co-formers will inhibit its degradation in acidic medium ensuring fast release in the stomach. The acid-labile drugs for oral administration may also be protected from gastric acidity by inhibiting its degradation upon entering into acidic environment. So, the current approach includes co-crystallization of the provided drug with appropriate co-former which prevents degradation of drug by quick absorption and protects the drug from low pH. Apart from that, the formulations also modulate or control the drug release for an immediate action. Keywords: Pantoprazole sodium, Co-crystal, solvent drop method, Co-former.

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