Elimination Half-time Research Articles

Liver injury in COVID-19: two clinical cases

COVID-19 (coronavirus disease 2019, a disease caused by a new coronavirus 2019) continues to threaten world public healthcare. Epidemiological data indicate that patients with metabolic disorders and chronic illnesses are most susceptible to SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Potential factors for organ involvement include systemic hyperimmune-mediated inflammation due to the “cytokine storm”, cytopathic effects, hypoxia, drug toxicities, etc. In addition, SARS-CoV-2, by interaction with ACE2 (angiotensin-converting enzyme 2) receptors in the vasculature endothelium results in endothelial dysfunction, increased permeability, microcirculatory abnormalities, vascular thrombophilia and thrombus formation. The diagnosis of COVID-19 is confirmed by detection of SARS-CoV-2 RNA in biological samples and serum antibodies. The infection is associated with leukopenia and thrombocytopenia, increased С-reactive protein, ferritin, lactate dehydrogenase, and D-dimer. Abnormalities in functional liver tests seen in COVID-19 are associated with progression and severity of the infection. The mechanism of direct cytotoxicity due to active SARS-CoV-2 replication in hepatocytes are not fully understood and is likely to be related to potential proliferation of hepatocytes, liver injury in response to systemic inflammation, and development of drug hepatic toxicity. We present a clinical case of drug-induced hepatitis in a patient with COVID-19 treated with tocilizumab, an inhibitor of interleukin 6 receptors. Prolonged increase in blood enzymes after treatment cessation is likely related to a longer half-elimination time of tocilizumab, which affects the oxidation-reduction system of liver cytochromes. Patients with chronic liver disorders are more vulnerable to clinical sequelae of СOVID-19, while the infection is frequently associated with hypoxia and hypoxemia due to severe pneumonia or the “cytokine storm”. In addition, patients who have been diagnosed with liver cirrhosis are at high risk of morbidity and mortality due to their higher proneness to infections, first of all, due to systemic immune deficiency that was demonstrated in the second clinical case. Decompensated liver cirrhosis is related not only to a higher risk of more severe COVID-19, but also to progression of chronic liver disease as such. To achieve effective results of causal and nosotropic therapy for COVID-19, it is highly significant to provide thorough clinical monitoring, tailored approach to the treatment of each patient with consideration of their comorbidities, immune status, and drug interactions.

Effect Effect of Black Rice Bran on the Pharmacokinetics Profile of Glibenclamide in Hyperglycemic Rats

Black rice bran (BBH) which contains anthocyanins has the ability to lower blood sugar. In therapy diabetes mellitus (DM) it is possible that BBH is used together with the oral antidiabetic Glibenclamide (Gli). Glibenclamide, a weak acid, is well absorbed in the gastrointestinal tract. The absorption of BBH is also good under acidic conditions. So, it is necessary to study the pharmacokinetic interactions between Gli and BBH.
 The study was designed using a one-way completely randomized design of ten (10) hyperglycemic rats, divided into two groups. Group I rats received Gli 5 mg / kgBW treatment, and group II received Gli 5 mg/kgBW along with BBH 50 mg / kgBW. Sampling was carried out at 1, 2, 4,6, 8 and 24 hours after treatment. Gli levels in the blood were determined by Liquid Chromatography/Mass Spectroscopy (LC/MS).
 The results showed that in the absorption phase, giving BBH with Gli did not affect the Gli profile in terms of parameters Tmax, Cmax and AUC0-inf. Likewise, in the distribution and elimination phases in terms of parameters VD, ClT and elimination half-time (t1/2). So that the provision of BBH does not affect the pharmacokinetic parameters of Gli in hyperglycemic rats.

Synthesis and Pharmacokinetics of 2-(4-amino-3,5-dichlorophenyl)-2-(alkylamino)ethanols - Structural Isomers of β2 Agonists Clenproperol and Clenpenterol

Methods for the synthesis of 2-(4-amino-3,5-dichlorophenyl)-2-(isopropylamino)ethanol and 2-(4-amino-3,5-dichlorophenyl)-2-(tert-amylamino)ethanol, which are structural isomer of the β2 agonists clenproperol and clenpenterol, were developed. The pharmacokinetics of these compounds were studied on p.o. administration to rats at doses of 270 and 540 μg/kg. Chromatomass spectrometry studies showed that increases in dose led to proportionate increases in the maximum blood substance concentration. Times to maximum concentration were 0.25 – 1.5 h. The times during which substances were detectable in blood with a sensitivity of 0.1 ng/ml were determined: values were 72 h for 2-(4-amino-3,5-dichlorophenyl)-2-(isopropylamino)ethanol and more than 96 h for 2-(4-amino-3,5-dichlorophenyl)-2-(tert-amylamino)ethanol. Halogen atoms present in the molecules of the study compounds prevented their rapid metabolic inactivation. The main pharmacokinetic parameters were computed: area under pharmacokinetic curve; half-elimination time; mean retention time; plasma clearance.

Pharmacokinetic study of tanshinol and ligustrazine in rat plasma after intravenous administration of tanshinol and Danshen Chuanxiongqin Injection.

To investigate the effect of ligustrazine on the pharmacokinetic profile of tanshinol after intravenous administration in rats, a sensitive liquid chromatography tandem mass spectrometry method was developed and validated for quantitative determination of tanshinol and ligustrazine in rat plasma. After prepared by protein precipitation, the analytes were separated on a Waters Acquity HSS T3 column (100 × 2.1 mm, 1.8μm) and eluted by 0.1% formic acid in water and acetonitrile at a flow rate of 0.4 ml/min. The precursor-product ion transitions were m/z 197.0 → 135.0 for tanshinol, m/z 417.1 → 255.1 for liquiritin (internal standard) in negative ion mode and m/z 137.1 → 55.0 for ligustrazine in positive ion mode. To avoid the interference of tanshinol metabolite transformation, the stability of analytes in samples collected after administration was assessed. The validated method was successfully applied to a pharmacokinetic study after intravenous administration of single tanshinol and Danshen Chuanxiongqin Injection. After Danshen Chuanxiongqin injection administration, the values of elimination half-time, area under the concentration-time curve and Co were 0.36 ± 0.13 h, 1.29 ± 0.37 μg/ml h and 10.51 ± 2.58 μg/ml for male rats, respectively. In the single tanshinol group, the corresponding values were 0.56 ± 0.24 h, 1.85 ± 0.44 μg/ml h and 14.11 ± 2.26 μg/ml for male rats-30-40% higher than those for the Danshen Chuanxiongqin Injection group. There was a significant different between male and female rats. This study provided information on the influence of ligustrazine on the pharmacokinetic characteristics of tanshinol after intravenous administration of Danshen Chuanxiongqin Injection in rats, which will be helpful for its clinical application.

Exploring Elimination Kinetics of Four 5-Nitrofuran Derivatives by Microbes Present in Rural and Municipal Activated Sludge

The wastewater treatment plants (WWTPs) are the biggest reservoirs of pharmaceutical residues discharged into the environment. Among many pharmaceuticals, derivatives of 5-nitrofuran, whose cytotoxicity and neurotoxicity have been proved, are widely used. The ability of such compounds to accumulate in water and sediments motivated us to analyze the ability of microbial communities of rural and municipal WWTPs to eliminate nitrofurantoin (NFT), nitrofurazone (NFZ), furaltadone (FTD), and furazolidone (FZD). Metagenomic analysis of microbial communities in rural and municipal activated sludge has provided information about the bacterial biodiversity in the WWTPs. In both samples, the most dominant phylum in terms of abundance was Proteobacteria followed by Bacteroidetes; however, microbial community of the municipal WWTP exhibited greater biodiversity than the one of the rural WWTP. The results of high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis of the samples and elimination kinetic calculations allowed the determination of FZD, FTD, NFT, and NFZ elimination half-time varying from 104 to 327 h and test system first-order half-lives in the examined WWTP samples (from 31 to 231 h). Moreover, a comparison of the effectiveness of the microbials from two treatment plants, a rural one and a municipal one, revealed the poorer performance of the microbial communities from the smaller, rural WWTP in disposal of the analyzed pharmaceuticals, as after 24 days, the rural WWTP community was able to eliminate from 20 to 62% of 5-nitrofuran derivatives, while the municipal consortium removed over 85% of the compounds from the cultures.

Comparative Pharmacokinetic Profiles of Puerarin in Rat Plasma by UHPLC-MS/MS after Oral Administration of Pueraria lobata Extract and Pure Puerarin.

Puerarin is the main biologically active isoflavone in Pueraria lobata and has a wide range of biological activities. However, due to its poor water solubility and low oral bioavailability, its clinical applications are restricted. Compared with puerarin, the Pueraria lobata extract (PLE) has better water solubility, lower toxicity, and less side effects. In this study, the pharmacokinetics of orally administered puerarin (100 mg/kg) and PLE (763 mg/kg, equivalent to 100.0 mg/kg of puerarin) to rats was investigated by the UHPLC-MS/MS method. Results showed that when the rats were administered PLE, the area under the concentration-time curve from zero to infinity (AUC0-inf) dramatically increased from 219.83 ± 64.37 μg h/L to 462.62 ± 51.74 μg h/L (p < 0.01). The elimination half-time (t1/2) also increased from 1.60 ± 0.38 h to 12.04 ± 5.10 h (p < 0.01). The maximum concentration (Cmax) of puerarin decreased from 101.64 ± 41.82 ng/mL to 48.64 ± 21.47 ng/mL (p < 0.01), and time to reach the maximum plasma concentration (Tmax) of puerarin decreased from 1.46 ± 1.08 h to 0.54 ± 0.30 h (p < 0.01). Results indicated that the pharmacokinetics of puerarin in Pueraria lobata may be dramatically different from pure puerarin in the plasma of rat, and oral bioavailability of puerarin may be increased when PLE was administrated to rats.

Extensive Therapeutic Drug Monitoring of Colistin in Critically Ill Patients Reveals Undetected Risks.

(1) Background: With the rise of multi-/pan-drug resistant (MDR/PDR) pathogens, the less utilized antibiotic Colistin has made a comeback. Colistin fell out of favor due to its small therapeutic range and high potential for toxicity. Today, it is used again as a last resort substance in treating MDR/PDR pathogens. Although new guidelines with detailed recommendations for Colistin dosing are available, finding the right dose in critically ill patients with renal failure remains difficult. Here, we evaluate the efficiency of the current guidelines’ recommendations by using high resolution therapeutic drug monitoring of Colistin. (2) Methods: We analyzed plasma levels of Colistin and its prodrug colisthimethate sodium (CMS) in 779 samples, drawn from eight PDR-infected ICU patients, using a HPLC-MS/MS approach. The impact of renal function on proper Colistin target levels was assessed. (3) Results: CMS levels did not correlate with Colistin levels. Over-/Underdosing occurred regardless of renal function and mode of renal replacement therapy. Colistin elimination half-time appeared to be longer than previously reported. (4) Conclusion: Following dose recommendations from the most current guidelines does not necessarily lead to adequate Colistin plasma levels. Use of Colistin without therapeutic drug monitoring might be unsafe and guideline adherence does not warrant efficient target levels in critically ill patients.

Safety, tolerability, pharmacokinetics, and immunogenicity of a human monoclonal antibody targeting the G glycoprotein of henipaviruses in healthy adults: a first-in-human, randomised, controlled, phase 1 study

The monoclonal antibody m102.4 is a potent, fully human antibody that neutralises Hendra and Nipah viruses in vitro and in vivo. We aimed to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of m102.4 in healthy adults. In this double-blind, placebo-controlled, single-centre, dose-escalation, phase 1 trial of m102.4, we randomly assigned healthy adults aged 18-50 years with a body-mass index of 18·0-35·0 kg/m2 to one of five cohorts. A sentinel pair for each cohort was randomly assigned to either m102.4 or placebo. The remaining participants in each cohort were randomly assigned (5:1) to receive m102.4 or placebo. Cohorts 1-4 received a single intravenous infusion of m102.4 at doses of 1 mg/kg (cohort 1), 3 mg/kg (cohort 2), 10 mg/kg (cohort 3), and 20 mg/kg (cohort 4), and were monitored for 113 days. Cohort 5 received two infusions of 20 mg/kg 72 h apart and were monitored for 123 days. The primary outcomes were safety and tolerability. Secondary outcomes were pharmacokinetics and immunogenicity. Analyses were completed according to protocol. The study was registered on the Australian New Zealand Clinical Trials Registry, ACTRN12615000395538. Between March 27, 2015, and June 16, 2016, 40 (52%) of 77 healthy screened adults were enrolled in the study. Eight participants were assigned to each cohort (six received m102.4 and two received placebo). 86 treatment-emergent adverse events were reported, with similar rates between placebo and treatment groups. The most common treatment-related event was headache (12 [40%] of 30 participants in the combined m102.4 group, and three [30%] of ten participants in the pooled placebo group). No deaths or severe adverse events leading to study discontinuation occurred. Pharmacokinetics based on those receiving m102.4 (n=30) were linear, with a median half-life of 663·3 h (range 474·3-735·1) for cohort 1, 466·3 h (382·8-522·3) for cohort 2, 397·0 h (333·9-491·8) for cohort 3, and 466·7 h (351·0-889·6) for cohort 4. The elimination kinetics of those receiving repeated dosing (cohort 5) were similar to those of single-dose recipients (median elimination half-time 472·0 [385·6-592·0]). Anti-m102.4 antibodies were not detected at any time-point during the study. Single and repeated dosing of m102.4 were well tolerated and safe, displayed linear pharmacokinetics, and showed no evidence of an immunogenic response. This study will inform future dosing regimens for m102.4 to achieve prolonged exposure for systemic efficacy to prevent and treat henipavirus infections. Queensland Department of Health, the National Health and Medical Research Council, and the National Hendra Virus Research Program.

Pharmacokinetics interaction study of 99mTc-glutathione radiopharmaceutical with doxorubicin in mice (mus musculus)

The use of radiopharmaceuticals for cancer diagnosis and therapy is increasing. The radiopharmaceutical is also used to monitor the progress of a disease and determine the appropriate treatment. However, the use of radiopharmaceuticals needs to pay attention to the alteration in pharmacokinetics, pharmacology, and toxicity that are influenced by the drugs consumed by patients. Interaction between drugs with radiopharmaceuticals will cause alteration in pharmacokinetic effects. Therefore, this study aimed to determine the pharmacokinetic interaction of “-Tc-Glutathione radiopharmaceuticals with doxorubicin cancer drug in mice (Mus musculus). The pharmacokinetic studies were performed using four groups of animal model and each group consists of three rats. The groups were classified to normal mice without treatment of doxorubicin as normal mice control (I), normal mice treated with doxorubicin (II), cancer model mice without treatment of doxorubicin as cancer model mice control (III), and cancer model mice treated with doxorubicin (IV). The radioactivity in blood at a certain interval was then calculated to determine the distribution and elimination half-time. The distribution halftime of group I, II, III, and IV were 0.004±0.001, 0.0037±0.0001, 0.003±0.0001, and 0.0037±0.0001 hours, respectively, while the elimination half-time were 5.310±1.050, 10.7344±0.4692, 72.712±2.427, and 26.9320±7.8152 hours, respectively. The results of the T-test showed that there was a significant difference in elimination half-life of 99mTc-Glutathione between the treated group and the control group. These results indicate that administration of the doxorubicin before administration of 99m-Tc-Glutathione needs to be avoided because it can alter the elimination half-life of »-Tc-Glutathione. The results of this study are expected to provide benefits for clinicians in nuclear medicine to avoid the interpretation of incorrect diagnosis results, to achieve high-quality health service and will have a positive impact on the appropriate treatment for patients.

ES11.06 Toxicology of Tobacco and Metabolites, and Impact on Cancer

ES11.06 Toxicology of Tobacco and Metabolites, and Impact on Cancer

2-Deoxyglycoside Conjugates of Lupane Triterpenoids with High Cytotoxic Activity-Synthesis, Activity, and Pharmacokinetic Profile.

A set of 41 glycosidic conjugates of pentacyclic triterpenes was synthesized in order to improve the solubility of highly cytotoxic parent compounds. Their in vitro cytotoxic activity was evaluated in 25 cancer cell lines and 2 noncancer fibroblasts. Fifteen compounds had high cytotoxicity on the T-lymphoblastic leukemia cell line CCRF-CEM and 6 of them were active in multiple cell lines of various histogenic origin and not toxic in fibroblasts. Compound 11a had IC50 of 0.64 μM in CCRF-CEM cells, 0.60 μM in K-562 cells, and 0.37 μM in PC-3 cells; compound 12a had IC50 of 0.64 μM in CCRF-CEM cells and 0.71 μM in SW620 cells; compound 17b had IC50 of 0.86 μM in HCT116 cells and 0.92 μM in PC-3 cells. Compounds 11b and 12b were slightly less active than the previously mentioned derivatives; however, their solubility was significantly better, and therefore they were selected for the in vivo evaluation of the pharmacokinetic profile in mice. In both compounds, the maximum concentration in plasma was achieved very rapidly-the highest level in plasma was found 1 h after administration (22.2, respectively, 6.4 μM). For compound 12b, the resorption was followed with fast elimination, and 12 h after administration, the compound was not detected in plasma. In contrast, compound 11b was eliminated more slowly; it was still present in plasma after 12 h, but its concentration dropped below the detection limit after 24 h. The elimination half-time determined for compound 11b was 2.4 h and for compound 12b just about 1.4 h. These values are reasonable for further drug development.

Phase I safety and pharmacokinetic study of KN035, the first subcutaneously administered, novel fusion anti-PD-L1 antibody in Japanese patients with advanced solid tumors.

2609 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc, formulated for subcutaneous (SC) injection. A phase I safety and pharmacokinetic (PK) study was conducted in Japanese patients. Methods: Patients with advanced solid tumors were treated with KN035 SC once every-7-days (QW) or once every-14-days (Q2W) schedules with the dose limiting toxicities (DLT) evaluation period of 28 days. For the QW schedule, the starting dose was 1 mg/kg (n=3) with escalations to 2.5 (n=4), and 5 (n=3) mg/kg. For the Q2W schedule, 6 patients were planned at the dose levels of 2.5 and 5 mg/kg. Results: No DLT was observed up to the highest dose level of 5 mg/kg QW. No maximum tolerated dose (MTD) was reached. Among evaluable treated subjects (n=14), there were two confirmed partial responses. Preliminary PK analysis suggested that after SC administration, KN035 was slowly absorbed (Tmax ∼ 4 d) and the mean residual time (MRT) was 21 days. Apparent clearance (CL/F) and volume of distribution (Vz/F) were on average 0.58 L/day and 11 L, respectively. Plasma levels generally decreased mono-exponentially with an average terminal elimination half time around 13 days after reaching the peak concentration post SC administration. Exposures of KN035 increased approximately proportionally with dose. Trough concentrations were maintained above 15 µg/mL post administration of 5 mg/kg Q2W. No apparent exposure-body weight relationship was observed. Conclusions: KN035 exhibits a favorable safety profile in patients with advanced malignancies and preliminary results demonstrate encouraging anti-tumor activity. Based on PK data from the Q2W schedule, a fixed dose with less frequent dosing schedule of every 3 or 4 weeks is presently being evaluated. Clinical trial information: NCT03248843.

Respirable aerosol exposures of nicotine dry powder formulations to in vitro, ex vivo, and in vivo pre-clinical models demonstrate consistency of pharmacokinetic profiles

Background: Nicotine, because of its volatility, has a complex dosimetry following inhalation as a vapor/aerosol mix. To better control the dosimetry, nicotine could be formulated with a suitable dry powder excipient for use in a clinical inhaler.Aim and Methods: The aim of this study was to investigate the pharmacokinetic PK profile of two dry powder formulations containing 2.5% or 5% nicotine using three experimental models associated to the PreciseInhale™ aerosolization system: the in vitro DissolvIt dissolution system; the ex vivo isolated, ventilated, and perfused lung (IPL) of the rat; and the in vivo intratracheally intubated rat. Results and Discussion: Following exposure, both nicotine formulations had very rapid and similar dissolution and absorption kinetics in both the DissolvIt and IPL exposure models, with an initial half-time of absorption to the single-pass perfusate of 34 and 72 seconds, respectively. In the intratracheally intubated rat, following a rapid initial equilibration between the lungs and systemic compartments, nicotine had a systemic elimination half-time of 2.3–2.4 hours for both formulations. The rapid pulmonary PK of nicotine was likely close to the theoretical equilibration of a low-binding substance with a tissue-blood partition coefficient close to 1. Conclusions: The data generated with the three experimental models provided a comprehensive picture of the inhalation PK of the two nicotine formulations. In particular, the results showed a very rapid dissolution and absorption of the two nicotine formulations and these results could be highly useful for improving the design and calibration of physiologically based PK models to produce more robust predictions. Abbreviations: AED: animal equivalent dose; BW: body weight; HPLC: high-performance liquid chromatography; IPL: isolated, ventilated, and perfused lung; PK: pharmacokinetics; SEM: scanning electron microscopy; USP: United States Pharmacopeia.

Fast and direct determination of catechol-3, 6-bis(methyleiminodiacetic acid) prototype in beagle dog plasma using liquid chromatography tandem mass spectrometry: A simplified and high throughput in-vivo method for the metal chelator

It is usually somewhat difficult to analyze the metal chelators, especially in complex biological matrix, because of the interference of metal ions in both the matrix and analyzing system. In this study, an innovative and simple bioanalytical method was established and validated for the quantification of a newly developed uranium chelator catechol-3, 6-bis (methyleiminodiacetic acid) (CBMIDA) in beagle dog plasma. Different analytical columns and mobile phase were tested for effective chromatography resolution and sensitive and reproducible response of CBMIDA and the internal standard. An Agilent Zorbax SB AQ column was chosen. Excessive peak tailing, peak asymmetry, low recovery, and poor reproducibility, which are generally observed in chromatographic analysis of metal chelators, were overcome by the use of a pulse gradient method and addition of ethylene diamine tetraacetic acid (EDTA) to the mobile phase at 8 μg mL−1, enabling good peak shape, low matrix interference, high precision and good linearity for CBMIDA quantification in beagle dog plasma. Plasma sample pretreatment was performed by a simple, high throughput protein precipitation step with 2.5 mM EDTA methanol solution in a 96-well protein precipitation plate without complexing with the metal ions, and the sample was directly analyzed by electrospray ionization mass spectrometry. By shifting the analysis target from the metal complex to metal chelator itself, the method has an advantage over the existing method for determination of EDTA and diethylenetriaminepentaacetic acid owing to increased sample throughput and apparent simplicity. The assay was validated in accordance with the United States Food and Drug Administration guidelines and successfully applied to the pharmacokinetic study of CBMIDA in beagles after intramuscular injection of CBMIDA at different doses. The method was sensitive enough for the detection of CBMIDA concentration at 4 elimination half-times. The experimental strategies presented herein may be helpful for the measurement of other radionuclide chelators in biological matrices.

Stimuli-responsive polymer-doxorubicin conjugate: Antitumor mechanism and potential as nano-prodrug

Polymer-drug conjugates has significantly improved the anti-tumor efficacy of chemotherapeutic drugs and alleviated their side effects. N-(1,3-dihydroxypropan-2-yl) methacrylamide (DHPMA) copolymer was synthesized via RAFT polymerization and polymer-doxorubicin (DOX) (diblock pDHPMA-DOX) were formed by conjugation, resulting in a self-aggregation-induced nanoprodrug with a favorable size of 21 nm and great stability. The nanoprodrug with a molecular weight (MW) of 95 kDa released drugs in response to tumor microenvironmental pH variations and they were enzymatically hydrolyzed into low MW segments (45 kDa). The nanoprodrug was transported through the endolysosomal pathway, released the drug into the cytoplasm and some was localized in the mitochondria, resulting in disruption of the cellular actin cytoskeleton. Cellular apoptosis was also associated with reduction in the mitochondrial potential caused by the nanoprodrug. Notably, the nanoprodrug had a significantly prolonged blood circulation time with an elimination half time of 9.8 h, displayed high accumulation within tumors, and improved the in vivo therapeutic efficacy against 4T1 xenograft tumors compared to free DOX. The tumor xenograft immunohistochemistry study clearly indicated tumor inhibition was through the inhibition of cell proliferation and antiangiogenic effects. Our studies demonstrated that the diblock pDHPMA-DOX nanoprodrug with a controlled molecular structure is promising to alleviate adverse effects of free DOX and have a great potential as an efficient anticancer agent. Statement of SignificanceIn this work, we prepared a biodegradable diblock DHPMA polymer-doxorubicin conjugate via one-pot of RAFT polymerization and conjugate chemistry. The conjugate-based nanoprodrug was internalized by endocytosis to intracellularly release DOX and further induce disruption of mitochondrial functions, actin cytoskeleton alterations and cellular apoptosis. The nanoprodrug with a high molecular weight (MW) (95 kDa) showed a long blood circulation time and achieved high accumulation into tumors. The nanoprodrug was degraded into low MW (∼45 kDa) products below the renal threshold, which ensured its biosafety. Additionally, the multi-stimuli-responsive nanoprodrug demonstrated an enhanced antitumor efficacy against 4T1 breast tumors and alleviated side effects, showing a great potential as an efficient and safe anticancer agent.

Ultralong Circulating Lollipop‐Like Nanoparticles Assembled with Gossypol, Doxorubicin, and Polydopamine via π–π Stacking for Synergistic Tumor Therapy

AbstractLong blood circulation in vivo remains a challenge to dual‐drug‐loaded nanocarriers for synergistic chemotherapy. Herein, a novel strategy to prepare lollipop‐like dual‐drug‐loaded nanoparticles (DOX–PDA–gossypol NPs) is developed based on the self‐assembly of gossypol, doxorubicin (DOX), and polydopamine (PDA) via π–π stacking. Dopamine polymerizes to PDA and fills the gaps between the gossypol and DOX molecules to form the super compact long‐circulating nanoparticles. The DOX–PDA–gossypol NPs show a suitable particle size of 59.6 ± 9.6 nm, high drug loading of 91%, superb stability, high maximum‐tolerated dose (MTD) of over 60 mg kg‐1, and negligible toxicity. These NPs also exhibit pH‐dependent drug release and low combination index (0.23). Notably, they show dramatically ultralong blood circulation (&gt;192 h) with elimination half times 458‐fold and 258‐fold longer than that of free DOX and free gossypol, respectively. These values are markedly higher than most of the reported results. Therefore, the DOX–PDA–gossypol NPs have a high tumor accumulation of 12% remaining on the 8th day postinjection. This characteristic contributes to the excellent tumor comprehensive synergistic therapeutic efficacy (TIR &gt; 90%) with low administration dosage and is benefitted for widening the drug therapeutic window. Thus, the proposed strategy has remarkable potential for tumor synergistic therapy.

The Effect of Calcium Carbonate and Cholecalciferol on Pharmacokinetic Interaction of 99m/Tc-CTMP Radiopharmaceuticals for Bone Scanning in Rats (Rattus norvegicus)

Hypocalcemia is one of manifestation of bone metastases which could be treated using calcium carbonate and chole calciferol. Tc-99 m radiolabeled 1,4,8,11-tetraazacyclo tetradecyl-1,4,8,11-tetramethylene phosponic acid ( against 99m Tc-CTMP ) on the other hand is a radioactive complex compound which has an affinity toward bone. Therefore, it could be used as bone tracer (radiopharmaceutical) in bone imaging. However, there has been a concern regarding the use 99m Tc- CTMP on patients who have been treated with calcium carbonate and chole calciferol . In this circumstance 99m Tc- CTMP could interact with calcium carbonate and chole calciferol and it might then interefere with the imaging results. Therefore, th e aim of this study was to determine the pharmacokinetic behavior of 99m Tc-CTMP in rats ( Rattus norvegicus ) that had been previously treated with calcium carbonate and cholecalciferol. The pharmacokinetic studies were performed using four groups of animal model and each groups consists of three rats. The groups were classified as control (I) , rats treated with calcium carbonate (II) , rats treated with chole calciferol (III) , and rats treated with both calcium carbonate and cholecalciferol (IV) . After the rats were treated for 3 days , 99m Tc-CTMP radiopharmaceutical was injected through a tail vein of each rat. At specific time intervals after 99m Tc-CTMP administration , blood was then extracted from the tail , weigh ed and counted using a single channel analyzer. The percentage of r adioactivity in blood at a certain interval was then calculated to determine the distribution half-time and the elimination half-time. The distribution half-time of group I, II, II, and IV were 0.43 + 0.1 3 , 0.2 5 + 0.1 8 , 0.32 + 0.10, and 0.47 + 0.07 hours, respectively, while the elimination half-time were 2.56 + 0.1 8 , 4.48 + 0.5 6 , 4.47 + 1.13, 6.19 + 1.9 7 respectively. The results of T-test showed that there was no significant difference of distribution half-time between the three treated groups and the control group. However, there was significant difference of elimination half-time between the three treatment groups and control. This research showed that giving calcium carbonate or, chole calciferol, and both for 3 days prior administration of 99m Tc-CTMP would mantain elimination half-time which resulted in longer excretion / elimination time.

Re-defining kinetic lung overload: Time for new paradigms

This paper compares two previously published 13-week inhalation studies with poorly soluble, low-toxicity particles (PSLTs) in rats to identify the unifying key metric of kinetic lung overload. The PSLTs compared are Multi-Walled Carbon Nanotubes (MWCNT) and black iron oxide (Fe3O4, magnetite). Their material densities and related displacement volumes differ approximately 30-fold. This offers an opportunity for analyzing the impact of the PSLT-density of agglomerates on endpoints currently conceived to be involved in kinetic lung overload. Corpuscular volumes and counts of cells retrieved by bronchoalveolar lavage (BAL) are analyzed to interrelate modeled cumulative lung burdens of solid aerosol to predict the no observed adverse effect concentration (NOAEC) and range of conditions causing various degrees of kinetic lung overload up to and beyond the maximum tolerated cumulative dose (MTD). Both descriptors are a reflection of accumulated lung burdens and, by design, bracket repeated exposure inhalation studies with PSLTs. This comparative analysis of high- and low-density PSLTs reveals that the leading adverse outcome pathway (AOP) is caused by a markedly increased pool-size of BAL-cells rather than any increased corpuscular volume of cells. The overload-related increased pool-size of BAL-cells is shown to be the dependent variable for the prorated increased elimination half-time of PSLTs. This interrelationship was used to predict the exposure concentrations for attaining a NOAEC and MTD of guideline-based repeated exposure inhalation studies with PSLTs. Earlier approaches suggesting a loss of the migratory capabilities of particle-laden, enlarged alveolar macrophages to be the cause for any increased elimination half-time of PSLTs could not be confirmed. In summary, kinetic modeling provides a versatile means to predict the cornerstones of repeated inhalation studies with PSLTs on rats. Such possibilities leverage adjustment of studies from different sources to identical degrees of kinetic overload. They also facilitate and foster AOP-facilitated read-across approaches. The course taken enables risk assessors to better differentiate lung pathologies caused by generic lung overload and substance-specific pathologies.

IN VIVO INTERACTION OF PROPYLTHIOURACIL WITH SODIUM IODIDE (Na131I) RADIOPHARMACEUTICAL IN RATS (Rattus norvegicus)

IN VIVO INTERACTION OF PROPYLTHIOURACIL WITH SODIUM IODIDE (Na131I) RADIOPHARMACEUTICAL IN RATS (Rattus norvegicus).. The aim of this research is to determine the effect of propylthiouracil (PTU) treatment to pharmacokinetics interaction and biodistribution profile of Na131I radiopharmaceuticals. Three groups of animal model were used in this experiment, i.e. experimental animals which given PTU for 1 time (onset or A groups), PTU for six days (B Groups) and without treatment (control or C Groups). Pharmacokinetics and biodistribution test were conducted by giving PTU per oral and after 24 hours, continued by giving Na131I solution per oral. In pharmacokinetics test, percentage of injection dose/gram of blood (%ID/g) was calculated to determine the absorption, distribution and elimination half time. In biodistribution test, percentage of injection dose/gram of organs was calculated to determine the accumulation of Na131I in spesific organs. The results showed that the absorption half time of A, B and C groups were 3.14 ± 1.42, 2.49 ± 0.49 and 2.52 ± 0.7 hours, respectively. The distribution half time of A, B and C groups were 10.58 + 5.85, 12.92 + 3.75 and 11.42 + 3.15 hours, respectively. The elimination half time of A, B and C groups were 113.03 + 46.03, 96.57+ 47.76 and 196.71 + 145.21 hours, respectively. Biodistribution test results showed that the accumulation of Na131I in thyroid of A, B and C groups were 1.31 + 0.45, 5.03 + 0.55 and 4.45 + 2.24 % respectively. This research was concluded that PTU treatment cannot alter absorption, distribution and elimination half time Na131I, but the accumulation in thyroid was decrease in A group to control.

Pharmacokinetic Effects of Antidrug Antibodies Occurring in Healthy Subjects After a Single Dose of Intravenous Infliximab.

BackgroundInfliximab pharmacokinetic studies have been performed in patients receiving chronic infliximab therapy. In these patients, infliximab antidrug antibodies (ADAs) increase infliximab clearance and decrease serum levels and drug efficacy.ObjectiveThis study analyzed the pharmacokinetic effect of infliximab ADAs in healthy subjects receiving a single dose of intravenous infliximab.MethodsData were obtained from a single-blind, parallel-group, single-dose study of healthy subjects receiving 5 mg/kg of intravenous SB2 (infliximab biosimilar), EU-sourced Remicade (EU-IFX) or US-sourced Remicade (US-IFX). Serum infliximab was measured at 1, 2, 3, 6, 12, 24, 48, and 72 h and at 5, 7, 14, 21, 28, 42, 56, and 70 days after administration. ADAs were measured pre-dose and at 29 and 71 days. Data from the first ten subjects randomized to each treatment arm were utilized for this study. A two-compartment model of the serum infliximab vs. time curve was developed using nonlinear regression.ResultsAt 10 weeks, 11 subjects (37%) developed ADAs. ADAs were detected in four subjects after SB2, one subject after EU-IFX, and six subjects after US-IFX infusion. Of these, neutralizing antibodies occurred in one subject after SB2, in no subjects after EU-IFX, and in three subjects after US-IFX infusion. Infliximab clearance was increased in subjects with ADAs vs. those without ADAs (12.89 ± 2.69 vs. 9.90 ± 1.74 ml/h; p < 0.0005). The elimination half-time was shorter in subjects with ADAs (282.4 ± 56.4 vs. 343.3 ± 61.9 h; p < 0.01). Serum infliximab measured at 8 weeks correlated closely with infliximab clearance (R 2 = 0.5494; p < 0.0001).ConclusionADAs are common in healthy subjects after a single intravenous dose of infliximab and result in faster infliximab clearance, shorter elimination time, and lower serum infliximab levels. These data confirm that ADAs are common with biologic therapy and significantly impact the efficacy of these drugs.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-017-0211-y) contains supplementary material, which is available to authorized users.