Renal Clearance Rate Research Articles

Pressure-Controlled Encapsulation of Graphene Quantum Dots into Liposomes by the Reverse-Phase Evaporation Method.

Ultrasmall nanoparticles (USNPs) with sizes below 10 nm have shown great potentials in medical applications owing to their outstanding physical, chemical, optical, and biological properties. However, they suffer from a rapid renal clearance and biodegradation rate in the biological environment due to the small size. Liposomes are one of the most promising delivery nanocarriers for loading USNPs because of their excellent biocompatibility and lipid bilayer structure. Encapsulation of USNPs into liposomes in an efficient and controllable manner remains a challenge. In this study, we achieved a high loading of graphene quantum dots (GQDs, ∼4 nm), a typical USNP, into the aqueous core of liposomes (45.68 ± 1.44%), which was controllable by the pressure. The GQDs-loaded liposomes (GQDs-LPs) exhibited a very good aqueous stability for over a month. Furthermore, indocyanine green (ICG), an efficient near-infrared (NIR) photothermal agent, was introduced in the GQDs-LP system that could convert NIR laser energy into thermal energy and break down the liposomes, causing the release of GQDs in 6 min. Moreover, this NIR light-controlled release system (GQDs-ICG-LPs) also exhibited a good photothermal therapeutic performance in vitro, and 75% of cancer cells were killed at a concentration of 200 μg/mL. Overall, the successful development of the NIR light-controlled release system has laid a solid foundation for the future biomedical application of USNPs-loaded liposomes.

Rhenium nanoparticles for the delivery of HSP 90 inhibitors: A new drug delivery platform designed by molecular dynamics simulation

Owing to its degradability in vivo, the renal clearance rate of ReNPs is much higher than that of AuNPs. It is of great significant to explore the possibility of ReNPs to construct drug delivery platform. In this work, ReNPs drug delivery platform for the HSP 90 inhibitors (17-AAG and RGD) was evaluated by means of molecular dynamics simulation, and the molecular mechanism of drug release was further studied. The results indicated that ReNPs platform not only possessed good biocompatibility and stability, but also was more suitable for the delivery of HSP 90 inhibitors than AuNPs platform. This study proposed a complete solution of molecular simulation for the design and evaluation of novel nanoparticle drug platforms, which could be a convenient technical support to investigate the application of nanomaterials in biomedicine.

Radiation Increases Bioavailability of Lisinopril, a Mitigator of Radiation-Induced Toxicities.

There are no FDA-approved drugs to mitigate the delayed effects of radiation exposure that may occur after a radiological attack or nuclear accident. To date, angiotensin-converting enzyme inhibitors are one of the most successful candidates for mitigation of hematopoietic, lung, kidney, and brain injuries in rodent models and may mitigate delayed radiation injuries after radiotherapy. Rat models of partial body irradiation sparing part of one hind leg (leg-out PBI) have been developed to simultaneously expose multiple organs to high doses of ionizing radiation and avoid lethal hematological toxicity to study the late effects of radiation. Exposures between 9 and 14 Gy damage the gut and bone marrow (acute radiation syndrome), followed by delayed injuries to the lung, heart, and kidney. The goal of the current study is to compare the pharmacokinetics (PK) of a lead angiotensin converting enzyme (ACE) inhibitor, lisinopril, in irradiated vs. nonirradiated rats, as a step toward licensure by the FDA. Methods: Female WAG/RijCmcr rats were irradiated with 12.5–13 Gy leg-out PBI. At day 35 after irradiation, during a latent period for injury, irradiated and nonirradiated siblings received a single gavage (0.3 mg, 0.6 mg) or intravenous injection (0.06 mg) of lisinopril. Plasma, urine, lung, liver and kidney levels of lisinopril were measured at different times. PK modeling (R package) was performed to track distribution of lisinopril in different compartments. Results: A two-compartment (central plasma and periphery) PK model best fit lisinopril measurements, with two additional components, the gavage and urine. The absorption and renal clearance rates were similar between nonirradiated and irradiated animals (respectively: ratios 0.883, p = 0.527; 0.943, p = 0.605). Inter-compartmental clearance (from plasma to periphery) for the irradiated rats was lower than for the nonirradiated rats (ratio 0.615, p = 0.003), while the bioavailability of the drug was 33% higher (ratio = 1.326, p < 0.001). Interpretation: Since receptors for lisinopril are present in endothelial cells lining blood vessels, and radiation induces vascular regression, it is possible that less lisinopril remains bound in irradiated rats, increasing circulating levels of the drug. However, this study cannot rule out changes in total amount of lisinopril absorbed or excreted long-term, after irradiation in rats.

Effect of haemodialysis on renal profile in chronic renal failure patients at a tertiary care centre

: In chronic renal failure there is a steady and continued decrease in renal clearance or glomerular filtration rate (GFR), which leads to the gathering of urea, creatinine and other waste metabolites in the blood. Haemodialysis is considered as a good therapeutic option in the context of the renal replacement therapies in which different body waste products including urea, creatinine and free water are removed from the blood. In view of that, the present study was conducted to evaluate the effect of haemodialysis on different renal biochemical parameter in CRF patients.The present study was a hospital based study including 84 chronic renal failure patients on haemodialysis attending a tertiary care hospital in Bihar. Blood samples were collected before and four hours after haemodialysis and serum urea, creatinine, uric acid, potassium, sodium and calcium were estimated.Our results revealed that there was significant decrease in the serum level of urea, creatinine, uric acid and potassium in post dialysis samples with p-value (&amp;#60;0.001, 0.001 0.003 and 0.001) respectively when compared to pre dialysis samples, while showed significant increase of sodium and calcium level in post dialysis samples with p-value (&amp;#60;0.004 and 0.005)The Study concludes that, haemodialysis increase serum sodium and calcium level and decrease serum urea, creatinine, uric acid and potassium level.

Differences between Holstein dairy cows in renal clearance rate of urea affect milk urea concentration and the relationship between milk urea and urinary nitrogen excretion

Urine and fecal excretions from cattle contribute to global nitrogen (N) emissions. The milk urea nitrogen (MUN) concentration in dairy cows is positively correlated with urinary urea N (UUN) emissions, and both decline with the reduction in crude protein intake. However, MUN concentration may differ between individual cows despite feeding the same ration. Thus, we hypothesized that due to differences in endogenous N utilization cows with high MUN concentration excrete more UUN than cows with a low MUN concentration. The objective of the present study was to elucidate N partitioning and urea metabolism in dairy cows with divergent MUN concentrations fed two planes of crude protein. Twenty Holstein dairy cows with high (HMU; n = 10) and low (LMU; n = 10) milk urea concentrations were fed two isocaloric diets with a low (LP) and normal (NP) crude protein level. Methane and ammonia emissions were recorded in respiration chambers. Feed intake, feces and urine excretions and milk yield were recorded for four days and subsamples were analyzed for total N and N-metabolites. A carbon-13 labeled urea bolus was administered intravenously followed by a series of plasma samplings. Total N and UUN excretions and ammonia emissions from excreta were lower on the LP diet, however, methane emissions, urinary N excretions and ammonia emissions were comparable between groups. Although plasma and salivary urea concentrations, urea pool size and urea turnover were higher, HMU cows had lower renal urea clearance rates. Additionally, HMU cows had lower renal clearance rates for creatinine, uric acid and creatine and excreted less uric acid (on the LP diet only) and creatine with urine. In conclusion, contrary to our hypothesis, HMU cows did not excrete more UUN than LMU cows. The lower urinary creatine excretion of HMU cows suggests that these animals have a lower environmental nitrogen footprint.

Evaluation of designs for renal drug studies based on the European Medicines Agency and Food and Drug Administration guidelines for drugs that are predominantly secreted.

Dose adjustment for drugs eliminated by the kidneys generally assume a linear relationship between renal drug clearance (CLR ) and glomerular filtration rate (GFR). This assumption may not hold for drugs that undergo extensive tubular secretion where nonlinearity in drug handling is expected. The aim of this study is to determine if renal drug study designs recommended by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) could distinguish linear from nonlinear renal drug handling. In this simulation and estimation study, the study designs based on the EMA and FDA guidelines for Phase I renal drug studies were evaluated for their ability to discriminate a linear from a nonlinear relationship between CLR and GFR. The number of subjects for each simulated study ranged from 4 to 960. Power, relative standard error and bias were calculated. Study designs under the EMA and FDA guidelines required ≥8 and ≥48 subjects, respectively, to achieve ≥80% power to discriminate a linear from nonlinear relationship between CLR and GFR. The relative standard error of estimated parameters were 13-37 and 17-44% for the designs with 24 subjects under the EMA and FDA guidelines, respectively. The bias in parameter estimates under the EMA designs were not evident, however, they were biased (13-21%) under the FDA designs. The EMA design was found to require fewer subjects (n = 8) compared to the FDA (n = 48) to discriminate linear from nonlinear drug renal handling at ≥80% study power while both the designs perform poorly for the parameter precision.

A Multiparametric Assay Platform for Simultaneous In Vivo Assessment of Pronephric Morphology, Renal Function and Heart Rate in Larval Zebrafish.

Automated high-throughput workflows allow for chemical toxicity testing and drug discovery in zebrafish disease models. Due to its conserved structural and functional properties, the zebrafish pronephros offers a unique model to study renal development and disease at larger scale. Ideally, scoring of pronephric phenotypes includes morphological and functional assessments within the same larva. However, to efficiently upscale such assays, refinement of existing methods is required. Here, we describe the development of a multiparametric in vivo screening pipeline for parallel assessment of pronephric morphology, kidney function and heart rate within the same larva on a single imaging platform. To this end, we developed a novel 3D-printed orientation tool enabling multiple consistent orientations of larvae in agarose-filled microplates. Dorsal pronephros imaging was followed by assessing renal clearance and heart rates upon fluorescein isothiocyanate (FITC)-inulin microinjection using automated time-lapse imaging of laterally positioned larvae. The pipeline was benchmarked using a set of drugs known to induce developmental nephrotoxicity in humans and zebrafish. Drug-induced reductions in renal clearance and heart rate alterations were detected even in larvae exhibiting minor pronephric phenotypes. In conclusion, the developed workflow enables rapid and semi-automated in vivo assessment of multiple morphological and functional parameters.

Dendrimer size effects on the selective brain tumor targeting in orthotopic tumor models upon systemic administration.

Malignant gliomas are the most common and aggressive form of primary brain tumors, with a median survival of 15–20 months for patients receiving maximal interventions. Advances in nanomedicine have provided tumor‐specific delivery of chemotherapeutics to potentially overcome their off‐target toxicities. Recent advances in dendrimer‐based nanomedicines have established that hydroxyl‐terminated poly(amidoamine) dendrimers can intrinsically target neuroinflammation and brain tumors from systemic administration without the need for targeting moieties. The size of nanocarriers is a critical parameter that determines their tumor‐targeting efficiency, intratumor distribution, and clearance mechanism. In this study, we explore the dendrimer size effects on brain tumor targeting capability in two clinically relevant orthotopic brain tumor models, the 9L rat and GL261 mouse models, which capture differing aspects of gliomas. We show that increasing dendrimers from Generation 4 to Generation 6 significantly enhances their tumor accumulation (~10‐fold greater at 24 hr), tumor specificity (~2–3 fold higher), and tumor retention. The superior tumor targeting effect of G6 dendrimers is associated with its reduced renal clearance rate, resulting in longer circulation time compared to G4 dendrimers. Additionally, the increase in dendrimer generation does not compromise its homogeneous tumor distribution and intrinsic targeting of tumor‐associated macrophages. These results validate the potential for these dendrimers as an effective, clinically translatable platform for effectively targeting tumor‐associated macrophages in malignant gliomas.

Quantitative Prediction of the Role of Placental Efflux to Optimize Dosing Regimens of Dexamethasone and Betamethasone to Prevent Respiratory Distress Syndrome

IntroductionRespiratory distress syndrome is one of the major causes of newborn deaths. Dexamethasone (DEX) and Betamethasone (BET) may promote fetal lung maturation when administered to pregnant women at risk of preterm birth. Usually, DEX‐phosphate (6 mg) is administered IM q 12 hrs over 48 hrs while BET is administered IM as a 50:50 phosphate and acetate combination (12 mg total) q 24 hrs over 48 hrs. Recent non‐clinical trials suggest lower concentration would result in effective treatment for these drugs. In sheep, fetal BET plasma concentrations &gt;1 ng/mL appears to adequately promote fetal lung maturation. Therefore, there is a need to optimize the dosing regimen of these drugs. DEX and BET are substrates of P‐gp, a placental efflux transporter, that can reduce their fetal plasma concentrations. We have recently developed a maternal‐fetal PBPK model to predict maternal‐fetal plasma concentrations of drugs throughout pregnancy. The model has been populated with physiological changes observed in pregnancy including that in hepatic activity of CYP enzymes. Using this model, our aims were to 1) predict maternal plasma concentration‐time profiles of DEX and BET, after IM administration, and compare them with those observed; 2) determine the extent of placental P‐gp activity necessary to match the predicted and observed fetal DEX/BET plasma concentrations; 3) use these data to design maternal dosing regimens of DEX and BET that minimize maternal plasma concentrations while maintaining fetal plasma concentrations &gt; 1 ng/ml.MethodNon‐pregnant PBPK model for both drugs was developed in SimCYP where hepatic intrinsic clearance by CYP3A (CLhep,int), renal clearance and absorption rate constants of IM DEX and BET, were optimized based on literature data. A single first‐order absorption rate was used for IM DEX‐phosphate. Distinct absorption rate constants were used for IM BET‐phosphate and IM BET‐acetate. The maternal PBPK model was developed in MATLAB Simulink and populated with maternal gestational age‐dependent changes as well as placental passive diffusion and fetal hepatic clearance of the drugs. Theoretical DEX and BET fetal plasma concentration‐time profiles were simulated with varying magnitudes of P‐gp efflux until their predicted fetal plasma concentration‐time profiles adequately encompassed the observed data and the fetal PK parameters (AUC and Cmax) fell within 0.8 to 1.25‐fold of observed values.Results and DiscussionBoth non‐pregnant and pregnancy PBPK models for DEX were verified with the observed data. The pregnancy model for BET (i.e CLhep, int) needed to be optimized to describe the observed maternal plasma concentration data. Sensitivity analysis showed that the fraction of DEX and BET transported by placental P‐gp needed to be 0.6 and 0.5, respectively, to best describe the observed fetal plasma concentration data. Using these data, we are devising dosing regimens of DEX and BET for pregnant women that have the potential to maximize their efficacy and minimize their toxicity. These dosing regimens will be presented.Support or Funding InformationThis work is Supported by Bill &amp; Melinda Gates Foundation grant OPP1190468

Estimating renal and hepatic clearance rates of organophosphate esters in humans: Impacts of intrinsic metabolism and binding affinity with plasma proteins

The renal and hepatic clearance rates of organophosphate esters (OPEs) in humans were estimated. Six OPEs and their corresponding diester metabolites (mOPEs) were quantified respectively in 30 paired human plasma and urine samples collected in Hengshui, Hebei province, China. The renal clearance rate (CLrenal) of triphenyl phosphate (TPHP), tris(chloroethyl) phosphate (TCEP) and tris(1,3-dichloro-isopropyl) phosphate (TDCIPP) was estimated to be 68.9, 50.9 and 33.3 mL/kg/day, respectively, while it was not calculated for other three OPEs due to the low detection frequencies in human samples. To estimate the clearance rates of the target OPEs, hepatic clearance rates (CLh) of OPEs were extrapolated from their in vitro intrinsic clearance data in human liver microsomes (CLHLM). The calculated CLh values of TCEP and TDCIPP were comparable to their CLrenal, indicating that the in vitro extrapolation method was suitable for estimating the clearance rates of OPEs. The higher binding affinity of TDCIPP with plasma proteins could reduce its renal clearance. The estimated half-lives of Cl-OPEs in human were longer than those of the aryl- and alkyl-OPEs. This study provided a feasible in vitro method to predict the clearance and half-lives of OPEs in human, which is significant for their accurate health risk assessment.

Measuring Kidney Perfusion, pH, and Renal Clearance Consecutively Using MRI and Multispectral Optoacoustic Tomography

Purpose: To establish multi-modal imaging for the assessment of kidney pH, perfusion, and clearance rate using magnetic resonance imaging (MRI) and multispectral optoacoustic tomography (MSOT) in healthy mice. Kidney pH and perfusion values were measured on a pixel-by-pixel basis using the MRI acidoCEST and FAIR-EPI methods. Kidney filtration rate was measured by analyzing the renal clearance rate of IRdye 800 using MSOT. To test the effect of one imaging method on the other, a set of 3 animals were imaged with MSOT followed by MRI, and a second set of 3 animals were imaged with MRI followed by MSOT. In a subsequent study, the reproducibility of pH, perfusion, and renal clearance measurements were tested by imaging 4 animals twice, separated by 4 days. The contrast agents used for acidoCEST based pH measurements influenced the results of MSOT. Specifically, the exponential decay time from the kidney cortex, as measured by MSOT, was significantly altered when MRI was performed prior to MSOT. However, no significant difference in the cortex to pelvis area under the curve (AUC) was noted. When the order of experiments was reversed, no significant differences were noted in the pH or perfusion values. Reproducibility measurements demonstrated similar pH and cortex to pelvis AUC; however, perfusion values were significantly different with the cortex values being higher and the pelvic values being lower in the second imaging time. We demonstrate that using a combination of MRI and MSOT, physiological measurements of pH, blood flow, and clearance rates can be measured in the mouse kidney in the same imaging session.

Antimicrobial Disposition During Pediatric Continuous Renal Replacement Therapy Using an Ex Vivo Model.

Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model. An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole). University research laboratory. None. Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug. Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates. Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy.

Recent Advances in Half-life Extension Strategies for Therapeutic Peptides and Proteins.

Peptides and proteins are two classes of molecules with attractive possibilities for therapeutic applications. However, the bottleneck for the therapeutic application of many peptides and proteins is their short halflives in vivo, typically just a few minutes to hours. Half-life extension strategies have been extensively studied and many of them have been proven to be effective in the generation of long-acting therapeutics with improved pharmacokinetic and pharmacodynamic properties. In this review, we summarize the recent advances in half-life extension strategies, illustrate their potential applications and give some examples, highlighting the strategies that have been used in approved drugs and for drugs in clinical trials. Meanwhile, several novel strategies that are still in the process of discovery or at a preclinical stage are also introduced. In these strategies, the two most frequently used half-life extension methods are the reduction in the rate of renal clearance or the exploitation of the recycling mechanism of FcRn by binding to the albumin or IgG-Fc. Here, we discuss half-life extension strategies of recombinant therapeutic protein via genetic fusion, rather than chemical conjugation such as PEGylation. With the rapid development of genetic engineering and protein engineering, novel strategies for half-life extension have been emerged consistently. Some of these will be evaluated in clinical trials and may become viable alternatives to current strategies for making next-generation biodrugs.

Is tamsulosin effective for the passage of symptomatic ureteral stones: A systematic review and meta-analysis.

Background:Some trials have stated that there is no benefit to tamsulosin administration for clearing ureteral stones, which is contrary to previous studies. To confirm the efficacy of tamsulosin for treating symptomatic ureteral stones, we performed this review.Methods:We searched the PubMed, Embase, and Cochrane Library databases to identify all studied variables, including tamsulosin, urinary stones, expulsion, and side effects. In addition, for all patients and different stone sizes, the treatment efficacy, expulsion rate, and expulsion time were also recorded for this treatment.Results:Forty-nine studies involving 6436 patients met the inclusion criteria. The data synthesized from these studies indicated that tamsulosin improved the renal stone clearance rate (80.5% vs 70.5%; mean difference (MD), 1.16; 95% confidence interval (CI), 1.13–1.19; P <.00001) and reduced the expulsion time (MD, −3.61; 95% CI, −3.77 to −3.46; P ≤.00001). Regarding complications, no significant difference was found between the 2 groups in terms of the total side effects (MD, 1.15; 95% CI, 0.97–1.35; P = .10) or divided complications, including retrograde ejaculation (P = .01), hypotension (P = .52), dizziness (P = .07), diarrhea (P = .58), vomiting (P = .88), headache (P = .84), nausea (P = .91), and fatigue (P = .10).Conclusions:Tamsulosin should be strongly recommended for patients with ureteral stones to increase treatment efficacy. The side effects were not significantly different between the tamsulosin and control treatments.

Intact bioactivities and improved pharmacokinetic of the SL335-IFN-β-1a fusion protein that created by genetic fusion of SL335, a human anti-serum albumin fab, and human interferon-β

Recombinant human interferon beta (rIFN-β) has long been used as a first-line treatment for multiple sclerosis (MS), and any attempt to develop a long-acting rIFN-β is desirable since only one pegylated version of long-acting rIFN-β-1a (Plegridy) is currently available in clinics. Previously, we reported that SL335, a human Fab molecule specific to serum albumin, exhibits an extended serum half-life via utilizing the FcRn recycling mechanism. With the ultimate goal of developing a long-acting rIFN-®, we generated a fusion construct by linking human IFN-β cDNA to the C-terminus of the SL335 H chain at the DNA level followed by expression of the fusion protein, referred to as SL335-IFN-β-1a, in Chinese hamster ovary-S (CHO-S) cells. In its N-linked glycosylated form, the resulting fusion protein was easily purified from the culture supernatant via a three-step chromatography process. In vitro functional assays revealed that the fusion protein retained its intrinsic binding capabilities to human serum albumin (HSA) and interferon α/β receptor (IFNAR) that were almost identical to those of parental SL335 and rIFN-β-1a (Rebif). In addition, the fusion protein possessed an antiviral potency and anti-proliferation activity comparable to those of Rebif. In pharmacokinetic (PK) analyses using Lewis rats and cynomolgus monkeys, SL335-IFN-β-1a exhibited at least a two-fold longer serum half-life and a significantly reduced renal clearance rate compared to those of Rebif. Finally, a four-week repeated dose toxicity study revealed no abnormal toxicological signs. In conclusion, our results clearly demonstrated that SL335-IFN-β-1a is worthy of further development as an alternative long-acting IFN-β therapeutic.

Reversibly Stabilized Polycation Nanoparticles for Combination Treatment of Early- and Late-Stage Metastatic Breast Cancer.

Metastatic breast cancer is a major cause of cancer-related female mortality worldwide. The signal transducer and activator of transcription 3 (STAT3) and the chemokine receptor CXCR4 are involved in the metastatic spread of breast cancer. The goal of this study was to develop nanomedicine treatment based on combined inhibition of STAT3 and CXCR4. We synthesized a library of CXCR4-inhibiting polymers with a combination of beneficial features that included PEGylation, fluorination, and bioreducibility to achieve systemic delivery of siRNA to silence STAT3 expression in the tumors. An in vivo structure-activity relationship study in an experimental lung metastasis model revealed superior antimetastatic activity of bioreducible fluorinated polyplexes when compared with nonreducible controls despite similar CXCR4 antagonism and the ability to inhibit in vitro cancer cell invasion. When compared with nonreducible and nonfluorinated polyplexes, improved siRNA delivery was observed with the bioreducible fluorinated polyplexes. The improvement was ascribed to a combination of enhanced physical stability, decreased serum destabilization, and improved intracellular trafficking. Pharmacokinetic analysis showed that fluorination decreased the rate of renal clearance of the polyplexes and contributed to enhanced accumulation in the tumors. Therapeutic efficacy of the polyplexes with STAT3 siRNA was assessed in early stage breast cancer and late-stage metastatic breast cancer with primary tumor resection. Strong inhibition of the primary tumor growth and pronounced antimetastatic effects were observed in both models of metastatic breast cancer. Mechanistic studies revealed multifaceted mechanism of action of the combined STAT3 and CXCR4 inhibition by the developed polyplexes relying both on local and systemic effects.

Toxicokinetics of the neonicotinoid insecticide imidacloprid in rainbow trout (Oncorhynchus mykiss)

Studies were conducted to determine the distribution and elimination of imidacloprid (IMI) in rainbow trout. Animals were injected with a low (47.6 μg/kg), medium (117.5 μg/kg) or high (232.7 μg/kg) dose directly into the bloodstream and allowed to depurate. The fish were then sampled to characterize the loss of IMI from plasma and its appearance in expired water (all dose groups) and urine (medium dose only). In vitro biotransformation of IMI was evaluated using trout liver S9 fractions. Mean total clearance (CLT) values determined by non-compartmental analysis of plasma time-course data were 21.8, 27.0 and 19.5 mL/h/kg for the low, medium and high dose groups, respectively. Estimated half-lives for the same groups were 67.0, 68.4 and 68.1 h, while fitted values for the steady-state volume of distribution (VSS) were 1.72, 2.23 and 1.81 L/kg. Branchial elimination rates were much lower than expected, suggesting that IMI is highly bound in blood. Renal clearance rates were greater than measured rates of branchial clearance (60% of CLT in the medium dose group), possibly indicating a role for renal membrane transporters. There was no evidence for hepatic biotransformation of IMI. Collectively, these findings suggest that IMI would accumulate in trout in continuous waterborne exposures.

Peptibodies: An elegant solution for a long-standing problem.

Chimeric proteins composed of a biologically active peptide and a fragment crystallizable (Fc) domain of immunoglobulin G (IgG) are known as peptibodies. They present an extended half-life due to neonatal Fc receptor (FcRn) salvage pathway, a decreased renal clearance rate owing to its increased size (≈70 kDa) and, depending on the peptide used in the design of the peptibody, an active-targeting moiety. Also, the peptides therapeutic activity is boosted by the number of peptides in the fusion protein (at least two peptides) and to some peptides' alterations. Peptibodies are mainly obtained through recombinant DNA technology. However, to improve peptide properties, "unnatural" changes have been introduced to the original peptides' sequence, for instance, the incorporation of D- or non-natural amino acid residues or even cyclization thus, limiting the application of genetic engineering in the production of peptibodies, since these peptides must be obtained via chemical synthesis. This constrains prompted the development of new methods for conjugation of peptides to Fc domains. Another challenge, subject of intense research, relates to the large-scale production of such peptibodies using these new techniques, which can be minimized by their proved value. To date, two peptibodies, romiplostim and dulaglutide, have been approved and stay as the standard of care in their areas of action. Furthermore, a considerable number of peptibodies are currently in preclinical and clinical development.

Hyperpolarized [1-13C]-acetate Renal Metabolic Clearance Rate Mapping

11C-acetate is a positron emission tomography (PET) tracer of oxidative metabolism, whereas hyperpolarized 13C-acetate can be used in magnetic resonance imaging (MRI) for investigating specific metabolic processes. The aims of this study were to examine if the kinetic formalism of 11C-acetate PET in the kidneys is comparable to that of 13C-acetate MRI, and to compare the dynamic metabolic information of hyperpolarized 13C-acetate MRI with that obtained with 11C-acetate PET. Rats were examined with dynamic hyperpolarized 13C-acetate MRI or 11C-acetate PET before and after intravenous injection of furosemide, a loop diuretic known to alter both the hemodynamics and oxygen consumption in the kidney. The metabolic clearance rates (MCR) were estimated and compared between the two modalities experimentally in vivo and in simulations. There was a clear dependency on the mean transit time and MCR for both 13C-acetate and 11C-acetate following furosemide administration, while no dependencies on the apparent renal perfusion were observed. This study demonstrated that hyperpolarized 13C-acetate MRI is feasible for measurements of the intrarenal energetic demand via the MCR, and that the quantitative measures are correlated with those measured by 11C-acetate PET, even though the temporal window is more than 30 times longer with 11C-acetate.

A retrospective, observational study of supine percutaneous nephrolithotomy

Objective: The objective of this study is to assess stone clearance and perioperative complication rates of supine percutaneous nephrolithotomy (PCNL). Methods: This was a retrospective, observational study of supine PCNL performed in a surgical unit at a district general hospital by two surgeons in the United Kingdom. Data collected included patient demographics, comorbidities, complexity of renal calculi, perioperative complications and stone clearance rates. Results: A total of 112 supine PCNL procedures were observed in this study. The mean (SD) American Society of Anesthesiologists (ASA) grade and Guy’s Stone Score were 2.0 (0.75) and 2.3 (1.06) respectively. The median (interquartile range (IQR)) duration of in-patient admission was four (one) nights. Complete stone clearance was achieved in 74 (67.3%) of the procedures, while more than 90% clearance of the renal stone burden was achieved in a further eight (7.3%). The most common perioperative complications recorded were blood loss requiring blood transfusion (three (2.7%)) and postoperative fever (two (1.8%)). Conclusion: This case series shows that supine PCNL can lead to good stone clearance and low complication rates.