Increase In Circulation Time Research Articles

Site-Selective Zwitterionic Poly(caprolactone-carboxybetaine)-Growth Hormone Receptor Antagonist Conjugate: Synthesis and Biological Evaluation.

Zwitterionic polymers have been found to be biocompatible alternatives to poly(ethylene glycol) (PEG) for conjugation to proteins. This work reports the site-selective conjugation of poly(caprolactone-carboxybetaine) (pCLZ) to human growth hormone receptor antagonist (GHA) B2036-alkyne and investigation of safety, activity, and pharmacokinetics. Azide-end-functionalized pCLZs were synthesized and conjugated to GHA B2036-alkyne via copper-catalyzed click reaction. The resulting inhibitory bioactivity concentration responses in Ba/F3-GHR cells were compared to those of PEGylated GHA B2036. IgG and IgM antibody production was tested in mice, and no measurable antibody or cytokine production was detected for the pCLZ conjugate. Using 18F-labeled PET/CT imaging, the pCLZ conjugate showed an increase in circulation time compared to that of GHA B2036. Acute toxicity of the polymer was investigated in vivo and found to be nontoxic. Ex vivo degradation of the polymer on the conjugate was investigated. The results suggest that pCLZ-GHA is a potentially safe alternative to PEG-GHA.

Alginate nanogel-embedded liposomal drug carriers facilitate drug delivery efficiency in arthritis treatment

Despite numerous advantages of liposomes in treating rheumatoid arthritis (RA), the in vivo stability remains a critical issue. Current strategies for improving liposomal stability often compromise their original properties. Herein, we designed an alginate nanogel-embedded liposome aiming at retaining those inherent advantages while enhancing their in vivo stability. The introduction of alginate network within the liposome core can provide mechanical support and controlled drug release without affecting the surface properties. Results showed the cross-linking of alginate network within the inner core of liposomes elevated the particle rigidity to 3 times, allowing for improved stability and decreased drug leakage. Moreover, this nanogel-embedded liposome with optimized elasticity obviously facilitated cellular uptake in inflammatory macrophages. When entering blood circulation, increased rigidity altered the composition of protein corona on the particle surface, resulting in 2-fold increase in circulation time and improved drug accumulation in arthritic joints. When anti-inflammatory chlorogenic acid (CA) was encapsulated into the nanogel network, this CA-loaded nanogel-embedded liposome significantly inhibited ROS production and inflammatory response, ultimately achieved superior therapeutic outcome in arthritic rats. Results demonstrated that this nanogel-embedded liposomes can essentially retain the inherent advantages and overcome the drawbacks of liposomes, thereby improving the drug delivery efficiency.

Blood-Nanoparticle Interactions Create a Brain Delivery Superhighway for Doxorubicin.

This study investigated the brain targeting mechanism of doxorubicin-loaded polybutyl cyanoacrylate (PBCA) nanoparticles, particularly their interactions with the blood-brain barrier (BBB). The BBB protects the brain from drugs in the bloodstream and represents a crucial obstacle in the treatment of brain cancer. An advanced computer model analyzed the brain delivery of two distinct formulations, Doxil® and surfactant-coated PBCA nanoparticles. Computational learning was combined with in vitro release and cell interaction studies to comprehend the underlying brain delivery pathways. Our analysis yielded a surprising discovery regarding the brain delivery mechanism of PBCA nanoparticles. While Doxil® exhibited the expected behavior, accumulating in the brain through extravasation in tumor tissue, PBCA nanoparticles employed a unique and previously uncharacterized mechanism. They underwent cell hitchhiking, resulting in a remarkable more than 1000-fold increase in brain permeation rate compared to Doxil® (2.59 × 10-4 vs 0.32 h-1). The nonspecific binding to blood cells facilitated and intensified interactions of surfactant-coated PBCA nanoparticles with the vascular endothelium, leading to enhanced transcytosis. Consequently, the significant increase in circulation time in the bloodstream, coupled with improved receptor interactions, contributes to this remarkable uptake of doxorubicin into the brain.

Liposomal carriers: Development, evaluation, applications with its regulatory aspects

Liposomes are the initially introduced nano targeted drug delivery systems that have been successfully transferred and commercialized due to its high therapeutic index by its clinical applications. Liposomes are colloidal spheres that contain cholesterol, non-toxic surfactants, sphingolipids, glycolipids, long-chain fatty acids, and even membrane proteins and medicinal compounds. These are the most often employed drug delivery vehicles due to their size and amphiphilic characteristics. Drugs that are therapeutically active can be delivered easily using liposomes, including tiny compounds and macromolecules like proteins, peptides, and genes. These range from 25-1000 nm. It used for the administration of various types of drugs and the active substance to treat various diseases by targeting the site. It involves the mechanism of targeting the site without affecting the other cells that is majorly useful in the treatment of cancer. The major advantages of the liposome application are the protection of active compounds from degradation; the increase in circulation time and the possibility to achieve partial or total selectivity. The regulatory aspects are developed over time are described, followed by the lipid family, vesicular drug carrier systems. This review discusses briefly about liposomes and its advantages, disadvantages, types, methods of preparation with its evaluation and the regulatory aspects of the new drug and generic drugs.

Generation and Influence of Carbon Dioxide Nanobubbles on Physicochemical Properties Including the Surface Tension of Clarified Apple Juice

AbstractThis work aims at examining the impact of generated CO2 nanobubbles (NBs) via the membrane-based method on physicochemical properties and surface tension of commercial clarified apple juice. The gas was injected at 300 kPa pressure for variable liquid circulation times (5, 13 and 26 min) to produce the CO2 NBs. Sets of 13- and 26-min circulation time to mix CO2 and liquid gave the desirably nano-size (~ 80–200 nm) NBs and significantly (p ≤ 0.05) reduced surface tension (by ~ 20–25%) of the juice dispersed with these formed tiny gas bubbles (NB-juice). An increase in circulation time also resulted in more negative zeta potential and higher dissolved CO2 concentration of the NB-juice. Density values of apple juice remained unchanged with and without incorporating CO2 NBs. These experimental outcomes provide the potential use of NBs in controlling the characteristics of liquid food as an environment-friendly approach to minimise chemical usages.

Prediction Model and Distribution Law Study of Temperature and Pressure of the Wellbore in drilling in Arctic Region

The low temperature condition of permafrost in Arctic region affects the rheology of drilling fluids and the distribution of temperature and pressure in the wellbore during drilling. In order to understand the influence law of permafrost in Arctic region on the temperature and pressure distribution in wellbore and provide a basis for the design and construction for drilling in Arctic region, a model to predict the wellbore temperature and pressure of drilling in Arctic region was built. It was based on the analysis of the influence of low temperatures on the rheology of water-based and oil-based drilling fluids, considering the coupling between permafrost and wellbore. By comparing the measured and test results, it was verified that the prediction accuracy of the proposed model met the requirements of drilling in Arctic region. The model was used to simulate the temperature and pressure distribution in a wellbore in Arctic region under the conditions of no circulation or pump function. The results showed that the drilling fluids absorbed the heat of the high-temperature formation and returned to the annulus transferring the heat to the permafrost in shallow part of the wellbore during the circulation. This process thawed the permafrost near the wellbore and the wellbore temperature was lowered due to the heat consumed by thawing. The circulating friction in annulus increases with the increase of circulation time. The longer the pump shutdown lasts, the closer the temperature of drilling fluid to the formation temperature in the wellbore. The larger the annular circulation pressure loss, and the higher the pump pressure. The research results can provide a basis and guidance for design and construction of drilling in Arctic region.

Abstract 4586: The Leukosome: A biomimetic liposome for the targeting of inflamed tumor vasculature

Abstract The development of targeted cancer treatments with increased therapeutic efficacy is still a major challenge in drug delivery. To date, nanoscale platforms are able to extend their circulation time and accumulate in the tumor through surface functionalization with polyethylene glycol and with antibodies, peptides or ligands directed against tumor biomarkers, respectively. Despite these modifications, the mononuclear phagocytic system efficiently clears these particles from circulation while opsonization proteins prevent the proper recognition between targeting ligands and target biomarkers. Additionally, most cancers are characterized by strong inflammation and increased affinity for circulating leukocytes. The surface of the leukocyte is enriched with transmembrane proteins that determine self-tolerance, adhesion, and negotiation of the inflamed vascular barrier. As result, leukocytes can efficiently recognize and infiltrate the tumor tissues. The Leukosome is a liposomal formulation based on leukocyte membranes able to provide biocompatibility, self-tolerance and targeting. The Leukosome was enriched with up to 82 different leukocyte membrane proteins in their intact native, active configuration with the appropriate post-translational modification and orientation. Among them, CD45 favored extended circulation time and avoided unspecific clearance, while Leukocyte Associated Function-1 facilitated the targeting to and permeability of the tumor inflamed vasculature. The Leukosome retained loading capabilities similar to current liposomal formulations but sustained the release of the chemotherapeutic drug for twice as long. The physical (size, surface charge and polydispersity index), chemical (surface composition and modification, loading and release kinetics), biochemical (protein content and stability), and biological (inhibition of particle clearance, tumor targeting, effect on the vascular barrier function) properties of the Leukosomes confirmed our ability to mimic the biological features and functions of leukocytes. Compared to unmodified liposomes, Leukosomes showed 5-fold increase in circulation time, 50-fold reduction of liver accumulation and 70-fold accumulation of the payload in breast, pancreatic and melanoma models in mouse. We believe this platform will provide a superior tool for the targeting and personalization of therapeutic intervention in cancer. Citation Format: Roberto Molinaro, Alessandro Parodi, Nima Taghipour, Brandon Brown, Dickson Kirui, Michael Evangelopoulos, Francesca Taraballi, Claudia Corbo, Ennio Tasciotti. The Leukosome: A biomimetic liposome for the targeting of inflamed tumor vasculature. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4586. doi:10.1158/1538-7445.AM2014-4586

The topology and polarization of subbeams associated with the ‘drifting’ subpulse emission of pulsar B0943+10 - VI. Analysis of an 8-h Giant Metrewave Radio Telescope observation

We report analysis of an 8-h observation of PSR B0943+10 at 325 MHz performed at the Giant Metrewave Radio Telescope (GMRT) in India. B0943+10 is well known for displaying regular subpulse drifting and two emission modes. We investigate the modal behaviour of B0943+10. By reconstructing an entire ‘B’ mode from two consecutive ‘B’ modes, we estimate that the pulsar spends roughly 7.5 h in the ‘B’ mode and about 2.2 h in the ‘Q’ mode, on average. Although the pulsar can switch modes within one pulse, the subpulse drift rate changes with a characteristic time of 1.2 h over the course of a ‘B’ mode. Under the subbeam carousel model we find the drift rate changes are produced by a 10 per cent increase in the average number of subbeams and a 16 per cent increase in the carousel circulation time. We speculate that under the partially screened gap model the increase in circulation time should be related to a small increase in the neutron star surface temperature.

Amphiphilic polyether branched molecules to increase the circulation time of cationic particles

The preparation, physicochemical and biological properties of amphiphilic polyether branched molecules is described. These ‘bunch shaped’ molecules when inserted into cationic liposomes/DNA complexes have shown efficient surface charge shielding. As a consequence they efficiently inhibited the non specific interactions with blood components and significantly enhanced circulation time of the particles in the blood track. Formulations containing these molecules compared positively with those containing PEG lipids, providing a 5-fold increase in circulation time.

The effect of surface coverage and conformation of poly(ethylene oxide) (PEO) chains of poloxamer 407 on the biological fate of model colloidal drug carriers

Poloxamer 407 was adsorbed onto the surface of model colloidal drug carriers, polystyrene nanoparticles of 40, 70 and 137 nm in diameter, and the effect of the degree of surface coverage and the conformation of the poly(ethylene oxide) (PEO) chains on biological fate was studied. The relationship between the physicochemical and the biological properties of the nanoparticle systems was also investigated. The adsorbed layer of poloxamer 407 was characterised in terms of percentage surface coverage, thickness of the adsorbed layer and average surface area per PEO chain. Computer modelling of the adsorbed layer was performed (applying the self-consistent field technique), to obtain the structural information of the PEO chains in the layer. The in vitro interaction of the nanoparticles with different degrees of poloxamer 407 surface coverage with serum components and the in vivo biodistribution in the rat model were assessed. The results demonstrated that an increase in the surface coverage with poloxamer 407 resulted in an increased volume fraction of the PEO in the adsorbed layer, further extension of the PEO chains from the surface and closer packing of the chains at the surface. With regard to the interaction with the serum components, an increased surface coverage resulted in a reduction of the amount of serum proteins adsorbed, and, importantly, affected the type of proteins adsorbed. High molecular weight proteins were not adsorbed onto the nanoparticles with a surface coverage above approx. 25%. Following the intravenous administration to rats, even the nanoparticles with the lowest degree of surface coverage (approx. 5%) showed improved circulation profiles relative to the uncoated nanoparticles. The effect was more pronounced for the 40 nm nanoparticles. A further increase in the surface coverage to approx. 25% resulted in a significant increase in circulation time, as compared to uncoated and 5% coated systems, for all sizes of nanoparticles. Importantly, it was found that a long in vivo blood circulation time could be achieved for nanoparticles with a relatively low degree of surface coverage with PEO chains.

Liposphere based lipoprotein-mimetic delivery system for 6-mercaptopurine.

Long-circulating lipospheres containing 6-mercaptopurine (6-MP) were prepared by solidification of warm microemulsion at low temperature. Palmitoyl PEG was incorporated in the system to confer stealth-type nature. The size of lipospheres was in the range of 60-70 nm and was inversely proportional to sonication time. The size range was attained after 8 h. of sonication. The entrapped 6-MP contained 0.12 mmol/mole of lipid. The coating efficiency of 63-71% was attained. The zeta potential substantially decreased after PEG coating, however, the lipospheres were stable due to steric repulsion and exhibited no aggregation. The release of 6-MP was found to be 18-25% of administered dose in 24 h. and followed a mixed profile for stealth lipospheres. The percent dose remaining in plasma was found to be high even after 24 h as compared to control, indicating an increase in circulation time of lipospheres. Tissue accumulation of drug correlated with the pharmacokinetic behavior of lipospheres. The system seems to be an ideal carrier for anticancer drug delivery.

Two future generations of blood substitutes based on polyhemoglobin–SOD–catalase and nanoencapsulation

This paper discusses our research on two new generation blood substitutes. One is based on the crosslinking of hemoglobin, superoxide dismutase(SOD) and catalase (CAT) to form polyhemoglobin–SOD–CAT. This is being investigated for use in conditions with potential problems related to ischemia–reperfusion injuries as in severe hemorrhagic shock, stroke and other conditions. The second one is based on biodegradable polymeric nanocapsules containing hemoglobin and enzymes. In this form, the hemoglobin and enzymes are separated from the external environment. Furthermore, modifications of the polymeric membrane can result in increase in circulation time.

A Mechanistic Model for Circulating Fluid Temperature

Abstract An accurate fluid temperature profile in both tubing and annulus during circulation is desirable to allow computation of circulation rates. However, because the circulating fluid exchanges heat with the formation, fluid temperature changes both with time and depth. Consequently, the fluid's intrinsic properties of density and viscosity would change with an increase in circulation time, thereby influencing the optimal pumping rate. Existing analytic methods for solving the heat transfer problem at hand generally assume a constant fluid inlet temperature plus a constant heat flux (or temperature) at the wellbore/ formation interface. These assumptions ignore the reality that the temperature of the circulating fluid entering the wellbore from the holding tank increases with time because of the heat carried by this fluid from the hot formation. Fluid circulation also causes a gradual decrease in heat flux between the wellbore and the formation. These assumptions inherent in the available methods may reduce their reliability in many situations. In this work, we present a generalized analytical model for circulating fluid temperature in both conduits, for both forward and reverse circulation cases, as a function of circulation time and well depth. We use an energy balance for the fluid in the tank to express its temperature as a function of time. To account for the changing heat flux at the wellbore/formation interface, the principle of superposition in time is used. The heat flux schedule is represented by adding constant heat sources at successive times. This model is flexible to adapt any transient temperature distribution model, TD, and presupposes unsteady heat transport in the formation while steady heat flow occurs in the tubular. Our results show that, under some circumstances, thud temperatures estimated using these approaches deviate significantly from that estimated without account for the varying nature of tank temperature or formation heat flux This difference is especially true when the temperature difference between the bottomhole and the wellhead is large. Thus, varying mud tank temperature and formation heat flux need to be accounted for when estimating flowing fluid or circulating mud temperature in the Arctic. However, when the bottomhole and wellhead temperature difference is small, the extra computation involved in this procedure is probably not worth the marginal gain in accuracy. Field examples illustrate the model's application.

Effect of circulation time on plasma high density lipoprotein cholesterol in rats.

The effect of circulation time on plasma high density lipoprotein cholesterol concentrations was investigated in 20 male Wistar rats injected with alcohol, stressed with lighting, or fed a high fat diet. Circulation time was measured during anaesthesia with a computerised dichromatic earpiece densitometer. Indocyanine green, 0.5% concentration and 0.05 ml volume, was injected directly into the intracardiac cavity. The densitometer was held against the right foot of the rat, where the concentration of indocyanine green was measured by a light absorption method. Circulation time was defined as the time during which indocyanine green passed from the heart to the foot. At the same time blood was collected for determining high density lipoprotein cholesterol concentration. The rats were randomly divided into three groups, and control circulation time and high density lipoprotein cholesterol concentrations were obtained. In six rats injected with 100% ethyl alcohol, 0.03 ml.100 g-1 body weight in volume, into the abdominal cavity and five rats placed under 400 Lux lighting for 48 h the increase in circulation time was inversely proportional to the increase in high density lipoprotein cholesterol concentration (r = -0.644, p less than 0.05). Of nine rats given a high fat diet containing 7.0% fat for 48 h, all showed increased high density lipoprotein cholesterol concentration, but no correlation was noted between the increases in circulation time and high density lipoprotein cholesterol (r = -0.303).(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral Circulation Times in Subarachnoid Haemorrhage

Publisher Summary Spasm of cerebral vessels is, to surgeons at least, a well recognized hazard. In subarachnoid haemorrhage it would appear to bear some fairly constant time relationship to the ictus, to the angiographic appearances of spasm and to cerebral blood flow. It may also be related to biochemical changes in the CSF, in particular a lowering of pH and the appearance of 5-hydroxytryptamine in the region of the basal blood vessels. Connolly and McKissock have observed that subarachnoid haemorrhage patients with spasm seen angiographically have a poorer operative prognosis, and a larger percentage of ischaemic lesions. It seems likely that both the spasm and the infarction are associated with a diminished total or regional cerebral blood flow. This paper describes the result of cerebral circulation studies on 90 patients with subarachnoid haemorrhage. The cerebral circulation times are related to the arterial spasm seen at angiography and the operative complication rate, morbidity and mortality. It is suggested that serial estimations of cerebral circulation time may be a useful guide to the timing of angiography and surgery in the management of patients with subarachnoid haemorrhage. Cerebral circulation studies, using a simple isotope method, were carried out on 90 patients following subarachnoid haemorrhage; 80 also had angiographic studies. It was found that an increase in circulation time was closely related to the occurrence of arterial spasm, and also to the post-operative morbidity and mortality. Serial observations were particularly helpful in indicating the best time for operative intervention. Two illustrative case reports are quoted showing where cerebral circulation studies have reinforced clinical judgement.

Effect of autonomic blocking agents on the cardiovascular effects of octapressin in the rat

Cardiovascular effects of Octapressin were studied in anesthetized male albino rats. The effect of pretreatment with the following blocking agents was evaluated: atropine, phenoxybenzamine, propranolol, hexamethonium and chlorpromazine. A decrease in blood pressure and in heart rate was induced by phenoxybenzamine; propranolol treatment caused a decrease in heart rate and an increase in circulation time. Injections of 2, 6 and 18 mU Octapressin caused no changes in cardiac output or in central venous pressure. The increase in blood pressure following Octapressin was found to be dose-dependent in the saline-treated controls as well as in the rats pretreated with the autonomic blocking agents. The pressor response to Octapressin was increased by atropine, phenoxybenzamine, propranolol and chlorpromazine. From these data it is concluded that the increase in blood pressure following Octapressin is caused by an increase in vascular resistance in the systemic circulation.

The effects of posture on the velocity of blood flow from arm to tongue

A marked divergence of opinion exists as to the effects of posture on the velocity of blood flow and on cardiac output. Thompson Alper, and Thompson, 1 employing brilliant vital red, observed a pronounced increase in both the arm-to-foot and foot-to-arm circulation times in the standing-still posture, as compared to the recumbent position. Further, when they produced moderate venous congestion in a lower extremity by the application of a tourniquet, with the subject in the recumbent position, the appearance of the dye was delayed to approximately the same degree as in the standing-still position. Bock, Dill, and Edwards 2 found that the histamine circulation time (ankle-to-face) in the standing position was 1 1 2 to 4 1 2 times greater than in the recumbent position. Mayerson, Sweeney, and Toth, 3 who studied eleven normal male subjects, observed a marked increase in circulation time when the subject was tilted passively from the horizontal position to an angle of 75° with the horizontal; the testing agent 4 was injected into the foot vein. However, in those instances in which the agent was injected into the antecubital vein, their results were equivocal. Kvale and Allen 5 noted a longer arm-to-foot circulation time 4 in the upright posture than in the recumbent position, but the arm-to-tongue results were variable, i.e., the time was increased in 4 subjects, reduced in three, and unchanged in one. More recently, Main and Baker 6 found no significant difference in arm-to-tongue circulation time (calcium gluconate) between the recumbent and standing positions in eleven subjects. In accord with the observation that there is a reduction in velocity of blood flow in the upright posture, many investigators 7–13 have found that the minute cardiac output is reduced in the upright posture. Conversely, the contention of some workers 14, 15, 16 that posture exerts no influence on cardiac output would tend to support those studies in which blood velocity was found to be unaffected by changes in posture. The present study was undertaken to compare the arm-to-tongue time in two positions, namely, with the body horizontal, and with the legs dependent.