Assessment of Patiromer Monotherapy for Hyperkalemia in an Acute Care Setting.

Importance: Hyperkalemia is a common electrolyte disorder in hospitalized patients; however, the clinical usefulness of administering patiromer for reduction of serum potassium levels in this setting is unknown. Objective: To evaluate the outcomes associated with patiromer as monotherapy in patients with acute hyperkalemia in an acute care setting. Design, Setting, and Participants: This cohort study used electronic health record data from adult patients treated with patiromer for acute hyperkalemia in emergency departments, inpatient units, and intensive care units at an urban, academic medical center in the Bronx, New York, between January 30, 2018, and December 30, 2019. Data analysis was conducted between June 2020 and February 2021. Exposures: A single dose of oral patiromer (8.4 g, 16.8 g, or 25.2 g). Main Outcomes and Measure: The primary outcome was the mean absolute reduction in serum potassium level from baseline at 3 distinct time intervals after patiromer administration: 0 to 6 hours, greater than 6 to 12 hours, and greater than 12 to 24 hours. Key secondary outcomes were the incidence of hypokalemia and potassium reduction stratified by baseline potassium level and care setting. Results: Among 881 encounters of patiromer treatment, the mean (SD) age of patients was 67.4 (14.4) years; 463 encounters (52.6%) were for male patients, and most (338 [38.4%]) were for patients who identified as non-Hispanic Black. The mean (SD) baseline serum potassium level was 5.60 (0.35) mEq/L (to convert to mmol/L, multiply by 1.0), and within the first 6 hours after patiromer administration, the mean (SD) potassium reduction was 0.50 (0.56) mEq/L (P < .001). Both absolute and relative potassium reduction from baseline varied across baseline hyperkalemia severity but not by care setting. The lowest dose of patiromer (8.4 g) was used in 721 encounters (81.8%), and in 725 encounters (82.3%), no further doses of a potassium binder were required. Hypokalemia was noted in 2 encounters (0.2%) at 24 hours after patiromer administration. Conclusions and Relevance: In this cohort study of patients with acute, non-life-threatening hyperkalemia, a single dose of patiromer was associated with a significant decrease in serum potassium levels and a low incidence of hypokalemia. These findings suggest that patiromer monotherapy may be useful in an institutional setting for managing elevated potassium levels and minimizing the risk of hypokalemia associated with other potassium control measures.

Assessment of the Potential for Veverimer Drug-Drug Interactions.

Veverimer is a polymer being developed as a potential treatment of metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral, or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiologic concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs. SIGNIFICANCE STATEMENT: Patients with chronic kidney disease, who are usually on many drugs, are vulnerable to drug-drug interactions (DDIs). The potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the gastrointestinal tract. Based on the findings from in vitro and human studies, we conclude that veverimer is unlikely to have clinically significant DDIs.

Cost-Effectiveness Analysis of Patiromer in Combination with Renin-Angiotensin-Aldosterone System Inhibitors for Chronic Kidney Disease in Sweden.

OBJECTIVES: Patients with chronic kidney disease (CKD) are commonly treated with renin-angiotensin-aldosterone system inhibitors (RAASi) in order to delay progression of renal disease. However, research has shown that RAASi in CKD patients increases hyperkalaemia (HK) prevalence, which leads to RAASi discontinuation or dose reduction with the loss of benefits on the kidney. Patiromer is a novel therapy for HK treatment and may enable patients to remain on their RAASi regimen. This study aimed to assess the cost-effectiveness of patiromer from a Swedish healthcare perspective. METHODS: A Markov model was developed to evaluate the economic outcomes of patiromer versus no patiromer in HK patients with stage 3-4 CKD taking RAASi. The model consisted of six health states reflecting disease progression and hospitalisations. The analysis mainly considered clinical data from the OPAL-HK trial and national costs. The main outcomes of interest were incremental costs (euro [EUR] 2016) and quality-adjusted life years (QALYs), discounted at 3%, and the incremental cost-effectiveness ratio (ICER). Extensive uncertainty analyses were performed. RESULTS: In comparison to no patiromer, a patiromer patient gained 0.14 QALYs and an incremental cost of EUR 6109 (Swedish krona [SEK] 57,850), yielding an ICER of EUR 43,307 (SEK 410,072)/QALY gained. The results were robust to a range of sensitivity analyses. At a willingness-to-pay threshold of EUR 52,804 (SEK 500,000)/QALY, patiromer had a 50% chance of being cost-effective. CONCLUSIONS: The results indicate that patiromer may demonstrate value for money in Swedish patients with stage 3-4 CKD, by enabling RAASi treatment. However, there is a considerable degree of uncertainty.

Safety assessment of poly(N-vinylcaprolactam) as a potential drug carrier in extenders for boar sperm cryopreservation.

Polymers may be used to deliver compounds in freezing extenders to minimize injuries in spermatozoa during cryopreservation, although their activity and toxicity for boar sperm are unknown. This study investigated the effects of the polymer (N-vinylcaprolactam) (PNVCL), when included in extenders for boar sperm cryopreservation. In Experiment 1, sperm was exposed to PNVCL at: 0 (control); 39.1; 78.1; 156.3; and 312.5 µg/mL. Spermatozoa structure, kinetics and biochemical functions were unaltered in contact with PNVCL at 38 °C (P > .05) but declined with prolonged exposure (10, 60 and 120 min) in all treatments (P > .05). In Experiment 2, after inclusion of PNVCL in the freezing extender at the same concentrations, post-thawing sperm quality did not differ compared to the control (P > .05). Lipid peroxidation and the production of reactive oxygen species were the only parameters of sperm quality that were unaffected in both experiments, even after contact with PNVCL for 120 min (P > .05). As no negative effects were observed in post-thawing boar sperm quality, PNVCL did not incur in cytotoxicity and may be a potential carrier for antioxidants in freezing extenders.

Cost-Effectiveness Analysis of Patiromer and Spironolactone Therapy in Heart Failure Patients with Hyperkalemia.

BACKGROUND AND OBJECTIVE: Certain patients with heart failure (HF) are unable to tolerate spironolactone therapy due to hyperkalemia. Patiromer is a novel agent used to treat hyperkalemia and has been shown to be efficacious, safe, and well-tolerated. The potential clinical outcomes and economic value of using patiromer and spironolactone in patients with HF unable to otherwise tolerate spironolactone due to hyperkalemia are unclear. The objective of this analysis was to model the potential pharmacoeconomic value of using patiromer and spironolactone in patients with a history of hyperkalemia that prevents them from utilizing spironolactone. METHODS: We performed a cost-effectiveness analysis of treatment with patiromer, spironolactone, and an angiotensin-converting enzyme inhibitor (ACEI) in patients with New York Heart Association (NYHA) class III-IV HF compared with ACEI alone. A Markov model was constructed to simulate a cohort of 65-year-old patients diagnosed with HF from the payer perspective across the lifetime horizon. Clinical inputs were derived from the RALES and OPAL-HK randomized trials of spironolactone and patiromer, respectively. Utility estimates and costs were derived from the literature and list prices. Outcomes assessed included hospitalization, life expectancy, and quality-adjusted life-years (QALYs), costs, and the incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analyses were performed to test the robustness of the model findings. RESULTS: Treatment with patiromer-spironolactone-ACEI was projected to increase longevity compared with ACEI alone (5.29 vs. 4.62 life-years gained, respectively), greater QALYs (2.79 vs. 2.60), and costs (US$28,200 vs. US$18,200), giving an ICER of US$52,700 per QALY gained. The ICERs ranged from US$40,000 to US$85,800 per QALY gained in 1-way sensitivity analyses. CONCLUSION: Our results suggest that the use of spironolactone-patiromer-ACEI may provide clinical benefit and good economic value in patients with NYHA class III-IV HF unable to tolerate spironolactone due to hyperkalemia.

Assessment of Patient Exposure to Leachables From Lyophilized Drug Formulations Following Reconstitution, Storage, and Administration via Polymeric Packaging/Delivery Systems.

It has been demonstrated that lyophilized drug formulations have an increased propensity to leach substances from the rubber stoppers comprising their primary packaging system when compared to aqueous liquid formulations stored in the same manner. Unfortunately, patient exposure to leachables originating in lyophilized drug products is not known. To that end, the goal of this study was to assess patient exposure to these leachables after reconstitution, storage, and administration of the lyophilized drug. To achieve this goal, several leachables present in 2 commercial lyophilized drug products were quantified after contact with polyvinyl chloride and non-polyvinyl chloride medication bags as well as an infusion set for durations of 15 min to 7 days at refrigerated and ambient temperature. The results obtained from this study showed that the bag's material of construction and the drugs formulation did not impact the mass of the leachables administered. Conversely, the mass of each leachable administered to the patient was reduced or eliminated as the contact duration with the intravenous bag and the temperature increased. However, for shorter contact durations, refrigerated storage, and higher molecular weight compounds, the patient would be exposed to a majority of the leachables originating from the vial.

Feasibility of dose enhancement assessment: Preliminary results by means of Gd-infused polymer gel dosimeter and Monte Carlo study.

This work reports the experimental development of an integral Gd-infused dosimeter suitable for Gd dose enhancement assessment along with Monte Carlo simulations applied to determine the dose enhancement by radioactive and X-ray sources of interest in conventional and electronic brachytherapy. In this context, capability to elaborate a stable and reliable Gd-infused dosimeter was the first goal aimed at direct and accurate measurements of dose enhancement due to Gd presence. Dose-response was characterized for standard and Gd-infused PAGAT polymer gel dosimeters by means of optical transmission/absorbance. The developed Gd-infused PAGAT dosimeters demonstrated to be stable presenting similar dose-response as standard PAGAT within a linear trend up to 13 Gy along with good post-irradiation readout stability verified at 24 and 48 h. Additionally, dose enhancement was evaluated for Gd-infused PAGAT dosimeters by means of Monte Carlo (PENELOPE) simulations considering scenarios for isotopic and X-ray generator sources. The obtained results demonstrated the feasibility of obtaining a maximum enhancement around of (14 ±â€¯1)% for 192Ir source and an average enhancement of (70 ±â€¯13)% for 241Am. However, dose enhancement up to (267 ±â€¯18)% may be achieved if suitable filtering is added to the 241Am source. On the other hand, optimized X-ray spectra may attain dose enhancements up to (253 ±â€¯22) %, which constitutes a promising future alternative for replacing radioactive sources by implementing electronic brachytherapy achieving high dose levels.

Delivery Considerations of Highly Viscous Polymeric Fluids Mimicking Concentrated Biopharmaceuticals: Assessment of Injectability via Measurement of Total Work Done "WT".

An account is given of the recent development of the highly viscous complex biopharmaceuticals in relation to syringeability and injectability. The specific objective of this study is to establish a convenient method to examine problem of the injectability for the needle-syringe-formulation system when complex formulations with diverse viscosities are used. This work presents the inter-relationship between needle size, syringe volume, viscosity, and injectability of polymeric solutions having typical viscosities encountered in concentrated biologics, by applying a constant probe crosshead speed on the plunger-syringe needle assembly and continuously recording the force-distance profiles. A computerized texture analyzer was used to accurately capture, display, and store force, displacement, and time data. The force-distance curve and area under the curve are determined, and total work done for complete extrusion of the syringe content was calculated automatically by applying an established Matlab program. Various concentrations (i.e., 0.5-4% w/v of polymeric fluids/dispersions) of polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) with viscosity ranges of 5-100 cP mimicking concentrated monoclonal antibody solutions and complex biopharmaceutical formulations are investigated. Results indicate that calculated values of total work done to completely extrude the syringe content are the most appropriate parameter that describes viscosity-injection force of dispersed formulations. Additionally, the rheological properties of HPMC and PEO fluids in the context of syringeability and injectability are discussed.

Comparison of polyvinyl alcohol copolymer with detachable balloons for the embolisation of direct carotid cavernous fistula: a single-centre experience.

OBJECTIVES: To characterise the safety, efficacy and cost of direct carotid-cavernous fistula (CCF) treatment using polyvinyl alcohol copolymer or detachable balloons. METHODS: We reviewed retrospectively patients with direct CCFs treated with either a detachable balloon or polyvinyl alcohol copolymer at our hospital from 2005 to 2015 and identified 94 patients with 105 CCFs. All patients had follow-up angiograms. The CCF occlusion rate, procedure complication rate, treatment expense and operation time were recorded. RESULTS: With a mean of 5.4 months of angiographic follow-up, the complete occlusion rate and recanalisation rate of the polyvinyl alcohol copolymer group was not significantly different from that of the detachable balloon group. The treatment expense was much higher and the operation time was much longer in the polyvinyl alcohol copolymer group than the detachable balloon group (P < 0.001). CONCLUSIONS: Embolisation of CCF with polyvinyl alcohol copolymer is as safe and effective as detachable balloon but has a much higher cost and longer operation time. KEY POINTS: • Carotid-cavernous fistula results from a damaged carotid artery. • Detachable balloons have been used with success for many years. • Some reported excellent outcomes after embolisation with polyvinyl alcohol copolymer. • Treatment expense is much higher in the polyvinyl alcohol copolymer group.

Using eHealth strategies in delivering dietary and other therapies in patients with irritable bowel syndrome and inflammatory bowel disease.

Health-care systems around the world are facing increasing costs. Non-adherent, chronically ill patients are one such expense incurred by health-care providers. Web-based home-monitoring of patients-or eHealth-has been shown to increase adherence to medical therapy, facilitate contact between patients and health-care professionals, and reduce time to remission for patients with inflammatory bowel disease (IBD). Web-based treatment is a supportive tool for the health-care provider in an out-patient clinic. eHealth web-programs, such as the Constant Care application, visualize disease activity in a traffic light system and empower patients to screen for disease activity, enabling them to respond appropriately to their symptoms. The eHealth screening procedure for monitoring both pediatric and adult IBD patients is based on a self-obtained symptom score, together with a fecal biomarker for inflammation (fecal calprotectin) that the patients can measure independently using their smart phone, providing both patient and physician with an immediate disease status that they can react to instantaneously. Likewise, web applications for IBD patients, web applications for irritable bowel syndrome (IBS) patients and also IBD patients with co-existing IBS, have proven valuable for monitoring and treating IBS symptoms with a diet low in fermentable oligo-, di-, monosaccharides and polyols (low-FODMAP diet). With careful disease monitoring via the web application and increased patient adherence, eHealth might be capable of improving the natural disease course of IBD and IBS.

A Computational/Experimental Assessment of Antitumor Activity of Polymer Nanoassemblies for pH-Controlled Drug Delivery to Primary and Metastatic Tumors.

PURPOSE: Polymer nanoassemblies (PNAs) with drug release fine-tuned to occur in acidic tumor regions (pH < 7) while sparing normal tissues (pH = 7.4) were previously shown to hold promise as nanoparticle drug carriers to effectively suppress tumor growth with reduced systemic toxicity. However, therapeutic benefits of pH-controlled drug delivery remain elusive due to complex interactions between the drug carriers, tumor cells with varying drug sensitivity, and the tumor microenvironment. METHODS: We implement a combined computational and experimental approach to evaluate the in vivo antitumor activity of acid-sensitive PNAs controlling drug release in pH 5 ~ 7.4 at different rates [PNA1 (fastest) > PNA2 > PNA3 (slowest)]. RESULTS: Computational simulations projecting the transport, drug release, and antitumor activity of PNAs in primary and metastatic tumor models of colorectal cancer correspond well with experimental observations in vivo. The simulations also reveal that all PNAs could reach peak drug concentrations in tumors at 11 h post injection, while PNAs with slower drug release (PNA2 and PNA3) reduced tumor size more effectively than fast drug releasing PNA1 (24.5 and 20.3 vs 7.5%, respectively, as fraction of untreated control). CONCLUSION: A combined computational/experimental approach may help to evaluate pH-controlled drug delivery targeting aggressive tumors that have substantial acidity.

A systematic review of filler agents for aesthetic treatment of HIV facial lipoatrophy (FLA).

HIV facial lipoatrophy (FLA) is characterized by facial volume loss. HIV FLA affects the facial contours of the cheeks, temples, and orbits, and is associated with social stigma. Although new highly active antiretroviral therapy medications are associated with less severe FLA, the prevalence of HIV FLA among treated individuals exceeds 50%. The goal of our systematic review is to examine published clinical studies involving the use of filler agents for aesthetic treatment of HIV FLA and to provide evidence-based recommendations based on published efficacy and safety data. A systematic review of the published literature was performed on July 1, 2015, on filler agents for aesthetic treatment of HIV FLA. Based on published studies, poly-L-lactic acid is the only filler agent with grade of recommendation: B. Other reviewed filler agents received grade of recommendation: C or D. Poly-L-lactic acid may be best for treatment over temples and cheeks, whereas calcium hydroxylapatite, with a Food and Drug Administration indication of subdermal implantation, may be best used deeply over bone for focal enhancement. Additional long-term randomized controlled trials are necessary to elucidate the advantages and disadvantages of fillers that have different biophysical properties, in conjunction with cost-effectiveness analysis, for treatment of HIV FLA.

Biological assessment of self-assembled polymeric micelles for pulmonary administration of insulin.

Pulmonary delivery of drugs for both local and systemic action has gained new attention over the last decades. In this work, different amphiphilic polymers (Soluplus®, Pluronic® F68, Pluronic® F108 and Pluronic® F127) were used to produce lyophilized formulations for inhalation of insulin. Development of stimuli-responsive, namely glucose-sensitive, formulations was also attempted with the addition of phenylboronic acid (PBA). Despite influencing the in vitro release of insulin from micelles, PBA did not confer glucose-sensitive properties to formulations. Lyophilized powders with aerodynamic diameter (<6 µm) compatible with good deposition in the lungs did not present significant in vitro toxicity for respiratory cell lines. Additionally, some formulations, in particular Pluronic® F127-based formulations, enhanced the permeation of insulin through pulmonary epithelial models and underwent minimal internalization by macrophages in vitro. Overall, formulations based on polymeric micelles presenting promising characteristics were developed for the delivery of insulin by inhalation. FROM THE CLINICAL EDITOR: The ability to deliver other systemic drugs via inhalation has received renewed interests in the clinical setting. This is especially true for drugs which usually require injections for delivery, like insulin. In this article, the authors investigated their previously developed amphiphilic polymers for inhalation of insulin in an in vitro model. The results should provide basis for future in vivo studies.

Cost utility analysis of urethral bulking agents versus midurethral sling in stress urinary incontinence.

OBJECTIVE: The aim of this study was to determine the cost utility of urethral bulking agents (BA) compared with midurethral slings (MUS) in the treatment of stress urinary incontinence (SUI) in patients without urethral hypermobility. METHODS: A decision tree was constructed to compare the cost utility of urethral BA versus MUS in the setting of SUI without urethral hypermobility. Probability estimates for success, failure, and complications were obtained from the published literature. Immediate-term, short-term, and longer-term complications were accounted for over a 1-year time horizon in the model. One-way and 2-way sensitivity analyses and Monte Carlo simulations were performed to assess the robustness of our results. RESULTS: Our model demonstrated that MUS cost $436,465 more than BA for every 100 women treated in 1 year. Using MUS compared with BA leads to an incremental cost-effectiveness ratio of $70,400 per utility gained. Assuming a willingness to pay of $50,000, this makes MUS not cost-effective as a first-line treatment in many situations. When MUS costs less than $5132, it becomes a cost-effective first-line treatment, and when it costs less than $2035, it is cost saving. CONCLUSIONS: Bulking agents are more cost-effective than MUS over a 1-year time horizon in the treatment of SUI in patients without urethral hypermobility. In women who lack urethral hypermobility, BA remain a cost-effective option in this patient population.

Trojan horses and guided missiles: targeted therapies in the war on arthritis.

Despite major advances in the treatment of rheumatoid arthritis (RA) led by the success of biologic therapies, the lack of response to therapy in a proportion of patients, as well as therapy discontinuation owing to systemic toxicity, are still unsolved issues. Unchecked RA might develop into progressive structural joint damage, loss of function and long-term disability, disorders which are associated with a considerable health-economic burden. Therefore, new strategies are required to actively target and deliver therapeutic agents to disease sites in order to promote in situ activity and decrease systemic toxicity. Polymer-drug conjugates can improve the pharmacokinetics of therapeutic agents, conferring desirable properties such as increased solubility and tissue penetration at sites of active disease. Additionally, nanotechnology is an exciting modality in which drugs are encapsulated to protect them from degradation or early activation in the circulation, as well as to reduce systemic toxicity. Together with the targeting capacity of antibodies and site-specific peptides, these approaches will facilitate selective accumulation of therapeutic agents in the inflamed synovium, potentially improving drug efficacy at disease sites without affecting healthy tissues. This Review aims to summarize key developments in the past 5 years in polymer conjugation, nanoparticulate drug delivery and antibody or peptide-based targeting--strategies that might constitute the platform for the next generation of RA therapeutics.

Quantitative assessment of the longevity of poly-L-lactic acid as a volumizing filler using 3-dimensional photography.

OBJECTIVE: To demonstrate the efficacy and longevity of injectable poly-L-lactic acid as a volumizing injectable in the midface region quantitatively using 3-dimensional (3-D) imaging. DESIGN, SETTING, AND PARTICIPANTS: Prospective study assessing changes in midfacial volume in 15 women aged between 40 and 60 years using a 3-D imaging system at 12, 24, 36, and 48 weeks after 3 treatments with poly-L-lactic acid. Three-dimensional imaging was acquired using the 3-D camera and software. INTERVENTION: Patients were treated with poly-L-lactic acid. The first 2 treatments were 6 weeks apart. The third treatment was performed 12 weeks after the second treatment. MAIN OUTCOMES AND MEASURES: Changes in midfacial volume following 3 treatments of poly-L-lactic acid were measured quantitatively using the 3-D imaging system. A paired t test was used to analyze the difference between pretreatment and posttreatment values at each study time point. RESULTS: Of the 15 patients, 1 only received 2 treatments and was therefore excluded from the statistical analysis. There was a statistically significant increase in mean midfacial volume at all study time points, 12 weeks (mean [range], 7.2 [1.6-20.7] mL; P < .001), 24 weeks (mean [range], 7.2 [1.9-19.4] mL; P < .001), 36 weeks (mean [range], 4.6 [1.1-9.2] mL; P = .002), and 48 weeks (mean [range], 4.1 [0.8-6.4] mL; P < .001), compared with pretreatment volume. There was no significant change in volume between each of the follow-up time points. CONCLUSIONS AND RELEVANCE: Our prospective investigation quantitatively demonstrates the efficacy of poly-L-lactic acid as a long-acting volumizing agent, with an increase in midfacial volume from baseline sustained at least 1 year after treatment. LEVEL OF EVIDENCE: 2. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01307865.

Brain delivery of intranasal in situ gel of nanoparticulated polymeric carriers containing antidepressant drug: behavioral and biochemical assessment.

This study was aimed for brain delivery of Tramadol HCl (centrally acting synthetic opioid) following intranasal administration for treatment of depression. Chitosan nanoparticles (NPs) were prepared by ionic gelation method followed by the addition of developed NPs with in the Pluronic and HPMC-based mucoadhesive thermo-reversible gel. Developed formulation optimized based on the various parameters such as particle size, entrapment efficiency, in vitro release study. Depression induction was done by forced swim test and evaluated by various behavioral and biochemical parameters. Furthermore, results showed significantly increased in locomotors activity, body weight as compared to control group. It also showed alteration in biochemical parameters such glutathione level and catalase levels significantly increased other than lipid peroxidation and nitrite level was found to be decreased after intranasal administration of formulation. Thus, intranasal TRM HCl NP-loaded in situ gel was found to be a promising formulation for the treatment of depression.

Cetyl gellan copolymer micelles and hydrogels: in vitro and pharmacodynamic assessment for drug delivery.

In this study, gellan polymer was conferred amphiphilic character by conjugating alkyl carbon chain (C16) to its backbone via etherification reaction. The amphiphilic copolymer self-assembled into water and formed spherical micellar structures with a mean diameter of 832 nm. Copolymer micellization caused a considerable rise in solubility of simvastatin in water. Later on, the micelle-incorporated drug and pure drug were loaded into aluminium gellan hydrogel beads and characterized. Scanning electron microscopy revealed spherical shape of the beads. The drug entrapment efficiency of the beads (917-927 µm) was found to be 90-94%. Higher dissolution efficiency and consequently, higher rate of drug dissolution was evident in phosphate buffer solution (pH 6.8) than in HCl solution (pH 1.2). The changes in drug release rate as a function of pH correlated with the swelling behaviour of beads. The release of drug was controlled by anomalous diffusion mechanism. Fourier transform infrared spectroscopy and X-ray diffraction analyses suggested compatibility of drug in the beads. The gellan beads, loaded with micellar drug, reduced 83.45% LDL-cholesterol level in rabbit model following 18 h of oral administration. Thus, the gellan beads containing micellar drug showed their potential in controlling drug release rate and improving pharmacodynamic activity.

In-vitro thrombogenicity assessment of polymer filament modified and native platinum embolic coils.

BACKGROUND: Embolic coils have been used to treat intracranial aneurysms using an endovascular approach for more than two decades. However, significant aneurysm recanalization rates have been reported specifically in large and giant aneurysms. Adding filaments to bare Platinum coils is considered a modification and has been proposed to achieve higher aneurysm occlusion rates as compared to bare Platinum coils. Quantitative information - in terms of thrombin generation potential of these modifications - is however lacking. OBJECTIVE: We report here in vitro thrombogenicity of Platinum coils containing Nylon (Axium™ MicroFx™ Nylon coil) and PGLA (Axium™ MicroFx™ PGLA coil) filaments and compare them with equivalent bare Platinum Axium™ coils. METHOD: We utilize a quantitative method that tracks the formation of thrombin upon exposure of the test samples to human platelet rich plasma using a slow binding fluorogenic substrate. RESULTS: We report a significant increase in the total thrombin turnover, the peak thrombin amount and the rate of thrombin generation for the Axium™ MicroFx™ coils and filaments compared to the Axium™ coils and Platinum wire. CONCLUSION: Nylon and PGLA filaments added to bare Platinum coils increase thrombogenicity of coils. This study offers a robust quantitative method to compare thrombus formation efficacy of embolic coils under static conditions.

Assessment of the safety and immunogenicity of Rhodococcus equi-secreted proteins combined with either a liquid nanoparticle (IMS 3012) or a polymeric (PET GEL A) water-based adjuvant in adult horses and foals--identification of promising new candidate antigens.

Rhodococcus equi is the most common infectious cause of mortality in foals between 1 and 6 months of age. Because of an increase in the number of antibiotic-resistant strains, the optimization of a prophylactic strategy is a key factor in the comprehensive management of R. equi pneumonia. The objectives of this study were to assess the safety and immunogenicity of R. equi-secreted proteins (ReSP) co-administered with either the nanoparticular adjuvant Montanide™ IMS 3012 VG, or a new polymeric adjuvant Montanide™ PET GEL A, and to further investigate the most immunogenic proteins for subsequent immunization/challenge experiments in the development of a vaccine against rhodoccocal pneumonia. The approach involved two phases. The first phase aimed to investigate the safety of vaccination in six adult horses. The second phase aimed to determine the safety and immunogenicity of vaccination in twelve 3-week-old foals. We set out to develop a method based on ultrasound measurements for safety assessment in adult horses in order to evaluate any in situ changes at the injection site, in the skin or the underlying muscle, with quantitative and qualitative data revealing that administration of ReSP combined with the Pet Gel A adjuvant led to an increase in local inflammation, associated with 4- to 7-fold higher levels of anti-R. equi IgGa, IgGb and IgGT, compared to administration of ReSP associated with IMS 3012 adjuvant, but without any impact on animal demeanor. Investigations were then performed in foals with serological and clinical follow-up until 6 months of age. Interestingly, we observed in foals a much lower incidence of adverse local tissue reactions at the injection site than in adult horses, with transient and moderate swelling for the group that received ReSP combined with Pet Gel A. Immunized foals with Pet Gel A adjuvant exhibited a similar response in both IgGa and IgGT levels, but a lower response in IgGb levels, compared to adult horses, with a subisotype profile that may however reflect a bias favorable to R. equi resistance. From the crude extract of secreted proteins, dot-blot screening enabled identification of cholesterol oxidase, mycolyl transferase 3, and PSP (probable secreted protein) as the most immunogenic candidates. Taken together, these results are encouraging in developing a vaccine for foals.