Prednisolone Phosphate Research Articles

The Development of a Chocolate-Based Chewable Tablet of Prednisolone-Enhancing the Palatability of Steroids for Pediatric Use.

Oral liquid prednisolone medications have poor acceptance among paediatric patients due to ineffective masking of the bitterness taste of prednisolone. This study aimed to develop a child-friendly prednisolone tablet using a patented chewable chocolate-based delivery system (CDS) previously applied successfully to mask the bitterness tastes of midazolam and tramadol. Prednisolone sodium phosphate (PSP) and prednisolone base (PB) CDS tablets were prepared, and the manufacturing process was optimised using a design of experiments (DoE) approach. Stability was assessed by quantifying residual drug content via a validated HPLC assay. A pilot randomised crossover taste study involving 25 young adult volunteers evaluated taste-masking effectiveness against Redipred™, a commercial oral PSP liquid medicine. The results showed that the PSP CDS tablet was chemically stable following storage for three months at ambient temperature, while the PB CDS tablet was unstable. The optimised PSP CDS tablet, manufactured at 50 °C with a stirring time of 26 h, was found to release over 80% of its drug load within 20 min in 0.1 M HCl and had a significantly better mean taste score compared to Redipred™ (7.08 ± 2.40 vs. 5.60 ± 2.33, p = 0.03). Fifty six percent of the participants preferred the PSP CDS tablet. In conclusion, compared to Redipred™, the CDS technology provided a more effective taste masking of PSP, potentially offering a child-friendly prednisolone formulation with improved compliance, dosing accuracy, and storage stability.

Targeting of M2 macrophages with IL-13-functionalized liposomal prednisolone inhibits melanoma angiogenesis in vivo

The intricate cooperation between cancer cells and nontumor stromal cells within melanoma microenvironment (MME) enables tumor progression and metastasis. We previously demonstrated that the interplay between tumor-associated macrophages (TAMs) and melanoma cells can be disrupted by using long-circulating liposomes (LCLs) encapsulating prednisolone phosphate (PLP) (LCL-PLP) that inhibited tumor angiogenesis coordinated by TAMs. In this study, our goal was to improve LCL specificity for protumor macrophages (M2-like (i.e., TAMs) macrophages) and to induce a more precise accumulation at tumor site by loading PLP into IL-13-conjugated liposomes (IL-13-LCL-PLP), since IL-13 receptor is overexpressed in this type of macrophages. The IL-13-LCL-PLP liposomal formulation was obtained by covalent attachment of thiolated IL-13 to maleimide-functionalized LCL-PLP. C57BL/6 mice bearing B16.F10 s.c melanoma tumors were used to investigate the antitumor action of LCL-PLP and IL-13-LCL-PLP. Our results showed that IL-13-LCL-PLP formulation remained stable in biological fluids after 24h and it was preferentially taken up by M2 polarized macrophages. IL-13-LCL-PLP induced strong tumor growth inhibition compared to nonfunctionalized LCL-PLP at the same dose, by altering TAMs-mediated angiogenesis and oxidative stress, limiting resistance to apoptosis and invasive features in MME. These findings suggest IL-13-LCL-PLP might become a promising delivery platform for chemotherapeutic agents in melanoma.

Glucocorticoids rescue cell surface trafficking of R451C Neuroligin3 and enhance synapse formation.

Neuroligins are synaptic cell adhesion proteins with a role in synaptic function, implicated in neurodevelopmental disorders. The autism spectrum disorder-associated substitution Arg451Cys (R451C) in NLGN3 promotes a partial misfolding of the extracellular domain of the protein leading to retention in the endoplasmic reticulum (ER) and the induction of the unfolded protein response (UPR). The reduced trafficking of R451C NLGN3 to the cell surface leads to altered synaptic function and social behavior. A screening in HEK-293 cells overexpressing NLGN3 of 2662 compounds (FDA-approved small molecule drug library), led to the identification of several glucocorticoids such as alclometasone dipropionate, desonide, prednisolone sodium phosphate, and dexamethasone (DEX), with the ability to favor the exit of full-length R451C NLGN3 from the ER. DEX improved the stability of R451C NLGN3 and trafficking to the cell surface, reduced the activation of the UPR, and increased the formation of artificial synapses between HEK-293 and hippocampal primary neurons. The effect of DEX was validated on a novel model system represented by neural stem progenitor cells and differentiated neurons derived from the R451C NLGN3 knock-in mouse, expressing the endogenous protein. This work shows a potential rescue strategy for an autism-linked mutation affecting cell surface trafficking of a synaptic protein.

3D-printed prednisolone phosphate suppositories with tunable dose and rapid release for the treatment of inflammatory bowel disease

Established medicines are often not tailored to the needs of the pediatric population, causing difficulties with administration or dosing. Three-dimensional (3D) printing technology allows novel approaches for compounding of personalized medicine, as is exemplified in this study for the automated compounding of rectal preparations for children. We investigated the material requirements to print prednisolone phosphate-loaded suppositories with tunable dose and rapid drug release for the treatment of inflammatory bowel diseases. Three formulations containing 4 % w/w prednisolone sodium phosphate (PSP) and different amounts of hydroxypropyl cellulose (HPC) and mannitol as excipients were printed as suppositories with a fused deposition modeling (FDM) 3D-printer. Dissolution studies showed that the PSP release rate was increased when higher weight fractions of mannitol were added as a pore former, with 90 % drug release within 30 min for mannitol 48 % w/w. We further printed suppositories with 48 % mannitol with different infill densities and dimensions to tune the dose. Our findings demonstrated that 3D-printed suppositories with PSP doses ranging from 6 to 30 mg could be compounded without notably affecting the dissolution kinetics, ensuring equivalent therapeutic efficacies for different doses.

Evaluation of a steroid delivery system to mitigate the severity of proliferative vitreoretinopathy in a minipig model.

To investigate the efficacy of liposomal prednisolone phosphate to mitigate the severity of proliferative vitreoretinopathy (PVR) in a minipig model of PVR. A total of 18 eyes of 9 minipigs underwent PVR induction surgically. Eyes were randomized equally into three groups: intravitreal injection of liposomal prednisolone phosphate (LPP), triamcinolone acetonide (TA), and controls. PVR severity was graded on fundoscopic examination using a modified version of the Silicon Study Classification System. Severe PVR was defined as grade 2-5 on this classification, and the proportion of eyes with retinal detachment from severe PVR, defined as retinal re-detachment, i.e., PVR grade 2-5, was compared between treatment and control groups. On day 28, five eyes (83.3%) in the control group were observed to have severe PVR. Within the LPP group, one (16.7%) eye developed retinal detachment due to severe PVR. Grade 0 PVR was observed in four (66.7%) eyes, grade 1 in one (16.7%) eye, and grade 5 in one (16.7%) eye. Within the TA group, grade 0 PVR was observed in four eyes (66.7%), grade 1 in two eyes (16.6%), and grade 5 in one (16.7%) eye. The difference in the proportion of eyes with severe PVR was significantly lower in the LPP group compared to controls at day 28 (16.7% vs 83.3%, p=0.02). There was no significant difference in the rate of severe PVR or median PVR grade between the liposomal prednisolone phosphate and triamcinolone acetonide groups. Liposomal prednisolone phosphate reduces the severity of PVR in a minipig model of PVR.

Hard-Shelled Glycol Chitosan Nanoparticles for Dual MRI/US Detection of Drug Delivery/Release: A Proof-of-Concept Study.

This paper describes a novel nanoformulation for dual MRI/US in vivo monitoring of drug delivery/release. The nanosystem was made of a perfluoropentane core coated with phospholipids stabilized by glycol chitosan crosslinked with triphosphate ions, and it was co-loaded with the prodrug prednisolone phosphate (PLP) and the structurally similar MRI agent Gd-DTPAMA-CHOL. Importantly, the in vitro release of PLP and Gd-DTPAMA-CHOL from the nanocarrier showed similar profiles, validating the potential impact of the MRI agent as an imaging reporter for the drug release. On the other hand, the nanobubbles were also detectable by US imaging both in vitro and in vivo. Therefore, the temporal evolution of both MRI and US contrast after the administration of the proposed nanosystem could report on the delivery and the release kinetics of the transported drug in a given lesion.

Formulation development and characterization of dual drug loaded hot-melt extruded inserts for better ocular therapeutic outcomes: Sulfacetamide/prednisolone

The present investigation was intended to formulate and evaluate a hot-melt extruded (HME) bioadhesive ophthalmic inserts containing a fixed-dose combination of Prednisolone Sodium Phosphate (PSP) and Sulfacetamide Sodium (SA) to improve the treatment outcomes of multiple ocular bacterial infections. The inserts were prepared using FDA-authorised biocompatible polymers, including Polyox WSR N10 LEO NF (polyethylene oxide; PEO), Klucel™ HF (hydroxypropyl cellulose; HPC-HF), and Ethocel™ (Ethylcellulose; EC). The inserts were then assessed for physicochemical characteristics, weight variation, surface pH, uniformity of thickness, drug content, swelling index, thermal analysis, drug–excipient compatibility, moisture uptake and loss, surface morphology, mucoadhesive strength, in vitro release, ex-vivo transcorneal permeation and deposition, and stability. The HPC-HF and EC-containing inserts extended the release of both drugs compared to PEO-N10-based inserts that showed the release of the loaded amount of both drugs immediately (<1 h). All fabricated inserts were stable over 90-day storage at room temperature (25 °C) and accelerated conditions (40 °C) for drug content and thermal behavior. The developed PSP-SA inserts exhibited optimum bioadhesive strength and smooth surface favorable for topical ocular application. Ex vivo transcorneal permeation studies using freshly isolated rabbit corneas demonstrated that the extended-release inserts slowed down the transcorneal flux of the drug in comparison to the immediate-release inserts and the commercial solution eyedrops. Overall, the inserts were fabricated using a solvent-free, scalable, and continuous manufacturing process and could reduce the frequency of administration to once-daily application, affording a new topical delivery vehicle with prolonged antibacterial and anti-inflammatory activity during ocular bacterial infections treatment.

Two Types of Liposomal Formulations Improve the Therapeutic Ratio of Prednisolone Phosphate in a Zebrafish Model for Inflammation.

Glucocorticoids (GCs) are effective anti-inflammatory drugs, but their clinical use is limited by their side effects. Using liposomes to target GCs to inflammatory sites is a promising approach to improve their therapeutic ratio. We used zebrafish embryos to visualize the biodistribution of liposomes and to determine the anti-inflammatory and adverse effects of the GC prednisolone phosphate (PLP) encapsulated in these liposomes. Our results showed that PEGylated liposomes remained in circulation for long periods of time, whereas a novel type of liposomes (which we named AmbiMACs) selectively targeted macrophages. Upon laser wounding of the tail, both types of liposomes were shown to accumulate near the wounding site. Encapsulation of PLP in the PEGylated liposomes and AmbiMACs increased its potency to inhibit the inflammatory response. However, encapsulation of PLP in either type of liposome reduced its inhibitory effect on tissue regeneration, and encapsulation in PEGylated liposomes attenuated the activation of glucocorticoid-responsive gene expression throughout the body. Thus, by exploiting the unique possibilities of the zebrafish animal model to study the biodistribution as well as the anti-inflammatory and adverse effects of liposomal formulations of PLP, we showed that PEGylated liposomes and AmbiMACs increase the therapeutic ratio of this GC drug.

Intravenous pegylated liposomal prednisolone outperforms intramuscular methylprednisolone in treating rheumatoid arthritis flares: A randomized controlled clinical trial

Glucocorticoids (GCs) are potent anti-inflammatory drugs but their use is limited by systemic exposure leading to toxicity. Targeted GC delivery to sites of inflammation via encapsulation in long-circulating liposomes may improve the therapeutic index. We performed a randomized, double-blind, active-controlled, multi-center study in which intravenously (i.v.) administered pegylated liposomal prednisolone sodium phosphate (Nanocort) was compared to equipotent intramuscular (i.m.) methylprednisolone acetate (Depo-Medrol®; i.e. a current standards-of-care for treating flares in rheumatoid arthritis patients). We enrolled 172 patients with active arthritis who met all eligibility criteria, eventually resulting in 150 patients randomized in three groups: (1) Nanocort 75 mg i.v. infusion plus i.m. saline injection; (2) Nanocort 150 mg i.v. infusion plus i.m. saline injection; and (3) Depo-Medrol® 120 mg i.m. injection plus i.v. saline infusion. Dosing in each group occurred at baseline and on day 15 (week 2). Study visits occurred at week 1, 2, 3, 4, 6, 8 and 12, to assess both efficacy and safety. The primary endpoint was the “European League Against Rheumatism” (EULAR) responder rate at week 1. Safety was determined by the occurrence of adverse events during treatment and 12 weeks of follow-up. Treatment with Nanocort was found to be superior to Depo-Medrol® in terms of EULAR response at week 1, with p-values of 0.007 (good response) and 0.018 (moderate response). Treatments were well tolerated with a comparable pattern of adverse events in the three treatment groups. However, the Nanocort groups had a higher incidence of hypersensitivity reactions during liposome infusion. Our results show that liposomal Nanocort is more effective than Depo-Medrol® in treating patients with rheumatoid arthritis flares and has similar safety. This is the first clinical study in a large patient population showing that i.v. administered targeted drug delivery with a nanomedicine formulation improves the therapeutic index of glucocorticoids.

A Potential Alternative Orodispersible Formulation to Prednisolone Sodium Phosphate Orally Disintegrating Tablets.

The orally disintegrating tablet (ODT) has shown vast potential as an alternative oral dosage form to conventional tablets wherein they can disintegrate rapidly (≤30 s) upon contact with saliva fluid and should have an acceptable mouthfeel as long as their weight doesn’t exceed 500 mg. However, owing to the bitterness of several active ingredients, there is a need to find a suitable alternative to ODTs that maintains their features and can be taste-masked more simply and inexpensively. Therefore, electrospun nanofibers and solvent-cast oral dispersible films (ODFs) are used in this study as potential OD formulations for prednisolone sodium phosphate (PSP) that is commercially available as ODTs. The encapsulation efficiency (EE%) of the ODFs was higher (≈100%) compared to the nanofibers (≈87%), while the disintegration time was considerably faster for the electrospun nanofibers (≈30 s) than the solvent-cast ODFs (≈700 s). Hence, accelerated release rate of PSP from the nanofibers was obtained, due to their higher surface area and characteristic surface morphology that permitted higher wettability and thus, faster erosion. Taste-assessment study using the electronic-tongue quantified the bitterness threshold of the drug and its aversiveness concentration (2.79 mM). Therefore, a taste-masking strategy would be useful when further formulating PSP as an OD formulation.

2-Methyl-β-cyclodextrin grafted ammonium chitosan: synergistic effects of cyclodextrin host and polymer backbone in the interaction with amphiphilic prednisolone phosphate salt as revealed by NMR spectroscopy.

Reduced molecular weight chitosan was quaternized with 2-chloro-N,N-diethylethylamine to obtain a water soluble derivative (N+-rCh). Methylated-β-cyclodextrin (MCD), with 0.5molar substitution, was covalently linked to N+-rCh through 1,6-hexamethylene diisocyanate spacer to give the derivatized ammonium chitosan N+-rCh-MCD. To shed light on the role of the cyclodextrin pendant in guiding binding interactions with amphiphilic active ingredients, corticosteroid prednisolone phosphate salt (PN) was considered. The deep inclusion of PN into cyclodextrin in PN/MCD model system was pointed out by analysis of 1H NMR complexation shifts, 1D ROESY spectra, and diffusion measurements (DOSY). By using proton selective relaxation rates measurements as investigation tool, the superior affinity of N+-rCh-MCD towards PN was demonstrated in comparison with parent ammonium chitosan N+-rCh.

Overcoming Intrinsic Doxorubicin Resistance in Melanoma by Anti-Angiogenic and Anti-Metastatic Effects of Liposomal Prednisolone Phosphate on Tumor Microenvironment.

Regardless of recent progress, melanoma is very difficult to treat, mainly due to the drug resistance modulated by tumor cells as well as by the tumor microenvironment (TME). Among the immune cells recruited at the tumor site, tumor associated macrophages (TAMs) are the most abundant, promoting important tumorigenic processes: angiogenesis, inflammation and invasiveness. Furthermore, it has been shown that TAMs are involved in mediating the drug resistance of melanoma cells. Thus, in the present study, we used liposomal formulation of prednisolone disodium phosphate (LCL-PLP) to inhibit the protumor function of TAMs with the aim to sensitize the melanoma cells to the cytotoxic drug doxorubicin (DOX) to which human melanoma has intrinsic resistance. Consequently, we evaluated the in vivo effects of the concomitant administration of LCL-PLP and liposomal formulation of DOX (LCL-DOX) on B16.F10 melanoma growth and on the production of key molecular markers for tumor development. Our results demonstrated that the concomitant administration of LCL-PLP and LCL-DOX induced a strong inhibition of tumor growth, primarily by inhibiting TAMs-mediated angiogenesis as well as the tumor production of MMP-2 and AP-1. Moreover, our data suggested that the combined therapy also affected TME as the number of infiltrated macrophages in melanoma microenvironment was reduced significantly.

Herpetic Eye Disease Study: A Controlled Trial of Topical Corticosteroids for Herpes Simplex Stromal Keratitis

To evaluate the efficacy of topical corticosteroids in treating herpes simplex stromal keratitis. The authors performed a randomized, double-masked, placebo-con- trolled, multicenter clinical trial of 106 patients with active herpes simplex stromal keratitis who had not received any corticosteroids for at least 10 days before study enrollment. Patients were assigned to the placebo group (n= 49) or the steroid group (topical prednisolone phosphate; n= 57); both regimens were tapered over 10 weeks. Both groups received topical trifluridine. Visual acuity assessment and slit-lamp biomicroscopy were performed weekly for 10 weeks, every other week for an additional 6 weeks or until removal from the trial, and at 6 months after randomization. The time to treatment failure (defined by specific criteria as persistent or progressive stromal keratouveitis or an adverse event) was significantly longer in the steroid group compared with the placebo group. Compared with placebo, corticosteroid therapy reduced the risk of persistent or progressive stromal keratouveitis by 68%. The time from randomization to resolution of stromal keratitis and uveitis was significantly shorter in the steroid group compared with the placebo group even though both groups included patients who were removed from the study and treated with topical corticosteroids according to best medical judgment. Nineteen (33%) of the steroid-treated patients and 11 (22%) of the placebo-treated patients completed the 10 weeks of protocol therapy and had stable, noninflamed corneas after 16 weeks. At 6 months after randomization, no clinically or statistically significant differences in visual outcome or recurrent herpetic eye disease were identified between the steroid and placebo groups. The topical corticosteroid regimen used in this study was significantly better than placebo in reducing persistence or progression of stromal inflammation and in shortening the duration of herpes simplex stromal keratitis. Postponing steroids during careful observation for a few weeks delayed resolution of stromal keratitis but had no detrimental effect as assessed by visual outcome at 6 months.

Изучение влияния комбинации антимикробных препаратов и преднизолона в форме преднизалона натрия фосфата на микроэкологическое состояние нижних отделов женских половых органов

Изучение влияния комбинации антимикробных препаратов и преднизолона в форме преднизалона натрия фосфата на микроэкологическое состояние нижних отделов женских половых органов

Unusual case of dystrophic calcification mimicking infective keratitis post cataract surgery- Managed with lamellar keratoplasty

Introduction: To report a case of dystrophic calcification mimicking infective keratitis managed with lamellar keratoplasty. Materials and Methods: A 75yr old patient, one month post eventful (DMD) cataract surgery presented to us with diminution of vision RE. She was on post op prednisolone phosphate eye drops lost to follow up. Results: On examination non healing epithelial defect was noted with dense whitish opacities in the central and paracentral parts of full thickness corneal stroma mimicking infective infiltrate deposits. On anterior segment OCT deposits appeared to be at deep stromal layer with clear demarcation along the descemets membrane hence underwent deep anterior lamellar keratoplasty. Histopathology showed the presence of dystrophic calcification along the stromal tissue and no growth on culture. Patient was followed up regularly with final visual outcome of 6/18. Conclusion: Dystrophic calcification of the cornea, involving corneal stroma is most commonly seen in chronic uveitis, prolonged use of medications over years. Our case shows high index of suspicion must be kept in patients with phosphate medication even for short period of time. AS OCT plays an important role in the decision of lamellar keratoplasty over PKP. With due deligence and use of recent advanced equipments treatment with simple lamellar keratoplasty was possible instead of full thickness keratoplasty avoiding long term visual rehabilitation complications. Keywords: Dystrophic calcification, Topical steroids, Lamellar keratoplasty.

FORMULATION AND EVALUATION OF NIOSOMAL IN SITU GEL OF PREDNISOLONE SODIUM PHOSPHATE FOR OCULAR DRUG DELIVERY

Objective: The main purpose of the study was to develop niosomal in situ gel of prednisolone sodium phosphate (PSP) with increased bioavailability (enhanced permeation) and sustained action (drug retention at the target site).&#x0D; Methods: Using different ratios of span 60 and cholesterol (chol), niosomes were prepared by thin film hydration method and optimized by evaluating different parameters like drug content, entrapment efficiency, particle size and in vitro drug diffusion study. The niosomal pellets were further incorporated in in situ gel, prepared by the cold method and further optimized by parameters like gelling parameters, mucoadhesive strength and in vitro, in vivo drug release study.&#x0D; Results: The optimized niosomal formulation containing span 60 and chol in equal proportion (1:1) showed better drug content (DC) i.e. 86.3±0.39% and entrapment efficiency (EE) i.e. 83.4±0.22 with vesicle size of 465±0.24 nm. The in vitro drug diffusion study indicated t90 value of 490 min thus proving sustained action of the formulation. The optimized in situ gel containing poloxamer 407 (P407) and poloxamer 188 (P188) in the ratio of 1:2.7 showed gelation temperature at 37 ⁰C (physiological temperature of the body) and t90 value of 10 h thus depicting sustained action. The increased area under curve (AUC) value by 1.75 folds proved increased bioavailability of the drug.&#x0D; Conclusion: Thus sustained drug delivery with increased bioavailability was designed for prednisolone sodium phosphate for the treatment of ocular inflammation.

Ophthalmic medication price variation across the United States: Anti-inflammatory medications.

Background:Cost-related nonadherence to medication can impact ophthalmic treatment outcomes. We aimed to determine whether medication prices vary between US cities and between different types of pharmacies within one city.Methods:We conducted a phone survey of eight nationwide and five independent pharmacies in five cities across the United States: Boston, Massachusetts; Charlotte, North Carolina; Denver, Colorado; Detroit, Michigan; and Seattle, Washington. A researcher called each pharmacy asking for price without insurance for four common anti-inflammatory ophthalmic medications: prednisolone acetate, prednisolone sodium phosphate, difluprednate (Durezol™), and loteprednol etabonate (Lotemax™).Results:Prednisolone sodium phosphate price could only be obtained by a small subset of pharmacies (45.2%) and was excluded from additional analysis; however, preliminary data demonstrated lower cost of prednisolone sodium phosphate over prednisolone acetate. Three-way analysis of variance revealed no interaction between pharmacy type (chain versus independent), city, and drug (F = 0.40, p = 0.92). A significant interaction was identified between pharmacy type and drug (F = 5.0, p = 0.008), but not city and pharmacy type (F = 0.66, p = 0.62) or city and drug (F = 0.27, p = 0.97). Average drug prices were lower at independent pharmacies compared with chain pharmacies for difluprednate (US$211.36 versus US$216.85, F = 1.09, p = 0.297) and significantly lower for loteprednol etabonate (US$255.49 versus US$274.86, F = 14.7, p < 0.001). Prednisolone acetate was cheaper at chain pharmacies, but not statistically significantly cheaper (US$48.82 versus US$51.61, F = 0.34, p = 0.559).Conclusions:Medication prices do not differ significantly between US cities. High variation of drug prices within the same city demonstrates how comparison shopping can provide cost savings for patients and may reduce cost-related nonadherence.

The availability of drug by liposomal drug delivery

SummaryLately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied. However, drug release in the tumor seems more extended than in the other tissues and the non-encapsulated drug concentration decreases more slowly in the tumor than in the liver and spleen. The spleen shows a high affinity for the uptake of encapsulated drug as well as the release of drug from the liposomes. Subsequently, released drug in the spleen, and possibly also in other tissues, is probably quickly redistributed towards the blood and other tissues. This also impairs the drug delivery effect of the liposomes. In contrast to the released drug in the central circulation, liver and spleen, the released drug concentration in the tumor remains at a fairly constant level likely due to the extended release kinetics from the liposomes. These extended release characteristics in the tumor most probably contribute to the beneficial effect. Nevertheless, it should be noted that larger released drug concentrations are formed in healthy tissues.

Combination Therapy of Prednisolone and Toceranib Phosphate in a Dog with Malignant Metastatic Insulinoma

Combination Therapy of Prednisolone and Toceranib Phosphate in a Dog with Malignant Metastatic Insulinoma

Influenza A/H3N2 virus infection in immunocompromised ferrets and emergence of antiviral resistance.

Influenza viruses can cause severe life threatening infections in high-risk patients, including young children, the elderly and patients with compromised immunity due to underlying medical conditions or immunosuppressive treatment. The impaired immunity of these patients causes prolonged virus infection and combined with antiviral treatment facilitates the emergence of viruses with resistance mutations. The diverse nature of their immune status makes them a challenging group to study the impact of influenza virus infection and the efficacy of antiviral therapy. Immunocompromised ferrets may represent a suitable animal model to assess influenza virus infection and antiviral treatment strategies in immunocompromised hosts. Here, ferrets were given a daily oral solution of mycophenolate mofetil, tacrolimus and prednisolone sodium phosphate to suppress their immune system. Groups of immunocompromised and immunocompetent ferrets were inoculated with an A/H3N2 influenza virus and were subsequently treated with Oseltamivir or left untreated. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was performed on the throat and nose specimens to study virus replication during the course of infection. All immunocompromised ferrets had prolonged presence of viral RNA and a higher total amount of virus shedding compared to the immunocompetent ferrets. Although Oseltamivir reduced the total amount of virus shedding from the nose and throat of treated ferrets, it also resulted in the emergence of the neuraminidase R292K resistance substitution in all these animals, as determined by mutation specific RT-PCR and next-generation sequencing. No additional mutations that could be associated with the emergence of the R292K resistance mutation were detected. The immunocompromised ferret model can be used to study A/H3N2 virus shedding and is a promising model to study new antiviral strategies and the emergence of antiviral resistance in immunocompromised hosts.