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Among various complications of end-stage liver disease, hepatorenal syndrome has the highest mortality. Patients with both end-stage liver disease and end-stage renal disease are candidates for combined liver-kidney transplantation. However, patients with cirrhosis with decompensation presenting in the form of hepatorenal syndrome, are also likely candidates for the procedure. Herein, we present a patient who underwent combined liver-kidney transplantation for hepatorenal syndrome. [ABSTRACT FROM AUTHOR]

De novo esophageal malignancy following liver transplantation is very rare. Esophageal squamous cell carcinoma following liver transplant is closely associated with history of alcohol intake and tobacco chewing. We report on a 45-year-old man, chronic tobacco chewer and alcoholic who underwent liver transplantation for alcoholic cirrhosis and developed esophageal squamous cell carcinoma 23 months following the procedure. He was treated surgically and has had a tumor-free survival after 34 months of regular follow-up. [ABSTRACT FROM AUTHOR]

Simple UV and third derivative spectrophotometric methods in methanol have been developed for the determination of fosinopril sodium in bulk drug and its pharmaceutical formulations. The simple UV spectrum of fosinopril sodium in methanol exhibits absorption maxima (λmax) at 208 nm, whereas in the third derivative spectrum the maxima occur at 217.4 nm and the minima at 223 nm. Both the methods were found to be simple, economical, accurate, reproducible and can be adopted in routine analysis of fosinopril sodium in bulk drug and in tablet dosage form. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the relationship between triptans (sumatriptan, rizatriptan, and zolmitriptan) and cardiovascular (CV) adverse events with data from the FDA Adverse Event Reporting System (FAERS). FAERS database was used to collect data on triptans from 1997 to 2023. Disproportionality methods were utilized to quantify triptan-associated CV events and to identify the potential risk. The reporting odds ratio was used to identify the risk signals. CV outcomes related to age, sex, clinical results, and other factors were also examined for triptans; 820 reports involving the triptans were recognized as CV adverse events out of total of 12 699 reports that were gathered from on FAERS database. Women reported more CV adverse events with rizatriptan and zolmitriptan as compared to men. The CV adverse event risk was highest among individuals aged 18-64. Clinical outcome analysis showed that sumatriptan carries a higher CV risk than rizatriptan and zolmitriptan, and most deaths and serious cases have been documented for sumatriptan. The patients prescribed sumatriptan or zolmitriptan were at a higher risk of reporting CV events for chest pain and chest discomfort, compared to rizatriptan. This finding may provide support for the clinical observation and risk evaluation of triptan treatment.

Norepinephrine-dopamine reputake inhibitors (NDRIs), including bupropion, methylphenidate, atomoxetine, and reboxetine, are commonly prescribed for psychiatric disorders such as narcolepsy, attention-deficit/hyperactivity disorder, and depression. Cardiovascular adverse events have been reported to the FDA despite their effectiveness. This pharmacovigilance study analyzed cardiovascular adverse events associated with NDRIs using the FDA Adverse Event Reporting System data from January 2004 to December 2021. A retrospective analysis of adverse event reports was conducted, employing time-trend analysis and disproportionality evaluation to assess cardiovascular risks. Bupropion had the greatest reported odds ratios (RORs) for tachycardia (ROR = 4.2, 95% CI: 4.0-4.4) and hypertension (ROR = 3.5, 95% CI: 3.3-3.7), while methylphenidate showed greater ROR for arrhythmias (ROR = 2.8, 95% CI: 2.6-3.0) and palpitations (ROR = 3.1, 95% CI: 2.9-3.3). Reboxetine had signals for palpitations (ROR = 3.0, 95% CI: 2.8-3.2) and myocardial infarction (ROR = 2.7, 95% CI: 2.5-2.9), whereas atomoxetine revealed signals for hypertension (ROR = 2.9, 95% CI: 2.7-3.1) and syncope (ROR = 2.5, 95% CI: 2.3-2.7). Time-trend analysis revealed temporal variability in the cardiovascular risks connected with NDRIs. Our research elucidates cardiovascular safety profiles for NDRIs, highlighting the necessity for continuous pharmacovigilance. The observed variations in adverse events emphasize the need for ongoing surveillance to mitigate potential cardiovascular risks and enhance patient safety and treatment outcomes., Competing Interests: The authors declare there are no competing interests.

The use of nanoparticles (NPs) has emerged as a potential tool for safe and effective drug delivery. In the present study, we developed small molecule P7C3-based NPs and tested its efficacy and toxicity along with the tissue specific aptamer-modified P7C3 NPs. The P7C3 NPs were prepared using poly (D, L-lactic-co-glycolic acid) carboxylic acid (PLGA-COOH) polymer, were conjugated with skeletal muscle-specific RNA aptamer (A01B P7C3 NPs) and characterized for its cytotoxicity, cellular uptake, and wound healing in vitro. The A01B P7C3 NPs demonstrated an encapsulation efficiency of 30.2 ± 2.6%, with the particle size 255.9 ± 4.3 nm, polydispersity index of 0.335 ± 0.05 and zeta potential of + 10.4 ± 1.8mV. The FTIR spectrum of P7C3 NPs displayed complete encapsulation of the drug in the NPs. The P7C3 NPs and A01B P7C3 NPs displayed sustained drug release in vitro for up to 6 days and qPCR analysis confirmed A01B aptamer binding to P7C3 NPs. The C2C12 cells viability assay displayed no cytotoxic effects of all 3 formulations at 48 and 72 h. In addition, the cellular uptake of A01B P7C3 NPs in C2C12 myoblasts demonstrated higher uptake. In vitro assay mimicking wound healing showed improved wound closure with P7C3 NPs. In addition, P7C3 NPs significantly decreased TNF-α induced NF-κB activity in the C2C12/NF-κB reporter cells after 24-hour treatment. The P7C3 NPs showed 3-4-fold higher efficacy compared to P7C3 solutions in both wound-closure and inflammation assays in C2C12 cells. Furthermore, the P7C3 NPs showed 3-4-fold higher efficacy in reducing the infarct size and protected mouse hearts from ex vivo ischemia-reperfusion injury. Overall, this study demonstrates the safe and effective delivery of P7C3 NPs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Intraperitoneal instillation of local anaesthetic agents alone or in combination with opioids, α2 agonists such as Dexmedetomidine have been found to reduce postoperative pain following laparoscopic cholecystectomy. The study was designed to compare the better drug among Bupivacaine alone and Bupivacaine with Dexmedetomidine with respect to their analgesic efficacy and safety profile. in patients undergoing laparoscopic cholecystectomy., Patients and Methods: The study was carried out on sixty patients of the American Society of Anaesthesiologists (ASA) physical status I-II of either sex with ages ranging from 18 to 60 years posted for elective laparoscopic cholecystectomy under General Anaesthesia, equally divided into two groups, randomly allocated to one of the Groups using the table of randomization. Group B received Intraperitoneal Bupivacaine 40 ml 0.25% +5 ml normal saline and Group BD received Intraperitoneal Bupivacaine 40 ml 0.25% + Dexmedetomidine1 μg/kg diluted in 5 ml Normal saline., Results: The mean heart rate and blood pressure (systolic, diastolic and mean) readings were significantly lower in Group BD than in Group B. The mean duration of analgesia in our study was longer in Group BD (7.5 ± 0.73 hours) when compared to Group B (5.9 ± 0.55 hours) with p-value & 0.0001 and CI 1.27 to 1.9, which was statistically significant. However, the post-operative analgesic requirement (rescue/demand) in Group B was clinically earlier and statistically significant as compared to Group BD. Postoperative VAS score ≥3 was considered the benchmark for providing rescue analgesia in the form of injection of Diclofenac 75 mg IV. In our study, we observed the pain scores via VAS/NRS at 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h and 24 h postoperatively. A comparison of pain scores from 30 min to 10hrs postoperatively showed a significant difference in both Groups with Group B having significantly higher VAS scores and lower VAS scores with Group BD., Conclusions: Our study suggests that there is a shorter duration of action of 0.25% Bupivacaine alone as compared to 0.25% Bupivacaine + Dexmedetomidine. Since the laparoscope is still inside the abdominal cavity the drugs are easy to administer with no adverse effects and with a good safety profile because of the visualization of drug deposition in the right place. Intraperitoneal instillation of Bupivacaine with Dexmedetomidine for postoperative analgesia was very promising as a part of multimodal analgesia in laparoscopic cholecystectomy., (Copyright © 2024 Copyright: © 2024 Journal of Minimal Access Surgery.)

Raloxifene (RLX), a biopharmaceutical classification system (BCS) class II drug, is a selective estrogen receptor modulator (SERM) having an estrogenic effect on the bone and an antiestrogenic effect on the endometrium and breast. Low solubility, high permeability, high metabolism, and low bioavailability are the characteristics of raloxifene. Although 60% is absorbed orally, raloxifene shows extremely poor bioavailability (2%) owing to its low solubility and extensive (>90%) intestinal/hepatic first-pass metabolism. Hence, it becomes important to increase the solubility of raloxifene to enhance its bioavailability. In this study, raloxifene nanostructured lipid carriers (RNLCs) were prepared using the melt dispersion ultrasonication method. The prepared RNLCs were characterized, and the in vitro studies were carried out in the human epithelial breast cancer cell line (MCF-7). The RNLCs had a size of 114.8 ± 0.98 nm and a zeta potential of +9.21 ± 0.58 mV. Transmission electron microscopy (TEM) images showed particle size ranging from 65 to 120 nm. With an entrapment efficiency of 75.04% ± 2.75%, the RNLCs showed sustained release over 7 days compared with the raloxifene drug solution. The prepared RNLCs were successfully taken up by the MCF-7 cells in a time-dependent manner, and the RNLCs showed increased cell cytotoxicity compared with the raloxifene drug. Using the parallel artificial membrane permeability assay (PAMPA), the permeability rate for raloxifene solution was calculated to be 8 × 10 -6 cm/s, and for the RNLCs, it was calculated to be 17.8 × 10 -6 cm/s. Hence, from the permeability rate calculated, we could conclude that raloxifene, when formulated as nanostructured lipid carriers, showed increased permeability. Overall, the prepared RNLCs were found to be superior to the raloxifene drug as such.

Age-related macular degeneration (AMD), a multifactorial age-related retinal hypoxic disorder resulting in irreversible loss of vision, is the foremost cause of blindness in the United States. Current treatment strategies involve multiple intraocular injections of antivascular endothelial growth factor (VEGF) agents into the vitreous of eye. In addition to the challenges of drug localization and targeted delivery, the need of frequent injections into the eye raises patient compliance issues, and thus call for development of sustained drug delivery systems. In this study, a sustained drug delivery system was prepared by loading an antihypoxia-induced factor (HIF) agent, honokiol (HON), into methoxy poly (ethylene glycol) polycaprolactone (MPEG-PCL) polymer. These HON-MPEG-PCL micelles were characterized by evaluating size, ζ potential, in vitro drug release profile, and morphology by transmission electron microscopy. The cytotoxic nature of developed micelles was assessed on human retinal pigment epithelial cell line (ARPE-19) cells by cytotoxicity assay. The cellular uptake and HIF and VEGF expression levels were determined in in vitro settings. Micelles formed had a particle size of 30.8 ± 0.8 nm with the poly dispersity index of 0.19 ± 0.0004 and ζ potential was found to be -5.46 ± 0.49 mv. Entrapment efficiency was calculated to be 64 ± 0.135%. In vitro drug release showed sustained release of drug from the formulation. Result from in vitro cytotoxicity study confirmed noncytotoxic nature of HON-MPEG-PCL micelles compared to HON drug solution. Furthermore, enzyme-linked immunosorbent assay studies performed showed the periodic downregulation of HIF and VEGF, which are major growth factors involved in underlying mechanism of AMD. The results showed successful development of HON-MPEG-PCL micelles, which may be useful for the effective treatment of AMD.

Background: A great array of nitrogen-containing heterocyclic rings were being extensively explored for their functional versatility in the field of medicine, especially in anticancer research. 1,3,4- thiadiazole is one of such heterocyclic rings with promising anticancer activity against several cancer cell lines, inhibiting diverse biological targets., Introduction: The 1,3,4-thiadiazole, when equipped with other heterocyclic scaffolds, has displayed enhanced anticancer properties. The thiourea, benzothiazole, imidazo[2,1,b][1,3,4]-thiadiazoles are such potential scaffolds with promising anticancer activity., Methods: A new series of 5-substituted-1,3,4-thiadiazoles linked with phenyl thiourea, benzothiazole and 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized and tested for invitro anticancer activity on various cancer cell lines., Results: The National Cancer Institute's preliminary anticancer screening results showed compounds 4b and 5b having potent antileukemic activity. Compound 4b selectively showed 32 percent lethality on Human Leukemia-60 cell line. The docking studies of the derivatives on aromatase enzyme (Protein Data Bank: 3S7S) have shown reversible interactions at the active site with good docking scores comparable to Letrozole and Exemestane. Furthermore, the selected derivatives were tested for anticancer activity on HeLa cell line based on the molecular docking studies., Conclusion: Compounds 4b and 5b showed effective inhibition equivalent to Letrozole. These preliminary biological screening studies have given positive anticancer activity for these new classes of derivatives. An additional research study like the mechanism of action of the anticancer activity of this new class of compounds is necessary. These groundwork studies illuminate a future pathway for research of this class of compounds enabling the discovery of potent antitumor agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Age-related macular degeneration, precisely neovascular form, is the leading cause of vision loss and the key treatment includes intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents. A method to increase local concentration of drug at posterior segment of the eye and to reduce the frequency of intravitreal injections is an unmet need. Resveratrol, a naturally occurring antioxidant and anti-inflammatory polyphenol, was loaded in PLGA polymeric nanoparticles to study their sustained release property and effectiveness in reducing expression of VEGF protein in vitro. Nanoparticles were characterized using FTIR, DSC, size, encapsulation efficiency, TEM, and in vitro drug release studies. Using MTT assay, the cytotoxicity of formulation was evaluated on ARPE-19 cells. The cellular uptake and VEGF expression levels were also evaluated in in vitro settings. The optimized formulation had a particle size of 102.7 nm with - 47.30 mV of zeta potential. Entrapment efficiency was found to be 65.21%. The cell viability results suggested compatibility of developed formulation. Cellular uptake and VEGF expression levels for the formulated nanoparticles specified that the developed formulation showed potential cellular uptake and had displayed anti-angiogenic property by inhibiting VEGF expression in vitro. The results showed successful development of resveratrol-loaded nanoparticles which may be used for neovascular AMD treatment alone or in combination with anti-VEGF agents.

Pathologic posterior neovascularization of eye is a major cause of irreversible vision loss and limitations of therapeutics to be successfully delivered to back of the eye has been a main obstacle for its effective treatment. Current pharmacological treatment using anti-VEGF agents being delivered intravitreally are effective but complicated due to anatomical and physiological barriers, as well as administration of high and frequent doses. With expanding horizons of nanotechnology, it can be possible to formulate promising nanoscale delivery system to improve penetration and sustained the release of therapeutic in posterior segment of the eye. Taking into consideration advances in the field of nanoscale delivery systems, this special report focuses on emerging strategies and their applications for treatment of posterior ocular neovascularization.

Anti-vascular endothelial growth factor agents have been widely used to treat several eye diseases including age-related macular degeneration (AMD). An approach to maximize the local concentration of drug at the target site and minimize systemic exposure is to be sought. Sunitinib malate, a multiple receptor tyrosine kinase inhibitor was encapsulated in poly(lactic-co-glycolic acid) nanoparticles to impart sustained release. The residence time in vitreal fluid was further increased by incorporating nanoparticles in thermo-reversible gel. Nanoparticles were characterized using TEM, DSC, FTIR, and in vitro drug release profile. The cytotoxicity of the formulation was assessed on ARPE-19 cells using the MTT assay. The cellular uptake, wound scratch assay, and VEGF expression levels were determined in in vitro settings. The optimized formulation had a particle size of 164.5 nm and zeta potential of - 18.27 mV. The entrapment efficiency of 72.0% ± 3.5% and percent drug loading of 9.1 ± 0.7% were achieved. The viability of ARPE-19 cells was greater than 90% for gel loaded, as such and blank nanoparticles at 10 μM and 20 μM concentration tested, whereas for drug solution viability was found to be 83% and 71% respectively at above concentration. The cell viability results suggest the compatibility of the developed formulation. Evaluation of cellular uptake, wound scratch assay, and VEGF expression levels for the developed formulations indicated that the formulation had higher uptake, superior anti-angiogenic potential, and prolonged inhibition of VEGF activity compared with drug solution. The results showed successful development of sunitinib-loaded nanoparticle-based thermo-reversible gel which may be used for the treatment of neovascular AMD.

Glucocorticoids, such as fluticasone propionate (FP), are used for the treatment of inflammation and alleviation of nasal symptoms and allergies, and as an antipruritic. However, both short- and long-term therapeutic use of glucocorticoids can lead to muscle weakness and atrophy. In the present study, we evaluated the feasibility of the nanodelivery of FP with poly(dl-lactide-co-glycolide) (PLGA) and tested in vitro function. FP-loaded PLGA nanoparticles were prepared via nanoprecipitation and morphological characteristics were studied via scanning electron microscopy. FP-loaded nanoparticles demonstrated an encapsulation efficiency of 68.6% ± 0.5% with a drug loading capacity of 4.6% ± 0.04%, were 128.8 ± 0.6 nm in diameter with a polydispersity index of 0.07 ± 0.008, and displayed a zeta potential of -19.4 ± 0.7. A sustained in vitro drug release pattern was observed for up to 7 days. The use of fluticasone nanoparticle decreased lipopolysaccharide (LPS)-induced lactate dehydrogenase release compared with LPS alone in C2C12 treated cells. FP also decreased expression of LPS-induced inflammatory genes in C2C12 treated cells as compared with LPS alone. Taken together, the present study demonstrates in vitro feasibility of PLGA-FP nanoparticle delivery to the skeletal muscle cells, which may be beneficial for treating inflammation.

Micro- (MPs) and nanoparticles (NPs) have been recently studied for their application in ophthalmic drug delivery. These drug delivery systems are able to circumvent the ocular barriers that currently limit the efficacy of conventional treatments, as well as provide a more sustained release of drug, reducing the frequency of administration and increasing patient compliance. This review summarizes the recent trends in ophthalmic research from conventional treatment to the utilization of MPs and NPs as drug carriers.

Objective: Polymeric nanoparticles (NPs) containing doxorubicin (DOX) were prepared for the inhibition of hypoxia-induced factor 1α (HIF-1α)., Significance: HIF-1α is responsible for the upregulation of several angiogenic factors, including vascular endothelial growth factor (VEGF). DOX inhibits HIF-1α but is highly toxic. By encapsulating DOX in NPs, drug delivery will be sustained and toxicity will be reduced without limiting efficacy., Methods: DOX NPs were prepared using both polylactic coglycolic acid (PLGA) and chitosan. PLGA NPs were prepared via nanoprecipitation (NPC) and single and double emulsion diffusion (SE; DE). Chitosan NPs were formulated using ionic gelation (IG), and complex coacervation (CC). Size, polydispersity index (PDI), and zeta potential (ZP) were determined via dynamic light scattering (DLS) (n = 3). The encapsulation efficiency (EE), drug loading capacity (DLC) (n = 3) and in vitro drug release profiles (IVR) at 37 °C (n = 4) were analyzed via spectroscopy at 480 nm (λ max ). The cytotoxicity of each formulation as well as free DOX solution in ARPE-19 cells was determined via MTT assay after 24 h (n = 3). HIF-1α and VEGF inhibition in ARPE-19 cells were measured via ELISA (n = 3)., Results: The results were consistent with the hypothesis; the NP formulations decreased HIF-1α and VEGF-A expression in ARPE-19 cells with reduced cytotoxicity. SE, DE, and CC demonstrated low ZP as well as the most rapid drug release of the tested formulations. FTIR confirmed the presence of DOX on the SE NP surface, indicating instability., Conclusions: SE, DE, and CC destabilized. NPC was the most efficient formulation for the nanodelivery of DOX for AMD.

Despite all the research aiming to treat ocular diseases, age-related macular degeneration (AMD) remains one of the serious diseases worldwide, which needs to be treated. Neovascularization is a key factor in AMD and thus antiangiogenic therapy is beneficial in reducing the development of new abnormal blood vessels. Axitinib, multireceptor tyrosine kinase inhibitor, is a small molecule that works by blocking vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR) responsible for developing neovascularization. The goal of this study is to develop a sustained release formulation of axitinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles to minimize frequent administration of the drug by intravitreal injection. The nanoparticles were characterized for particle size and zeta potential, as well as using differential scanning calorimetry, transmission electrode microscope, and in vitro drug release profile. The cytotoxicity of the formulation was evaluated on human retinal pigmented epithelium ARPE19 cells by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide salt] assay. The cellular uptake, antimigration assay, and vascular endothelial growth factor (VEGF) expression levels were found out in vitro using cells. The optimized formulation was 131.33 ± 31.20 nm in size with -4.63 ± 0.76 mV zeta potential. Entrapment efficiency was found to be 87.9% ± 2.7%. The cytotoxicity of ARPE19 cells was <12% for nanoparticles suggesting the in vitro compatibility at 10 μM concentration of drug. Cellular uptake, antimigration assay, and VEGF expression levels for the nanoparticles suggested greater uptake, significant antiangiogenic potential, and inhibition of VEGF activity. The results showed successful development of axitinib-loaded PLGA nanoparticles as an alternative potential treatment for AMD.

Background: Humanin is a novel neuronal peptide that has displayed potential in the treatment of Alzheimer's Disease through the suppression of inflammatory IL-6 cytokine receptors. Such receptors are found throughout the body, including the eye, suggesting its other potential applications. Age-related Macular Degeneration (AMD) is the leading cause of blindness in the developing world. There is no cure for this disease, and current treatments have several negative side effects associated with them, making finding other treatment options desirable., Objective: In this study, the potential applications in treating AMD for a more potent humanin derivative, AGA-HNG, were studied., Methods: AGA-HNG was synthesized and encapsulated in chitosan Nanoparticles (NPs), which were then characterized for their size, Encapsulation Efficiency (EE), and drug release. Their ability to suppress VEGF secretion and protect against oxidative apoptosis was studied in vitro using ARPE-19 cells. The chitosan NPs exhibited similar anti-VEGF properties and oxidative protection as the free protein while exhibiting superior pharmaceutical characteristics including biocompatibility and drug release., Results: Drug-loaded NPs exhibited a radius of 346nm with desirable pharmacokinetic properties including a stable surface charge (19.5 ± 3.7 mV) and steady drug release capacity. AGA-HNG showed great promise in mediating apoptosis in hypoxic cells. They were also able to significantly reduce VEGF expression in vitro with reduced cellular toxicity compared to the free drug., Conclusion: The ability of this drug delivery system to reduce retinal apoptosis with desirable pharmacokinetic and biocompatible properties makes this a promising therapeutic option for AMD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The current treatment of ocular neovascularization requires frequent intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents that cause severe side effects., Objective: The purpose of this study is to prepare and characterize a novel nanoscale delivery system of apatinib for ocular neovascularization., Methods: The optimized formulation showed a particle size of 135.04 nm, polydispersity index (PDI) of 0.28 ± 0.07, encapsulation efficiency (EE) of 65.92%, zeta potential (ZP) of -23.70 ± 8.69 mV, and pH of 6.49 ± 0.20. In vitro release was carried out to demonstrate a 3.13-fold increase in the sustainability of apatinib-loaded nanoparticles versus free apatinib solution., Result: Cell viability and VEGFA and VEGFR2 expression were analyzed in animal retinal pigment epithelial (ARPE-19) cells., Conclusion: The results confirmed the hypothesis that apatinib nanoparticles decreased toxicity (1.36 ± 0.74 fold) and efficient VEGF inhibition (3.51 ± 0.02 fold) via VEGFR2 mediation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the United States, affecting approximately 11 million patients. AMD is caused primarily by an upregulation of vascular endothelial growth factor (VEGF). In recent years, aflibercept injections have been used to combat VEGF. However, this treatment requires frequent intravitreal injections, leading to low patient compliance and several adverse side effects including scarring, increased intraocular pressure, and retinal detachment. Polymeric nanoparticles have demonstrated the ability to deliver a sustained release of drug, thereby reducing the necessary injection frequency. Aflibercept (AFL) was encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) via double emulsion diffusion. Scanning electron microscopy showed the NPs were spherical and dynamic light scattering demonstrated that they were uniformly distributed (PDI < 1). The encapsulation efficiency and drug loading were 75.76% and 7.76% respectively. In vitro release studies showed a sustained release of drug; 75% of drug was released by the NPs in seven days compared to the full payload released in 24 h by the AFL solution. Future ocular in vivo studies are needed to confirm the biological effects of the NPs. Preliminary studies of the proposed aflibercept NPs demonstrated high encapsulation efficiency, a sustained drug release profile, and ideal physical characteristics for AMD treatment. This drug delivery system is an excellent candidate for further characterization using an ocular neovascularization in vivo model.

The physicochemical and biological properties of active pharmaceutical ingredients (APIs) are greatly affected by their salt forms. The choice of a particular salt formulation is based on numerous factors such as API chemistry, intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. However, the incorrect salt form can have the opposite effect, and can be quite detrimental for overall drug development. This review summarizes several criteria for choosing the appropriate salt forms, along with the effects of salt forms on the pharmaceutical properties of APIs. In addition to a comprehensive review of the selection criteria, this review also gives a brief historic perspective of the salt selection processes.

Glucocorticoids are utilized for their anti-inflammatory properties in the skeletal muscle and arthritis. However, the major drawback of use of glucocorticoids is that it leads to senescence and toxicity. Therefore, based on the idea that decreasing particle size allows for increased surface area and bioavailability of the drug, in the present study, we hypothesized that nanodelivery of dexamethasone will offer increased efficacy and decreased toxicity. The dexamethasone-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared using nanoprecipitation method. The morphological characteristics of the nanoparticles were studied under scanning electron microscope. The particle size of nanoparticles was 217.5 ± 19.99 nm with polydispersity index of 0.14 ± 0.07. The nanoparticles encapsulation efficiency was 34.57% ± 1.99% with in vitro drug release profile exhibiting a sustained release pattern over 10 days. We identified improved skeletal muscle myoblast performance with improved closure of the wound along with increased cell viability at 10 nmol/L nano-dexamethasone-PLGA. However, dexamethasone solution (1 μmol/L) was injurious to cells because the migration efficiency was decreased. In addition, the use of dexamethasone nanoparticles decreased lipopolysaccharide-induced lactate dehydrogenase release compared with dexamethasone solution. Taken together, the present study clearly demonstrates that delivery of PLGA-dexamethasone nanoparticles to the skeletal muscle cells is beneficial for treating inflammation and skeletal muscle function.

An intrahepatic Arterioportal Fistula Refers (APF) to abnormal shunt or fistulous connection between the portal venous system and a hepatic arterial system within the liver. Here, we present a case of portal vein thrombosis with APF in post-transplant liver, developed 2 years and 6 months after transplantation. The condition was diagnosed by Triphasic CT angiography. In this case report we have discussed various causes and pathophysiology of APF with its imaging findings.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the US affecting millions yearly. It is characterized by intraocular neovascularization, inflammation and retinal damage which can be ameliorated through intraocular injections of glucocorticoids. However, the complications that arise from repetitive injections as well as the difficulty posed by targeting the posterior segment of the eye make this interesting territory for the development of novel drug delivery systems (DDS). In the present study, we described the development of a DDS composed of triamcinolone acetonide-encapsulated PEGylated PLGA nanoparticles (NP) incorporated into PLGA-PEG-PLGA thermoreversible gel and its use against VEGF expression characteristic of AMD. We found that the NP with mean size of 208 ± 1.0 nm showed uniform size distribution and exhibited sustained release of the drug. We also demonstrated that the polymer can be injected as a solution and transition to a gel phase based on the biological temperature of the eye. Additionally, the proposed DDS was non-cytotoxic to ARPE-19 cells and significantly reduced VEGF expression by 43.5 ± 3.9% as compared to a 1.53 ± 11.1% reduction with triamcinolone. These results suggest the proposed DDS will contribute to the development of novel therapeutic strategies for AMD.

Objectives: To prepare and characterize in vitro a novel brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles (NPs) for the treatment of brain cancer., Methods: Doxorubicin-loaded NPs were prepared by the nanoprecipitation method using PLGA-COOH (dl-lactide-co-glycolide). The NPs were coated with a glutathione-PEG conjugate (PEG-GSH) in order to target delivery to the brain. The NPs were characterized via in vitro studies to determine particle size, drug release, cellular uptake, immunofluorescence study, cytotoxic assay, and in vitro blood-brain barrier (BBB) assay., Results: The NPs showed a particle size suitable for BBB permeation (particle size around 200 nm). The in vitro release profile of the NPs exhibited no initial burst release and showed sustained drug release for up to 96 h. The immunofluorescence study showed the glutathione coating does not interfere with the drug release. Furthermore, in vitro BBB Transwell™ study showed significantly higher permeation of the doxorubicin-loaded NPs compared with the free doxorubicin solution through the coculture of rat brain endothelial (RBE4) and C6 astrocytoma cells (p < 0.05)., Conclusions: We conclude that the initial in vitro characterization of the NPs demonstrates potential in delivering doxorubicin to cancer cells with possible future application in targeting brain cancers in vivo.

We report anticarcinogenic effects of suicide gene therapy that relies on the use of resveratrol-responsive CArG elements from the Egr-1 promoter to induce GADD45α. In A549 lung cancer cells, endogenous GADD45α was not induced upon resveratrol treatment. Therefore, induction of exogenous GADD45α resulted in growth inhibition. Resveratrol transiently induced Egr-1 through ERK/JNK-ElK-1. Hence, we cloned natural or synthetic Egr-1 promoter upstream of GADD45α cDNA to create a suicide gene therapy vector. Since natural promoter may have antagonized effects, we tested synthetic promoter that contains either five, six or nine repeats of CArG elements essential in the Egr-1 promoter to drive the expression of GADD45α upon resveratrol treatment. Further analysis confirmed that both synthetic promoter and natural Egr-1 promoter were able to "turn on" the expression of GADD45α when combined with resveratrol, and subsequently led to suppression of cell proliferation and apoptosis.

Gliomas are some of the most aggressive types of cancers but the blood-brain barrier acts as an obstacle to therapeutic intervention in brain-related diseases. The blood-brain barrier blocks the permeation of potentially toxic compounds into neural tissue through the interactions of brain endothelial cells with glial cells (astrocytes and pericytes) which induce the formation of tight junctions in endothelial cells lining the blood capillaries. In the present study, we characterize a glutathione-coated docetaxel-loaded PEG-PLGA nanoparticle, show its in vitro drug release data along with cytotoxicity data in C6 and RG2 cells, and investigate its trans-blood-brain barrier permeation through the establishment of a Transwell cellular co-culture. We show that the docetaxel-loaded nanoparticle's size enables its trans-blood-brain barrier permeation; the nanoparticle exhibits a steady, sustained release of docetaxel; the drug is able to induce cell death in glioma models; and the glutathione-coated nanoparticle is able to permeate through the Transwell in vitro blood-brain barrier model.

Parkinson's disease (PD) is an age-related neurodegenerative disease affecting movement. To date, there are no currently available therapeutic agents which can prevent or slow disease progression. Here, we evaluated an azobenzene derivative, methyl yellow (MY), as a potential drug scaffold for PD; its inhibitory activity toward monoamine oxidase B (MAO-B) as well as drug-like properties were investigated. The inhibitory effect of MY on MAO activity was determined by a MAO enzyme inhibition assay. In addition, the in vitro properties of MY as a drug candidate (e.g., blood-brain barrier (BBB) permeability, serum albumin binding, drug efflux through P-glycoprotein (P-gp), drug metabolism by P450, and mitochondrial toxicity) were examined. In vivo effectiveness of MY was also evaluated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonian mouse model. MY selectively inhibited MAO-B in a dose-dependent and reversible manner. MY was BBB-permeable, bound relatively weakly to serum albumin, was an unlikely substrate for both systems of P-gp and P450, and did not cause mitochondrial toxicity. Results from the MPTP Parkinsonian mouse model indicated that, upon treatment with MY, neurotoxicity induced by MPTP was mitigated. Investigations of MY demonstrate its inhibitory activity toward MAO-B, compliant properties for drug consideration, and its neuroprotective capability in the MPTP Parkinsonian mouse model. These data provide insights into potential use, optimization, and new design of azobenzene derivatives for PD treatment., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Long-term exposure to arsenic, an environmental contaminant, leads to increased risks of cancers. In the present study, we investigated the sequential regulation of Elk-1 and Egr-1 on As3+-induced GADD45α, an effector of G2/M checkpoint. We found that As3+ transcriptionally induced both Elk-1 and Egr-1, and NF-κB binding site was necessary for As3+-induced Egr-1 promoter activity. However, specific inhibition of JNK, ERK, and Elk-1 inhibited Egr-1 induction. Furthermore, silencing of Egr-1 downregulated As3+-induced expression of GADD45α and ChIP assay confirmed the direct binding of Egr-1 to GADD45α promoter. Taken together, our data indicated that the increase of GADD45α in response to As3+ was mediated sequentially by Elk-1 and Egr-1.

Background: Choleliathisis, in patients with renal transplantation, carries high risk of complications. We, at our institute, perform prophylactic cholecystectomy for aymptomatic gallstones in patients with renal transplantation., Aim: To present our experience of laparoscopic cholecystectomy in patients with kidney transplantation., Subjects and Methods: Data, in the form of, demographics, medications used, indication of transplantation, manifestation of gallstones, operative findings, duration of hospitalization, and post-operative complications were obtained and results were analyzed. briefly summarize details of statistics including the soft ware used., Results: Twenty patients have undergone laparoscopic cholecystectomy. All patients were admitted on the day of surgery. Immunosuppression regimen was not modified during hospitalization. Indications of cholecystectomy were biliary colic (8/20 patients, 40%), acute cholecystitis (8/20 patients, 40%), asymptomatic gallstones (3/20 patients, 15%), and obstructive jaundice (1/20 patients, 5%). Laparoscopic cholecystectomy was uneventful in all cases. Post-operative complications were nausea and vomiting in two patients and port site infection in one patient., Conclusion: Laparoscopic cholecystectomy, when performed in renal transplant patients, is a safe procedure.

A potential means of pharmacological management of ischemic stroke is rapid intervention using potent neuroprotective agents. Thyroid hormone (T3) has been shown to protect against ischemic damage in middle cerebral artery occlusion (MCAO) model of ischemic brain stroke. While thyroid hormone is permeable across the blood-brain barrier, we hypothesized that efficacy of thyroid hormone in ischemic brain stroke can be enhanced by encapsulation in nanoparticulate delivery vehicles. We tested our hypothesis by generating poly-(lactide-co-glycolide)-polyethyleneglycol (PLGA-b-PEG) nanoparticles that are either coated with glutathione or are not coated. We have previously reported that glutathione coating of PLGA-PEG nanoparticles is an efficient means of brain targeted drug delivery. Encapsulation of T3 in PLGA-PEG delivery vehicle resulted in particles that were in the nano range and exhibited a zeta potential of -6.51 mV (uncoated) or -1.70 mV (coated). We observed that both glutathione-coated and uncoated nanoparticles are taken up in cells wherein they stimulated the expression of thyroid hormone response element driven reporter robustly. In MCAO model of ischemic stroke, significant benefit of administering T3 in nanoparticulate form was observed over injection of a T3 solution. A 34 % decrease in tissue infarction and a 59 % decrease in brain edema were seen upon administration of T3 solution in MCAO stroke model. Corresponding measurements for uncoated T3 nanoparticles were 51 % and 68 %, whereas for the glutathione coated were 58 % and 75 %. Our study demonstrates that using nanoparticle formulations can significantly improve the efficacy of neuroprotective drugs in ischemic brain stroke.

The purpose of this study is to investigate a thermoreversible gel using Pluronic F-127 to deliver an activin receptor-like kinase 5 (ALK-5) inhibitor SB-505124 in glaucoma filtration surgery (GFS). The gel was characterized for in vitro drug release and viscosity studies. Cytotoxicity of Pluronic F-127 was examined by MTT assay using cultured rabbit subconjunctival fibroblasts. In addition, Pluronic F-127 gel (18% w/v) containing 5 mg of SB-505124 was applied at the surgical site in an in vivo rabbit GFS model. In the in vitro viscosity study, the gel showed a change in viscosity (from 1000 cps to 45,000 cps) from low temperature (10°C) to body temperature (37°C). The in vitro drug release study demonstrated 100% drug release within 12 h. The gel did not show cytotoxicity to the cultured rabbit subconjunctival cells by MTT assay. In the in vivo rabbit GFS model, the drug was successfully delivered by injection and no severe post-surgical complications were observed. A thermoreversible gel system with SB-505124 was successfully prepared and delivered for the rabbit GFS model, and it may provide a novel delivery system in GFS.

Paclitaxel is not effective for treatment of brain cancers because it cannot cross the blood-brain barrier (BBB) due to efflux by P-glycoprotein (P-gp). In this work, glutathione-coated poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) of paclitaxel were developed for brain targeting for treatment of brain cancers. P-gp ATPase assay was used to evaluate the NP as potential substrates. The NP showed a particle size suitable for BBB permeation (particle size around 200 nm) and higher cellular uptake of the NP was demonstrated in RG2 cells. The P-gp ATPase assay suggested that the NP were not substrate for P-gp and would not be effluxed by P-gp present in the BBB. The in vitro release profile of the NP exhibited no initial burst release and showed sustained drug release. The proposed coated NP showed significantly higher cytotoxicity in RG2 cells compared with uncoated NP (p ≤ 0.05). Tubulin immunofluorescent study showed higher cell death by the NP due to increased microtubule stabilization. In vivo brain uptake study in mice showed higher brain uptake of the NP containing coumarin-6 compared with solution. The proposed brain-targeted NP delivery of paclitaxel could be an effective treatment for the brain cancers.

Brain-targeted Tempol-loaded poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) conjugated with a transferrin antibody (OX 26) were developed using the nanoprecipitation method. These NPs may have utility in treating neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Central to these diseases is an increased production of reactive oxygen and nitrogen species which may take part in the development of these conditions. As proof of principle, the NPs were loaded with Tempol, a free radical scavenger that has been shown to be protective against oxidative insults. To enhance the delivery of NPs to the central nervous system (CNS), we conjugated the transferrin receptor antibody covalently to PLGA NPs using the NHS-PEG3500-Maleimide crosslinker. The NPs showed a particle size suitable for blood brain barrier (BBB) permeation (particle size 80-110 nm) and demonstrated a sustained drug release behavior. A high cellular uptake of antibody-conjugated NPs was demonstrated in RG2 rat glioma cells. The ability of the Tempol-loaded NPs to prevent cell death by resveratrol in RG2 cells was determined using the MTT assay. The conjugated NPs containing Tempol were more effective in preventing cell viability by resveratrol when compared with unconjugated NPs or free Tempol in solution. Our findings suggest that transferrin-conjugated NPs containing antioxidants may be useful in the treatment of neurodegenerative diseases.

Purpose: Transforming growth factor-β (TGF-β) activity has been implicated in subconjunctival scarring in eyes following glaucoma filtration surgery (GFS). The purpose of this study is to determine whether an inhibitor for activin receptor-like kinase (ALK) 5 (also known as TGF-β receptor type I) could suppress TGF-β activity and thereby promote filtering bleb survival after GFS in a rabbit model., Methods: An ALK-5 inhibitor, SB-505124, was used. A docking study was performed to investigate the interaction between the inhibitor and the receptor. Immunofluorescence for connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA) was performed in cultured rabbit subconjunctival fibroblasts. Immunoblotting for phosphorylated Smad2 (pSmad2), CTGF, and α-SMA was also performed. In an in vivo rabbit GFS model, SB-505124 was delivered in a lactose tablet during surgery. Eyes were examined by slit-lamp and intraocular pressure (IOP) was measured until the time of bleb failure or up to 28 days after surgery. Tissue sections on day 5 after surgery were histologically evaluated after staining with hematoxylin and eosin. The sections were also immunostained for CTGF and α-SMA. In addition, cell outgrowth from dissected subconjunctival tissues placed in a cell culture flask with media was investigated., Results: The docking study indicated hydrogen bond interactions between SB-505124 and amino acids His-283 and Ser-280 of ALK-5. Suppression of pSmad2, CTGF, and α-SMA by SB-505124 was observed in cultured fibroblasts. Filtering blebs in the GFS with SB-505124 group were maintained for more than 10 days, and the period of bleb survival was significantly longer than that in controls. IOP levels after surgery seemed to be related to bleb survival. Histologically, subconjunctival cell infiltration and scarring at the surgical site in the GFS with SB-505124 and mitomycin C (MMC) groups were much subsided compared to controls. Suppression of CTGF and α-SMA by SB-505124 was also observed by immunofluorescence. Cell outgrowth from explants dissected from eyes to which SB-505124 was applied during GFS was robust while outgrowth was poor from those treated with MMC., Conclusions: The ALK-5 inhibitor SB-505124 was efficacious both in vitro and in vivo in suppressing the TGF-β action. The inhibitor may provide a novel therapy for preventing ocular inflammation and scarring.

Purpose: To determine the major routes of buccal transport of lamotrigine and to examine the effects of pH on drug permeation., Methods: Transbuccal permeation of lamotrigine across porcine buccal mucosa was studied by using in-line Franz type diffusion cell at 37 degrees C. The permeability of lamotrigine was determined at pH 4.0 to 9.0. The permeability of unionized (Pu) and ionized (Pi) species of drug were calculated by fitting the data to a mathematical model. Lamotrigine was quantified by using the HPLC method., Results: The steady state flux increased linearly with increasing the donor concentration (r2 = 0.9639) at pH 7.4. The permeability coefficient and the partition coefficient of the drug increased with increasing the pH. The values of Pu and Pi were 0.7291 x 10(-5) cm/sec and 0.2500 x 10(-5) cm/sec, respectively. The observed permeability coefficients and the permeability coefficients calculated from mathematical model at various pH showed good linearity (r(2) = 0.9267). The total permeability coefficient increased with increasing the fraction of unionized form of the drug. CONCLUSION. Lamotrigine permeated through buccal mucosa by a passive diffusion process. The partition coefficient and pH dependency of drug permeability indicated that lamotrigine was transported mainly via the transcellular route by a partition mechanism.