Vivo Toxicity Research Articles

Health Concerns of Various Nanoparticles: A Review of Their in Vitro and in Vivo Toxicity.

Nanoparticles (NPs) are currently used in diagnosis and treatment of many human diseases, including autoimmune diseases and cancer. However, cytotoxic effects of NPs on normal cells and living organs is a severe limiting factor that hinders their use in clinic. In addition, diversity of NPs and their physico-chemical properties, including particle size, shape, surface area, dispersity and protein corona effects are considered as key factors that have a crucial impact on their safe or toxicological behaviors. Current studies on toxic effects of NPs are aimed to identify the targets and mechanisms of their side effects, with a focus on elucidating the patterns of NP transport, accumulation, degradation, and elimination, in both in vitro and in vitro models. NPs can enter the body through inhalation, skin and digestive routes. Consequently, there is a need for reliable information about effects of NPs on various organs in order to reveal their efficacy and impact on health. This review covers the existing knowledge base on the subject that hopefully prepares us better to address these challenges.

Comparative Photothermal Performance among Various Sub-Stoichiometric 2D Oxygen-Deficient Molybdenum Oxide Nanoflakes and In Vivo Toxicity.

The present study deals with photothermal therapy of solid tumors using different forms of oxygen-deficient sub-stoichiometric two-dimensional (2D) molybdenum oxide nanoflakes (α-MoO3-x ). Upon exfoliation of molybdenum oxide power using fine gridding followed by ultrasonication, bluish green molybdenum oxide (BG α-MoO3 ) was obtained. Oxygen vacancies in BG were generated upon irradiation with an intense xenon lamp. Irradiating the BG for 3 and 5 h, deep blue (B) and olive green (G) oxygen-deficient nanoflakes were obtained respectively. All exhibited high NIR absorption, making these nanomaterials suitable for photothermal therapy. All three forms were functionalized with polypyrrole (PPy@BG, PPy@B, PPy@G) to boost the photothermal stability and transduction efficiency. After functionalization and irradiation with 808 nm laser, the enhancement of temperature for BG, B, G was 50, 65, 52 °C respectively and the corresponding photothermal transduction efficiencies (PTE) were 29.32, 44.42 and 42.00 %. Each of the nanoflakes were found to be highly biocompatible and photostable both in vitro and in vivo. There was substantial decrease in the size of tumors after seven days of treatment on tumor-bearing experimental mice models.

Exposure to Inorganic Nanoparticles: Routes of Entry, Immune Response, Biodistribution and In Vitro/In Vivo Toxicity Evaluation.

The development of different kinds of nanoparticles, showing different physico-chemical properties, has fostered their large use in many fields, including medicine. As a consequence, inorganic nanoparticles (e.g., metals or semiconductors), have raised issues about their potential toxicity. The scientific community is investigating the toxicity mechanisms of these materials, in vitro and in vivo, in order to provide accurate references concerning their use. This review will give the readers a thorough exploration on the entry mechanisms of inorganic nanoparticles in the human body, such as titanium dioxide nanoparticles (TiO2NPs), silicon dioxide nanoparticles (SiO2NPs), zinc oxide nanoparticles (ZnONPs), silver nanoparticles (AgNPs), gold nanoparticles (AuNPs) and quantum dots (QDsNPs). In addition, biodistribution, the current trends and novelties of in vitro and in vivo toxicology studies will be discussed, with a particular focus on immune response.

In Vivo Toxicity Assessment of Occupational Components of the Carbon Nanotube Life Cycle To Provide Context to Potential Health Effects.

Pulmonary toxicity studies on carbon nanotubes focus primarily on as-produced materials and rarely are guided by a life cycle perspective or integration with exposure assessment. Understanding toxicity beyond the as-produced, or pure native material, is critical, due to modifications needed to overcome barriers to commercialization of applications. In the first series of studies, the toxicity of as-produced carbon nanotubes and their polymer-coated counterparts was evaluated in reference to exposure assessment, material characterization, and stability of the polymer coating in biological fluids. The second series of studies examined the toxicity of aerosols generated from sanding polymer-coated carbon-nanotube-embedded or neat composites. Postproduction modification by polymer coating did not enhance pulmonary injury, inflammation, and pathology or in vitro genotoxicity of as-produced carbon nanotubes, and for a particular coating, toxicity was significantly attenuated. The aerosols generated from sanding composites embedded with polymer-coated carbon nanotubes contained no evidence of free nanotubes. The percent weight incorporation of polymer-coated carbon nanotubes, 0.15% or 3% by mass, and composite matrix utilized altered the particle size distribution and, in certain circumstances, influenced acute in vivo toxicity. Our study provides perspective that, while the number of workers and consumers increases along the life cycle, toxicity and/or potential for exposure to the as-produced material may greatly diminish.

Accumulation of Arsenic Speciation and In Vivo Toxicity Following Oral Administration of a Chinese Patent Medicine Xiao-Er-Zhi-Bao-Wan in Rats.

Realgar-containing traditional Chinese medicines such as Xiao-Er-Zhi-Bao-Wan (XEZBW), have been widely used for thousands of years. However, events associated with arsenic-induced ailments have increasingly become a public concern. To address the toxicity of XEZBW, we studied the histopathology and blood biochemistry of rats exposed to XEZBW using technology like high-performance liquid chromatography-inductively coupled mass spectrometry to determine arsenic speciation. Our results demonstrated that dimethylarsinic acid (DMA) increased from 18.57 ± 7.45 to 22.74 ± 7.45 ng/g in rat kidney after oral administration for 7 and 14 days, which was 10-fold higher than the levels observed in controls. Trivalent arsenite As(III) showed a large increase on day 7 (26.99 ± 1.98 ng/g), followed by a slight decrease on day 14 (13.67 ± 6.48 ng/g). Total arsenic levels on day 7 (185.52 ± 24.56 ng/g) and day 14 (198.57 ± 26.26 ng/g) were nearly twofold higher than that in the control group (92.77 ± 14.98 ng/g). Histopathological analysis showed mild injury in the liver and kidney of rats subjected to oral administration of realgar for 14 days. As in the XEZBW groups, a mild injury in these organs was observed after administration for 14 days. This study inferred that the toxicity of arsenic was concentration- and time-dependent. The accumulation of DMA, a byproduct of choline metabolism, was responsible for inducing higher toxicity. Therefore, we concluded that measuring the levels of DMA, instead of total arsenic, might be more suitable for evaluating the toxicity of realgar-containing traditional Chinese medicines.

In Vivo Anticancer Efficacy and Toxicity Studies of a Novel Polymer Conjugate N-Acetyl Glucosamine (NAG)-PEG-Doxorubicin for Targeted Cancer Therapy.

A novel polymer-drug conjugate, polyethylene glycol-N-(acetyl)-glucosamine-doxorubicin (PEG-NAG-DOX) was evaluated in this study for its in vivo potential for treatment of tumours demonstrating improved efficacy and reduced toxicity. The proposed polymer-drug conjugate comprised of polyethylene glycol-maleimide (mPEG-MAL, 30000 Da) as a carrier, doxorubicin (DOX) as an anticancer drug and N-acetyl glucosamine (NAG) as a targeting moiety as well as penetration enhancer. Doxorubicin has a potent and promising anticancer activity; however, severe cardiotoxicity limits its application in cancer treatment. By modifying DOX in PEG-NAG-DOX prodrug conjugate, we aimed to eliminate this limitation. In vivo anticancer efficacy of the conjugate was evaluated using BDF mice-induced skin melanoma model by i.v. administration of DOX conjugates. Anticancer efficacy studies were done by comparing tumour volume, body weight, organ index and percent survival rate of the animals. Tumour suppression achieved by PEG-NAG-DOX at the cumulative dose of 7.5mg/kg was two-fold better than that achieved by DOX solution. Also, the survival rate for PEG-NAG-DOX conjugate was >70% as compared to <50% survival rate for DOX solution. In addition, toxicity studies and histopathological studies revealed that while maintaining its cytotoxicity towards tumour cells, PEG-NAG-DOX conjugate showed no toxicities to major organs. Therefore, PEG-NAG-DOX conjugate can be suggested as a desirable candidate for targeted cancer therapy.

Effect-Directed Analysis of Toxicants in Sediment with Combined Passive Dosing and in Vivo Toxicity Testing.

Identifying key toxicants in sediment is a great challenge, particularly if nontarget toxicants are involved. To identify the contaminants responsible for sediment toxicity to Chironomus dilutus in Guangzhou reach of the Pearl River in South China, passive dosing and in vivo toxicity testing were incorporated into effect-directed analysis (EDA) to account for bioavailability. Fractionation of sediment extracts was performed with gel permeation chromatography and reverse phase liquid chromatography sequentially. Polydimethylsiloxane served as passive dosing matrix for midge bioassays. The fractions showing abnormal enzymatic response were subject to a nontarget analysis, which screened out 15 candidate toxicants. The concentrations of the screened contaminants (log-based organic carbon normalized) in sediments of 10 sites were compared to sediment toxicity (10 and 20 day mortality and 10 day enzymatic response) to C. dilutus using correlation analyses. The results suggested that oxidative stress induced by cypermethrin, dimethomorph, pebulate and thenylchlor may have in part caused the observed toxicity to C. dilutus. The present study shows that EDA procedures coupled with passive dosing and in vivo toxicity testing can be effective in identifying sediment-bound toxicants, which may pose high risk to benthic organisms but are not routinely monitored and/or regulated. The findings of the present study highlight the importance of incorporating environmentally relevant approaches in assessing sediment heavily impacted by a multitude of contaminants, which is often the case in many developing countries.

Use of Physiologically Based Kinetic Modeling-Based Reverse Dosimetry to Predict in Vivo Toxicity from in Vitro Data.

The development of reliable nonanimal based testing strategies, such as in vitro bioassays, is the holy grail in current human safety testing of chemicals. However, the use of in vitro toxicity data in risk assessment is not straightforward. One of the main issues is that concentration-response curves from in vitro models need to be converted to in vivo dose-response curves. These dose-response curves are needed in toxicological risk assessment to obtain a point of departure to determine safe exposure levels for humans. Recent scientific developments enable this translation of in vitro concentration-response curves to in vivo dose-response curves using physiologically based kinetic (PBK) modeling-based reverse dosimetry. The present review provides an overview of the examples available in the literature on the prediction of in vivo toxicity using PBK modeling-based reverse dosimetry of in vitro toxicity data, showing that proofs-of-principle are available for toxicity end points ranging from developmental toxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity to DNA adduct formation. This review also discusses the promises and pitfalls, and the future perspectives of the approach. Since proofs-of-principle available so far have been provided for the prediction of toxicity in experimental animals, future research should focus on the use of in vitro toxicity data obtained in human models to predict the human situation using human PBK models. This would facilitate human- instead of experimental animal-based approaches in risk assessment.

Synthesis, Characterization, In Vivo Imaging, Hemolysis, and Toxicity of Hydrophilic Ag2S Near-Infrared Quantum Dots

Ag2S quantum dots (Qds) are a new type of near-infrared Qds and hold great potential for in vivo imaging. There is great demand for versatile, practical, and environmentally-friendly processes for formation of hydrophilic Ag2S Qds. The present study prepared hydrophilic Ag2S near-infrared Qds using a simple, easy, one-step method. The Qds were characterized by TEM, XRD, FT-IR, UV–Visible and PL spectroscopy and the effect of the reaction variables of time, temperature, precipitation agent feeding rate, and S:Ag molar ratio on the size and PL spectrum of the Ag2S Qds was investigated. The Qds exhibited near-infrared photoluminescence and good photostability, which was evaluated under different conditions. Cytotoxicity tests were carried out on human A549 and Hep G2 cell lines at concentrations of 6.25–200 µg/ml. MTT assay revealed that the Qds showed no significant toxicity. The effect of plasma and corona proteins on the hemolytic activity of Ag2S Qds in four concentrations was evaluated for rat and human red blood cells. In vivo imaging showed that the Ag2S Qds penetrated the body of mice with excellent brightness. The hydrophilic Ag2S Qds can be safely applied as near-infrared optical imaging probes for nanodiagnostics or in vivo imaging.

Molecular Mechanism of Crocin Induced Caspase Mediated MCF-7 Cell Death: In Vivo Toxicity Profiling and Ex Vivo Macrophage Activation.

Crocus sativus and its major constituent crocin are well established to have anti-cancer properties in breast cancer cells (MCF-7). However the role of C. sativus extract (CSE) and crocin on caspase signaling mediated MCF-7 cell death at molecular level is remains unclear. In this study, we tried to unravel role of CSE and crocin on caspase mediated MCF-7 cells death and their in vivo preclinical toxicity profiling and immune stimulatory effect. CSE extract was fractionated by HPLC and crocin was isolated and characterized by NMR, IR, and MS. MCF-7 cells were treated with both CSE and crocin and expression of Bcl-2 and Bax was assessed after 24 and 36 hours. Furthermore, caspase 3, caspase 8 and caspase 9 expression was determined by Western blotting after 24 hours of treatment. DNA fragmentation analysis was performed for genotoxicity of CSE and crocin in MCF-7 cells. The in vivo toxicity profile of CSE (300 mg/kg of b.wt) was investigated in normal Swiss albino mice. In addition, peritoneal macrophages were collected from crocin (1, 1.5 and 2 mg/kg body weight) treated mice and analyzed for ex vivo yeast phagocytosis. Immunoblot analysis revealed that there was time dependent decline in anti-apoptotic Bcl-2 with simultaneous upregulation of Bax in CSE and crocin treated MCF-7 cells. Further CSE and crocin treatment downregulated caspase 8 and 9 and cleaved the caspase 3 after 24 hours. Both CSE and crocin elicited considerable DNA damage in MCF-7 cells at each concentration tested. In vivo toxicity profile by histological studies revealed no observable histopathologic differences in the liver, kidney, spleen, lungs and heart in CSE treated and untreated groups. Crocin treatment elicited significant dose and time dependent ex vivo yeast phagocytosis by peritoneal macrophages. Our study delineated involvement of pro-apoptotic and caspase mediated MCF-7 cell death by CSE and crocin at the molecular level accompanied with extensive DNA damage. Further we found that normal swiss albino mice can tolerate the maximum dose of CSE. Crocin enhanced ex vivo macrophage yeast phagocytic ability.

In Vivo Biodistribution and Toxicity of Highly Soluble PEG-Coated Boron Nitride in Mice.

The boron nitride (BN) nanoparticles, as the structural analogues of graphene, are the potential biomedicine materials because of the excellent biocompatibility, but their solubility and biosafety are the biggest obstacle for the clinic application. Here, we first synthesized the highly soluble BN nanoparticles coated by PEG (BN-PEG) with smaller size (~10 nm), then studied their biodistribution in vivo through radioisotope (Tc99mO4−) labeling, and the results showed that BN-PEG nanoparticles mainly accumulated in the liver, lung, and spleen with the less uptake by the brain. Moreover, the pathological changes induced by BN-PEG could be significantly observed in the sections of the liver, lung, spleen, and heart, which can be also supported by the test of biochemical indexes in serum. More importantly, we first observed the biodistribution of BN-PEG in the heart tissues with high toxicity, which would give a warning about the cardiovascular disease, and provide some opportunities for the drug delivery and treatment.

Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity.

Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.

In Vivo Toxicity and Immunological Characterization of Detoxified Recombinant Botulinum Neurotoxin Type A.

A double-mutant E224A/E262A full-length botulinum neurotoxin (BoNT) Type A with structural similarity to native BoNT/A but lacking the endopeptidase activity provides an ideal surrogate for testing pharmacokinetics and immunochemical characteristics of BoNT. We determined lethality (LD50) of deactivated recombinant botulinum neurotoxin (drBoNT/A) to be 24.0μg by intraperitoneal route (i.p). The polypeptide drBoNT/A labeled with near infra-red dye 800 (NIR 800) was used to examine its distribution to different organs using whole body imaging when administered to mice via intravenous (i.v) or i.p route. Also, drBoNT/A was used to evaluate its immunogenicity in Balb/C mice model. drBoNT/A was found to be highly immunogenic when tested under various in vivo conditions in Balb/C mice model. For the first time we have demonstrated that a full length 150kDa drBoNT/A, by administering via inhalation route in mice model, has evoked both circulating immunoglobulin levels of IgG and secretory IgA at the mucosal surface. The immunoglobulin levels were sufficient enough to protect against the challenge dose of native BoNT toxin in mice model. Tissue distribution of drBoNT/A seems to be similar to that of native toxin. Based on the characteristics described in this report this nontoxic holotoxin protein will assist us to explore the window of opportunity available for therapeutic treatment in case of unnatural poisoning, and also it can be an effective vaccine candidate.

Antiproliferative Activity and in Vivo Toxicity of Double-Point Modified Analogs of 1,25-Dihydroxyergocalciferol.

Analogs of 1,25-dihydroxyergocalciferol, modified in the side-chain and in the A-ring, were tested for their antiproliferative activity against a series of human cancer cell lines in vitro and in vivo toxicity. The proliferation inhibition caused by the analogs was higher than that of the parent compounds, while the toxicity, measured as the serum calcium level, was lower. All analogs were able to induce, in HL-60 and MV4-11 leukemic cells, G0/G1 cell cycle arrest and differentiation expressed as morphological signs typical for monocytes. The analogs also induced the expression of CD11b and/or CD14 cell-differentiation markers. The most potent analogs, PRI-5105, PRI-5106, PRI-5201 and PRI-5202, were also able to induce vitamin D receptor (VDR) protein expression, mainly in the cytoplasmic fraction of HL-60 or MV4-11 cells. The most active analogs were the 19-nor ones with an extended and rigidified side-chain (PRI-5201 and PRI-5202), as in the former analogs PRI-1906 and PRI-1907. Epimerization at C-24 (PRI-5101) or introduction of an additional hydroxyl at C-23 (PRI-5104) reduced the toxicity of the analog with retained antiproliferative activity.

In Vitro/In Vivo Toxicity Evaluation and Quantification of Iron Oxide Nanoparticles.

Increasing biomedical applications of iron oxide nanoparticles (IONPs) in academic and commercial settings have alarmed the scientific community about the safety and assessment of toxicity profiles of IONPs. The great amount of diversity found in the cytotoxic measurements of IONPs points toward the necessity of careful characterization and quantification of IONPs. The present document discusses the major developments related to in vitro and in vivo toxicity assessment of IONPs and its relationship with the physicochemical parameters of IONPs. Major discussion is included on the current spectrophotometric and imaging based techniques used for quantifying, and studying the clearance and biodistribution of IONPs. Several invasive and non-invasive quantification techniques along with the pitfalls are discussed in detail. Finally, critical guidelines are provided to optimize the design of IONPs to minimize the toxicity.

Introduction of Peripheral Carboxylates to Decrease the Charge on Tm(3+) DOTAM-Alkyl Complexes: Implications for Detection Sensitivity and in Vivo Toxicity of PARACEST MRI Contrast Agents.

A series of structurally modified Tm(3+) DOTAM-alkyl complexes as potential PARACEST MRI contrast agents has been synthesized with the aim to decrease the overall positive charge associated with these molecules and increase their biocompatibility. Two types of structural modification have been performed, an introduction of terminal carboxylate arms to the alkyl side chains and a conjugation of one of the alkyl side chains with aspartic acid. Detailed evaluation of the magnetic resonance imaging chemical exchange contrast associated with the structurally modified contrast agents has been performed. In contrast to the acutely toxic Tm(3+) DOTAM-alkyl complexes, the structurally modified compounds were found to be tolerated well during in vivo MRI studies in mice; however, only the aspartic acid modified chelates produced an amide proton-based PARACEST signal.

Synthesis of Carbohydrate Capped Silicon Nanoparticles and their Reduced Cytotoxicity, In Vivo Toxicity, and Cellular Uptake.

The development of smart targeted nanoparticles (NPs) that can identify and deliver drugs at a sustained rate directly to cancer cells may provide better efficacy and lower toxicity for treating primary and advanced metastatic tumors. Obtaining knowledge of the diseases at the molecular level can facilitate the identification of biological targets. In particular, carbohydrate-mediated molecular recognitions using nano-vehicles are likely to increasingly affect cancer treatment methods, opening a new area in biomedical applications. Here, silicon NPs (SiNPs) capped with carbohydrates including galactose, glucose, mannose, and lactose are successfully synthesized from amine terminated SiNPs. The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] analysis shows an extensive reduction in toxicity of SiNPs by functionalizing with carbohydrate moiety both in vitro and in vivo. Cellular uptake is investigated with flow cytometry and confocal fluorescence microscope. The results show the carbohydrate capped SiNPs can be internalized in the cells within 24 h of incubation, and can be taken up more readily by cancer cells than noncancerous cells. Moreover, these results reinforce the use of carbohydrates for the internalization of a variety of similar compounds into cancer cells.

In vivo efficacy and toxicity studies of a novel antibacterial agent: 14-o-[(2-amino-1,3,4-thiadiazol-5-yl)thioacetyl] mutilin.

A new pleuromutilin derivative with excellent antibacterial activity, 14-O-[(2-amino-1,3,4-thiadiazol-5-yl) thioacetyl] mutilin (ATTM), may serve as a possible lead compound for the development of antibacterial drugs. However, in vivo efficacy and toxicity evaluations of this compound have not been performed. In this study, we evaluated the efficacy of ATTM by measuring the survival of mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA), and the 50% effective dose (ED50) was 5.74 mg/kg by the intravenous route. In an oral single-dose toxicity study, ATTM was orally administered to mice at different doses and the 50% lethal dose (LD50) was calculated to be 2304.4 mg/kg by the Bliss method. The results of the subchronic oral toxicity study in rats showed no mortality, exterior signs of toxicity, or differences in the total weight gain or relative organ weights between the treated groups and control group after administration. The hematological and serum biochemical data showed no differences between the treated and control groups, except for the levels of alkaline phosphatase (ALP), creatinine (CR) and blood glucose (GLU), which were significantly different in the high-dose group. The differences in the histopathological findings between the treated groups and the control group were not considered to be treatment-related. Our results indicated that the no observed adverse effect level (NOAEL) for ATTM was 5 mg/kg in this study.

In Vivo Toxicity of Local Anesthetics and Corticosteroids on Chondrocyte and Synoviocyte Viability and Metabolism.

Objective:Intra-articular injection of local anesthetic and/or corticosteroid is an adjunct treatment for arthritic and inflammatory orthopedic conditions. Despite potential benefits, there is growing concern that these medications may cause significant morbidity, including potential toxicity to intra-articular chondrocytes and synoviocytes.Design:Twenty dogs underwent intra-articular injection of the shoulder joint using ultrasound guidance, with the following injectates (n = 5 each): negative control (saline), methylprednisolone/1.0% lidocaine, triamcinolone/1.0% lidocaine, and triamcinolone/0.0625% bupivacaine. The dogs were euthanized 24 hours postinjection for reasons unrelated to this study. Synovium/cartilage explants were harvested under sterile conditions and assessed immediately or cultured for 7 days. Synoviocyte and chondrocyte viability was determined on day 1 and day 7 using Calcien AM and Sytox Blue live/dead fluorescent stains, and cell metabolism determined on day 2 using the alamar blue additive test. Results were compared statistically.Results:On day 1 synovium exposed to 1%L/M demonstrated a significant decrease in cell metabolism (P = 0.0107) and subjective synoviocyte viability scores (P = 0.013) compared with the negative control. Cartilage exposed to 1%L/M demonstrated decreased chondrocyte viability and cell metabolism versus all other groups, although not significantly. After 7 days of culture, cartilage viable cell density in the 1%L/M group was significantly (P ≤ 0.001) lower than the negative control. Subjective synoviocyte viability scores was significantly lower in the 1%L/M (P = 0.013), 1%L/T (P ≤ 0.001), and 0.0625%B/T groups (P = 0.006) compared with the negative control.Conclusions:This study suggests potential negative effects of combination local anesthetic/corticosteroid on intra-articular cell viability and cell metabolism. Further study is needed before determining definitive clinical recommendations.

Development of Novel Chitosan Microcapsules for Pulmonary Delivery of Dapsone: Characterization, Aerosol Performance, and In Vivo Toxicity Evaluation.

Pneumocystis carinii pneumonia (PCP) is a major opportunistic infection that affects patients with human immunodeficiency virus. Although orally administered dapsone leads to high hepatic metabolism, decreasing the therapeutic index and causing severe side effects, this drug is an effective alternative for the treatment of PCP. In this context, microencapsulation for pulmonary administration can offer an alternative to increase the bioavailability of dapsone, reducing its adverse effects. The aim of this work was to develop novel dapsone-loaded chitosan microcapsules intended for deep-lung aerosolized drug delivery. The geometric particle size (D 4,3) was approximately 7 μm, the calculated aerodynamic diameter (d aero) was approximately 4.5 μm, and the mass median aerodynamic diameter from an Andersen cascade impactor was 4.7 μm. The in vitro dissolution profile showed an efficient dapsone encapsulation, demonstrating the sustained release of the drug. The in vitro deposition (measured by the Andersen cascade impactor) showed an adequate distribution and a high fine particles fraction (FPF = 50%). Scanning electron microscopy of the pulmonary tissues demonstrated an adequate deposition of these particles in the deepest part of the lung. An in vivo toxicity experiment showed the low toxicity of the drug-loaded microcapsules, indicating a protective effect of the microencapsulation process when the particles are microencapsulated. In conclusion, the pulmonary administration of the novel dapsone-loaded microcapsules could be a promising alternative for PCP treatment.