scholarly journals Enhanced Intradermal Delivery of Nanosuspensions of Antifilariasis Drugs Using Dissolving Microneedles: A Proof of Concept Study

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 346 ◽  
Author(s):  
Permana ◽  
McCrudden ◽  
Donnelly
Keyword(s):  
Animal Model ◽  
Proof Of Concept ◽  
Porcine Skin ◽  
Lymphatic Uptake ◽  
Dissolving Microneedles ◽  
Intradermal Delivery ◽  
Suitable Animal Model ◽  
Future Work ◽  
Delivery Approach

Conventional oral administration of antifilariasis drugs results in nonspecific targeting of the drugs and the intradermal delivery of nanoparticles with sizes of <100 nm could be used to improve lymphatic uptake. This study investigated the combination of nanosuspension and dissolving microneedles (MN-NS) as an alternative intradermal delivery approach for the delivery of antifilariasis drugs, namely doxycycline, albendazole, and ivermectin. NS were fabricated and optimized using a bottom-up technique. The NS were then incorporated into the MN arrays. The optimized NS were <100 nm in diameter. Furthermore, MN-NS had suitable mechanical strength and insertion capabilities. The dermatokinetic study revealed that the delivery of drugs into the dermis of excised neonatal porcine skin by MNs was significantly higher than that from a needle-free patch, with 29.29 ± 4.65%, 31.54 ± 5.35%, and 34.54 ± 4.98% of doxycycline, albendazole sulfoxide, and ivermectin retained in the dermis after 24 h. The results presented here serve as proof of concept for the significant enhancement of drug retention times in the dermis, following their formulation into NS and delivery via MN. Leading on from these studies, future work must investigate in vivo lymphatic pharmacokinetic profiling of drugs formulated into NS, in a suitable animal model.

scholarly journals The ascorbate-deficient guinea pig model of shigellosis allows the study of the entire Shigella life cycle

2020 ◽  
Author(s):  
Antonin C André ◽  
Céline Mulet ◽  
Mark C Anderson ◽  
Louise Injarabian ◽  
Achim Buch ◽  
...  
Keyword(s):  
Animal Model ◽  
Life Cycle ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Colonic Mucosa ◽  
Extended Period ◽  
Pig Model ◽  
Suitable Animal Model ◽  
Guinea Pig Model

AbstractShigella spp. are the causative agents of bacillary dysentery or shigellosis, mainly in children living in developing countries. The study of Shigella entire life cycle in vivo and the evaluation of vaccine candidates’ protection efficacy have been hampered by the lack of a suitable animal model of infection (1). None of the ones evaluated so far (mouse, rabbit, guinea pig) allows to recapitulate shigellosis symptoms upon Shigella oral challenge. Historical reports suggest that dysentery and scurvy are both metabolic diseases associated with ascorbate-deficiency. Mammals which are susceptible to Shigella infection (humans, non-human primates and guinea pigs) are the lonely ones which are unable to synthesize ascorbate. We optimized a low-ascorbate diet to induce moderate ascorbate-deficiency but not scurvy in guinea pigs (Ascplasma conc.=1.6 μM vs 36 μM with optimal ascorbate supply). We demonstrated that moderate ascorbate-deficiency increases shigellosis severity during extended period of time (up to 48h) with all strains tested (Shigella flexneri 5a and 2a, Shigella sonnei). At late time-points, a massive influx of neutrophils was observed both within the disrupted colonic mucosa and in the luminal compartment, although Shigella remains able to disseminate deep into the organ to reach the sub-mucosal layer and the bloodstream. This new model of shigellosis opens new doors for the study both of Shigella infection strategy and innate and adaptive immune responses to Shigella infection. It may be also of a great interest to study the virulence of other pathogen for which no suitable animal model of infection is available (Vibrio cholerae, Yersinia pestis, Mycobacterium tuberculosis or Campylobacter jejuni, among others).SignificanceThe study of Shigella virulence cycle in vivo has been hampered by the lack of a suitable animal model, which would allow the colonic mucosa infection upon oral challenge. Based on historical reports and physiological aspects, it was suggested that ascorbate-deficiency may stand as a new dysentery risk-factor. To test this hypothesis, we set up a new ascorbate-deficient guinea pig model and demonstrated for the first time that the Shigella infectious process occurred for extended period of time (up to 48h) and demonstrated that shigellosis severity was higher in ascorbate-deficient animal. Ascorbate-deficient guinea pig model of infection may be used to assess the virulence of other pathogens for which no suitable animal model of infection is still lacking.

scholarly journals A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

2020 ◽  
Author(s):  
Tien-Tzu Tai ◽  
Tzung-Ju Wu ◽  
Huey-Dong Wu ◽  
Yi-Chen Tsai ◽  
Hui-Ting Wang ◽  
...  
Keyword(s):  
Animal Model ◽  
Targeted Delivery ◽  
Potential Treatment ◽  
Proof Of Concept ◽  
Sprague Dawley ◽  
Dosing Regimen ◽  
Sd Rats ◽  
Lower Blood

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, lung concentration (6.7 µg/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 µg/g (Cmax) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (∼30-fold) lung exposure, longer (∼2.5-fold) half-life in lung, but lower blood exposure with ∼20% of Cmax and 74% of AUC and lower heart exposure with 24% of Cmax and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.

scholarly journals Genotoxic mechanisms for the carcinogenicity of the environmental pollutants and carcinogens o-anisidine and 2-nitroanisole follow from adducts generated by their metabolite N-(2-methoxyphenyl)hydroxylamine with deoxyguanosine in DNA

2009 ◽  
Vol 2 (1) ◽  
pp. 24-27 ◽  
Author(s):  
Marie Stiborová ◽  
Karel Naiman ◽  
Markéta Martínková ◽  
Václav Martínek ◽  
Martina Svobodová ◽  
...  
Keyword(s):  
Animal Model ◽  
Urinary Bladder ◽  
Environmental Pollutants ◽  
Carbenium Ions ◽  
Suitable Animal Model ◽  
Carcinogenic Metabolite ◽  
Rats And Mice ◽  
Rat Livers

Genotoxic mechanisms for the carcinogenicity of the environmental pollutants and carcinogenso-anisidine and 2-nitroanisole follow from adducts generated by their metaboliteN-(2-methoxyphenyl)hydroxylamine with deoxyguanosine in DNAAn aromatic amine,o-anisidine (2-methoxyaniline) and its oxidative counterpart, 2-nitroanisole (2-methoxynitrobenzene), are the industrial and environmental pollutants causing tumors of the urinary bladder in rats and mice. Both carcinogens are activated to the same proximate carcinogenic metabolite,N-(2-methoxyphenyl)hydroxylamine, which spontaneously decomposes to nitrenium and/or carbenium ions responsible for formation of deoxyguanosine adducts in DNAin vitroandin vivo. In other words, generation ofN-(2-methoxyphenyl)hydroxylamine is responsible for the genotoxic mechanisms of the o-anisidine and 2-nitroanisole carcinogenicity. Analogous enzymes of human and rat livers are capable of activating these carcinogens. Namely, human and rat cytochorme P450 2E1 is the major enzyme oxidizingo-anisidine toN-(2-methoxyphenyl)hydroxylamine, while xanthine oxidase of both species reduces 2-nitroanisole to this metabolite. Likewise,O-demethylation of 2-nitroanisole, which is the detoxication pathway of its metabolism, is also catalyzed by the same human and rat enzyme, cytochorme P450 2E1. The results demonstrate that the rat is a suitable animal model mimicking the fate of both carcinogens in humans and suggest that both compounds are potential carcinogens also for humans.

In Vitro Behavior and Design of a New Type Implant with Nanostructured Surface

2011 ◽  
Vol 1316 ◽  
Author(s):  
J.C. Mirza Rosca ◽  
D. Raducanu ◽  
D. Gonzalez Martin ◽  
J.A. Garcia Lorente ◽  
C. Vasilescu
Keyword(s):  
Animal Model ◽  
Melting Furnace ◽  
Sodium Titanate ◽  
Ringer Solution ◽  
In Vivo Experiments ◽  
Nano Crystalline ◽  
Complex Design ◽  
Suitable Animal Model

ABSTRACTThis study was aimed to investigate in vitro and in vivo behavior of a Ti6Al7Nb biomaterial with a nanostructured HA-type coating and also the design and realization of a new special knee implant together with a selection of a suitable animal model for preclinical experimentation of the implants.The metallic material used like substrate alloy for layer deposition was a Ti6Al7Nb alloy obtained by double electron beam melting furnace. In order to obtain a nano-crystalline HA-coating first sodium titanate layer was obtained on the surface and then the implant was immersed in Ringer solution with additional PAW1 biovitroceramic (particles under 20 μm). Different deposition times (5, 10 and 19 days) were employed. Microscopy analysis and corrosion tests of the implants relieves that the nanostructured HA layer after 19 days of immersion shows promising results as regarding the implant employ in preclinical experiments.After a complex design based on knee bone radiography there has been manufactured two different types of devices for the metallic implants: a metallic plate and a pin. Two plates and two pins were implanted in each animal.For in vivo experiments the chosen animal model was the mini-pig because of its strong chirurgical resistance and perfect anesthesia toleration. For the testing 10 animals were used for implantation and one for the control. When the plate is implanted the bone has to have a good blood supply after the cut in order to avoid bone to die. All experimented implants were maintained in the animal during six months and periodically inspected. No sign of infection or another problem were observed during this period.

scholarly journals Assessment of the ferret as an in vivo model for mumps virus infection

2013 ◽  
Vol 94 (6) ◽  
pp. 1200-1205 ◽  
Author(s):  
L. Parker ◽  
S. M. Gilliland ◽  
P. Minor ◽  
S. Schepelmann
Keyword(s):  
Animal Model ◽  
Cytokine Production ◽  
Serum Antibody ◽  
Clinical Signs ◽  
Mumps Virus ◽  
In Vivo Model ◽  
Live Virus ◽  
Suitable Animal Model ◽  
Tissue Homogenates

Humans are the sole reservoir for mumps virus (MuV), the causative agent of mumps. No animal model currently exists; therefore, in vivo knowledge of the virus is limited. Ferrets were assessed for their susceptibility to MuV based on their success as a model for influenza. We infected ferrets with clinical or attenuated vaccine MuVs by the nasal route and demonstrated evidence of immunogenicity in these animals with generation of a serum antibody response specific to MuV infection and cytokine production consistent with infection. However, no live virus or viral RNA was detected in nasal washes, oral swabs, urine, faeces or tissue homogenates, and no animals exhibited clinical signs. We suggest results to be obtained from ferrets are limited in fundamental in vivo MuV research and that they may not be a suitable animal model for this virus.

Paired helical filaments (PHF) in rats: An experimental animal model for Alzheimer's disease

1987 ◽  
Vol 45 ◽  
pp. 842-843
Author(s):  
V.J.A. Montpetit ◽  
S. Dancea ◽  
S.W. French ◽  
D.F. Clapin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Paired Helical Filaments ◽  
Ethanol Intoxication ◽  
Drg Neurons ◽  
Critical Difference ◽  
Suitable Animal Model ◽  
The Central Nervous System ◽  
Chronic Ethanol Intoxication

A continuing problem in Alzheimer research is the lack of a suitable animal model for the disease. The absence of neurofibrillary tangles of paired helical filaments is the most critical difference in the processes by which the central nervous system ages in most species other than man. However, restricting consideration to single phenomena, one may identify animal models for specific aspects of Alzheimer's disease. Abnormal fibers resembling PHF have been observed in dorsal root ganglia (DRG) neurons of rats in a study of chronic ethanol intoxication and spontaneously in aged rats. We present in this report evidence that PHF-like filaments occur in ethanol-treated rats of young age. In control animals lesions similar in some respects to our observations of cytoskeletal pathology in pyridoxine induced neurotoxicity were observed.Male Wistar BR rats (Charles River Labs) weighing 350 to 400 g, were implanted with a single gastrostomy cannula and infused with a liquid diet containing 30% of total calories as fat plus ethanol or isocaloric dextrose.

Production and Preliminary In Vivo Evaluations of a Novel in silico-designed L2-based Potential HPV Vaccine

2020 ◽  
Vol 21 (4) ◽  
pp. 316-324
Author(s):  
Manica Negahdaripour ◽  
Navid Nezafat ◽  
Reza Heidari ◽  
Nasrollah Erfani ◽  
Nasim Hajighahramani ◽  
...  
Keyword(s):  
In Silico ◽  
Group Versus ◽  
Tlr Agonists ◽  
E Coli ◽  
Metal Affinity ◽  
Th1 And Th2 Cytokines ◽  
Ifn Γ ◽  
Humoral Responses ◽  
Future Work

Background: L2-based Human Papillomavirus (HPV) prophylactic vaccines, containing epitopes from HPV minor capsid proteins, are under investigation as second-generation HPV vaccines. No such vaccine has passed clinical trials yet, mainly due to the low immunogenicity of peptide vaccines; so efforts are being continued. A candidate vaccine composed of two HPV16 L2 epitopes, flagellin and a Toll-Like Receptor (TLR) 4 agonist (RS09) as adjuvants, and two universal T-helper epitopes was designed in silico in our previous researches. Methods: The designed vaccine construct was expressed in E. coli BL21 (DE3) and purified through metal affinity chromatography. Following mice vaccination, blood samples underwent ELISA and flow cytometry analyses for the detection of IgG and seven Th1 and Th2 cytokines. Results: Following immunization, Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-5, IL-10) type cytokines, as well as IgG, were induced significantly compared with the PBS group. Significant increases in IFN-γ, IL-2, and IL-5 levels were observed in the vaccinated group versus Freund’s adjuvant group. Conclusion: The obtained cytokine induction profile implied both cellular and humoral responses, with a more Th-1 favored trend. However, an analysis of specific antibodies against L2 is required to confirm humoral responses. No significant elevation in inflammatory cytokines, (IL-6 and TNF-α), suggested a lack of unwanted inflammatory side effects despite using a combination of two TLR agonists. The designed construct might be capable of inducing adaptive and innate immunity; nevertheless, comprehensive immune tests were not conducted at this stage and will be a matter of future work.

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