Evaluation of Loco-Regional Skin Toxicity Induced by an In Situ Forming Depot after a Single Subcutaneous Injection at Different Volumes and Flow Rates in Gottingen Minipigs.
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SUBMITTER: Peloso C
PROVIDER: S-EPMC8431084 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundOwing to the human-like physiology, a minipig model of nonalcoholic steatohepatitis (NASH) could be valuable. Pigs, however, rarely develop substantial hepatic steatosis, even when fed diets with high fat, fructose, and cholesterol (FFC) content. The potential of choline-deficient, amino acid-defined high-fat diets (CDAHFD) was therefore evaluated in Göttingen Minipigs.MethodsCastrated male Göttingen Minipigs were fed either chow (n = 5) or one of the three NASH diets: FFC (n = 5), CDAHFD with sucrose (CDAHFD-S; n = 4), or fructose (CDAHFD-F; n = 4) for 8 weeks. Liver and blood samples were collected after 2 weeks and at termination.ResultsCompared with chow, the body weight was higher after FFC (9.8 ± 0.4 versus 8.5 ± 1.2 kg; mean ± SD) and less after CDAHFD-S (6.4 ± 0.8 kg) and CDAHFD-F (6.9 ± 0.8 kg). Liver weight per kg body weight was significantly increased in all 3 NASH groups (FFC 2.1 times; and both CDAHFD diets 3.1 times). Histologically, pronounced macrovesicular steatosis developed only in the CDAHFD groups. Inflammation was present in all three NASH groups. In the CDAHFD groups, inflammatory cells formed crown-like structures around steatotic hepatocytes. Sirius red staining revealed mild fibrosis in the two CDAHFD groups with the fibrotic potential being further supported by immunohistochemical staining for activated stellate cells and gene expression analyses. No noticeable differences were found between CDAHFD-S and CDAHFD-F.ConclusionsGöttingen Minipigs fed CDAHFD developed pronounced steatosis with inflammation around steatotic hepatocytes and incipient fibrosis, thereby showing potential as a model for human NASH. Further studies are needed to investigate the period needed for marked fibrosis to develop.
| S-EPMC7212300 | biostudies-literature
Project description:BackgroundGöttingen Minipigs (GMP) is the smallest commercially available minipig breed under a controlled breeding scheme and is globally bred in five isolated colonies. The genetic isolation harbors the risk of stratification which might compromise the identity of the breed and its usability as an animal model for biomedical and human disease. We conducted whole genome re-sequencing of two DNA-pools per colony to assess genomic differentiation within and between colonies. We added publicly available samples from 13 various pig breeds and discovered overall about 32 M loci, ~ 16 M. thereof variable in GMPs. Individual samples were virtually pooled breed-wise. FST between virtual and DNA pools, a phylogenetic tree, principal component analysis (PCA) and evaluation of functional SNP classes were conducted. An F-test was performed to reveal significantly differentiated allele frequencies between colonies. Variation within a colony was quantified as expected heterozygosity.ResultsPhylogeny and PCA showed that the GMP is easily discriminable from all other breads, but that there is also differentiation between the GMP colonies. Dependent on the contrast between GMP colonies, 4 to 8% of all loci had significantly different allele frequencies. Functional annotation revealed that functionally non-neutral loci are less prone to differentiation. Annotation of highly differentiated loci revealed a couple of deleterious mutations in genes with putative effects in the GMPs .ConclusionDifferentiation and annotation results suggest that the underlying mechanisms are rather drift events than directed selection and limited to neutral genome regions. Animal exchange seems not yet necessary. The Relliehausen colony appears to be the genetically most unique GMP sub-population and could be a valuable resource if animal exchange is required to maintain uniformity of the GMP.
| S-EPMC7161115 | biostudies-literature
Project description:Retinal prostheses hold the potential for artificial vision in blind people affected by incurable diseases of the outer retinal layer. Available technologies provide only a small field of view: a significant limitation for totally blind people. To overcome this problem, we recently proposed a large and high-density photovoltaic epiretinal device, known as POLYRETINA. Here, we report the in vivo assessment of POLYRETINA. First, we characterise a model of chemically-induced blindness in Göttingen minipigs. Then, we develop and test a minimally invasive injection procedure to insert the large epiretinal implant into the eye. Last, we show that POLYRETINA restores light-evoked cortical responses in blind animals at safe irradiance levels. These results indicate that POLYRETINA holds the potential for artificial vision in totally blind patients affected by retinitis pigmentosa.
| S-EPMC9237028 | biostudies-literature
Project description:Drug concentrations in cerebrospinal fluid (CSF) are typically used as a as a surrogate measure of their availability in the CNS, and CSF penetration in animal studies are used for assessment of CNS drug delivery in early preclinical drug development. The minipig is a valid alternative to dogs and non-human primates as non-rodent species in preclinical research, but this species presents anatomical peculiarities that make the serial collection of CSF technically challenging. A minimally-invasive serial cerebrospinal fluid collection model via catheterization of the subarachnoid space in conscious minipigs was developed allowing assessment of longitudinal drug pharmacokinetics in the central nervous system in preclinical research. Shortly, the subarachnoid space was accessed in the anesthetized minipig by puncture with a Tuohy needle; when CSF was flowing through the needle a catheter was advanced and thereafter tunneled and fixed on the back. The PK of peptide A administered subcutaneously was performed and CSF could be sampled in the conscious animals for up to 48 h. When compared to the plasma kinetic data, there was a clear difference in the elimination phase of Pept. A from CSF, with an apparent longer average terminal half-life in CSF. The 3Rs are addressed by reducing the number of animals needed for a pharmacokinetic profile in central nervous system and by improving the validity of the model avoiding biases due to anesthesia, blood contamination, and inter-individual variability.
| S-EPMC6706129 | biostudies-literature
Project description:ObjectiveThe worldwide prevalence of obesity has increased to 10% in men and 15% in women and is associated with severe comorbidities such as diabetes, cancer, and cardiovascular disease. Animal models of obesity are central to experimental studies of disease mechanisms and therapeutic strategies. Diet-induced obesity (DIO) models in rodents have provided important insights into the pathophysiology of obesity and, in most instances, are the first in line for exploratory pharmacology studies. To deepen the relevance towards translation to human patients, we established a corresponding DIO model in Göttingen minipigs (GM).MethodsYoung adult female ovariectomized GM were fed a high-fat/high-energy diet for a period of 70 weeks. The ration was calculated to meet the requirements and maintain body weight (BW) of lean adult minipigs (L-GM group) or increased stepwise to achieve an obese state (DIO-GM group). Body composition, blood parameters and intravenous glucose tolerance were determined at regular intervals. A pilot chronic treatment trial with a GLP1 receptor agonist was conducted in DIO-GM. At the end of the study, the animals were necropsied and a biobank of selected tissues was established.ResultsDIO-GM developed severe subcutaneous and visceral adiposity (body fat >50% of body mass vs. 22% in L-GM), increased plasma cholesterol, triglyceride, and free fatty acid levels, insulin resistance (HOMA-IR >5 vs. 2 in L-GM), impaired glucose tolerance and increased heart rate when resting and active. However, fasting glucose concentrations stayed within normal range throughout the study. Treatment with a long-acting GLP1 receptor agonist revealed substantial reduction of food intake and body weight within four weeks, with increased drug sensitivity relative to observations in other DIO animal models. Extensive adipose tissue inflammation and adipocyte necrosis was observed in visceral, but not subcutaneous, adipose tissue of DIO-GM.ConclusionsThe Munich DIO-GM model resembles hallmarks of the human metabolic syndrome with extensive adipose tissue inflammation and adipocyte necrosis reported for the first time. DIO-GM may be used for evaluating novel treatments of obesity and associated comorbidities. They may help to identify triggers and mechanisms of fat tissue inflammation and mechanisms preventing complete metabolic decompensation despite morbid obesity.
| S-EPMC6157610 | biostudies-literature
Project description:In this study, for the first time, we have reported a sustained transdermal drug delivery from thermoresponsive poloxamer depots formed within the skin micropores following microneedle (MN) application. Firstly, we have investigated the sol-gel phase transition characteristics of poloxamers (PF®127, P108, and P87) at physiological conditions. Rheological measurements were evaluated to confirm the critical gelation temperature (CGT) of the poloxamer formulations with or without fluorescein sodium (FS), as a model drug, at various concentrations. Optimized poloxamer formulations were subjected to in vitro release studies using a vial method. Secondly, polymeric MNs were fabricated using laser-engineered silicone micromolds from various biocompatible polymeric blends of Gantrez S-97, PEG 10000, PEG200, PVP K32, and PVP K90. The MN arrays were characterized for mechanical strength, insertion force determination, in situ dissolution kinetics, moisture content, and penetration depth. The optimized MN arrays with good mechanical strength and non-soluble nature were used to create micropores in the neonatal porcine skin. Microporation in neonatal porcine skin was confirmed by dye-binding study, skin integrity assessment, and histology study. Finally, the in vitro delivery of FS from optimized poloxamer formulations was conducted across non-porated vs microporated skin samples using vertical Franz diffusion cells. Results concluded that permeation of FS was sustained for 96 h across the MN-treated skin samples containing in situ forming depot poloxamer formulations compared to non-microporated skin which sustained the FS delivery for 72 h. Confocal microscopic images confirmed the distribution of higher florescence intensity of FS in skin tissues after permeation study in case of MN-treated skin samples vs intact skin samples.
| S-EPMC6606675 | biostudies-literature
Project description:Bleeding during surgical procedures is a common complication. Therefore, hemostatic agents have been developed to control bleeding, and fibrin sealants have several benefits. sFilm-FS is a novel fibrin sealant that comprises a biodegradable co-polymeric film embedded with human fibrinogen and thrombin. Herein, the safety and efficacy of sFilm-FS were compared using a liver and spleen puncture model of Göttingen minipigs with those of the standard hemostatic techniques (control animals) and EVARREST®, a reference fibrin sealant. Hemostasis and reduced blood loss were more effectively achieved with sFilm-FS than with the standard techniques in the control animals and comparable to those achieved with EVARREST®. No treatment-related adverse effects were observed in any of the groups. Histopathological evaluation indicated that sFilm-FS was slightly and moderately reactive at the liver puncture site and spleen, respectively, compared with the standard techniques in the control animals. These changes are expected degradation reactions of the co-polymeric film and are not considered as adverse events. No treatment-related abnormalities were noted in the other evaluated organs. Additionally, no evidence of local or systemic thromboses was noted. These results support the use of sFilm-FS for hemostasis in humans.
| S-EPMC8484930 | biostudies-literature
Project description:BackgroundBUP-XR (RBP-6000 or SUBLOCADE) is the first Food and Drug Administration-approved subcutaneously administered monthly extended-release buprenorphine medication for the treatment of moderate or severe opioid use disorder. The primary objective of this phase III study was to assess the long-term safety, tolerability, and efficacy of BUP-XR.MethodsThis open-label multicenter study in adults with moderate or severe opioid use disorder enrolled 257 participants from a previously conducted placebo-controlled, double-blind phase III study (rollover group) and 412 de novo participants not previously treated with BUP-XR. Participants received an initial injection of BUP-XR 300 mg and subsequent monthly 300 mg or 100 mg flexible doses. By study end, participants received up to 12 injections.ResultsOverall, 66.8% of participants reported more than 1 treatment-emergent adverse event (TEAE). Injection-site TEAEs (13.2% of participants) were mostly mild or moderate in severity. There were no clinically meaningful changes in safety assessments. An integrated analysis of the double-blind and open-label study participants showed that the incidence of TEAEs, including injection-site TEAEs, was lower in the second 6 months of treatment versus the first 6 months. After 12 months of treatment, 61.5% of the rollover participants and 75.8% of the de novo participants were abstinent. Retention rates after 12 months were 50.6% for the participants who initiated BUP-XR in the double-blind study and 50.5% for de novo participants.ConclusionsThis study demonstrates that the clinical benefits and acceptable safety profile of BUP-XR demonstrated in the 6-month double-blind study are sustained over a 12-month open-label study, with lower incidence of TEAEs in the second 6 months of treatment.
| S-EPMC7188268 | biostudies-literature
Project description:Background/objectivesCholecystokinin (CCK) is a regulator of appetite and energy intake in man. The aim of this study was to determine the effect of NN9056, a long-acting CCK-1 receptor-selective CCK analogue, on food intake and body weight (BW) in obese Göttingen Minipigs.Subjects/methodsTolerability of NN9056 and acute effects on food intake, pancreas histology, amylase and lipase levels were assessed in lean domestic pigs in doses up to 100 nmol/kg (n = 3-4). Subsequently, obese Göttingen Minipigs were treated subcutaneously (s.c.) once daily for 13 weeks with vehicle, NN9056 low dose (regulated from 5 to 2 nmol/kg) or NN9056 high dose (10 nmol/kg) (n = 7-8). Food intake was measured daily and BW twice weekly. At the end of the treatment period, an intravenous glucose tolerance test (IVGTT) and a 24-h exposure profile was obtained. Data are mean ± SD.ResultsThe acute studies in domestic pigs showed significant and dose-dependent effect of NN9056 on food intake, acceptable tolerability and no histopathological signs of pancreatitis. Sub-chronic treatment in obese Göttingen Minipigs was also well tolerated and accumulated food intake was significantly lower in both treated groups compared to vehicle, with no significant difference between the dose levels of NN9056 (41.8 ± 12.6, 51.5 ± 13.8 and 86.5 ± 19.5 kg in high-dose, low-dose and vehicle groups, respectively, p = 0.012 and p < 0.0001 for low and high dose vs. vehicle, respectively). Accordingly, there was a weight loss in both treated groups vs. a weight gain in the vehicle group (-7.2 ± 4.6%, -2.3 ± 3.2% and 12.3 ± 3.9% in the high-dose, low-dose and vehicle groups, respectively, p < 0.0001 for both vs. vehicle). IVGTT data were not significantly different between groups.ConclusionNN9056, a long-acting CCK-1 receptor-selective CCK analogue, significantly reduced food intake and BW in obese Göttingen Minipigs after once daily s.c. dosing for 13 weeks.
| S-EPMC6997118 | biostudies-literature
Project description:In situ forming implants (ISFIs) allow for a high initial intratumoral concentration and sustained release of the chemotherapeutic. However, clinical translation is impeded primarily due to limited drug penetration from the tumor/boundary interface and poor intratumoral drug retention. Therapeutic ultrasound (TUS) has become a popular approach for improving drug penetration of transdermal devices and increasing cellular uptake of nanoparticles. These effects are driven by the mechanical and thermal bioeffects associated with TUS. In this study, we characterize the released drug penetration, retention, and overall therapeutic response when exposing ISFI to the combination of the mechanical and thermal effects of TUS (C-TUS). ISFIs were intratumorally injected into subcutaneous murine tumors then exposed to C-TUS (exposure: 5 min, duty factor: 0.33, frequency: 3 MHz, intensity: 2.2 W/cm2, pulse duration: 2 ms, pulse repetition frequency: 165 Hz, effective radiating area: 5 cm2, energy delivered: 896 J, time average intensity: 0.88 W/cm2). Tumors treated with the combination of ISFI + C-TUS demonstrated a 2.5-fold increase in maximum drug penetration and a 3-fold increase in drug retention at 5- and 8-days post-injection, respectively, compared to ISFIs without TUS exposure. These improvements in drug penetration and retention translated into an enhanced therapeutic response. Mice treated with ISFI + C-TUS showed a 62.6% reduction in tumor progression, a 50.0% increase in median survival time, and a 26.6% increase in necrotic percentage compared to ISFIs without TUS exposure. Combining intratumoral ISFIs with TUS may be beneficial for addressing some long-standing challenges with local drug delivery in cancer treatment and may serve as a viable noninvasive method to improve the poor clinical success of local drug delivery systems.
| S-EPMC7725358 | biostudies-literature