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1.
PLoS One ; 18(6): e0281521, 2023.
Article in English | MEDLINE | ID: mdl-37319233

ABSTRACT

Dippity Pig Syndrome (DPS) is a well-known but rare complex of clinical signs affecting minipigs, which has not been thoroughly investigated yet. Clinically affected animals show acute appearance of red, exudating lesions across the spine. The lesions are painful, evidenced by arching of the back (dipping), and the onset of clinical signs is generally sudden. In order to understand the pathogenesis, histological and virological investigations were performed in affected and unaffected Göttingen Minipigs (GöMPs). The following DNA viruses were screened for using PCR-based methods: Porcine cytomegalovirus (PCMV), which is a porcine roseolovirus (PCMV/PRV), porcine lymphotropic herpesviruses (PLHV-1, PLHV-2, PLHV-3), porcine circoviruses (PCV1, PCV2, PCV3, PCV4), porcine parvovirus 1 (PPV1), and Torque Teno sus viruses (TTSuV1, TTSuV2). Screening was also performed for integrated porcine endogenous retroviruses (PERV-A, PERV-B, PERV-C) and recombinant PERV-A/C and their expression as well as for the RNA viruses hepatitis E virus (HEV) and SARS-CoV-2. Eight clinically affected and one unaffected GöMPs were analyzed. Additional unaffected minipigs had been analyzed in the past. The analyzed GöMPs contained PERV-A and PERV-B integrated in the genome, which are present in all pigs and PERV-C, which is present in most, but not all pigs. In one affected GöMPs recombinant PERV-A/C was detected in blood. In this animal a very high expression of PERV mRNA was observed. PCMV/PRV was found in three affected animals, PCV1 was found in three animals with DPS and in the unaffected minipig, and PCV3 was detected in two animals with DPS and in the unaffected minipig. Most importantly, in one animal only PLHV-3 was detected. It was found in the affected and unaffected skin, and in other organs. Unfortunately, PLHV-3 could not be studied in all other affected minipigs. None of the other viruses were detected and using electron microscopy, no virus particles were found in the affected skin. No porcine virus RNA with exception of PERV and astrovirus RNA were detected in the affected skin by next generation sequencing. This data identified some virus infections in GöMPs with DPS and assign a special role to PLHV-3. Since PCMV/PRV, PCV1, PCV3 and PLHV-3 were also found in unaffected animals, a multifactorial cause of DPS is suggested. However, elimination of the viruses from GöMPs may prevent DPS.


Subject(s)
Betaherpesvirinae , COVID-19 , Endogenous Retroviruses , Swine , Animals , Swine, Miniature , Transplantation, Heterologous , SARS-CoV-2
2.
Int J Toxicol ; 42(3): 254-268, 2023.
Article in English | MEDLINE | ID: mdl-36799227

ABSTRACT

Species selection plays a pivotal part during non-clinical safety assessment in drug development. If possible, use of non-human primates (NHPs) should be avoided due to ethical considerations. However, limiting factors as lack of pharmacologic activity in other species could necessitate use of NHPs. LAI-PCSK9i is a bi-functional molecule combining a long-acting insulin analogue with a PCSK9 inhibitor peptide aiming to provide glycaemic control and to reduce plasma LDL concentrations. The NHP was chosen for the safety assessment of LAI-PCSK9i being the most relevant species with basal levels and plasma lipid composition closest to humans, while the dog and initially also the minipig were deemed irrelevant due to lack of pharmacologic activity on LDL-lowering and biological differences in lipid profiles. An in vivo tolerability and toxicokinetic study of LAI-PCSK9i in NHPs showed recurrent and severe hypoglycaemia at very low doses. Therefore, the minipig was re-evaluated and a follow-up study thoroughly assessing blood glucose and cholesterol levels and clinical signs illustrated that minipigs dosed with LAI-PCSK9i, tolerated the compound and LAI-PCSK9i decreased glucose and LDL over time. This work underlines that careful consideration is required when selecting species during safety assessment in drug development. The tolerability issue in NHPs led to the subsequent selection of the minipig for safety evaluation of LAI-PCSK9i although as a suboptimal alternative, which unexpectedly had a measurable pharmacologic response on LDL lowering. In conclusion, the NHPs may be unsuitable as test species for safety assessment of long-acting insulin analogues due to high sensitivity to recurring hypoglycaemic episodes.


Subject(s)
Insulin, Long-Acting , Proprotein Convertase 9 , Animals , Swine , Dogs , Swine, Miniature , Follow-Up Studies , Primates , Lipids
3.
J Burn Care Res ; 44(5): 1140-1149, 2023 09 07.
Article in English | MEDLINE | ID: mdl-36639942

ABSTRACT

Partial-thickness thermal burn wounds are characterized by a prolonged inflammatory response, oxidative stress, tissue damage, and secondary necrosis. An optimal dressing for burn wounds would reduce inflammation and oxidative stress while providing a moist, absorbent, and protective cover. We have developed an extract from unfertilized salmon roe containing components with potential anti-inflammatory and antioxidative properties, called HTX. HTX has been combined with alginate from brown algae and nanocellulose from tunicates, and 3D printed into a solid hydrogel wound dressing called Collex. Here, Collex was tested on partial thickness burn wounds in Göttingen minipigs compared to Jelonet, and a variant of Collex without HTX. We found that dermal treatment of burn wounds with Collex resulted in accelerated healing at a majority of measured points over 23 days, compared to treatment with Jelonet. In comparison to Collex without HTX, Collex enhanced healing in the first week after trauma where wound progression was pronounced. Notably, Collex reduced the inflammatory response in the early post-injury phase. The anti-inflammatory response of Collex was investigated in more detail on activated M1 macrophages. We found that Collex, as well as HTX alone, significantly reduced the secretion of pro-inflammatory interleukin-1ß as well as intracellular levels of oxidative stress. The results from this study indicate that Collex is a potent dressing for the treatment of burn wounds, with the anti-inflammatory effect of HTX beneficial in the initial phase, and the moist qualities of the hydrogel favorable both in the initial and the proceeding proliferative phase of wound healing.


Subject(s)
Burns , Swine , Animals , Burns/drug therapy , Alginates/therapeutic use , Alginates/pharmacology , Swine, Miniature , Wound Healing , Bandages , Inflammation , Hydrogels , Salmon
4.
J Appl Toxicol ; 35(12): 1577-85, 2015 Dec.
Article in English | MEDLINE | ID: mdl-25752809

ABSTRACT

The human papillomavirus (HPV)-16/18 vaccine (Cervarix®) is a prophylactic vaccine for the prevention of cervical cancer. The vaccine contains recombinant virus-like particles assembled from the L1 major capsid proteins of the cervical cancer-causing viral types HPV-16 and HPV-18, and Adjuvant System 04 (AS04), which contains the immunostimulant MPL and aluminium salt. To evaluate potential local and systemic toxic effects of the HPV-16/18 vaccine or AS04 alone, three repeated-dose studies were performed in rabbits and rats. One rabbit study also included a single-dose evaluation. In rabbits (~2.5 kg), the full human dose (HD) of the vaccine was evaluated (0.5 ml per injection site), and in rats (~250 g), 1/5 HD of vaccine was evaluated, corresponding to ≥ 12 times the dosage in humans relative to body weight. In both animal models, the treatment-related changes included a slight transient increase in the number of circulating neutrophils as well as a local inflammatory reaction at the injection site. These treatment-related changes were less pronounced after four doses of AS04 alone than after four doses of the HPV-16/18 vaccine. Additional treatment-related changes in the rat included lower albumin/globulin ratios and microscopic signs of inflammation in the popliteal lymph nodes. In both animal models, 13 weeks after the fourth dose, recovery was nearly complete, although at the injection site in some animals there were signs of discoloration, muscle-fibre regeneration and focal points of macrophage infiltration. Therefore, in these non-clinical models, the single and repeated dose administrations of the HPV-16/18 vaccine or AS04 alone were safe and well tolerated.


Subject(s)
Aluminum Hydroxide/toxicity , Human papillomavirus 16/immunology , Human papillomavirus 18/immunology , Lipid A/analogs & derivatives , Papillomavirus Vaccines/toxicity , Aluminum Hydroxide/administration & dosage , Aluminum Hydroxide/immunology , Animals , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Injections, Intramuscular , Lipid A/administration & dosage , Lipid A/immunology , Lipid A/toxicity , Papillomavirus Infections/immunology , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/administration & dosage , Papillomavirus Vaccines/immunology , Rabbits , Rats , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/prevention & control
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