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1.
J Antimicrob Chemother ; 77(4): 1000-1004, 2022 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-35134162

RESUMEN

BACKGROUND: Islatravir (4'-ethynyl-2-fluoro-2'-deoxyadenosine; EFdA) is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) being investigated for HIV treatment and prevention. EFdA is intracellularly phosphorylated to EFdA-triphosphate (EFdA-tp), a competitive substrate of deoxyadenosine-triphosphate (dATP). Thus, translating safety and efficacy findings from preclinical studies relies on the assumption that EFdA's intracellular pharmacology can be extrapolated across species. OBJECTIVES: We investigated how EFdA is phosphorylated across animal species commonly used for preclinical models in drug development to identify those that most closely matched humans. METHODS: PBMCs were isolated from whole blood of six species (human, rhesus macaque non-human primate (rmNHP), rat, minipig, dog, and rabbit) using Ficoll separation and counted on a haemocytometer by Trypan blue staining. One million live cells were cultured in media supplemented with 10 U/mL human IL-2, 10% FBS and 1% antibiotics and treated with 0, 17, 170, and 1700 nM EFdA (n = 3 replicates per concentration). After 24 h, representative cell counts were derived from untreated control wells (as above), cells were washed in PBS, and lysed with 70:30 methanol:water. EFdA-tp and dATP concentrations were quantified by HPLC-MS/MS and normalized to the representative live cell counts for each species. RESULTS: When compared to human values, EFdA-tp concentrations for each EFdA treatment concentration were lower in all species (rmNHP 1.5-2.1-fold, rat 4.5-15-fold, minipig 37-71-fold, dog and rabbit >100-fold). Additionally, rmNHP and dog PBMCs exhibited significantly higher (7-10-fold; P < 0.001) dATP when compared with human PBMCs. CONCLUSIONS: Given intracellular pharmacology differences, these preclinical models may be a conservative estimate of EFdA's intracellular pharmacokinetics and efficacy in humans.


Asunto(s)
Desoxiadenosinas , Modelos Biológicos , Inhibidores de la Transcriptasa Inversa , Animales , Fármacos Anti-VIH/farmacología , Desoxiadenosinas/farmacología , Perros , Infecciones por VIH/tratamiento farmacológico , Macaca mulatta , Conejos , Ratas , Proyectos de Investigación , Inhibidores de la Transcriptasa Inversa/farmacología , Especificidad de la Especie , Porcinos , Porcinos Enanos , Espectrometría de Masas en Tándem
2.
BMC Cardiovasc Disord ; 22(1): 143, 2022 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-35366800

RESUMEN

BACKGROUND: The purpose of this study is to dynamically monitor the myocardial structure and function changes in diabetic mini-pigs by 1.5 T cardiac magnetic resonance. METHODS: Three male mini-pigs underwent cardiac magnet resonance (CMR) imaging, and histologic examination. T1-mapping was acquired at basal, mid and apical segments. CMR feature-tracking (CMR-FT) is used to quantify left ventricle global longitudinal (LVGLS), circumferential (LVGCS) and radial strain (LVGRS). Epicardial adipose tissue (EAT) was evaluated using a commercially available software. RESULTS: Left ventricular mass (LVM), myocardial native T1 value, extracellular volume (ECV) value and EAT were increased gradually after 6 months of modeling, while LVGLS decreased gradually after 6 months of modeling (LVM: 24.5 (23.4, 26.7) vs. 42.7 (41.4, 44.6) g/m2, p < 0.001; Native T1: 1005.5 (992.6, 1010.7) vs. 1028.7 (1015.5, 1035.6) ms, p = 0.041; EAT: 16.1 (14.5, 18.2) vs. 24.6 (20.8, 26.9) mL, p = 0.020; ECV: 21.4 (20.2, 23.9) vs. 28.9 (26.7, 30.3) %, p = 0.011; LVGLS: - 22.8 (- 21.4, - 23.9) vs. - 17.4 (- 17.2, - 19.2)%, p = 0.008). The diffuse myocardial interstitial fibrosis was found in histology samples. CONCLUSION: The progressive impairments in LV structure and myocardial deformation occurs in diabetic mini-pigs. T1 mapping and CMR-FT technology are promising to monitor abnormal changes of diabetic myocardium in the early stage of diabetic cardiomyopathy.


Asunto(s)
Diabetes Mellitus , Cardiomiopatías Diabéticas , Animales , Cardiomiopatías Diabéticas/diagnóstico por imagen , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/patología , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Masculino , Miocardio/patología , Porcinos , Porcinos Enanos , Función Ventricular Izquierda
3.
J Vet Sci ; 23(2): e35, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35363442

RESUMEN

BACKGROUND: The testis has been reported to be a naturally O2-deprived organ, dimethyloxaloylglycine (DMOG) can inhibit hypoxia inducible factor-1alpha (HIF-1α) subject to degradation under normal oxygen condition in cells. OBJECTIVES: The objective of this study is to detect the effects of DMOG on the proliferation and differentiation of spermatogonial stem cells (SSCs) in Bama minipigs. METHODS: Gradient concentrations of DMOG were added into the culture medium, HIF-1α protein in SSCs was detected by western blot analysis, the relative transcription levels of the SSC-specific genes were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Six days post-induction, the genes related to spermatogenesis were detected by qRT-PCR, and the DNA content was determined by flow cytometry. RESULTS: Results revealed that the levels of HIF-1α protein increased in SSCs with the DMOG treatment in a dose-dependent manner. The relative transcription levels of SSC-specific genes were significantly upregulated (p < 0.05) by activating HIF-1α expression. The induction results showed that DMOG significantly increased (p < 0.05) the spermatogenesis capability of SSCs, and the populations of haploid cells significantly increased (p < 0.05) in DMOG-treated SSCs when compared to those in DMOG-untreated SSCs. CONCLUSION: We demonstrate that DMOG can promote the spermatogenesis activity of SSCs.


Asunto(s)
Células Madre Germinales Adultas , Animales , Diferenciación Celular , Masculino , Espermatogénesis , Porcinos , Porcinos Enanos , Testículo
4.
Urologiia ; (2): 71-76, 2022 May.
Artículo en Ruso | MEDLINE | ID: mdl-35485817

RESUMEN

AIM: The aim of this experimental study was to evaluate the effect of low temperatures of carbon dioxide on a "living" blood-supplying organ (pig kidney), to determine the possibility of performing cryoablation of kidney tissue with carbon dioxide (carboxycryoablation), as well as to establish experimentally modes of carboxycryoablation of the kidney. MATERIALS AND METHODS: To carry out this experimental study, a female of the mini-pig line was used. We performed laparoscopic access to the kidney for carboxycryoablation. During the freezing of the kidney, three modes were compared: 60, 90, and 120 s on one kidney of one animal. Immediately after the completion of cryoablation, nephrectomy was performed, and the removed kidney was sent for histological examination. According to the histological study, the results of the use of carbon dioxide during cryoablation of porcine kidney tissue were evaluated. RESULTS: Cryoablation based on carbon dioxide (carboxycryoablation) leads to irreversible death (necrosis) and destruction of the affected tissue. A direct relationship between the exposure mode and the size of the cryonecrosis zone was noted. Thus, the most extensive zone of necrosis with a diameter of 10 mm was achieved when performing cryoablation in the exposure mode of 120 s. CONCLUSION: This experiment showed that carbon dioxide-based cryoablation remains a feasible procedure that leads to irreversible death (necrosis) and destruction of the affected tissue. However, further studies on the safety and efficacy of cryoablation of kidney tissue with carbon dioxide are required.


Asunto(s)
Dióxido de Carbono , Riñón , Animales , Femenino , Humanos , Riñón/patología , Riñón/cirugía , Necrosis/patología , Proyectos Piloto , Porcinos , Porcinos Enanos
5.
BMC Pulm Med ; 22(1): 136, 2022 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-35395795

RESUMEN

BACKGROUND: Bronchoscopy is critical in the treatment of patients with coronavirus disease (COVID-19), and its use is associated with the challenges of stringent sterilization and virus transmission risk. We developed a disposable and portable bronchoscope (YunSendo-R) and compared its safety and function with those of current reusable and single-use bronchoscopes using an animal model. METHODS: We compared the YunSendo-R system with a commercially available reusable bronchoscope (Olympus, BF-H290) and single-use bronchoscope (Ambu, Ambu® aScope3™). Eight physicians used the three types of bronchoscopes to operate on Guangxi Bama mini pigs. Each operator performed bronchoscopy and completed a 10-point Likert scale questionnaire for evaluating visual ability and manoeuvrability. Operation time and scores were collected. RESULTS: Operation time had no significant differences among the three bronchoscopes. In visual ability, the YunSendo-R bronchoscope showed superior performance to the Ambu bronchoscope in image clarity, colour contrast, and illumination (P < 0.05) and no significant difference in performance compared with the Olympus bronchoscope (P > 0.05). The YunSendo-R bronchoscope had similar manoeuvrability to the Olympus bronchoscope and better scope tip flexibility than the Ambu bronchoscope (P > 0.05). No relevant complications were reported. CONCLUSION: We have developed a new bronchoscopy system with the advantages of disposability and portability, which was effective and safe in an animal model. It has better visual ability than the Ambu bronchoscope and similar visual ability and manoeuvrability to the Olympus bronchoscope. The YunSendo-R bronchoscope is a promising device for clinical practice, especially in reusable-endoscope-transmitted infectious diseases such as COVID-19.


Asunto(s)
Broncoscopía , COVID-19 , Animales , Broncoscopios , Broncoscopía/métodos , China , Humanos , Porcinos , Porcinos Enanos
6.
Mediators Inflamm ; 2022: 5515305, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35399795

RESUMEN

Activation of NOD-like receptor (NLR) signaling pathway can promote downstream cytokine and proinflammatory cytokines release, and inflammation induced by excess nutrients leads to renal metabolic injury. How the NLRs influence metabolic progress and then lead to the renal injury remains poorly investigated. Compared with rodents, minipigs are more similar to humans and are more ideal animal models for human disease research. In this study, we established a diabetic minipig model through a high-sugar and high-fat diet combined with streptozotocin (STZ) injection. Blood biological markers and renal pathological markers, expression of NLRP subfamily members (NLRP1 and NLRP3) and their downstream cytokines (precursors of IL-1ß and IL-18 and mature forms of IL-1ß and IL-18), expression of NLRC subfamily members (NLRC1, NLRC2, and NLRC5) and their downstream nuclear factor-κB (NF-κB) signaling pathway molecules (IKKß, IκBα, and NF-κB p65), and inflammatory cytokines (TNF-α and interleukin-6 (IL-6)) were systematically evaluated. The expression of NLRP3 and its downstream cytokine signaling molecules, the precursors of IL-1ß and IL-18, and the mature forms of IL-1ß and IL-18 was significantly upregulated. The expression levels of NLRC1, NLRC2, and NLRC5 and activation of the downstream NF-κB pathway molecules phospho-IKKß, phospho-IκBα, NF-κB p65, and phospho-NF-κB p65 were significantly increased. The TNF-α and IL-6 levels were significantly increased in diabetic pig kidneys. The TGF-ß/Smad signaling molecules, TGF-ß and P-SMAD2/3, were also increased. These results suggested that the metabolic inflammation activated by NLRs might play an important role in diabetic renal injuries.


Asunto(s)
Diabetes Mellitus , FN-kappa B , Animales , Citocinas/metabolismo , Quinasa I-kappa B , Inflamación , Interleucina-18 , Interleucina-6/metabolismo , Riñón/metabolismo , Inhibidor NF-kappaB alfa , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas NLR , Porcinos , Porcinos Enanos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa
7.
Zhonghua Er Ke Za Zhi ; 60(4): 297-301, 2022 Apr 02.
Artículo en Chino | MEDLINE | ID: mdl-35385933

RESUMEN

Objectives: To examine the impact of probiotics on the lung development of preterm birth of Bama pig. Methods: From April 2020 to October 2021, this animal experimental research was performed by setting up preterm (birth at gestation 104 d), full-term (birth at gestation 113 d), preterm with probiotics (birth at gestation 104 d treated with probiotics given at 3 d after birth), and full-term with probiotics (birth at gestation 113 d treated with probiotics given at 3 d after birth) groups and using the preterm Bama minipig model, the body weights were recorded and lung, ileum, and intestinal content samples were collected at birth, 4 days, 9 days, and 21 days after births of the piglets in preterm and full-term groups, the same samples were collected on 9 days after births of the piglets in preterm with probiotics and full-term with probiotics groups. The body weight and radial alveolar counts (RAC) were compared to evaluate the lung development of the piglets. The lengths of ileal villus were compared to evaluate the development of ileum. The composition structures of bacteria in ileum were analyzed by 16 S rRNA sequencing. The statistical analyses between different groups were performed by t test. Results: There were totally 30 piglets (16 female piglets and 14 male piglets) involving 12 piglets in preterm and full-term groups respectively and 3 piglets in preterm with probiotics and full-term with probiotics groups respectively. The body weights of the piglets in preterm group were lower than those in full-term group at 4, 9 and 21 d after birth ((507±27) vs. (694±56) g, (620±35) vs. (1 092±154) g, (1 660±210) vs. (2 960±418) g,t=2.96, 2.99, 2.78, all P<0.05). The alveolarization of the preterm piglets at 9 days after birth was significantly lower than that of the full-term piglets at the equivalent time point (4.00±0.29 vs. 6.11±0.35, t=4.64, P<0.01). The bacteria genus with the highest abundance in ileum were all different between the preterm and the full-term groups at 4, 9 and 21 d after birth (4 d Escherichia-Shigella (26.63%) and Enterococcus (30.48%) respectively;9 d Turicibacter (35.94%) and Lactobacillus (27.33%) respectively;21 d Escherichia-Shigella (28.02%) and Lactobacillus (46.29%) respectively). The heights of ileal villus of the preterm piglets at 9 d after birth were significantly lower than those of the full-term minipigs at the equivalent time point ((297±21) vs. (411±32) µm, t=3.01, P=0.007).There were both no differences in the body weight and alveolarization ((692±36) vs. (767±67) g, 5.44±0.34 vs. 5.89±0.26, t=0.74, 1.04, both P>0.05) between the piglets in preterm with probiotics group and those in full-term with probiotics group. Turicibacter was the dominant genus in the piglets of both preterm with probiotics and the full-term with probiotics groups. The heights of ileal villus of the piglets in preterm with probiotics group were significantly longer that those of the piglets in preterm group ((371±13) vs. (297±21) µm, t=3.04, P=0.006), and were both not significantly different from those of the piglets in full-term with probiotics group and full-term group ((371±13) vs. (338±12) and (411±32) µm, t=1.90, 1.15, both P>0.05). Conclusions: Premature birth could impact the lung alveolarization of piglets. The probiotics could improve the lung alveolarization of preterm minipigs by promoting the development of ileum.


Asunto(s)
Nacimiento Prematuro , Probióticos , Animales , Peso Corporal , Femenino , Humanos , Pulmón , Masculino , Embarazo , Probióticos/farmacología , Probióticos/uso terapéutico , Porcinos , Porcinos Enanos
8.
Mol Pharm ; 19(5): 1540-1547, 2022 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-35393854

RESUMEN

Treatment of age-related macular degeneration (AMD) with anti-vascular endothelial growth factor (VEGF) biologic agents has been shown to restore and maintain visual acuity for many patients afflicted with wet AMD. These agents are usually administered via intravitreal injection at a dosing interval of 4-8 weeks. Employment of long-acting delivery (LAD) technologies could improve the therapeutic outcome, ensure timely treatment, and reduce burden on patients, caregivers, and the health care system. Development of LAD approaches requires thorough testing in pre-clinical species; however, therapeutic proteins of human origin may not be well tolerated during testing in non-human species due to immunogenicity. Here, we have engineered a surrogate porcine antibody Fab fragment (pigG6.31) from a human antibody for testing ocular LAD technologies in a porcine model. The engineered Fab retains the VEGF-A-binding and inhibition properties of the parental human Fab and has stability properties suitable for LAD evaluation. Upon intravitreal injection in minipigs, pigG6.31 showed first-order clearance from the ocular compartments with vitreal elimination rates consistent with other molecules of this size. Application of the surrogate molecule in an in vivo evaluation in minipigs of a prototype of the port delivery (PD) platform indicated continuous ocular delivery from the implant, with release kinetics consistent with both the results from in vitro release studies and the efficacy observed in human clinical studies of the PD system with ranibizumab (PDS). Anti-drug antibodies in the serum against pigG6.31 were not detected over exposure durations up to 16 weeks, suggesting that this molecule has low porcine immunogenicity.


Asunto(s)
Inhibidores de la Angiogénesis , Degeneración Macular Húmeda , Animales , Humanos , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Inyecciones Intravítreas , Ingeniería de Proteínas , Ranibizumab/uso terapéutico , Porcinos , Porcinos Enanos/metabolismo , Tecnología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Degeneración Macular Húmeda/tratamiento farmacológico
9.
PLoS One ; 17(4): e0266396, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35482719

RESUMEN

Porcine models of spinal cord injury (SCI) have an irreplaceable role in the development of experimental therapies. There is little literature regarding CT myelogram (CTM) techniques in swine and morphometry in miniature swine has not been established. A CT-guided method for performing myelography as well as reference values for spinal morphometry in healthy Yucatan miniature swine is lacking. The goal of this study is to describe a CT-guided method of performing CTM in a porcine model of SCI and to establish spinal morphometric reference values in mature Yucatan pigs. Six healthy, Yucatan sows, 9 months of age, weighing between 39-57.7kg, with no history of spinal disease, spinal injury, or neurologic deficits on physical exam were used in this study. CT myelography was performed in each sow under general anesthesia. CT scout images were used to guide needle placement at the L3-L4 intervertebral site. Once correct needle placement was confirmed using a 1ml test injection, a full dose of iodinated contrast (0.3ml/kg) was injected slowly over a 2-minute time period. Morphometry was performed using area measurements of the spinal cord (SC), vertebral body (VB), dural sac (DS), and vertebral canal (VC) at the mid-body and the intervertebral disc space of each spinal segment. Of the quantitative measurements, the spinal cord surface area had the widest range of values and the greatest coefficient of variance (CV) while those parameters for the vertebral canal had a low CV. Of the morphometric ratios, the DS:VC, had the lowest CV while the spinal cord ratios to DS and VC had the highest (>30). The vertebral canal surface area and the dural space: vertebral canal ratio may serve as reference values in future studies using this animal model.


Asunto(s)
Mielografía , Traumatismos de la Médula Espinal , Animales , Femenino , Mielografía/métodos , Mielografía/veterinaria , Canal Medular , Columna Vertebral/diagnóstico por imagen , Porcinos , Porcinos Enanos , Tomografía Computarizada por Rayos X/métodos
10.
Front Immunol ; 13: 848054, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35432364

RESUMEN

New vaccine design approaches, platforms, and immunization strategies might foster antiviral mucosal effector and memory responses to reduce asymptomatic infection and transmission in vaccinated individuals. Here, we investigated a combined parenteral and mucosal immunization scheme to induce local and serum antibody responses, employing the epitope-based antigens 3BT and NG19m. These antigens target the important emerging and re-emerging viruses PRRSV-2 and SARS-CoV-2, respectively. We assessed two versions of the 3BT protein, which contains conserved epitopes from the GP5 envelope protein of PRRSV-2: soluble and expressed by the recombinant baculovirus BacDual-3BT. On the other hand, NG19m, comprising the receptor-binding motif of the S protein of SARS-CoV-2, was evaluated as a soluble recombinant protein only. Vietnamese mini-pigs were immunized employing different inoculation routes: subcutaneous, intranasal, or a combination of both (s.c.-i.n.). Animals produced antigen-binding and neut1ralizing antibodies in serum and mucosal fluids, with varying patterns of concentration and activity, depending on the antigen and the immunization schedule. Soluble 3BT was a potent immunogen to elicit binding and neutralizing antibodies in serum, nasal mucus, and vaginal swabs. The vectored immunogen BacDual-3BT induced binding antibodies in serum and mucosae, but PRRSV-2 neutralizing activity was found in nasal mucus exclusively when administered intranasally. NG19m promoted serum and mucosal binding antibodies, which showed differing neutralizing activity. Only serum samples from subcutaneously immunized animals inhibited RBD-ACE2 interaction, while mini-pigs inoculated intranasally or via the combined s.c.-i.n. scheme produced subtle neutralizing humoral responses in the upper and lower respiratory mucosae. Our results show that intranasal immunization, alone or combined with subcutaneous delivery of epitope-based antigens, generates local and systemic binding and neutralizing antibodies. Further investigation is needed to evaluate the capability of the induced responses to prevent infection and reduce transmission.


Asunto(s)
COVID-19 , Virus del Síndrome Respiratorio y Reproductivo Porcino , Vacunas Virales , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Formación de Anticuerpos , COVID-19/prevención & control , Epítopos , Femenino , Inmunización , SARS-CoV-2 , Porcinos , Porcinos Enanos
11.
J Med Chem ; 65(7): 5593-5605, 2022 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-35298158

RESUMEN

We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of ∼20-70% of native insulin, and EC50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.


Asunto(s)
Diabetes Mellitus Tipo 2 , Hipoglucemia , Animales , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Perros , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Receptor de Insulina , Porcinos , Porcinos Enanos , Índice Terapéutico
12.
PLoS One ; 17(3): e0260855, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35324911

RESUMEN

BACKGROUND: The purpose of this study was to develop a swine model of surgically induced blood loss to evaluate the performances of a new autotransfusion system allowing red blood cells and platelets preservation while collecting, washing and concentrating hemorrhagic blood intraoperatively. METHODS: Two types of surgically induced blood loss were used in 12 minipigs to assess system performance and potential animal complications following autotransfusion: a cardiac model (cardiopulmonary bypass) and a visceral model (induced splenic bleeding). Animal clinical and hematological parameters were evaluated at different time-points from before bleeding to the end of a 72-hour post-transfusion period and followed by a post-mortem examination. System performances were evaluated by qualitative and quantitative parameters. RESULTS: All animals that received the autotransfusion survived. Minimal variations were seen on the red blood cell count, hemoglobin, hematocrit at the different sampling times. Coagulation tests failed to show any hypo or hypercoagulable state. Gross and histologic examination didn't reveal any thrombotic lesions. Performance parameters exceeded set objectives in both models: heparin clearance (≥ 90%), final heparin concentration (≤ 0.5 IU/mL), free hemoglobin washout (≥ 90%) and hematocrit (between 45% and 65%). The device treatment rate of diluted blood was over 80 mL/min. CONCLUSIONS: In the present study, both animal models succeeded in reproducing clinical conditions of perioperative cardiac and non-cardiac blood loss. Sufficient blood was collected to allow evaluation of autotransfusion effects on animals and to demonstrate the system performance by evaluating its capacity to collect, wash and concentrate red blood cells and platelets. Reinfusion of the treated blood, containing not only concentrated red blood cells but also platelets, did not lead to any postoperative adverse nor thrombogenic events. Clinical and comparative studies need to be conducted to confirm the clinical benefit of platelet reinfusion.


Asunto(s)
Plaquetas , Transfusión de Sangre Autóloga , Animales , Transfusión de Sangre Autóloga/efectos adversos , Eritrocitos , Hemoglobinas , Hemorragia , Heparina , Porcinos , Porcinos Enanos
13.
J Pharmacol Toxicol Methods ; 115: 107168, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35315338

RESUMEN

INTRODUCTION: Porcine animal models are used in biomedical research due to anatomical and physiological similarities with human patients. The study aimed to validate telemetric systemic blood pressure (BP) and heart rate (HR) monitoring in Göttingen Minipigs, and in addition to study the effects of three different anaesthesia protocols on telemetric BP and HR measurements. METHODS: Eight female Göttingen Minipigs had telemetry transmitters implanted in the right carotid artery. Over ten weeks, systemic 24-h BP and HR monitoring were repeated four times, each ending with an angiotensin II stimulation test. In addition, systemic BP and HR evaluated by telemetry, intra-arterial catheter (IAC) and oscillometric tail-cuff were compared before and after the 10-weeks period. Furthermore, changes in telemetric systemic BP and HR were monitored during anaesthesia in a cross-over design using three different protocols of general anaesthesia: Midazolam/ketamine (MK), propofol, and a combination of tiletamine, zolazepam, xylazine, ketamine and butorphanol (Zoletil-mix). RESULTS: One minipig was excluded and some data were missing due to central-venous catheter issues. The coefficient of variation was below 10% for the 24-h BP and HR measurements, but higher during angiotensin II stimulation. There was a disagreement between the tail-cuff measurement and telemetry/IAC, however the differences were independent of the BP and HR level. All anaesthesia protocols numerically influenced BP and HR, but only propofol statistically significantly decreased the BP. CONCLUSION: The study showed acceptable reproducibility of telemetric measurement of BP and HR over ten weeks in freely moving Göttingen Minipigs. There was a disagreement between direct and indirect BP measurement, and BP and HR were influenced by all anaesthesia protocols.


Asunto(s)
Anestesia , Ketamina , Propofol , Angiotensina II , Animales , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Humanos , Ketamina/farmacología , Propofol/farmacología , Reproducibilidad de los Resultados , Porcinos , Porcinos Enanos , Telemetría/métodos
14.
J Vis Exp ; (180)2022 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-35253787

RESUMEN

More than half of heart failure (HF) cases are classified as heart failure with preserved ejection fraction (HFpEF) worldwide. Large animal models are limited for investigating the fundamental mechanisms of HFpEF and identifying potential therapeutic targets. This work provides a detailed description of the surgical procedure of descending aortic constriction (DAC) in Tibetan minipigs to establish a large animal model of HFpEF. This model used a precisely controlled constriction of the descending aorta to induce chronic pressure overload in the left ventricle. Echocardiography was used to evaluate the morphological and functional changes in the heart. After 12 weeks of DAC stress, the ventricular septum was hypertrophic, but the thickness of the posterior wall was significantly reduced, accompanied by dilation of the left ventricle. However, the LV ejection fraction of the model hearts was maintained at >50% during the 12-week period. Furthermore, the DAC model displayed cardiac damage, including fibrosis, inflammation, and cardiomyocyte hypertrophy. Heart failure marker levels were significantly elevated in the DAC group. This DAC-induced HFpEF in minipigs is a powerful tool for investigating molecular mechanisms of this disease and for preclinical testing.


Asunto(s)
Insuficiencia Cardíaca , Animales , Modelos Anatómicos , Volumen Sistólico , Porcinos , Porcinos Enanos , Tibet
15.
PLoS One ; 17(3): e0265347, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35324926

RESUMEN

BACKGROUND: We recently reported that multilineage-differentiating stress enduring (Muse) cells intravenously administered after acute myocardial infarction (AMI), selectively engrafted to the infarct area, spontaneously differentiated into cardiomyocytes and vessels, reduced the infarct size, improved the left ventricular (LV) function and remodeling in rabbits. We aimed to clarify the efficiency of Muse cells in a larger animal AMI model of mini-pigs using a semi-clinical grade human Muse cell product. METHOD AND RESULT: Mini-pigs underwent 30 min of coronary artery occlusion followed by 2 weeks of reperfusion. Semi-clinical grade human Muse cell product (1x107, Muse group, n = 5) or saline (Vehicle group, n = 7) were intravenously administered at 24 h after reperfusion. The infarct size, LV function and remodeling were evaluated by echocardiography. Arrhythmias were evaluated by an implantable loop recorder. The infarct size was significantly smaller in the Muse group (10.5±3.3%) than in the Vehicle group (21.0±2.0%). Both the LV ejection fraction and fractional shortening were significantly greater in the Muse group than in the Vehicle group. The LV end-systolic and end-diastolic dimensions were significantly smaller in the Muse group than in the Vehicle group. Human Muse cells homed into the infarct border area and expressed cardiac troponin I and vascular endothelial CD31. No arrhythmias and no blood test abnormality were observed. CONCLUSION: Muse cell product might be promising for AMI therapy based on the efficiency and safety in a mini-pig AMI.


Asunto(s)
Alprostadil , Infarto del Miocardio , Animales , Arritmias Cardíacas , Modelos Animales de Enfermedad , Humanos , Conejos , Porcinos , Porcinos Enanos , Función Ventricular Izquierda
16.
J Pharmacol Toxicol Methods ; 115: 107167, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35301126

RESUMEN

Pending updates to ICH S7B/E14 guidelines will enable the substitution of human TQT studies with support from concomitant negative hERG and non-rodent CV studies. This retrospective analysis compared the effects of thioridazine (THD) (5-20 mg/kg) on heart rate (HR), blood pressure (BP), body temperature (Tc), and QT in the dog (n = 6), cynomolgus monkey (n = 4), and Goettingen minipig (n = 4) with data from previously completed studies employing crossover designs. As QT measurements are confounded by HR and Tc changes, QT effects were individually corrected for changes in HR (QTca) and Tc (QTcaT). THD-induced hemodynamic changes seen in humans were most accurately reflected in the monkey and, to a lesser extent, the dog, but not in the minipig. The minipig was most sensitive to THD QTc effects. When QTca was adjusted for THD-associated Tc decreases in minipigs and monkeys, the minipig revealed a lessened but pronounced QTcaT increase (48 ms). In the monkey, a persistent QTca increase was reduced to only a transient (0.5-3 h) QTcaT increase (20 ms). The dog's lack of THD QTca effects triggered co-administration of atenolol (AT) to attenuate THD-induced HR increases in the dog and monkey. THD + AT revealed peak QTcaT increases of 32 ms in the dog and 40 ms in the monkey, suggesting potential autonomic nervous system (ANS) interference in detecting repolarization changes. These results highlight critical species-specific differences in the outcome of parallel safety investigations. Species selection for nonclinical safety studies should consider the potential impact of Tc and ANS effects to avoid false-negative or overly positive outcomes.


Asunto(s)
Síndrome de QT Prolongado , Animales , Sistema Nervioso Autónomo , Temperatura Corporal , Perros , Electrocardiografía , Frecuencia Cardíaca , Síndrome de QT Prolongado/inducido químicamente , Macaca fascicularis , Estudios Retrospectivos , Porcinos , Porcinos Enanos , Telemetría/métodos , Tioridazina/efectos adversos
17.
Acta Cir Bras ; 37(1): e370103, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35262597

RESUMEN

INTRODUCTION: Portal hypertension still represents an important health problem worldwide. In the search for knowledge regarding this syndrome, experimental studies with animal models have proven to be useful to point the direction to be taken in future randomized clinical trials. PURPOSE: To validate the experimental model of portal hypertension and esophagogastric varices in a medium-sized animal. METHODS: This study included five minipigs br1. Midline laparotomy with dissection of the portal vein and production of a calibrated stenosis of this vein was performed. Measurement of pressure in the portal venous and digestive endoscopic were performed before and five weeks after the production of a stenosis. RESULTS: All animals were 8 months old, average weight of 17 ± 2.5 kg. The mean pressure of the portal vein immediately before the partial ligation of the portal vein was 8.9 + 1.6 mm Hg, with 26.6 + 5.4 mm Hg in the second measurement five weeks later (p < 0.05). No gastroesophageal varices or hypertensive portal gastropathy were seen at endoscopy procedures in our sample at any time in the study. CONCLUSION: Portal vein ligation in minipigs has been validated in the production of portal hypertension, but not in the formation of esophageal varices.


Asunto(s)
Várices Esofágicas y Gástricas , Hipertensión Portal , Várices , Animales , Endoscopía , Várices Esofágicas y Gástricas/cirugía , Modelos Teóricos , Proyectos Piloto , Vena Porta/cirugía , Porcinos , Porcinos Enanos
18.
BMC Vet Res ; 18(1): 99, 2022 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-35292024

RESUMEN

BACKGROUND: Hepatitis E virus (HEV) genotypes 3 and 4 are zoonotic. In this study, HEV infection in laboratory Bama miniature pigs in Sichuan Province of China was investigated. Firstly, one hundred rectal swabs were collected for HEV RNA testing, and chose positive samples for sequence analysis. Concurrently, for pathogenicity study, six healthy Bama miniature pigs were randomly divided into two groups of 3 pigs each. A total of 500 µL of HEV stock (positive fecal samples identified in this study) was inoculated intravenously into each pig in the experimental group, and the three pigs in the other group served as negative controls. Serum and fecal samples were collected at 1 to 10 weeks post-inoculation (wpi) for alanine aminotransferase (ALT) levels, anti-HEV antibodies and HEV RNA detection, respectively. During necropsies, liver lesions and HEV antigen in liver were observed at 10 wpi. RESULTS: The rate of fecal sample HEV RNA-positivity was 12% (12/100). Sequence comparisons indicated that partial ORF1 and ORF2 gene sequences of this isolate shared highest identities with corresponding sequences of genotype 4a HEV isolates (81.4%-96.1% and 89.9%-97.1%, respectively). Phylogenetic tree analysis further demonstrated that sequences of this isolate clustered together with sub-genotype 4a HEV isolate sequences. Experimentally, the pathogenicity of Bama miniature pigs infected with this isolate exhibited viremia, fecal virus shedding, seroconversion, ALT level increasing, liver lesions and HEV antigen in liver. CONCLUSIONS: This is the first study to confirm that HEV is currently circulating in laboratory Bama miniature pigs in China and this isolate can successfully infect Bama miniature pigs experimentally. More importantly, this study suggested HEV screening of laboratory pigs should be conducted to prevent research personnel from acquiring zoonotic HEV infections.


Asunto(s)
Virus de la Hepatitis E , Hepatitis E , Enfermedades de los Porcinos , Animales , Heces , Genotipo , Hepatitis E/veterinaria , Filogenia , ARN Viral , Porcinos , Porcinos Enanos/genética , Virulencia
19.
Int J Toxicol ; 41(2): 99-107, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35245984

RESUMEN

Polysorbate 80 (PS80) is commonly used in pre-clinical formulations. The dose threshold for cardiovascular (CV) changes and hypersensitivity reaction in the dog was assessed and compared to other species. PS80 was administered by intravenous (IV) bolus (.5, 1 mg/kg), IV infusion (.3, .5, 1, 3 mg/kg), subcutaneous (SC) injection (5, 10, 15 mg/kg) and oral gavage (10 mg/kg) to dogs with CV monitoring. Monkeys and minipigs received PS80 by IV infusion at 3 mg/kg. Plasma histamine concentration was measured following PS80 IV infusion and with diphenhydramine pre-treatment in dogs only. In dogs, PS80 was not associated with CV changes at doses up to 15 mg/kg SC and 10 mg/kg oral, but decreased blood pressure and increased heart rate with IV bolus at ≥ .5 mg/kg and IV infusion at ≥ 1.0 mg/kg and decreased body temperature with IV infusion at 3 mg/kg was observed. Transient edema and erythema were noted with all administration routes, in all three species including doses that were devoid of CV effects. In monkeys and minipigs, PS80 did not induce CV, cutaneous or histamine concentration changes. These results suggest that mild, transient skin changes occur following PS80 administration at doses that are not associated with CV effects in the dogs. In dogs, the cardiovascular effect threshold was <.5 mg/kg for IV bolus, .3 mg/kg for IV infusion, 15 mg/kg for SC injection, and 10 mg/kg for oral administration. Monkey and minipig were refractory to PS80-induced histamine release at 3 mg/kg by IV infusion over 15 minutes.


Asunto(s)
Anafilaxia , Polisorbatos , Anafilaxia/inducido químicamente , Animales , Perros , Histamina , Inyecciones Intravenosas , Polisorbatos/toxicidad , Porcinos , Porcinos Enanos
20.
Biomaterials ; 282: 121392, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35134701

RESUMEN

Critical-sized midfacial bone defects present a unique clinical challenge due to their complex three-dimensional shapes and intimate associations with sensory organs. To address this challenge, a point-of-care treatment strategy for functional, long-term regeneration of 2 cm full-thickness segmental defects in the zygomatic arches of Yucatan minipigs is evaluated. A digital workflow is used to 3D-print anatomically precise, porous, biodegradable scaffolds from clinical-grade poly-ε-caprolactone and decellularized bone composites. The autologous stromal vascular fraction of cells (SVF) is isolated from adipose tissue extracts and infused into the scaffolds that are implanted into the zygomatic ostectomies. Bone regeneration is assessed up to 52 weeks post-operatively in acellular (AC) and SVF groups (BV/DV = 0.64 ± 0.10 and 0.65 ± 0.10 respectively). In both treated groups, bone grows from the adjacent tissues and restores the native anatomy. Significantly higher torque is required to fracture the bone-scaffold interface in the SVF (7.11 ± 2.31 N m) compared to AC groups (2.83 ± 0.23 N m). Three-dimensional microcomputed tomography analysis reveals two distinct regenerative patterns: osteoconduction along the periphery of scaffolds to form dense lamellar bone and small islands of woven bone deposits growing along the struts in the scaffold interior. Overall, this study validates the efficacy of using 3D-printed bioactive scaffolds with autologous SVF to restore geometrically complex midfacial bone defects of clinically relevant sizes while also highlighting remaining challenges to be addressed prior to clinical translation.


Asunto(s)
Andamios del Tejido , Animales , Regeneración Ósea , Osteogénesis , Sistemas de Atención de Punto , Impresión Tridimensional , Porcinos , Porcinos Enanos , Microtomografía por Rayos X
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