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Article: Selective and Concentrative Enteropancreatic Recirculation of Antibiotics by Pigs.

Buddington, Karyl K / Pierzynowski, Stefan G / Holmes, William E / Buddington, Randal K

2023 Volume 13, Issue 1

Abstract: Antibiotics that are efficacious for infectious pancreatitis are present in pancreatic exocrine secretion (PES) after intravenous administration and above minimal inhibitory concentrations. We measured concentrations of four antibiotics by tandem liquid ... ...

Abstract	Antibiotics that are efficacious for infectious pancreatitis are present in pancreatic exocrine secretion (PES) after intravenous administration and above minimal inhibitory concentrations. We measured concentrations of four antibiotics by tandem liquid chromatography-mass spectroscopy in plasma and PES after enteral administration to juvenile pigs with jugular catheters and re-entrant pancreatic-duodenal catheters. Nystatin, which is not absorbed by the intestine nor used for infectious pancreatitis (negative control), was not detected in plasma or PES. Concentrations of amoxicillin increased in plasma after administration (
Language	English
Publishing date	2023-12-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2681345-2
ISSN	2079-6382
ISSN	2079-6382
DOI	10.3390/antibiotics13010012
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Article ; Online: Multiple Asparaginase Infusions Cause Increasingly Severe Acute Hyperammonemia.

Buddington, Randal K / Buddington, Karyl K / Howard, Scott C

Medical sciences (Basel, Switzerland)

2022 Volume 10, Issue 3

Abstract: Adverse reactions during and shortly after infusing asparaginase for the treatment of acute lymphoblastic leukemia can increase in severity with later doses, limiting further use and increasing relapse risk. Although asparaginase is associated with ... ...

Abstract	Adverse reactions during and shortly after infusing asparaginase for the treatment of acute lymphoblastic leukemia can increase in severity with later doses, limiting further use and increasing relapse risk. Although asparaginase is associated with hyperammonemia, the magnitude of the increase in serum ammonia immediately after the infusion and in response to multiple infusions has not been examined. The concurrence of hyperammonemia and infusion reactions was studied using weaned juvenile pigs that received 12 infusions of Erwinia asparaginase (Erwinase; 1250 U/kg) over 28 days, with two 5-day recovery periods without asparaginase after the eighth and eleventh doses. Infusion reactions and prolonged hyperammonemia (>50 µM ammonia 48 h after the infusion) began after the fourth dose and increased with later doses. Dense sampling for 60 min revealed an acute phase of hyperammonemia that peaked within 20 min after starting the first infusion (298 + 62 µM) and lasted less than 1 h, without apparent symptoms. A pronounced acute hyperammonemia after the final infusion (1260 + 250 µM) coincided with severe symptoms and one mortality during the infusion. The previously unrecognized acute phase of hyperammonemia associated with asparaginase infusion coincides with infusion reactions. The juvenile pig is a translational animal model for understanding the causes of acute and chronic hyperammonemia, differentiating from hypersensitivity reactions, and for improving infusion protocols to reduce acute hyperammonemia and to allow the continued use of asparaginase.
MeSH term(s)	Ammonia/therapeutic use ; Animals ; Antineoplastic Agents/toxicity ; Asparaginase/adverse effects ; Hyperammonemia/chemically induced ; Hyperammonemia/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/chemically induced ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Swine
Chemical Substances	Antineoplastic Agents ; Ammonia (7664-41-7) ; Asparaginase (EC 3.5.1.1)
Language	English
Publishing date	2022-08-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2754473-4
ISSN	2076-3271 ; 2076-3271
ISSN (online)	2076-3271
ISSN	2076-3271
DOI	10.3390/medsci10030043
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Article ; Online: Early clinical indicators of acute kidney injury caused by administering high-dose methotrexate therapy to juvenile pigs.

Buddington, Randal K / Wong, Thomas / Buddington, Karyl K / Mikkelsen, Torben S / Cao, Xueyuan / Howard, Scott C

Frontiers in nephrology

2023 Volume 3, Page(s) 1193494

Abstract: Introduction: Early identification of compromised renal clearance caused by high-dose methotrexate (HDMTX) is essential for initiating timely interventions that can reduce acute kidney injury and MTX-induced systemic toxicity.: Methods: We induced ... ...

Abstract	Introduction: Early identification of compromised renal clearance caused by high-dose methotrexate (HDMTX) is essential for initiating timely interventions that can reduce acute kidney injury and MTX-induced systemic toxicity. Methods: We induced acute kidney injury (AKI) by infusing 42 juvenile pigs with 4 g/kg (80 g/m2) of MTX over 4 hours without high-volume alkalinizing hydration therapy. Concentrations of serum creatinine and MTX were measured at 15 time points up to 148 hours, with 10 samples collected during the first 24 hours after the start of the HDMTX infusion. Results: During the first 28 hours, 81% of the pigs had increases in the concentrations of serum creatinine in one or more samples indicative of AKI (i.e., > 0.3g/dL increase). A rate of plasma MTX clearance of less than 90% during the initial 4 hours after the HDMTX infusion and a total serum creatinine increase at 6 and 8 hours after starting the infusion greater than 0.3 g/dL were predictive of AKI at 28 hours ( Conclusions: Our findings suggest that serum samples collected at conclusion and shortly after HDMTX infusion can be used to predict impending AKI. The pig model can be used to identify biological, environmental, and iatrogenic risk factors for HDMTX-induced AKI and to evaluate interventions to preserve renal functions, minimize acute kidney injury, and reduce systemic toxicity.
Language	English
Publishing date	2023-09-12
Publishing country	Switzerland
Document type	Journal Article
ISSN	2813-0626
ISSN (online)	2813-0626
DOI	10.3389/fneph.2023.1193494
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Article ; Online: Paracellular Filtration Secretion Driven by Mechanical Force Contributes to Small Intestinal Fluid Dynamics.

Buddington, Randal K / Wong, Thomas / Howard, Scott C

Medical sciences (Basel, Switzerland)

2021 Volume 9, Issue 1

Abstract: Studies of fluid secretion by the small intestine are dominated by the coupling with ATP-dependent generation of ion gradients, whereas the contribution of filtration secretion has been overlooked, possibly by the lack of a known mechanistic basis. We ... ...

Abstract	Studies of fluid secretion by the small intestine are dominated by the coupling with ATP-dependent generation of ion gradients, whereas the contribution of filtration secretion has been overlooked, possibly by the lack of a known mechanistic basis. We measured apical fluid flow and generation of hydrostatic pressure gradients by epithelia of cultured mouse enterocytes, Caco-2 and T-84 cells, and fibroblasts exposed to mechanical force provided by vigorous aeration and in response to ion gradients, inhibitors of ion channels and transporters and in vitro using intact mouse and rat small intestine. We describe herein a paracellular pathway for unidirectional filtration secretion that is driven by mechanical force, requires tight junctions, is independent of ionic and osmotic gradients, generates persistent hydrostatic pressure gradients, and would contribute to the fluid shifts that occur during digestion and diarrhea. Zinc inhibits the flow of fluid and the paracellular marker fluorescein isothyocyanate conjugated dextran (MW = 4 kD) across epithelia of cultured enterocytes (>95%;
MeSH term(s)	Animals ; Caco-2 Cells ; Diarrhea ; Humans ; Hydrodynamics ; Intestine, Small ; Mice ; Rats ; Tight Junctions
Language	English
Publishing date	2021-02-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2754473-4
ISSN	2076-3271 ; 2076-3271
ISSN (online)	2076-3271
ISSN	2076-3271
DOI	10.3390/medsci9010009
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Article: Effects of Phosphatidylserine Source of Docosahexaenoic Acid on Cerebellar Development in Preterm Pigs.

Chizhikov, Daniel / Buddington, Randal K / Iskusnykh, Igor Y

Brain sciences

2020 Volume 10, Issue 8

Abstract: Preterm birth, a major contributor to infant mortality and morbidity, impairs development of the cerebellum, the brain region involved in cognitive processing and motor function. Previously, we showed that at term-equivalent age, preterm pigs that ... ...

Abstract	Preterm birth, a major contributor to infant mortality and morbidity, impairs development of the cerebellum, the brain region involved in cognitive processing and motor function. Previously, we showed that at term-equivalent age, preterm pigs that received formula supplemented with docosahexaenoic acid (DHA) esterified to phosphatidylserine (PS) had cerebellar weights similar to those of newborn term pigs and were heavier than control preterm pigs. However, whether PS-DHA promotes the development of specific cerebellar cell populations or enhances key developmental processes remains unknown. Here we investigated the effects of the PS-DHA on development of the cerebellum in preterm pigs delivered via caesarean section and reared for ten days on a milk replacer with either PS-DHA (experimental group) or sunflower oil (control group). Upon necropsy, key cerebellar populations were analyzed using immunohistochemistry. Consumption of PS-DHA was associated with the expansion of undifferentiated granule cell precursors and increased proliferation in the external granule cell layer (EGL). Preterm pigs that received PS-DHA also had significantly fewer apoptotic cells in the internal granule cell layer (IGL) that contains differentiated granule neurons. PS-DHA did not affect the number of differentiating granule cells in the inner EGL, thickness of the inner EGL, density of Purkinje cells, or Bergmann glial fibers, or diameter of Purkinje cells. Thus, PS-DHA may support cerebellar development in preterm subjects by enhancing proliferation of granule cells, a process specifically inhibited by preterm birth, and increasing the survival of granule cells in the IGL. These findings suggest that PS-DHA is a promising candidate for clinical studies directed at enhancing brain development.
Language	English
Publishing date	2020-07-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci10080475
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Article ; Online: K

Peixoto-Neves, Dieniffer / Kanthakumar, Praghalathan / Afolabi, Jeremiah M / Soni, Hitesh / Buddington, Randal K / Adebiyi, Adebowale

American journal of physiology. Renal physiology

2022 Volume 322, Issue 2, Page(s) F197–F207

Abstract: ... ...

Abstract	K
MeSH term(s)	Animals ; Animals, Newborn ; Arterial Pressure/drug effects ; Chromans/pharmacology ; Gene Expression Regulation, Developmental ; Gestational Age ; Homeostasis ; KCNQ1 Potassium Channel/antagonists & inhibitors ; KCNQ1 Potassium Channel/genetics ; KCNQ1 Potassium Channel/metabolism ; Kidney/blood supply ; Microvessels/drug effects ; Microvessels/metabolism ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/metabolism ; Potassium Channel Blockers/pharmacology ; Renal Circulation/drug effects ; Signal Transduction ; Sulfonamides/pharmacology ; Sus scrofa ; Vasodilation/drug effects
Chemical Substances	Chromans ; HMR 1556 ; KCNQ1 Potassium Channel ; Potassium Channel Blockers ; Sulfonamides
Language	English
Publishing date	2022-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00568.2020
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Article ; Online: Allergic Reactions to E. coli Asparaginase are Associated with Decreased Asparaginase Activity in an Indonesian Pediatric Population with ALL.

Sari, Nur Melani / Berbudi, Afiat / Susanah, Susi / Reniarti, Lelani / Supriyadi, Eddy / Kaspers, Gertjan J L / Buddington, Randal K / Howard, Scott / Idjradinata, Ponpon

Asian Pacific journal of cancer prevention : APJCP

2023 Volume 24, Issue 8, Page(s) 2773–2780

Abstract: Purpose: The asparaginase's (ASP) utility for ALL treatment is limited by neutralizing antibodies, which is problematic in countries whose access limited to alternative preparations. ASP antibody levels and activity was measured during remission ... ...

Abstract	Purpose: The asparaginase's (ASP) utility for ALL treatment is limited by neutralizing antibodies, which is problematic in countries whose access limited to alternative preparations. ASP antibody levels and activity was measured during remission induction and associated with allergy manifestations. Methods: E. coli ASP was dosed at 7500 IU/m2. ASP IgG antibody levels were quantified at the beginning and end of induction. ASP activity was measured 24 hours after 1st and 5th dose (standard-risk) or 7th dose (high-risk patients) administration, and within 24 hours in case of allergic reactions. Allergy was monitored by CTCAE version 3. Parametric and non-parametric was performed for data analysis. Results: ASP antibody and activity levels were available in 41/63 consecutive patients. Allergic manifestations occurred in 13/41, with urticaria being the most frequent. There were no significant differences in subject characteristics based on allergic reactions. The 5th dose was the most frequent time of onset. Antibody levels in allergy group at the end of induction did not differ from those at baseline (p<0.05). Using a 24-hour level of 100 mU/mL as a threshold for adequate ASP activity, 6/13 patients with allergy had adequate levels compared to 26/28 patients without (p<0.05). The ASP activity level at the end of induction phase in both groups did not show a significant decrement. Conclusion: The E. coli ASP activity with adequate levels were significantly higher in non-allergy group. Its activity level was not accompanied by increment of IgG in allergic group indicates other factors might affect activity levels in allergy group.
MeSH term(s)	Child ; Humans ; Asparaginase/adverse effects ; Escherichia coli ; Indonesia ; Urticaria ; Antibodies
Chemical Substances	Asparaginase (EC 3.5.1.1) ; Antibodies
Language	English
Publishing date	2023-08-01
Publishing country	Thailand
Document type	Journal Article
ZDB-ID	2218955-5
ISSN	2476-762X ; 1513-7368
ISSN (online)	2476-762X
ISSN	1513-7368
DOI	10.31557/APJCP.2023.24.8.2773
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Article: Fasting Protocols Do Not Improve Intestinal Architecture and Immune Parameters in C57BL/6 Male Mice Fed a High Fat Diet.

Ageeli, Raed Y / Sharma, Sunita / Puppa, Melissa / Bloomer, Richard J / Buddington, Randal K / van der Merwe, Marie

Medicines (Basel, Switzerland)

2023 Volume 10, Issue 2

Abstract: Background: The intestinal ecosystem, including epithelium, immune cells, and microbiota, are influenced by diet and timing of food consumption. The purpose of this study was to evaluate various dietary protocols after ad libitum high fat diet (HFD) ... ...

Abstract	Background: The intestinal ecosystem, including epithelium, immune cells, and microbiota, are influenced by diet and timing of food consumption. The purpose of this study was to evaluate various dietary protocols after ad libitum high fat diet (HFD) consumption on intestinal morphology and mucosal immunity. Methods: C57BL/6 male mice were fed a 45% high fat diet (HFD) for 6 weeks and then randomized to the following protocols; (1) chow, (2) a purified high fiber diet known as the Daniel Fast (DF), HFD consumed (3) ad libitum or in a restricted manner; (4) caloric-restricted, (5) time-restricted (six hours of fasting in each 24 h), or (6) alternate-day fasting (24 h fasting every other day). Intestinal morphology and gut-associated immune parameters were investigated after 2 months on respective protocols. Results: Consuming a HFD resulted in shortening of the intestine and reduction in villi and crypt size. Fasting, while consuming the HFD, did not restore these parameters to the extent seen with the chow and DF diet. Goblet cell number and regulatory T cells had improved recovery with high fiber diets, not seen with the HFD irrespective of fasting. Conclusion: Nutritional content is a critical determinant of intestinal parameters associated with gut health.
Language	English
Publishing date	2023-02-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2777965-8
ISSN	2305-6320
ISSN	2305-6320
DOI	10.3390/medicines10020018
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Article ; Online: Intrauterine growth restriction compromises cerebellar development by affecting radial migration of granule cells via the JamC/Pard3a molecular pathway.

Iskusnykh, Igor Y / Fattakhov, Nikolai / Buddington, Randal K / Chizhikov, Victor V

Experimental neurology

2020 Volume 336, Page(s) 113537

Abstract: Intrauterine growth restriction (IUGR) affects ~10% of human pregnancies, results in infants born small for gestational age (SGA), and is associated with motor and cognitive deficits. Human studies suggest that some deficits in SGA patients originate in ... ...

Abstract	Intrauterine growth restriction (IUGR) affects ~10% of human pregnancies, results in infants born small for gestational age (SGA), and is associated with motor and cognitive deficits. Human studies suggest that some deficits in SGA patients originate in the cerebellum, a major motor-coordination and cognitive center, but the underlying mechanisms remain unknown. To identify the cerebellar developmental program affected by IUGR, we analyzed the pig as a translational animal model in which some fetuses spontaneously develop IUGR due to early-onset chronic placental insufficiency. Similar to humans, SGA pigs revealed small cerebella, which contained fewer mature granule cells (GCs) in the internal granule cell layer (IGL). Surprisingly, newborn SGA pigs had increased proliferation of GC precursors in the external granule cell layer (EGL), which was associated with an increased density of Purkinje cells, known to non-autonomously promote the proliferation of GCs. However, the GCs of SGA pigs did not properly initiate exit from the EGL to IGL, which was associated with a decreased density of guiding Bergmann glial fibers, reduced expression of pro-migratory genes Pard3a, JamC and Sema6a, and increased apoptosis. While proliferation spontaneously normalized during postnatal development, accumulation of pre-migratory GCs and apoptosis in the EGL were long-lasting consequences of IUGR. Using organotypic cerebellar slice cultures, we showed that normalizing expression of Pard3a and JamC, which operate in the same molecular pathway in GCs, was sufficient to rescue both migratory and, at a later time point, apoptotic defects of IUGR. Thus, a decreased exit of GCs from the EGL, due to disrupted Pard3a/JamC radial migration initiation pathway, is a major mechanism of IUGR-related cerebellar pathology.
MeSH term(s)	Animals ; Animals, Newborn ; Apoptosis ; Cell Count ; Cell Differentiation ; Cell Movement ; Cell Proliferation ; Cerebellum/growth & development ; Cerebellum/pathology ; Cytoplasmic Granules ; Female ; Fetal Growth Retardation/pathology ; Pregnancy ; Purkinje Cells/pathology ; Signal Transduction/genetics ; Swine
Language	English
Publishing date	2020-11-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2020.113537
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Article: Organ Growth and Intestinal Functions of Preterm Pigs Fed Low and High Protein Formulas With or Without Supplemental Leucine or Hydroxymethylbutyrate as Growth Promoters.

Buddington, Randal K / Yakimkova, Taisiya / Adebiyi, Adebowale / Chizhikov, Victor V / Iskusnykh, Igor Y / Buddington, Karyl K

Frontiers in nutrition

2021 Volume 8, Page(s) 687703

Abstract: The goal of enteral nutritional support for infants born preterm or small for gestational age (SGA) is to achieve normal growth and development. Yet, this is difficult to achieve because of intestinal immaturity. Our objective was to determine if birth ... ...

Abstract	The goal of enteral nutritional support for infants born preterm or small for gestational age (SGA) is to achieve normal growth and development. Yet, this is difficult to achieve because of intestinal immaturity. Our objective was to determine if birth weight, protein intake, and the growth promoters leucine (10 g/L) or calcium-ß-hydroxy-ß-methylbutryate (HMB; 1.1 g/L) would affect trajectories of intestinal growth and functions and weights of other organs. Preterm pigs were delivered at gestational day 105 (91% of term) and fed for 6 or 7 days isocaloric formulas that differed in protein content (50 g or 100 g protein/L), with and without the growth promoters leucine or HMB. For comparative purposes organ weights were measured within 12 h after delivery for six term pigs of low and six of average birth weights. The responses of intestinal growth and total intestinal brush border membrane carbohydrases to protein level and supplemental leucine were of greater magnitude for preterm pigs of lower birth weight. Forskolin stimulated chloride secretion in the proximal small intestine was lower for pigs fed the low protein milk replacers. Capacities of the entire small intestine to transport glucose (mmol/kg-day) were not responsive to protein level, leucine, or HMB, and did not differ between small and large pigs. Relative organ weights of the small and average weight term pigs were similar, but some differed from those of the preterm pigs suggesting preterm birth and the standards of care used for this study altered the trajectories of development for the intestine and other organs. Although leucine is an effective generalized growth promoter that enhances gut development of small preterm pigs, it does not mitigate compromised neurodevelopment. Our findings using preterm pigs as a relevant preclinical model indicate nutrition support strategies can influence development of some gastrointestinal tract characteristics and the growth of other organs.
Language	English
Publishing date	2021-06-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2776676-7
ISSN	2296-861X
ISSN	2296-861X
DOI	10.3389/fnut.2021.687703
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