Long-term administration of high-dose deferoxamine 2 days per week in thalassemic patients

We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments β-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of β-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9+ (Sox9+) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing β cells in an in vitro culture. Whether Sox9+ ductal cells in the adult pancreas can give rise to β cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin- or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9+ ductal cell differentiation into insulin-producing β cells, and medium hyperglycemia (300–450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting β-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9+ ductal cell differentiation into β cells in adult mice.

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The Molecular Mechanism of Chronic High-Dose Corticosterone-Induced Aggravation of Cognitive Impairment in APP/PS1 Transgenic Mice

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.613421 ◽

2021 ◽

Vol 13 ◽

Author(s):

Shen-Qing Zhang ◽

Long-Long Cao ◽

Yun-Yue Liang ◽

Pu Wang

Keyword(s):

Preclinical Model ◽

High Dose ◽

Term Administration ◽

Amyloid Aβ ◽

Β Amyloid ◽

Stimulation Of ◽

Bace 1

Clinical studies have found that some Alzheimer’s disease (AD) patients suffer from Cushing’s syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of β-amyloid (Aβ). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 in in vitro and in vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1 via the PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons.

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DDEL-09. HIGH DOSE MTX110 (SOLUBLE PANOBINOSTAT) SAFELY ADMINISTERED INTO THE FOURTH VENTRICLE IN A NON-HUMAN PRIMATE MODEL

Neuro-Oncology ◽

10.1093/neuonc/noaa222.044 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii285-iii285

Author(s):

Rachael W Sirianni ◽

Natasha Kharas ◽

Bangning Yu ◽

Christopher F Janssen ◽

Amanda Trimble ◽

...

Keyword(s):

Fourth Ventricle ◽

High Dose ◽

Short Term ◽

Primate Model ◽

Lumbar Drain ◽

Group I ◽

Term Administration ◽

Mri Scans ◽

Group Ii

Abstract OBJECTIVE This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma, UK) into the fourth ventricle of non-human primates. METHODS Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In Group I (n=2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess cerebrospinal fluid (CSF) distribution after short-term infusions. MTX110 (0.5 ml of 300 μM panobinostat solution) was infused into the fourth ventricle daily for five consecutive days. Serial CSF and serum panobinostat levels were measured. In Group II (n=2), fourth ventricle catheters were connected to a subcutaneously-placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5 daily infusions (0.5 ml of 300 μM panobinostat solution), were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and post-mortem histological analysis. RESULTS Neurological assessments, MRI, and histology confirmed catheter placement and an absence of neurotoxicity. Panobinostat was undetectable in serum collected two and four hours after infusions in all samples in both groups. In Group I, mean peak panobinostat level in fourth ventricle CSF (6242 ng/ml) was significantly higher than in lumbar CSF (9 ng/ml; p < 0.0001). In Group II, mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than mean trough CSF level (33 ng/ml; p<0.0001). CONCLUSION MTX110 can be safely delivered via 4th ventricle at supra-therapeutic doses. These results provide data for a pilot clinical trial in patients with recurrent medulloblastoma.

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Effects of Long-term Administration of High-dose Recombinant Human Antithrombin in Immunosuppressed Primate Recipients of Porcine Xenografts

Transplantation Journal ◽

10.1097/01.tp.0000178377.55615.8b ◽

2005 ◽

Vol 80 (10) ◽

pp. 1501-1510 ◽

Cited By ~ 29

Author(s):

Emanuele Cozzi ◽

Paolo Simioni ◽

Massimo Boldrin ◽

Michela Seveso ◽

Fiorella Calabrese ◽

...

Keyword(s):

High Dose ◽

Term Administration

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Toxicological evaluation of chronic oral administration of Melissa officinalis hydro-ethanol extract in Sprague-Dawley rats

Veterinary Science Development ◽

10.4081/vsd.2017.6298 ◽

2017 ◽

Vol 7 (1) ◽

Author(s):

Mohammad Hashemnia ◽

Farid Rezaei ◽

Zahra Nikousefat ◽

Maral Bahiraei

Keyword(s):

Mononuclear Cells ◽

Control Group ◽

High Dose ◽

Alcoholic Extract ◽

Sprague Dawley ◽

Melissa Officinalis ◽

Medicinal Uses ◽

Sprague Dawley Rats ◽

Term Administration

Melissa officinalis is a plant that has been widely used as an herbal medicine in many countries. Unfortunately, despite the prevalent medicinal uses of the plant, there are no reports on the possible toxic effects of M. officinalis. This study was designed to evaluate the effect of long-term administration of hydro-alcoholic extract of M. officinalis on some biochemical and hematological parameters and histopathology of organs. Thirty Sprague-Dawley rats were allocated to three equal groups. The animals in groups A and B received 600 and 1200 mg/kg M. officinalis extract, respectively, for 30 days. The rats in group C were given gavaged saline as control. The animals were euthanized at the end of experiment and the blood samples were collected for biochemical and hematology analysis. Additionally, appropriate tissue samples were collected from kidney, liver, spleen, heart and lung for light microscopic examination. M. officinalis caused a significant increase in the alanine aminotransferase level in the treated rats. Although the increase in creatine phosphokinase and lactate dehydrogenase levels were observed in group A and B, respectively, but there were no significant differences. A significant decrease was observed in the total protein and albumin concentrations in serum of treated rats as compared to the control group. The creatinine concentrations were significantly higher in the group B when compared to the other groups. There were no significant differences in cholesterol, triglyceride and urea concentrations between all groups of rats. The main histopathologic findings in the liver were included hepatocyte degeneration, congestion and dilation of sinusoids, proliferation of bile ducts and infiltration of mononuclear cells around the portal area. Histopathologic examination of the kidneys showed a tubular degeneration and necrosis, tubular and glomerular atrophy and congestion. These lesions were more prominent in the high dose treated rats. The findings suggest that long-term administration of M. officinalis extract even at low doses induces hepatic and renal lesions in rats.

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Carcinogenicity Study of 3-(5-Nitro-2-Furyl)-Imidazo(1,2-α) Pyridine in Mice and Rats

Tumori Journal ◽

10.1177/030089168006600201 ◽

1980 ◽

Vol 66 (2) ◽

pp. 131-144 ◽

Cited By ~ 1

Author(s):

José R. Cabral ◽

Lorenzo Rossi ◽

Tommaso A. Dragani ◽

Giuseppe Delia Porta

Keyword(s):

Wistar Rats ◽

Female Rats ◽

High Dose ◽

Short Term ◽

Kidney Tumors ◽

Carcinogenicity Study ◽

Male And Female Rats ◽

Term Administration ◽

Dose Levels

3-(5-nitro-2-furyl)-imidazo(1,2-α)pyridine was tested for carcinogenicity by long-term administration in the diet to CTM mice at 0.1, 0.2 and 0.4 % dose levels and to Wistar rats at 0.2 and 0.4 % dose levels, and by short-term intraperitoneal injections to suckling BALB/c mice. The compound was a strong carcinogen. In CTM mice it induced carcinomas of the esophagus and forestomach at all dose levels and thymic lymphosarcomas at the two highest doses. In male and female rats, esophagus and forestomach papillomas were observed at all dose levels, whereas esophagus and forestomach carcinomas and kidney tumors were observed only at the high dose. In female rats, an increased incidence of mammary tumors was seen at the high dose. The treatment of BALB/c suckling mice by intraperitoneal injections did not induce a clear carcinogenic response.

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