scholarly journals Sustained In-Vivo Release of Triptorelin Acetate from a Biodegradable Silica Depot: Comparison to Pamorelin® LA

Nanomaterials ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1578
Author(s):  
Ari-Pekka Forsback ◽  
Panu Noppari ◽  
Jesse Viljanen ◽  
Jari Mikkola ◽  
Mika Jokinen ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
In Vitro Release ◽  
Subcutaneous Administration ◽  
Silica Sol ◽  
Male Rats ◽  
Acetate Solution ◽  
Sprague Dawley ◽  
Triptorelin Acetate ◽  
In Vivo Pharmacokinetics

Triptorelin acetate was encapsulated into silica microparticles by spray-drying a mixture of colloidal silica sol and triptorelin acetate solution. The resulting microparticles were then combined with another silica sol containing silica nanoparticles, which together formed an injectable silica-triptorelin acetate depot. The particle size and surface morphology of the silica-triptorelin acetate microparticles were characterized together with the in vitro release of triptorelin, injectability and rheology of the final injectable silica-triptorelin acetate depot. In vivo pharmacokinetics and pharmacodynamics of the silica-triptorelin acetate depot and Pamorelin® were evaluated and compared in Sprague-Dawley male rats after subcutaneous administration. Serum samples up to 91 days were collected and the plasma concentrations of triptorelin and testosterone were analyzed with ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In vivo pharmacokinetics showed that injections of the silica-triptorelin acetate depot gave 5-fold lower Cmax values than the corresponding Pamorelin® injections. The depot also showed a comparable sustained triptorelin release and equivalent pharmacodynamic effect as the Pamorelin® injections. Detectable triptorelin plasma concentrations were seen with the depot after the 91-day study period and testosterone plasma concentrations remained below the human castration limit for the same period.

scholarly journals Vitamin B12 Conjugation of Peptide-YY3–36 Decreases Food Intake Compared to Native Peptide-YY3–36 Upon Subcutaneous Administration in Male Rats

Endocrinology ◽  
2015 ◽  
Vol 156 (5) ◽  
pp. 1739-1749 ◽  
Author(s):  
Kelly E. Henry ◽  
Clinton T. Elfers ◽  
Rachael M. Burke ◽  
Oleg G. Chepurny ◽  
George G. Holz ◽  
...  
Keyword(s):  
Food Intake ◽  
Vitamin B12 ◽  
Day Treatment ◽  
Subcutaneous Administration ◽  
Male Rats ◽  
Sprague Dawley ◽  
In Vivo Experiments ◽  
Sprague Dawley Rats

Challenges to peptide-based therapies include rapid clearance, ready degradation by hydrolysis/proteolysis, and poor intestinal uptake and/or a need for blood brain barrier transport. This work evaluates the efficacy of conjugation of vitamin B12 (B12) on sc administered peptide tyrosine tyrosine (PYY)3–36 function. In the current experiments, a B12-PYY3–36 conjugate was tested against native PYY3–36, and an inactive conjugate B12-PYYC36 (null control) in vitro and in vivo. In vitro experiments demonstrated similar agonism for the neuropeptide Y2 receptor by the B12-PYY3–36 conjugate (EC50 26.5 nM) compared with native PYY3–36 (EC50 16.0 nM), with the null control having an EC50 of 1.8 μM. In vivo experiments were performed in young adult male Sprague Dawley rats (9 wk). Daily treatments were delivered sc in five 1-hour pulses, each pulse delivering 5–10 nmol/kg, by implanted microinfusion pumps. Increases in hindbrain Fos expression were comparable 90 minutes after B12-PYY3–36 or PYY3–36 injection relative to saline or B12-PYYC36. Food intake was reduced during a 5-day treatment for both B12-PYY3–36- (24%, P = .001) and PYY3–36-(13%, P = .008) treated groups relative to baseline. In addition, reduction of food intake after the three dark cycle treatment pulses was more consistent with B12-PYY3–36 treatment (−26%, −29%, −27%) compared with the PYY3–36 treatment (−3%, −21%, −16%), and B12-PYY3–36 generated a significantly longer inhibition of food intake vs PYY3–36 treatment after the first two pulses (P = .041 and P = .036, respectively). These findings demonstrate a stronger, more consistent, and longer inhibition of food intake after the pulses of B12-PYY3–36 conjugate compared with the native PYY3–36.

scholarly journals Stamina-Enhancing Effects of Human Adipose-Derived Stem Cells

2021 ◽  
Vol 30 ◽  
pp. 096368972110354
Author(s):  
Eun-Jung Yoon ◽  
Hye Rim Seong ◽  
Jangbeen Kyung ◽  
Dajeong Kim ◽  
Sangryong Park ◽  
...  
Keyword(s):  
Physical Activity ◽  
Stem Cells ◽  
Locomotor Activity ◽  
Tissue Injury ◽  
Male Rats ◽  
Adipose Derived Stem Cells ◽  
Sprague Dawley ◽  
Serum Triglycerides

Stamina-enhancing effects of human adipose derived stem cells (hADSCs) were investigated in young Sprague-Dawley rats. Ten-day-old male rats were transplanted intravenously (IV) or intracerebroventricularly (ICV) with hADSCs (1 × 106 cells/rat), and physical activity was measured by locomotor activity and rota-rod performance at post-natal day (PND) 14, 20, 30, and 40, as well as a forced swimming test at PND 41. hADSCs injection increased the moving time in locomotor activity, the latency in rota-rod performance, and the maximum swimming time. For the improvement of physical activity, ICV transplantation was superior to IV injection. In biochemical analyses, ICV transplantation of hADSCs markedly reduced serum creatine phosphokinase, lactate dehydrogenase, alanine transaminase, and muscular lipid peroxidation, the markers for muscular and hepatic injuries, despite the reduction in muscular glycogen and serum triglycerides as energy sources. Notably, hADSCs secreted brain-derived neurotrophic factor (BDNF) and nerve growth factor in vitro, and increased the level of BDNF in the brain and muscles in vivo. The results indicate that hADSCs enhance physical activity including stamina not only by attenuating tissue injury, but also by strengthening the muscles via production of BDNF.

Differential effects of passive immunization with somatostatin antiserum on adenohypophysial hormone secretions in starved rats

1986 ◽  
Vol 109 (2) ◽  
pp. 169-174 ◽  
Author(s):  
J. N. Hugues ◽  
A. Enjalbert ◽  
E. Moyse ◽  
C. Shu ◽  
M. J. Voirol ◽  
...  
Keyword(s):  
Binding Capacity ◽  
Hormone Secretion ◽  
Plasma Concentrations ◽  
Passive Immunization ◽  
Negative Control ◽  
Prolactin Secretion ◽  
Male Rats ◽  
Minimal Effective Dose ◽  
Gh Secretion

ABSTRACT The role of somatostatin (SRIF) on adenohypophysial hormone secretion in starved rats was reassessed by passive immunization. Because of the absence of pulsatile GH secretion in starved rats, the effects of the injection of SRIF antiserum on GH levels can be clearly demonstrated. To determine whether starvation modifies the sensitivity of the adenohypophysis to SRIF, we measured 125I-labelled iodo-N-Tyr-SRIF binding. There was no difference in the dissociation constant (Kd) nor in the maximal binding capacity (Bmax) in fed (n = 15) and starved (n = 15) animals (Kd = 0·38 ± 0·09 (s.e.m.) and 0·45 ± 0·09 nmol; Bmax = 204 ± 39 and 205 ± 30 fmol/mg protein respectively). Administration of SRIF antiserum resulted in a dose-dependent increase in plasma concentrations of GH, TSH and prolactin. The minimal effective dose of SRIF antiserum was 50 μl for GH, 100 μl for TSH and 200 μl for prolactin. Our results show that: (1) starvation does not modify adenohypophysial SRIF-binding sites, (2) in starved male rats endogenous SRIF exerts a negative control on prolactin secretion in vivo and (3) sensitivity to endogenous SRIF seems to be different for each hypophysial cell type. J. Endocr. (1986) 109, 169–174

scholarly journals Bone Regeneration Capacity of Newly Developed Uncalcined/Unsintered Hydroxyapatite and Poly-l-lactide-co-glycolide Sheet in Maxillofacial Surgery: An In Vivo Study

Nanomaterials ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 22
Author(s):  
Huy Xuan Ngo ◽  
Quang Ngoc Dong ◽  
Yunpeng Bai ◽  
Jingjing Sha ◽  
Shinji Ishizuka ◽  
...  
Keyword(s):  
Bone Regeneration ◽  
Reconstructive Surgery ◽  
Early Stage ◽  
Maxillofacial Surgery ◽  
Male Rats ◽  
Regeneration Ability ◽  
Sprague Dawley ◽  
Micro Computed Tomography ◽  
Rat Mandible

Uncalcined/unsintered hydroxyapatite and poly-l-lactide-co-glycolide (u-HA/PLLA/PGA) is a new bioresorbable nanomaterial with superior characteristics compared with current bioresorbable materials, including appropriate mechanical properties, outstanding bioactive/osteoconductive features, and remarkably shorter resorption time. Nevertheless, the bone regeneration characteristics of this nanomaterial have not been evaluated in maxillofacial reconstructive surgery. In this study, we used a rat mandible model to assess the bone regeneration ability of u-HA/PLLA/PGA material, compared with uncalcined/unsintered hydroxyapatite and poly-l-lactide acid (u-HA/PLLA) material, which has demonstrated excellent bone regenerative ability. A 4-mm-diameter defect was created at the mandibular angle area in 28 Sprague Dawley male rats. The rats were divided into three groups: u-HA/PLLA/PGA (u-HA/PLLA/PGA graft + defect), u-HA/PLLA (u-HA/PLLA graft + defect), and sham control (defect alone). At 1, 3, 8, and 16 weeks after surgeries, the rats were sacrificed and assessed by micro-computed tomography, histological analysis with hematoxylin and eosin staining, and immunohistochemical analyses. The results confirmed that the accelerated bone bioactive/regenerative osteoconduction of u-HA/PLLA/PGA was comparable with that of u-HA/PLLA in the rat mandible model. Furthermore, this new regenerative nanomaterial was able to more rapidly induce bone formation in the early stage and had great potential for further clinical applications in maxillofacial reconstructive surgery.

Abstract 034: Characterization of A Novel Maternally Restricted Pro-angiogenic Therapeutic for Preeclampsia

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
William H Stewart ◽  
Eric George ◽  
Gene L Bidwell ◽  
Heather Chapman ◽  
Fakhri Mahdi ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Half Life ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Chronic Administration ◽  
Health Concern ◽  
Pathogenic Factors ◽  
Clearance Kinetics

Background: Preeclampsia is a major obstetrical health concern, affecting 5-8% of all pregnancies. Hallmarked by hypertension and endothelial dysfunction the origin of the disease remains obscure, though it is generally accepted that placental insufficiency/ischemia is a central cause. In response, the placenta secretes pathogenic factors, in particular the anti-angiogenic protein sFlt-1. Currently, there is no effective therapy for the management of the preeclampsia patient. We have recently produced a novel synthetic peptide based on placental growth factor (PlGF) which is maternally restricted by fusion to the synthetic carrier elastin like polypeptide (ELP). Here, we describe its in vivo pharmacokinetics and biodistribution. Methods: Fluorescently labeled ELP-PLGF was administered i.v. and blood sampled serially to determine clearance kinetics. Long-term pharmacokinetics and biodistribution was performed after subcutaneous administration of labeled peptide. Measurements were made on serially drawn blood, and in the whole animal by in vivo imaging. Results: ELP-PlGF exhibited markedly more favorable pharmacokinetics than the normal half life of PlGF, with a terminal half-life of ~10 hours as opposed to ~30 minutes for PlGF alone. Chronic administration found highest levels accumulating in placenta and kidney (two favorable targets for preeclampsia) and liver. A single subcutaneous administration at 100mg/kg resulted in sustained therapeutic plasma concentrations for over 10 days. Conclusion: These data demonstrate that ELP-PlGF has favorable pharmacokinetic and biodistribution profiles. Previous data suggest ELP-PlGF directly antagonizes sFlt-1 in culture. Future studies to assess the in vivo effectiveness of ELP-PlGF in managing placental ischemia induced hypertension and endothelial dysfunction are currently in progress. Acknowledgment: This work was supported by NIH grants R0121527 (GLB), T32HL105324 (OCL), P01HL51971, P20GM104357 (EMG), and R00HL116774 (EMG)

scholarly journals Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Rosario Russo ◽  
Angelo Mancinelli ◽  
Michele Ciccone ◽  
Fabio Terruzzi ◽  
Claudio Pisano ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Time Curve ◽  
Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

scholarly journals Bone Regeneration Potential of Uncalcined and Unsintered Hydroxyapatite/Poly l-lactide Bioactive/Osteoconductive Sheet Used for Maxillofacial Reconstructive Surgery: An In Vivo Study

Materials ◽  
2019 ◽  
Vol 12 (18) ◽  
pp. 2931 ◽  
Author(s):  
Quang Ngoc Dong ◽  
Takahiro Kanno ◽  
Yunpeng Bai ◽  
Jingjing Sha ◽  
Katsumi Hideshima
Keyword(s):  
Bone Regeneration ◽  
Maxillofacial Surgery ◽  
Male Rats ◽  
Regeneration Ability ◽  
Sprague Dawley ◽  
Control Groups ◽  
Critical Size Defect ◽  
Hematoxylin And Eosin ◽  
Regenerative Ability

Uncalcined and unsintered hydroxyapatite/poly l-lactide (u-HA/PLLA) material has osteoconductive characteristics and is available for use as a maxillofacial osteosynthetic reconstruction device. However, its bone regeneration ability in the maxillofacial region has not been fully investigated. This study is the first to assess the bone regenerative potential of osteoconductive u-HA/PLLA material when it is used for repairing maxillofacial bone defects. A total of 21 Sprague-Dawley male rats were divided into three groups—the u-HA/PLLA, PLLA, or sham control groups. A critical size defect of 4 mm was created in the mandible of each rat. Then, the defect was covered with either a u-HA/PLLA or PLLA sheet on the buccal side. The rats in each group were sacrificed at 2, 4, or 8 weeks. The rats’ mandibles were sampled for histological analysis with hematoxylin and eosin staining, histomorphometry, and immunohistochemistry with Runx2 and osteocalcin (OCN) antibody. The amount of newly formed bone in the u-HA/PLLA group was significantly higher than that of the PLLA group. The expression of Runx2 and OCN in the u-HA/PLLA group was also significantly higher. These results demonstrate that the u-HA/PLLA material has excellent bone regenerative ability and confirm its applicability as a reconstructive device in maxillofacial surgery.

scholarly journals Metabolic and cardiac signaling effects of inhaled hydrogen sulfide and low oxygen in male rats

2012 ◽  
Vol 112 (10) ◽  
pp. 1659-1669 ◽  
Author(s):  
Asaf Stein ◽  
Zhengkuan Mao ◽  
Joanna P. Morrison ◽  
Michelle V. Fanucchi ◽  
Edward M. Postlethwait ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Tissue Injury ◽  
Biological Effects ◽  
Male Rats ◽  
Sprague Dawley ◽  
Low Oxygen ◽  
Creatine Kinase Mb ◽  
Gsk 3Β

Low concentrations of inhaled hydrogen sulfide (H2S) induce hypometabolism in mice. Biological effects of H2S in in vitro systems are augmented by lowering O2 tension. Based on this, we hypothesized that reduced O2 tension would increase H2S-mediated hypometabolism in vivo. To test this, male Sprague-Dawley rats were exposed to 80 ppm H2S at 21% O2 or 10.5% O2 for 6 h followed by 1 h recovery at room air. Rats exposed to H2S in 10.5% O2 had significantly decreased body temperature and respiration compared with preexposure levels. Heart rate was decreased by H2S administered under both O2 levels and did not return to preexposure levels after 1 h recovery. Inhaled H2S caused epithelial exfoliation in the lungs and increased plasma creatine kinase-MB activity. The effect of inhaled H2S on prosurvival signaling was also measured in heart and liver. H2S in 21% O2 increased Akt-PSer473 and GSK-3β-PSer9 in the heart whereas phosphorylation was decreased by H2S in 10.5% O2, indicating O2 dependence in regulating cardiac signaling pathways. Inhaled H2S and low O2 had no effect on liver Akt. In summary, we found that lower O2 was needed for H2S-dependent hypometabolism in rats compared with previous findings in mice. This highlights the possibility of species differences in physiological responses to H2S. Inhaled H2S exposure also caused tissue injury to the lung and heart, which raises concerns about the therapeutic safety of inhaled H2S. In conclusion, these findings demonstrate the importance of O2 in influencing physiological and signaling effects of H2S in mammalian systems.

scholarly journals Oestradiol decreases rat apolipoprotein AI transcription via promoter site B

2000 ◽  
Vol 25 (2) ◽  
pp. 207-219 ◽  
Author(s):  
AH Taylor ◽  
AE Fox-Robichaud ◽  
C Egan ◽  
J Dionne ◽  
DE Lawless ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Target Genes ◽  
Inhibitory Effect ◽  
Male Rats ◽  
Sprague Dawley ◽  
Male Adult ◽  
Nuclear Extracts ◽  
Major Mode ◽  
Apo Ai

Oestrogens protect against ischaemic heart disease in the post-menopausal female by increasing serum concentrations of apolipoprotein (apo) AI and the abundance of high-density lipoprotein particles. In men and experimental male animals, the administration of oestrogen has variable effects on apo AI expression. As the major mode of oestrogen action on target genes involves regulating promoter activity and hence transcription, oestrogen is expected to alter transcription of the apo AI gene. To test this hypothesis, the effect of 17beta-oestradiol (E(2)), on rat apo AI promoter activity in male hepatoma HuH-7 cells, was tested by co-transfecting a reporter template, pAI.474.CAT containing-474 to-7 of the rat apo AI promoter and an oestrogen receptor (ER) expression vector, pCMV-ER. Transfected cells exposed to E(2) showed a dose-dependent decrease in chloramphenicol acetyltransferase (CAT)-activity, with a maximum 91+/-1.5% reduction at 1 microM E(2). Deletional analysis of the promoter localized the inhibitory effect of ER and E(2) to site B (-170 to-144) with an adjacent 5' contiguous motif, site S (-186 to-171) acting as an amplifier. HuH-7 cell nuclear extracts showed binding activities with both sites S and B, but recombinant human ER did not. Furthermore, nuclear extracts from E(2)-treated HuH-7 cells showed weaker binding activity to site B, but not to site S. In summary, the inhibitory effect of ER and E(2) on rat apo AI gene activity is mediated by a promoter element, site B. This inhibitory effect arises from a mechanism that does not involve direct ER binding to the B-element. The conclusion that E(2) inhibits apo AI transcription was confirmed in vivo. Treatment of male adult Sprague-Dawley rats with up to 200 microg E(2) for 7 days decreased apo AI protein and hepatic mRNA by 72+/-21% and 68+/-1.4% respectively. Results of 'run-on' transcription of the apo AI gene in isolated hepatic nuclei showed a 55% decrease in hormone-treated male rats. These findings suggest that E(2) exerts primarily an inhibitory effect within male hepatic nuclei.

Functional and morphological changes of the thyroid gland following 5 days of pulsatile TRH stimulation in male rats

1995 ◽  
Vol 146 (2) ◽  
pp. 339-348 ◽  
Author(s):  
C Hoang-Vu ◽  
G Brabant ◽  
H Leitolf ◽  
A von zur Mühlen ◽  
H Dralle ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Morphological Changes ◽  
Dominant Role ◽  
Major Product ◽  
Male Rats ◽  
Ultrastructural Changes ◽  
Sprague Dawley ◽  
Immunogold Staining ◽  
Trh Stimulation

Abstract The aim of the present study was to evaluate in vivo the selective effects of a small increase in plasma TSH levels on thyroid function, proliferation and morphology. Chronically catheterized male Sprague–Dawley rats were stimulated i.v. over 5 days either with TRH (2 μg TRH in 100 μl 0·9% (w/v) NaCl (TRH-P) or the NaCl carrier alone (P), both given as pulses every 2 h. Control groups were cotreated i.v. with 10 μg thyroxine (T4)/100 g body weight per day (TRH-P+T4) starting 2 days before pulsatile stimulation. TSH plasma levels were approximately doubled by TRH-P (P≤0·001), T4 plasma levels significantly increased (P≤0·001) but tri-iodothyronine plasma levels did not change compared with treatment with P. No significant changes between groups were found in thyroid weight and in intrathyroidal iodine content, but the percentage of 5-bromo-2′-desoxyuridinelabelled thyrocytes as a marker of proliferation in TRH-P-treated animals was significantly increased over P or TRH-P+T4 (P≤0·001). Ultrastructural analysis of the thyroid evaluated by electron microscopy revealed a significant increase in the number of lysosomes (P≤0·001). The size of the endoplasmic reticulum (ER) in relation to the cytoplasm was significantly increased when treated with TRH-P compared with P or TRH-P+T4 (P≤0·001). Post-embedding immunogold staining revealed Tg as a major product within ER cisternae. Immunogold labelling was moderate in controls and higher densities of gold particles were obtained in TRH-P-treated animals (P≤0·001). In conclusion, short-term pulsatile TRH stimulation increasing the plasma levels of immunoreactive TSH only twofold is capable of inducing hypertrophy of the thyrocytes by gross ultrastructural changes which are paralleled by an increase in circulating T4. These data underscore the dominant role of TSH on thyroid ultrastructure within the narrow boundaries of normal physiological regulation. Journal of Endocrinology (1995) 146, 339–348

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