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)

Glucose regulates lipid metabolism in fasting king penguins

2003 ◽  
Vol 285 (2) ◽  
pp. R313-R320 ◽  
Author(s):  
Servane F. Bernard ◽  
Jord Orvoine ◽  
René Groscolas
Keyword(s):  
Lipid Metabolism ◽  
Plasma Concentration ◽  
Energy Production ◽  
Important Determinant ◽  
Plasma Concentrations ◽  
Glucose Infusion ◽  
Nonesterified Fatty Acids ◽  
Fat Stores

This study aims to determine whether glucose intervenes in the regulation of lipid metabolism in long-term fasting birds, using the king penguin as an animal model. Changes in the plasma concentration of various metabolites and hormones, and in lipolytic fluxes as determined by continuous infusion of [2-3H]glycerol and [1-14C]palmitate, were examined in vivo before, during, and after a 2-h glucose infusion under field conditions. All the birds were in the phase II fasting status (large fat stores, protein sparing) but differed by their metabolic and hormonal statuses, being either nonstressed (NSB; n = 5) or stressed (SB; n = 5). In both groups, glucose infusion at 5 mg·kg-1·min-1 induced a twofold increase in glycemia. In NSB, glucose had no effect on lipolysis (maintenance of plasma concentrations and rates of appearance of glycerol and nonesterified fatty acids) and no effect on the plasma concentrations of triacylglycerols (TAG), glucagon, insulin, or corticosterone. However, it limited fatty acid (FA) oxidation, as indicated by a 25% decrease in the plasma level of β-hydroxybutyrate (β-OHB). In SB, glucose infusion induced an ∼2.5-fold decrease in lipolytic fluxes and a large decrease in FA oxidation, as reflected by a 64% decrease in the plasma concentration of β-OHB. There were also a 35% decrease in plasma TAG, a 6.5- and 2.8-fold decrease in plasma glucagon and corticosterone, respectively, and a threefold increase in insulinemia. These data show that in fasting king penguins, glucose regulates lipid metabolism (inhibition of lipolysis and/or of FA oxidation) and affects hormonal status differently in stressed vs. nonstressed individuals. The results also suggest that in birds, as in humans, the availability of glucose, not of FA, is an important determinant of the substrate mix (glucose vs. FA) that is oxidized for energy production.

scholarly journals Subcutaneous Immunization of Leishmania HSP70-II Null Mutant Line Reduces the Severity of the Experimental Visceral Leishmaniasis in BALB/c Mice

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 141
Author(s):  
José Carlos Solana ◽  
Laura Ramírez ◽  
Emma CL Cook ◽  
Elena Hernández-García ◽  
Silvia Sacristán ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Cell Line ◽  
Subcutaneous Administration ◽  
Chronic Phase ◽  
Severe Form ◽  
Vaccine Potential ◽  
Dilution Experiments ◽  
Subcutaneous Immunization

Leishmania infantum parasites cause a severe form of visceral leishmaniasis in human and viscerocutaneous leishmaniasis in dogs. Recently, we reported that immunization with an attenuated L. infantum cell line, lacking the hsp70-II gene, protects against the development of murine cutaneous leishmaniasis. In this work, we analyzed the vaccine potential of this cell line towards the long-term protection against murine visceral leishmaniasis. This model shows an organ-dependent evolution of the disease. The infection can resolve in the liver but chronically affect spleen and bone marrow. Twelve weeks after subcutaneous administration of attenuated L. infantum, Bagg Albino (BALB/c) mice were challenged with infective L. infantum parasites expressing the luciferase-encoding gene. Combining in vivo bioimaging techniques with limiting dilution experiments, we report that, in the initial phase of the disease, vaccinated animals presented lower parasite loads than unvaccinated animals. A reduction of the severity of liver damage was also detected. Protection was associated with the induction of rapid parasite-specific IFN-γ production by CD4+ and CD8+ T cells. However, the vaccine was unable to control the chronic phase of the disease, since we did not find differences in the parasite burdens nor in the immune response at that time point.

PHARMACOKINETICS OF A LOW MOLECULAR WEIGHT HEPARIN (KABI 2165, FRAGMIN) ATFER INTRAVENOUS AND SUBCUTANEOUS ADMINISTRATION IN HUMAN VOLUNTEERS AND ITS IN VIVO NEUTRALIZATION BY PROTAMINE SULFATE

1987 ◽  
Author(s):  
J Albada ◽  
K K Nieuwenhuis ◽  
J J Sixma
Keyword(s):  
Molecular Weight ◽  
Healthy Volunteers ◽  
Half Life ◽  
Low Molecular Weight Heparin ◽  
Subcutaneous Administration ◽  
Low Molecular Weight ◽  
Protamine Sulphate ◽  
Original Curve ◽  
Rebound Phenomenon

Pharmacokinetics of a low molecular weight heparin (LMWH) were studied in healthy volunteers. After an intravenous bolus injection of 5000 anti-Xa U in 5 healthy volunteers anti Xa activity disappeared according to the combination of saturable and a linear mechanism, preceded by a rapid initial disappearance. The apparent half-life of the anti Xa activity is about twice as long as that of standard heparin. In another set of experiments 5000 anti Xa U of LMWH were immediately followed by 50 mgr of Protamine Sulphate (PS). The curve of the anti Xa-activity parallelled the original curve at a level of about 30-40%. No rebound phenomenon was observed. The same dose of the LMWH followed by 100 mg of PS resulted in an anti Xa disappearance curve at an obvious higher level of about 50%. Also at this dose no rebound phenomenon was noticed.A continuous infusion of 10.000 anti Xa U/24 h during 10 hours was followed by 15.000 anti Xa U/24 h for another 10 hours after which the dose was raised to 20.000 anti Xa U/24 h for another 10 hours. Only the first infusion period resulted in a plateau fase. At the end of these experiments anti Xa activity was neutralized by 50 mg P.S. i.v. resulting in the disappearance of less than 50% of anti Xa activity. After subcutaneous administration of 15.000 anti Xa U (corresponding to the dose for i.v. treatment per day with this LMWH) peak levels of 1,1-1,8 anti Xa were reached after 3-4 hours. Supra-optimal anti Xa levels (higher than 0.9) were observed in all volunteers during a period of 5 hours. After 24 hours in none of the volunteers any anti Xa-activity could be detected.Conclusions:In contrast to previous reports pharmacokinetics of this LMWH do not essentially differ from those of standard heparin apart from its longer half-life and its high bioavialability after subcutaneous injection.

scholarly journals The effect of short-term and long-term application of fisetin on experimentally induced airway hyperreactivity

2017 ◽  
Vol 64 (1) ◽  
pp. 7-9
Author(s):  
I. Kazimierová ◽  
L. Pappová ◽  
M. Šútovská ◽  
S. Fraňová
Keyword(s):  
Airway Inflammation ◽  
Airway Resistance ◽  
Chronic Administration ◽  
Airway Hyperreactivity ◽  
Whole Body ◽  
Short Term ◽  
Specific Airway Resistance ◽  
Term Administration

AbstractBackground:Fisetin, a derivate from the flavonol group may possess a variety of pharmacological effects. The aim of the presented study was to evaluate the bronchodilatory effect of fisetin after the acute or the chronic administration to guinea pigs with allergic airway inflammation.Methods:Experimental animals were sensitized and challenged by ovalbumin. Fisetin was administered in dose 5mg/kg/p.o., either once after the end of 21-days sensitization or daily during the 21-days sensitization. By using the whole-body plethysmograph, we monitored the specific airway resistance, a parameter of airway hyperreactivityin vivo. The changes of the specific airway resistance were evaluated after the short-term inhalation of the bronchoconstriction mediator-histamine (10−6mol.1−1).Results:Our results showed that the short-term as well as the long-term administration of fisetin caused decrease of the specific airway resistance values. The bronchodilatory effect of fisetin was comparable to the long-acting beta2sympathomimetic – salmeterol after the long-term administration. The measurements of the bronchodilatory activity after single administration have revealed more prolonged effect of fisetin comparing to the short-acting beta2sympathomimetic – salbutamol, as this remained even after the 5 hours, when salbutamol was already ineffective.Conclusion:In conclusion, flavonol – fisetin has shown bronchodilatory potential. In the light of this fact, fisetin may represent potential substance that can be effective in both prevention as well as control of airway inflammation symptoms.

Mod-5014, a Long-Acting FVIIa-CTP, Proposing a Novel Prophylactic Treatment Supporting Less Frequent Subcutaneous or Intravenous Injections with a Similar Mechanism of Action to rFVIIa: Proof-of-Concept in Hemophilic Animal Models

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4670-4670 ◽  
Author(s):  
Lior Binder ◽  
Ahuva Bar-Ilan ◽  
Malka Hoffman ◽  
Gili Hart
Keyword(s):  
Mechanism Of Action ◽  
Half Life ◽  
Prophylactic Treatment ◽  
Conflicts Of Interest ◽  
Clinical Stage ◽  
Routes Of Administration ◽  
Hemostatic Effect ◽  
Long Acting

Abstract Introduction: OPKO Biologics is a clinical-stage public company developing bio-better long-acting versions of existing therapeutic proteins, utilizing a technology termed CTP. The technology involves fusion of the C-terminal peptide of hCG to a target protein. The aim of this work was to comprehensively assess the feasibility of intravenous (IV) or subcutaneous (SC) administration of FVIIa-CTP (MOD-5014) utilizing the most relevant in vivo pre-clinical models, and to characterize the FVIIa-CTP mechanism of action in preparation for an on-going clinical study. Methods: FVII-CTP was expressed in CHO cells, purified and activated utilizing a CTP-specific purification process. FVIIa-CTP's pharmacokinetics (PK), pharmacodynamics (PD), long-term hemostatic effect and safety parameters were extensively characterized following SC and IV administration in transient FVII-/- rats and FVIII-/- mice. In addition, the long-term hemostatic effect of FVIIa-CTP was evaluated following a bleeding challenge and compared to commercial rFVIIa. Finally, interaction with co-factors, activity, and the off-target effect of FVIIa-CTP was comprehensively characterized. Results: The studies demonstrated that FVIIa-CTP provides long-term exposure (AUC) and half-life that are significantly superior to those of rFVIIa, and consistent with the prolonged half-life of FVIIa-CTP (at an average of 3- and 5-fold, respectively) when compared to IV or SC administration of FVIIa. In addition, a 30% increase in bioavailability was observed relative to commercial FVIIa. A profound improvement in clotting parameters and survival rate following TVT, as well as a reduction of bleeding duration and intensity in tail-clip studies were obtained for both routes of administration for up to 48 hours. Moreover, the safety profile of FVIIa-CTP was further confirmed. Conclusion: Attachments of CTP to FVIIa led to a pronounced enhancement of PK and PD, increased exposure as reflected by AUC, elevated half-life, and improved recovery in mice, rats and pigs following SC and IV administration. FVIIa-CTP injection resulted in an improved bioavailability that translated to a marked in vivo hemostatic effect. Our data suggest that CTP-fused FVIIa can potentially provide a novel approach for IV or SC prophylactic treatment of hemophilic patients (both pediatric and adult), with the major benefit of significant improvement in quality of life. Disclosures No relevant conflicts of interest to declare.

Non-pituitary actions of somatostatin. A review on the therapeutic role of SMS 201-995 (sandostatin)

1986 ◽  
Vol 113 (2_Suppla) ◽  
pp. S41-S55 ◽  
Author(s):  
Steven W. J. Lamberts
Keyword(s):  
Half Life ◽  
Potential Role ◽  
Somatostatin Analogs ◽  
Subcutaneous Administration ◽  
Term Treatment ◽  
Acute Administration ◽  
Intestinal Function ◽  
Long Term Treatment

Abstract. Natural Somatostatin has a short half-life (3 min), is only active after intravenous administration and causes a rebound hypersecretion of hormones after discontinuation of administration. Recently a longacting powerful Somatostatin analog was developed (SMS 201-995; Sandostatin) which has a half-life of 113 min after subcutaneous administration. After administration of this analog no rebound hypersecretion of hormones was observed. In the present review the effects of the acute administration and of long-term treatment with SMS 201-995 in acromegalic patients is discussed. In addition the potential role of therapy with Somatostatin analogs and the preliminary effects of Somatostatin and/or SMS 201-995 are discussed in disorders of gastro-intestinal function (haemorrhages, diarrhoea, pancreatitis and endocrine pancreatic tumours), diabetes mellitus, central nervous system disturbances and oncology. Finally, several aspects of the tolerance, tachyphylaxis and side effects of SMS 201-995 are discussed.

scholarly journals Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes

2015 ◽  
Author(s):  
Brian K Whitlock ◽  
Joseph A Daniel ◽  
Lisa L Amelse ◽  
Valeria M Tanco ◽  
Kelly A Chameroy ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Half Life ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Similar Efficacy ◽  
Comparable Efficacy ◽  
Breeding Management ◽  
Gonadotropic Axis

Kisspeptin receptor (KISS1R) agonists with increased half-life and similar efficacy to kisspeptin in vitro may provide beneficial applications in breeding management of many species. However, many of these agonists have not been tested in vivo. These studies were designed to test and compare the effects of a KISS1R agonist (FTM080) and kisspeptin on luteinizing hormone (LH) in vivo. In experiment 1 (pilot study), sheep were treated with FTM080 (500 pmol/kg BW) or sterile water (VEH) intravenosuly. Blood was collected every 15 min before (1 hr) and after (1 hr) treatment. In experiment 2, sheep were treated with KP-10 (human Metastin 45-54; 500 pmol/kg BW), one of three dosages of FTM080 [500 (FTM080:500), 2500 (FTM080:2500), or 5000 (FTM080:5000) pmol/kg BW], or VEH intravenously. Blood was collected every 15 min before (1 hr) and after (4 hr) treatment. In experiment 1, FTM080:500 increased (P < 0.05) plasma LH concentrations when compared to VEH. The area under the curve (AUC) of LH following FTM080:500 treatment was also increased (P < 0.05). In experiment 2, plasma LH concentrations increased (P < 0.05) following treatment with KP-10 and FTM080:5000 when compared to VEH and FTM080:500. The AUC of LH following KP-10 was greater than (P < 0.05) all other treatments and the AUC of LH following FTM080:5000 was greater than (P < 0.05) all treatments except KP-10. These data provide evidence to suggest that FTM080 stimulates the gonadotropic axis of ruminants in vivo. Any increased half-life and comparable efficacy of FTM080 to KP-10 in vitro does not appear to translate to in vivo in sheep.

scholarly journals Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes

PeerJ ◽  
2015 ◽  
Vol 3 ◽  
pp. e1382 ◽  
Author(s):  
Brian K. Whitlock ◽  
Joseph A. Daniel ◽  
Lisa L. Amelse ◽  
Valeria M. Tanco ◽  
Kelly A. Chameroy ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Half Life ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Similar Efficacy ◽  
Comparable Efficacy ◽  
Breeding Management ◽  
Gonadotropic Axis

Kisspeptin receptor (KISS1R) agonists with increased half-life and similar efficacy to kisspeptinin vitromay provide beneficial applications in breeding management of many species. However, many of these agonists have not been testedin vivo. These studies were designed to test and compare the effects of a KISS1R agonist (FTM080) and kisspeptin on luteinizing hormone (LH)in vivo. In experiment 1 (pilot study), sheep were treated with FTM080 (500 pmol/kg BW) or sterile water (VEH) intravenosuly. Blood was collected every 15 min before (1 h) and after (1 h) treatment. In experiment 2, sheep were treated with KP-10 (human Metastin 45-54; 500 pmol/kg BW), one of three dosages of FTM080 (500 (FTM080:500), 2500 (FTM080:2500), or 5000 (FTM080:5000) pmol/kg BW), or VEH intravenously. Blood was collected every 15 min before (1 h) and after (4 h) treatment. In experiment 1, FTM080:500 increased (P< 0.05) plasma LH concentrations when compared to VEH. The area under the curve (AUC) of LH following FTM080:500 treatment was also increased (P< 0.05). In experiment 2, plasma LH concentrations increased (P< 0.05) following treatment with KP-10 and FTM080:5000 when compared to VEH and FTM080:500. The AUC of LH following KP-10 was greater than (P< 0.05) all other treatments and the AUC of LH following FTM080:5000 was greater than (P< 0.05) all treatments except KP-10. These data provide evidence to suggest that FTM080 stimulates the gonadotropic axis of ruminantsin vivo. Any increased half-life and comparable efficacy of FTM080 to KP-10in vitrodoes not appear to translate toin vivoin sheep.

scholarly journals Systemic and presystemic conversion of carbamazepine to carbamazepine-10,11-epoxide during long term treatment

2006 ◽  
Vol 12 (1) ◽  
pp. 13-16 ◽  
Author(s):  
Pietro Fagiolino ◽  
Marta Vázquez ◽  
Ivette Olano ◽  
Aurora Delfino
Keyword(s):  
Plasma Concentrations ◽  
Chronic Administration ◽  
Hplc Method ◽  
Term Treatment ◽  
Published Data ◽  
Long Term Treatment ◽  
Important Pathway ◽  
Kinetics Of ◽  
Dose Dependent

INTRODUCTION: Carbamazepine (CBZ) undergoes biotransformation, being CYP3A4 the major cytocrome P450 (CYP) enzyme catalyzing the carbamazepine-10,11-epoxide (EPOX) formation, which is quantitatively the most important pathway in CBZ metabolism. There is evidence of dose-dependent elimination of this drug due to its autoinduction capacity. Moreover, published data showed an incomplete bioavailability of CBZ since its absorption increases when grapefruit juice was administered. Both CYP3A4 and MRP2 (located in the enterocyte) are autoinduced during long term use of CBZ. As the other enzymes involved in CBZ metabolism are negligible in the gut, presystemic biotransformation through CYP3A4 could be responsible for the bioavailability of the drug as well as EPOX formation. OBJECTIVE: The purpose of our study was to assess the importance of presystemic formation of EPOX during the autoinduction of CBZ versus the daily administered dose. PATIENTS AND METHODS: 40 adults (average age: 28 years) and 29 children (average age: 9 years) receiving CBZ as monotherapy were included in the study. CBZ and EPOX plasma concentrations were analyzed by a previous validated HPLC method. RESULTS AND CONCLUSION: The results obtained confirmed the metabolic induction after chronic administration and provided new elements to suggest a strong contribution of dose-dependent bioavailability in the non linear kinetics of CBZ.

scholarly journals Rhesus Theta Defensin 1 Promotes Long Term Survival in Systemic Candidiasis by Host Directed Mechanisms

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Virginia Basso ◽  
Dat Q. Tran ◽  
Justin B. Schaal ◽  
Patti Tran ◽  
Yoshihiro Eriguchi ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Mouse Serum ◽  
Term Survival ◽  
Long Term Survival ◽  
Immunosuppressed Patients ◽  
Time Of Infection

AbstractInvasive candidiasis is an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp., highlighting the urgent need of new antifungal therapies. Rhesus theta (θ) defensin-1 (RTD-1), a natural macrocyclic antimicrobial peptide, was recently shown to be rapidly fungicidal against clinical isolates of MDR C. albicans in vitro. Here we found that RTD-1 was rapidly fungicidal against blastospores of fluconazole/caspofungin resistant C. albicans strains, and was active against established C. albicans biofilms in vitro. In vivo, systemic administration of RTD-1, initiated at the time of infection or 24 h post-infection, promoted long term survival in candidemic mice whether infected with drug-sensitive or MDR strains of C. albicans. RTD-1 induced an early (4 h post treatment) increase in neutrophils in naive and infected mice. In vivo efficacy was associated with fungal clearance, restoration of dysregulated inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-10, and IL-17, and homeostatic reduction in numbers of circulating neutrophils and monocytes. Because these effects occurred using peptide doses that produced maximal plasma concentrations (Cmax) of less than 1% of RTD-1 levels required for in vitro antifungal activity in 50% mouse serum, while inducing a transient neutrophilia, we suggest that RTD-1 mediates its antifungal effects in vivo by host directed mechanisms rather than direct fungicidal activity. Results of this study suggest that θ-defensins represent a new class of host-directed compounds for treatment of disseminated candidiasis.

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