Preproenkephalin B-derived opioid peptides in human phaeochromocytomas

1987 ◽  
Vol 114 (3) ◽  
pp. 446-451 ◽  
Author(s):  
Toshihiko Yanase ◽  
Hajime Nawata ◽  
Ken-ichi Kato ◽  
Hiroshi Ibayashi
Keyword(s):  
Plasma Concentration ◽  
Opioid Peptides ◽  
Significant Positive Correlation ◽  
Plasma Catecholamines ◽  
Wide Distribution ◽  
Molecular Forms ◽  
Concomitant Increase ◽  
Tissue Contents

Abstract. We demonstrated the presence and the secretion in vivo and in vitro of immunoreactive preproenkephalin B-derived opioid peptides (α-neoendorphin, dynorphin and leumorphin) in human phaeochromocytomas. In senventeen human phaeochromocytomas and two human adrenal medullas, the tissue contents of immunoreactive preproenkephalin B-derived opioid peptides (α-neoendorphin, dynorphin and leumorphin) and leu-enkephalin were studied by specific RIAs. Compared with a remarkable wide distribution in amounts of immunoreactive leu-enkephalin (1063 ± 437 pg/mg, mean ± se), small amounts of immunnoreactive α-neoendorphin (22.6 ± 6.4 pg/mg) and dynorphin (8.5 ± 1.2 pg/mg) were detected in all seventeen human phaeochromocytomas and the two human adrenal medullas. Leumorphin-like immunoreactivity was detected in only four tumours. Gel chromatographic studies revealed the presence of preproenkephalin B-derived peptides and their high molecular forms. A significant positive correlation between the tumour tissue contents of immunoreactive α-neoendorphin and of dynorphin was observed. Nicotine (10−5, 10−4 mol/l) significantly stimulated the secretion of immunoreactive α-neoendorphin and dynorphin as well as leuenkephalin and catecholamines from cultured human phaeochromocytoma cells. Administration of 1 mg of glucagon to a patient with medullary phaeochromocytoma induced a rapid increase in the plasma concentration of immunoreactive α-neoendorphin with a concomitant increase in plasma catecholamines. These results indicate the presence of preproenkephalin B-derived opioid peptides in human phaeochromocytomas and human adrenal medullas and their secretion in human phaeochromocytomas.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals The mutual relationship between the two molecular forms of the major fibrinolysis inhibitor alpha-2-antiplasmin in blood

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 616-622 ◽  
Author(s):  
C Kluft ◽  
P Los ◽  
AF Jie ◽  
VW van Hinsbergh ◽  
E Vellenga ◽  
...  
Keyword(s):  
Human Cell Line ◽  
Molecular Forms ◽  
Phase Reaction ◽  
Mutual Relationship ◽  
Congenital Deficiency ◽  
Fibrinolysis Inhibitor ◽  
Streptokinase Therapy ◽  
Relationship Of

Alpha-2-antiplasmin, a major inhibitor of fibrinolysis, is synthesized in the liver and occurs in blood in two molecular forms: a very active plasminogen-binding (PB) form and a less active nonplasminogen-binding (NPB) form. This study investigates the origin and mutual relationship of these two forms in vivo and in vitro. Despite wide variation in plasma concentration of the inhibitor (16% to 138%), the ratio between the two forms in vivo was found to be, in the main, constant among healthy volunteers, heterozygotes for a congenital deficiency of alpha- 2-antiplasmin, and patients with a stable liver cirrhosis: PB/NPB = 2.41 +/- 0.34 (SD). Resynthesis after depletion or increased synthesis in the acute-phase reaction showed a specific increase of the PB form of the molecule in blood after discontinuation of L-asparaginase or streptokinase therapy and after myocardial infarction. In vitro studies demonstrated that only the PB form was present after one day in the culture medium of the human cell line Hep G2, while the NPB form appeared after 11 days. Clearance after inhibition of synthesis by L- asparaginase therapy revealed a more rapid decrease in the PB form relative to the NPB form in blood, demonstrated by a change in the PB- NPB ratio from 2.86 +/- 0.55 to 1.74 +/- 0.24 (mean of 6, SD). An apparently spontaneous first order conversion from the PB to NPB form, with an apparent half-life of about eight days, was demonstrated at 37 degrees C in plasma and serum in vitro. The conversion was found to be temperature dependent and uninfluenced by the fibrinolytic components fibrinogen, fibrin, and plasminogen. Additions of a variety of enzymes or inhibitors did not interfere with the process. These results demonstrate that the PB form of alpha-2-antiplasmin is produced by the liver and that the NPB form is formed in the circulation.

scholarly journals Radiocontrast agents induce endothelin release in vivo and in vitro.

1992 ◽  
Vol 3 (1) ◽  
pp. 58-65 ◽  
Author(s):  
S N Heyman ◽  
B A Clark ◽  
N Kaiser ◽  
K Spokes ◽  
S Rosen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasma Concentration ◽  
Plasma Level ◽  
Vascular Endothelium ◽  
Radiocontrast Agent ◽  
Transient Rise ◽  
Bovine Endothelial Cells ◽  
Radiocontrast Agents

The intravascular administration of the ionic radiocontrast agent sodium iothalamate (2.9 g of iodine/kg body wt) to rats induced an increase in plasma concentration of immunoreactive endothelin from 21.3 +/- 1.2 to 36 +/- 3 fmol/mL, preceded by a transient rise in the plasma level of atrial natriuretic peptide and associated with a fall in RBF. Equi-iodine amounts of the nonionic agents ioxaglate and iohexol elicited similar or more marked changes in plasma endothelin, but hypertonic solutions of NaCl, mannitol, or glucose did not. Comparable levels of endothelin produced by infusions of endothelin-1 induced a reduction of up to 29% in RBF. Iothalamate and iohexol stimulated endothelin release from cultured bovine endothelial cells, suggesting a direct effect of ionic and nonionic agents on vascular endothelium. The data invite speculation that under some circumstances endothelin release might play a role in the circulatory changes caused by these compounds and in the pathogenesis of radiocontrast nephropathy.

Calcification Modelling in Artificial Heart Valves

1992 ◽  
Vol 15 (5) ◽  
pp. 284-288 ◽  
Author(s):  
A.C. Fisher ◽  
G.M. Bernacca ◽  
T.G. Mackay ◽  
W.R. Dimitri ◽  
R. Wilkinson ◽  
...  
Keyword(s):  
Artificial Heart ◽  
Heart Valves ◽  
Test Protocol ◽  
Tissue Sections ◽  
Artificial Heart Valves ◽  
In Vivo Tests ◽  
Tissue Contents ◽  
Histological Staining

This study has examined a range of methods of studying the calcification process in bovine pericardial and polyurethane biomaterials. The calcification methods include static and dynamic, in vitro and in vivo tests. The analytical methods include measurement of depletion rates of calcium and phosphate from in vitro calcifying solutions, analysis of tissue contents of calcium, histological staining of tissue sections for calcium, X-ray elemental analysis, by scanning electron microscopy, of calcium and phosphorus distributions over valve leaflets calcified in vitro under dynamic conditions. Bovine pericardium, in all test settings, calcified to a much greater degree than polyurethane biomaterials. Polyurethane extracts calcified to a greater degree than bulk polyurethanes. The test protocol used allows progress through increasily demanding calcification tests, with the possibility of eliminating unsuitable materials with tests of limited complexity and expense.

Developing a new formulation of sodium phenylbutyrate

2012 ◽  
Vol 97 (12) ◽  
pp. 1081-1085 ◽  
Author(s):  
Nathalie Guffon ◽  
Yves Kibleur ◽  
William Copalu ◽  
C Tissen ◽  
Joerg Breitkreutz
Keyword(s):  
Plasma Concentration ◽  
Healthy Adult ◽  
Taste Perception ◽  
In Vitro Dissolution ◽  
Time Curve ◽  
New Formulation ◽  
Adult Volunteers ◽  
Sodium Phenylbutyrate

BackgroundSodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control.ObjectivesA new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers.ResultsThe in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of ∼10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (Cmax) or for area under the plasma concentration–time curve (AUC). CI for Cmax and AUC0–inf of NaPB were included in the bioequivalence range of 0.80–1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements.ConclusionsIn vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD.

Anthocyanin suppresses the toxicity of Aβ deposits through diversion of molecular forms in in vitro and in vivo models of Alzheimer's disease

2015 ◽  
Vol 19 (1) ◽  
pp. 32-42 ◽  
Author(s):  
Miho Yoshida Yamakawa ◽  
Kazuyuki Uchino ◽  
Yasuhiro Watanabe ◽  
Tadashi Adachi ◽  
Mami Nakanishi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Forms ◽  
In Vivo Models

scholarly journals Development of Level A In Vitro–Vivo Correlation for Electrosprayed Microspheres Containing Leuprolide: Physicochemical, Pharmacokinetic, and Pharmacodynamic Evaluation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 36
Author(s):  
Dong-Seok Lee ◽  
Dong Wook Kang ◽  
Go-Wun Choi ◽  
Han-Gon Choi ◽  
Hea-Young Cho
Keyword(s):  
Plasma Concentration ◽  
Prediction Error ◽  
Subcutaneous Administration ◽  
In Vitro Dissolution ◽  
Burst Release ◽  
Maximum Plasma ◽  
Time Curve ◽  
In Vivo Dissolution

This study optimized the preparation of electrosprayed microspheres containing leuprolide and developed an in vitro–in vivo correlation (IVIVC) model that enables mutual prediction between in vitro and in vivo dissolution. The pharmacokinetic (PK) and pharmacodynamic (PD) study of leuprolide was carried out in normal rats after subcutaneous administration of electrosprayed microspheres. The parameters of the IVIVC model were estimated by fitting the PK profile of Lucrin depot® to the release compartment of the IVIVC model, thus the in vivo dissolution was predicted from the in vitro dissolution. From this correlation, the PK profile of leuprolide was predicted from the results of in vivo dissolution. The IVIVC model was validated by estimating percent prediction error (%PE) values. Among prepared microspheres, an optimal formulation was selected using the IVIVC model. The maximum plasma concentration and the area under the plasma concentration–time curve from zero to infinity from the predicted PK profile were 4.01 ng/mL and 52.52 h·ng/mL, respectively, and from the observed PK profile were 4.14 ng/mL and 56.95 h·ng/mL, respectively. The percent prediction error values of all parameters did not exceed 15%, thus the IVIVC model satisfies the validation criteria of the Food and Drug Administration (FDA) guidance. The PK/PD evaluation suggests that the efficacy of OL5 is similar to Lucrin depot®, but the formulation was improved by reducing the initial burst release.

scholarly journals Increases in circulating megakaryocyte growth-promoting activity in the plasma of rats following whole body irradiation

Blood ◽  
1984 ◽  
Vol 63 (5) ◽  
pp. 1060-1066 ◽  
Author(s):  
M Miura ◽  
CW Jackson ◽  
SA Lyles
Keyword(s):  
Bone Marrow ◽  
Plasma Concentration ◽  
Bone Marrow Cells ◽  
Single Cells ◽  
Rat Plasma ◽  
Whole Body ◽  
Growth Promoting ◽  
Marrow Cells

Abstract To gain insight into the regulation of megakaryocyte precursors in vivo, we assayed (in vitro) megakaryocyte growth-promoting activity (Meg-GPA) in plasma of rats in which both marrow hypoplasia and thrombocytopenia had been induced by irradiation. Rats received whole body irradiation of 834 rad from a 137Cs source. Plasma was collected at intervals of hours to days, up through day 21 postirradiation, and was tested, at a concentration of 30%, for Meg-GPA on bone marrow cells cultured in 1.1% methylcellulose with 5 X 10(-5) M 2-mercaptoethanol. With normal rat plasma, no megakaryocyte colonies (defined as greater than or equal to 4 megakaryocytes) were seen and only a few single megakaryocytes and clusters (defined as 2 or 3 megakaryocytes) were formed. Two peaks of plasma Meg-GPA were observed after irradiation. The first appeared at 12 hr, before any decrease in marrow megakaryocyte concentration or platelet count. The second occurred on days 10–14 after irradiation, after the nadir in megakaryocyte concentration and while platelet counts were at their lowest levels. A dose-response study of plasma concentration and megakaryocyte growth, using plasma collected 11 days postirradiation, demonstrated that patterns of megakaryocyte growth were related to plasma concentration; formation of single megakaryocytes was optimal over a range of 20%-30% plasma concentration, while cluster and colony formation were optimal at a plasma concentration of 30%. All forms of megakaryocyte growth were decreased with 40% plasma. There was a linear relationship between the number of bone marrow cells plated and growth of single cells, clusters, and colonies using a concentration of 30% plasma collected 11 days after irradiation. We conclude that irradiation causes time- related increases in circulating megakaryocyte growth-promoting activity. We suggest that the irradiated rat is a good model for studying the relationships between Meg-GPA and megakaryocyte and platelet concentration in vivo.

Formulation and Characterization of Transethosomes for Enhanced Transdermal Delivery of Propranolol Hydrochloride

2020 ◽  
Vol 12 (1) ◽  
pp. 38-47 ◽  
Author(s):  
Lalit Kumar ◽  
Puneet Utreja
Keyword(s):  
Plasma Concentration ◽  
Skin Permeation ◽  
Laser Scanning Microscopy ◽  
Prolonged Release ◽  
Propranolol Hydrochloride ◽  
Oral Tablet ◽  
In Vitro Skin Permeation ◽  
Oral Propranolol

Objective: The objective of the present work was to develop transethosomes loaded with propranolol hydrochloride using Lipoid S100 as phospholipid, and oleic acid as permeation enhancer and evaluate them for prolonged release effect, in-vitro skin permeation, and in-vivo plasma concentration. Methods: Transethosomes loaded with propranolol hydrochloride were prepared by homogenization method. Furthermore, they were characterized by using Transmission Electron Microscopy (TEM), zeta sizer, Differential Scanning Calorimetry (DSC), and Confocal Laser Scanning Microscopy (CLSM) for in-vitro skin permeation. Plasma concentration profile of transethosomal gel was determined using Sprague Dawley rats and compared with a marketed oral tablet of propranolol hydrochloride. Results: Developed transethosomes loaded with propranolol hydrochloride showed acceptable size (182.7 ± 5.4 nm), high drug entrapment (81.98 ± 2.9%) and good colloidal characteristics [polydispersity index (PDI) = 0.234 ± 0.039, zeta potential = -21.91 ± 0.65 mV]. Transethosomes showed prolonged in-vitro release of propranolol hydrochloride for 24 h. Results of in-vitro skin permeation studies of transethosomal gel showed 74.34 ± 2.33% permeation of propranolol hydrochloride after 24 h and confocal microscopy revealed accumulation of transethosomes in the stratum basale layer of the skin. Transethosomal gel was capable to prolong the in-vivo release of propranolol hydrochloride upto 24 h. The value of peak plasma concentration (Cmax) of propranolol hydrochloride was found to be 93.8 ± 3.6 ng/mL which was very high compared to the marketed oral tablet of propranolol hydrochloride (45.6 ± 3.1 ng/mL). Conclusion: The results suggested that transethosomal gel of propranolol hydrochloride could be a better alternative to oral propranolol hydrochloride as it can avoid various disadvantages of oral propranolol hydrochloride like high dosing frequency, first pass effect, and organ toxicity.

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