NON-SELECTIVE INHIBITION OF BASAL GLUCAGON RELEASE BY [d-CYS14]-ANALOGUES OF SOMATOSTATIN IN THE RAT

1979 ◽  
Vol 81 (3) ◽  
pp. 315-323 ◽  
Author(s):  
FRITZ MÄRKI ◽  
BRUNO KAMBER ◽  
HANS RINK ◽  
PETER SIEBER
Keyword(s):  
Time Course ◽  
Dose Range ◽  
Subcutaneous Administration ◽  
Selective Inhibition ◽  
Glucagon Release ◽  
Basal Plasma ◽  
Dose Dependent Decrease ◽  
High Doses ◽  
Glucagon And Insulin ◽  
Dose Dependent

The effects of two [d-Cys14]-analogues of somatostatin on basal plasma levels of glucagon, insulin and glucose were determined in unanaesthetized rats to re-examine a glucagon-selective action of these peptides which has been claimed by others. Somatostatin, [d-Cys14]-somatostatin and [d-Trp8, d-Cys14]-somatostatin caused a short-lasting, dose-dependent decrease of plasma glucagon and insulin but they had no significant influence on plasma glucose. Glucagon and insulin reached the nadir 2 min after intravenous injection of the peptides (dose range 1–10 μg/kg) or 5 min after subcutaneous administration (30 and 300 μg/kg). At the nadir, insulin was decreased to a greater extent than glucagon and the effects of all three peptides were equipotent. However, in the period after the nadir and at high doses, the time-course of some effects of the analogues on either glucagon or insulin differed from that of somatostatin. Thus, these [d-Cys14]-analogues may show partial kinetic dissociation of effects on glucagon and insulin but they are not truly selective inhibitors of glucagon release.

Retinoic acid application to chick wing buds leads to a dose-dependent reorganization of the apical ectodermal ridge that is mediated by the mesenchyme

Development ◽  
1989 ◽  
Vol 106 (4) ◽  
pp. 691-705 ◽  
Author(s):  
C. Tickle ◽  
A. Crawley ◽  
J. Farrar
Keyword(s):  
Retinoic Acid ◽  
Gap Junctions ◽  
Time Course ◽  
Apical Ectodermal Ridge ◽  
Threshold Response ◽  
Epithelial Morphology ◽  
Early Effects ◽  
High Doses ◽  
Columnar Cells ◽  
Dose Dependent

Local application of retinoic acid to wing buds of chick embryos leads to dose- and position-dependent changes in the pattern of cellular differentiation. Early effects of retinoid treatment on the apical ectodermal ridge coordinate pattern changes and morphogenesis. The length of the apical ridge increases when additional digits will form but decreases when digits are lost. These changes in length can be understood in terms of a threshold response to the local retinoid concentration that results in either disappearance or maintenance of the ridge (Lee & Tickle, J. Embryol. exp. Morph. 90, 139–169 (1985)). Here, we have analysed the mechanisms involved in ridge disappearance by locally applying retinoic acid to the apex of stage 20 chick wing buds. With this treatment regime, low doses give duplicated digit patterns and higher doses truncations. The height of the apical ridge is progressively reduced with increasing doses of retinoid and the time course of ridge flattening indicates that the height of the ridge is correlated with bud outgrowth. With high doses of retinoic acid, the typical ridge, a pseudostratified epithelium in which the columnar cells are tightly packed, disappears and the epithelium at the tip of the bud consists of loosely packed cuboidal cells. Shortly after treatment, there is a decrease in the number of gap junctions between ridge cells. This early change in cell contacts suggests that gap junctions may be involved in maintaining epithelial morphology. When treated epithelium is recombined with untreated mesenchyme, an apical ridge is reestablished and distal structures can be generated. In contrast, when treated mesenchyme is recombined with the epithelium from normal buds, only proximal structures are formed. Therefore, retinoids can lead to a reorganization of the apical ectodermal ridge which is mediated and maintained by the mesenchyme.

Intracerebroventricular injection of prostaglandin E2 increases splenic sympathetic nerve activity in rats

1995 ◽  
Vol 269 (3) ◽  
pp. R662-R668 ◽  
Author(s):  
T. Ando ◽  
T. Ichijo ◽  
T. Katafuchi ◽  
T. Hori
Keyword(s):  
Prostaglandin E2 ◽  
Sympathetic Nerve ◽  
Time Course ◽  
Sympathetic Nerve Activity ◽  
Dependent Manner ◽  
Central Administration ◽  
Nerve Activity ◽  
High Doses ◽  
Alpha Chloralose ◽  
Dose Dependent

The effects of central administration of prostaglandin E2 (PGE2) and its selective agonists on splenic sympathetic nerve activity (SNA) were investigated in urethan- and alpha-chloralose-anesthetized rats. An intra-third-cerebroventricular (13V) injection of PGE2 (0.1-10 nmol/kg) increased splenic SNA in a dose-dependent manner. An I3V injection of an EP1 agonist, 17-phenyl-omega-trinor PGE2 (1-30 nmol/kg), also resulted in a dose-dependent increase in splenic SNA, with a time course similar to that of PGE2-induced responses. In contrast, EP2 agonists, butaprost (10-100 nmol/kg I3V) and 11-deoxy-PGE1 (10-100 nmol/kg I3V), had no effect on splenic SNA. An I3V injection of M & B-28767 (an EP3/EP1 agonist, EP3 >> EP1) increased splenic SNA only at high doses (10-100 nmol/kg). Pretreatment with an EP1 antagonist, SC-19220 (200 and 500 nmol/kg), completely blocked the responses of splenic SNA to PGE2 (0.1 nmol/kg) and M & B-28767 (10 nmol/kg), respectively. These findings indicate that brain PGE2 increases splenic SNA through its action on EP1 receptors.

scholarly journals Birthweight Depression in Male Rats Contiguous to Male Siblings in Utero Exposed to High Doses of 1,3-Butanediol during Organogenesis

1986 ◽  
Vol 5 (4) ◽  
pp. 189-196 ◽  
Author(s):  
R. F. Mankes ◽  
V. Renak ◽  
J. Fieseher ◽  
R. Lefevre
Keyword(s):  
Developmental Toxicity ◽  
In Utero ◽  
Cellular Damage ◽  
Male Rats ◽  
Body Weights ◽  
Fetal Repair ◽  
Dose Dependent Decrease ◽  
High Doses ◽  
Embryotoxic Effects ◽  
Dose Dependent

The embryotoxic effects of high doses of the narcotizing ethanol dimer 1,3-butanediol were evaluated in pregnant Long-Evans rats during the “critical period” of organogenesis. Butanediol was given by gavage at levels of 0,7060,4236, or 706 mg/kg per day (24,14.4, or 2.4% of the acute oral LD50 value for rats). Maternal sedation was observed at 7060 and 4236 mg/kg, but feed consumptions and maternal body weights were unaffected. Butanediol caused a significant, dose-dependent decrease in offspring birthweights. At the highest butanediol dose, birthweights were preferentially and significantly decreased in male pups not contiguous in utero to female siblings. Other group I1 offspring were not affected and did not differ significantly from controls. As butanediol was given prior to the period of greatest fetal growth and fetal sex steroidogenests, it is concluded that intra-uterine levels of female sex steroids (estradiol) enhance fetal repair of cellular damage (restitution ad integrum), whereas testosterone inhibits fetal repair or exacerbates previous embryonic damage by some unknown mechanism. Such interaction furthers the concept that intrauterine position affects the endpoints of developmental toxicity, as expressed at partuition.

scholarly journals Degradation of  T Cell Receptor (TCR)–CD3-ζ Complexes after Antigenic Stimulation

1997 ◽  
Vol 185 (10) ◽  
pp. 1859-1864 ◽  
Author(s):  
Salvatore Valitutti ◽  
Sabina Müller ◽  
Mariolina Salio ◽  
Antonio Lanzavecchia
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Time Course ◽  
Cell Activation ◽  
Specific Antigen ◽  
Cell Receptor ◽  
Bafilomycin A1 ◽  
Dose Dependent Decrease ◽  
Antigen Presenting ◽  
Dose Dependent

T cell activation by specific antigen results in a rapid and long-lasting downregulation of triggered T cell receptors (TCRs). In this work, we investigated the fate of downregulated TCR– CD3-ζ complexes. T cells stimulated by peptide-pulsed antigen-presenting cells (APCs) undergo an antigen dose-dependent decrease of the total cellular content of TCR-β, CD3-ε, and ζ chains, as detected by FACS® analysis on fixed and permeabilized T–APC conjugates and by Western blot analysis on cell lysates. The time course of CD3-ζ chain consumption overlaps with that of TCR downregulation, indicating that internalized TCR–CD3 complexes are promptly degraded. Inhibitors of lysosomal function (bafilomycin A1, folimycin) markedly reduced ζ chain degradation, leading to the accumulation of ζ chain in large Lamp1+ vesicles. These results indicate that in T cell–APC conjugates, triggered TCRs are rapidly removed from the cell surface and are degraded in the lysosomal compartment.

Oral Administration of Fucosylated Chondroitin Sulfate Oligomers in Gastro-Resistant Microcapsules Exhibits a Safe Antithrombotic Activity

2020 ◽  
Author(s):  
Lufeng Yan ◽  
Mengshan Zhu ◽  
Danli Wang ◽  
Wenyang Tao ◽  
Donghong Liu ◽  
...  
Keyword(s):  
Oral Administration ◽  
Chondroitin Sulfate ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
Selective Inhibition ◽  
Antithrombotic Effect ◽  
Antithrombotic Activity ◽  
Antithrombotic Effects ◽  
Dose Dependent ◽  
Coagulation Pathway

AbstractFucosylated chondroitin sulfate (FCS) polysaccharide isolated from sea cucumber has potent anticoagulant activity. Based on its resistance to the enzymes present in vertebrates, it may serve as an anticoagulant and shows antithrombotic effects when delivered through gastro-resistant (GR) tablets. However, due to the multiple plasma targets of FCS polysaccharide in the coagulation pathway, bleeding can occur after its oral administration. In the current study, we used FCS oligomers, in particular a mixture of oligosaccharides having 6 to 18 saccharide units, as the active ingredient in GR microcapsules for oral anticoagulation. In a Caco-2 model, the FCS oligomers showed higher absorption than native FCS polysaccharides. Oral administration of FCS oligomer-GR microcapsules provided a dose-dependent, prolonged anticoagulant effect with a selective inhibition of the intrinsic coagulation pathway when compared with subcutaneous administration of FCS oligomers or oral administration of unformulated FCS oligomers or native FCS-GR microspheres. Continued oral administration of FCS oligomer-GR microcapsules did not result in the accumulation of oligosaccharides in the plasma. Venous thrombosis animal models demonstrated that FCS oligomers delivered via GR microcapsules produced a potent antithrombotic effect dependent on their anticoagulant properties in the plasma, while oral administration of unformulated FCS oligomers at the same dose exhibited a weaker antithrombotic effect than the formulated version. Oral administration of FCS oligomer-GR microcapsules resulted in no bleeding, while oral administration of native FCS-GR microcapsules resulted in bleeding (p < 0.05). Our present results suggest that a FCS oligomer-GR microcapsule formulation represents an effective and safe oral anticoagulant for potential clinical applications.

Thermoregulatory responses to lipopolysaccharide in the mouse: dependence on the dose and ambient temperature

2005 ◽  
Vol 289 (5) ◽  
pp. R1244-R1252 ◽  
Author(s):  
Alla Y. Rudaya ◽  
Alexandre A. Steiner ◽  
Jared R. Robbins ◽  
Alexander S. Dragic ◽  
Andrej A. Romanovsky
Keyword(s):  
Ambient Temperature ◽  
Dose Range ◽  
Dose Dependence ◽  
Experimental Conditions ◽  
Thermoregulatory Responses ◽  
Hypothermic Response ◽  
High Doses ◽  
The Relationship ◽  
Dose Dependent ◽  
Higher Doses

Most published studies of thermoregulatory responses of mice to LPS involved a stressful injection of LPS, were run at a poorly controlled and often subneutral ambient temperature (Ta), and paid little attention to the dependence of the response on the LPS dose. These pitfalls have been overcome in the present study. Male C57BL/6 mice implanted with jugular vein catheters were kept in an environmental chamber at a tightly controlled Ta. The relationship between the Tas used and the thermoneutral zone of the mice was verified by measuring tail skin temperature, either by infrared thermography or thermocouple thermometry. Escherichia coli LPS in a wide dose range (100-104μg/kg) was administered through an extension of the jugular catheter from outside the chamber. The responses observed were dose dependent. At a neutral Ta, low (just suprathreshold) doses of LPS (100-101μg/kg) caused a monophasic fever. To a slightly higher dose (101.5μg/kg), the mice responded with a biphasic fever. To even higher doses (101.75-104μg/kg), they responded with a polyphasic fever, of which three distinct phases were identified. The dose dependence and dynamics of LPS fever in the mouse appeared to be remarkably similar to those seen in the rat. However, the thermoregulatory response of mice to LPS in a subthermoneutral environment is remarkably different from that of rats. Although very high doses of LPS (104μg/kg) did cause a late (latency, ∼3 h) hypothermic response in mice, the typical early (latency, 10–30 min) hypothermic response seen in rats did not occur. The present investigation identifies experimental conditions to study LPS-induced mono-, bi-, and polyphasic fevers and late hypothermia in mice and provides detailed characteristics of these responses.

lmmunotoxicological Investigation of SCMF, a New Pyrethroid Pesticide in Mice

1994 ◽  
Vol 13 (5) ◽  
pp. 337-343 ◽  
Author(s):  
Olga Siroki ◽  
L. Institoris ◽  
E. Tatar ◽  
I. Desi
Keyword(s):  
Oral Treatment ◽  
Dose Range ◽  
High Dose ◽  
Experimental Conditions ◽  
Cell Content ◽  
Pyrethroid Pesticide ◽  
Dose Dependent Decrease ◽  
Dose Dependent ◽  
Higher Doses ◽  
Femoral Bone Marrow

The toxicity of a new pyrethroid pesticide Supercypermethrin Forte (SCMF) was studied in male CFLP mice using classic toxicological (body weight, organ weights) and haematological (white blood cell count, haematocrit, nucleated cell content of femoral bone marrow) methods and immune function tests (PFC assay, DTH reaction). Four weeks of oral treatment in a 5 days per week system at doses of 1/10, 1/20, or 1/40 x LD50 did not cause evaluable changes in the measured parameters. When single calculated LD20, LD10, or LD5 doses of SCMF were administered on different days before termination to different groups of mice the two higher doses caused a time- and dose-dependent decrease in the splenic PCF number, Apart from some temporary toxic signs and an increase of haematocrit at the top dose the other examined parameters did not show evaluable changes. Under these experimental conditions toxic changes appeared only at the high dose range and, of those applied, the PFC assay proved to be the most sensitive method for detecting the toxicity of SCMF.

Selective pulmonary vasodilation with ATP-MgCl2 during pulmonary hypertension in lambs

1990 ◽  
Vol 69 (5) ◽  
pp. 1836-1842 ◽  
Author(s):  
J. R. Fineman ◽  
M. R. Crowley ◽  
S. J. Soifer
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Systemic Arterial Pressure ◽  
Pulmonary Vasodilation ◽  
Potent Vasodilator ◽  
Pulmonary Arterial ◽  
Dose Dependent Decrease ◽  
High Doses ◽  
Dose Dependent

We investigated the effects of infusions of ATP-MgCl2 on the circulation in 11 spontaneously breathing newborn lambs during pulmonary hypertension induced either by the infusion of U-46619, a thromboxane A2 mimetic, or by hypoxia. During pulmonary hypertension induced by U-46619, ATP-MgCl2 (0.01-1.0 mg.kg-1.min-1) caused a significant dose-dependent decrease in pulmonary arterial pressure (12.4-40.7%, P less than 0.05), while systemic arterial pressure decreased only at the highest doses (P less than 0.05). Left atrial infusions of ATP-MgCl2 caused systemic hypotension without decreasing pulmonary arterial pressure. During hypoxia-induced pulmonary hypertension, ATP-MgCl2 caused a similar significant dose-dependent decrease in pulmonary arterial pressure (12.0-41.1%, P less than 0.05), while systemic arterial pressure decreased only at high doses (P less than 0.05). Regression analysis showed selectivity of the vasodilating effects of ATP-MgCl2 for the pulmonary circulation during pulmonary hypertension induced either by U-46619 or hypoxia. ATP-MgCl2 is a potent vasodilator with a rapid metabolism that allows for selective vasodilation of the vascular bed first encountered (pulmonary or systemic). We conclude that infusions of ATP-MgCl2 may be clinically useful in the treatment of children with pulmonary hypertension.

Modeling and simulation of neutropenia to support dosing regimens for liposome-encapsulated paclitaxel easy-to-use (LEP- ETU)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13011-13011
Author(s):  
T. H. Grasela ◽  
G. J. Fetterly ◽  
J. L. Dul ◽  
D. LeComte ◽  
A. Y. Grahn ◽  
...  
Keyword(s):  
Modeling And Simulation ◽  
Time Course ◽  
Mean Transit Time ◽  
Dose Range ◽  
Two Phase ◽  
Pkpd Model ◽  
Advanced Malignancies ◽  
Dosing Regimens ◽  
Mitotic Time ◽  
Dose Dependent

13011 Background: LEP-ETU is a liposomal formulation of paclitaxel designed to reduce toxicities while maintaining or enhancing the efficacy of the drug. A PKPD model was used to characterize the time course of neutrophils in relation to blood exposure of LEP-ETU in patients with solid tumors. Simulations were performed to provide justification for dosing schedule in Phase 3 trials. Methods: Data from 63 patients in two phase I studies with advanced malignancies were utilized. LEP-ETU was infused intravenously over 90 min. at 135, 175, 225, 275, 325, and 375 mg/m2 every 21 days (Q3W). A separate cohort received 175 mg/m2 of LEP-ETU infused over 3 hours following a Q3W regimen. Population PKPD modeling and simulations were performed to assess the influence of dose and schedule (275 - 325 mg/m2 Q3W vs. 90 - 110 mg/m2 QW) on neutropenia. Results: The temporal relationship between circulating neutrophils and paclitaxel concentrations was adequately characterized using a model representative of progenitor cells undergoing differentiation and maturation into neutrophils. Mean predicted (%SEM) baseline ANC was 4.3 (6) x 109/L, representative of a normal neutrophil count. Mean transit time (%SEM) was 80 (8) hr, representing a post-mitotic time delay to neutrophil maturation. The neutrophil T1/2 was 14 hr, comparable to published values. The drug effect (Slope·Cp) on the proliferation rate constant is decreased by 9- and 91-fold when 10 or 100 units of drug is present, indicative of paclitaxel’s inhibition of progenitor cell production in bone marrow. Simulations suggest a higher risk of neutropenia with the Q3W regimen and dose-dependent severity for both the Q3W and QW regimens. The predicted incidence of grade 4 toxicity increased from 33% - 42% across the dose range of 275 - 325 mg/m2 Q3W. For a dose of 110 mg/m2 given QW, the incidence of grade 4 neutropenia was 16% compared to 42% for the same total dose of 325 mg/m2 given Q3W. Conclusions: Modeling and simulation predict that a Q3W regimen of 325 mg/m2 LEP- ETU (MTD) provides acceptable neutropenia outcomes comparable to 175 mg/m2 paclitaxel Q3W, while minimizing the Cremophor- associated adverse events. Future consideration of QW regimens may be explored. No significant financial relationships to disclose.

Dose-Dependent Modulation of Cell Death: Apoptosis Versus Necrosis in Thioacetamide Hepatotoxicity

1998 ◽  
Vol 17 (2) ◽  
pp. 193-211 ◽  
Author(s):  
Raja S. Mangipudy ◽  
Prathibha S. Rao ◽  
Annette Andrews ◽  
Thomas J. Bucci ◽  
Frank A. Witzmann ◽  
...  
Keyword(s):  
Cell Death ◽  
Time Course ◽  
Dose Range ◽  
Early Time ◽  
Inverse Relation ◽  
Hsp 70 ◽  
Transmission Electron ◽  
Induced Apoptosis ◽  
Apoptosis And Necrosis ◽  
Dose Dependent

Apoptosis is programmed cell death, morphologically and biochemically distinct from necrosis. The objective of the present study was to examine thioacetamide-induced apoptosis over an early time course of 0 to 8 h after administration of a 12-fold dose range (50, 150, 300, and 600 mg/kg, ip) of thioacetamide (TA). Male Sprague-Daw ley rats (200-225 g) were used for the study. The incidence of apoptosis was determined by in situ end labeling, transmission electron microscopy, and charge modification of heat shock protein 70 (Hsp 70). Light microscopic examination of liver sections revealed apoptotic bodies (ABs)as early as 2 h after TA administration. A dose-dependent increase in the incidence of ABs was seen with all doses until 4 h. Thereafter, the incidence of ABs continued to increase in a temporal manner with 50 and 150 mg/kg, while it decreased in the rats treated with 300 and 600 mg/kg. Between 4 and 8 h, while necrosis as assessed by serum alanine aminotransferase (ALT) and histopathology declined in the sixfold dose range (50, 150, and 300 mg TA/kg), it increased in a temporal manner with 600 mg TA/kg. Preliminary studies indicate an inverse relation between Hsp 70 abundance and the incidence of apoptosis. Hsp 70 expression was significantly higher in the 600 mg TA/kg group compared to the lower doses. Lowest abundance was recorded in the groups receiving 50 and 150 mg TA/kg, where maximum apoptosis was noted. These findings collectively suggest that although the processes of apoptosis and necrosis are initiated simultaneously, the proportion of cells dying via either mechanism seems to be regulated by the dose of TA. Lower doses seem to favor cell death via apoptosis, while higher doses favor cell death via necrosis. Additionally, the inverse relation between Hsp 70 and apoptosis at lower doses suggests a regulatory role for Hsp 70.

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