scholarly journals Effect of long-acting gestagen levonorgestrel butanate on the spermatogenesis and endocrine function of the adrenals and gonads of papio hamadrias

1996 ◽  
Vol 42 (1) ◽  
pp. 37-40
Author(s):  
N. P. Goncharov ◽  
G. V. Katsiya ◽  
V. Yu. Butnev ◽  
V. M. Gorlushkin
Keyword(s):  
Peripheral Blood ◽  
Inhibitory Effect ◽  
Endocrine Function ◽  
Maximal Dose ◽  
Testosterone Secretion ◽  
Gonadotropic Function ◽  
Minimal Dose ◽  
Long Acting ◽  
Hormonal Concentration ◽  
Dose Injection

Tlie efficacy of levonorgestrel butanate in doses 1, 2, 4, and 8 mg/kg in spermatogenesis suppression was studied in adult male Papio hamadrias. The drug was injected intramuscularly twice with 3 month interval. All gestagen doses had an inhibitory effect of spermatogenesis, this effect increasing with the dosage build-up. None of the animals developed azoospermia, which was due to incomplete suppression of the pituitary gonadotropic function and of testosterone secretion. Hormonal concentration in the peripheral blood was 55-60% reduced in response to the minimal dose and 60-80% reduced in response to the maximal dose. Injection of long-acting gestagen did not influence the secretion of adrenocortical hormones hydrocortisone, dehydroepiandrosterone, and pregnenolone.

scholarly journals EXTH-14. A NOVEL LONG-ACTING INTERLEUKIN-7 AGONIST, NT-I7, INCREASES CYTOTOXIC CD8 CELLS AND ENHANCES SURVIVAL IN MOUSE GLIOMA MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii89-ii89
Author(s):  
Subhajit Ghosh ◽  
Ran Yan ◽  
Sukrutha Thotala ◽  
Arijita Jash ◽  
Anita Mahadevan ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cervical Lymph Nodes ◽  
Cd8 Cells ◽  
Interleukin 7 ◽  
Long Acting ◽  
Spleen And Lymph Nodes ◽  
Mouse Glioma

Abstract BACKGROUND Patients with glioblastoma (GBM) are treated with radiation (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia, which is associated with shorter survival. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 would protect T cells from treatment-induced lymphopenia and improve survival. METHODS C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-17 (10 mg/kg on the final day of RT completion). We followed for survival and profiled CD3, CD8, CD4, FOXP3 in peripheral blood over time. In parallel, we assessed cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. RESULTS Median survival in mice treated with NT-I7 combined with RT was significantly better than RT alone (GL261: 40d vs 34d, p< 0.0021; CT2A: 90d vs 40d, p< 0.0499) or NT-I7 alone (GL261: 40d vs 24d, p< 0.008; CT2A: 90d vs 32d, p< 0.0154). NT-17 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261 (40d vs 47d) and CT2A (90d vs 90d). NT-I7 treatment significantly increased the amount of CD8+ cells in the peripheral blood and tumor. NT- I7 rescued CD8+ T cells from RT induced lymphopenia in peripheral blood, spleen, and lymph nodes. NT-I7 alone or NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood and tumor while reducing the FOXP3+ T-reg cells in the tumor microenvironment. CONCLUSIONS NT-I7 protects T-cells from RT induced lymphopenia, improves cytotoxic CD8+ T lymphocytes systemically and in the tumor, and improves survival. Presently, a phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

565 A novel long-acting interleukin-7 agonist, NT-I7, increases cytotoxic CD8+ T cells and enhances survival in mouse glioma models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A599-A599
Author(s):  
Subhajit Ghosh ◽  
Ran Yan ◽  
Sukrutha Thotala ◽  
Arijita Jash ◽  
Anita Mahadevan ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Standard Of Care ◽  
Control Group ◽  
Cervical Lymph Nodes ◽  
Cd8 Cells ◽  
Interleukin 7 ◽  
Long Acting

BackgroundRadiation (RT) and temozolomide (TMZ), which are standard of care for patients with glioblastoma (GBM), can cause prolonged severe lymphopenia. Lymphopenia, in turn, is an independent risk factor for shorter survival. Interleukin-7 (IL-7) is a cytokine that is required for T cell homeostasis and proliferation. IL-7 levels are inappropriately low in GBM patients with lymphopenia. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 rescues treatment-induced lymphopenia and improves survival.MethodsImmunocompetent C57BL/6 mice bearing two intracranial glioma models (GL261 and CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-I7 (10 mg/kg on the final day of RT completion). We profiled the CD3, CD8, CD4, FOXP3 cells in peripheral blood over time. We also immunoprofiled cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. Survival was monitored daily.ResultsMedian survival in mice treated with NT-I7 combined with RT was significantly longer than RT alone (GL261: 40d vs 34d, p<0.0021; CT2A: 90d vs 40d, p<0.0499) or NT-I7 alone (GL261: 40d vs 24d, p<0.008; CT2A: 90d vs 32d, p<0.0154). NT-I7 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261(40d vs 47d) and CT2A (90d vs 90d). Cytotoxic CD8+ T cells were increased in both peripheral blood (0.66 x 105 to 3.34 x 105; P≤0.0001) and tumor (0.53 x 103 to 1.83 x 103; P≤0.0001) in mice treated with NT-I7 when compared to control. Similarly, NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood (0.658 x 105 to 1.839 x 105 P≤0.0001) when compared to RT alone. There were decreases in tumor infiltrating FOXP3+ T-reg cells in mice treated with NT-I7 (1.9 x 104 to 0.75 x 104 P≤0.0001) and NT-I7 + RT (1.9 x 104 to 0.59 x 104 P≤0.0001) when compared to the control group without NT-I7. In addition, NT- I7 treatment increased CD8+ T cells in thymus, spleen, and lymph nodes.ConclusionsNT-I7 enhances cytotoxic CD8+ T lymphocytes systemically and in the tumor microenvironment, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4197-4205 ◽  
Author(s):  
J.M. Herbert ◽  
J.P. Hérault ◽  
A. Bernat ◽  
R.G.M. van Amsterdam ◽  
J.C. Lormeau ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Therapeutic Index ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
Treatment And Prevention ◽  
Long Acting

Abstract SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

scholarly journals Inhibitory Effect of Glucocorticoid for Osteoblast Apoptosis Induced by Activated Peripheral Blood Mononuclear Cells

Endocrinology ◽  
1998 ◽  
Vol 139 (4) ◽  
pp. 2032-2040 ◽  
Author(s):  
Tomoki Nakashima ◽  
Hitoshi Sasaki ◽  
Masahiko Tsuboi ◽  
Atsushi Kawakami ◽  
Kaoru Fujiyama ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Inhibitory Effect ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Osteoblast Apoptosis

SMALLPOX VACCINATION OF ECZEMA PATIENTS WITH A STRAIN OF ATTENUATED LIVE VACCINIA (CVI-78)

PEDIATRICS ◽  
1968 ◽  
Vol 42 (6) ◽  
pp. 980-985
Author(s):  
C. Henry Kempe ◽  
Vincent Fulginiti ◽  
Mikio Minamitani ◽  
Henry Shinefield
Keyword(s):  
Primary Vaccination ◽  
Smallpox Vaccination ◽  
Chick Embryos ◽  
Maximal Dose ◽  
Standard Strain ◽  
Normal Children ◽  
Virus Dissemination ◽  
Systemic Reactions ◽  
Minimal Dose ◽  
Infectivity Titer

A group of 1,009 patients suffering from eczema or other skin disorders have received elective vaccination with the CVI-78 strain of vaccinia. The vaccine is attenuated by repeated passages through chick embryos; its infectivity titer is 8.4 (TCID50/ml). It is free of bacteria and known viruses, including avian leukosis virus. It was administered by one of two routes (multiple pressure or subcutaneously) with a minimal dose of 1,000 TCID50 and a maximal dose of 30,000 TCID50. Local and systemic reactions and temperature elevations in these eczematous patients were significantly less marked than those experienced with a standard strain of vaccinia in normal children. No virus dissemination or other complications occurred, except for two instances of mild erythema multiforme. Seroconversion was noted in all 387 patients tested to date. Multiple pressure revaccinations with a standard strain 1 to 6 months later resulted in marked modification of the vaccination reaction without systemic reactions. It would appear that the CVI-78 strain of vaccinia virus is effective and safe for elective primary vaccination of children suffering from eczema.

scholarly journals T Helper Cells in the Immunopathogenesis of Systemic Sclerosis – Current Trends

2017 ◽  
Vol 44 (1) ◽  
pp. 57-63
Author(s):  
E. Krasimirova ◽  
D. Kyurkchiev
Keyword(s):  
Systemic Sclerosis ◽  
Peripheral Blood ◽  
Absolute Number ◽  
Inhibitory Effect ◽  
Major Effect ◽  
Autoimmune Response ◽  
T Helper ◽  
Th Cell ◽  
Cutaneous Form ◽  
Ifn Γ

Abstract Systemic sclerosis (SSc) is a chronic progressive autoimmune disease characterized by skin and multiorgan involvement with alterations in both the innate and adaptive immunities. The hallmark of the disease is widespread fibrosis engaging the skin and multiple internal organs, as well as the musculoskeletal system. There is mounting evidence that T cells are key players in the pathogenesis of scleroderma. The current review discusses the role of the different T helper (Th) lymphocyte subsets in the processes of inflammation and fibrosis, characteristics for the pathogenesis of the disease. Cytokines produced by Th cell populations have a major effect on endothelial cells and fibroblasts in the context of favoring/inhibiting the vasculopathy and the fibrosis spread. The Th2 pro-fibrotic cytokines IL-4 and IL-13 have been shown to induce collagen synthesis by fibroblasts, whereas IFN-γ demonstrates an inhibitory effect. Increased Th17 cells are present in the scleroderma skin infiltrates. The combination of IL-17, IFN-γ and TGF-β levels in CD45RO and CD45RA cells from patients with SSc is useful to distinguish between the limited and the diffuse phenotype of the disease. There are accumulating data for functional and numerical alterations in the Tregs in SSc. High levels of TNF-α which might reduce the suppressive ability of Tregs have been described. According to some studies, the number of Tregs in scleroderma skin biopsies has been decreased against the normal absolute number of Tregs in peripheral blood of the same patients, which suggests suppressed immunomodulatory response. Other studies reported increased frequency of Tregs in peripheral blood of patients with systemic sclerosis and established a correlation with disease activity. The main immunological challenge remains the identification of the trigger of the autoimmune response in SSc, the causes for preferential Th2-type cell responses and the immunological differences between the diffuse and the limited cutaneous form of the disease.

scholarly journals Prolactin regulation of testosterone secretion and testes growth in DLS rams at the onset of seasonal testicular recrudescence

Reproduction ◽  
2010 ◽  
Vol 139 (1) ◽  
pp. 197-207 ◽  
Author(s):  
L M Sanford ◽  
S J Baker
Keyword(s):  
Peripheral Blood ◽  
Entire Period ◽  
Testosterone Levels ◽  
Testosterone Secretion ◽  
Testicular Recrudescence ◽  
The Times ◽  
Transition Stages

Our objective was to test the hypothesis that prolactin (PRL) acts at both the pituitary and testis levels to regulate testosterone secretion in the adult ram. The focus was on the mid-regression to mid-redevelopment stages of a photoperiod-condensed ‘seasonal’ testicular cycle. DLS rams (six per group) were given daily s.c. injections of bromocriptine (4 mg) or vehicle during the entire period. Serum PRL concentration in control rams peaked at 103.4±22.1 ng/ml in late regression and then steadily declined (P<0.01) to 19.5±4.3 ng/ml, whereas PRL in treated rams was always ≤4.0 ng/ml. Suppression of PRL tended (P<0.10) to increase the amplitude of natural LH pulses (transition stages) or reduce the number of LH receptors in the testis (regressed stage), although neither change disturbed testosterone levels in peripheral blood. These subtle changes were accompanied by significant (P<0.05) alterations in the capability of the pituitary to release LH (85% more) and of the testes to secrete testosterone (20% less). These effects of PRL were unmasked when rams were given highly stimulative i.v. injections of GNRH (single 3 μg dose) and NIH-oLH-S24 (three 5 μg doses given 20 min apart) respectively. PRL insufficiency also appeared to slow down the ‘seasonal’ rise in FSH secretion and slightly delayed (2 weeks) the times when the testes began to grow and were first significantly (P<0.05) enlarged from the regressed state. We conclude that PRL is an important part of the intricate regulation of the pituitary–gonadal system in moderately seasonal DLS rams.

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