In vivo administration of a GnRH antagonist to male mice: effects on pituitary gonadotropin secretion in vitro

1989 ◽  
Vol 120 (3) ◽  
pp. 308-314
Author(s):  
A. M. Ultee-van Gessel ◽  
G.J. van Steenbrugge ◽  
F. G. Leemborg ◽  
F. H. Schroeder ◽  
F. H. de Jong
Keyword(s):  
Gnrh Antagonist ◽  
Term Treatment ◽  
Plasma Testosterone ◽  
High Dose ◽  
Male Mice ◽  
Short Term Treatment ◽  
Gonadotropin Secretion ◽  
Long Term Treatment

Abstract. The potent luteinizing hormone-releasing hormone antagonist [N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]GnRH (4 mg/kg) was administered sc once or daily for 21 days to immune-deficient (nude) and normal immune-competent (NIC) male mice derived from the same genetic background. Effects of in vivo pretreatment with the antagonist on gonadotropin secretion from hemipituitary glands from both types of mice were studied in vitro in the presence or absence of synthetic GnRH. Treatment with the GnRH antagonist caused differential effects on release of FSH and LH from and amounts of FSH and LH in hemipituitary glands. Pituitary FSH secretion was effectively inhibited, whereas effects on pituitary LH were less evident or nonsignificant under these experimental conditions. Long-term treatment with the antagonist caused larger effects on pituitary secretion and content of FSH, when compared with short-term treatment. No significant effects of duration of treatment on secretion or pituitary content of LH were detected. Addition of synthetic GnRH to the incubation medium caused stimulation of gonadotropin release. Therefore, it was concluded that the high doses of this GnRH antagonist were not able to block GnRH receptors effectively in the pituitary glands of nude and NIC male mice. The incomplete suppression of LH secretion by this high dose of the GnRH antagonist may partly explain the inability of the antagonist to suppress plasma testosterone levels and the growth of androgen-dependent tumours in male mice.

scholarly journals Evaluation of cytotoxicity and mutagenicity of the benzodiazepine flunitrazepam in vitro and in vivo

2014 ◽  
Vol 50 (2) ◽  
pp. 251-256
Author(s):  
Igor Vivian de Almeida ◽  
Giovana Domingues ◽  
Lilian Capelari Soares ◽  
Elisângela Düsman ◽  
Veronica Elisa Pimenta Vicentini
Keyword(s):  
Rattus Norvegicus ◽  
Bone Marrow Cells ◽  
Micronucleus Test ◽  
Term Treatment ◽  
Genotoxic Effects ◽  
Short Term ◽  
Short Term Treatment ◽  
Chromosomal Aberration Test

Flunitrazepam (FNZ) is a sedative benzodiazepine prescribed for the short-term treatment of insomnia. However, there are concerns regarding possible carcinogenic or genotoxic effects of this medicine. Thus, the aim of this study was to evaluate the cytotoxic, clastogenic and aneugenic effects of FNZ in hepatoma cells from Rattus norvegicus (HTC) in vitro and in bone marrow cells of Wistar rats in vivo. These effects were examined in vitro following treatment with 0.2, 1.0, 5.0 or 10 μg/mL FNZ using a micronucleus test with a cytokinesis block or in vivo using a chromosomal aberration test following treatment with 7, 15 or 30 μg/mL/kg body weight. The results showed that the benzodiazepine concentrations tested were not cytotoxic, aneugenic or clastogenic. However, considering the adverse effects of using this benzodiazepine, more studies are required.

Vasoactive intestinal peptide prevents PKCε-induced intestinal epithelial barrier disruption during EPEC infection

2015 ◽  
Vol 308 (5) ◽  
pp. G389-G402 ◽  
Author(s):  
V. Morampudi ◽  
V. S. Conlin ◽  
U. Dalwadi ◽  
X. Wu ◽  
K. C. Marshall ◽  
...  
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Critical Role ◽  
Term Treatment ◽  
Epithelial Barrier ◽  
Protective Effects ◽  
Short Term Treatment ◽  
Barrier Integrity ◽  
Barrier Disruption ◽  
Long Term Treatment

We previously showed that vasoactive intestinal peptide (VIP) protects against bacterial pathogen-induced epithelial barrier disruption and colitis, although the mechanisms remain poorly defined. The aim of the current study was to identify cellular pathways of VIP-mediated protection with use of pharmacological inhibitors during enteropathogenic Escherichia coli (EPEC) infection of Caco-2 cell monolayers and during Citrobacter rodentium-induced colitis. EPEC-induced epithelial barrier disruption involved the PKC pathway but was independent of functional cAMP, Rho, and NF-κB pathways. VIP mediated its protective effects by inhibiting EPEC-induced PKC activity and increasing expression of the junctional protein claudin-4. Short-term treatment with TPA, which is known to activate PKC, was inhibited by VIP pretreatment, while PKC degradation via long-term treatment with TPA mimicked the protective actions of VIP. Immunostaining for specific PKC isotypes showed upregulated expression of PKCθ and PKCε during EPEC infection. Treatment with specific inhibitors revealed a critical role for PKCε in EPEC-induced barrier disruption. Furthermore, activation of PKCε and loss of barrier integrity correlated with claudin-4 degradation. In contrast, inhibition of PKCε by VIP pretreatment or the PKCε inhibitor maintained membrane-bound claudin-4 levels, along with barrier function. Finally, in vivo treatment with the PKCε inhibitor protected mice from C. rodentium-induced colitis. In conclusion, EPEC infection increases intracellular PKCε levels, leading to decreased claudin-4 levels and compromising epithelial barrier integrity. VIP inhibits PKCε activation, thereby attenuating EPEC-induced barrier disruption.

Biocompatibility of Charcoal Hemoperfusion. Effects of Long-Term Treatment on Lymphocyte Characteristics and Function

1986 ◽  
Vol 9 (5) ◽  
pp. 301-304 ◽  
Author(s):  
S. Stefoni ◽  
A. Nanni Costa ◽  
G. Liviano D'Arcangelo ◽  
M. Biavati ◽  
S. lannelli ◽  
...  
Keyword(s):  
Antigen Expression ◽  
Term Treatment ◽  
T Cell Subsets ◽  
Long Term Treatment ◽  
Circulating Lymphocytes ◽  
And Function ◽  
Charcoal Hemoperfusion

Biocompatibility of charcoal hemoperfusion was studied in a group of 15 uremic patients, evaluating the effects of long-term treatment on some structural and functional parameters of circulating lymphocytes: in vivo distribution of T-cell subsets; surface T3, T4 and T8 antigen expression, in vivo and in vitro DNA synthesis. A comparative analysis was performed with patients on conventional dialysis using cuprophan membranes.

Plasma extracellular superoxide dismutase and erythrocyte Cu, Zn-containing superoxide dismutase in alcoholics treated with disulfiram

1986 ◽  
Vol 70 (4) ◽  
pp. 365-369 ◽  
Author(s):  
Michael Öhman ◽  
Stefan L. Marklund
Keyword(s):  
Superoxide Dismutase ◽  
Chronic Alcoholism ◽  
Term Treatment ◽  
Extracellular Superoxide Dismutase ◽  
Healthy Controls ◽  
Efficient Inhibitor ◽  
Long Term Treatment

1. Disulfiram has long been used in the treatment of chronic alcoholism. It is in vivo partially reduced to diethyldithiocarbamate, which is an efficient inhibitor of Cu, Zn-containing superoxide dismutase both in vitro and in vivo. The recently described extracellular superoxide dismutase is even more sensitive to diethyldithiocarbamate than Cu, Zn-superoxide dismutase. 2. To test for the possibility that long term treatment with disulfiram leads to inhibition of the superoxide dismutases, plasma extracellular superoxide dismutase and erythrocyte Cu, Zn-superoxide dismutase were determined in 12 disulfiram-treated alcoholics, and compared with 11 non-treated alcoholics and 19 healthy controls. 3. Plasma extracellular superoxide dismutase was moderately reduced (about 20%) in the disulfiram-treated alcoholics as compared with the non-treated alcoholics and the healthy controls. No effect of disulfiram treatment on erythrocyte Cu, Zn-superoxide dismutase activity was demonstrated.

scholarly journals Long-term treatment with valganciclovir improves lentiviral suicide gene therapy of glioblastoma

2019 ◽  
Vol 21 (7) ◽  
pp. 890-900 ◽  
Author(s):  
Jubayer A Hossain ◽  
Md A Latif ◽  
Lars A R Ystaas ◽  
Sandra Ninzima ◽  
Kristoffer Riecken ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Tumor Cells ◽  
Suicide Gene ◽  
Term Treatment ◽  
Suicide Gene Therapy ◽  
Short Term ◽  
Short Term Treatment ◽  
Long Term Treatment

Abstract Background Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to short-term treatment (14 days), especially when replication-defective vectors were used. We previously showed that a substantial fraction of herpes simplex virus thymidine kinase (HSV-TK) transduced tumor cells survive ganciclovir (GCV) treatment in an orthotopic glioblastoma (GBM) xenograft model. Here we analyzed whether these TK+ tumor cells are still sensitive to prodrug treatment and whether prolonged prodrug treatment can enhance treatment efficacy. Methods Glioma cells positive for TK and green fluorescent protein (GFP) were sorted from xenograft tumors recurring after suicide gene therapy, and their sensitivity to GCV was tested in vitro. GBM xenografts were treated with HSV-TK/GCV, HSV-TK/valganciclovir (valGCV), or HSV-TK/valGCV + erlotinib. Tumor growth was analyzed by MRI, and survival as well as morphological and molecular changes were assessed. Results TK-GFP+ tumor cells from recurrent xenograft tumors retained sensitivity to GCV in vitro. Importantly, a prolonged period (3 mo) of prodrug administration with valganciclovir (valGCV) resulted in a significant survival advantage compared with short-term (3 wk) application of GCV. Recurrent tumors from the treatment groups were more invasive and less angiogenic compared with primary tumors and showed significant upregulation of epidermal growth factor receptor (EGFR) expression. However, double treatment with the EGFR inhibitor erlotinib did not increase therapeutic efficacy. Conclusion Long-term treatment with valGCV should be considered as a replacement for short-term treatment with GCV in clinical trials of HSV-TK mediated suicide gene therapy.

scholarly journals Combined Inhibition of Epigenetic Readers and Transcription Initiation Targets the EWS-ETS Transcriptional Program in Ewing Sarcoma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 304 ◽  
Author(s):  
Günther H.S. Richter ◽  
Tim Hensel ◽  
Oxana Schmidt ◽  
Vadim Saratov ◽  
Kristina von Heyking ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Transcription Initiation ◽  
Combined Treatment ◽  
Term Treatment ◽  
Transcriptional Elongation ◽  
Transcriptional Program ◽  
Development Of Resistance ◽  
Long Term Treatment

Background: Previously, we used inhibitors blocking BET bromodomain binding proteins (BRDs) in Ewing sarcoma (EwS) and observed that long term treatment resulted in the development of resistance. Here, we analyze the possible interaction of BRD4 with cyclin-dependent kinase (CDK) 9. Methods: Co-immunoprecipitation experiments (CoIP) to characterize BRD4 interaction and functional consequences of inhibiting transcriptional elongation were assessed using drugs targeting of BRD4 or CDK9, either alone or in combination. Results: CoIP revealed an interaction of BRD4 with EWS-FLI1 and CDK9 in EwS. Treatment of EwS cells with CDKI-73, a specific CDK9 inhibitor (CDK9i), induced a rapid downregulation of EWS-FLI1 expression and block of contact-dependent growth. CDKI-73 induced apoptosis in EwS, as depicted by cleavage of Caspase 7 (CASP7), PARP and increased CASP3 activity, similar to JQ1. Microarray analysis following CDKI-73 treatment uncovered a transcriptional program that was only partially comparable to BRD inhibition. Strikingly, combined treatment of EwS with BRD- and CDK9-inhibitors re-sensitized cells, and was overall more effective than individual drugs not only in vitro but also in a preclinical mouse model in vivo. Conclusion: Treatment with BRD inhibitors in combination with CDK9i offers a new treatment option that significantly blocks the pathognomonic EWS-ETS transcriptional program and malignant phenotype of EwS.

Consequences of differential effects of ADH and other peptide hormones on thick ascending limb of mammalian kidney

1991 ◽  
Vol 260 (6) ◽  
pp. R1023-R1035 ◽  
Author(s):  
C. De Rouffignac ◽  
A. Di Stefano ◽  
M. Wittner ◽  
N. Roinel ◽  
J. M. Elalouf
Keyword(s):  
Term Treatment ◽  
Thick Ascending Limb ◽  
Adenylate Cyclase System ◽  
Nacl Transport ◽  
Differential Effects ◽  
Physiological Relevance ◽  
Long Term Treatment ◽  
Nephron Segment

Several hormones stimulate the adenylate cyclase system of the thick ascending limb (TAL). There are, however, some species differences concerning the cyclase sensitivity and the hormonal response in this nephron segment. In the mouse, antidiuretic hormone (ADH), parathyroid hormone, glucagon, calcitonin, and isoproterenol stimulate Na+, Cl-, Mg2+, and Ca2+ transports in the cortical TAL, whereas ADH, glucagon, and isoproterenol stimulate NaCl transport only in the medullary TAL. Many of these effects are different from those previously described for the corresponding segments of the rabbit nephron. The close similarity of the cyclase responsiveness to hormones of the mouse and rat TALs makes it possible to interpret the micropuncture data obtained in vivo in the rat superficial (S) and juxtamedullary (JM) nephrons, in the light of the in vitro data obtained in the mouse. Long-term treatment of Brattleboro rats with ADH also elicits differential effects along the TAL. Their consequences on the function of the S and JM nephrons are also examined. There are several indications supporting the view that the newly described hormonal effects in the mouse and rat are of physiological relevance.

scholarly journals Unraveling Natural Products’ Role in Osteoarthritis Management—An Overview

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 348 ◽  
Author(s):  
Georgia-Eirini Deligiannidou ◽  
Rafail-Efraim Papadopoulos ◽  
Christos Kontogiorgis ◽  
Anastasia Detsi ◽  
Eugenia Bezirtzoglou ◽  
...  
Keyword(s):  
Natural Products ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Meta Analysis ◽  
Term Treatment ◽  
Naturally Occurring ◽  
Long Term Treatment ◽  
Living Organisms

The natural process of aging gradually causes changes in living organisms, leading to the deterioration of organs, tissues, and cells. In the case of osteoarthritis (OA), the degradation of cartilage is a result of both mechanical stress and biochemical factors. Natural products have already been evaluated for their potential role in the prevention and treatment of OA, providing a safe and effective adjunctive therapeutic approach. This review aimed to assess the therapeutic potential of natural products and their derivatives in osteoarthritis via a systematic search of literature after 2008, including in vitro, in vivo, ex vivo, and animal models, along with clinical trials and meta-analysis. Overall, 170 papers were obtained and screened. Here, we presented findings referring to the preventative and therapeutic potential of 17 natural products and 14 naturally occurring compounds, underlining, when available, the mechanisms implicated. The nature of OA calls to initially focus on the management of symptoms, and, in that context, several naturally occurring compounds have been utilized. Underlying a global need for more sustainable natural sources for treatment, the evidence supporting their chondroprotective potential is still building up. However, arriving at that kind of solution requires more clinical research, targeting the implications of long-term treatment, adverse effects, and epigenetic implications.

scholarly journals Activity of ketoconazole against Mycobacterium tuberculosis in vitro and in the mouse model

2007 ◽  
Vol 56 (8) ◽  
pp. 1047-1051 ◽  
Author(s):  
Sean T. Byrne ◽  
Steven M. Denkin ◽  
Peihua Gu ◽  
Eric Nuermberger ◽  
Ying Zhang
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Term Treatment ◽  
New Drugs ◽  
Bacteriostatic Effect ◽  
Short Term ◽  
Short Term Treatment ◽  
Neutral Conditions

There is an urgent need for the development of new drugs that are active against drug-resistant Mycobacterium tuberculosis strains and can shorten tuberculosis (TB) therapy. It has previously been reported that the azole class of antifungals has anti-TB activity in vitro. This study evaluated ketoconazole (KTC) for activity against M. tuberculosis. The MIC of KTC for different M. tuberculosis strains ranged from 8 to 16 μg ml−1 under both acidic and neutral conditions, with the minimum bactericidal concentration being about twofold higher than the MIC. KTC had enhanced activity against old, non-growing bacilli in vitro when combined with pyrazinamide (PZA) and rifampicin (RIF). A single oral dose of KTC at 75 mg kg−1 led to an inhibitory serum concentration 2 h after administration. The in vivo activity of KTC was evaluated in established pulmonary TB in the murine model, compared alone and in combination with isoniazid (INH), PZA and RIF. KTC alone exhibited little effect after short-term treatment, with a borderline bacteriostatic effect on spleen colony counts but not on lung counts. KTC, when added in combination with INH, PZA and RIF, significantly improved the treatment outcome in the lungs (compared with treatment with INH, PZA and RIF). The lowest numbers of bacilli in lungs were found in mice treated with KTC, PZA and RIF. Further investigation is necessary to determine the role of KTC in the treatment of TB.

scholarly journals A retrospective, observational, single center study of gonadotropin-releasing hormone agonist protocols at the Reproductive Center of Farah Hospital in Jordan

2019 ◽  
Vol 7 (8) ◽  
pp. 3103
Author(s):  
Zaid Kilani ◽  
Mohammad Shaban
Keyword(s):  
Term Treatment ◽  
Gonadotropin Releasing Hormone ◽  
Clinical Pregnancy ◽  
Short Term ◽  
Short Term Treatment ◽  
Releasing Hormone ◽  
Long Term Treatment ◽  
Group A

Background: Data on infertility and in vitro fertilization (IVF) are incomplete and uncertain in Jordan and worldwide because of difficulties in evaluating infertility in the general population. This study aimed at comparing the effectiveness of the gonadotropin-releasing hormone agonists (GnRH-a) long and short protocols as part of IVF or intracytoplasmic sperm injection.Methods: This observational, retrospective, comparative, longitudinal study was conducted in a reproductive center in Jordan. It reviewed data charts from women who took GnRH-a for IVF, from 2010 to 2013. These were categorized in Group A (long-term GnRH-a: single 3.75 mg-monthly injection) or Group B (short-term GnRH-a: multiple daily 0.1 mg injections). The primary endpoint was the rate of ongoing clinical pregnancy (number of pregnancies/number of women) and live birth rate in fresh cycle/protocols.Results: Out of 1,946 eligible women, 471 underwent the long-term treatment of GnRH-a administration and 1,523 the short-term treatment. The women’s mean age was 29.61±3.80 years old. Out of the 471 women in Group A, 216 (45.9%) women had ongoing clinical pregnancy, of whom 69 (31.9%) had live births. In the short-protocol group, 485 (31.8%) women had ongoing clinical pregnancy, of whom 133 (27.4%) had live births.Conclusions: GnRH-a long protocol is more effective than the short protocol regardless of the agonist formulation used in subfertile women/men who underwent IVF/ intracytoplasmic sperm injection.

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