Changes in the binding of oestradiol to uterine oestrogen receptors induced by some progesterone and 19-nor-testosterone derivatives

1983 ◽  
Vol 98 (3) ◽  
pp. 385-389 ◽  
Author(s):  
Francesco Di Carlo ◽  
Elena Gallo ◽  
Giuseppe Conti ◽  
Silvia Racca
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Medroxyprogesterone Acetate ◽  
The Other ◽  
Receptor Interaction ◽  
Oestrogen Receptors ◽  
Rat Uterus ◽  
The Hours

The effects of two progesterone derivatives, namely medroxyprogesterone acetate (MPA) and chlormadinone, and two 19-nor-testosterone derivatives, namely norgestrel and norethisterone, on the binding of oestradiol to its cytoplasmic receptors in the rat uterus were compared. In experiments performed in vivo, the rats were given a single oral dose (15 mg/kg) of one of the four progestins and killed 1, 6, 24 and 48 h later. Norgestrel, norethisterone and MPA induced a prompt and remarkable decrease in oestradiol–receptor interaction 1 h after treatment. This reduction lasted almost unchanged for 24 h in rats treated with MPA or norgestrel, but was much lower in animals given norethisterone. In the hours that followed, the effect of MPA and norgestrel began to decrease, but was still detectable after 48 h, whereas the effect of norethisterone had disappeared by this time. The effect of chlormadinone was much less than that induced by both MPA and norgestrel 1, 6 and 24 h after treatment. On the other hand, this effect was less than that caused by norethisterone 1 h after administration, equal after 6 h and much greater after 24 and 48 h. In experiments performed in vitro, the different ability of the four progestins to interfere with the capacity of oestradiol to bind to its receptors was confirmed. In conclusion, all the synthetic progestins used were able to reduce the binding of oestradiol to its cytoplasmic receptors, although there was a clear difference between the progestins in the intensity and duration of this effect. This could be one of the mechanisms by which progestins modulate the activity of oestrogens in target tissues.

scholarly journals Probenecid inhibits SARS-CoV-2 replication in vivo and in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jackelyn Murray ◽  
Robert J. Hogan ◽  
David E. Martin ◽  
Kathy Blahunka ◽  
Fred D. Sancilio ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Virus Replication ◽  
Mammalian Cells ◽  
Clinical Utility ◽  
Plasma Concentrations ◽  
Hamster Model ◽  
Potential Clinical Utility

AbstractEffective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC90 value are achievable for 24 h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans.

INTERFERENCE OF GESTAGENS AND ANDROGENS WITH RAT UTERINE OESTROGEN RECEPTORS

1978 ◽  
Vol 77 (1) ◽  
pp. 49-55 ◽  
Author(s):  
F. DI CARLO ◽  
G. CONTI ◽  
C. REBOANI
Keyword(s):  
Medroxyprogesterone Acetate ◽  
Binding Capacity ◽  
Inhibitory Effect ◽  
Receptor Interaction ◽  
Plot Analysis ◽  
Specific Receptors ◽  
Dose Dependent ◽  
Intact Rats

The inhibitory effect of some gestagens and calusterone on the binding of oestradiol-17β to its specific uterine receptors has been investigated in intact rats. Progesterone, medrogestone, clogestone, medroxyprogesterone acetate and calusterone reduce the specific oestradiol– receptor interaction in vitro; this effect is dose-dependent and does not differ significantly from one drug to the other. A more relevant decrease in the amount of oestradiol-17β bound to specific receptors has been observed with calusterone. Progesterone, clogestone, medrogestone, medroxyprogesterone acetate and calusterone given orally induce a marked decrease (between 30 and 70% depending on the dose) in the binding capacity of oestradiol-17β to specific uterine receptors in vivo. Results from a Scatchard plot analysis suggest that the interference with the binding of oestradiol-17β caused by both progestogens and calusterone is due to a non-competitive interaction.

scholarly journals Glycyrrhetinic acid might increase the nephrotoxicity of bakuchiol by inhibiting cytochrome P450 isoenzymes

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2723 ◽  
Author(s):  
Aifang Li ◽  
Nana Ma ◽  
Zijing Zhao ◽  
Mei Yuan ◽  
Hua Li ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Liver Microsomes ◽  
Glycyrrhetinic Acid ◽  
Internal Exposure ◽  
Functional Markers ◽  
Dependent Manner ◽  
Cyp Isoforms

BackgroundLicorice, a popular traditional Chinese medicine (TCM), is widely used to moderate the effects (detoxification) of other herbs in TCM and often combined withFructus Psoraleae. However, the classical TCM book states thatFructus Psoraleaeis incompatible with licorice; the mechanism underlying this incompatibility has not been identified. Glycyrrhetinic acid (GA), the active metabolite of licorice, may increase the toxicity of bakuchiol (BAK), the main chemical ingredient inPsoralea corylifolia, by inhibiting its detoxification enzymes CYP450s.MethodsThe effect of concomitant GA administration on BAK-induced nephrotoxicity was investigated, and the metabolic interaction between BAK and GA was further studied in vitro and in vivo. The cytotoxicity was assessed using an MTT assay in a co-culture model of HK-2 cell and human liver microsomes (HLMs). The effect of GA on the metabolism of BAK, and on the activities of CYP isoforms were investigated in HLMs. The toxicokinetics and tissue exposure of BAK as well as the renal and hepatic functional markers were measured after the administration of a single oral dose in rats.ResultsIn vitrostudies showed that the metabolic detoxification of BAK was significantly reduced by GA, and BAK was toxic to HK-2 cells, as indicated by 25∼40% decreases in viability when combined with GA. Further investigation revealed that GA significantly inhibited the metabolism of BAK in HLMs in a dose-dependent manner. GA strongly inhibits CYP3A4 and weakly inhibits CYP2C9 and CYP1A2; these CYP isoforms are involved in the metabolism of BAK.In vivoexperiment found that a single oral dose of BAK combined with GA or in the presence of 1-aminobenzotriazole (ABT), altered the toxicokinetics of BAK in rats, increased the internal exposure, suppressed the elimination of BAK prototype, and therefore may have enhanced the renal toxicity.ConclusionThe present study demonstrated that GA inhibits CYP isoforms and subsequently may increase the nephrotoxicity of BAK, which underlie one of the possible mechanisms responsible for the incompatibility of Licorice withFructus Psoraleae.

scholarly journals Probenecid Inhibits SARS-CoV-2 Replication In Vivo and In Vitro

2021 ◽  
Author(s):  
Jackelyn Murray ◽  
Robert J. Hogan ◽  
David E. Martin ◽  
Kathy Blahunka ◽  
Fred Sancillo ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Virus Replication ◽  
Mammalian Cells ◽  
Clinical Utility ◽  
Plasma Concentrations ◽  
Hamster Model ◽  
Potential Clinical Utility

Effective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC90 value are achievable for 24h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans.

A single dose of lithium carbonate acutely elevates intact parathyroid hormone levels in humans

1989 ◽  
Vol 121 (2) ◽  
pp. 174-176 ◽  
Author(s):  
Ellen W. Seely ◽  
Thomas J. Moore ◽  
Meryl S. LeBoff ◽  
Edward M. Brown
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Human Subjects ◽  
Lithium Carbonate ◽  
Serum Levels ◽  
Ionized Calcium ◽  
Intact Parathyroid Hormone ◽  
Intact Pth

Abstract. Hyperparathyroidism has been reported in patients receiving lithium therapy, and lithium alters calcium-regulated PTH release in vitro. Previous studies in vivo have used assays which measure fragments of PTH as well as the intact hormone. To determine if lithium acutely elevates intact PTH levels, we studied 9 subjects who received a single oral dose of lithium carbonate (600 mg). Serum levels of intact PTH, ionized calcium, and lithium were measured before, 2 and 14 h after the dose of lithium. PTH levels rose significantly 2 h following the dose of lithium (before 22 ± 5.0, post 32 ± 7.3 ng/l, p < 0.02). PTH levels had returned to baseline at 14 h (22 ± 3.8 ng/l). There were no significant changes in ionized calcium levels. Therefore, a single oral dose of lithium carbonate acutely elevates intact PTH values in human subjects.

scholarly journals 731. Pharmacokinetics of Gepotidacin (GSK2140944) in Subjects with Hepatic Impairment

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S327-S327
Author(s):  
Jonathan T Hands ◽  
Yu Tao ◽  
Courtney Tiffany ◽  
Caroline R Perry ◽  
Etienne Dumont ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Hepatic Impairment ◽  
Geometric Mean ◽  
Hepatic Clearance ◽  
Hepatic Function ◽  
Major Route ◽  
Bacterial Replication

Abstract Background Gepotidacin (GEP), a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro and in vivo efficacy activity against key pathogens, including drug-resistant strains, associated with a range of infections. In a previous absorption, distribution, metabolism, and excretion study for GEP, the mean recovery of radioactivity in urine and feces accounted for approximately 31.2% and 52.5%, respectively, of [14C]-GEP administered as a single oral dose. GEP was eliminated mainly as parent in urine, accounting for approximately 20% of the administered dose. Elimination via metabolism accounted for a total of 13% to 19% of the dose. Average total intravenous clearance of approximately 43 L/hour and renal clearance (CLr) of approximately 16 L/hour provides a hepatic clearance of 27 L/hour, suggesting that hepatic clearance is a major route of elimination of GEP. Methods Participants with normal and varying degrees of hepatic impairment (HI) received a single oral dose of GEP 1,500 mg. PK collections of blood, urine and saliva were performed. Results Relative to normal hepatic function, GEP Cmax and AUC(0-∞) in plasma were increased by 1.2-fold in subjects with moderate, and between 1.7-fold to 1.9-fold in severe HI. The fraction of dose excreted in urine increased with an increase in hepatic impairment. GEP urine concentrations remained high over a 12-hour period. Saliva concentrations displayed a linear relationship with plasma (both total and unbound) concentrations (R2 = 0.76). The geometric mean ratio of saliva AUC to unbound plasma AUC values ranged from 0.746 to 0.839 across all groups. Administration of 1,500 mg oral GEP was generally tolerated. Conclusion An increase in the dosing interval or dose reduction may be required in patients with severe hepatic impairment. Disclosures All authors: No reported disclosures.

Effects of alcoholic extract from Ma-Klua (Diospyros mollis) on adults and larvae of the dwarf tapeworm, Hymenolepis nana in mice and on the infectivity of the eggs

Parasitology ◽  
1983 ◽  
Vol 87 (1) ◽  
pp. 103-111 ◽  
Author(s):  
Jun Maki ◽  
Asami Kondo ◽  
Toshio Yanagisawa
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Drug Administration ◽  
Post Infection ◽  
Alcoholic Extract ◽  
Severe Damage ◽  
Hymenolepis Nana ◽  
Anthelmintic Effect

SUMMARYThe anthelmintic effect of an alcoholic extract from a shrub, Diospyros mollis, popularly known as Ma-Klua in Thailand, on the adults and larvae of the dwarf tapeworm, Hymenolepis nana, in mice was studied in comparison with that of flubendazole. The experimentally infected mice were given a single oral dose of 10–1000 mg of Ma-Klua extract or flu-bendazole/kg body wt 1, 2, 3, 4, or 12 days post-infection and autopsied 14 days post-infection. Ma-Klua extract was effective in the elimination of adults (ED50 = 79 mg/kg) but not larvae. Drastic effects of Ma-Klua extract on the motility and structure of adults were observed and the number of the adults in mice decreased with time after administration of the drug 12 days post-infection. The small numbers of adults remaining in the host intestine 2 days after the drug administration showed severe damage in the gravid segments. These facts were thought to be responsible for the significant reduction in egg output observed 1 and 2 days after medication. Fresh eggs exposed to Ma-Klua extract in vitro and in vivo, or in vivo alone showed reduced infectivity. The effect of flubendazole on adults and larvae was minimal.

Enhancement of ADP-induced Platelet Aggregation by Adrenaline in Vivo and Its Prevention

1973 ◽  
Vol 29 (02) ◽  
pp. 490-498 ◽  
Author(s):  
Hiroh Yamazaki ◽  
Itsuro Kobayashi ◽  
Tadahiro Sano ◽  
Takio Shimamoto
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
The Other ◽  
Endothelial Surface ◽  
Important Interaction ◽  
Blood Coagulability ◽  
The Difference

SummaryThe authors previously reported a transient decrease in adhesive platelet count and an enhancement of blood coagulability after administration of a small amount of adrenaline (0.1-1 µg per Kg, i. v.) in man and rabbit. In such circumstances, the sensitivity of platelets to aggregation induced by ADP was studied by an optical density method. Five minutes after i. v. injection of 1 µg per Kg of adrenaline in 10 rabbits, intensity of platelet aggregation increased to 115.1 ± 4.9% (mean ± S. E.) by 10∼5 molar, 121.8 ± 7.8% by 3 × 10-6 molar and 129.4 ± 12.8% of the value before the injection by 10”6 molar ADP. The difference was statistically significant (P<0.01-0.05). The above change was not observed in each group of rabbits injected with saline, 1 µg per Kg of 1-noradrenaline or 0.1 and 10 µg per Kg of adrenaline. Also, it was prevented by oral administration of 10 mg per Kg of phenoxybenzamine or propranolol or aspirin or pyridinolcarbamate 3 hours before the challenge. On the other hand, the enhancement of ADP-induced platelet aggregation was not observed in vitro, when 10-5 or 3 × 10-6 molar and 129.4 ± 12.8% of the value before 10∼6 molar ADP was added to citrated platelet rich plasma (CPRP) of rabbit after incubation at 37°C for 30 second with 0.01, 0.1, 1, 10 or 100 µg per ml of adrenaline or noradrenaline. These results suggest an important interaction between endothelial surface and platelets in connection with the enhancement of ADP-induced platelet aggregation by adrenaline in vivo.

Effect of Aspirin on the Thrombelastogram of Human Blood

1973 ◽  
Vol 30 (03) ◽  
pp. 494-498 ◽  
Author(s):  
G de Gaetano ◽  
J Vermylen
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Platelet Function ◽  
Human Blood ◽  
Platelet Rich Plasma ◽  
Plasma Samples ◽  
Release Reaction ◽  
Platelet Release

SummaryThrombelastograms of both native blood and re-calcified platelet-rich plasma samples taken from subjects given a single oral dose of aspirin (1 gram) were not significantly different from the pretreatment recordings. Aspirin also did not modify the thrombelastogram when preincubated in vitro with platelet-rich plasma at concentrations inhibiting the platelet “release reaction” by collagen. Thrombelastography therefore cannot evaluate the effect of aspirin on platelet function.

Oxytocin analogues with non-coded amino acid residues in position 8: [8-Neopentylglycine]oxytocin and [8-cycloleucine]oxytocin

1987 ◽  
Vol 52 (9) ◽  
pp. 2317-2325 ◽  
Author(s):  
Jan Hlaváček ◽  
Jan Pospíšek ◽  
Jiřina Slaninová ◽  
Walter Y. Chan ◽  
Victor J. Hruby
Keyword(s):  
Amino Acid ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
The Other ◽  
Amino Acid Residues ◽  
Phase Synthesis ◽  
Other Hand ◽  
Fragment Condensation

[8-Neopentylglycine]oxytocin (II) and [8-cycloleucine]oxytocin (III) were prepared by a combination of solid-phase synthesis and fragment condensation. Both analogues exhibited decreased uterotonic potency in vitro, each being about 15-30% that of oxytocin. Analogue II also displayed similarly decreased uterotonic potency in vivo and galactogogic potency. On the other hand, analogue III exhibited almost the same potency as oxytocin in the uterotonic assay in vivo and in the galactogogic assay.

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