Lipids Part 2: Steroids
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Pharmaceutical preparations for the targeted substitution of the estrogen deficiency in the central nervous system. The invention relates to the use of selected steroids to produce pharmaceutical preparations for the targeted substitution of the estrogen deficiency in the central nervous system without influencing other organs or systems. An abrupt or gradual decrease in estrogen levels in the body can both women and men under physiological increasing age, menopause may occur and pathological conditions Gonadectomy, use of GnRH analogues as supplementary cancer therapy.
Among the best known clinical symptoms of estrogen loss include disorders of thermoregulation in the form of hot flashes, osteoporosis and increased predisposition to heart and vascular diseases Netter A, The menopause. Recent clinical studies van den Beld AW et al. This is underlined in aging men, the presence and pathophysiological relevance of a specific "Estrogen deficiency syndrome". The brain is a very important target organ of estrogen. Estrogens have a decisive physiological influence on many neurobiological processes.
Their effects can be generally classified into two large groups -organisierende and activating - classify BS McEwen et al, steroid hormones as mediators of neural plasticity, J Steroid Biochem Mol Biol The activating effects of estrogens in the CNS are, inter alia in the following physiological processes expressed: Regulation of neuroendocrine reactivity to stress Viau V, Meaney MJ, Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat, Endocrinology The enormous neurotropic potential of estrogens finds expression in their ability to induce the expression of a number of CNS-specific genes whose products for the survival of nerve cells of critical importance Miranda RC, Sohrabji F, Toran-Allerand CD , presumptive estrogen target neurons express mRNA for Both the neurotrophins and neurotrophin receptors: Clinical findings implied the estrogen deficiency as a causal factor in the pathogenesis of Alzheimer's disease and point to the possibility of estrogen replacement to halt the clinical manifestation or progression of the disease Henderson VW et al, estrogen replacement therapy in older women.
Comparisons between Alzheimer's disease cases and controls, Arch Neurol A series of neuropeptides, whose gene transcription is affected by physiological amounts of estrogen z. Vasopressin play an important role in controlling emotional behavior components Adan RA, Burbach JP, regulation of vasopressin and oxytocin gene expression by estrogen and thyroid hormonal ne, Progr Brain Res The excess of free radicals is implicated in mechanisms of cellular damage in multiple organs and systems in the pathogenesis of neurodegenerative ER- diseases brought in connection Smith CD et al.
Insights from an animal model of Parkinsonism In: Therefore, estrogen replacement will also have a role in the sense of maintaining and increasing endogenic antioxidative capacity attached Behl C, et al, 17b-estradiol protects neurons from oxidative stress-induced cell death in vitro, Biochem Biophys Res Commun. At the present time takes place the estrogen replacement with natural and synthetic estrogens, whose action occurs in all Estro- genrezeptor-containing organs and systems, ie practically the entire body.
For this reason, estrogen replacement in men, despite proven indications, was never seriously considered. The use of natural and synthetic estrogens with system-stemischer effect - that is, in all organs and systems of the body.
As an example of. Substance with slight "sexual activity" and neuroprotek- tive effect is given 17a-estradiol. The se compounds can be used for prophylaxis and therapy of radical-mediated cell damage.
In all these patents, the therapeutic and neuroprotekti- ve efficiency of the substances contained should be based on one or more of the following end effects:.
Stimulation of biosynthesis of natural neuronal growth factors; men stimulation of the activity of acetylcholine-synthesizing enzymes or the uptake uptake of substrates of the acetylcholine Iin-. Synthesis; direct cytoprotection by increasing the resistance of nerve zel len against the withdrawal of Nährsubtraten or Wachstumsfak factors; - reduction of the sensitivity of nerve cells to free radicals and reactive oxygen species that are released as a result of a traumatic or neurotoxic action.
However, in none of the patents listed steroids are shown with selective estrogen-like neurotropic transcription effects; ie, those at a dosage in vivo, which do not exhibit significant biological activity in the reproductive system, influence the transcription of estrogen-dependent genes in the CNS in an estrogen-like mode.
A substance that has a reduced estrogenicity in the genital tract Clark JH et al, Effects of estradiol 17a on nuclear OC cupancy of the estrogen receptor, stimulation of nuclear type II sites, and 8 uterine growth, J steroid Biochem From this we can conclude that any evidence of selective neurotropic effect of 17a-estradiol or its derivatives are missing from the previously published studies and patents, while 1 7b-estradiol is known to have no CNS selectivity and thus classified as an estrogen with systemic action is.
A dissociated neurotropic effect of 17a-estradiol that are based on a Siert influence the transcription of estrogen-sensitive genes, was studied either within the patent, nor have been reported in the literature about it.
The invention is based on the object of finding pharmaceutical compositions for the targeted substitution of the estrogen deficiency in the central nervous system CNS without influencing other organs or systems. The object is inventively achieved in that selected steroids to produce pharmaceutical preparations are used, which ensure the substitution of the estrogen deficiency in the central nervous system without influencing other organs or systems.
The steroids are characterized in that they possess selective neurotropic estrogen-like transcription effect, unlike sy stemisch effective natural and synthetic oestrogens, including 17a-estradiol. It has been found, surprisingly, that the selected steroids cause in their use in the invention, a selective effect on the transcription of estrogen-dependent genes in the central nervous system and changes corresponding physiological parameters;.
An advantageous embodiment of the invention is the use of the compounds according to the invention for preparing pharmaceutical 1 1. Preparations for the prophylaxis and therapy of age-dependent reduction in cognitive performance of age-related and perimenopau- salen dysphoria, of premenstrual syndrome, of neurosis and neurasthenia, of anxiety states and -neurosen, of hot flushes after estrogen deprivation menopause, gonadectomy, treatment with GnRH analogues and psychogenic inhibition of sexual behavior.
It was found that while the risk of interference with hormone-sensitive tissues of the reproductive system endometrium, myometrium, prostate, mammary gland can be largely excluded in the sense of uncontrolled proliferation ind carcinogenesis. The present invention also relates to pharmaceutical preparations for oral and parenteral, incl. Topical, rectal, sub-cutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal or sublinguaien application, in addition to conventional carriers and diluents, a in the claim 1 contain-indicated compound as an active ingredient.
The pharmaceutical compositions of the invention will correspond with the usual solid or liquid substrates or diluents and the pharmaceutical auxiliaries customarily used as Example 1 Effect on uterine weight following chronic subcutaneous application-in vivo. After 14 days the animals were subku- tan with osmotic mini-pumps Alzett, USA were implanted, a daily dose of 0.
On 7th day of treatment, the animals were sacrificed and the uterine wet weights based on g body weight determined. It can be seen that a significant increase in the uterine even at daily doses of 0. Example 2 activation of transcription of a estrogen receptor-dependent reporter gene in vitro. The reporter contains the estrogen response element ERE of vitellogenin, a thymidine kinase promoter and the luciferase gene coding for Photinus pyralis.
The figure represents the mean of two independent experiments. It can be seen that the tested substances stimulate dose-dependent transcription of the reporter. Example 3 Stimulation of the transcription of the oxytocin gene in the brain after chronic treatment in vivo with doses that are ineffective in the uterus.
After 14 days, the animals subcutaneously with osmotic minipumps Alzett, USA were implanted, the gesdosis a Ta of 0. Immediately after sacrifice of the animals, the uterine wet weights relative to g body weight were determined.
The messenger ribonucleic acid mRNA encoding the biosynthesis of oxytocin, was assembled by in situ hybridization with a specific radioactive-marked oligodeoxynucleotide probe, after a established method Fischer D et al, Lactation as a model of naturally reversible hypercorticalism: Treatment-related changes in the transcription of the oxytocin gene were quantified by densitometric measurements of the specific hybridizing signals within the defined anatomic Stukturen.
The lower panel shows the effects of the tested substances on uterine weight. The shaded field shows the dispersion width of the corresponding parameter in vehicle-treated rats. Stimulation of the transcription of the antiapoptotic gene bcl-2 in the hippocampus after chronic treatment in vivo with doses that do not show uterotropic effect.
The study material originated from animals that were treated in the process described in Example 3 experiment. The gene bcl-2 encodes the synthesis of a protein which is involved in the cascade of cell proliferation and programmed cell death apoptosis counteracts Merry DE, Korsmeyer SJ, Bcl-2 genes family in the nervous system, Ann Rev Neurosei Transcription of this gene is stimulated by estrogens Kandouz M et al, Antagonism between estradiol and progestin on Bcl-2 expression in breast cancer cells, Int J Cancer.
Hippocampus of ovariectomized rats; Symbols and abbreviations as in Fig. The effect was to that, triggered by the same doses of 17b-estradiol, identical. The substance 17a-estradiol had at the dosages no effect on the transcription of bcl-2 - seen from FIG.
Binding sites with identical biochemical characteristics for the peptide hormone oxytocin are present in the myometrium and in the CNS. In both organs, acute or chronic estrogen treatment causes an increase in the number density of Oxytozin- receptors. The brain structures in which these parameters is particularly sensitive to estrogens, are interstitial nucleus striae terminalis, nucleus ventromedial and the amygdaloid nuclear complex. Estrogen-related induction of oxytocin receptors in these structures is in a causal relation to the expression of a number of pro-social behaviors, including sexual behavior Insel TR, oxytocin - a neuropeptide for affiliation: For determinations of the density of oxytocin receptors in defined anatomical structures, the autoradiographic representation by binding of the radioactively labeled oxytocin receptor antagonists d CH 2 5 Tyr Me 2, Thr 4, Orn 8 - [12S I] Tyr 9 - vasotocin I-OVTA the method-of choice Kremarik P et al, Histoautoradiographic detection of oxytocin and vasopressin-binding sites in the telencephalon of the rat, J Comp Neurol Subsequently film autoradiograms were prepared, which were used for densitometric determination of the oxytocin binding sites according to an established procedure Patchev VK et al, Oxytocin binding sites in rat iimbic and hypothalamic structures Site-specific modulation by adrenal and gonadal steroids Neuroscience The right-hand graph represents the effects of the tested substances on the proliferation of the endometrium.
The results of this study are also shown in Fig. The treatment with 17b-estradiol and 15SS H, 3'H- The substance 17a-estradiol was effective in the dosage in any brain structure. One week after the operation was started with daily subcutaneous administration of the substances in the following daily doses: The total duration of treatment was 14 days.
On 5 and 6 of treatment, training sessions for learning a conditioned escape behavior according to an established method Diaz-Veliz G et al. Each animal was exposed 50 times to the combination of an unconditional electrical stimulation and two conditioned stimuli light and sound signal in a session. On 7th day of treatment the retention of the learned behavior pattern was tested. After a 6-day interruption of the learning sessions, the extinction of the learned conditioned response was determined on the 14th day of treatment.
The number of correct behavioral reactions Escape into the "safe" compartment of the apparatus within three seconds after presentation of the conditioning signals from 50 successive exposures was used as the criterion for evaluating the retention or extinction of the learned behavior. The Zodiac show significant differences compared to placebo-treated animals OVX at the corresponding test day. Example 7 Biotransformation von17a-hydroxy, 15a-methylene-estra-3,5 10 , 8-tetraeneol and 17a-estradiol to 17b-estradiol.
On the last day of treatment, the serum concentrations of 17b-estradiol were determined in the three experimental groups and compared with denenigen in vehicle-treated control animals. It is apparent that measurable concentrations of 17b-estradiol are registered in the serum after administration of 17b-estradiol and 17a-estradiol in the above-mentioned doses. Kind code of ref document: Country of ref document: Selected steroids are used to produce pharmaceutical preparations for selectively supplementing oestrogen deficiency in the central nervous system CNS without influencing other organs or systems.
These steroids are characterised in that they have a selective, neurotropic, oestrogen-like transcription effect, unlike the systemically active natural and synthetic oestrogens, including 17a-estradiol.
It has been surprisingly discovered that the selected steroids, when used according to the invention, selectively influence the transcription of oestrogen-dependent genes in the central nervous system and cause alterations of the corresponding physiological parameters; have transcription effects specific to the central nervous systems in doses which have no biological effects on the tissues of the reproductive system; have transcription effects specific to the central nervous system at doses at which neither 17b-estradiol nor 17a-estradiol have any effect; and do not influence the transcription of oestrogen-dependent genes in the central nervous system to a greater extent than the secondary 17b-estradiol.
Pharmaceutical preparations for the targeted substitution of the estrogen deficiency in the central nervous system The invention relates to the use of selected steroids to produce pharmaceutical preparations for the targeted substitution of the estrogen deficiency in the central nervous system without influencing other organs or systems.
The use of natural and synthetic estrogens with system-stemischer effect - that is, in all organs and systems of the body - for the treatment of neurodegenerative diseases is claimed by the following patents: As an example of Substance with slight "sexual activity" and neuroprotek- tive effect is given 17a-estradiol. In all these patents, the therapeutic and neuroprotekti- ve efficiency of the substances contained should be based on one or more of the following end effects: Stimulation of biosynthesis of natural neuronal growth factors; men stimulation of the activity of acetylcholine-synthesizing enzymes or the uptake uptake of substrates of the acetylcholine Iin- Synthesis; direct cytoprotection by increasing the resistance of nerve zel len against the withdrawal of Nährsubtraten or Wachstumsfak factors; - reduction of the sensitivity of nerve cells to free radicals and reactive oxygen species that are released as a result of a traumatic or neurotoxic action.
These steroids are compounds of general formula in which R 1 is a hydrogen atom, a hydroxyl group or an alkylene loxygruppe from 1 to 5 carbon atoms, R 2 represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an acyl group of 1 to 5 carbon atoms, a grouping of the general formula SO 2 NR 10 R 1, wherein R 10 and Rn are each independently a hydrogen atom, an alkyl group of from 1 to 5 carbon atoms or together with the nitrogen form a pyrrolidino, piperidino or morpholino, R 3 represents a hydrogen atom or a hydroxyl group, R 4 represents a hydrogen atom, a hydroxyl group or an alkyl group to 5 carbon atoms, R 5 and R 6 are each independently a hydrogen 10 atom or a halogen atom, R 7 represents a hydrogen atom or a methyl group, R 8 represents a hydrogen atom and a hydroxyl group, an oxo group or a group of the general Forme!
An advantageous embodiment of the invention is the use of the compounds according to the invention for preparing pharmaceutical 1 1 Preparations for the prophylaxis and therapy of age-dependent reduction in cognitive performance of age-related and perimenopau- salen dysphoria, of premenstrual syndrome, of neurosis and neurasthenia, of anxiety states and -neurosen, of hot flushes after estrogen deprivation menopause, gonadectomy, treatment with GnRH analogues and psychogenic inhibition of sexual behavior.
As pharmaceutical formulations can be used:
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bundenes Testosteron liegt nur zu 2 % vor und kann als freies Steroid in die Zelle diffundie- ren (96). mechanisms during sperm capacitation. boutiquedababr3.xyz (33) Deepinder F, Braunstein GD () Drug-induced gynecomastia: an evidence- based review. .. chiatric effects of anabolic steroids in male normal volunteers. In athletics and bodybuilding, it is used as an ancillary compound to be added to a cycle of Anabolic Steroids. In this respect it is also used for. Most anabolic steroids, especially the androgens, cause inhibition of the This feedback mechanism is known as the hypothalamic-pituitary-testes axis This minimises the negative effects like gynecomastia and water.