The concentration of norethindrone in plasma samples from subjects receiving norethindrone (norethisterone) and lynestrenol orally was measured by high pressure liquid chromatography (HPLC). Norethindrone is a synthetic gestagen widely used in contraceptive formulations, and lynestrenol is also a synthetic gestagen which is metabolized to norethindrone in humans.
Although /little/ is known about the transformation of lynestrenol and norethynodrel, it appears that lynestrenol first undergoes hydroxylation at carbon 3 and then oxidation of the hydroxyl group to form norethisterone.
There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. ...
Lynestrenol, given 48 hr beforehand, enhances the elimination of phenobarbital and phenytoin from mouse plasma and consequently diminishes their anticonvulsant effect. The hexobarbital sleeping time is shortened and the in vitro metabolism of hexobarbital is accelerated by the same pretreatment. The increase of the rate of phenobarbital and phenytoin elimination may be due to acceleration of their metabolism by lynestrenol.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
人类毒性摘录
/HUMAN EXPOSURE STUDIES/ 8 women, aged 22-28, with normal, ovulatory menstrual cycles, volunteered to take different doses of Lynestrenol to determine its effects on Luteineizing Hormone (LH) secretion, and on plasma progesterone levels. Blood samples were taken in the morning and plasma was immediately separated. Results showed that body temperature varied unpredictably during the cycle, and therefore could not be considered a reliable parameter of ovulation. 0.35 mg of Lynestrenol administered daily was enough to suppress ovulation, as evidenced by the absence of LH during midcycle. Although differences exists in individual reactions, administration of Lynestrenol beyond 0.6 mg. daily always suppresses ovulation because of hypothalamo-pituitary inhibition, while doses below 0.5mg. daily can bring about episodic peaks. It is still not clear how Lynestrenol influences gonadotropins, especially LH, while intermittent bleeding seems to be the only sure side effect.
人类暴露研究/ 8名年龄在22-28岁之间的女性，月经周期正常，自愿服用不同剂量的Lynestrenol，以确定其对促黄体生成激素（LH）分泌和血浆孕酮水平的影响。早晨采集血液样本，并立即分离血浆。结果显示，在周期中体温变化不可预测，因此不能被视为排卵的可靠参数。每天服用0.35毫克的Lynestrenol足以抑制排卵，这通过中期缺乏LH得到证明。尽管个体反应存在差异，但每天服用超过0.6毫克的Lynestrenol总是会因下丘脑-垂体抑制而抑制排卵，而每天剂量低于0.5毫克可能会引起周期性高峰。目前尚不清楚Lynestrenol如何影响促性腺激素，尤其是LH，而断续出血似乎是唯一确定的副作用。
/HUMAN EXPOSURE STUDIES/ 8 women, aged 22-28, with normal, ovulatory menstrual cycles, volunteered to take different doses of Lynestrenol to determine its effects on Luteineizing Hormone (LH) secretion, and on plasma progesterone levels. Blood samples were taken in the morning and plasma was immediately separated. Results showed that body temperature varied unpredictably during the cycle, and therefore could not be considered a reliable parameter of ovulation. 0.35 mg of Lynestrenol administered daily was enough to suppress ovulation, as evidenced by the absence of LH during midcycle. Although differences exists in individual reactions, administration of Lynestrenol beyond 0.6 mg. daily always suppresses ovulation because of hypothalamo-pituitary inhibition, while doses below 0.5mg. daily can bring about episodic peaks. It is still not clear how Lynestrenol influences gonadotropins, especially LH, while intermittent bleeding seems to be the only sure side effect.
The tissue distribution of 4-14C-lynestrenol (17 alpha-ethynyl-oestr-4-en-17 beta-ol) following oral administration to pregnant rats was studied by whole body autoradiography and liquid scintillation counting. Pregnant females were sacrificed on days 10, 12, 14 and 19 of gestation, in each case 5 hours after oral administration of 43 uCi 4-14C-lynestrenol per animal. The isotopelabelled compound was distributed throughout most tissues, including the fetuses. The highest concentrations were found in the liver, while there was lower activity in the fatty tissues and the activity in the fetuses was comparable with that in the brain. The placental transfer was verified by the results of liquid scintillation counting. The concentration of labelled substance in the fetuses increased with the duration of pregnancy.
... The evaluation of plasma norethindrone levels in subjects receiving lynestrenol has not yet been reported. After the administration of norethindrone, the peak level of norethindrone in the plasma was obtained within 2 hours, and the peak concentration in the plasma was about 3.5 ng/mL/mg norethindrone. During a period of 2-6 hours after the administration of norethindrone, the half-life of norethindrone in the plasma was approximately 1.8 hours, and during the period of 6-24 hours, half-life was variable. On the other hand, after lynestrenol administration, the peak level of norethindrone in the plasma was obtained within 4 hours, and the peak concentration of norethindrone was about 1.9 ng/mL/mg lynestrenol. During a period of 4-12 hours, the half-life of norethindrone was about 2.5 hours. The peak of norethindrone level after lynestrenol administration was lower and appeared later than that after administration of the same dose of norethindrone. Norethindrone in plasma in subjects receiving lynestrenol could be measured for a longer period than in those receiving the same dose of norethindrone. These results suggest that lynestrenol is stored in fat tissue and is slowly metabolized to norethindrone.
The peak concentration, peak time, the area under the serum concentration time curve (AUC) and half-life of serum norethisterone (NET) after a single application of lynestrenol (LYN) to female volunteers demonstrated that 0.7 mg NET is bioequivalent to 1 mg LYN which is rapidly converted to NET. There was a decrease of the peak values and an increase of half-life of NET during the periovulatory and luteal phase which was, however, not significant due to the great individual differences. The shift of the peak time to longer intervals and the increase of half-life of NET after ingestion of higher LYN doses indicate a certain limitation of the metabolic capacity of the liver. ...
... Eleven normal males were administer either 1 capsule containing 2.5 mg lynestrenol and 0.05 mg ethynylestradiol or tablets containing the same dose of steroids. Blood samples were taken just before and 1,2,4,8, and 24 hours after the drugs were administered. 8 days later the subjects were given the opposite formulations and blood samples were again obtained at the same time intervals. Radioimmunoassay was used to assess levels of free and conjugated ethynylestradiol and norethisterone in the serum samples. Biovailability assessments were made by calculating the areas under the time-concentration curves. Results demonstrated that the conversion of lynestrenol to norethisterone in vivo was complete. Unconjugated ethynylestradiol mean values, 2 and 4 hours after administration of the drugs, were higher for capsules than for tablets. For blood samples taken at other time periods the mean values of unconjugated ethynylestradiol were similar for both capsules and tablets. For conjugated ethynylestradiol the mean values and the areas under the curve, for blood samples obtained at each time interval, showed no significant difference for tablets and capsules.
167 women were treated with 0.5 mg lynestrenol/day for a period of 8-32 weeks immediately postpartum. The lactation periods of 67 of the women were observed during the stay in hospital (maximum 7 days) in comparison with a control group (n = 20) of untreated women in the puerperium. There was no quantitative difference in milk production between the lynestrenol-treated women and the control group. ...
Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.
[EN] 1,2,4-SUBSTITUERTE 1,2,3,4-TETRAHYDRO-AND 1,2 DIHYDRO-QUINOLINE AND 1,2,3,4-TETRAHYDRO-QUINOXALINE DERIVATIVES AS CETP INHIBITORS FOR THE TREATMENT OF ATHEROSCLEROSIS AND OBESITY<br/>[FR] DERIVES DE 1,2,3,4-TETRAHYDRO- ET 1,2 DIHYDRO-QUINOLEINE ET 1,2,3,4-TETRAHYDRO-QUINOXALINE 1,2,4-SUBSTITUES, UTILES COMME INHIBITEURS DE CETP POUR LE TRAITEMENT DE L'ATHEROSCLEROSE ET DE L'OBESITE
申请人：PFIZER PROD INC
公开号：WO2004085401A1
公开（公告）日：2004-10-07
Quinoline and quinoxaline compounds of formula I and III wherein the subtituent are as defined in claims 1 and 15, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.
[EN] BINDING-SITE MODIFIED LECTINS AND USES THEREOF<br/>[FR] LECTINES DE SITE DE LIAISON MODIFIÉES ET USAGE CORRESPONDANT
申请人：SMARTCELLS INC
公开号：WO2010088261A1
公开（公告）日：2010-08-05
In one aspect, the disclosure provides cross-linked materials that include multivalent lectins with at least two binding sites for glucose, wherein the lectins include at least one covalently linked affinity ligand which is capable of competing with glucose for binding with at least one of said binding sites; and conjugates that include two or more separate affinity ligands bound to a conjugate framework, wherein the two or more affinity ligands compete with glucose for binding with the lectins at said binding sites and wherein conjugates are cross-linked within the material as a result of non-covalent interactions between lectins and affinity ligands on different conjugates. These materials are designed to release amounts of conjugate in response to desired concentrations of glucose. Depending on the end application, in various embodiments, the conjugates may also include a drug and/or a detectable label.
[EN] PHENYL SUBSTITUTED PIPERIDINE COMPOUNDS FOR USE AS PPAR ACTIVATORS<br/>[FR] COMPOSES DE PIPERIDINE PHENYLE A SUBSTITUTION PHENYLE S'UTILISANT COMME ACTIVATEURS DE PPAR
申请人：PFIZER PROD INC
公开号：WO2004048334A1
公开（公告）日：2004-06-10
PPAR alpha activators, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases, in mammals, including humans.
[EN] ATAZANAVIR (ATV) ANALOGUES FOR TREATING HIV INFECTIONS<br/>[FR] ANALOGUES D'ATAZANAVIR (ATV) POUR TRAITER DES INFECTIONS PAR LE VIH
申请人：GILEAD SCIENCES INC
公开号：WO2018145021A1
公开（公告）日：2018-08-09
The invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of Formula I, processes for preparing compounds of Formula I, the compound of formula (I) for use in therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS symptoms in a mammal using compounds of Formula I. Preferred compounds are N-[(2S) -1-[2-[(2S,3S)-2-hydroxy-3-[[(2S)-2-(methoxycarbonylamino) -3,3-dimethylbutanoyl]amino]-4-phenylbutyl]-2-[(phenyl) methyl]hydrazinyl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate atazanavir (ATV) analogues substituted by several heterocycles, such as e.g. pyrazole (Rl); e.g. oxetane (substituent of X2); e.g. pyridine or pyrimidine (X1); e.g. piperazine or 3,8-diazabicyclo[3.2.1]octan (X2).
