CRYSTALS WITH 2.5 MOL WATER OF CRYSTALLIZATION; CRYSTALS FROM DILUTE ALCOHOL
熔点：
174-175 °C after drying of solvated crystals
溶解度：
In water, 140 mg/l @ 25 °C
稳定性/保质期：
Quinidine gluconate, quinidine polygalacturonate, and quinidine sulfate darken on exposure to light and should be stored in well-closed, light resistant containers. Solutions of quinidine salts slowly acquire a brownish tint on exposure to light. Only colorless, clear solutions of quinidine gluconate injection should be used. Quinidine gluconate injection should be stored at 15-30 °C. When diluted to a concentration of 16 mg/ml with 5% dextrose injection, quinidine gluconate injection is stable for 24 hours at room temperature and up to 48 hours when refrigerated. /Quinidine salts/
旋光度：
Specific optical rotation @ 15 °C/D + 230 deg (concn by volume = 1.8 in chloroform); specific optical rotation @ 17 °C/D + 258 deg (alcohol); +322 deg (concn by volume = 1.6 in 2 M HCl); UV absorption spectrum is identical with that of quinine; blue fluorescence in dilute H2SO4.
分解：
When heated to decomposition it emits toxic fumes of oxides of nitrogen.
In vitro studies using human liver microsomes and recombinant P450 enzymes have shown that quinine is metabolized mainly by CYP3A4. Depending on the in vitro experimental conditions, other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 were shown to have some role in the metabolism of quinine.
Quinine is metabolized almost exclusively via hepatic oxidative cytochrome P450 (CYP) pathways, resulting in four primary metabolites, 3-hydroxyquinine, 2'-quinone, O-desmethylquinine, and 10,11-dihydroxydihydroquinine. Six secondary metabolites result from further biotransformation of the primary metabolites. The major metabolite, 3-hydroxyquinine, is less active than the parent drug.
IDENTIFICATION AND USE: Quinine is a bulky, white, amorphous powder or crystalline alkaloid, used as medication: non-narcotic analgesics; antimalarial; central muscle relaxants. It is also used as flavor in carbonated beverages. HUMAN EXPOSURE AND TOXICITY: Serious hypersensitivity reactions, including anaphylactic shock, anaphylactoid reactions, urticaria, serious skin rashes, angioedema, facial edema, bronchospasm, and pruritus, have been reported with quinine. In addition, thrombocytopenia, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), immune thrombocytopenic purpura, blackwater fever, disseminated intravascular coagulation, leukopenia, neutropenia, granulomatous hepatitis, and acute interstitial nephritis have been reported and may also be due to hypersensitivity reactions to the drug. Potentially fatal cardiac arrhythmias, including torsades de pointes and ventricular fibrillation, have been reported rarely during quinine therapy. At least 1 case of fatal ventricular arrhythmia has been reported in a geriatric patient with preexisting prolonged QT interval treated with IV quinine sulfate for Plasmodium falciparum malaria. Visual impairment can range from blurred vision and defective color perception, to visual field constriction and permanent blindness. Cinchonism occurs in virtually all patients with quinine overdose. There have been a large number of case reports of malformations following quinine ingestion in human pregnancy. Many of these pregnancies involved large doses of quinine used as an abortifacient. The most frequently reported abnormality following quinine exposure during early pregnancy is hypoplasia of the auditory nerve with resultant deafness. Other major malformations involving most organ systems have been reported also. However, the Perinatal Collaborative Study reported no association between first trimester exposure to quinine and birth defects. In general, there has been no proven association between quinine at doses used for malarial prophylaxis and an increased risk of malformations. Third trimester exposure to quinine does not appear to adversely affect uterine contractility. However, an increase in insulin secretion associated with hypoglycemia has been reported. Therefore, monitoring of blood or serum glucose levels during quinine therapy is advisable. Although the United States Food and Drug Administration banned its use for nocturnal leg cramps due to lack of safety and efficacy, quinine is widely available in beverages including tonic water and bitter lemon. Numerous anecdotal reports suggest that products containing quinine may produce neurological complications, including confusion, altered mental status, seizures, and coma, particularly in older women. ANIMAL STUDIES: Rabbits given 20 to 100 mg quinine hydrochloride/kg intravenously or intramuscularly 3 times a week for 10 weeks have been reported to show no ophthalmoscopic or histologic abnormalities in the fundus or optic nerve, and /another study/ similarly found no abnormality in most rabbits injected intraperitoneally with 10 mg/kg/day for 21 to 27 days showed degeneration of rods and cones and vacuoles in the retinal ganglion cells. In animal developmental studies conducted in multiple animal species, pregnant animals received quinine by the subcutaneous or intramuscular route at dose levels similar to the maximum recommended human dose based on body surface area (BSA) comparisons. There were increases in fetal death in utero in rabbits at maternal doses = 100 mg/kg/day and in dogs at = 15 mg/kg/day cochlea at maternal doses of 200 mg/kg corresponding to a dose level of approximately 1.4 times the MRHD based on BSA comparison. There were no teratogenic findings in rats at maternal doses up to 300 mg/kg/day and in monkeys at doses up to 200 mg/kg/day corresponding to doses approximately 1 and 2 times the MRHD respectively based on BSA comparisons. Quinine produces testicular toxicity in mice at a single intraperitoneal dose of 300 mg/kg, and in rats at an intramuscular dose of 10 mg/kg/day, 5 days/week, for 8 weeks. The findings include atrophy or degeneration of the seminiferous tubules, decreased sperm count and motility, and decreased testosterone levels in the serum and testes. Genotoxicity studies of quinine were positive in the Ames bacterial mutation assay with metabolic activation and in the sister chromatid exchange assay in mice. The sex-linked recessive lethal test performed in Drosophila, the in vivo mouse micronucleus assay, and the chromosomal aberration assay in mice and Chinese hamsters were negative.
◉ Summary of Use during Lactation:Because of the low levels of quinine in breastmilk, amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants. The dosage in milk is far below those required to treat an infant for malaria. However, quinine should not be used in mothers with an infant who is glucose-6-phosphate dehydrogenase (G6PD) deficient. Even the relatively small amounts of quinine in tonic water ingested by the mother have caused hemolysis in G6PD-deficient infants.
◉ Effects in Breastfed Infants:Four breastfed infants of 3 mothers, 3 boys and 1 girl (one set of twins) developed severe hemolysis following maternal ingestion of beverages containing quinine (e.g., tonic water). All infants had low levels of G6PD and were jaundiced on admission. Cessation of breastfeeding and tonic water and phototherapy and/or transfusion resolved the jaundice. One of the infants who was severely jaundiced had abnormal brainstem automatized evoked potentials at discharge. At 4 months of age he had a slight decrease in reactivity and a profound bilateral deafness. The breastmilk of one of the mothers was qualitatively positive for quinine. The hemolysis was probably caused by quinine in breastmilk.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Cinchona alkaloids, including quinine, may depress the hepatic synthesis of vitamin K-dependent coagulation factors, and the resulting hypoprothrombinemic effect may enhance the action of warfarin and other oral anticoagulants. In patients receiving these anticoagulants and concomitant therapy with quinine, the prothrombin time (PT), partial thromboplastin time (PTT), or international normalized ratio (INR) should be closely monitored as indicated.
The pharmacokinetics of quinine was investigated in patients with acute Falciparum malaria treated with quinine alone or in the presence of doxycycline. Twenty six patients divided into two groups of equal number were enrolled in the study. In the absence of doxycycline, the volume of distribution of quinine (mean + or - standard deviation) was estimated to be 1.32 + or - 0.32 l/kg, and its clearance was 0.125 + or - 0.47 l/hr/kg, which was only in partial agreement with previously published data. No effect of doxycycline on the pharmacokinetics of quinine was observed.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
奎宁是P-糖蛋白的底物，并且是P-糖蛋白的抑制剂，有可能影响作为P-糖蛋白底物的药物的转运。
Quinine is a substrate for and an inhibitor of P-glycoprotein, and has the potential to affect the transport of drugs that are P-glycoprotein substrates.
Following oral administration of a single 600-mg dose of quinine sulfate in healthy adults, the mean plasma clearance was 0.08-0.47 L/hour per kg (median: 0.17 L/hour per kg) and the mean plasma elimination half-life was 9.7-12.5 hours. Following oral administration of 10 mg/kg of quinine sulfate in patients with uncomplicated malaria, mean total clearance of quinine was decreased (approximately 0.09 L/hour per kg) during the acute phase of the infection and increased (approximately 0.16 L/hour per kg) during the recovery or convalescent phase.
Following oral administration of a single 600-mg dose of quinine sulfate in geriatric and younger adults, the mean clearance of the drug was decreased (0.06 versus 0.08 L/hour per kg) and the mean elimination half-life was significantly increased (18.4 versus 10.5 hours) in geriatric adults compared with younger adults. Although renal clearance of quinine was similar in geriatric and younger adults, geriatric adults excreted a larger proportion of the dose in urine as unchanged drug compared with younger adults (16.6 versus 11.2%). The steady-state pharmacokinetics after a quinine sulfate dosage of 648 mg 3 times daily for 7 days were similar in healthy geriatric adults 65-78 years of age and healthy younger adults 20-39 years of age; however, the mean elimination half-life was 24 hours in the geriatric individuals compared with 20 hours in the younger adults.
Following oral administration of a single dose of 10 mg/kg of quinine sulfate in healthy children or pediatric patients 1.5-12 years of age with uncomplicated Plasmodium falciparum malaria, the mean total clearance (0.06 versus 0.3 L/hour per kg) is reduced and the plasma elimination half-life increased (12.1 versus 3.21 hours) in pediatric patients with malaria as compared to that observed in healthy children.
In 15 patients with uncomplicated malaria who received a 10 mg/kg oral dose of quinine sulfate, the mean total clearance of quinine was slower (approximately 0.09 L/hr/kg) during the acute phase of the infection, and faster (approximately 0.16 L/hr/kg) during the recovery or convalescent phase.
[EN] SMALL MOLECULES THAT SENSITIZE HIV-1 INFECTED CELLS TO ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY [FR] PETITES MOLÉCULES QUI SENSIBILISENT DES CELLULES INFECTÉES PAR LE VIH-1 À UNE CYTOTOXICITÉ CELLULAIRE DÉPENDANTE DES ANTICORPS
of noble metal catalysts in homogeneouscatalysis has been well established. Due to their price and limited availability, there is growing interest in the substitution of such precious metal complexes with readily available and bio‐relevant catalysts. In particular, iron is a “rising star” in catalysis. Herein, we present a general and selective iron‐catalyzed monoisomerization of olefins, which allows
The invention relates to sulfamoyl sulfonate prodrugs of general formula I,
a process for their production, pharmaceutical compositions that contain these compounds, and their use for the production of orally available pharmaceutical agents. The compounds according to the invention bind to carbonic anhydrases and inhibit these enzymes.
Iron-catalyzed Minisci acylation of N-heteroarenes with α-keto acids
作者：Xiu-Zhi Wang、Cheng-Chu Zeng
DOI：10.1016/j.tet.2019.01.060
日期：2019.3
protocol has been developed for the Minisci acylation reactions of nitrogen-containing heteroarenes with α-keto acids. Distinct from the conventional Minisci acylation conditions, the chemistry was performed using non-noble metal Fe(II), instead of expensive Ag(I) salt, as catalyst. A wide range of substrates, including aliphatic or aromatic α-keto acids, as well as various N-heteroarenes, proved to
The present invention pertains to Benzyl-substituted tetracyclic heterocyclic compounds of formula (I), as well as the resulting pharmaceutical compositions, and their use in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases. Furthermore, the present invention pertains to the methods of manufacturing these Benzyl -substituted tetracyclic heterocyclic compounds.
[EN] BENZYL-SUBSTITUTED TETRACYCLIC HETEROCYCLIC COMPOUNDS AS PDE5 INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES TÉTRACYCLIQUES À SUBSTITUTION BENZYLE COMME INHIBITEURS DE PDE5
申请人：NYCOMED GMBH
公开号：WO2010015589A1
公开（公告）日：2010-02-11
The present invention pertains to Benzyl-substituted tetracyclic heterocyclic compounds, as well as the resulting pharmaceutical compositions, and their use in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases. Furthermore, the present invention pertains to the methods of manufacturing these Benzyl-substituted tetracyclic heterocyclic compounds.
