Artesunate is the sodium salt of the hemisuccinate ester of artemisinin. It is soluble in water but has poor stability in aqueous solutions at neutral or acid pH. In the injectable form, artesunic acid is drawn up in sodium bicarbonate to form sodium artesunate immediately before injection.
Following administration to humans, artesunate is rapidly hydrolyzed to its principle active metabolite, dihydroartemisinin. Data from in vitro studies with human liver microsomes and from clinical studies suggest that DHA-glucoronide (10-position) is the principal Phase II metabolite of DHA and that uridine diphosphate glucuronyl transferase isoforms 1A1, 1A8-9, or 2B7 may be the main conjugating enzyme.
Artemisinin is completely and rapidly absorbed after oral administration in rats. However, a very low plasma level was obtained even after a dose of 300 mg/kg. Liver was found to be the chief site of inactivation. When artemisinin was given i.m., significant and more persistent plasma levels were detected. Artemisinin was shown to pass the blood-brain and blood-placenta barriers after i.v. injection. Very little unchanged artemisinin was found in the urine or feces in 48 hours regardless of the route of administration. Metabolites identified after administration to humans include deoxyartemisinin, deoxydihydroartemisinin, and 9,10-dihydroxydeoxyartemisinin.
◉ Summary of Use during Lactation:Limited information indicates that a maternal dose of 200 mg orally produced low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Withholding breastfeeding for 6 hours after a dose should markedly reduce the dose the infant receives.
In general, very small amounts of antimalarial drugs are excreted in the breast milk of lactating women. Because the quantity of antimalarial drugs transferred in breast milk is insufficient to provide adequate protection against malaria, infants who require chemoprophylaxis must receive the recommended dosages of antimalarial drugs.
◉ Effects in Breastfed Infants:Breastfed infants who were given dihydroartemisinin and piperaquine as a treatment for malaria had a higher frequency of vomiting than non-breastfed infants given the drugs. Whether this finding applies to infants who receive dihydroartemisinin via breastmilk has not been studied.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
The activity of artemisinin in combination with other antimalarial drugs against P. falciparum was measured in vitro and against P. berghei in vivo. A combination of artemisinin with mefloquine was synergistic whereas that with pyrimethamine was antagonistic in vitro and in vivo. A combination of artemisinin with other antimalarials (sulfadiazine, sulfadoxine, sulfadoxine-pyrimethamine, cycloguanil, and dapsone) was also shown to be antagonistic in vivo.
There has been some concern that antipyretics might attenuate the host defense against malaria, as their use is associated with delayed parasite clearance. However, this appears to result from delaying cytoadherence, which is likely to be beneficial. There is no reason to withhold antipyretics in malaria. ...Paracetamol (acetaminophen) and ibuprofen are the preferred options for reducing fever.
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/
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/
Following administration to humans, artesunate is rapidly hydrolyzed to its principal active metabolite, dihydroartemisinin. The pharmacokinetics of artesunate are characterized by marked inter-subject variability, differing significantly between healthy volunteers and infected patients, and among patients with different disease severity.
The pharmacokinetic of artesunate and dihydroartemisin are characterized by marked inter-subject variability. The pharmacokinetic parameters of artesunate and dihydroartemisinin differ significantly between healthy volunteers and infected patients, and among patients with different disease severity. Pharmacokinetic data from unbound plasma concentrations of artesunate or dihydroartemisinin should be interpreted with caution because the drug accumulates selectively in parasitized RBC's In in vitro experiments, accumulation of dihydroartemisinin in infected RBC's is in concentrations approximately 300-fold higher than those in plasma .
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
口服二氢青蒿素（DHA）2毫克/千克和4毫克/千克体重剂量以及口服青蒿琥酯（AS）4毫克/千克体重剂量的药代动力学在20名健康的泰国志愿者（10名男性，10名女性）中进行了研究。所有制剂普遍耐受性良好。口服DHA从胃肠道迅速吸收，个体间差异显著。两种剂量水平下的DHA药代动力学相似，动力学线性关系明显。根据模型无关的药代动力学分析，2毫克/千克和4毫克/千克体重剂量给药后1.5小时达到的Cmax中位数（95%置信区间）分别为181（120-306）和360（181-658）ng/ml。相应的AUC0-infinity、t1/2z、CL/f和Vz/f分别为377（199-1,128）vs 907（324-2,289）ng.hr/mL、0.96（0.70-1.81）vs 1.2（0.75-1.44）小时、7.7（4.3-12.3）vs 6.6（3.1-10.1）L/kg和90.5（28.6-178.2）vs 6.6（3.1-10.1）mL/min/kg（2 vs 4毫克/千克剂量）。口服AS迅速生物转化为DHA，AS给药后15分钟内在血浆中即可检测到DHA。在4毫克/千克剂量下，Cmax的中位数（95%置信区间）为519（236-284）ng/mL，在0.7（0.25-1.5）小时达到。AUC0-infinity和t1/2z分别为657（362-2,079）ng.hr/mL和0.74（0.34-1.42）小时。口服AS后DHA的Cmax显著更高，但在相同剂量水平（4毫克/千克体重）下，口服DHA的总系统暴露量更大。DHA的药代动力学在性别上没有显著差异。
The pharmacokinetics of oral dihydroartemisinin (DHA) following the dose of 2 and 4 mg/ kg body weight dihydroartemisinin and 4 mg/kg body weight oral artesunate (AS) were investigated in 20 healthy Thai volunteers (10 males, 10 females). All formulations were generally well tolerated. Oral DHA was rapidly absorbed from gastrointestinal tract with marked inter-individual variation. The pharmacokinetics of DHA following the two dose levels were similar and linearity in its kinetics was observed. Based on the model-independent pharmacokinetic analysis, median (95% CI) values for Cmax of 181 (120-306) and 360 (181-658) ng/ml were achieved at 1.5 hours following 2 and 4 mg/kg body weight dose, respectively. The corresponding values for AUC0-infinity, t1/2z, CL/f and Vz/f were 377 (199-1,128) vs 907 (324-2,289) ng.hr/mL, 0.96 (0.70-1.81) vs 1.2 (0.75-1.44) hours, 7.7 (4.3-12.3) vs 6.6 (3.1-10.1) L/kg, and 90.5 (28.6-178.2) vs 6.6 (3.1-10.1) mL/min/kg, respectively (2 vs 4 mg/kg dose). Oral AS was rapidly biotransformed to DHA, which was detectable in plasma as early as 15 minutes of AS dosing. Following 4 mg/kg dose, median (95% CI) value for Cmax of 519 (236-284) ng/mL was achieved at 0.7 (0.25-1.5) hours. AUC0-infinity, and t1/2z were 657 (362-2,079) ng.hr/mL, 0.74 (0.34-1.42) hours, respectively. Cmax of DHA following oral AS were significantly higher, but total systemic exposure was greater following oral DHA at the same dose level (4 mg/kg body weight). There was no significant sex difference in pharmacokinetics of DHA
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
本研究旨在确定单次200毫克口服和直肠用青蒿琥酯在健康志愿者中的药代动力学参数，并为直肠给药提出合理的剂量方案。研究设计为一项随机开放交叉研究，共有12名健康志愿者参与... 由于青蒿琥酯从血浆中迅速消失，药代动力学参数是从主要代谢物二氢青蒿素的数据中得出的。口服青蒿琥酯后二氢青蒿素的AUC(0-无穷大)显著较高（P<0.05，95%置信区间（CI）-1168.73, -667.61 ng x hr/mL(-1)）和Cmax（P<0.05; 95% CI -419.73, -171.44 ng/mL(-1)），并且tmax更短（P<0.05; 95% CI -0.97, -0.10 hr），比直肠用青蒿琥酯的这些指标都要高。两种给药途径的消除半衰期之间没有统计学上的显著差异（P>0.05; 95% CI -0.14, 0.53 hr）。直肠用青蒿琥酯的相对生物利用度为[平均值（变异系数%）54.9（24.8%）%。
The aims of this study were to determine the pharmacokinetic parameters of a single dose of 200 mg oral and rectal artesunate in healthy volunteers, and to suggest a rational dosage regimen for rectal administration. The study design was a randomized open cross-over study of 12 healthy volunteers... Pharmacokinetic parameters were derived from the main metabolite alpha-dihydroartemisinin data due to the rapid disappearance of artesunate from the plasma. Dihydroartemisinin following oral administration of artesunate had a significantly higher AUC(0-infinity) (P<0.05 95% confidence interval (CI) -1168.73, -667.61 ng x hr/mL(-1)) and Cmax (P<0.05; 95% CI -419.73, -171.44 ng/mL(-1)), and had shorter tmax (P<0.05; 95% CI -0.97, -0.10 hr) than that following rectal artesunate. There was no statistically significant difference in the elimination half-life between both routes of administration (P>0.05; 95% CI -0.14, 0.53 hr). The relative bioavailability of rectal artesunate was [mean (coefficient of variation %) 54.9 (24.8%) %].
申请人：The Provost, Fellows, Foundation Scholars, & the other Members of Board, of the College of the Holy
公开号：US20150018566A1
公开（公告）日：2015-01-15
The invention provides combretastatin A-4 like compounds that are modified to have enhanced tubulin binding activity and in some embodiments the ability to promote accumulation in the vasculature undergoing angiogenesis (homing activity). The compounds are based on the combretastatin A-4 skeletal structure having a tubulin-binding pharmacophore comprising two fused rings (A and B rings) in which the B ring is substituted with (a) an aromatic ring structure (C ring) and (b) a second substituent/functional group that comes off the B ring. The aromatic ring structure is typically a six membered ring phenolic or aniline structure, or may also be a fused ring structure such as a substituted or unsubstituted naphthalene. The second substituent on the B ring may for example be a substituent which has been found to provide enhanced tubulin binding activity (for example a carbonyl group), or may be a substituent that facilitates functionalisation of the B ring (for example an hydroxyl or amine group), or it may be a binding agent for a target that is preferentially expressed on vasculature undergoing angiogenesis, and not expressed on quiescent vasculature.
ved prodrugs, in which the phenolate group was modified with a variety of hydrophobic moieties. This esterification fine‐tuned the polarity of the SN‐38 molecule and enhanced the lipophilicity of the formed prodrugs, thereby inducing their self‐assembly into biodegradable poly(ethylene glycol)‐block‐poly(d,l‐lactic acid) (PEG‐PLA) nanoparticulate structures. Our strategy combining the rational engineering
