Efinaconazole is extensively metabolized. It is oxidatively metabolized, cleaved and conjugated to glucuronic acid. The studies have identified 5 metabolites (H1, H2, H3, H4 and H5) of efinaconazole. In rats and minipigs, H3 was the major efinaconazole plasma metabolite, and its levels usually equaled or exceeded those of parent drug. The in vitro and in vivo metabolite profiles in nonclinical species were similar to human with no unique human metabolite(s).
Jublia (efinaconazole) is extensively metabolized through oxidative/reductive processes, with the potential of additional metabolite glucuronidation. Analysis of human plasma confirmed that H3 is the only major efinaconazole metabolite.
Efinaconazole metabolites, but not parent drug, were excreted in the bile and urine of rats and dogs which suggests complete metabolism of efinaconazole prior to excretion. Most of the absorbed radioactivity was eliminated during the first 72 hours after dermal and SC dosing in urine and feces.
IDENTIFICATION AND USE: Efinaconazole is used as antifungal agent. It is indicated for the topical treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes. HUMAN EXPOSURE AND TOXICITY: Efinaconazole 10% solution did not cause contact sensitization and induced only minimal skin irritation in human studies. ANIMAL STUDIES: Efinaconazole was generally well tolerated in rats with repeated daily doses of up to 30 (males) and 40 (females) mg/kg. In 13 week dermal toxicity in mice, an increase in liver weight and minimal to mild panlobular hepatocellular hypertrophy was observed, the local application of the drug and/or the vehicle alone resulted in higher incidences of hyperkeratosis, epidermal hyperplasia, and mononuclear infiltrates in the treated skin. Higher concentration of the test article were associated with higher severity of these cutaneous changes compared to controls, and a low incidence of the formation of erosion/ulcers at the treated site. Efinaconazole 10% solution applied intratympanically to the guinea pig middle ear caused significant middle ear inflammation and hearing impairment. In dermal toxicity studies, efinaconazole was well tolerated in minipigs at doses up to 150-200 mg /kg/day. Slight to moderate skin reactions were noted macroscopically and microscopically in all test article groups and vehicle control and consisted of hyperkeratosis, acanthosis and localized inflammation. These skin effects were attributed to the vehicle and were not considered adverse due to the mild severity of changes. A 2-year dermal carcinogenicity study in mice was conducted with daily topical administration of 3%, 10% and 30% efinaconazole solution. Severe irritation was noted at the treatment site in all dose groups, which was attributed to the vehicle and confounded the interpretation of skin effects by efinaconazole. The high dose group was terminated at week 34 due to severe skin reactions. No drug-related neoplasms were noted at doses up to 10% efinaconazole solution (248 times the MRHD based on AUC comparisons). In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day efinaconazole were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal toxicity (increased pre-natal pup mortality, reduced live litter sizes and increased post-natal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (17 times the MRHD based on AUC comparisons). No effects on post-natal development were noted at 25 mg/kg/day (89 times the MRHD based on AUC comparisons). Subcutaneous doses of 1, 5, and 10 mg/kg/day efinaconazole were administered during the period of organogenesis (gestational days 6-19) to pregnant female rabbits. In the presence of maternal toxicity, there was no embryofetal toxicity or malformations at 10 mg/kg/day (154 times the MRHD based on AUC comparisons). Efinaconazole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosome aberration assay) and one in vivo genotoxicity test (mouse peripheral reticulocyte micronucleus assay).
◉ Summary of Use during Lactation:Topical efinaconazole has not been studied during breastfeeding. Because maternal blood levels are very low after topical application to the toenails, it is unlikely that a measurable amount of the drug will enter the breastmilk.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
/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/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和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 TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) 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/
Administration of Jublia by the topical route leads to low systemic efinaconazole concentrations. Systemic absorption of efinaconazole in 18 patients with severe onychomycosis was determined after application of Jublia once daily for 28 days to patients' 10 toenails and adjacent skin. The concentration of efinaconazole in plasma was determined at multiple time points over the course of 24-hour periods on days 1, 14, and 28. Efinaconazole mean plasma Cmax on Day 28 was 0.67 ng/mL. The mean plasma concentration versus time profile was generally flat over the course of treatment. In onychomycosis patients, the steady state plasma concentration range was 0.1-1.5 ng/mL for efinaconazole and 0.2-7.5 ng/mL for H3 metabolite.
/MILK/ Efinaconazole and or its metabolites were excreted in milk from lactating rats. The radioactivity concentration in milk was higher than that in plasma concentration for 24 hours after the administration of 14C-efinaconazole to lactating rats. However, the elimination half-life of the milk radioactivity was about one half of that of the plasma radioactivity, suggesting that efinaconazole or its metabolites was not retained in milk.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
/MILK/ 目前尚不清楚efinaconazole是否会在人类乳汁中排出。
/MILK/ It is not known whether efinaconazole is excreted in human milk.
Efinaconazole penetrates through nails in vitro after Jublia administration, suggesting drug penetrations to the site of fungal infection in the nail and the nail bed, though clinical relevance is unknown. The penetration of Jublia was evaluated in an in vitro investigation after daily application of radiolabelled efinaconazole (10%) to human nails for 28 days at 55.1 uL/sq cm. After 28 days, the cumulative radioactivity in the receptor fluid and in the nail plate, on a percent basis of total administered radioactivity, was 0.03% and 0.16% (3.11 mg eq/g), respectively. The flux rate was relatively constant from Days 18 to 28, mean 1.40 ug eq/sq cm/day, suggesting steady state attainment.
An enantioselective epoxidation of α-substituted vinyl ketones was realized to construct the key epoxide intermediates for the synthesis of various triazole antifungal agents. The reaction proceeded efficiently in high yields with good enantioselectivities by employing a chiral N,N′-dioxide/ScIII complex as the chiral catalyst and 35% aq. H2O2 as the oxidant. It enabled the facile transformation for
实现了α-取代乙烯基酮的对映选择性环氧化，构建了合成各种三唑类抗真菌剂的关键环氧化物中间体。通过使用手性N,N'-二氧化物/Sc III配合物作为手性催化剂和 35% 的水溶液，该反应以高产率和良好的对映选择性有效进行。H 2 O 2作为氧化剂。它使光学活性艾沙康唑、依氟康唑和其他潜在的抗真菌剂的转化成为可能。
<i>anti</i>-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients
nitroalkanes and α-ketoesters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized
There is disclosed a fungicide containing, effective ingredient, a compound having the general formula (I): ##STR1## or an acid addition salt thereof, particularly the compound wherein an absolute configuration of the asymmetric carbon atoms is R,R-configuration or an acid addition salt thereof.
