/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/
/ALTERNATIVE and IN VITRO TESTS/ Shikonin has the potential to prevent, or be used in the treatment of bladder transitional cell carcinoma induced by arylamines. /Investigators/ evaluated its effectiveness by measuring the amount of acetylated 2-aminofluorene (AF), AF-DNA adducts, changes of / N-acetyltransferase (NAT)/ mRNA and the amount of NAT enzyme. T24 human bladder cancer cells were incubated with 30 uM AF with different concentrations of shikonin for various times. T24 cells treated with shikonin (16 uM) were then harvested and used in 2 experiments: 1). T24 cells were incubated with 22.5 uM AF and shikonin (0, 16 uM) (co-treatment) for 6, 12, 18, 24 and 48 hr). T24 cells were incubated with various concentrations of AF and shikonin (0, 16 uM) for 24 hr AF and AAF were measured by HPLC. Then in the prepared human T24 cell cytosols different concentrations of AF and shikonin were added to measure the kinetic constants of NAT. Next, AF-DNA adducts in human T24 cells with or without treatment with shikonin were detected and measured. The final two steps included measuring the NAT Ag-Ab complex after treatment with and without shikonin and evaluating the effect of shikonin on the NAT genes. Higher concentrations of shikonin induced decreasing AF acetylation. /It was/ found that the longer the culture period, the greater the difference in AF acetylation in the same shikonin concentrations. It was also noted that increase in AAF was proportional to incubation time. In the presence of 16 uM of shikonin, N-acetylation of AF decreased by up to 72-84%. Shikonin decreased the amount of AAF production in human T24 cells in all examined AF doses. Both Km and Vmax values in the cytosolic NAT decreased after the addition of shikonin to the cytosol. Finally, shikonin decreased the amount of AAF production and AF-DNA adducts formation in human 724 cells in all examined AF doses. The percentage of cells stained by antibody was significantly different after treatment with shikonin, especially with the higher shikonin concentrations. The NAT1 mRNA level and the NAT1/beta-actin ratio decreased significantly with higher concentrations (16-24 uM) of shikonin. Shikonin affected NAT activity, gene expression (NAT1 mRNA), AF-DNA adducts formation and formation of NAT Ag-Ab in human bladder tumor T24 cells...
/ALTERNATIVE and IN VITRO TESTS/ Shikonin isolated from the roots of the Chinese herb Lithospermum erythrorhizon has been associated with anti-inflammatory properties. /Investigators/ evaluated shikonin's chemotherapeutic potential and investigated its possible mechanism of action in a human cutaneous neoplasm in tissue culture. Shikonin preferentially inhibits the growth of human epidermoid carcinoma cells concentration- and time-dependently compared to SV-40 transfected keratinocytes, demonstrating its anti-proliferative effects against this cancer cell line. Additionally, shikonin decreased phosphorylated levels of EGFR, ERK1/2 and protein tyrosine kinases, while increasing phosphorylated JNK1/2 levels. Overall, shikonin treatment was associated with increased intracellular levels of phosphorylated apoptosis-related proteins, and decreased levels of proteins associated with proliferation in human epidermoid carcinoma cells.
Alkannin and shikonin are naturally occurring hydroxynaphthoquinones with a well-established spectrum of wound healing, antimicrobial, anti-inflammatory, and antioxidant activities. Recently, extensive scientific effort has been focused on their effectiveness on several tumors and mechanism(s) of antitumor activity. Liposomes have been proved as adequate drug carriers offering significant advantages over conventional formulations, such as controlled release and targeted drug delivery, leading to the appearance of several liposomal formulations in the market, some of them concerning anticancer drugs. The aim of the present study was to prepare shikonin-loaded liposomes for the first time in order to enhance shikonin therapeutic index. An optimized technique based on the thin film hydration method was developed and liposomes characterization was performed in terms of their physicochemical characteristics, drug entrapment efficiency, and release profile. Results indicated the successful incorporation of shikonin into liposomes, using both 1,2-dipalmitoylphosphatidylcholine and egg phosphatidylcholine lipids. Liposomes presented good physicochemical characteristics, high entrapment efficiency and satisfactory in vitro release profile. In vitro cytotoxicity of liposomes was additionally tested against three human cancer cell lines (breast, glioma, and non-small cell lung cancer) showing a moderate growth inhibitory activity. Practical applications: Shikonin is a naturally occurring hydroxynaphthoquinone and extensive scientific research (in vitro, in vivo, and clinical trials) has been conducted during the last years, focusing on its effectiveness on several tumors and mechanism(s) of antitumor action. The purpose of this work was to prepare and characterize shikonin-loaded liposomes as a new drug delivery system for shikonin. Liposomal formulations provide significant advantages over conventional dosage forms, such as controlled release and targeted drug delivery for anticancer agents. Thus, liposomes could reduce shikonin's side effects, enhance selectivity to cancer cells and protect shikonin from internal biotransformations and instability matters (oxidization and polymerization). Furthermore, liposomal delivery helps overcome the low aqueous solubility of shikonin, which is the major barrier to its oral and internal administration, since it cannot be dissolved and further absorbed from the receptor.
A New Efficient Route for Multigram Asymmetric Synthesis of Alkannin and Shikonin
摘要：
A short and convergent approach for the synthesis of alkannin, shikonin and shikalkin is presented. A Hauser-type annulation of cyanophthalide 26 with enone 7 affords the complete aromatic system in just one step with concomitant attachment of the entire side chain. Subsequent Corey's oxazaborolidine mediated asymmetric reduction of the above advanced intermediate, leads to the required isomer in high enantiomeric excess. Finally, a selective and high yielding deprotection protocol furnishes the title compounds as pure crystalline precipitates. Thus, a multigram synthesis of shikonin, alkannin and shikalkin is achieved in high yield and enantioselectivity.
2-formyl-1,4,5,8-tetramethoxynaphthalene, was prepared through 1,4,5,8-tetramethoxynaphthalene, which was obtained from 1,5-naphthalenediol via three steps or from naphthazarin via one step. A totalsynthesis of shikalkin and dihydroshikalkin have been accomplished with this aldehyde via a side-chain introductions with Grignard reactions and the following demethylations.
Vanadium(II)-assisted cross-coupling of 1,4,5,8-tetramethoxynaphthalene-2-carbaldehyde and 3-methyl-2-butenal was employed for introduction of the side chain of dl-shikonin. 2-(1-Hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene was prepared by the pinacol coupling and the subsequent palladium-catalyzed hydrogenolysis of the carbon–oxygen bond at the allylic position of the diol carbonate. Electrochemical oxidation of the 2-substituted 1,4,5,8-tetramethoxynaphthalene, followed by reductive acetylation with zinc and the subsequent electrooxidation of the resulting 5,8-diacetoxy-1,4-dimethoxynaphthalene, afforded the corresponding 5,8-diacetoxy-1,4-naphthoquinone, whose alkaline hydrolysis furnished dl-shikonin.
Shikonin and its O-acylderivatives are attracting increasing levels of attention among medicinal chemists due to their potencies as highly selective cytotoxic agents against cancer cells. However,...
