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Questions And Answer

• Alkaloids

  Homoharringtonine (HHT) is an alkaloid isolated from the total alkaloid of Cephalotaxus. It is a highly effective antineoplastic agent in our country. It has been clinically proved to be well effective against acute myeloid leukemia, acute monocytic leukemia, erythroid leukemia and other acute non-lymphocytic leukemia and chronic myeloid leukemia, but it has a strong cytotoxicity and can also lead to cardiac toxicity and bone marrow suppression, limiting the increase in chemotherapy dose.
  The above information is edited by Chemicalbook.;

• Physical and chemical properties

  It appears as white crystalline or yellowish amorphous solid with bitter taste. It has a melting point of 141-143 ° C, density of 1.33g/cm3, boiling point of 713.1 ° C and a flash point of 385.1 °C. It has hygroscopicity. Its color will turn deep in case of light, being easily soluble in methanol, ethanol, chloroform, but slightly soluble in water and ether.;

• Plant source

  Homoharringtonine is an alkaloid derived from cephalotaxus or its genera. There are 9 species of Cephalotaxus in Cephalotaxus, among which 8 species are found in China. This genus contains a variety of alkaloids, that is, harringtonine, and homoharringtonine, isohetonium and isochitraline deoxyspermatine base; in addition, there is also non-ester base form of cephalotaxine (That is, harringtonine).;

• Cephalotaxus fortune

  Cephalotaxus fortune belongs to Cephalotaxus genus plant, which only contains Cephalotaxus, one genus including 9 species. It is mainly distributed in the south of the Yangtze River and in Hubei, Sichuan, Shaanxi, Gansu and other places. There are 7 species and 3 varieties in China, which are mainly distributed in the south of Yangtze River. Cephalotaxus contains alkaloids in branches, leaves, roots and seeds especially having high alkaloid content at leaves and seeds, including cephalotaxine type (Cephalotaxine type) alkaloids and anti-cancer are closely related, the content is also high, being the major component of Cephalotaxus, harringtonine, isoflavone, homoharringtonine and deoxy-oxytocin. It has been isolated of two new anticancer alkaloids, named Neoharringtonine and Anhydroharringtonine from Cephalotaxus fortunei in recent years.
  Cephalotaxus fruit is used for removing food retention, anthelmintic. In the early 1970s, the United States scientists Powell et al had found that Harringtonine compounds had effects of inhibiting the growth of mouse leukemia cells, drawing wide study and attention from researchers on the alkaloid component.
  
  Fig. 1 is a photograph of leaves and fruits of Cephalotaxus fortunei.;

• Analytical method

  High-performance liquid chromatography (US HP 1100); UV scanner (UV300-type). Column: Hypersil BDS (4.0 mm × 250 mm, 5 Lm); mobile phase: 0.0008 mol/L-1 ammonium carbonate solution-methanol (42:58); the detection wavelength was 290 nm and the flow rate was 110 mL/min-1. Injection volume: 20 μL.;

• Plant extracts

  The root, stem and bark of Cephalotaxus fortunei can be made into coarse powder; further added with alcohol to extract the solution. The obtained solution is separated by column chromatography with aluminum hydroxide, and then the silica gel column is used to separate the eluents. Homoharringtonine and harringtonine can be successively obtained.;

• Synthesis method

  The homoharringtonine is synthesized using δ-methyl-δ-caprolactone (1) and ethanol as starting materials via ring opening and elimination of ethyl 5-methyl-4-hexenoate (2), 2 has condensation reaction with diethyl oxalate to give diethyl 2-(3-methyl-2-butenyl) malonate (3), 3 has β-decarboxylation reaction with aqueous dimethylsulfoxide in the presence of sodium chloride to generate 6-methyl-2-oxo-5-heptenoic acid ethyl ester (4); 4 is subject to alkaline hydrolysis, oxalylation and further acylation of cephalotaxine to obtain 6-methyl-2-Oxo-5-heptenoic acid cephalomannine ester (6) and then subjected to a Rafalmacky reaction to give methyl 2-hydroxy-2-(4-methyl-3-pentenyl) succinate Cephalotaxine ester (7), 7 is subject to mercury hydroxylation and mercury removal reaction to obtain the end product, homoharringtonine. The reaction scheme is as follows:
  
  Figure 2 is a chemical reaction route map for the laboratory synthesis of homoharringtonine.;

• Pharmacological activity

  This product has bitter taste and high toxicity and has effect on the kidney, liver and lung. It can eliminate stasis to subdue swelling as well as reducing phlegm and resolving masses.
  Inhibition of leukemia cells by homoharringtonine is mediated by induction of leukemic cells into normal differentiation. One of its molecular pharmacological pathways may be through inhibition cell Na-K-ATPase activity and further inhibition of activities of tumor cell membrane thymidine carrier and protein kinase C. It has also been reported that the harringtonine and homoharringtonine can activate the apoptosis mechanism of tumor cells, and it is believed that these compounds can inhibit tumor growth partly through tumor cell programmed death.;

• uses

  Homoharringtonine mainly inhibit leukemia cell DNA and protein synthesis, dissolving the nucleus and causing its necrosis with remarkable nucleolus lesions. It also inhibits the cell in any phases within the proliferation cycle; the most significant effect is the S phase; it can also inhibit and destroy G2 phase cells so that most of the G2 phase cells were inhibited from entering into the M phase, being the cell cycle non-specific drugs. It is used for the treatment of acute monocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia and red blood leukemia, acute myelogenous leukemia and malignant lymphoma. It is also of certain efficacy against the malignant lymphoma and polycythemia Vera as well as some other types of leukemia.;

• Toxicology

  Toxicity of harringtonine (HA) and homoharringtonine (HO) was studied in mice, rabbits and dogs. Rabbits and dogs, after five or seven days of continuous administration, have their main target organ of toxicity be gastrointestinal, cardiac and hematopoietic organs. Most of the toxic deaths can be attributed to cardiac dysfunction. With the lethal dose, there are also individual cases of mild to moderate liver and kidney damage. Intermittent repeated administration of a total of three courses causes no other significant toxicity, but the heart and hematopoietic study exhibit mild to moderate cumulative toxicity with the toxicity correlating well with the dose size and is completely reversible after drug withdrawal. No significant late-onset toxicity was observed during at least six weeks of observation, and no significant differences were found between the two species in terms of inter-individual, inter-individual or gender-related toxicities. The toxic dosage of HA and HO were 0.45 mg/kg/day × 5 and 0.16 mg/kg/day × 7, respectively. The acute LD_ (50) (± S.E.) in mice was 4.17 ± 0.30 and 3.17 ± 0.19mg/kg, respectively. HA, compared with HO, has no significant toxicity difference in nature while the extent of HO is significantly greater than HA.;

• Metabolism

  1. In vivo metabolism: 2 hours after intravenous injection, the concentration of the products undergoes rapid decline in each tissue while the decline rate in the bone marrow is slower. The half-life is 3~50 min and the metabolism in the body are more active with the main metabolism processing in the liver, but its metabolite is not clear. When being excreted by the kidneys and biliary tract, a small amount is subject to excretion through the feces. In the discharge, the prototype drug accounted for 1/3. At 24 hours after administration, the excretion was about 50% of the total dose, of which 42.2% was excreted in the urine and 6.3% in the feces.
  2. Clinical Metabolism: Homoharringtonine is in two-compartment distribution inside the body with the pharmacokinetics varying significantly in different individual.
  3. Chemotherapy Metabolism: The parameters related to chemotherapy efficacy were K12/K21, the difference between the effective and ineffective groups was very significant (P <0.01).
  
  (n=41) Due to that in one case, the tests of P170, mdrl and sensitization are all positive, indicating that this patient is drug-tolerant, thus not included in this statistic.;

• Side effects

  1. Gastrointestinal reactions: anorexia, dry mouth, nausea, vomiting, abdominal pain, diarrhea; a small number of patients can get liver damage with very few people having oral ulcers.
  2. Cardiac toxicity: seen in large doses and rapid injection or patients originally having heart disease; manifested as arrhythmia, myocardial damage, palpitations sinus tachycardia, atrial or ventricular premature beats and other cardiac toxicity and hypotension. In some cases, it can be seen of myocardial damage. Patients of organic heart disease, arrhythmia, liver and kidney dysfunction should take with caution.
  3. Bone marrow suppression: mainly exhibits as leukopenia. Moreover, the product has inhibitory effect against different series of bone marrow hematopoietic cells, stronger inhibition against granulocyte series, followed by red blood cell series. The inhibition of megakaryocyte series is lighter.
  4. Other: individual patients can get hair loss, rash and so on.;

• Usage amount

  This product has no cross-resistance with Ara-C and mercaptopurine. Intramuscular injection or oral absorption is slow and incomplete. It is mainly administrated through intravenous injection. After intravenous injection, the highest concentration is found in bone marrow, followed by kidney, liver, lung, spleen, heart and stomach, followed by the intestine and muscle and brain tissue has the lowest level.;

• Precautions

  1. To avoid fetal death and congenital malformations, pregnant women and lactating women should take with caution.
  2. As the elderly patients have poor tolerance to chemotherapy, and thus administration of this product should also be accompanied with strengthened supportive therapy, and close observation of various adverse reactions.
  3. The diagnosis of interference: a large number of leukemia cells damage upon leukemia; destruction will become more severe upon using this product; the urine and uric acid concentration in the blood may be increased.
  4. Cardiovascular disease: rapid intravenous infusion or long-term sustained or repeated administration will produce a variety of cardiac toxicity. Animal experiments show that high doses of homoharringtonine intravenously can significantly reduce the coronary blood flow, so upon FDA, the intravenous infusion rate should be slow. For patients of original arrhythmia and various types of organic cardiovascular disease should take with caution; for patients of serious or frequent arrhythmias and organic cardiovascular disease, they should not use this product. The above cardiotoxicity, except in very severe cases, will generally disappear after disabling this product.
  5. In the following cases, it should be used with caution: bone marrow function was significantly inhibited or blood phase exhibited severe neutropenia or thrombocytopenia, arrhythmia and have other organic cardiovascular disease history; liver dysfunction or renal dysfunction, gout or having uric acid salt kidney history.
  6. During the treatment period, it should be checked regularly of the following stuffs:
  ① peripheral blood, weekly follow-up for white blood cell count and classification, platelet, hemoglobin for 1 or 2 times; For patients undergoing a sudden decline in blood cells in the short term, they should be observed daily of the blood phase.
  ② liver function, including serum 1min bilirubin, total bilirubin, alanine aminotransferase and so on.
  ③ cardiac signs and ECG examination.;

• Storage methods

  Shade, sealed, stored in the shade.;

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