USH271H - Treatment of malaria with esters of cephalotaxine - Google Patents

Treatment of malaria with esters of cephalotaxine Download PDF

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Publication number
USH271H
USH271H US06/819,130 US81913085A USH271H US H271 H USH271 H US H271H US 81913085 A US81913085 A US 81913085A US H271 H USH271 H US H271H
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malaria
homoharringtonine
days
animals
remission
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US06/819,130
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June M. Whaun
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United States Department of the Army
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • This invention deals with a novel use of harringtonine, homoharringtonine and deoxyhomoharringtonine for treating malaria.
  • Malaria has become an increasing problem in the tropical zones with the advent of chloroquine resistant strains of malaria parasites coupled with a decreased effectiveness of long acting insecticides such as DDT.
  • the magnitude of the problem is reflected in the fact that malaria is the largest infectious disease in the world. Of the one billion people residing in malaria endemia areas, approximately 25 to 200 million people are diseased at any given time. In Africa alone, over one million children die each year from malaria.
  • the problem is becoming more serious as more stains of malaria become resistant to the major anti-malaria drug chloroquine.
  • the major human pathogen is Plasmodium falciparum. More and more chloroquine resistant strains of Plasmodium falciparum have emerged in Central and South America, Africa, and Southeast Asia.
  • Homoharringtonine is derived from a well-known Chinese herb used for many years in Fujian, China as a folk medicine for cancer. It is one group of cephalotoxus, yew-like evergreen coniferous trees, widely distributed in southern and northeastern China. Homoharringtonine, a white powder insoluble in water but soluble in alcohol, is a large heterocyclic molecule with a molecular weight of 545.6.
  • the structures of harringtonine, homoharringtonine, and deoxyharringtonine are shown below: ##STR1##
  • Harringtonine and homoharringtonine have been tested by the National Cancer Instiute and the results of those studies published in a clinical brochure titled "Homoharringtonine" NSC 141633, published by Investigational Drug Branch Cancer Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute Bethesda, Md. July 1, 1981, revised August 1982.
  • the brochure reports of 3 Chinese clinical studies and an Australian use of cephalotoxus alkaloid drugs for the treatment of leukemia.
  • the doses of harringtonine used in the Chinese studies range from 0.15-0.3 mg/kg per day for 5 to 10 days repeated every 7 to 14 days. The method of administration was not reported. Doses of homoharringtonine were 0.05-0.1 mg/kg administered using the same sectionine.
  • Homoharringtonine was tested in vitro and in vivo to determine its effectiveness against chloroquine-resistant strains of malaria parasites. Both in vivo and in vitro tests showed significant antimalarial activity.
  • a comparison of the ED 50 of homoharringtonine and chloroquine for 3 strains for malaria is listed in Table 1.
  • L1210 tumor cells in culture exposed to homoharringtonine demonstrated karyorrhexis of nuclear constituents. Similar morphological changes were seen on blood film of Plasmodium falciparum infected red cell cultures exposed to homoharringtonine.
  • Homoharringtonine acts by inhibiting protein and nucleic acid synthesis of both DNA and RNA in tumor cells. It is thought to block peptide bond formation and aminoacyl-tRNA binding. It is somewhat cell-cycle specific, with the most marked action on cells in G 1 and G 2 in monolayer cell cultures of synchronized human oral epidermoid carcinoma cells and human cervical carcinoma cells as well as murine fibroblast cells. However, radiolabeled thymidine studies of tumors in vivo show it is a cell cycle nonspecific agent.
  • mice were divided into sixteen groups of seven mice each and inoculated with 2.5 ⁇ 10 5 sporozoites of Plasmodium yoelii parasites intraperitoneally. Homoharringtonine was administered twice a day orally and subcutaneously in a volume of 10 ml/kg on the third, fourth and fifth days after inoculation of parasites. The homoharringtonine was mixed in aqueous 0.5% hydroxyethyl cellulose--0.1% Tween-80 and ultrasonicated when necessary. The doses were prepared using 100% free base of the drug.
  • Groups 8 and 16 of the infected mice received the vehicle alone and served as a negative control.
  • the blood films and final group weights were taken on the sixth day after inoculation of parasites.
  • Microscope examination of Giensa-stained blood smears was made to determine the percent parasitemia (percentage of cells parasitized), and percent suppression of parasitemia. The percent suppression of parasitemia is determined by comparing the average parasitemia of the surviving mice with the parasitemia of the negative controls. Toxicity is attributed to drug action when a 14% or greater weight change occurs or when one or more mice die before the blood smears are taken.
  • Tables 2 and 3 graphically in FIGS. 1 and 2 for subcutaneous and oral treatments respectively.
  • An effective dosage occurs when the drug produces 90% suppression.
  • This effective dosage for homoharringtonine given subcutaneously is 3.8 mg/kg per day and given orally is 2.8 mg/kg per day.
  • mice studies suggest a daily dosage between 2.8 mg/kg to 3.8 mg/kg.
  • the clinical cancer studies showed safe dosages of 5.0 mg/m 2 administered by continuous infusion.
  • An average man has a surface area of about 1.7 m 2 , therefore, the clinical studies would indicate safe daily doses of 8.5 mg.
  • An average man weighs 80 kg, therefore, the mice studies suggest daily doses of about 224-304 mg per day for a man.
  • prospective dosages in mice cannot be extrapolated to humans. The physiology is so different as to make any comparisons about dosages worthless. Mice are not susceptible to the human parasite Plasmodium falciparum and had to be treated using the mouse parasite Plasmodium yoelii. This difference also makes dosage comparisons between mice and humans useless.
  • homoharringtonine was found to be extremely effective at slowing the parasite's growth in human red cells. Referring to Table 1, homoharringtonine was found to be from 4 to 47 times more effective against malaria infected red cells than the standard antimalaria drug, chloroquine. The increased effectiveness of homoharringtonine should be sufficient for the treatment of malaria in doses safe for humans.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A method of treating animals for the control of malaria using the esters of cephalotaxine--harringtonine, homoharringtonine and deoxyharringtonine.

Description

GOVERNMENT INTEREST
The invention described herein may be manufactured, used, and licensed by or for the Government for governmental purposes without payment to me of royalty thereon.
This is a continuation-in-part of application Ser. No. 638,082 filed on Aug. 6, 1984, abandoned.
This invention deals with a novel use of harringtonine, homoharringtonine and deoxyhomoharringtonine for treating malaria.
Malaria has become an increasing problem in the tropical zones with the advent of chloroquine resistant strains of malaria parasites coupled with a decreased effectiveness of long acting insecticides such as DDT. The magnitude of the problem is reflected in the fact that malaria is the largest infectious disease in the world. Of the one billion people residing in malaria endemia areas, approximately 25 to 200 million people are diseased at any given time. In Africa alone, over one million children die each year from malaria.
The problem is becoming more serious as more stains of malaria become resistant to the major anti-malaria drug chloroquine. The major human pathogen is Plasmodium falciparum. More and more chloroquine resistant strains of Plasmodium falciparum have emerged in Central and South America, Africa, and Southeast Asia.
Researchers have synthesised chemical variants of chloroquine to combat new resistant malaria strains, however, these strains have already become resistant to the new drugs. A totally new drug having chemical properties different from chloroquine is needed to stem the increasing epidemic of resistant malaria strains.
While studying the biological processes of malaria parasite-infected cells, I noticed a resemblance to tumor cells. Both tumor cells and parasite-infected cells exhibit exponetial growth rates independent of the host. From this observation, I began testing antitumor drugs for their effectiveness as antimalarials. The most promising antitumor drugs are the esters of cephalotaxine--harringtonine, homoharringtonine and deoxyharringtonine. Synthesis of these compounds is described in U.S. Pat. Nos. 3,870,227 and 3,959,312.
Homoharringtonine is derived from a well-known Chinese herb used for many years in Fujian, China as a folk medicine for cancer. It is one group of cephalotoxus, yew-like evergreen coniferous trees, widely distributed in southern and northeastern China. Homoharringtonine, a white powder insoluble in water but soluble in alcohol, is a large heterocyclic molecule with a molecular weight of 545.6. The structures of harringtonine, homoharringtonine, and deoxyharringtonine are shown below: ##STR1##
Harringtonine and homoharringtonine have been tested by the National Cancer Instiute and the results of those studies published in a clinical brochure titled "Homoharringtonine" NSC 141633, published by Investigational Drug Branch Cancer Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute Bethesda, Md. July 1, 1981, revised August 1982. The brochure reports of 3 Chinese clinical studies and an Australian use of cephalotoxus alkaloid drugs for the treatment of leukemia. The doses of harringtonine used in the Chinese studies range from 0.15-0.3 mg/kg per day for 5 to 10 days repeated every 7 to 14 days. The method of administration was not reported. Doses of homoharringtonine were 0.05-0.1 mg/kg administered using the same regimine. Mixtures of 1:3 and 2:1 harringtonine to homoharringtonine were also tested. The 1:3 mixture was administered in doses of 2 mg intramuscular, and 4 mg intravenous and the 2:1 mixture was administered in doses of 4 mg intravenous. Both mixtures were given daily for an unspecified number of days. The Chinese reported these dosages to be safe; producing mild side effects which abated when the drug was stopped.
Researchers in the U.S. studied the possibility of administering homoharringtonine as a continuous infusion to avoid acute autonomic toxicity. The primary side effect from homoharringtonine is hypotension. Hypotension is dose related and blood pressure returns to normal after treatment ends. See Coonley, et al., Cancer Treat Rep 67:693-696, 1983 and Warrell et al., J. Clin On col 3:617-621. Warrell et al. concluded that dose levels up to 5 mg/m2 per day administered by continuous infusion for 9 days was safe and effective for acute nonlymphoelastic leukemia. Patients exhibited alopecia, diarrhea, hyperglycemia, and some weight gain in addition to hypotension. All side effects subsided after treatment stopped. The studies recommend continuous infusion of the drug to reduce the drugs toxic effects.
Homoharringtonine was tested in vitro and in vivo to determine its effectiveness against chloroquine-resistant strains of malaria parasites. Both in vivo and in vitro tests showed significant antimalarial activity. Applicant tested homoharringtonine in an in vitro malaria-infected red cell system. In this system, one parasite multiplies to 20 within 48 hours when left untreated. The dose required to cause 50% inhibition of parasite growth in 48 hours is called ED50. A comparison of the ED50 of homoharringtonine and chloroquine for 3 strains for malaria is listed in Table 1.
              TABLE 1                                                     
______________________________________                                    
In vitro suppression of Plasmodium falciparum when treated with           
homoharringtonine and chloroquine.                                        
          Concentration of  Concentration of                              
Strain    Homoharringtonine Chloroquine                                   
______________________________________                                    
Smith/Vietnam                                                             
          1.48 ± 0.02 ng/ml (2.7 nM)                                   
                            70.0 ng/ml                                    
                            (219 nM)                                      
Camp/Malay                                                                
          1.36 ± 0.02 ng/ml (2.5 nM)                                   
                            6.12 ng/ml                                    
                            (19 nM)                                       
FCR-3/Gambia                                                              
          1.88 ± 0.02 ng/ml (3.4 nM)                                   
                            10.25 ng/ml                                   
                            (32 nM)                                       
______________________________________                                    
 To convert chloroquine dosages from ng/ml to nM divide by 0.320 to conver
 homoharringtonine dosages from ng/ml to nM divide by 0.5456.
Pathologically, L1210 tumor cells in culture exposed to homoharringtonine demonstrated karyorrhexis of nuclear constituents. Similar morphological changes were seen on blood film of Plasmodium falciparum infected red cell cultures exposed to homoharringtonine.
Homoharringtonine acts by inhibiting protein and nucleic acid synthesis of both DNA and RNA in tumor cells. It is thought to block peptide bond formation and aminoacyl-tRNA binding. It is somewhat cell-cycle specific, with the most marked action on cells in G1 and G2 in monolayer cell cultures of synchronized human oral epidermoid carcinoma cells and human cervical carcinoma cells as well as murine fibroblast cells. However, radiolabeled thymidine studies of tumors in vivo show it is a cell cycle nonspecific agent.
Tests in vivo with malaria-infected mice showed homoharringtoninine to be effective in treating malaria. Mice were divided into sixteen groups of seven mice each and inoculated with 2.5×105 sporozoites of Plasmodium yoelii parasites intraperitoneally. Homoharringtonine was administered twice a day orally and subcutaneously in a volume of 10 ml/kg on the third, fourth and fifth days after inoculation of parasites. The homoharringtonine was mixed in aqueous 0.5% hydroxyethyl cellulose--0.1% Tween-80 and ultrasonicated when necessary. The doses were prepared using 100% free base of the drug. Groups 8 and 16 of the infected mice received the vehicle alone and served as a negative control. The blood films and final group weights were taken on the sixth day after inoculation of parasites. Microscope examination of Giensa-stained blood smears was made to determine the percent parasitemia (percentage of cells parasitized), and percent suppression of parasitemia. The percent suppression of parasitemia is determined by comparing the average parasitemia of the surviving mice with the parasitemia of the negative controls. Toxicity is attributed to drug action when a 14% or greater weight change occurs or when one or more mice die before the blood smears are taken. The results of the in vivo test are shown in Tables 2 and 3 and graphically in FIGS. 1 and 2 for subcutaneous and oral treatments respectively. An effective dosage occurs when the drug produces 90% suppression. This effective dosage for homoharringtonine given subcutaneously is 3.8 mg/kg per day and given orally is 2.8 mg/kg per day.
                                  TABLE 2                                 
__________________________________________________________________________
In Vivo Suppression of Plasmodium yoelii in mice when treated             
subcutaneously with                                                       
homoharringtonine.                                                        
    Daily Dose                                                            
          Total                                                           
              % parasitemia                                               
                          Total No.                                       
                                Average                                   
                                      %                                   
Group                                                                     
    (mg/kg)                                                               
          Dosage                                                          
              of each mouse                                               
                          Survivors                                       
                                Parasitemia                               
                                      Suppression                         
__________________________________________________________________________
1   64.0  192.0                                                           
              --, --, --, --, --, --, --,                                 
                          0     N.D.  N.D.                                
2   32.0  96.0                                                            
              --, --, --, --, --, --, --,                                 
                          0     N.D.  N.D.                                
3   16.0  48.0                                                            
              --, --, --, --, --, --, --,                                 
                          0     N.D.  N.D.                                
4   8.0   24.0                                                            
              0.15, 1.0, 0.05,                                            
                          5     0.49  98.85                               
              1.0, 0.25, --, --                                           
5   4.0   12.0                                                            
              3.0, 13.0, 4.0,                                             
                          7     3.73  91.21                               
              0.02, 1.0, 0.1,                                             
              5.0                                                         
6   2.0   6.0 16, 40, 20, 13, 5,                                          
                          7     20.71 51.18                               
              28, 23                                                      
7   1.0   3.0 33, 42, 65, 31,                                             
                          7     36.29 14.48                               
              23, 25, 35                                                  
8   Negative  59, 42, 39, 58,                                             
                          7     42.43                                     
     Control    40, 30, 29                                                  
__________________________________________________________________________
 90% Suppression vs Daily Dose = 3.8 mg/kg                                
 1. -- Signifies mouse died toxic death before day 6.                     
 2. N.D. signifies not determined because of toxic death.                 

                                  TABLE 3                                 
__________________________________________________________________________
In Vivo suppression of Plasmodium yoelii in mice when treated orally with 
homoharringtonine.                                                        
    Daily Dose                                                            
          Total                                                           
              % Parasitemia                                               
                          Total No.                                       
                                Average                                   
Group                                                                     
    (mg/kg)                                                               
          Dosage                                                          
              For Each Mouse                                              
                          Survivors                                       
                                Parasitemia                               
                                      % Suppression                       
__________________________________________________________________________
 9  32.0  96.0                                                            
              --, --, --, --, --, --, --,                                 
                          0     N.D.  N.D.                                
10  16.0  48.0                                                            
              --, --, --, --, --, --, --,                                 
                          0     N.D.  N.D.                                
11  8.0   24.0                                                            
              0.02, 0.01, 0.01                                            
                          3     0.01  99.97                               
              --, --, --, --,                                             
12  4.0   12.0                                                            
              0.05, 1.0, 0.25,                                            
                          7     1.22  97.55                               
              0.5, 6.0, 0.25, 0.5                                         
13  2.0   6.0 8, 12, 14, 5, 22,                                           
                          7     12.71 74.50                               
              16, 12                                                      
14  1.0   3.0 13, 10, 15, 35, 31                                          
                          7     19.29 61.32                               
              24, 7                                                       
15  0.5   1.5 44, 21, 16, 39, 29,                                         
                          7     33.14 33.52                               
              27, 56                                                      
16  Negative  35, 29, 66, 71, 45,                                         
                          7     49.86                                     
    Control   50, 53                                                      
__________________________________________________________________________
  90% Suppression vs Daily Dose = 2.8 mg/kg                               
 1. -- Signifies mouse died toxic death before daily 6.                   
 2. N.D. signifies not determined because of toxic death.
The mice studies suggest a daily dosage between 2.8 mg/kg to 3.8 mg/kg. The clinical cancer studies showed safe dosages of 5.0 mg/m2 administered by continuous infusion. An average man has a surface area of about 1.7 m2, therefore, the clinical studies would indicate safe daily doses of 8.5 mg. An average man weighs 80 kg, therefore, the mice studies suggest daily doses of about 224-304 mg per day for a man. But prospective dosages in mice cannot be extrapolated to humans. The physiology is so different as to make any comparisons about dosages worthless. Mice are not susceptible to the human parasite Plasmodium falciparum and had to be treated using the mouse parasite Plasmodium yoelii. This difference also makes dosage comparisons between mice and humans useless. Homoharringtonine was found to be extremely effective at slowing the parasite's growth in human red cells. Referring to Table 1, homoharringtonine was found to be from 4 to 47 times more effective against malaria infected red cells than the standard antimalaria drug, chloroquine. The increased effectiveness of homoharringtonine should be sufficient for the treatment of malaria in doses safe for humans.
I wish it to be understood that I do not desire to be limited to the exact details of construction shown and described for obvious modifications will occur to a person skilled in the art, without departing from the spirit and scope of the appended claims.

Claims (9)

I claim:
1. A method of treating animals for remission of malaria strains of Plasmodium falciparum comprising administering to said animals by injecting an amount of an active alkaloid compound, said compound having the following structure: ##STR2## where R is selected from the group consisting of ##STR3## in a dosage effective to cause remission.
2. The method as described in claim 1 wherein R is: ##STR4##
3. The method as described in claim 1 wherein R is: ##STR5##
4. The method as described in claim 1 wherein R is: ##STR6##
5. The method as described in claim 1 wherein said alkaloid compound is administered by continuous infusion.
6. The method as described in claim 2 wherein 5.0 mg/m2 per day of alkaloid compound is administered by continuous infusion for up to nine days.
7. A method of treating animals for remission of malaria strains of Plasmodium faciparum comprising administering to said animals by continuous infusion 0.15-0.30 mg/kg per day up to 10 days repeated after 7 to 14 days of active alkaloid compound having the following structure: ##STR7##
8. A method of treating animals for remission of malaria strains of Plasmodium yoleii comprising administering to said animals by injecting an amount of an active alkaloid compound, said compound having the following structure: ##STR8## where R is selected from the group consisting of ##STR9## in a dosage effective to cause remission.
9. The method as described in claim 8 wherein R is ##STR10## and said alkaloid compound is administered subcurtaneously in daily doses of approximately 3.8 mg/kg for six days.
US06/819,130 1984-08-06 1985-12-18 Treatment of malaria with esters of cephalotaxine Abandoned USH271H (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074314A1 (en) * 2001-03-09 2002-09-26 Oncopharm Corporation Therapeutical method involving subcutaneous administration of drugs containing cephalotaxine derivatives
US20040082565A1 (en) * 2002-07-17 2004-04-29 Chemgenex Therapeutics, Inc. Formulations and methods of administration of cephalotaxines including homoharringtonine
US20090068236A1 (en) * 2007-04-13 2009-03-12 Chemgenex Pharmaceuticals, Inc. Oral Cephalotaxine Dosage Forms
USRE45128E1 (en) 1998-03-20 2014-09-09 IVAX International GmbH Cephalotaxane derivatives and their processes of preparation and purification

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3870727A (en) 1970-04-09 1975-03-11 Us Agriculture Production of harringtonine and isoharringtonine
US3959312A (en) 1974-12-20 1976-05-25 The United States Of America As Represented By The Secretary Of Agriculture Synthesis of antitumor alkaloid deoxyharringtonine and its precursor 3'-0-(5-methyl-2-oxohexanoyl)-cephalotaxine
US4203996A (en) 1978-02-22 1980-05-20 The United States Of America As Represented By The Secretary Of Agriculture Synthetic cephalotaxine esters having antileukemic P388 activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3870727A (en) 1970-04-09 1975-03-11 Us Agriculture Production of harringtonine and isoharringtonine
US3959312A (en) 1974-12-20 1976-05-25 The United States Of America As Represented By The Secretary Of Agriculture Synthesis of antitumor alkaloid deoxyharringtonine and its precursor 3'-0-(5-methyl-2-oxohexanoyl)-cephalotaxine
US4203996A (en) 1978-02-22 1980-05-20 The United States Of America As Represented By The Secretary Of Agriculture Synthetic cephalotaxine esters having antileukemic P388 activity

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Coonley et al., Cancer Treatment Reports, vol. 67, pp. 693-696 (1983).
Homoharringtonine NSC 141633, published by Investigational Drug Branch Car Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute, Bethesda, Maryland, Jul. 1, 1981, revised Aug. 1982.
Warrell et al., Journal of Clinical Oncology, vol. 3, pp. 617-621 (1985) by American Society of Clinical Oncology.

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE45128E1 (en) 1998-03-20 2014-09-09 IVAX International GmbH Cephalotaxane derivatives and their processes of preparation and purification
WO2002074314A1 (en) * 2001-03-09 2002-09-26 Oncopharm Corporation Therapeutical method involving subcutaneous administration of drugs containing cephalotaxine derivatives
US20040082565A1 (en) * 2002-07-17 2004-04-29 Chemgenex Therapeutics, Inc. Formulations and methods of administration of cephalotaxines including homoharringtonine
US20060269622A1 (en) * 2002-07-17 2006-11-30 Chemgenex Pharmaceuticals, Inc. Formulations and methods of administration of cephalotaxines, including homoharringtonine
US7683050B2 (en) 2002-07-17 2010-03-23 Chemgenex Pharmaceuticals, Inc. Formulations and methods of administration of cephalotaxines, including homoharringtonine
US20120058991A1 (en) * 2002-07-17 2012-03-08 Chemgenex Pharmaceuticals, Inc. Formulations and Methods of Administration of Cephalotaxines, Including Homoharringtonine
US20090068236A1 (en) * 2007-04-13 2009-03-12 Chemgenex Pharmaceuticals, Inc. Oral Cephalotaxine Dosage Forms

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