Compositions and methods of use of phorbol esters

A technology of crotyl ester and crotyl alcohol, applied in the field of cell disease, can solve the problems of bone marrow function decline, toxicity, side effects, etc.

Inactive Publication Date: 2010-03-24
BIOSUCCESS BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, it can be difficult to obtain a clear border around a tumor, leaving some residual tumor tissue and increasing the chance of disease recurrence
Almost all current chemotherapy agents are toxic, and chemotherapy causes significant side effects, including severe nausea, decreased bone marrow function, and immune suppression

Method used

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  • Compositions and methods of use of phorbol esters
  • Compositions and methods of use of phorbol esters
  • Compositions and methods of use of phorbol esters

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Effects of TPA on the number of white blood cells (WBC) and heme (Hb) in mice injected with S180 cells:

[0107] Sarcoma 180 (S180) cells were injected into Kunming (Kwen-Ming) mice. On the third day, mice were given 50, 100 or 200 micrograms / kg / day of TPA intraperitoneally (i.p.) for 7 days. The day after completion of treatment, blood samples were taken from the tails of treated mice for WBC and Hb analysis. The number of WBCs in the treatment groups (50, 100, or 200 μg / kg / day for 7 days) were 16.1±7.4, 18.7±3.0, and 20.7±3.4×10 per liter, respectively 9 ; while the number of WBCs in the control group was 13.6±1.8×10 per liter 9 . The Hb of the treatment group was 136 ± 11, 149 ± 12 and 149 ± 10 g / L, while the Hb of the control group was 134 ± 15 g / L. The results indicated that the i.p. injection of TPA could increase the peripheral white blood cell count (WBC) in mice depending on the dose level, however, the amount of Hb in the TPA-treated mice was not significa...

Embodiment 2

[0109] Dose Range Studies

[0110] TPA is administered to patients as an intravenous (i.v.) injection due to the strong local irritation that TPA can cause. The TPA solvent in a sterile syringe was injected with 200 ml of sterile physiological saline and mixed well for i.v. injection.

[0111] Toxicity and side effects of different TPA doses in clinical practice:

[0112] (1) Dosing of TPA at a dose of 1 mg per patient per week:

[0113] One milligram of TPA in solvent was mixed well with 200 ml of sterile physiological saline for intravenous injection at a rate of 16 micrograms per minute over 1 hour. One hour after TPA administration, the patient started to have chills for 30 minutes, followed by fever (the patient's body temperature reached 37.5-39.5°C for 3-5 hours, and then returned to normal), accompanied by varying degrees of sweating . The above symptoms can be alleviated by administering glucocorticoid to the patient. TPA at this dose caused bleeding in a small n...

Embodiment 3

[0119] Phase 1 clinical trial of HIV+patients treated with TPA

[0120] Twelve symptomatic patients (five men and seven women) were treated with TPA, aged 35 to 52, all of whom were HIV-infected by blood transfusion in 1995, And are resistant to standard HIV treatment. Each patient was administered intravenously (i.v.) a weight-adjusted dose of TPA (75 μg / sq m) in 200 ml of sterile saline over 1 hour. This dose is given once daily for the first to three days of treatment. Each patient was then given this dose every two days from day 4 to day 8, followed by a 6-month rest period before the second phase of treatment according to the same program.

[0121] Blood samples were collected prior to the first dose and on Days 4 and 40 of the treatment cycle. The amount of CD3, CD4 and CD8 in peripheral blood was measured by monoclonal antibody (Becton Dickson Scientific Co., Franklin Lakes, NJ) and flow cytometer (B.D. Bioscience, San Diego, CA).

[0122] As shown in Table 1, no sy...

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Abstract

Methods and compositions containing a phorbol ester or a derivative of a phorbol ester are provided for the treatment of cytopathic diseases. Cytopathic diseases may be caused by a variety means suchas viral infections like HIV and AIDS, or the development of neoplasms in a mammalian subject. The methods and compositions of the invention are effective for inhibiting de novo HIV infection, upregulating viral expression from latent provirus, inhibiting HIV-induced cytopathic effects, down regulating the HIV receptor, increasing ThI cytokine expression, decreasing Th2 cytokine expression, increasing ERK phosphorylation, inducing apoptosis in malignant cells, inducing remission, maintaining remission, as chemotherapeutic agents, as well as for decreasing symptoms of cytopathic diseases and opportunistic infections that may accompany such diseasesl. Additional compositions and methods are provided which employ a phorbol ester or derivative compound in combination with at least one additional agent such as those used in HAART protocols, therapeutic agents used to treat opportunistic infections due to HIV, or chemotherapeutic agents to yield more effective treatment tools against cytopathic diseases in mammalian subjects.

Description

【Technical field】 [0001] The present invention relates generally to the field of cytopathies. More specifically, the present invention is directed to a compound comprising a crotonate and a method of using the crotonate for the treatment of cytopathic conditions and the treatment of diseases causing such cytopathic conditions. 【Background technique】 [0002] Crotyl alcohol is a naturally occurring organic compound from plants, which belongs to diterpenes. Crotyl alcohol was first isolated in 1934 as a hydrolyzate of croton oil produced from the seeds of croton (corton tiglium), a leafy shrub native to the family Euphorbiaceae in Southeast Asia. Various esters of crotyl alcohol have important biological properties, including the well-known diacylglycerols and the ability to activate Protein Kinase C, regulating downstream cellular signaling pathways, including mitogen-activated proteins Kinase (mitogen activated protein kinase, MAPK) pathway. Crotonyl esters are also thoug...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/00A01N43/46A61K31/55
CPCA61K31/573A61K31/606A61K31/225A61K45/06A61K31/55A01N43/46A01N63/00A61K31/23A61K31/60A61K31/618C07C69/013C07C69/22C07C69/33C07C2603/40A61P31/18A61P35/02A61P35/00Y02A50/30A61K31/222
Inventor 张立才韩正涛
Owner BIOSUCCESS BIOTECH CO LTD
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