WO1995003810A1 - Use of esculentoside a for treatment of lipopolysaccharide and macrophage mediated disorders - Google Patents
Use of esculentoside a for treatment of lipopolysaccharide and macrophage mediated disorders Download PDFInfo
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- WO1995003810A1 WO1995003810A1 PCT/US1994/007961 US9407961W WO9503810A1 WO 1995003810 A1 WO1995003810 A1 WO 1995003810A1 US 9407961 W US9407961 W US 9407961W WO 9503810 A1 WO9503810 A1 WO 9503810A1
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- esculentoside
- esa
- patient
- lipopolysaccharide
- disease
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
Definitions
- the present invention relates generally to therapeutic uses of Esculentoside A.
- Esculentoside A is a novel triterpenoid saponin having phytoaccagenin as the aglycone isolated from the roots of Phytolacca esculent a Van Ho te (Yi et al. (1984) Chinese Medicine 15:7). Related compounds have been isolated from this source (Wang and Yi (1984) Acta Pharmaceutica Sinica 19:825-829) .
- the structure of EsA is: 3-0[jS-D-glycopyranosyl-(l-4)/3-D-xylopyranosyl]-2- phytolaccagenin. It is known that in vitro EsA inhibits release of various mediators of inflammation.
- the present invention is based on the discovery that EsA blocks lipopolysaccharide (LPS)-stimulated production of nitric oxide at ⁇ 0.1 ⁇ g/ml.
- the invention is further based on the discovery that in vivo EsA suppresses acute and chronic inflammation in animal models.
- EsA 5-20 mg/kg ip markedly lowered acetic acid (0.7%) induced vascular permeability and swelling induced by xylene applied topically to the ears.
- rats EsA 5-30 mg/kg ip suppressed carrageenan-induced paw edema.
- EsA given 5 mg/kg ip qd for 7d inhibited proliferation of granuloma induced by cotton pellets.
- EsA inhibited carragenan-induced paw edema in adrenalectomized rats its antiinflammatory properties are not dependent on the pituitary-adrenal axis. These data suggest the EsA may have pharmaceutical use for treatment of a diverse group of immunoinflammatory diseases.
- the present invention provides methods for modulating a biological response in a patient, particularly a human patient, comprising administering to the patient an amount of Esculentoside A effective to modulate said response.
- Esculentoside A is meant to include Esculentoside A itself, as well as all biologic and therapeutic equivalent salts, derivatives, and the like, which retain the desired biological activity of Esculentoside A.
- Esculentoside A is particularly useful for inhibiting lipopolysaccharide induction of nitric oxide, which induction is related to conditions such as septic shock, adult respiratory disease syndrome, renal failure, liver failure, adrenal failure, and the like.
- Esculentoside A is also particularly useful for inhibiting the activation of macrophages in patients.
- Such macrophage activation is related to a variety of conditions, such as autoimmune diseases, e.g., rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, type I diabetes, and the like; graft versus host disease (transplantation rejection) ; and a variety of conditions which result from the overproduction of cytokines (which may result from macrophage activation) , such as reperfusion injury, hepatitis, acquired immune deficiency syndrome (AIDS) , cell injury, and the like.
- the Esculentoside A will also be useful for the treatment of psoriasis and other inflammatory skin conditions, preferably by topical application in appropriate carriers.
- Esculentoside A and/or its therapeutic and biologic equivalents, will be incorporated as component(s) of pharmaceutical compositions useful to attenuate, inhibit, or prevent the lipopolysaccharide- associated and macrophage activation-associated disorders described above.
- Such pharmaceutical compositions should contain a therapeutic or prophylactic amount of the Esculentoside A present in a pharmaceutically acceptable carrier.
- therapeutically effective it is meant that the Esculentoside A will be present in an amount or concentration effective to modulate the target biological response to lessen the diseased condition.
- prophylactic amounts it is meant that the Esculentoside A will be present in an amount effective to prevent or inhibit the onset of the disease condition.
- Such therapeutic and prophylactic amounts may, and will often, fall within the same ranges.
- the pharmaceutically acceptable carrier can be any compatible, non-toxic substance suitable to deliver the Esculentoside A to the patient.
- Sterile water, alcohol, fats, waxes, and inert solids may be used as a carrier.
- Pharmaceutically acceptable adjuvants, buffering agents, dispersing agents, and the like, may also be incorporated into the pharmaceutical compositions.
- Such compositions will be useful for oral or parenteral, i.e., subcutaneous, intravascular, or intravenous administration.
- Alternative modes of administration include nasal delivery, respiratory delivery, transder al delivery, and the like.
- Suitable topical delivery vehicles include gels, ointments, creams, lotions, controlled-release articles, e.g., skin patches, and the like.
- the concentration of the Esculentoside A in the pharmaceutical composition can vary widely, i.e., from less than about 0.01% by weight, usually being at least about 0.1% by weight, more usually being at least about 1% by weight and potentially being as much as about 20% by weight, or more.
- the specific methods for preparing pharmaceutical compositions are well known in the art and described in more detail in various publications, such as Remington's Pharmaceutical Science, 15th Edition, Mack
- the pharmaceutical Esculentoside A compositions of the present invention can be administered for prophylactic and/or therapeutic treatment of both the lipopolysaccharide-associated and macrophage activation-associated disorders described above.
- the pharmaceutical compositions will be administered to a patient already showing signs of the condition, such as septic shock, adult respiratory disease syndrome, renal failure, liver failure, adrenal failure, autoimmune disease, reperfusion injury, viral disease, cell injury, and the like.
- the Esculentoside A compositions will be administered to a patient prior to appearance of the symptoms, including each of the above conditions as well as graft versus host disease.
- the pharmaceutical compositions will be administered to the patient in amounts and on dosage schedules which are therapeutically and/or prophylactically effective.
- the pharmaceutical compositions will be administered at least once per day while the patient is suffering from the disease condition or at risk from developing the diseased condition. More usually, the pharmaceutical compositions will be administered at least twice a day, and frequently three times a day or more, during the time period of the disease and/or risk of the disease.
- EsA inhibits LPS-induced nitric oxide production by murine RAW 264.7 cells.
- LPS stimulates the induction of nitric oxide synthase a P450-like enzyme that uses one of the guanido nitrogens of arginine to generate nitric oxide (NO) .
- NO nitric oxide
- Nitric oxide mediates a number important physiological functions including regulation of blood pressure and macrophage cytotoxicity. Uncontrolled synthesis of NO plays an important role in the dysregulation of vascular tone characteristic of sepsis.
- Figure 1 demonstrates that EsA inhibits LPS induction of NO. EsA probably interferes with a specific pathway of intracellular activation.
- EsA is shown NOT to block the growth inhibitory effect of LPS. Drugs that block LPS directly will reverse LPS-induced growth inhibition.
- EsA inhibits capillary leak induced by 0.7% acetic acid and this inhibition is equivalent to cortisol (see Table 1) .
- EsA inhibits the edema caused by topical application of the irritant xylene at a potency similar to cortisol (see Table 2) .
- Table 2 EsA attenuates murine ear edema induced by xylene.
- mice 24 ⁇ 2gm were given EsA ip. After 30 min. 0.03 ml xylene was placed on the right ear. Mice were sacrificed at 2 hr. , ears removed and weighed.
- EsA was shown to effectively attenuate inflammation (edema formation) in a standard model of inflammation: the carrageenan induced rat hind paw edema model.
- the results are set forth in Table 3.
- RESULTS Wistar rats (190 ⁇ 25 gm) were give 0.1 ml of 1% carrageenan by subcutaneous injection into hind paws. Edema was measured hourly.
- EsA The therapeutic effect of EsA was shown to NOT depend upon the adrenals (Table 4) .
- Granulomas were induced in rats using cotton pellets.
- EsA attenuated the granuloma size and the attendant increase in thymus weight but did not affect the adrenals.
- Table 4 Effect ofEsA on the weight ofgranuloma, adrenal and thymus in rats.
- Table 5 EsA attenuates carrageenan-induced rat hind paw edema in adrenalectomized rats.
Abstract
Esculentoside A is incorporated into pharmaceutical compositions and used for treating patients to modulate biological response. In particular, biological responses such as lipopolysaccharide induction of nitric oxide and macrophage activation are inhibited in order to treat a variety of disease conditions.
Description
USE OF ESCULENTOSIDE A FOR TREATMENT OF LIPOPOLYSACCHARIDE AND MACROPHAGE MEDIATED DISORDERS BACKGROUND OF THE INVENTION The present invention relates generally to therapeutic uses of Esculentoside A.
Esculentoside A (EsA) is a novel triterpenoid saponin having phytoaccagenin as the aglycone isolated from the roots of Phytolacca esculent a Van Ho te (Yi et al. (1984) Chinese Medicine 15:7). Related compounds have been isolated from this source (Wang and Yi (1984) Acta Pharmaceutica Sinica 19:825-829) . The structure of EsA is: 3-0[jS-D-glycopyranosyl-(l-4)/3-D-xylopyranosyl]-2- phytolaccagenin. It is known that in vitro EsA inhibits release of various mediators of inflammation. EsA (IC50 = 1.5 uM) inhibits calcium ionophore (A23187) induced release of platelet activating factor (PAF) from rat peritoneal macrophages. EsA inhibits production of IL1 and TNF at similar concentrations. Fang and Zheng (1991) Acta Pharmaceutica Sinica 26:721-724.
SUMMARY OF THE INVENTION The present invention is based on the discovery that EsA blocks lipopolysaccharide (LPS)-stimulated production of nitric oxide at <0.1 μg/ml. The invention is further based on the discovery that in vivo EsA suppresses acute and chronic inflammation in animal models. In mice EsA 5-20 mg/kg ip markedly lowered acetic acid (0.7%) induced vascular permeability and swelling induced by xylene applied topically to the ears. In rats EsA 5-30 mg/kg ip suppressed carrageenan-induced paw edema. EsA given 5 mg/kg ip qd for 7d inhibited proliferation of granuloma induced by cotton pellets. Because EsA inhibited carragenan-induced paw edema in adrenalectomized rats its antiinflammatory properties are not dependent on the pituitary-adrenal axis. These data
suggest the EsA may have pharmaceutical use for treatment of a diverse group of immunoinflammatory diseases.
In particular, the present invention provides methods for modulating a biological response in a patient, particularly a human patient, comprising administering to the patient an amount of Esculentoside A effective to modulate said response. "Esculentoside A" is meant to include Esculentoside A itself, as well as all biologic and therapeutic equivalent salts, derivatives, and the like, which retain the desired biological activity of Esculentoside A. Esculentoside A is particularly useful for inhibiting lipopolysaccharide induction of nitric oxide, which induction is related to conditions such as septic shock, adult respiratory disease syndrome, renal failure, liver failure, adrenal failure, and the like. Esculentoside A is also particularly useful for inhibiting the activation of macrophages in patients. Such macrophage activation is related to a variety of conditions, such as autoimmune diseases, e.g., rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, type I diabetes, and the like; graft versus host disease (transplantation rejection) ; and a variety of conditions which result from the overproduction of cytokines (which may result from macrophage activation) , such as reperfusion injury, hepatitis, acquired immune deficiency syndrome (AIDS) , cell injury, and the like. The Esculentoside A will also be useful for the treatment of psoriasis and other inflammatory skin conditions, preferably by topical application in appropriate carriers.
Esculentoside A, and/or its therapeutic and biologic equivalents, will be incorporated as component(s) of pharmaceutical compositions useful to attenuate, inhibit, or prevent the lipopolysaccharide- associated and macrophage activation-associated disorders described above. Such pharmaceutical compositions should
contain a therapeutic or prophylactic amount of the Esculentoside A present in a pharmaceutically acceptable carrier. By "therapeutically effective," it is meant that the Esculentoside A will be present in an amount or concentration effective to modulate the target biological response to lessen the diseased condition. By "prophylactic amounts," it is meant that the Esculentoside A will be present in an amount effective to prevent or inhibit the onset of the disease condition. Such therapeutic and prophylactic amounts may, and will often, fall within the same ranges.
The pharmaceutically acceptable carrier can be any compatible, non-toxic substance suitable to deliver the Esculentoside A to the patient. Sterile water, alcohol, fats, waxes, and inert solids may be used as a carrier. Pharmaceutically acceptable adjuvants, buffering agents, dispersing agents, and the like, may also be incorporated into the pharmaceutical compositions. Such compositions will be useful for oral or parenteral, i.e., subcutaneous, intravascular, or intravenous administration. Alternative modes of administration include nasal delivery, respiratory delivery, transder al delivery, and the like. Suitable topical delivery vehicles include gels, ointments, creams, lotions, controlled-release articles, e.g., skin patches, and the like.
The concentration of the Esculentoside A in the pharmaceutical composition can vary widely, i.e., from less than about 0.01% by weight, usually being at least about 0.1% by weight, more usually being at least about 1% by weight and potentially being as much as about 20% by weight, or more. The specific methods for preparing pharmaceutical compositions are well known in the art and described in more detail in various publications, such as Remington's Pharmaceutical Science, 15th Edition, Mack
Publishing Company, Easton, Pennsylvania (1980) , which is incorporated herein by reference. The pharmaceutical
Esculentoside A compositions of the present invention can be administered for prophylactic and/or therapeutic treatment of both the lipopolysaccharide-associated and macrophage activation-associated disorders described above. For therapeutic applications, the pharmaceutical compositions will be administered to a patient already showing signs of the condition, such as septic shock, adult respiratory disease syndrome, renal failure, liver failure, adrenal failure, autoimmune disease, reperfusion injury, viral disease, cell injury, and the like. For prophylactic applications, the Esculentoside A compositions will be administered to a patient prior to appearance of the symptoms, including each of the above conditions as well as graft versus host disease. The pharmaceutical compositions will be administered to the patient in amounts and on dosage schedules which are therapeutically and/or prophylactically effective. Usually, the pharmaceutical compositions will be administered at least once per day while the patient is suffering from the disease condition or at risk from developing the diseased condition. More usually, the pharmaceutical compositions will be administered at least twice a day, and frequently three times a day or more, during the time period of the disease and/or risk of the disease.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: EsA inhibits LPS-induced nitric oxide production by murine RAW 264.7 cells.
Figure 2: EsA does NOT inhibit LPS-induced growth inhibition by murine RAW 264.7 cells.
The following examples are offered by way of illustration, not by way of limitation.
EXPERIMENTAL
A. JΛ vitro data
1. I.n iJitiojι of LPS stimulated nitric oxide production . LPS stimulates the induction of nitric oxide synthase a P450-like enzyme that uses one of the guanido nitrogens of arginine to generate nitric oxide (NO) . Nitric oxide mediates a number important physiological functions including regulation of blood pressure and macrophage cytotoxicity. Uncontrolled synthesis of NO plays an important role in the dysregulation of vascular tone characteristic of sepsis. Figure 1 demonstrates that EsA inhibits LPS induction of NO. EsA probably interferes with a specific pathway of intracellular activation. In Figure 2 EsA is shown NOT to block the growth inhibitory effect of LPS. Drugs that block LPS directly will reverse LPS-induced growth inhibition.
B. In vivo data
1. Inhibition of vascular permeability. a. Acetic acid model .
Several studies demonstrate the activity of EsA in vivo . EsA inhibits capillary leak induced by 0.7% acetic acid and this inhibition is equivalent to cortisol (see Table 1) .
Mean ± SD; * p < 0.05; + p < 0.01 [compared to saline control].
METHODS: Mice [20 ± 3 gm] were give EsA 30 min. prior to i.v. 0.5% Evans blue [5 mg/kg]. After 5 min. 0.7% acetic acid [10 mg/kg] was given ip. Peritoneal fluid was collected and neutralized with 0.1 ml of the NaOH (0.1 M) and the OD590 read on the intraperitoneal fluid.
b . Xylene model .
EsA inhibits the edema caused by topical application of the irritant xylene at a potency similar to cortisol (see Table 2) .
Table 2: EsA attenuates murine ear edema induced by xylene.
Drug Dose Weight of ear flap (mg/kg) (mg)
Saline — 16.7 ± 3 .2
EsA 5 12. 0 ± 3 .9*
EsA 10 10.7 ± 6.8+
EsA 20 11.6 ± 3 .7*
Cortisol 10 8 .4 ± 2 .5*
Mean ± SD; * p < 0.05; + p < 0.01 [compared to saline control].
METHODS: Mice (24 ± 2gm) were given EsA ip. After 30 min. 0.03 ml xylene was placed on the right ear. Mice were sacrificed at 2 hr. , ears removed and weighed.
c. Carageenan model .
EsA was shown to effectively attenuate inflammation (edema formation) in a standard model of inflammation: the carrageenan induced rat hind paw edema model. The results are set forth in Table 3.
Table 3: EsA reduces carrageenan-induced rat hind paw edema
Drug Dose n Rat hind paw edema (ml) mg/kg
1h 2h 3h 4h 5h
Saline - 13 0.48±0.19 0.80±0.25 1.05 ±0.20 0.94±0.16 0.76±0.23
EsA 5 6 0.20±0.11 + 0.44±0.27 0.68±0.26 0.75±0.18 0.71 ±0.17
+ + *
EsA 10 6 0.19±0.09 + 0.25±0.14 0.45 ±0.26 0.62 ±0.22 0.57±0.16
+ + + 00
EsA 15 6 0.11±0.10 + 0.24±0.21 0.24±0.18 0.34±0.18 0.34±0.21
+ + + +
EsA 30 6 0.06 ±0.05 + 0.11 ±0.20 0.18±0.30 0.17±0.29 0.19±0.18
+ + + +
Cortisol 10 13 0.15±0.10 + 0.29±0.18 0.48±0.25 0.64±0.16 0.64±0.18
+ + +
Mean ± SD; * p < 0.05; + p < 0.01 [compared to saline control]. METHODS: Wistar rats (190 ± 25 gm) were give 0.1 ml of 1% carrageenan by subcutaneous injection into hind paws. Edema was measured hourly.
The therapeutic effect of EsA was shown to NOT depend upon the adrenals (Table 4) . Granulomas were induced in rats using cotton pellets. EsA attenuated the granuloma size and the attendant increase in thymus weight but did not affect the adrenals. Further experiments demonstrated that EsA effectively inhibited carageenan-induced hind paw edema in adrenalectomized rats (Table 5) .
Table 4: Effect ofEsA on the weight ofgranuloma, adrenal and thymus in rats.
Drug Organ weight (gm/kg body wt.) (mg/kg/day x 7d) Granuloma Adrenals Thymus
Saline 0.64 ± 0.10 0.22 ± 0.07 0.93 ± 0.27
EsA (5) 0.35 ± 0.07* 0.19 ± 0.08 0.35 ± 0.07*
Cortisol (10) 0.31 ± 0.03* 0.20 ± 0.07 0.28 ± 0.18*
Mean ± SD; n = 6-10; * p < 0.05; [compared to saline control].
METHODS: Wistar rats (193 ± 21 gm) were given daily injections of EsA ip for 7 days. On day 8 the animals were sacrificed. The granuloma, adrenals and thymus were separated, dried at 90°C for 1 hr and weighed.
Table 5: EsA attenuates carrageenan-induced rat hind paw edema in adrenalectomized rats.
Drug Swelling of hind paws (ml) (mg/kg) lh 2h 3h 4h
Saline 0.43 ± 0.16 0.89 ± 0.29 0.94 ± 0.28 1.16 ± 0.19
EsA (5) 0.31 ± 0.13 0.54 ± 0.08* 0.72 ± 0.09 0.73 ± 0.18*
EsA (10) 0.15 ± 0.07* 0.35 ± 0.18* 0.54 ± 0.22* 0.71 ± 0.15*
Mean ± SD; n = 6-8; * p < 0.05; [compared to saline control]
METHODS: Wistar rats (203 ± 34 gm) underwent bilateral adrenalectomy. On day 3 post adrenalectomy rats were injected ip with EsA. After 1 hr, 0.1 ml of 1% carrageenan was given by subcutaneous injection into hind paws. Edema was measured hourly.
Although the foregoing invention has been described in detail for purposes of clarity of understanding, it will be obvious that certain modifications may be practiced within the scope of the appended claims.
Claims
1. A method for modulating a biological response in a patient, said method comprising administering to the patient an amount of Esculentoside A effective to modulate said response.
2. A method as in claim 1, wherein the biological response is the effect is to inhibit lipopolysaccharide induction of nitric oxide.
3. A method as in claim 2, wherein the lipopolysaccharide induction is related to a condition selected from the group consisting of septic shock, adult respiratory disease syndrome, renal failure, liver failure, and adrenal failure.
4. A method as in claim 1, wherein the effect is to inhibit the activation of macrophages.
5. A method as in claim 4, wherein the macrophage activation is related to a condition selected from the group consisting of autoimmune disease, graft versus host disease, reperfusion injury, viral disease, and cell injury.
6. A method fcr treating an inflammatory skin disorder in a patient, said method comprising topically applying Esculentoside A to a region of inflammation on the patient's skin.
7. A method as in claim 6, wherein the inflammatory skin disorder is psoriasis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU73349/94A AU7334994A (en) | 1993-07-30 | 1994-07-15 | Use of esculentoside a for treatment of lipopolysaccharide and macrophage mediated disorders |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10069393A | 1993-07-30 | 1993-07-30 | |
| US08/100,693 | 1993-07-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995003810A1 true WO1995003810A1 (en) | 1995-02-09 |
Family
ID=22281062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1994/007961 WO1995003810A1 (en) | 1993-07-30 | 1994-07-15 | Use of esculentoside a for treatment of lipopolysaccharide and macrophage mediated disorders |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU7334994A (en) |
| WO (1) | WO1995003810A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998033379A1 (en) * | 1997-02-04 | 1998-08-06 | The General Hospital Corporation | A novel method for treating epidermal or dermal conditions |
| EP1811839A2 (en) * | 2004-11-18 | 2007-08-01 | University of Rochester | Methods and compositions related to esculentoside a |
| CN109432111A (en) * | 2019-01-08 | 2019-03-08 | 遵义医学院 | A kind of application of pokeroot saponin A in hypoglycemic |
-
1994
- 1994-07-15 WO PCT/US1994/007961 patent/WO1995003810A1/en active Application Filing
- 1994-07-15 AU AU73349/94A patent/AU7334994A/en not_active Abandoned
Non-Patent Citations (5)
| Title |
|---|
| ACTA PHARMACEUTICA SINICA, Vol. 26, No. 10, issued 1991, J. FANG et al., "Inhibitory Effect of Esculentoside A on Platelet Activating Factor Released From Calcimycin Induced Rat Peritoneal Macrophages", pages 721-724. * |
| ACTA PHARMACEUTICA SINICA, Vol. 29, No. 4, issued April 1994, D.W. JU et al., "Inhibitory Effects of Esculentoside A on Mouse Macrophages and Antibody Production", pages 252-255. * |
| MEDIATORS OF INFLAMMATION, Vol. 1, issued 1992, FANG et al., "Effects of Esculentoside A on Tumour Necrosis Factor Production by Mice Peritoneal Macrophages", pages 375-377. * |
| SHOYAKUGAKU ZASSHI, Vol. 33, No. 2, issued 1979, HIROSHI SAITO et al., "Pharmacological Studies of Phytolaccasaponin E", pages 111-116. * |
| ZHONGCAOYAO (CHINESE MEDICINE), Vol. 15, No. 2, issued 1984, YANGHUA YI et al., "Active Principles of Phytolacca Esculenta. I. Isolation and Identification of the Triterpene Saponins", pages 55-59. * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998033379A1 (en) * | 1997-02-04 | 1998-08-06 | The General Hospital Corporation | A novel method for treating epidermal or dermal conditions |
| US6160021A (en) * | 1997-02-04 | 2000-12-12 | The General Hospital Corporation | Method for treating epidermal or dermal conditions |
| EP1811839A2 (en) * | 2004-11-18 | 2007-08-01 | University of Rochester | Methods and compositions related to esculentoside a |
| EP1811839A4 (en) * | 2004-11-18 | 2008-08-06 | Univ Rochester | Methods and compositions related to esculentoside a |
| CN109432111A (en) * | 2019-01-08 | 2019-03-08 | 遵义医学院 | A kind of application of pokeroot saponin A in hypoglycemic |
Also Published As
| Publication number | Publication date |
|---|---|
| AU7334994A (en) | 1995-02-28 |
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