WO2014184615A1 - Extracts of astragalus membranaceus, their preparation and use as antihyperalgesic and antiallodynic drugs - Google Patents
Extracts of astragalus membranaceus, their preparation and use as antihyperalgesic and antiallodynic drugs Download PDFInfo
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- A61K36/185—Magnoliopsida (dicotyledons)
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- Extracts of Astragalus membranaceus their preparation and use as antihyperalgesic and antiallodynic drugs
- the present invention relates to the field of plant product extracts.
- neuropathic pain As: "An unpleasant sensory and emotional experience that is associated with actual or potential tissue damage or otherwise described as such”. It is a major problem in neurology as it is frequent and often debilitating on account of its chronic nature.
- oxaliplatin is a third generation platinum-organic compound that induces the appearance of a neuropathic syndrome characterised by paresthesia and dysesthesia of the extremities accompanied by cramps. These symptoms occur in 85-95% of patients treated. While the acute toxicity disappears within a few days of administration, repeated treatment induces a chronic form that does not subside in the interval between the treatment cycles (Gamelin et al., Semin Oncol 29, 2002; Extra et al. Semin Oncol 25, 1998; Andre et al., J Clin Oncol 17, 1999; Cersosimo Ann Pharmacother 39, 2005).
- Oxa!iplatin induces two types of peripheral neuropathy, an acute and a chronic type both characterised by hyperalgesia and allodynia until there is impairment of daily activities.
- This painful symptomatology is the main reason for suspension of antitumor therapy (Extra et alirri 1998; Andre et al., 1999; Gamelin et al., 2002; Cersosimo et al., 2005).
- taxane-based antineoplastic therapy contemplates a distal, symmetrical, axonal, predominantly sensory neuropathy among the side effects (Argyriou, et al.. Critical Reviews in Oncology/Hematology 66:218-228, 2008).
- Some epidemiological data reports an onset of peripheral neuropathy in 60% of patients taking taxanes. Even in this case, the symptoms most frequently reported by patients include paresthesia and motor peripheral neuropathies that determine pain in distal segments of the limbs.
- Figure 1 shows the IR spectrum of the extract according to the invention
- Figure 2 shows the spectrum obtained by nuclear magnetic resonance technique
- Figure 3 shows the profile of the two-dimensional HETCOR spectrum (called HMQC).
- Hydroalcoholic extracts of Astragalus membranaceus useful as antihyperalgesic and antiallodynlc drugs, are described.
- Astragalus membranaceus is a plant belonging to the Fabacease family that has powerful antioxidant properties (Sheng et al., Chin. Med. J. 5:43-49, 2005, Li et al, Urol. Res. 34:277-282, 2006, Luo et al. Phytother. Res. 23:761-767, 2009) of which the dried root is used.
- the extracts according to the invention are hydroalcoholic extracts substantially obtained following the methodologies known in this field.
- Alcohols for the extraction Water or alcohol/water mixtures can be used as alcohols for the extraction; ethanol is one example of alcohol that can be used for the extraction.
- the amount of alcohol is normally between 0 - 80% (calculated in volume with respect to the total volume of the mixture), preferably 70%.
- Extraction is carried out at room temperature by maceration and under stirring for a few days in order to obtain an exhaustive extraction of the phytocomplex, possibly by renewing the solvent employed one or more times.
- the extraction can be performed by percolation with hydroalcoholic solutions as defined above or for decoction.
- the alcohol is subsequently evaporated and the aqueous solution is lyophilized thus obtaining the desired product.
- the resulting solutions are pooled and the ethanol is evaporated with a rotary evaporator at low pressure.
- the resulting aqueous solution is lyophilized thus obtaining a white-pale yellow powder that is analysed by various methods to obtain a fingerprint.
- the powder obtained was analysed by infrared, by the nuclear magnetic resonance technique thus respectively obtaining the spectra set out in Figure 1 and 2.
- HMQC profile of the two-dimensional HETCOR spectrum
- the sample is prepared by mixing with nujol to obtain a preparation of semisolid consistency which under IR analysis has the following fingerprint:
- HMQC profile of the two-dimensional HETCOR spectrum
- the anomeric proton at 5.3 ppm has a cross-peak with an anomeric carbon ⁇ 92.0 ppm
- the group of carbinolic proton signals in the area between 3 and 4 ppm has characteristic cross-peaks with the carbons falling within the area between 60.0 and 82.0 ppm, which correspond to the carbinolic carbons of the saccharides.
- the signals at 60.0 ppm belong to the free methylenes (-CH2), while the signals at 82.0 ppm belong to the carbons on the positions of bonds in the polysaccharide chain.
- the lyophilized extract thus obtained can then be formulated for administration, preferably in oral form and, if necessary, can see the addition of the usual excipients used in this type of formulation such as for example inorganic excipients (such as for example silica gel) or excipients of a polysaccharide nature (such as for example: maltodextrin or lactose).
- excipients used in this type of formulation such as for example inorganic excipients (such as for example silica gel) or excipients of a polysaccharide nature (such as for example: maltodextrin or lactose).
- hydroalcoholic extract only exerts its pain threshold increasing action in the cold plate test. It is interesting to observe that the hydroalcoholic extract of Astragalus membranaceus does not induce analgesia per se in the absence of a painful condition (Tab. 1 a, 1 b, 1 c).
- the hydroalcoholic extract is also capable of improving the motor coordination of rats subjected to treatment with oxaliplatin.
- Tab. 2 shows the antihyperalgesic effect of the hydroalcoholic extract under analysis at the dose of 300 mg kg '1 p.o. on paclitaxel-induced hyperalgesia evaluated in rats in the paw pressure test.
- the hydroalcoholic extract of Astragalus membranaceus in animals is free of antihyperalgesic effect as regards some neuropathic pains such as for example pain induced by antiviral agents, loose ligation of the sciatic nerve and by experimental osteoarthritis induced by monoiodoacetate.
- the histopathological analysis carried out on liver and kidney samples from rats subjected to co-treatment with oxaliplatin and hydroalcoholic extract of Astragalus membranaceus has shown an appreciable protective effect on the part of the plant extract under analysis in respect of the alterations consequent to the cytotoxic effect of the chemotherapeutic drug.
- the pathological picture indicative of the presence of acute crescentic and/or focal segmental glomerulonephritis caused by treatment with oxaliplatin is significantly reduced by the administration of the hydroalcoholic extract of Astragalus membranaceus.
- the administration of the hydroalcoholic extract of Astragalus membranaceus at a dose of 300 mg/kg p.o. once/day, in conjunction with oxaliplatin, has shown to have a statistically significant protective effect, in respect to the damage induced by chemotherapeutic drugs, at the level of the basal ganglia attached to the posterior roots.
- the immunohistochemical evaluation has allowed us to use to highlight that the treatment in question was capable of increasing neuofilament expression levels (NF200) that were reduced due to the chemotherapeutic drug.
- a normalisation of the increased expression in the nuclei of ganglion neurons induced by chemotherapy has also been highlighted for transcription factor ATF3 (activating transcription factor 3), which is subject to nuclear dislocation in the course of damage.
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Abstract
Herein are described hydroalcoholic extracts of Astragalus membranaceus, their preparation and use as antihyperalgesic and antiallodynic drugs.
Description
Extracts of Astragalus membranaceus, their preparation and use as antihyperalgesic and antiallodynic drugs
Field of the invention
The present invention relates to the field of plant product extracts.
Background of the invention
The International Association for the Study of Pain (lASP) defines neuropathic pain as: "An unpleasant sensory and emotional experience that is associated with actual or potential tissue damage or otherwise described as such". It is a major problem in neurology as it is frequent and often debilitating on account of its chronic nature.
The characteristics of this pain vary from patient to patient, but in general there are continuous burning sensations or electric shocks; paraesthesias, i.e. abnormal sensations in the areas surrounding the primary location of the pain, are often present. Examples are post-herpetic pain, phantom limb pain, which can occur following an amputation, pain in peripheral neuropathies such those present in diabetes or in AIDS, pain in the so-called complex regional syndromes or reflex sympathetic dystrophies and pain from lesions of the central nervous system. The latter can be sequelae of a stroke, of a trauma, of tumours or due to systemic diseases. In recent years, interest has focused on the neuropathic pain induced by chemotherapeutic drugs (oxaliplatin, paclitaxel, etc.).
In particular, oxaliplatin is a third generation platinum-organic compound that induces the appearance of a neuropathic syndrome characterised by paresthesia and dysesthesia of the extremities accompanied by cramps. These symptoms occur in 85-95% of patients treated. While the acute toxicity disappears within a few days of administration, repeated treatment induces a chronic form that does not subside in the interval between the treatment cycles (Gamelin et al., Semin Oncol 29, 2002; Extra et al. Semin Oncol 25, 1998; Andre et al., J Clin Oncol 17, 1999; Cersosimo Ann Pharmacother 39, 2005). An accumulation of the drug in the ganglia of the dorsal roots seems to be the first phenomenon at the basis of the development of the neuropathy (Ta et al., Neurotoxicology 27: 992-1002, 2006).
Oxa!iplatin induces two types of peripheral neuropathy, an acute and a chronic type both characterised by hyperalgesia and allodynia until there is impairment of daily activities. This painful symptomatology is the main reason for suspension of antitumor therapy (Extra et al„ 1998; Andre et al., 1999; Gamelin et al., 2002; Cersosimo et al., 2005).
Even taxane-based antineoplastic therapy contemplates a distal, symmetrical, axonal, predominantly sensory neuropathy among the side effects (Argyriou, et al.. Critical Reviews in Oncology/Hematology 66:218-228, 2008). Some epidemiological data reports an onset of peripheral neuropathy in 60% of patients taking taxanes. Even in this case, the symptoms most frequently reported by patients include paresthesia and motor peripheral neuropathies that determine pain in distal segments of the limbs.
Classic analgesics (NSAIDS, tramadol and morphine) and also anti-epileptics (gabapentin and pregabalin) are only partially effective in treating neuropathic syndromes caused by the administration of chemotherapeutic drugs and there are no compounds to date capable of completely controlling this type of increased pain perception (Albers et al. Cochrane Database Syst Rev CD005228, 2011 ; Kaley & Deangeli, 2009). The neuropathic pain, being difficult to treat, is therefore one of the most frustrating problems of analgesic therapy.
Is thus clear, in the light of the foregoing, the interest in availing of different drugs so as to be able to intervene on this type of pain without the above drawbacks. Brief description of the drawings
Figure 1 shows the IR spectrum of the extract according to the invention
Figure 2 shows the spectrum obtained by nuclear magnetic resonance technique Figure 3 shows the profile of the two-dimensional HETCOR spectrum (called HMQC).
Summary of the invention
Hydroalcoholic extracts of Astragalus membranaceus , useful as antihyperalgesic and antiallodynlc drugs, are described.
Detailed description of the invention
It has now been surprisingly found that extracts of Astragalus membranaceus are useful for overcoming the above problems.
Astragalus membranaceus is a plant belonging to the Fabacease family that has powerful antioxidant properties (Sheng et al., Chin. Med. J. 5:43-49, 2005, Li et al, Urol. Res. 34:277-282, 2006, Luo et al. Phytother. Res. 23:761-767, 2009) of which the dried root is used.
The extracts according to the invention are hydroalcoholic extracts substantially obtained following the methodologies known in this field.
Water or alcohol/water mixtures can be used as alcohols for the extraction; ethanol is one example of alcohol that can be used for the extraction.
The amount of alcohol is normally between 0 - 80% (calculated in volume with respect to the total volume of the mixture), preferably 70%.
Extraction is carried out at room temperature by maceration and under stirring for a few days in order to obtain an exhaustive extraction of the phytocomplex, possibly by renewing the solvent employed one or more times. Alternatively the extraction can be performed by percolation with hydroalcoholic solutions as defined above or for decoction.
The alcohol is subsequently evaporated and the aqueous solution is lyophilized thus obtaining the desired product.
For the sake of completeness and clarity, an example of hydroalcoholic extraction according to the invention, is set out below.
Example 1
Preparation of a hydroalcoholic extract of Astragalus membranaceus
100 grams of dried root and finely powdered Astragalus membranaceus root are macerated in 500 ml of an ethanol/water solution (70% v/v of ethanol) by extracting under stirring by prolonged maceration (for example two days); the solvent is changed and the extraction continued until exhaustive extraction (extraction takes place 3 or 4 times) of the phytocomplex.
The resulting solutions are pooled and the ethanol is evaporated with a rotary evaporator at low pressure. The resulting aqueous solution is lyophilized thus obtaining a white-pale yellow powder that is analysed by various methods to obtain a fingerprint.
In particular, the powder obtained was analysed by infrared, by the nuclear magnetic resonance technique thus respectively obtaining the spectra set out in Figure 1 and 2.
Further is shown the profile of the two-dimensional HETCOR spectrum called HMQC, which also represents the fingerprint of the extract in question (see Figure 3).
In the first technique, the sample is prepared by mixing with nujol to obtain a preparation of semisolid consistency which under IR analysis has the following fingerprint:
-in the area between 3600-3100 (peak at 3370 cm-1 )) cm-1 , a wide band resulting from stretching vibrations of O-H bonds, can be observed
-a 2900-2850 cm*1 two narrow bands, resulting from stretching vibrations of C-H bonds, can be observed
-a 1460 cm-1 a narrow band, resulting from vibrations of stretching vibrations of bonds C-O, can be observed
-1200-1000 cm-1 characteristic region of vibrations resulting from stretching vibration rings of the bonds (C-OH) and vibration of the bonds (C-O-C)→ 1 139 -1049: attributed to arabinofuranose and ramnopyranose
In the case of analysis by nuclear magnetic resonance, the extract is dissolved in dimethyl sulfoxide deuterate (50 mg extract/ml solvent), as can be seen in Figure 2:
- the majority of the signals are present in the area between 3.0-4.1 ppm carbinolic protons of the saccharide units
- at 5.3 ppm the anomeric protons of the saccharide units can be observed.
In addition, the profile of the two-dimensional HETCOR spectrum called HMQC shows that:
- The anomeric proton at 5.3 ppm has a cross-peak with an anomeric carbon ~ 92.0 ppm
- The group of carbinolic proton signals in the area between 3 and 4 ppm has characteristic cross-peaks with the carbons falling within the area between 60.0 and 82.0 ppm, which correspond to the carbinolic carbons of the saccharides.
The signals at 60.0 ppm belong to the free methylenes (-CH2), while the signals at 82.0 ppm belong to the carbons on the positions of bonds in the polysaccharide chain.
The lyophilized extract thus obtained can then be formulated for administration, preferably in oral form and, if necessary, can see the addition of the usual excipients used in this type of formulation such as for example inorganic excipients (such as for example silica gel) or excipients of a polysaccharide nature (such as for example: maltodextrin or lactose).
PHARMACOLOGICAL RESULTS
In rats, the repeated administration over three weeks of the hydroalcoholic extract of Astragalus membranaceus solubilised in carboxymethylcellulose 1 % at a dose of 100 mg and 300 mg kg'1 p.o. proved capable of preventing the onset of the reduction of the pain threshold caused by treatment with oxaliplatin at a dose of 2.4 mg kg-1 i.p. for 21 days (5 days per week). In particular, full restoration of the normal pain threshold can be observed at the higher dose. At the reported doses, the extract under analysis proved to be effective in rats, both in conditions of hyperalgesia (paw-pressure) as shown in the below Table,
Tab. 1a.
In both the allodynia ones in the presence of both a mechanical stimulus (Von Frey) and thermal stimulus (cold plate) as respectively shown in the following Tables 1b and 1 c
Tab.1b
Tab.1c
These same tables also show how an antihyperalgesic action, albeit characterised by lesser effectiveness, is also performed by the aqueous and alcoholic extract of Astragalus membranaceus. Only the alcoholic extract maintains a significant efficacy against mechanical allodynia (Tab. 1 b), while neither the alcoholic nor the aqueous extract are able to exert a protective effect towards the thermal allodynia (Tab. 1 c).
The 30 mg kg'1 p.o. dose of hydroalcoholic extract only exerts its pain threshold increasing action in the cold plate test. It is interesting to observe that the hydroalcoholic extract of Astragalus membranaceus does not induce analgesia per se in the absence of a painful condition (Tab. 1 a, 1 b, 1 c).
The hydroalcoholic extract is also capable of improving the motor coordination of rats subjected to treatment with oxaliplatin.
In the following Table 1d
Tab. 1 d
It can indeed be seen that in the rota-rod test the rats that were also, throughout treatment with oxaliplatin, co-administered hydroalcoholic extract at the doses of 100 and 300 mg kg-1 p.o., show a better motor coordination with respect to those only treated with the chemotherapeutic drug. This effect is not only expressed with a reduction in the number of falls from the rotating rod but also with an increase in the balancing time. The dose of 30 mg kg-1 p.o., is also active on this last parameter. (Tab. 1d).
The alcoholic extract at the dose of 300 mg kg-1 p.o. significantly increases the time spent on the rotating rod even if with less efficacy with respect to the hydroalcoholic extract. On the contrary, the aqueous extract shows no effectiveness with respect to the oxaliplatin-induced motor alterations (Tab. 1d).
Tab. 2 shows the antihyperalgesic effect of the hydroalcoholic extract under analysis at the dose of 300 mg kg'1 p.o. on paclitaxel-induced hyperalgesia evaluated in rats in the paw pressure test.
An analogous result was obtained by the same extract at a dose of 300 mg kg-1 p.o. in the presence of a reduction of the pain threshold in streptozotocin-induced pain in an animal model of diabetes. See Tab. 3.
This is in line with what is written in the introduction, since the oxidative damage is a common factor in both neuropathies from chemotherapeutic drugs that the metabolic diseases such as diabetes where the hypergiycaemia translates into an increased production of mitochondrial superoxide radical with consequent increased exposure of cells to ROS (Lowell & Shulman 2005).
The hydroalcoholic extract of Astragalus membranaceus in animals is free of antihyperalgesic effect as regards some neuropathic pains such as for example pain induced by antiviral agents, loose ligation of the sciatic nerve and by experimental osteoarthritis induced by monoiodoacetate.
It is effective in reversing, in the test animals, oxaliplatin-induced neuropathic pain, it does not alter the viability of the HT-29 cells treated with the same chemotherapeutic drug, which allows exclusion of its causing the survival of tumour cells by invalidating the action of oxaliplatin.
In the context of the study, we have focused attention on a tumouraf line of human colon carcinoma ceils (neoplasia that is particularly sensitive to oxaliplatin) where we induced the damage with the chemotherapeutic agent under analysis. The value of IC50 exercised by oxaliplatin in this cell type was evaluated in the presence and in the absence of the extract of hydroalcoholic preparation. Testing by means of cell viability assay. The treatment has not altered viability.
The administration of 6 g kg-1 of hydroalcoholic extract does not alter, in rats, the motor coordination evaluated by means of the rota-rod and the spontaneous motility test.
The histopathological analysis carried out on liver and kidney samples from rats subjected to co-treatment with oxaliplatin and hydroalcoholic extract of Astragalus membranaceus has shown an appreciable protective effect on the part of the plant extract under analysis in respect of the alterations consequent to the cytotoxic effect of the chemotherapeutic drug. In particular, at the level of the kidney, the pathological picture indicative of the presence of acute crescentic and/or focal segmental glomerulonephritis caused by treatment with oxaliplatin, is significantly reduced by the administration of the hydroalcoholic extract of Astragalus membranaceus. Similarly, in the liver, the acute inflammatory process arising as a result of metabolic damage caused by the presence of the chemotherapeutic drug, damage that primarily manifests as ballooning degeneration, appear strongly reduced by treatment with the hydroalcoholic extract of Astragalus membranaceus which is therefore also an effective protector against drug-induced hepatotoxicity. The administration of the hydroalcoholic extract of Astragalus membranaceus at a dose of 300 mg/kg p.o. once/day, in conjunction with oxaliplatin, has shown to have a statistically significant protective effect, in respect to the damage induced by chemotherapeutic drugs, at the level of the basal ganglia attached to the posterior roots. This effect is evidenced by alterations of the nuclei and of the nucleoli of the ganglion neurons. In particular, the increase in the number of multinucleated neurons and of neurons whose nucleolus occupies an eccentric position, and significantly reduced by co-treatment with the hydroalcoholic extract of Astragalus membranaceus.
Analogously to what has just been described from a morphological point of view, the expression levels of certain biochemical parameters, which are known due to their alteration in the course of damage, was also improved in rats that were administered the hydroalcoholic extract of Astragalus membranaceus at a dose of 300 mg/kg p.o. once daily simultaneously with oxaliplatin. At peripheral nerve level, the immunohistochemical evaluation has allowed us to use to highlight that the treatment in question was capable of increasing neuofilament expression levels (NF200) that were reduced due to the chemotherapeutic drug. A normalisation of the increased expression in the nuclei of ganglion neurons induced by chemotherapy has also been highlighted for transcription factor ATF3 (activating transcription factor 3), which is subject to nuclear dislocation in the course of damage.
Since in relation to the above-mentioned biochemical parameters, treatment with the hydroalcoholic extract of Astragalus membranaceus was responsible for a partial restoration of NF200 levels and for a decrease in the number of ATF3- positive nuclei, it can be stated that the hydroalcoholic extract of Astragalus membranaceus shows a neuroprotective effect in both SIMP regions.
It has also been possible, at the level of the central nervous system (CNS), in particular in the spinal cord, using immunohistochemistry techniques in fluorescence microscopy, to highlight the significant role played by the hydroalcoholic extract of Astragalus membranaceus in normalising the density of the glial cells and, more particularly, of microglia and astrocytes that result numerically altered by treatment with oxaliplatin alone.
Claims
1. Hydroalcoholic or aqueous extracts of Astragalus membranaceus as antihyperalgesic and antiallodynic drugs.
2. Extracts according to claim 1 , wherein said extracts are obtained by treating the dried, powdered root of Astragalus membranaceus with water or water/alcohol mixtures wherein the alcohol is between 0 and 80% (amount expressed in volume on the total amount of mixture).
3. Extracts according to claims 1 and 2, wherein said alcohol is ethyl alcohol.
4. Extracts according to claim 3, wherein ethanol is present in the amount of 70% (expressed in volume on the total amount of mixture).
5. Extracts according to claims 1 - 4, wherein the extraction is carried out at room temperature by maceration and under stirring for a few days in order to obtain an exhaustive extraction of the phytocomplex, possibly by renewing the solvent employed one or more times.
6. Extracts according to claims 1 to 4, wherein the extraction is carried out by percolation of the hydroalcoholic solutions or by decoction.
7. Process for preparing the extracts according to claims 1 - 5, wherein:
- an amount of finely pulverised, dried root of Astragalus membranaceus is treated with an ethanol/water solution extracting under stirring by prolonged maceration;
- the solvent is changed and the extraction continued until the exhaustive extraction of the phytocomplex;
- the resulting solutions are pooled and the ethanol is evaporated with a rotary evaporator at low pressure;
- the aqueous solution is lyophilized and the resulting powder is collected.
8. Pharmaceutical formulations for treating neuropathic pain, comprising extracts according to claims 1 - 6, in a form suitable for oral administration.
9. Formulations according to claim 8, wherein said neuropathic pain is of the post-herpetic pain, phantom limb pain, pain in peripheral neuropathies present in diabetes or in AIDS, pain in the so-called complex regional syndromes or reflex sympathetic dystrophies, and pain from lesions of the central nervous system.
IS
10. Formulations according to claim 9, wherein said pain is neuropathic pain induced by chemotherapeutic drugs.
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CN101095789A (en) * | 2007-08-03 | 2008-01-02 | 司马蕾 | Compound Chinese traditional medicine for treating neuropathic pain |
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