CN101657199A - Methods and pharmaceutical preparations for contributing to the treatment of chemotherapy-induced neuropathy - Google Patents
Methods and pharmaceutical preparations for contributing to the treatment of chemotherapy-induced neuropathy Download PDFInfo
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- CN101657199A CN101657199A CN200780028717A CN200780028717A CN101657199A CN 101657199 A CN101657199 A CN 101657199A CN 200780028717 A CN200780028717 A CN 200780028717A CN 200780028717 A CN200780028717 A CN 200780028717A CN 101657199 A CN101657199 A CN 101657199A
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Abstract
Methods and pharmaceutical preparations for using a leteprinim suspension to contribute to the treatment of chemotherapy-induced neuropathy.
Description
Invention field
The present invention relates to help therapeutical chemistry therapy inductive (for example cisplatin induction) neuropathic method and pharmaceutical preparation.
Background of invention
Although chemotherapeutant is vital to treatment of cancer, their use may be subjected to side effect such as neuropathic restriction, and described neuropathy can cause losing to small part somatosensory (bodilysensation).A kind of example of this class chemotherapeutant is cisplatin (cisplatin), and it is widely used in some kinds of cancers and comprises in the treatment of tumor of bladder, tumor of testis and ovarian tumor (Williams et al., (1979) Br.Med.J.1:1689-1691).Although cisplatin can provide beneficial effect in treatment for cancer, toxic effect has limited the accumulated dose that can use (Mollman, (1990) N.Engl.J.Med 322:126-127) to peripheral nervous system for it.Especially, the pathological examination with the patient of plus cisplatin in treatment has been disclosed the selective injury or the disappearance of a large amount of Sensory nerve fibres, this can cause the forfeiture (Thompson et al., (1984) Cancer 54:1269-1275) of a plurality of parts sensations of health.It is unsettled recovering from this nerve injury, and many cancer survivors with plus cisplatin in treatment suffer persistent nerve injury and anesthesia.(Cavaletti?et?al.，(1994)Anticancer?Res?14：1287-1292)。
In clinical trial, plurality of reagents has shown the lateral reactivity as the nerve injury of neuroprotective opposing cisplatin induction.In these reagent some comprise ACTH 4-9 fragment (ORG2766) (the Gerritsen et al. with growth factor activity, (1990) N.Engl.J.Med.322:89-94), with mercaptan amifostine (thiols amifostine) (Kemp et al., J.Clin.Oncol.14:2101-2112) and glutathion (Pirovano et al., (1992) Tumori 78:253-257) (1996).In preclinical study, as nerve growth factor (Apfel et al., (1992) neurotrophin-3 (Gao et al. Ann.Neurol.31:76-80),, (1995) Ann.Neurol.38 (1): 30-37) and glutamate, Glu chemical compounds such as (Boyle et ai, (1999) J.NeuroOncol.41:107-116) shown the ability that helps the nerve injury that prevention causes by cisplatin.Although all these reagent show the potential of the nerve injury that helps prevention of cisplatin-induced, still there are needs to the additional agents that can reach this function.The invention provides such reagent.
Summary of the invention
The present invention relates to contain to come Puli's peaceful (leteprinim) (its various ways arbitrary, comprise coming peaceful salt of Puli and acid) compositions, and help the purposes of in cancer patient prevention of chemotherapy inductive (for example cisplatin induction) nerve injury.The present invention also provides and has used Puli's peace to come the peaceful formulation of Puli to help to alleviate the neuropathic method of chemotherapy-induced.Therefore, the present invention includes the method and the pharmaceutical preparation that can be used to help prevention of chemotherapy inductive (for example cisplatin induction) nerve injury.
Especially, comprise a kind of method according to one embodiment of the invention, described method comprises uses Puli peaceful (SPI-082) thereby the inductive neuropathy of help therapeutical chemistry therapy to the patient.Comprise a kind of method according to another embodiment of the invention, described method comprises uses Puli peaceful (SPI-082) thereby the neuropathy of help treatment cisplatin induction to the patient.Another kind of method according to the present invention comprise use chemotherapeutant (for example cisplatin) thus to help the treatment cancer and to use peaceful (for example cisplatin induction) neuropathy that helps the therapeutical chemistry therapeutic-induced of Puli.Thereby comprising, other method according to the present invention uses cisplatin to help the treatment cancer and to use the peaceful neuropathy that helps the treatment cisplatin induction of Puli.
According to the present invention, come peaceful the using of Puli before beginning, to begin, or come peaceful the using of Puli after beginning, to begin with chemotherapeutant (for example cisplatin) treatment with chemotherapeutant (for example cisplatin) treatment.In certain embodiments, can (but being not limited to) be less than once a day (being each Zhou Qitian six times at the most) on basis weekly, more preferably twice (being each all seven days twice) uses Puli peaceful weekly.Can (but being not limited to) use from any effective dose to chemotherapeutant up to its poisonous amount.For example, administered twice cisplatin weekly.Come using also and can taking place substantially simultaneously of Puli's peace chemotherapeutant (for example cisplatin).When using when taking place substantially simultaneously, coming Puli's peace chemotherapeutant (for example cisplatin) can be the part of different pharmaceutical preparation or the part of same medicine preparation.Suitable come the peaceful dosage of Puli can include, but is not limited to from about 25mg/kg to about 100mg/kg for example about 50mg/kg.In one embodiment, come another optional activating agent of Puli's peace can be configured to suspension, randomly be configured to buffered suspension.
Embodiment of the present invention also comprise the pharmaceutical preparation that comprises to come Puli peaceful, and wherein this pharmaceutical preparation is sold with descriptive information, and described information guiding administration of pharmaceutical preparations is to help (for example cisplatin induction) neuropathy of therapeutical chemistry therapeutic-induced.In certain embodiments, descriptive information can instruct in the mode of one or more said methods and use Puli peaceful.The pharmaceutical preparation that is accompanied by this class declaration information can comprise to come Puli rather as unique active component, maybe can also comprise at least a other activating agents (for example chemotherapeutant, as cisplatin).These pharmaceutical preparatioies also can comprise other active or inactive compositions.
Can comprise also according to pharmaceutical preparation of the present invention comprising chemotherapeutant (for example cisplatin) and coming the peaceful pharmaceutical preparation of Puli that wherein the chemotherapeutant in the pharmaceutical preparation is intended to help the treatment cancer, comes Puli rather to be intended to help to treat the neuropathy of cisplatin induction.
Summary of drawings
The influence that Fig. 1 shows to come Puli rather the body weight of cisplatin induction to be changed.
The influence that Fig. 2 shows to come Puli rather the sensory perception (sensory perception) of cisplatin induction to be changed, measurement in hot plate example (hot plate paradigm).
Fig. 3 and 4 shows to come Puli peaceful respectively to the H-wave amplitude of cisplatin induction and the influence that changes incubation period (latency).
The influence that Fig. 5 shows to come Puli rather the sensitive nerve conduction velocity (SNCV) of cisplatin induction to be changed.
The influence that Fig. 6 shows to come Puli rather the axon diameter of cisplatin induction to be changed.
The influence that Fig. 7 shows to come Puli rather the g-ratio of cisplatin induction to be changed.
Fig. 8 shows to come Puli rather to the influence that changes with proportion of fibers not degeneration that degenerate after the cisplatin administration.
Detailed Description Of The Invention
I. definition
Tutorial message: term used herein " tutorial message " is accompanied by the material of drug products with expression, and it provides the description of how to use this pharmaceutical preparation.This tutorial message is generally known as pharmaceutical preparation " label ".Tutorial message can occur with many forms, includes but not limited to contain the paper insert relevant for the information of pharmaceutical preparation, C.D.Rom or station address.
Prodrug: following chemical compound will be represented in term used herein " prodrug ", and it for example is converted into chemical compound useful among the present invention by hydrolysis in vivo fast.The thorough discussion of prodrug is at Higuchi etal., Prodrugs as Novel Delivery Systems, Vol.14, of the A.C.S.D.SymposiumSeries and Roche (ed.), Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press provides in 1987.
Simultaneously basic: this paper uses term " simultaneously basic " will represent to use simultaneously two kinds of pharmaceutical preparatioies (i.e. Puli's peace cisplatin).According to this definition, " simultaneously " will be understood to include accurately simultaneously and in about 10 minutes scopes.
Treatment and help treatment: use term " treatment " and " help is treated " will represent to prevent, suppress, slow down or partly or entirely reverse the development of the nerve injury after the cisplatin administration herein.About cancer, this term comprises prophylaxis of cancer, postpones the development or the growth of cancer, dwindles or eliminates cancer, and described cancer comprises solid tumor.Comprise when therefore, these terms are suitable therapeutic treatment and/or prophylactic treatment the two.
The interior pharmaceutical preparation of cycle that this paper uses term " biweekly " to be illustrated in 7 days is applied twice.Usually, these are used can be by equipartition in the process in 7 day cycle, but this feature is optional and can take place at any interval between the administered twice in the process in 7 day cycle.
Term used herein " come Puli peaceful " is meant N-4-carboxyl phenyl-3-(6-oxo hydrogen purine-9-yl) propionic acid amide. (N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide) and various ways thereof, for example comes Puli's thujic acid and salt form thereof.Come the rather also known AIT-082 of being called as of Puli, SPI-082 and SPI-205.
The peaceful compositions of the Puli of coming of the present invention can be used to treat to the small part peripheral neurophaty relevant with using of any chemotherapeutant with method.Exemplary chemotherapeutic classes includes, but are not limited to podophyllotoxin (podophyllotoxin), terpenoid (terpenoid) (for example taxane and vinca alkaloids (vinca alkaloids)), antimetabolite, anthracycline drug (anthracycline), alkylating agent (for example platinum (platin)) and other antitumor agents.Vinca alkaloids is particularly including vincristine (vincristine), vinblastine (vinblastine), vinorelbine (vinorelbine) and vindesine (vindesine).Other exemplary chemotherapeutants include, but are not limited to etoposide (etoposide), teniposide (teniposide), cisplatin (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), paclitaxel (paclitaxel), Docetaxel (docetaxel), suramin (suramin), altretamine (altretamine), chlorambucil (chlorambucil), cytosine arabinoside (cytarabine), dacarbazine (dacarbazine), Docetaxel (docetaxel), etoposide (etoposide), fludarabine (fludarabine), ifosfamide (ifosfamide) and mesna (mesna), tamoxifen (tamoxifen), teniposide (teniposide) and thioguanine (thioguanine).The peripheral neurophaty that is associated with using of oncolytic cell drug is at C.M.Haskell, " Cancer Treatment " (5.sup.thEd., W.B.Saunders, Philadelphia, 2001), and Ch.10 describes among the pp.104-214.In one embodiment, the present invention relates to treatment with use vinca alkaloids (for example vincristine), taxane (for example paclitaxel/
) or the drug-induced peripheral neurophaty that is associated of alkylating agent (for example cisplatin).In another embodiment, the present invention relates to treat the drug-induced peripheral neurophaty that is associated with using of cisplatin.
Cisplatin is a kind of antitumor agent of extensive use in many common and oncotherapys of being difficult to treat.Cisplatin is owing to its effect as the DNA synthetic inhibitor is suitable as anticarcinogen, and this inhibitor hinders cell division.At present, neuropathy (for example nerve injury) is considered to be subjected to the toxicity of dose limitation, and its symptom is more than about 300mg/m
2Accumulated dose after take place.Cisplatin neuropathy mainly influences big fiber sensory neuron, and relevant with sensorineural signal amplitude decline usually, causes serious incompetent sensory ataxia (sensory ataxia).This neuropathy can stop the follow-up supervention exhibition of plus cisplatin in treatment.The present invention shows to come Puli rather can help to treat or the nerve injury of prevention of cisplatin-induced.
According to the concrete needs of the individual subjects that relates to, the peaceful compositions of the Puli of coming of the present invention can be used so that effective treatment to be provided with multiple dosage and drug regimen.The effective dose of the peaceful compositions of the selected Puli of coming can change based on following factor, described factor includes but not limited to activity, patient's physiology, disease of patient or the disease of chemotherapy compound and the application process/frequency/mode of coming the peaceful and/or chemotherapeutant of Puli.At first, scalable dosage and dosage regimen are to determine the dose,optimum at concrete patient.
In alleviating the neuropathy of chemotherapeutic-induced effectively minimum to come the peaceful dose concentration of Puli (medicine weight ratio patient weight) be about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg or about 45mg/kg.Effectively maximal dose is about 100mg/kg, 75mg/kg, about 65mg/kg, about 60mg/kg or about 55mg/kg in alleviating the neuropathy of chemotherapeutic-induced.Effective a kind of dose concentration is about 50mg/kg in alleviating (for example cisplatin induction) neuropathy of chemotherapeutic-induced.Come the peaceful compositions of Puli on the basis in seven days weeks, to be less than once a day (for example on every Wendesdays to six times) weekly and be applied, or twice weekly.Irrelevant with drug regimen, but the interval between using needn't equate can equate.
Can use a large amount of different approach (comprising oral, local, percutaneous, intraperitoneal, subcutaneous or intravenous) to use the peaceful compositions of Puli.Also can enter the chemical compound that brain is used effective dose by being injected into cerebrospinal fluid or directly inculcating.In one embodiment, administering mode is a subcutaneous administration.
Can rather be administered to patient's (for example need treat mammal) by Puli in future and realize method of the present invention, the described Puli of coming is rather used separately or is used as medicament preparation.In addition, come Puli to make up with pharmaceutically acceptable excipient and carrier material (as inert solid diluent, aqueous solution or nonpoisonous organic solvent).If necessary, these pharmaceutical formulation also can contain antiseptic and stabilizing agent or the like, and auxiliary substance in a small amount such as other material of wetting agent or emulsifying agent, pH buffer agent and enhanced activity composition effectiveness etc.Pharmaceutically suitable carrier can be selected from generally known in the art those, include but not limited to human serum albumin, ion-exchanger, glucose, aluminium oxide, lecithin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, propylene glycol, Polyethylene Glycol and salt or electrolyte such as protamine sulfate, sodium chloride or potassium chloride.Can use other carriers.Fluid composition also can contain the additional liquid beyond dewatering.The example of this class additional liquid is glycerol, vegetable oil such as Oleum Gossypii semen, organic ester such as ethyl oleate, and water-oil emulsion.In one embodiment, come the peaceful formulation of Puli can be by buffered hydrophobic suspension randomly.In another embodiment, come the peaceful formulation of Puli can be by buffered lipid suspension randomly.Available conventional buffer (for example acid or salt) cushions formulation.In another embodiment, peaceful salt or sour form (for example coming the peaceful potassium salt form of Puli) the buffering formulation of use-case Tathagata Puli.In another embodiment, coming the peaceful formulation of Puli is to be used for the buffered lipid suspension of the peaceful potassium salt form of Puli.
Material and method
1. animal
(France) random assortment is in 5 test group for Janvier, Le Genest-St-Isle: (a) accept subcutaneous (s.c.) and come the matched group (n=17) of Puli's thujic acid suspension placebo treatment with the female Dark Agouti rat in ten ages in week; (b) accept the subcutaneous matched group (n=17) that comes the peaceful salt of Puli (0.9%NaCl) placebo treatment; (c) use the group (n=17) of cisplatin treated separately; (d) accept the group (n=17) of the usefulness cisplatin treated that the subcutaneous Puli's of the coming thujic acid of 50mg/kg/d suspension handles; (e) accept the group (n=17) of the usefulness cisplatin treated that the peaceful potassium salt soln of the subcutaneous Puli of coming of 50mg/kg/d handles.Two inhabitations of animal per cage, and maintain in the room in have controlled temperature (21-22 ℃) and light-dark cycle (12h/12h) of reversing, food and water can unrestrictedly obtain.All experimental basis rule of managements are carried out.
2. induce cisplatin neuropathy, Yao Lixuezhiliao ﹠amp; Monitoring and testing time table
(Sigma, L ' Isled ' Abeau Chesnes France) continue 4 weeks to induce neuropathy, and dosage is per injection 2mg/kg by the injection of twice intraperitoneal (i.p.) weekly 0.1mg/ml cisplatin solution.When playing research from first day of cisplatin administration and finishing (the 7th week), every day, Puli rather handled.Cisplatin and come the peaceful potassium salt of Puli to be dissolved in the sterile solution (saline) of 0.9%NaCl.Come Puli's thujic acid suspension and placebo form thereof in 5% glucose solution, to prepare.Prepared fresh was come Puli's thujic acid suspension and placebo thereof and was come the peaceful potassium salt soln of Puli every day.Write down body weight and survival rate every day.Carry out the check of a hot plate (Hot plate) and electromyogram graphy (EMG) weekly.The sciatic nerve of 5 animals is used for histologic analysis in collecting every group in the 5th week.
3. sensory test: hot plate
With the rat individuality place the hot plate that is heated to 52 ℃ (Medite OTS 40, Microm, Francheville,
France) glass jar on (highly: 17cm; Diameter: 21cm).Observe and the record animal behavior especially sufficient beating (licking) and the jump of adjusting (jump) to escape heat.Feel that the required time of hot pain (by patting and the proof of jumping) is relevant with the temperature-sensitive lightness, and when heat sensitivity reduces, trend towards improving.
4. electromyogram graphy
(Dantec, Les Ulis France) carry out electrophysiological recording to use Neuromatic 2000M electromyograph (EMG).By peritoneal injection 60mg/kg ketamine hydrochlorate (Imalgene 500,
M é rieux, Lyon, France) (Rompum 2%, BayerPharma, Kiel, Germany) anesthetized rat with 4mg/kg hyaline (hyaline).With heating lamp normal body temperature is maintained 30 ℃ and by placing contact thermometer on the tail surface (Quick, Bioblock Scientific, Illkirch, France) control.
Write down the intramuscular H-wave reflection of metapedes pad after stimulating sciatic nerve.Reference electrode and grounding pin (ground needle) are placed back under the rat.Stimulate sciatic nerve with single 0.2ms pulse with supramaximal intensity.The incubation period of record amplitude (mV) and H-ripple.
Also write down sensitive nerve conduction velocity (SNCV).Following placement tail skin electrode: the base portion at tail inserts the reference pin, and is placing the anode pin from reference pin 30mm place towards the tail end-to-end distance.Grounding pin is inserted between anode and the reference pin.With the intensity stimulation coccygeal nerve of a series of 20 pulses (0.2ms) with 12.8mA.Speed is that unit expresses with m/s.
5. morphometric analysis
When research finished, selected every group of five animals were used for histologic analysis, came Puli rather to the influence of the pathological change of cisplatin induction thereby estimate 50mg/kg.With peritoneal injection 100mg/kgImalgene 500 with Animal Anesthesia.The sciatic nerve section that downcuts 5mm is used for Histological research.(France) solution spends the night fixation of tissue and in keeping until use in 30% sucrose under+4 ℃ for Sigma, L ' Isle d ' Abeau-Chesnes with 4% glutaraldehyde in the phosphate buffered solution (pH=7.4).(Sigma, L ' Isle d ' Abeau-Chesnes France) will fix 2 hours behind the neural sample in the solution to 1% Osmic acid. in phosphate buffer, dewaters in the gradient alcoholic solution, and is embedded among the Epon.Then the tissue with embedding place+70 ℃ following three days, allow to organize the wax polymerization.Cut the slices across of 1.5 μ m with microtome, (France) dyeing is 2 minutes for Sigma, L ' Isle d ' Abeau-Chesnes, dewaters and places Eukitt with 1% toluidine blue solution.
(Japan) inspection is from a section of each sciatic nerve sample for Nikon, Tokyo to use optical microscope.(Biocom France) analyzes on the whole surface of section to use semi-automatic digital image analysis software.For every fiber, aixs cylinder and myelin size are calculated and automatically with surface area (μ m
2) report.These two kinds of parameters are used to calculate the equivalent area (i.e. [A/ (A+M)] 0.5, A=aixs cylinder area, M=myelin area) of every fiber g-ratio (axon diameter/fibre diameter), and it shows relative myelin thickness.Myelin thickness and g-ratio are inversely proportional to.
Manually the fiber number of degenerating is counted by computer then.Following fiber is considered to experience the fiber of degenerative process: amacrine have myelin fiber, Feng Yu myelin (redundant myelin) and compare the fiber that demonstration has excessive sheath thickness with its axon diameter.
6. data analysis
In experimentation, compare body weight by dual pathways variance analysis (ANOVA).Analyze behavioral data, electric physiological data and histological data by ANOVA at each individual time point, and use Fisher Protected Least Significant Difference subsequently as check (PLSD) afterwards.Significance level is set in p＜0.05.Expression of results is the standard deviation (s.e.m.) of mean value average.
The result
1. body weight
Opposite with the control rats that shows progressive weight increase under study for action all the time, all animals of accepting cisplatin just show (p≤0.001, the double channel A NOVA) (see figure 1) that loses weight significantly that day after using cisplatin.Cisplatin administration the 3rd the week and the 4th week observed the most serious losing weight.After cancelling plus cisplatin in treatment, rat shows progressive weight increase, but keeps the level (about 20%) that is lower than contrast.These results proof is used for Puli's thujic acid or come the peaceful potassium salt of Puli to handle the appearance that can not prevent growth retardation, is accompanied by improved growth pattern (being higher than independent cisplatin treated group about 10%) but compare with independent cisplatin treated group.
2. sensory test: hot plate
Fig. 2 showed since the 2nd week, compared with matched group, from rat display threshold fractional the significantly improving incubation period (p≤0.05, Fisher ' s PLSD check) of cisplatin individual processing group.Observe the most serious dysfunction in the 4th week (last week of cisplatin administration), its time mark is higher by about 30% than matched group.Even when research finishes, do not recover the performance level of control animal yet from the animal of cisplatin individual processing group.
In Fig. 2, also can find out, be used for Puli's thujic acid or be used for the peaceful potassium salt of Puli and handle the hot plate performance (p≤0.05, Fisher ' s PLSD check) of the rat of having improved cisplatin treated significantly.From the 3rd week up to the 7th week, observe significant effect.Observe handicapped the 4th week of the most serious cisplatin, be used for Puli's thujic acid or be used for cisplatin-rat that the peaceful potassium salt of Puli handles and show the time score that only exceeds control value about 15%.When research finishes (the 7th week), accept Puli's thujic acid or come the performance of rat of usefulness cisplatin treated of the peaceful potassium salt of Puli suitable with the performance of control rats.These results prove Puli rather can help to prevent the condition of illness relevant with plus cisplatin in treatment.
3. electrophysiologicalmeasurements measurements
The a.H-wave-amplitude
As shown in Figure 3, after the beginning cisplatin administration, just in cisplatin individual processing group, observe the remarkable reduction of H-wave-amplitude 1 week.The 4th week that was reduced in that the H-wave-amplitude is the most serious takes place, and this moment, loss exceeded 45% of control level.(back-cisplatin time point) begins recovery and finishes recovery in the 7th week (when research finishes) after the cisplatin treated cancelling.
Compare with cisplatin individual processing group, it is peaceful or be used for the cisplatin rat that the peaceful potassium salt of Puli handles and show that the H-wave table that improves is existing to be used for Puli.As far back as the 2nd all these differences is exactly tangible.When the 4th week (loss of H-wave amplitude is maximum in the cisplatin individual processing group at this moment), accept the peaceful cisplatin rat demonstration of Puli only to hang down about 20% H-wave amplitude than control value.Till the 5th week, be used for the peaceful cisplatin rat of handling of Puli to return to the H-wavelength-division number of control rats.These results also prove Puli rather can help to prevent or alleviate the physiology relevant with cisplatin administration and change.
B.H-ripple incubation period
Fig. 4 demonstration is compared with control rats, the preclinical significant prolongation of H-ripple since the 2nd all cisplatin individual processing groups (p≤0.05, Fisher ' s check).Observe the most serious change in the 4th week, its, mark prolonged about 12% incubation period.In the 7th week, the rat of cisplatin individual processing recovers on this tolerance fully.
Be used for Puli's thujic acid or be used for the peaceful potassium salt of Puli and handle the H-ripple that weakens cisplatin induction significantly and change (p≤0.05, Fisher ' s check) incubation period.When in cisplatin individual processing group, changing the 4th maximum week, in accepting the peaceful cisplatin group of handling of Puli, only observe mark about 4% prolongation (comparing) incubation period with control value.
C. sensory nerve conduction velocity
As far back as the gradual reduction that begins just in the cisplatin group, to observe SNCV the 1st week (p≤0.05, Fisher ' s check) (Fig. 5).Observe the most serious dysfunction in the 4th week, mark is lower than control value about 15%.Recovery is not returned to control level since the 5th all still performances.
Being used for the peaceful processing of Puli has improved the SNCV performance of the rat of cisplatin treated significantly.In the 4th of SNCV dysfunction maximum the when week in cisplatin individual processing group, the cisplatin rat relevant dysfunction peaceful with accepting Puli is lower than control value at the most 7%.In the 7th when week, it is suitable to be used for the performance of the performance of the peaceful cisplatin rat of handling of Puli and control rats.
4. morphometric analysis
A. axon diameter
Although the nerve fiber axon diameter of gathering in the crops from the rat of cisplatin individual processing bigger than in other groups do not exist significant significant difference (p＞0.05, ANOVA) (Fig. 6) between organizing.Being used for the peaceful treatment of Puli does not significantly change the aixs cylinder size of the rat of cisplatin treated.
B. myelin thickness
There are not statistically-significant difference (p＞0.05, ANOVA) (Fig. 7) between each group about nerve fiber myelin thickness.
C. the degenerate percentage ratio of fiber
As shown in Figure 8, the ratio control rats of degeneration fiber significantly bigger (p≤0.05, Fisher ' s check) in the sciatic nerve of cisplatin individual processing group.In addition, being used for the peaceful processing of Puli has significantly reduced the ratio of degeneration fiber in the sciatic nerve of rat of cisplatin treated.
Above-described result shows that using of chemotherapeutant (in this case for cisplatin) induce significant delayed ischemic neurological deficits, described delayed ischemic neurological deficits is changed by H-ripple signal change (wave amplitude is lowered, and be extended incubation period) and SNCV and the reactivity to heat of delay shows.These signs of esthesioneurosis are organized learns support as a result, and described histological examination showed has the significantly improving of sciatic nerve proportion of fibers of axonai degeneration feature, although the character of these fibers that are affected (sensory fiber or motor fiber) is not identified.
Above-described result proves that also being used for the peaceful processing of Puli can alleviate (in this case for cisplatin induction) delayed ischemic neurological deficits of chemotherapeutic-induced significantly, and can quicken to reply from this disease.These improve is significantly in the parameter (H-wave amplitude and incubation period, SNCV and axonai degeneration) that major part is studied, and demonstration conforms to observed improvement in the hot plate test.
The axon diameter of histological examination showed cisplatin individual processing group is slightly improved.This may represent axonai degeneration, and this is the result's observed phenomenon (Rzeski et al., (2004) Ann.Neurol.56:351-360) in the rat brain of growing as cisplatin administration.Come the peaceful treatment of Puli as if to prevent this aixs cylinder swelling fully.Generally speaking, these results show that being used for Puli handles can improve the relevant esthesioneurosis of cisplatin peaceful every day.
The pharmaceutical preparation that contains described active component is applicable to and is administered to people or other mammal.Typically, described pharmaceutical preparation is aseptic, does not contain deleterious, the carcinogenic or mutagenic chemical compound that can cause adverse reaction when using.Using of this pharmaceutical preparation can be before chemotherapeutant be used beginning, among or carry out afterwards.
Method of the present invention can use aforesaid active component or the acceptable salt of its physiology, derivant, prodrug or solvate to finish.Active component can be used as pure compound and uses, or uses as the pharmaceutical preparation that contains any or all the components.
Pharmaceutical preparation comprises following compositions, wherein uses active component with the effective dose that reaches its expectation purpose.More particularly, " treatment effective dose " is meant the consumption that effective prevention solid tumor takes place, makes it disappear, delay its development or reduce its size.The treatment effective dose fixes in those skilled in the art's the ability really, the detailed disclosure of particularly considering this paper and being provided.
" treatment effective dose " is meant and causes the active component consumption that reaches desired effect.The toxicity of this active component and treatment are renderd a service and can be determined by the standard drug operation in cell culture or laboratory animal, for example determine LD
50(colony's 50% lethal dosage) and ED
50(the effective dosage of colony's 50% treatment).It is therapeutic index that dose ratio between toxic effect and the treatment effect is arranged, and it is represented as LD
50And ED
50Between ratio.High therapeutic index is preferred.The data that obtain can be used for illustrating the dosage range that is used for the people.The dosage of active component is preferably placed at and comprises almost not having toxicity or do not have toxic ED
50The circulation composition scope in.Dosage can change according to employed dosage form and employed route of administration in this scope.
Accurate prescription and dosage are considered patient's conditional decision by solo practitioner.Dosage and interval can be adjusted separately, so that the active component level of enough keeping treatment or preventive effect to be provided.
The consumption of the pharmaceutical preparation of being used can be depending on the patient that treated, patient's body weight, painful seriousness, the mode of using and the doctor's that prescribes judgement.
Active component can be used separately, or uses with mixing according to the route of administration of expection and the pharmaceutical carrier of standard drug choice of practice.Therefore, can use one or more physiologys can accept carrier (comprising excipient and adjuvant) and prepare the pharmaceutical preparation that is used for purposes of the present invention in a usual manner, but described carrier is a preparation of being convenient to active component is processed as drug use.
When the administering therapeutic effective amount of actives, compositions can be pyrogen-free, the acceptable aqueous solution of parenteral.The preparation that the parenteral that this class has suitable pH, isotonicity, a stability etc. can be accepted solution belongs within those skilled in the art's level.Be used for intravenous preferred formulation and typically should contain etc. and to ooze carrier, although this feature is optional.
For veterinary purpose, active component is used according to normal veterinary practice as the suitable prescription accepted.The veterinarian can easily determine the dosage regimen of suitable particular animals.
Can carry out multiple change and modification to embodiment, use and do not depart from scope and spirit of the present invention, described change and modification can be put into practice according to the mode that is different from the specific description of this paper.Foregoing description is intended to be illustrative rather than definitive thereof.Scope of the present invention is only determined by claims.
The term that this paper has used and expressing as the description of term and unrestricted use, and shown in the use of this class term and expression, being not intended to get rid of and being equal to or its part of described feature, admit that multiple modification may be in scope of the presently claimed invention.In addition, any one of any embodiment of the present invention or various features can with arbitrarily any one or various features combination of other embodiment of the present invention, and do not depart from scope of the present invention.
Except as otherwise noted, all numerals etc. that are used for the expression composition consumption, character (as molecular weight), reaction condition etc. of description and claims are interpreted as being modified by term " about " in all cases.Therefore, unless the counter-example of pointing out, disclosed quantity parameter is an approximation in description and additional claims, the required character that it can go for according to the present invention and changing.At least, intended is not applied to the scope of claims with doctrine of equivalents, and each quantity parameter at least should be according to through the figure place of the significant digits of report and by using conventional approximate number technical interpretation.Although the quantitative range and the parameter of the open vast scope of the present invention are approximate number, disclosed quantitative value is then as far as possible accurately reported in the specific embodiment.Yet any amount value comprises error inherently, and this is to detect the standard deviation of finding the measurement separately from them to produce inevitably.
Unless explanation arranged in addition or obviously conflict with context at this paper, describe term " " (" a ", " an ") and " this " (" the ") that (particularly in following claims context) uses in the context of the present invention and similarly refer to and be interpreted as comprising odd number and plural number.Narration to this paper numerical range only is intended to be used as the stenography method (shorthand method) of quoting each the independent value that falls into this scope.Unless this paper has explanation in addition, each independent value all is merged in description, just as it is incorporated into this paper individually.Unless at this paper explanation or clearly contradicted by context is arranged in addition, all methods as herein described can be carried out with any suitable order.The use of any and all examples that this paper provided or exemplary language (for example " for example ") only is intended to be used for setting forth better the present invention, but not the present invention's scope required for protection is set restriction.The literal of not mentioning in the description should be interpreted as referring to enforcement any element that does not require protection required in this invention.
The grouping of alternative elements disclosed herein or embodiment should not be construed as restriction.Each group membership can be mentioned separately or be claimed, or other member or other element combination in any of the group of finding with this paper.Should be appreciated that because facility and/or patent, delete during one or more members of one group can be comprised into one group or from this group.When any this class comprised or deletes generation, present specification was considered to contain the group through rewriting, to satisfy the literal support to all used in claims Ma Kushi groups.
This paper has described certain embodiments of the present invention, comprises the known realization of the present inventor optimal mode of the present invention.Certainly, routine techniques personnel in this area read the change that can understand these embodiments behind the foregoing description.The inventor expects that those skilled in the art can suitably adopt this class change, and the inventor is intended to make that the present invention uses in the mode different with the specific description of this paper.Therefore, applicable law allows at least, the present invention includes all modifications and the equivalent of the body matter described in additional claims.In addition, unless this paper has explanation or clearly contradicted by context in addition, in it might change, any combination of said elements was included by the present invention.
In addition, in present specification, a large amount of patents and printed publication have been quoted as a reference.Above-mentioned each list of references and printed publication its integral body are by reference incorporated this paper into.
At last, should understand embodiment of the present invention disclosed herein and only be used to set forth principle of the present invention.Other spendable modification also within the scope of the invention.Therefore, the unrestricted mode by example can be utilized alterative version of the present invention according to the instruction of this paper.Therefore, the present invention is restricted to as shown in accurately and described.
Claims (44)
1. method, thus comprise and use the peaceful suspension of Puli to help the inductive neuropathy of therapeutical chemistry therapy the patient that needs are arranged.
2. according to the process of claim 1 wherein that peaceful being applied in of the described Puli of coming begins with beginning before the chemotherapeutant treatment; Being applied in that the described Puli of coming is peaceful begins with beginning after the described chemotherapeutant treatment; Or peaceful the using with using substantially simultaneously of described chemotherapeutant of the described Puli of coming takes place.
3. according to the process of claim 1 wherein that the described Puli of coming rather uses weekly six times or still less.
4. according to the process of claim 1 wherein that the described Puli of coming rather uses weekly twice.
5. according to the method for claim 2, use and using substantially simultaneously of described chemotherapeutant that the wherein said Puli of coming is peaceful are taken place.
6. according to the method for claim 5, the described chemotherapeutant of the wherein said Puli's of coming peace is the part of same pharmaceutical preparation.
7. according to the process of claim 1 wherein that the peaceful dosage of using to be less than about 100mg/kg of the described Puli of coming carries out.
8. according to the process of claim 1 wherein that the peaceful dosage of using with about 50mg/kg of the described Puli of coming carries out.
9. according to the method for claim 2, wherein said chemotherapeutant is selected from podophyllotoxin, terpenoid, antimetabolite, anthracycline drug, alkylating agent, other antitumor agents, and their combination.
10. according to the method for claim 2, wherein said chemotherapeutant is selected from vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide, cisplatin, carboplatin, oxaliplatin, paclitaxel, Docetaxel, suramin, altretamine, chlorambucil, cytosine arabinoside, dacarbazine, Docetaxel, etoposide, fludarabine, ifosfamide and mesna, tamoxifen, teniposide, thioguanine, and their combination.
11. according to the method for claim 2, wherein said chemotherapeutant is selected from vinca alkaloids, taxane, alkylating agent, and their combination.
12. according to the method for claim 2, wherein said chemotherapeutant is selected from vincristine, paclitaxel, cisplatin, and their combination.
13. according to the method for claim 2, wherein said chemotherapeutant is a cisplatin.
14. according to the method for claim 13, wherein said cisplatin is used weekly twice.
15. help the inductive neuropathic pharmaceutical preparation of therapeutical chemistry therapy, it comprises to come the peaceful suspension of Puli.
16. according to the pharmaceutical preparation of claim 15, the wherein said Puli of coming rather comprises the dosage that is less than about 100mg/kg.
17. according to the pharmaceutical preparation of claim 15, the wherein said Puli of coming rather comprises the dosage of about 50mg/kg.
18. according to the pharmaceutical preparation of claim 15, it is a form of suspension.
19. a method, thereby comprise the neuropathy of the patient that needs are arranged being used the peaceful help treatment of Puli cisplatin induction.
20. a method, thereby comprise that the patient that needs are arranged is used help to be treated the cisplatin of cancer and use the peaceful suspension of Puli to help the neuropathy of treatment cisplatin induction.
21. according to the method for claim 19, being applied in that the wherein said Puli of coming is peaceful begins to begin with before the plus cisplatin in treatment, or peaceful being applied in of the described Puli of coming begins to begin with after the plus cisplatin in treatment.
22. according to the method for claim 20, the wherein said Puli of coming uses peaceful every day.
23. according to the method for claim 20, wherein said cisplatin is used weekly twice.
24. according to the method for claim 20, the wherein said Puli of coming uses peaceful every day and described cisplatin is used weekly twice.
25. according to the method for claim 20, use and using substantially simultaneously of described cisplatin that the wherein said Puli of coming is peaceful are taken place.
26. according to the method for claim 25, the described cisplatin of the wherein said Puli's of coming peace is the part of same pharmaceutical preparation.
27. according to the method for claim 19, the dosage that the wherein said Puli of coming rather uses to be less than about 100mg/kg carries out.
28. according to the method for claim 27, the dosage that the wherein said Puli of coming rather uses with about 50mg/kg carries out.
29. comprise to come the pharmaceutical preparation of the peaceful suspension of Puli, wherein said pharmaceutical preparation is sold with following descriptive information, described information guiding is used described pharmaceutical preparation to help the neuropathy of treatment cisplatin induction to the patient who needs is arranged.
30. according to the pharmaceutical preparation of claim 29, wherein said descriptive information instructs being applied in of described pharmaceutical preparation to begin to begin with before the plus cisplatin in treatment, or being applied in of described pharmaceutical preparation begins to begin with after the plus cisplatin in treatment.
31. according to the pharmaceutical preparation of claim 29, wherein after using of plus cisplatin in treatment and described pharmaceutical preparation all begun, described descriptive information instructed described pharmaceutical preparation to be used by every day.
32. according to the pharmaceutical preparation of claim 29, wherein after using of plus cisplatin in treatment and described pharmaceutical preparation all begun, described descriptive information instructed described cisplatin to be applied weekly twice.
33. according to the pharmaceutical preparation of claim 29, wherein after using of plus cisplatin in treatment and described pharmaceutical preparation all begun, described descriptive information instructs described pharmaceutical preparation to be used by every day and described cisplatin is applied weekly twice.
34. according to the pharmaceutical preparation of claim 29, wherein after using of plus cisplatin in treatment and described pharmaceutical preparation all begun, described descriptive information instructed using with described plus cisplatin in treatment of described pharmaceutical preparation to take place substantially simultaneously.
35. according to the pharmaceutical preparation of claim 34, wherein said pharmaceutical preparation also comprises cisplatin.
36. according to the pharmaceutical preparation of claim 29, wherein said descriptive information instructs described pharmaceutical preparation to use to send to be less than about 100mg/kg and to come the consumption of the peaceful dosage of Puli to carry out.
37. according to the pharmaceutical preparation of claim 29, wherein said descriptive information instructs described pharmaceutical preparation to use to send about 50mg/kg to come the consumption of the peaceful dosage of Puli to carry out.
38. comprise cisplatin and come the peaceful pharmaceutical preparation of Puli, the described cisplatin in the wherein said pharmaceutical preparation to be intended to help the treatment cancer, the described Puli of coming rather is intended to help to treat the neuropathy of cisplatin induction.
39. according to the pharmaceutical preparation of claim 15, wherein said preparation is by subcutaneous administration.
40., wherein saidly come Puli rather by subcutaneous administration according to each method in the claim 1,19 or 20.
41. according to the pharmaceutical preparation of claim 15, what the wherein said Puli of coming rather comprised sour form comes Puli peaceful.
42. according to each method in the claim 1,19 or 20, what the wherein said Puli of coming rather comprised sour form comes Puli peaceful.
43. according to the pharmaceutical preparation of claim 15, what the wherein said Puli of coming rather comprised salt form comes Puli peaceful.
44. according to each method in the claim 1,19 or 20, what the wherein said Puli of coming rather comprised salt form comes Puli peaceful.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82108206P | 2006-08-01 | 2006-08-01 | |
| US60/821,082 | 2006-08-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101657199A true CN101657199A (en) | 2010-02-24 |
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ID=38744846
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200780028717A Pending CN101657199A (en) | 2006-08-01 | 2007-08-01 | Methods and pharmaceutical preparations for contributing to the treatment of chemotherapy-induced neuropathy |
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| Country | Link |
|---|---|
| EP (1) | EP2046335A2 (en) |
| JP (1) | JP2009545619A (en) |
| KR (1) | KR20090047501A (en) |
| CN (1) | CN101657199A (en) |
| BR (1) | BRPI0715504A2 (en) |
| CA (1) | CA2659477A1 (en) |
| IL (1) | IL196824A0 (en) |
| MX (1) | MX2009001116A (en) |
| NO (1) | NO20090279L (en) |
| RU (1) | RU2009107123A (en) |
| WO (1) | WO2008017000A2 (en) |
| ZA (1) | ZA200900728B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2385931T3 (en) * | 2000-07-07 | 2012-08-03 | Spectrum Pharmaceuticals, Inc. | METHODS FOR THE TREATMENT OF PERIPHERAL NEUROPATHY INDUCED BY A DISEASE AND RELATED AFFECTIONS. |
-
2007
- 2007-08-01 WO PCT/US2007/075008 patent/WO2008017000A2/en active Application Filing
- 2007-08-01 RU RU2009107123/15A patent/RU2009107123A/en not_active Application Discontinuation
- 2007-08-01 CN CN200780028717A patent/CN101657199A/en active Pending
- 2007-08-01 BR BRPI0715504-2A patent/BRPI0715504A2/en not_active IP Right Cessation
- 2007-08-01 EP EP07840646A patent/EP2046335A2/en not_active Withdrawn
- 2007-08-01 KR KR1020097004261A patent/KR20090047501A/en not_active Application Discontinuation
- 2007-08-01 JP JP2009523049A patent/JP2009545619A/en not_active Withdrawn
- 2007-08-01 CA CA002659477A patent/CA2659477A1/en not_active Abandoned
- 2007-08-01 MX MX2009001116A patent/MX2009001116A/en not_active Application Discontinuation
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2009
- 2009-01-19 NO NO20090279A patent/NO20090279L/en not_active Application Discontinuation
- 2009-01-30 ZA ZA200900728A patent/ZA200900728B/en unknown
- 2009-02-01 IL IL196824A patent/IL196824A0/en unknown
Also Published As
| Publication number | Publication date |
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| CA2659477A1 (en) | 2008-02-07 |
| KR20090047501A (en) | 2009-05-12 |
| WO2008017000A8 (en) | 2009-04-30 |
| ZA200900728B (en) | 2010-03-31 |
| IL196824A0 (en) | 2009-11-18 |
| MX2009001116A (en) | 2009-02-10 |
| RU2009107123A (en) | 2010-09-10 |
| WO2008017000A3 (en) | 2008-03-20 |
| WO2008017000A2 (en) | 2008-02-07 |
| NO20090279L (en) | 2009-02-26 |
| BRPI0715504A2 (en) | 2014-05-06 |
| JP2009545619A (en) | 2009-12-24 |
| EP2046335A2 (en) | 2009-04-15 |
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