Patent Application
20210252004
The present invention refers to the use of sodium channel blockers such as tetrodotoxin or saxitoxin, its analogues/derivatives as well as their acceptable salts, for the production of a medicament for the treatment of neuropathic pain resulting from chemotherapy.
The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a specific treatment of pain conditions or as well a treatment of specific pain conditions which is right for the patient, which is to be understood as the successful and satisfactory treatment of pain for the patients, is documented in the large number of scientific works which have recently and over the years appeared in the field of applied analgesics or on basic research on nociception.
PAIN is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210). Even though pain is always subjective its causes or syndromes can be classified. Especially neuropathic pain which in the past years has developed into a major health problem in broad areas of the population needs a very specific treatment, especially considering that any treatment of neuropathic pain is extremely sensitive to the causes behind the pain, be it the agent/disease ultimately causing it or the mechanistic pathway over which it develops. So, in a majority of cases a substance being able to treat one subtype of neuropathic pain is not—or is at least not necessarily—able to treat other specific subtypes due to the highly diverse nature of this generalized symptom called neuropathic pain.
On the other hand cancer and the therapy thereof are one of the biggest health concerns in the world. Besides surgery and close to allways supplementing it chemotherapy is the method of choice for controlling or helping patients struck by carcinomas.
Chemotherapy is the use of chemical substances to treat disease and in the sense of this invention refers primarily to the use of cytotoxic drugs (called chemotherapeutic drugs) to treat cancer. Chemotherapy ‘in cancer consists of a personalized combination of potent chemotherapy drugs, designed to slow rapid cancer tumor growth, shrink tumors, kill cancer cells, and prevent the spread of cancer. The chemotherapeutic drugs prevent cells from replicating in the typical, out-of-control manner in which cancer cells divide.
Peripheral neurotoxicity is a clinically significant complication of cancer chemotherapy. For several of the most effective drugs (e.g. taxanes, vincristine, cisplatin), neurotoxicity is dose-limiting and sometimes forces the termination of otherwise successful therapy (Polomano and Bennett, 2001). Since these drugs are the treatment of choice for a multitude of lymphoid and solid tumours, hundred of thousands of patients each year are affected, Sensory abnormalities from antineoplastic-evoked neurotoxicity range from mild paresthesiae or dysesthesiae in many patients to a chronic painful peripheral neuropathy in a subset (Quasthoff and Hartung, 2002). The occurrence and severity of the neuropathy is dependent on single dose intensity, duration of treatment, cumulative dose, prior or concurrent treatment with other neuropathic drugs and co-existing conditions such as diabetes and alcohol abuse (Alberts et al., 1995; Postma et al., 1995; Forsyth et al., 1997; Quasthoff and Hartung, 2002). Thus it is known that as a result of Chemotherapy in a considerable number of cases neuropathic pain/allodynia/hyperalgesia develops. This is a very specific, development of symptoms coming from neurotoxicity of the chemotherapeutic drug and treatment of that is crucial for assuring quality of live.for patients suffering these consequences of chemotherapy.
Therefore. the objective of the present invention was to provide a new form of treatment for neuropathic pain/allodynia/hyperalgesia developing as a consequence of Chemotherapy.
It is surprising that administration of TTX is highly effective for the treatment for neuropathic pain/allodynia/hyperalgesia developing after Chemotherapy.
Thus, the present invention relates to the use of sodium channel Mockers such as TTX or STX, its analogues/derivatives, optionally in the form of its racernate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate for the production of a rmidicament for the treatment of neuropathic pain developing as a consequence of Chemotherapy.
“Chemotherapy” in the sense of this invention is defined as the use of a chemotherapeutic drug for the treatment of cancer or ‘tumors or malign neoplasia respectively.
“Developing as a consequence of Chemotherapy” according to this invention is defined as a) developing after or with the initiating of Chemotherapy and b) thus coinciding with or following the use of a chemotherapeutic drug. Therefore the symptom to be treated—in all scientific likelihood—is being caused by or is due to the to toxicity/citotoxiolty, especially the neurotoxicity, of the chemotherapeutic drug.
“Chemotherapeutic drugs in the sense of this invention are compounds used in chemotherapy, especially those working by impairing mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells they are termed cytotoxic. Some drugs cause cells to undergo apoptosis (so-called “cell suicide”). Especially preferred chemotherapeutic drugs in the sense of this invention are drugs derived from platin, especially the platin-derivatives cisplatin, carboplatin and oxaliplatim plant alkaloids and terpenes (terpenoids).
“Plant alkaloids” (and terpenoids) are alkaloids derived from plants and block cell division by preventing microtubule function. Microtubules are vital for cell division and without them it can not occur. The main examples are vinca alkaloids and taxanes.
“Vinca alkaloids” bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle). They are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). The vinca alkaloids include: Vincristine, Vinblastine, Vinorelbine, Vindesine.
“Taxanes” are derived from the Pacific yew tree, Taxus brevifolia. Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase. Taxanes include: Paclitaxel and Docetaxel.
Below is a list of chemotherepeutic drugs (by their trademarks), including pactitaxel (Taxol®), Iressa, Gefintinib and Xyotax:
13-cis-Retinoic Acid, 2-CdA, 2-Ch1orodeoxyadenosine, 5-fluorouracil 5-FU, 6-Mercaptopurine, 6-MP, 6-TG 6-Thioguanine, Abraxane, Accutane®, Actinomycin-D, Adriamycin®, Adrucil Agrylin®, Ala-Cort®, Aidesleukin, Alemtuzumab, ALIMTA, Alitretinoin, Alkaban-AQ®, Alkeran®, All-transrelinoic acid, Alpha interferon, Altretamine, Amethopterin, Amifostine, Aminoglutethimide, Anagrelide, Anandron®, Anastrozole, Arabinosylcytosine, Ara-C, Aranesp®, Aredia®, Arimidex®, Aromasin®, Arranon®, Arsenic trioxide, Asparaginase, ATRA, Avestin®, Azacitidine BCG, BCNU, Bevacizumab, Bexarotene, BEXXAR®, Bicalutamide, BiCNU, Blenoxane®, Bleomycin, Bortezomib, Busulfan, Busuifex®, C225, Calcium Leucovorin, Campath®, Camptosar®, Camptothecin-11, Capecitabine, Carac™, Carboplatin, Carmustine, Carmustine wafer, Casodex®, CC-5013, CCNU (o), CDDP (t), CeeNU (t), Cerubidine (t) cetuximab, Chlorambucil, Cisplatin, Citrovorum Factor, Cladribine, Cortisone, Cosmegen (t), CPT-11 (o), Cyclophosphamide, Cytadren (t), Clarabine, Cybarabine liposomal, Cytosar-U (t). Cytoxan®, Dacarbazine, Dactinomycin, Darbepoetin alfa, Daunomycin, Daunorubicin, Daunorubicin hydrochloride (t), Daunorubicin liposomal, DaunoXome (t), Decadron, Delta-Cortef (t), Deltasone (t), Deniteukin, diftitox, DepoCyt (t), Dexamethasone, Dexamethasone acetate, dexamethasone sodium phosphate, Dexasone (t), Dexrazoxane. DHAD (o), DIC (l), Diodex (t), Docetaxel, Doxil (t), Doxorubicin, Doxorubicin liposomal, Droxia (t), DTIC, DTIC-Dome (t), Duralone (t), Efudex (t), Eligard (t), Ellence (t), Eloxatin (t), Elspar (t), Emcyt (t), Epirubicin, Epoetin alfa, Erbitux, Eriotinib, Erwinia L-asparaginase (t), Estramustine, Etnyol, Etopophos (t), Etoposide, Eloposide phosphate (t), Eulexin (t), Evista (t), Exemestane, Fareston (t), Faslodex (t), Femara®, Filgrastim, Floxuridine, Fludara (t), Fluderabine, Fluorplex (t), Fluorouracil. Fluotouracil (cream), Fluoxymesterone, Flutamide, Folinic Acid (o), FUDR (t), Fulvestrant, G-CSF (t), Gefitinib, Gemecitabine, Gemtuzumab ozogamicin, Gemzar (t), Gleevec™, Gliadel wafer (t), GM-CSF (o), Goserelin, granulocyte—colony stimulating factor (l), Granulocyte macrophage colony stimulating factor (o), Halotestin (t), Herceptin (t), Hexadrol (t), Hexalen (t), Hexamethylmelamine (l), HMM (t), Hycamtin (t), Hydrea (t), Hydrocort Acetate (t), Hydrocortisone, Hydrocortisone sodium phosphate, Hydrocortisone sodium succinate, Hydrocortone phosphate (t), Hydroxyurea, Ibritumomab, Ibritamomab Tiuxetan, Idamycin®, Idarubicin iflex ®, IFN-alpha, Ifosfamide, 1L-11, 1L-2, Imatinib mesylate, Imidazole Carboxamide, Interferon elfa, Interferon Ala-2b (PEG conjugate) (o), Interleukin—2(t), Intertetikin-11 (o), intron A® (interferon alfa-2b), Iressa®, Irinotecan, Isotretinoin, Kidrolase (t), Lanacort (t), L-asparaginase (t), LCR (o), Lenalidomide, Letrozole, Leucovorin, Loukeran (t), Leukine (t), Leuprolide, Leurocristine (o), Leustatin (t), Liposomal Ara-C (t), Liquid Pred (t), Lomustine, L-PAM (o), L-Sarcolysin (o), Lupron (t), Lupron Depot (t), Matulane (t), Maxidex (t), Mechlorethamine, Mechlorethamine Hydrochloride, Medralone (t), Medrol®, Megace (t), Megestrol, Megestrol Acetate (o), Melphalan, Mercaptopurine, Mesna, Mesnex (t), Methotrexate, Methotrexate Sodium (a), Methylprednisolone, Meticorten (t), Mitomycin, Mitomycin-C (o), Mitoxantrone, M-Prednisol (t), MTC (a), MTX (o), Mustargen (t), Mustine, Mutamycin (t), Myteran (t), Mylocel (t), Mylotarg (t), Navelbine (t), Nelarabine, Neosar (t), Neulasta (t), Neumega (t). Neupogen (t), Nexavar®, Nilandron (t), Nilutamide, Nipent®, Nitrogen Mustard (o), Novaldex (t), Novantrone (t), Octreotide, Octreiatide acetate (o), Oncaspar (t), Oncovin (t), Ontak (t), Onxal (t), Oprevelkin, Orapred (t), Orasone (t), Oxaliplatin, Paclitaxel, Paclitaxel Protein-bound, Pamidronate, Panretin (t), Paraplatin (t), Pediapred (t), PEG Interferon, Pegaspargase, Pegfilgrastim, PEG-INTRON (t), PEG-L-asparaginase, PEMETREXED, Pentostatin, Phenylalanine Mustard (o). Platinol (t), Platinol-AQ (t), Prednisolone, Prednisone, Prelone (t), Procarbazine, PROCRIT®, Proleukin (t), Prolifeprospan 20 with Carmustine implant (t), Purinethol (t). Raloxilfene, Revlimid®, Rheumetrex (t), Rituxan (t), Rituximab, Roferon-A®, (interferon alfa-2a) Rubex (t), Rubidomycin hydrochloride (t), Sandostatin®, Sandostatin LAR (t), Sargramostim, Solu-Cortef (t), Solu-Medrol (t), Sorafenib, ST1-571, Streptozocin, SU11248, Sunitinib, Sutent®, Tamoxifen, Tarceva®, Targretin (t), Taxol®, Taxotere (t), Temodar®, Temozolomide, Teniposide, TESPA (o), Thalidomide, Thalomid®, TheraCys (t), Thioguanine, Thioguanine Tabloid (t), Thiophosphoamide (o), Thioplex (t), Thiotepa, TICE®, Toposar (t), Topotecan, Toremifena, Tositumomab, Trastuzumab, Tretinoin. Trexati (t), Trisenox (t), TSPA VCR (o), Valban (t), Velcade®, VePesid (t), Vesanoid (t), Viadur (t), Vidaza (t), Vinblastine, Vinblastine Sulfate (o), Vincasar Pfs (t), Vincristine, Vinorelbine, Vinorelbine tartrate (o), VLB (o), VM-26 (o), VP-16 (t), Vumon (t), Xeroda®, Xyotax, Zunosar (t), Zevalin™, Zinecard (t), Zoladex®, Zoledronic acid, Zomela®.
In addition there is another list of drugs used in cancer-therapy (mostly as chemotherapeutics):
(as trademarks): Aldara, Alimta, Androcur, Armidex, Borea, Caelyx, Campto, Casodex, Decapeptyl, Eloxatin, Eutirox, Faslodex, Ferrara, Gemzar, Gonapeptyl, Grisetin, Herceptin, Isoverin, Lysodren, Megefren, Metvix, Navelbine, Novaldex, Novantrone, Paraplatin, Procrin,
Prostacur, Suprefact, Tamoxifeno Funk, Taxol, Taxotere, Testex, Elmu/Prolongatum, Tomudex, Utefos, Vepesid, Xeloda, Zoladex;
(as active compounds): Anastrozole, Bilcalutamide, Busereflne, Capecetabine, Cisplalin, Carboplatin, Desoxorubicin, Docetaxel, Etoposid, Fulvestrant, Gemcitabine, Gosereline, Irinotecan, Letrozole, Leuproroline, Megestrol, Mitotane, Mifoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Raltitrexed, Tamoxiphen, Tegafur, Triptoreline, Vincristine, Vinblastine, Vinorelbine, Vindesine.
Paclitaxel (Taxol®) is one of the most effective and commonly used antineoplastic drugs for the treatment of solid tumours. It has two serious side effects, myelosupression and peripheral neurotoxicity. Granulocyte colony-stimulating factor effectively counteracts the noutrepenia in most patients. Unfortunately, there are no acceptable therapies to prevent or minimize the nerve damage, making neuroloxicity a significant dose-limiting side effect (Rowinsky et al., 1993a, b; Wasserheit et al., 1996; Gordon et al., 1997). Paclitaxal-induced neurotoxicity typically presents as a sensory neuropathy, with the most common complaints being numbness, tingling, burning pain and cold allodynia (Rowinsky et al., 1993a; Chaudhry et al., 1994; Forsyth et al., 1997; Dougherty et al., 2004). Sensory symptoms usually start symmetrically in the feet, but sometimes appear simultaneously in both hands and feet (Rowinsky et al., 1993a; Quasthroff and Hartung, 2002). A clinically significant number of patients with paclitaxel-induced neuropathy experience neuropathic pain. For example, in a study of 27 patients treated with paclitaxel-induced neuropathy experience neuropathic pain. For example, in a study of 27 patients treated with paclitaxel doses 135, 175 and 250-300 mg/m2, neuropathic symptoms occurred in 50, 79 and 100% of patients, progressing to dose-limiting neurotoxicity in 0, 21 and 71% of patients, respectively (Postma et al., 1995).
“Neuropathic pain” is defined by the IASP as “pain initiated or caused by a primary lesion or dysfunction in the nervous system” (IASP, classification of chronic paid, 2nd edition, IASP Press (2002), 210). For the purpose of this invention included under this heading or to be treated as synonymous is “Neurogenic Pain” which is defined by the IASP as “pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral or central nervous system”. In regards to this invention the neuropathic pain treated according to this Invention is restricted to the neuropathic pain resulting from chemotherapy, meaning being caused by the use of a chemotherapeutic drug in chemotherapy. The most likely cause of this is neurotoxicity of the chemotherapeutic drug, especially peripheral neurotoxicity.
Neurotoxicity of the chemotherapeutic drug often leads to sensory neuropathy, which i.a. results in burning pain and/or cold allodynia, especially cold allodynia.
The term “analogues” as used in this application is defined here as meaning a chemical compound that is a derivative of a compound which has similar biochemical activity to that compound. For example, “Analogues” of TTX bind to the same site on the alpha subunit of sodium channels as does TTX.
The term “derivatives” as used in this application is defined here as meaning a chemical compound having undergone a chemical derivation such as substitution or addition of a further chemical group to change (for pharmaceutical use) any of its physico-chemical properties, such as solubaity or bioavailability, Derivatives include so-called prodrugs, e.g. ester and ether derivatives of an active compound that yield the active compound per se after administration to a subject.
Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g, in Krogsgaard-Larsen et al., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002).
“Sodium channel blockers” or “sodium channel blocking compounds” encompass any chemicals that bind selectively to a sodium channel and thereby deactivate the sodium channel. In particular they include chemicals which bind to the SS1 or SS2 extracellular domains of an alpha subunit of a sodium channel. Sodium channel blocking compounds that bind to the SS1 or SS2 subunit of a sodium channel, particularly tetrodotoxin and saxitoxin, are found to possess similar pharmaceutical activity (U.S. Pat. No. 6,407,088, hereby incorporated by reference).
Tetrodotoxin (alternatively in the context of this application abbreviated TTX), also known as Ti Qu Duo Xin is an alkaloid found in puffer fish (Tetradontiae). The chemical name is Octashydro-12-(Hydroxymethyl)-2-imino-5, 9, 7, 10a-dimethano-10H-[1,3]dioxocino[6,5] pyrimidine-4, 7, 10, 11, 12-pentol with a molecular formula C11H17N3O8 and a Molecular weight of 319.27. It is a potent non-proteln neurotoxin and an indispensable tool for the study of neurobiology and physiology. Tetrodotoxin (TTX) is a marine organic toxin which is mainly found in testicles, ovaries, eggs, livers, spleens, eyeballs, and blood of puffer fish as well as in diverse animal species, including goby fish, newt, frogs and the blue ringed octopus and even in marine alga. Several processes for producing TTX are known. Usually TTX is extracted from marine organisms (e.g. JP 270719 Goto and Takahashi) but besides numerous others methods of synthesis are also described (and used for the preparation of tetrodotoxin in connection to this invention) in U.S. Pat. Nos. 6,562,191, 6,478,966, 6,562,968 or 2002/0086997, all of which are included here by reference. Tetrodotoxin is a well known compound described for example in WQ02/22129 as systemically acting as analgesic. For one of the many descriptions of TTX it is recommended turn to e.g. Tu, Anthony (Ed.) Handbook of Natural Toxins, Vol. 3: Marine Toxins and Venoms, 1988, 185-210 as well as Kao (1966), Pharmacol. Rev. 18:997-1049 and others.
The phrase “its (tetrodoxin's) derivatives” according to this invention is defined—using the definition of U.S. Pat. No. 6,030,974 (included here by reference)—as meaning amino perhydroquinazoline compounds having the molecular formula C11H17N3O5, “Tetrodoxin's derivatives” according to this invention encompasses compounds described in U.S. Pat. No. 5,846,975 (included here by reference) as amino hydrogenated quinazolines and derivatives including the substances set forth from column 3 line 40 to column 6 line 40. Specifically exemplified “derivatives of tetrodotoxin” according to this invention are including but are not limited to anhydro-tetrodotoxin, tetrodaminotoxin, methoxytetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin and tetrodonic acid, 6 epi-tetrodotoxin, 11-deoxytetrodoloxin as well as the hemilactal type TTX derivatives (e.g. 4-epi-TTX, 6-epi-TTX, 11-deoxy-TTX, 4-epi-11-deoxy-TTX, TTX-8-O-hemisuccinate, chiniquitoxin, 11-nor-TTX-6(S)-ol, 11-nor-TTX-6(R)ol, 11-nor-TTX-6,6-diol, 11-oxo-TTX and TTX-11-carboxylic acid), the lactone type TTX derivatives (e.g, 6-epi-TTX (lactone), 11-deoxy-TTX (lactone), 11-nor-TTX-6(S)-ol (lactone), 11-nor-TTX-6(R)-ol (lactone), 11-nor-TTX-6,6-diol (lactone), 5-deoxy-TTX, 5,11-dideoxy-TTX, 4-epi-5,11-didroxy-TTX, 1-hydroxy-5,11-dideoxy-TTX, 5,6,11-trideoxy-TTX and 4-epi-5,6,11-trideoxy-TTX) and the 4,9-anhydro type TTX analogs (e.g. 4,9-anhydro-TTX, 4,9-anhydro-6-epi-TTX, 4,9-anhydro-11-deoxy-TTX, 4,9-anhydro-TTX-8-O-hemisuccinate, 4,9-anhydro-TTX-11-O-hemisuccinate). The typical derivatives of TTX possess only ⅛ to 1/40 of the toxicity of TTX in mice, based upon bioassay in mice. It has been observed that these derivatives produce joint action, and do not interact adversely. Examples of TTX derivatives include novel TTX derivatives isolated from various organisms, as well as those that are partially or totally chemically synthesized (see e.g., Yotsu, M. et al. Agric. Biol. Chem., 53(3):893-895 (1989)).
“Derivatives and analogues of TTX”, as referred to in the present invention, may include compounds having the general formula I
wherein, R2 and R5 can be selected from the group consisting of H, OH, OAC, respectively;
R1 call be H, or an alkyl with C1-C4, OH, OR, OC(O)R′, NH2, NHR″, NR″R′″, among them R can be an alkyl with C1-C6, R′ can be an alkyl with C1-C3, and R″, R′″ can be an alkyl with C1-C4, respectively;
R3 and R4 can be ═O, or
when R3 is H, R4 can be selected from the group consisting of:
—ROH, and R is a branched or straight chain alkyl with C1-C7,
—CH(OH)NHOMe,
—NAP-gly,
—NAP-en,
—CH2NH2,
—CH2NHCH3,
-AAG,
—NMAG, and
-ANT;
when R3 is OH or OC(O)R and R is an alkyl with C1-C3, R4 can be selected from the group consisting of:
—CHO,
—CH2-gly,
—CH2-β-Ala,
—CH2-Lys,
—CH2-en,
—CH2—NAP-Lys
—CH2—NAP-en,
—CH(OH)CH(NH2)COOH; and,
—NH(CH2)nCOOH,
—NH(CH2)nNH2; and
—NH(CH2)nCH(NH2)COOH,
wherein:
n=1-6.
en is ethylene;
NAP is 4-triazo-2-nitrobenzoic amide, indicated as formula (a);
AAG is 2-triazo-O-aminobenzoic amide, indicated as formular (b);
NMAG is O-methylaminobenzoic amide, indicated as formula (c);
ANT is O-aminobenzoic amide, indicated as formula (d);
Among them, three kinds of compounds with the general formula II, III, IV are alternative.
The amino hydrogenated quinazoline compounds and derivatives thereof are compounds having following general formula II,
wherein: R1 can be selected from the group consisting of OH, an alkyl or a oxyalkyl with C1-C4, NH2, NHR″, NR″R′″, among them R″ and R′″ can be an alkyl with C1-C4.
Among them, the more preferred compounds are:
Tetrodotoxin RS═OH (1);
deoxytetrodotoxin RI═H (2);
The amino hydrogenated quiniazoline compounds and derivatives thereof are compounds having following general formula III
wherein:
R3, R4 are ═O, or
when R3 is H, R4 is selected from the group consisting of:
CH2OH,
CH(OH)NHOMe,
—NAP-gly,
—CH2NH2,
—CH2NHCH3,
-AAG,
—NMAG, and
-ANT.
Among them, the more preferred compounds are:
AAG-degradation Tetrodotoxin R4=AAG (3);
NMAG-degradation Tetrodotoxin R4═NMAG (4);
ANT-degradation Tetrodotoxin R4=ANT (5); and,
degradation Tetrodotoxin R3, R4 is ═O (6).
The amino hydrogenated quinazoline and their derivatives are compounds having following general formula IV;
wherein, R4 can be selected from the group consisting of:
—CHO,
—CH2-Gly,
—CH2-β-Ala,
—CH2-Lys
—CH2-en,
—CH2—NAP-Lys
—CH2—NAP-en,
—CH(OH)CH(NH2)COOH;
NH(CH2)4CH(NH2)COOH;
—NHCH2COOH;
—NHCH2CH2COOH; and
—NHCH2CH2NH2.
Among them, the more preferred compounds are:
oxytetrodotoxin R4═CHO (7);
chiriquitoxin R4═CH(OH)CH(NH2)COOH (8);
and the compounds with the substituted groups of R4:
—NH(CH2)4 CH(NH2)COOH (9);
—NHCH2COOH (10);
—NHCH2CH2COOH (11); and,
—NHCH2 CH2 NH2 (12).
Preferably, the derivatives/analogues of tetrodotoxin comprise tetrodotoxin, anhydro-tetrodotoxin, tetrodaminotoxin. methoxytetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin, epi-tetrodotoxin and tetrodortic acid, more preferably the derivatives/analogues of tetrodotoxin a consisting of tetrodotoxin, anhydro-tetrodotoxin, tetradaminotoxin, methoxytetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin, epi-tetrodotoxin (4- and 6-epi-tetrodotoxin) and tetrodonic acid.
Saxitoxin (STX) and its pharmacologically acceptable salts are species of 2,6-diamino-4-((aminocarbonyl)oxy) methyl-3a.4.8,9 -tetrahydro-1H, 10H-pyrrolo(1,2-o) purine-10,10-diol (3aS-(3a-a-a-4-a,10aR*)). The molecular formula of Saxitoxin is C10H17N7O4, it has a molecular weight of 299.3 and a general structure of:
This, and its derivatives and its analogues may be used in accordance with the disclosure. Saxitoxin is readily soluble in water and can be dispersed in aerosols. It is toxic by ingestion and by inhalation, with inhalation leading to rapid respiratory collapse and death. Chemically, saxitoxin is stable, although it can be inactivated by treatment with strong alkali. It is naturally-occurring, produced by bacteria that grow in other organisms, including the dinoflagellates Gonyaulax catenella and G. tamarensis; which are consumed by the Alaskan butter clam Saxidomus giganteus and the California sea mussel, Mytilus californianeus. The toxin can be isolated from S. giganteus or M. califomianeus. The first synthesis of STX was completed by Kishi and co-workers at Harvard in 1977 (J. Am. Chem. Soc. 1977, 99, 2818). A second synthesis was carried out by Jacobi and his collaborators whilst at Wesleyan University, Conn. (J. Am. Chem. Soc. 1984, 106, 5594). A range of alternative methods for the synthesis and purification of saxitoxin will be apparent to those skilled in the art. Analogues and derivatives of saxitoxin include but are not limited to neosaxitoxin and anhydrosaxitoxin, any other biologically active variants of the above saxitoxin structure, and pharmaceutically acceptable salts thereof.
It will be appreciated that for the purposes set out herein, tetrodotoxin, saxitoxin, and their derivatives or analogues or metabolite, can be optionally in the form of their racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate.
In this application “about” means “approximately,” and illustratively, the use of the term “about” indicates that dosages slightly outside the cited ranges may also be effective and safe, and such dosages are also encompassed by the scope of the present claims.
Compounds that are “administered together with TTX” or “in combination with TTX” may be administered as part of the same composition, or may be administered separately, at the same or at separate times, in the same therapeutic regimen.
In connection with this invention “neutral form” refers either to a non-ionic form or to a neutrally net charged form, for example a Zwitter-Ion at its isoelectric point.
The term “salt” according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound assumes an ionic form or is charged and—if applicable—is also coupled with a counter-ion (a cation or anion). By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes which are complexed via ionic interactions. As preferred examples of salts this includes the acetate, monotrifluoracetate, acetate ester salt, citrate, formate, picrate, hydrobromide, monohydrobromide, monohydrochloride or hydrochloride.
The term “physiologically acceptable salt” in the context of this invention is understood as meaning a “salt” (as defined above) of at least one of the compounds according to the invention which are physiologically tolerated by humans and/or mammals.
The term “solvate” according to this invention is to be understood as meaning any form of the active compound according to the invention which has another molecule (most likely a polar solvent) attached to it via non-covalent bonding. Examples of solvates include hydrates and alcoholates, e.g. methanolate.
The term “treatment” or “to treat” in the context of this specification means administration of a compound or formulation according to the invention to prevent, ameliorate or eliminate one or more symptoms associated with neuropathic pain, hyperalgesia and/or allodynia.
Furthermore, the terms “to treat” or “treatment” according to this invention include the treatment of symptoms of neuropathic pain, hyperalgesia and/or allodynia, the prevention or the prophylaxis of the symptoms of neuropathic pain, hyperalgesia and/or allodynia, the prevention or prophylaxis causing the symptoms of neuropathic pain, hyperalgesia and/or allodynia, as well as the prevention or the prophylaxis of the consequences causing the symptoms.
According to the various embodiments, the sodium channel blockers such as TTX or STX, their analogues/derivatives or the pharmaceutical compositions comprising them, may be administered, in unit dosage form, intestinally, enterally, parenterally or topically, orally, subcutaneously, intranasally, by inhalation, by oral absorption, intravenously, intramuscularly, percutaneously, intraperitoneally, rectally, intravaginally, transdermally, sublingually, buccally, orally transmucosally. Administrative dosage forms may include the following: tablets, capsules, dragees, lozenges, patches, pastilles, gels, pastes, drops, aerosols, pills, powders, liquors, suspensions, emulsions, granules, ointments, creams, suppositories, freeze-dried injections, injectable compositions, in food supplements, nutritional and food bars, syrups, drinks, liquids, cordials etc, which could be regular preparation, delayed-released preparation, controlled-released preparation and various micro-granule delivery system, in food supplements, nutritional and food bars, syrups, drinks, liquids, cordials. In case of tablet, various carriers known in the art may be used, e.g. dilutent and resorbent such as starch, dextrin, calcium sulfate, kaolin, microcrystalline cellulose, aluminium silicate, etc; wetting agent and adhesives such as water, glycerin, polyethylene glycol, ethanol, propanol, starch mucilage, dextrin, syrup, honey, glucose solution, acacia, gelatin, carboxymethylcellulose sodium, shellac, methylcellulose, potassium phosphate, polyvinylpyrolidone, etc; disintegrating agent, such as dried starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol aliphatic ester, lauryl sodium sulfate, methylcellulose, ethylcellulose, lactose, sucrose, maltose, mannitol, fructose, various disaccharides and polysaccharides etc; disintegration inhibiting agent, such as sucrose, tristearin, cacao butter, hydrogenated oil, etc; absorption accelerator, such as quaternary ammonium salt, lauryl sodium sulfate, etc; lubricant, with as talc, silica, corn starch, stearate, boric acid, fluid wax, polyethylene, etc. The tablet may be further formulated into coated tablet, e.g. sugar-coated tablet, film-coated tablet, enteric-coated tablet, or double-layer tablet and multi-layer tablet. In the case of pill, various carriers known in the art may be used, e.g. dilutent and resorbent, such as glucose, lactose, starch, cacao better, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc; adhesives, such as acacia, bassora gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc; disintegrating agent, such as agar powder, dried starch, alginate, lauryl sodium sulfate, methylcellulose, ethylcellulose. In case of suppository, various carriers known in the art may be used, e.g. polyethylene, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride, etc. In the case of capsule, it may be prepared by mixing said sodium channel blockers as active ingredient with the above mentioned carriers, followed by placing the mixture into a hard gelatin capsule or soft capsule.
Also, said sodium channel blockers may he applied in the following dosage forms; microcapsules, suspension in an aqueous phase, hard capsule, or injection. In the case of injection, such as liquor, emulsion, freeze-dried injection, and suspension, all the dilutents common in the art may be used, e.g. water, ethanol, polyethylene glycol, propylene glycol, oxyethylated isostearyl alcohol, polyoxidated isostearyl alcohol, polyoxyethylene sorbitol aliphatic ester, etc. In addition, in order to obtain isotonic injection, a suitable amount of sodium chloride, glucose or glycerin may be added into the preparation, as well as regular cosolvent, buffer, pH adjusting agent, etc. In addition, coloring agent, antiseptic, perfume, correctives, food sweetening agent or other materials may be added to the pharmaceutical preparation if necessary.
In certain embodiments a formulation or pharmaceutical composition according to the invention contains the active ingredient (TTX, its derivatives and/or its analogues) as well as optionally at least one auxiliary material and/or additive and/or optionally another active ingredient.
In certain embodiments the auxiliary material and/or additive can be specifically selected from conserving agents, emulsifiers and/or carriers for parenteral application. The selection of these auxiliary materials and/or additives and of the amounts to be used depends upon how the pharmaceutical composition is to be applied. Examples include here especially parenteral like intravenous subcutaneous or intramuscular application formulations but which could also be used for other administration routes.
In certain embodiments routes of administration of tetrodotoxin its derivatives and its analogues can include intramuscular injection, intraveneous injection, subcutaneous injection, sublingual, bucal, patch through skin, oral ingestion, implantable osmotic pump, collagen implants, aerosols or suppository.
In alternative embodiments the sodium channel blockers such as TTX or STX, their analogues/derivatives may be administered in a schedule of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more doses per day, alone or in combination with other medications, over range of time periods including but not limited to periods of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, or more days; or over a period of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, thirty six, forty eight, sixty, seventy two, eighty four or more months.
In particular embodiments the sodium channel blockers such as TTX or STX, their analogues/derivatives may be a voltage-gated sodium channel blocker and may bind to a SS1 or SS2 a subunit of a sodium channel. The maximum daily dose of sodium channel blocker may be up to about 10 μg, up to about 50 μg, up to about 100 μg, up to about 144 μg, up to about 150 μg, up to about 300 μg, tip to about 500 μg, up to about 750 μg, up to about 1000 μg, up to about 1250 μg, up to about 1500 μg, up to about 1750 μg, up to about 2000 μg or more. In particular embodiments the sodium channel blocker may be administered in an amount ranging between 5 and 4000 μg/day, or in ranges between 10 and 2000 μg/day, 10 and 1000 μg a day, 10 and 750 μg a day, 10 and 500 μg a day, 10 and 400 μg a day, 10 and 300 μg a day, 10 and 200 μg a day, or 10 and 100 μg/day.
In particular embodiments the daily applied dose may be from about 10 to about 160 μg, about 10 to about 140 μg, about 10 to about 120 μg, about 10 to about 100 μg, about 10 to about 90 μg, about 10 to about 80 μg, about 10 to about 70 μg, about 10 to about 60 μg, about 10 to about 50 μg, about 10 to about 40 μg, about 10 to about 30 μg, or 1 to 20 μg. In other embodiments the daily dosage of the sodium channel blacker may be about 0.1 to about 40 μg per kilogram of body weight, about 1 to about 35 μg per kilogram of body weight, about 5 to about 30 μg per kilogram of body weight, about 10 to about 30 μg per kilogram of body weight, about 15 to about 30 μg per kilogram of body weight, about 10 to about 35 μg per kilogram of body weight, or about 20 to about 40 μg per kilogram of body weight. The unit dose may be within a range of about 5 μg to about 2000 μg and may be about 5 to about 10 μg, about 10 to about 15 μg, about 15 to about 20 μg, about 20 to about 25 μg, about 25 to about 30 μg, about 30 to about 40 μg, about 40 μg to about 50 μg, about 50 μg to about 75 μg, about 75 to about100 μg, about 100 to about 150 μg, about 150 to about 200 μg, about 200 to about 250 μg, about 250 to about 500 μg, about 500 to about 1000 μg, about 1000 to about 1500 μg or about 1500 to about 2000 μg or more than 2000 μg.
In some embodiments the dose administered is between 10 and 4000 μg/day of tetrodotoxin, its derivatives or its analogues, especially the dose of tetrodotoxin administered is normally between 10 and 4000 μg/day or—given the likely twice per day treatment—between 5 to 2000 μg each given dose, sometimes preferably between 250 and 1000 μg each given dose, sometimes preferably between 25 and 50 μg each given dose depending on the route of administration.
In some embodiments the effectiveness of a course of treatment of one, two, three. four, five or more doses or one, two or three days may last for up to about five, ten, fifteen, twenty, twenty five or thirty. In some embodiments dosing is only performed once every day or once every two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty or more days.
According to the present disclosure, the dosage of said sodium channel blocker such as TTX or STX, their analogues/derivatives, depends on a variety of factors, including the nature and severity of the diseases, the sex, age, weight and individual reaction of the subject, the particular compound employed, the route and frequency of administration, etc. Said sodium channel blockers such as TTX or STX, their analogues/derivatives or the pharmaceutical compositions comprising them may be administered in single or divided dosage form, e.g. one to four doses per day. Those skilled in the art will readily understand and implement the changes to the treatment methods exemplified herein that are necessary or desirable to reflect varied therapeutic requirements.
A substance named as an “active ingredient” will have a purity of at least 97%. For example, a formulation said to have “500 μg of TTX as the active ingredient” may contain as much as 15 μg of anhydrotetrodotoxin as an impurity. On the other hand, a formulation said to have “500 μg of TTX and 500 μg of anhydrotetrodotoxin as active ingredients” will contain at least 485 μg of TTX and 485 μg of anhydrotetrodotoxin, but may contain as much as 30 μg of other substances as impurities of the active ingredients. Of course, substances named as other components of a formulation are not included when the purity of the active ingredient is considered.
In a highly preferred embodiment of the use according to the invention the neuropathic pain is peripheral neuropathic pain or peripheral neurogenic pain.
According to the IASP “peripheral neuropathic pain” is defined as “a pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system” and “peripheral neurogenic pain” is defined as “a pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral nervous system” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 213).
In another preferred embodiment of the use according to the invention the neuropathic pain is allodynia.
According to the IASP “allodynia” is defined as “a pain due to a stimulus which does not normally provoke pain” (IASP, Classification of chronic pain, 2nd Edition, (IASP Press (2002), 210).
In another preferred embodiment of the use according to the invention the neuropathic pain is causalgia,
According to the IASP “causalgia” is defined as “a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210).
In another preferred embodiment of the use according to the invention the neuropathic pain is hyperalgesia.
According to the IASP “hyperalgesia” is defined as “an increased response to a stimulus which is normally painful (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 211).
In another preferred embodiment of the use according to the invention the neuropathic pain is hyperesthesia.
According to the IASP “hyperesthesia” is defined as “increased sensitivity to stimulation, excluding the senses” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 211).
In another preferred embodiment of the use according to the invention the neuropathic pain is hyperpathia.
According to the IASP “hyperpathia” is defined as “a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212).
The IASP draws the following difference between “allodynia’, “hyperalgesia” and “hyperpathia” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212);
In another preferred embodiment of the use according to the invention the neuropathic pain is neuralgia.
According to the IASP “neuralgia” is defined as “Pain in the distribution of a nerve or nerves” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212).
In another preferred embodiment of the use according to the invention the neuropathic pain is neuritis.
According to the IASP “neuritis” is defined as “inflammation of a nerve or nerves” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212).
In another preferred embodiment of the use according to the invention the neuropathic pain is neuropathy/neuritis.
According to the IASP “neuritis” is defined as “a disturbance of function or pathological change in a nerve: in one nerve mononeuropathy, in several nerves mononeuropathy multiplex, if diffuse and bilateral, polyneuropathy” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212).
In another preferred embodiment of the use according to the invention the neuropathic pain is orofacial pain.
Another aspect of the present invention relates to the use of sodium channel blockers such as TTX or STX, its analogues/derivatives, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers. In any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate for the production of a medicament for the treatment of allodynia developing as a consequence of Chemotherapy.
Another aspect of the present invention relates to the use of sodium channel blockers such as TTX or STX, its analogues/derivatives, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate for the production of a medicament for the treatment of hyperalgesia developing as a consequence of chemotherapy.
In a highly preferred embodiment of the invention the use according to the invention tetrodotoxin, its derivative and/or one of its analogues is used in an amount between 10 μg/day and 4 mg/day.
In a highly preferred embodiment of the invention the use according to the invention the used tetrodotoxin, its derivative or its analogue is isolated from a biological source, preferably from fish, especially puffer fish.
In a highly preferred embodiment of the invention the use according to the invention the used tetrodotoxin, its derivative or its analogue is synthesized/synthetic.
In a highly preferred embodiment of the invention at least one chemotherapeutic agent used in the chemotherapy is selected from a platin-derivative, a vinca alkaloid or a taxane.
In a highly preferred embodiment of the invention at least one chemotherapeutic agent used in the chemotherapy is selected from the group consisting of cisplatin, carboplatin and oxaliplatin; vincristine, vinblastine, vinorelbine and vindesine; paclitaxel and docetaxel.
Preferably at least one chemotherapeutic agent used in the chemotherapy is cisplatin.
Preferably at least one chemotherapeutic agent used in the chemotherapy is carboplatin.
Preferably at least one chemotherapeutic agent used in the chemotherapy is oxaliplatin.
Preferably at least one chemotherapeutic agent used in the chemotherapy is vincristine.
Preferably at least one chemotherapeutic agent used in the chemotherapy is vinblastine.
Preferably at least one chemotherapeutic agent used in the chemotherapy is vinorelbine.
Preferably at least one chemotherapeutic agent used in the chemotherapy is vindesine.
Preferably at least one chemotherapeutic agent used in the chemotherapy is paclitaxel.
Preferably at least one chemotherapeutic agent used in the chemotherapy is docetaxel.
Included in this invention are especially also methods of treatment of a patient or a mammal, including men, suffering from neuropathic pain developing as a consequence of Chemotherapy using a sodium channel blocker such as tetrodotoxin or saxitoxin and/or one of its analogues or derivatives optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate. It is also preferred if the method of treatment is restricted to tetrodotoxin, and/or one of its analogues or derivatives, especially if it is restricted to tetrodotoxin, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate. It is also preferred if the method of treatment is restricted to tetrodotoxin, in neutral form or as a salt, especially a physiologically acceptable salt, whereas preferably tetrodotoxin, its derivative and/or one of its analogues is used in an amount between 10 μg/day and 4 mg/day, is isolated from a biological source, preferably from fish, especially puffer fish, or is synthesized. It is also preferred if the method of treatment is restricted to embodiments in which at least one chemotherapeutic agent used in the chemotherapy is selected from a platin-derivative, a vinca alkaloid or a taxane; especially if at least one chemotherapeutic agent used in the chemotherapy is selected from the group consisting of cisplatin, carboplatin and oxaliplatin; vincristine, vinblastine, vinorelbine and vindesine; paclitaxel and docetaxel.
Especially the above method of treatment includes also a co-treatment during chemotherapy, in which the chemotherapeutic drug/drugs are administered together with the sodium channel blocker such as tetrodotoxin or saxitoxin and/or one of its analogues or derivatives, especially TTX or in combination with sodium channel blocker such as tetrodotoxin or saxitoxin and/or one of its analogues or derivatives, especially with TTX. This co-treatment could possible happen during the whole chemotherapy, during parts of the chemotherapy, in the beginning of the chemotherapy, in the middle of the chemotherapy or at the end of the chemotherapy.
Another alternative embodiment of the present invention refers to a kit comprising TTX and/or one of its analogues or derivatives, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers; preferably in any suitable ratio; in neutral form in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate.
Another aspect of the invention is an active substance combination comprising
Another alternative embodiment of this invention is an active substance combination, wherein the sodium channel blocker (A) is selected from saxitoxin, its analogues and/or its derivatives; and/or tetrodotoxin, its analogues and/or its derivatives, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate;
Another alternative embodiment of this invention is an active substance combination, wherein the chemotherapeutic drug (B) is selected from a platin-derivative, a vinca alkaloid or a taxane, especially the chemotherapeutic drug (B) is selected from cisplatin, carboplatin and oxaliplatin; vincristine, vinblastine, vinorelbine and vindesine; paclitaxel and docetaxel.
Another alternative embodiment of this invention is an active substance combination, wherein the sodium channel blocker (A) is selected from saxitoxin, its analogues and/or its derivatives; and/or tetrodotoxin, its analogues and/or its derivatives, optionally in the form of as racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate:
Another highly preferred alternative embodiment of this invention is an active substance combination, wherein the sodium channel blocker (A) is tetrodotoxin, and the chemotherapeutic drug (B) is selected from cisplatin, carboplatin and oxaliplatin; vincristine, vinblastine, vinorelbine and vindesine: paclitaxel and docetaxel,
Another highly preferred alternative embodiment of this invention is an active substance combination, of tetrodotoxin and cisplatin.
Another highly preferred alternative embodiment of this invention is an active substance combination, of tetrodotoxin and carboplatin.
Another highly preferred alternative embodiment of this invention is an active substance combination, of tetrodotoxin and oxaliplatin.
Another highly preferred alternative embodiment of this invention is an active substance combination, of tetrodotoxin and vincristine.
Another highly preferred alternative embodiment of this invention is an active substance combination, of tetrodotoxin and vinblastine.
Another highly preferred alternative embodiment of this invention is an active substance combination, of tetrodotoxin and vinorelbine.
Another highly preferred alternative embodiment of this invention is an active substance combination, of tetrodotoxin and vindesine.
Another highly preferred alternative embodiment of this invention is an active substance combination, of tetrodotoxin and paclitaxel.
Another highly preferred alternative embodiment of this invention is an active substance combination, of tetrodotoxin and docetaxel.
Another highly preferred aspect of the invention is the use of a sodium channel blocker and/or its derivatives, such as TTX or STX, its analogues/derivatives, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate for the production of a medicament for the treatment of orofacial pain, preferably in the form of neuropathic pain, hyperalgesia or allodynia, more preferably in the form of neuropathic pain, hyperalgesia or allodynia, developing as a consequence of chemotherapy.
The orofacial region, the face and mouth, represent sites of some of the most common pains in the body. Epidemiological studies have revealed the high prevalence of several orofacial pain conditions such as temporomandibular disorders (TMD), burning mouth syndrome, and toothaches, (Dworkin, 2001; Feinman and Newton-John, 2004; LeResche, 2001; Lipton et al., 2001). Many of the difficulties experienced by clinicians with the management of acute and chronic orofacial pain conditions stem from a lack of recognition and understanding of their complex factors and interactions, from uncertainties of the aetiology or pathogenesis of many of the conditions, as well as from the lack of information of the comparative effectiveness of the analgesic drugs on orofacial pain.
The examples and figures in the following section describing pharmacological trials are merely illustrative and the invention cannot he considered in any way as being restricted to these applications.
Pharmacological Experiments
Experimental Group 1
Recently, models of paclitaxel-induced painful neuropathy have been developed in mice and rats. These models demonstrated that repeated administration of paclitaxel produced mechanical hyperalgesia and allodynla (Authler et al., 2000; Polomano et al., 2001; Dina et al., 2001 y 2004; Smith et al., 2004; Flatters y Bennett, 2004), cold allodynia (Polomano et al., 2001; Smith et al., 2004; Flatters y Bennett, 2004) and in some studies a thermal (warm) hyperalgesia (Polomano et al., 2001; Dina et al., 2001; Flatters y Bennett, 2004); however, other studies did not find this thermal hyperalgesia (Authier at al., 2000; Smith et al., 2004). Therefore, paclitaxel-induced painful neuropathy in rodents represents an interesting model to test the effects of drugs in neuropathic pain.
Methods:
In General:
Experiments were performed in CD-1 mice (Charles River, S.A) with n=10/experimental group.
Paclitaxel-induced painful peripheral neuropathy was produced by i.p. administration of paclitaxel once daily during two weeks as previously described (Dina et al., 2001), control animals received the same volume of solvent (a mixture of ethanol and erernophor EL)
Mechanical hyperalgesia and allodynia was evaluated with Von Frey filaments and a Randall-Sellito paw-pressure analgesymeter (Dina et al., 2001; Flatters and Bennet, 2004), cold allodynia was evaluated using the acetone drop method (Polomano et al., 2001; Smith et al., 2004), whereas thermal hyperalgesia was measured with the Hargreaves method (Dina et al., 2001; Polomano et al., 2001).
TTX exerted clear analgesic effects in this model of neuropathic pain.
TTX was injected s.c. immediately before each paclitaxel injection to test whether TTX affect the development of the painful peripheral neuropathy or in the third week (when paclitaxel injection have ended and the neuropathy is fully developed) to test whether TTX interferes with the expression of the different signs of paclitaxel-induced neuropathic pain.
Specific Description:
Animals. Female CD-1 mice weighing 25-30 g were used. The animals were housed in colony cages with free access to food and water prior to the experiments. They were maintained in temperature- and light-controlled rooms (22±1° C., lights on at 08.00 h and off at 20.00 h, air replacement every 20 min). Testing took place during the light phase (from 9.00 h to 15.00 h).
Paclitaxel was dissolved in a solution made up of 50% Cremophor EL and 50% absolute ethanol to obtain a concentration of 6 mg/ml. This paclitaxel solution was conserved at −20° C. during a maximum of 14 days and was diluted in normal saline (NaCl 0.9%), just before administration, to a final concentration of 2 mg/10 ml. The vehicle of paclitaxel was diluted at the time of injection with saline (NaCl 0.9%) in the same proportion as the paclitaxel solution.
Paclitaxel (2 mg/kg) was administered intraperitoneously (i.p.), in a volume of 10 ml/kg, once per day for five consecutive days. Therefore, the cumulative dose was 10 mg/kg per mouse. In the control group the vehicle of paclitaxel was administered following the same schedule.
TTX base solution (concentration of 15 μg/ml), was diluted in normal saline just before administration to final concentrations of 3 and 6 μg/5 ml. The injection of TTX (3 or 6 μg/kg) or its solvent (normal saline) was administered subcutaneously (s.c.) in the interscapular area, using an injection volume of 5 ml/kg.
The effects of s.c. TTX on paclitaxel-induced neuropathic pain were examined in two different ways. To evaluate the effect of TTX on the development of paclitaxel-induced pain, the animals received firstly a s.c. infection of TTX 30 min before each i.p, injection of paclitaxel for five consecutive days. Posteriorly the response of the animals to the different nociceptive stimuli was tested during 2-4 weeks, depending on the test (see below), without any additional treatment. Each animal was tested only in one nociceptive model. To test the effect of TTX on the expression of paclitaxel-induced pain a single TTX injection was performed the day of maximum expression of thermal hyperalgesia (day 7 from the beginning of paclitaxel administration), mechanical allodynia (day 10) or cold allodynia (day 14) (sea results for details). Each animal received only one dose of TTX and was tested in only one nociceptive model.
Procedure for assessment of heat hyperalgesia. Thermal hyperalgesia was assessed by the following method; Mice were habituated in individual Plexiglas chambers (7×7×22 cm), placed atop a glass floor, during two hours. During this time, mice initially exhibited exploratory behaviour but subsequently stopped exploring and stood quietly with occasional bouts of grooming. After habituation, a beam of radiant heat was focused to the plantar surface of the hind paws, using a plantar test apparatus (Ugo Basile, Comerio, Italy), until the mouse made a withdrawal response. The nocifensive withdrawal reflex interrupts the light reflected from the paw onto a photocell and automatically turns off the light and a timer. Therefore, the latency to withdrawal value (that indirectly indicated the heat-pain threshold) was automatically recorded. The intensity of the light was adjusted at the start of the experiments such that average baseline latencies were about 8 s. This intensity was never changed. Each mouse was tested three times alternately on each hind paw and the latencies for both paws were averaged together in each measurement time, At least, one minute was allowed between consecutive same paw attempts. A cut-off latency time of 16 seconds was imposed in each measurement in order to avoid lesions to the skin and unnecessary suffering to the animals,
To elucidate the time-course of paclitaxel-induced heat hyperalgesia in control mice, pretreatment baseline latencies were obtained three days before drug treatment. Then, animals were treated with paclitaxel or its vehicle once daily during 5 days. Postreatment latencies were assessed on days 7, 10, 14 and 17 after the first injection of paclitaxel. When the effect of TTX on the development of paclitaxel-induced heat hyperalgesia was tested, the procedure was the same except that TTX or its solvent was s.c. injected 30 min before each daily dose of paclitaxel or its vehicle (i.p.) during the 5 days of treatment. The effect of TTX on the expression of paclitaxel-induced heat-hyperalgesia was tested on day 7 after the first injection of paclitaxel, since the maximum heat hyperalgesia was observed that day. Therefore, on day 7, after the habituation period to the apparatus, baseline latencies were recorded and immediately later TTX or its solvent was injected s.c., paw withdrawal latencies were assessed again 30, 60, 90, 120 and 180 minutes after the injection. Around 9% of the animals treated with paclitaxel did not developed thermal hyperalgesia the day 7 after paclitaxel-treatment. These animals were not used to evaluated the effect of TTX on the expression of paclitaxel-induced thermal hyperalgesia.
Procedure for assessment of cold allodynia. Cold allodynia was tested as previously described by Smith et al., 2004. by gently touching the plantar skin of the hind paws with an acetone bubble formed with a syringe connected to a thin polyethylene tube. The mice were housed and habituated for 30 min in transparent plastic boxes (7×7×13 cm) with a floor made of wire mesh. After the adaptation period, acetone was applied alternately three times to each paw at intervals of 30 s, and the duration and frequency of licking or biting were recorded. A small mirror was placed behind the chambers to allow clear observation of the paws. The time spent licking or biting the paw was recorded by a stopwatch and represented as the cumulative time of licking/biting in the six measurements. Since in the experiments licking persisting more than 10 s was very unusual, a cut-off time of 10 s was used to each trial. The frequency of licking/biting was expressed as a percentage, and calculated with the following formula: (number of trials accompanied by licking or biting/total number of trials)×100.
To elucidate the time-course of paclitaxel-induced cold allodynia in control mice, the animals were tested previously to paclitaxel administration (pretreatment value) and on different days (days 7, 10, 14, 17, 21 and 24) after the first paclitaxel or vehicle injection. The same procedure was followed to test the effect of TTX on the development of cold allodynia, but in this case, TTX or its solvent was s.c. injected 30 min before each of the 5 paclitaxel i.p. injections. Because the maximum allodynia effect induced by paclitaxel was observed on days 10-14 after its first injection, the effects of TTX on the expression of cold allodynia was assessed on day 14. This day, once baseline response to acetone was recorded the animals received an s.c. injection of TTX or its solvent, and the response to acetone was recorded again at 60, 120 and 180 min after the injection. Around 33% of the control animals treated with paclitaxel did not show cold allodynia; therefore, it was differentiated between ‘responders’ and ‘non-responders’ mice in this test. The ‘non-responders’ mice were easily identified because they spent less than 2 s licking/biting the paw stimulated with acetone on days 7 and 10 after paclitaxel administration. The ‘non-responder’ animals were not used to test the effect of TTX on the expression of cold allodynia since they do not express enough cold allodynia.
Procedure for assessment of mechanical allodynia. To assess mechanical allodynia, paw withdrawal thresholds were measured using a Dynamic Plantar Aesthesiometer (Ugo Basile, Italy). The electronic Von Frey device employs a single nonflexible filament which applies a progressively increasing force (from 0 to 10 g) against the plantar surface of the hind paw over a 20 s period. The nocifensive withdrawal reflex automatically turns off the stimulus and the mechanical threshold value is showed in a screen. The day of the experiment, mice were placed individually in test compartments (9×9×14 cm) with a wire mesh bottom and allowed to acclimatize to them for 2 h. After habituation, each mouse was tested three times alternately in each hind paw.
To elucidate the time-course of paclitaxel-induced mechanical allodynia in control mice, the animals were tested previously to paclitaxel administration (pretreatment value) and on different days (days 7, 10, 14 and 17) after the first paclitaxel or vehicle injection. The same procedure was followed to test the effect of TTX on the development of paclitaxel-induced mechanical allodynia, except that TTX or its solvent was s.c. injected 30 min before each daily dose of paclitaxel or its vehicle (i.p.) during the 5 days of treatment. The effect of TTX on the expression of paclitaxel-induced mechanical allodynia was evaluated on day 10, because the maximum change of the mechanical threshold was observed on that day. Therefore, the day 10, after the habituation period to the apparatus, baseline latencies were recorded, subsequently TTX or its solvent was injected s.c. and paw withdrawal latencies were assessed again 30, 60, 90, 120 and 180 minutes after the injection. Most animals (96%) treated with paclitaxel showed a reduction of the mechanical threshold; those animals that did not show mechanical allodynia were not used to test the effect of TTX on the expression of paclitaxel-induced mechanical allodynia.
Results
Time-course of paclitaxel-induced thermal hyperalgesia, cold- and mechanical-allodynia in control mice. The values obtained on the pre-treatment day in paclitaxel- and vehicle-treated animals were not significantly different in plantar test (
In the acetone test, administration of paclitaxel (2 mg/kg, i.p,) once daily during 5 days permit to distinguish two groups of animals depending on their response. Most animals (67%) treated with paclitaxel significantly (p<0,01) increased the time spent licking/biting the paw stimulated (
Administration of paclitaxel (2 mg/kg, i.p., during 5 days) induced mechanical allodynia in mice, since it significantly reduced the threshold force for paw withdrawal in the Von Frey test on day 10, in comparison both with the pre-treatment day value and with the value obtained the same day in the paclitaxel-vehicle treated animals (
Effect of tetrodotoxin (TTX) on the development of paclitaxel-induced thermal hyperalgesia, cold- and mechanical-allodynia. The pre-treatment values were similar in the two experimental groups (paclitaxel+saline and paclitaxel+TTX) in all test performed (plantar, acetone and Von Frey tests) (
In the plantar test, the paw withdrawal latency values were significantly lower than the pre-treatment values in both experimental groups at all lines evaluated from 7 to 17 days after the first injection of paclitaxel (
The group of animals in which paclitaxel (i.p.) and saline (s.c.) were co-administered during days 1 to 5 showed a significant increase on duration of paw licking/biting (
The paw withdrawal threshold force values (Von Frey test) in paclitaxel+saline treated animals were significantly lower than the pre-treatment values on days 10 and 14 after the first injection of paclitaxel (
Effect of tetrodotoxin (TTX) on the expression of paclitaxel-induced thermal hyperalgesia. The values of paw withdrawal latency in the plantar test, recorded on day 7, before the administration of TTX or saline (time 0), were significantly different from their values on pre-treatment day in all groups of animals that have been treated with paclitaxel (
As expected, 5 days of treatment with paclitaxel-vehicle did not significantly change the paw withdrawal latency value on day 7 (
Effect of tetrodotoxin (TTX) on the expression at paclitaxel-induced cold allodynia. The duration and the frequency of paw licking/biting on day 14, before the treatment with TTX or saline, were significantly different from their values on pre-treatment day in all groups of animals treated during 5 days with paclitaxel (
Effect of tetrodotoxin (TTX) on the expression of paclitaxel-induced mechanical allodynia. On day 10, before the administration of TTX or saline the values of threshold force in the Von Frey test were significantly lower than the values on pre-treatment day in paclitaxel-treated group (
As expected, 5 days of treatment with paclitaxel-vehicle did not significantly change the value of the threshold force for hind paw withdrawal on day 10 (
Discussion
It was found that acute administration of TTX inhibited the expression of paclitaxel induced heat-hyperalgesia, mechanical- and cold-allodynia in mice, and that repeated co-administration of TTX and paclitaxel prevented the development of both kinds of allodynia without clearly affecting heat-hyperalgesia
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Chaudhry V, Rowinsky E K, Sartorius S E, Donehower R C, Cornblath D R. Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol. 1994 March; 35(3):304-11.
Dina O A, Chen X, Reichling D, Levine J D. Role of protein kinase Cepailon and protein kinase A in a model of paclitaxel-induced painful peripheral neuropathy in the rat. Neuroscience. 2001; 108(3):507-15.
Dina O A, Parada C A, Yeh J, Chen X, McCarter G C, Levine J D. Integrin signaling in inflammatory and neuropathic pain in the rat. Eur J Neurosci. 2004 February; 19(3):634-42.
Flatters S J, Bennett G J. Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain. 2004 May; 109(1-2):150-61.
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Experimental Group 2
Recently, several new animal models have been proposed to study the mechanisms underlying the development of these neuropathies, such as continuous intravenous injection of vincristine in rats and intraperitoneal (i.p.) administration of paclitaxel (Polomano et al., 2001).
Analgesic effectiveness of TTX was tested on a model of neuropathic pain induced by paclitaxel.
Figures
Methods
Adult (200-250 g) male Wister rats (Harlari Iberica, Spain) were used in all the experiments. The animals were housed in clear plastic cages under Standard laboratory conditions: controlled temperature 23±1° C., 12/12-h light/dark cycle and free access to food and water. Spontaneous behaviour was observed in the cages before starting the experimental procedures, rats showing aggressiveness or alterations of the motility were discarded (2%). Number of animals per separated experimental group was at least 8.
Paclitaxel Induced Peripheral Neuropathy
After habituation to the test environment and baseline measurements of pain sensitivity (see below), animals were i.p. injected on four alternate days (days 1, 3, 5 and 7) with paclitaxel (1 mg/kg), using an injection volume of 1 ml/kg. The final cumulative paclitaxel dose administered was 4.0 mg/kg (Polomano et al., 2001). The vehicle was a mixture of saline and Cremophor EL 10%, a derivative of castor oil and ethylene oxide. This vehicle is used clinically for paclitaxel injections. Body weight was recorded (pre-treatment, and days 3. 5, 7, 13, 16, 18, 22, 24 and 29 after the first paclitaxel or vehicle administration) in the group of animals given paclitaxel (n=9) and in those treated with vehicle (n=9),
Behavioral Assays
Heat Hyperalgesia and Mechanical Allodynia.
The plantar surface of hind paws (sciatic nerve territory) was tested for heat-hyperalgesia and tactile-allodynia and the vibrissal zone (trigeminal nerve territory) to evaluate the effect of the administration of the different treatments.
Heat Hyperalgesia at Sciatic Nerve Territory (Hind Paw)
Heat-hyperalgesia of the hind paw was tested by measuring the latency (withdrawal time) of the hind paws from a focused beam of radiant heat applied to the plantar surface using a plantar test apparatus (Ugo Basile). Briefly, the rat was placed within a plastic compartment on a glass floor; a light source beneath the floor was aimed at the mid plantar surface of the hind paw. The withdrawal reflex interrupts the light and automatically turns off the light and a timer. The intensity of the light was adjusted at the Start of the experiment such that the control average baseline latencies were about 8 sec and a cut-off latency of 30 sec was imposed. The withdrawal latency of each paw was measured during three trials at 2 min intervals and the mean of the three readings was used for data analysis.
Tactile Allodynia at Sciatic Nerve Territory (Hind Paw)
Tactile allodynia was assessed by measuring the withdrawal threshold to calibrated von Frey hairs with intensities ranging from 0.9 to 40 g. Filaments exerting a force above 40 g were not used as they lifted the paws. On the day of the experiment animals were placed in a Perspex chamber with a mesh metal floor and allowed to acclimatize for 15 min. Starting with the lowest filament force, von Frey hairs were applied perpendicular to the mid plantar surface of both hind paws, with sufficient force to cause slight bending against the paw, and held until a response was achieved, the mechanical Stimulation was maintained for 2 seconds (maximum), this was repeated five times at an interval of 1-2 s. When the paw was sharply withdrawn, or when there was flinching upon removal of the hair, a positive response was noted; when at least 3 out of 5 responses were positive (60%), this value was accepted as tactile threshold. The process was repeated with the next higher force hair if less than 3 positive responses were noted to any hair trial.
Tactile Allodynia at Trigeminal Nerve Territory (Orofacial Region)
The effect of the paclitaxel administration in the trigeminal territory has not been previously studied. Paclitaxel was administered as previously described to test peripheral neuropathies on spinal nerves (Polomano et al., 2001).
The orofacial area was defined as the skin above the perioral (PO) skin. We measured the withdrawal threshold to calibrated von Frey hairs with intensities ranging from 0.9 to 40 g. A descending series of the filaments were used when the rat responded to the starting filament. Each filament was tested five times at an interval of a few seconds. If head withdrawal was observed at least three times after probing with a filament, the rat was considered responsive to that filament. The response threshold was defined as the lowest force of the filaments that produced at least three withdrawal responses in five tests.
Mechanical and thermal withdrawal thresholds were tested consecutively on the following groups of animals:
After these procedures (day 22 after first administration of paclitaxel) rats received 3 μg/kg s.c. Tests were carried out 30 min after i.p. or s.c. injection. Mechanical and thermal withdrawal thresholds were tested in both paws in each group in this sequence. Tactile allodynia in the orofacial were tested at the end of the experiment.
To assess if TTX was able to prevent or reduce the development of nociceptive behaviours induced by paclitaxel, another procedure of administration was followed. Rats were simultaneously treated for one week with twice daily s.c. injections of TTX (3 μg/kg) and the usual protocol of paclitaxel administration (see above). Nociceptive behaviours were tested 3 weeks later.
3.1. Paclitaxel Induced Peripheral Neuropathy
As the effect of the repeated administration of paclitaxel on nociceptive behaviour has not been previously evaluated on the trigeminal territory, the first step was to compare the development of allodynia in the perioral region with that recorded on the hind paw (sciatic territory).
To evaluate the effect of acute TTX, tactile and thermal thresholds were evaluated on days 0 (before paclitaxel), on day 21 (control of allodynia and hyperalgesia induced by paclitaxel) and on day 22 after rats were i.p. injected with the drug.
Treatment with a single dose of TTX induced a partial but significant decrease of the allodynia in the trigeminal and sciatic territories (
TTX did not significantly reduce this hyperalgesia, even though a slight tendency to do so can be seen.
Finally, the simultaneous treatment with paclitaxel and TTX was able to prevent the development of allodynia in the orofacial region and in the paw as well as the hyperalgesia in the paw (
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With the guidance provided herein, once the required parameters of a composition or method are known, those skilled in the art will be readily able to determine the amounts and proportions of active components and other components required to manufacture a required dosage form, manufacture a kit or composition, or use the methods and compositions disclosed. The foregoing embodiments have been described in detail by way of illustration and example for purposes of clarity and understanding. As is readily apparent to one skilled in the art, the foregoing are only some of the methods and compositions that illustrate the possible embodiments. It will be apparent to those of ordinary skill in the art that a range of equivalents. variations, changes, modifications and alterations may be applied to the compositions and methods described herein without departing from the true spirit, concept and scope of the invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 06384006.0 | Mar 2006 | EP | regional |
| 06025476.0 | Dec 2006 | EP | regional |
This is a continuation of U.S. application Ser. No. 12/294,843, filed Jun. 30, 2009, which national phase under 35 U.S.C., 371 of International Application Number PCT/EP2007/002662, filed internationally on Mar. 26, 2007 which claims the benefit of European Application Number 06384006.0, filed Mar. 27, 2006 and European Application Number 06025476.0, filed Dec. 8, 2006. The related applications are hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16264155 | Jan 2019 | US |
| Child | 16786789 | US | |
| Parent | 14688489 | Apr 2015 | US |
| Child | 16264155 | US | |
| Parent | 12294843 | Jun 2009 | US |
| Child | 14688489 | US |
