N,n-BIS-2-mercaptoethyl isophthalamide for use in the treatment of pain

Abstract

There is provided the compound N,N-bis-2-mercaptoethyl isophthalamide (NBMI), or a pharmaceutically-acceptable salt and / or derivative thereof, for use in the treatment of pain.

Description

[0001]NEW USE OF N,N-BIS-2-MERCAPTOETHYL ISOPHTHALAMIDE Field of the Invention The present invention relates to new medical uses of the compound N,N-bis-2- mercaptoethyl isophthalamide (NBMI) and pharmaceutically acceptable salts and / or derivatives thereof. In particular, the invention relates to the use of such compounds in treating pain. Background of the Invention The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. Many analgesic (pain-relieving) treatments such as ibuprofen inhibit the activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and thereby the synthesis of prostaglandins and thromboxanes. It is thought that such drugs, labelled NSAIDs, inhibit COX-2, leading to antiinflammatory, analgesic and antipyretic effects. However, those NSAIDs also inhibiting COX-1 may cause gastrointestinal bleeding and ulcers. Although targeting selectively COX-2 is thought to reduce the risk of peptic ulceration, and several such inhibitors have been approved for for use in the treatment of pain / inflammation, data from subsequent clinical trials have revealed that they are linked to a significant increase in heart attack and stroke. For example, the drug rofecoxib was withdrawn from the market in 2004 because of these concerns, and the drug celecoxib and traditional NSAIDs received boxed warnings on their labels. Given this, there is a significant clinically-unmet need for the development of novel and effective alternative therapies for the treatment of pain (and inflammation). N,N-bis-2-mercaptoethyl isophthalamide (NBMI) was first disclosed in a patent application granted as US patent number US 6,586,600 B2. Its use as a dietary supplement is disclosed in US patent application 2010 / 0227812, and it is also known to be a chelator of heavy metals, such as mercury, cadmium and lead. Analogues of NBMI have been disclosed in, inter alia, granted US patent US 8,426,368 B2, and international patent applications WO 2011 / 038385 and WO 2012 / 121798. However, there has been no teaching or suggestion relating to the potential use of NBMI or derivatives thereof in the treatment of pain. Description of the Invention We have now surprisingly found that administration of NBMI reduces the expression of prostaglandins following exposure to lipopolysaccharide (LPS, a component of the bacterial wall of gram-positive bacteria). In particular, NBMI has been shown in vitro to reduce prostaglandin F1 (PGF1) levels to a greater extent than ibuprofen, a common NSAID. These findings may render NBMI of potential use in the treatment of pain. According to a first aspect of the invention there is provided NBMI, or a pharmaceutically- acceptable salt and / or derivative thereof, for use in the treatment of pain. Unless specified otherwise, NBMI and pharmaceutically-acceptable salts and / or derivatives thereof may be referred to herein as “compounds of the invention”. In an alternative aspect of the invention there is provided the use of NBMI or a pharmaceutically-acceptable salt and / or derivative thereof, in the manufacture of a medicament for the treatment of pain. In a further aspect of the invention there is provided a method for the treatment of pain, which method comprises the administration of an effective amount of NBMI or a pharmaceutically-acceptable salt and / or derivative thereof, to a patient in need of such treatment. Unless indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Particular features and embodiments described in relation to a given aspect of the invention should, unless the context indicates otherwise, be regarded as having been disclosed in combination with any and all other particular features and embodiments of that aspect of the invention. For the avoidance of doubt, the compound NBMI as described herein may also be referred to by the trade name Irminix® or by the international non-proprietary name (INN) Emeramide. The structure of the compound (in non-salt form) is represented below. Pharmaceutically acceptable salts as referred to within the scope of the present invention include acid addition salts and base addition salts. Such salts may be formed by conventional means; for example, by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. under reduced pressure, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example, using a suitable ion exchange resin. Particular acid addition salts that may be mentioned include carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxy-benzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulphonate salts (e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxy-ethanesulphonate, 1- or 2- naphthalene-sulphonate or 1,5-naphthalenedisulphonate salts) or sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like. Particular base addition salts that may be mentioned include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts. Particular pharmaceutically-acceptable salts that may be mentioned include base addition salts, such as those formed with alkali metals (e.g. salts formed with Na or K). The skilled person will understand that references to pharmaceutically-acceptable derivatives of NBMI will include compounds formed by derivatisation of NBMI following procedures known to those skilled in the art, such as through modification of one or more of the -NH- and / or -SH moieties therein. For example, references to such derivatives may include derivatisation of -NH- moieties through alkylation thereof (e.g. to form an -NR1- moiety, wherein R1represents C1-3alkyl optionally substituted with one or more fluoro group, such as wherein R1represents methyl) and / or derivatisation of -SH moieties through alkylation thereof (e.g. to form an -SR2moiety, wherein R2represents C1-3alkyl optionally substituted with one or more fluoro group, such as wherein R2represents methyl) or esterification thereof (e.g. to form an -SC(O)R3moiety, wherein R3represents C1-3alkyl optionally substituted with one or more fluoro group, such as wherein R3represents methyl, or another moiety resulting from reaction of a pharmaceutically- acceptable compound capable of forming such thioesters, such as a pharmaceutically- acceptable carboxylic acid or ester). Particular pharmaceutically-acceptable derivatives of NBMI that may be mentioned include glutathione, cysteine, alphadihydrolipoic acid, cystamine, thiolphosphate, 5'- thioladenosine, L-homocysteine, co-enzyme A, 2-mercaptoethanol, dithiothreitol, iodoacetate, bromoacetate, fluoroacetate and chloroacetate derivatives. Such derivatives may be prepared by analogy to the procedures described in, for example, US patent application 2011 / 0237776, the contents of which are hereby incorporated by reference. For the avoidance of doubt, references to “N,N-bis-2-mercaptoethyl isophthalamide (NBMI), or a pharmaceutically-acceptable salt and / or derivative thereof” will indicate that NBMI may be present in the form of a pharmaceutically-acceptable salt thereof, a pharmaceutically-acceptable derivative thereof, or a pharmaceutically-acceptable salt of a pharmaceutically-acceptable derivative thereof. Particular compounds of the invention that may be mentioned include NBMI and pharmaceutically-acceptable salts thereof. More particular compounds of the invention that may be mentioned include NBMI. For the avoidance of doubt, compounds of the invention may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof. Where compounds of the invention exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention. Compounds of the invention may also exist in solution. The present invention also embraces isotopically-labelled compounds of the invention, which are identical, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, references to the compounds of the invention also includes deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium. Compounds of the invention are hereby indicated for use in the treatment of pain. The skilled person will understand that references herein to the “treatment” of a condition (or, similarly, to “treating” that condition) take their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition. Although the term treatment may also refer herein to “prevention” of a particular condition (and, similarly, to “preventing”, or “prophylaxis” of, that condition), all of which also take their normal meanings in the art (i.e. achieving a reduction in the likelihood of developing the relevant condition or symptoms associated with the relevant condition), compounds of the invention are preferably indicated in the therapeutic treatment of pain, by which we mean the direct therapeutic treatment of the pain itself, that is the relief of pre-existing pain, irrespective of the cause, rather than the treatment of an underlying disease or condition, whether mentioned herein or otherwise, in which pain is a potential symptom. The treatments are thus unrelated to, and are independent of, any non-symptomatic, preventative, therapeutic, palliative and / or curative treatment of any underlying disease or condition, whether mentioned herein or otherwise. In all of the above situations, pain may either idiopathic, that is, it is has no discernible or diagnosed cause; it is a known symptom of an underlying pre-diagnosed, or as yet undiagnosed, condition; or it is provoked by something external, such a taking a medication or agent in which pain is known to be a side-effect. Treatment of pain may be characterized by, for example, a reduction of at least 10% when compared to a baseline level, such as a reduction of at least 20% or, more particularly, a reduction of at least 30%. Such an effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of, or feels, an effect). Typically, subjective measurements of pain are conducted using numeric rating scales (NRSs) and / or visual analogue scales (VASs). Pain may thus be acute (intense and / or short-lived), which may be an indicative of an injury and / or inflammation, or chronic, or longer-lasting, mild, moderate or severe. Pain may thus be nociceptive (in which specific pain receptors are stimulated) or non-nociceptive. Nociceptive pain includes somatic pain (felt on specific organs, such as the musculo- skeletal system, joints, etc) and visceral pain, which is felt in internal organs and body cavities (thorax, abdomen or the pelvis area). Nociceptive pain may result from inflammation, irrespective of the cause (injury, underlying disease such as cancer, tissue damage resulting from operative procedures, or ischemia), and includes cramping sensations and various types of back pain and referred pain. Non-nociceptive pain is generally not associated with specific pain receptors and includes neuropathic (nerve) pain (resulting from e.g. pinched or trapped nerves, or torn or slipped discs, or resulting from nerve degeneration, which may be caused by a disease such as stroke or multiple sclerosis, by an infection (e.g. shingles), or by oxygen starvation), and sympathetic pain, which generally occurs generally after a fracture or a soft tissue injury. Treatment of all types of pain are envisaged by way of the present invention. Specific pain types that be mentioned include inflammatory pain (i.e. is pain associated with inflammation, such as pain mediated by prostaglandin (e.g. PGE) expression (prostaglandin-mediated pain, and rheumatic pain)). There is thus described and provided herein NBMI, or a pharmaceutically-acceptable salt and / or derivative thereof, for use in the treatment of prostaglandin-mediated inflammation. Particular features and embodiments described herein in relation to the use of NBMI in the treatment of pain generally, or in any other given aspect of the invention described herein should, unless the context indicates otherwise, be regarded as also having been disclosed as relating equally to this particular aspect of the invention (alone or in combination with any and all other particular features and embodiments). In this aspect of the invention, prostaglandin-mediated inflammation may be characterised by elevated serum prostaglandin levels, which may be determined by those skilled in the art using well known techniques, and also that compounds of the invention may treat prostaglandin mediated inflammation by inhibiting prostaglandin expression. Thus, the skilled person will understand that prostaglandin-mediated inflammation (and therefore, potentially, pain) may decrease with decreasing prostaglandin levels. As used herein, references to “patients” will refer to a living subject being treated, including mammalian (in particular, human) patients, and as such “patients” may also be referred to as “subjects”, and vice versa. References to “patients” (and therefore also to “subjects”) also should be considered to refer to individuals displaying no symptoms of the relevant condition. For the avoidance of doubt, references to patients may also include references to animals, such as non-mammalian animals (e.g. birds) and, particularly, mammalian animals (e.g. cats, dogs, rabbits, rodents, horses, sheep, pigs, goats, cows, primates, and the like). As used herein, the term “effective amount” will refer to an amount of a compound that confers the desired therapeutic effect on the treated subject (i.e. the desired treatment, as described herein). The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and / or feels an effect). Thus, the skilled person will understand that references to pain may refer to conditions characterised by the clinical effects experienced by a patient, and so may be assessed subjectively (e.g. through questioning of the patient in relation to the extent and severity of their symptoms, as described hereinbefore). The skilled person will understand that amount of pain experienced by a patient may be highly variable and may depend on a number of factors, such as the general health of the patient. Thus, the extent of any reduction in such pain being indicative of treatment may be judged to a relative to the extent of the relevant symptoms. The skilled person will understand that the treatment of pain may be combined with (i.e. administered as part of the same medical intervention as; either concomitantly or sequentially with) other treatments (i.e. medications and / or therapeutic methods) used for such purposes. For example, NBMI, salts and derivatives thereof may be combined with administration of analgesic and / or anti-inflammatory agent and / or similar preparations. Further, such treatments may be combined by administering (e.g. by way of concomitant or sequential administration) one or more other therapeutic agent useful in the treatment of pain (e.g. inflammatory pain) as known to those skilled in the art, such as those described hereinafter. As used herein, references to “sequential administration” may refer to separate administration of the therapeutic agents as part of the same medical intervention (e.g. within four hours, such as within two hours or, particularly within one hour, of each other). Thus, NBMI, salts or derivatives thereof may be combined for use in the treatment of pain with paracetamol, NSAIDs, COX-2 inhibitors, and other analgesic or antiinflammatory compounds in a manner as known to those skilled in the art. Such combinations (i.e. with other compounds such as described above) may be particularly useful when administered to patients with greater pain, such as those described herein, and / or in patients receiving or requiring treatment with greater doses of analgesic and / or anti-inflammatory compounds than those normally used. The uses and methods described herein may also allow for lower doses of such other agents than would otherwise be used. Pharmaceutical Compositions and Dosages The skilled person will understand that, when employed in the uses and methods described herein, compounds of the invention may be administered in a manner allowing for systemic absorption, which absorption may occur via a number of possible routes; for example, compounds of the invention may be administered orally, intravenously or intraarterially, intramuscularly, cutaneously, subcutaneously, transmucosally (e.g. sublingually or buccally), rectally, transdermally, nasally, pulmonarily (e.g. by inhalation, tracheally or bronchially), or by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form. In particular, compounds of the invention may be administered orally, rectally or intravenously (e.g. by intravenous infusion). The compounds of the invention will generally be administered in the form of one or more pharmaceutical formulations in admixture with a pharmaceutically acceptable excipient, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable excipients may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use. Such pharmaceutically acceptable excipients may also impart an immediate (e.g. rapid), or a modified (e.g. delayed), release of the compounds of the invention. Suitable pharmaceutical formulations may be commercially available or otherwise are described in the literature (see, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995) and Martindale – The Complete Drug Reference (35thEdition), and the documents referred to therein), the relevant disclosures in all of which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques. Suitable pharmaceutical formulations for use with the compounds of the invention are also described in US patent application 2010 / 0227812. As described herein, pharmaceutical formulations may be prepared in a manner suitable for the desire route of administration, using techniques and materials known to those skilled in the art. In particular, pharmaceutical formulations may take the form of oral formulations or intravenous formulations (or formulations, e.g. concentrated formulations, suitable for use in the preparation of intravenous formulations). For example, when intended for oral administration, pharmaceutical formulations comprising compounds of the invention may be provided in the form of a tablet, or an oral powder or solution, each optionally comprising suitable excipients, which may be prepared using techniques known to those skilled in the art. Similarly, when intended for intravenous (I.V.) administration, pharmaceutical formulations comprising compounds of the invention may be provided in the form of solutions suitable for I.V. administration, or as solutions suitable for the preparation of solutions suitable for I.V. administration, which may be prepared using techniques known to those skilled in the art. Similarly, when intended for rectal administration, pharmaceutical formulations comprising compounds of the invention may be provided in the form of a tablet (e.g. a suppository), or a powder or solution, each optionally comprising suitable excipients, which may be prepared using techniques known to those skilled in the art. Depending on the patient to be treated, the route of administration and the severity of the condition (e.g. the level of pain and the severity of the effects thereof), compounds of the invention may be administered at varying therapeutically effective doses (to the relevant patient in need thereof). Suitable doses may be determined by the skilled person using routine techniques, such as by routine dose titration studies and the like. Similarly, the amount of the compounds of the invention included in the relevant pharmaceutical formulations may be determined based on the desired dosage of the compound of the invention, the ease of formulation and the route of administration (which may in turn determine the availability of the compound of the invention for systemic adsorption). Suitable doses of the compounds of the invention may include dosages (e.g. for I.V. administration) in the range of from about 0.05 to 300 mg / kg, such as from about 0.5 to about 200 mg / kg (e.g. about 1 to about 100 mg / kg, such as about 5 mg / kg or about 50 mg / kg). In particular, such doses may administered by I.V. administration over a period of time, such as about one hour. Moreover, such doses may be repeated as necessary, such as in the form of periodic, sequential infusions, which infusions may be of decreasing dose. For the avoidance of doubt, wherever the word “about” is employed herein, for example in the context of amounts (e.g. doses of active ingredients), it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5% and preferably ± 2% (e.g. ± 1%) from the numbers specified herein. For the avoidance of doubt, the skilled person will understand that dose of compounds of the invention administered (e.g. to a human) should be sufficient to effect the desired therapeutic response or effect within (and over) a reasonable timeframe. For example, compounds of the invention may be provided in a form suitable for rapid (i.e. quick or immediate) release of the active ingredient(s), such as in the form of a rapidly disintegrating tablet, which tablets may be formulated using techniques and materials known to those skilled in the art. In any event, the skilled person will be able to determine routinely the actual dosage which will be most suitable for an individual patient. While the above-mentioned dosages are exemplary of the average case, there can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of the invention. Administration of the compounds of the invention may be continuous (e.g. by continuous I.V. infusion) or intermittent (e.g. by bolus injection or through periodic administration of a tablet or solution), or may be provided in the form of a single dose (e.g. by injection or through administration of a tablet or solution). The dosage form may also be determined by the timing and frequency of administration, and vice versa. Combinations and Kits-of-Parts In the uses and methods described herein, the compounds of the invention may also be combined with one or more active ingredients that are potentially useful, or have been indicated for use, in the treatment of pain. According to a further aspect of the invention, there is provided a pharmaceutical formulation comprising: (a) NBMI, or a pharmaceutically-acceptable salt and / or derivative thereof; and (b) one or more other therapeutic agent that is useful in the treatment of pain (and / or inflammation), and optionally one or more pharmaceutically-acceptable excipients, for use in the treatment of pain. According to a further aspect of the invention, there is provided a kit-of-parts comprising components: (A) a pharmaceutical formulation comprising NBMI, or a pharmaceutically-acceptable salt and / or derivative thereof, and optionally one or more pharmaceutically-acceptable excipients; and (B) a pharmaceutical formulation comprising one or more other therapeutic agent that is useful in the treatment of pain (and / or inflammation), and optionally one or more pharmaceutically-acceptable excipients, which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other, for use in the treatment of pain. For the avoidance of doubt, all embodiments and particular features described in relation to previously mentioned aspects of the invention (and combinations thereof) will also apply to these aspects of the invention. The skilled person will understand that the kits-of-parts described herein may comprise more than one formulation including an appropriate quantity / dose of the compounds of the invention, and / or more than one formulation including an appropriate quantity / dose of one or more other therapeutic agent capable of treating pain, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and / or physical form(s). With respect to the kits-of-parts as described herein, by “administration in conjunction with” (and similarly “administered in conjunction with”) we include that respective formulations comprising the compounds of the invention, and one or more other therapeutic agent capable of treating pain, are administered, sequentially, separately or simultaneously, as part of the same medical intervention. Therefore, in relation to the present invention, the term “administration in conjunction with” (and similarly “administered in conjunction with”) includes that the two active ingredients (i.e. a compound of the invention, and one or more other therapeutic agent capable of treating pain are administered (optionally repeatedly) either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising a compound of the invention, or a formulation comprising one or more other therapeutic agent capable of treating pain, or pharmaceutically acceptable salt thereof, are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of, treatment of the relevant condition may be achieved routinely by the skilled person. Further, in the context of the present invention, the term “in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and / or at the same time as, administration of the other component. When used in this context, the terms “administered simultaneously” and “administered at the same time as” include that individual doses of a compound of the invention and one or more other therapeutic agent capable of treating pain are administered within 24 hours (e.g. within 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other. Thus, there is also provided a kit-of-parts comprising: (I) one of components (A) or (B) as described hereinbefore; and (II) instructions to use that component in combination with the other of the two components. Suitable therapeutic agents useful in the treatment of pain with include those referred to as agents suitable for use in combination treatments hereinbefore. Preparation of Compounds and Formulations Compounds of the invention may be obtained commercially or may be prepared using techniques known to those skilled in the art, such as those described in the disclosures referenced herein. For example, NBMI may be prepared in accordance with the procedure described in US patent number US 6,586,600 B2, the contents of which (in particular, the procedures as described in the examples provided therein) are hereby incorported by reference. As described herein, pharmacetical formulations (including those containing more than one active ingredient as described in the third aspect of the invention) may be prepared using techniques known to those skilled in the art. Similarly, a kit-of-parts (as described in the fourth aspect of the invention) may be prepared using techniques known to those skilled in the art. According to further aspects of the invention, there is provided: - a method of preparing a pharmaceutical formulation as described hereinbefore which comprises bringing into admixture (i.e. into the same formulation) components (a) and (b) as described hereinbefore in relation to the relevant aspects of the invention, optionally together with one or more pharmaceutically acceptable excipients; and - a method of preparing a kit-of-parts as described hereinbefore which comprises bringing into association components (A) and (B) as described hereinbefore in relation to the relevant aspects of the invention. For the avoidance of doubt, by bringing the components “into association with” each other, we include that components (A) and (B) of the kit-of-parts as described hereinbefore may be: - provided as separate formulations (i.e. independently of each other), which are subsequently brought together for use in conjunction with each other in combination therapy; or - packaged and presented as separate components of a “combination pack” for use in conjunction with each other in combination therapy. When employed in the uses and methods described herein, compounds of the invention may have the advantage that, in the treatment of pain, may be more convenient for the physician and / or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it may have other useful pharmacological properties over, similar treatments (or preventative measures) known in the prior art. The invention is further illustrated, but not limited, by the following examples, in which Figure 1 illustrates the results of an in vitro study comparing reduction of prostaglandin F1 (PGF1) levels obtained using NBMI with those obtained using ibuprofen, as described in Example 1 herein below; and Figure 2 illustrates the results of an in vivo study showing the reduction or inhibition of prostaglandin E2 (PGE2) expression, as described in Example 2 herein below. Example 1 Macrophages were incubated with either vehicle (control), ibuprofen or NBMI, and then exposed to lipopolysaccharide (LPS), which is known to trigger an increase of prostaglandin levels. The results are presented in Figure 1. The cells have a base level of PGF1 of approximately 0.5 nM. LPS exposed cells incubated with vehicle reached PGF1 levels of approximately 8 nM, cells incubated with ibuprofen reached PGF1 levels of approximately 2.5 nM, while cells incubated with NBMI reached PGF1 levels of approximately 1-1.6 nM. Example 2 Wild type mice were exposed to a single injection of LPS. Control mice have a base level of PGE2 of approximately 0.25 nM in the brain (n=3). Mice injected with LPS and subsequently treated with vehicle (n=3) increased their PGE2 levels of approximately 2.5 nM with very little variation among the animals, while mice treated with NBMI (n=3) did not increase PGE2 levels above base level of approximately 0.25 nM, with very little variation among the animals.

Claims

Claims 1. N,N-bis-2-mercaptoethyl isophthalamide, or a pharmaceutically-acceptable salt and / or derivative thereof, for use in the treatment of pain.

2. The use of N,N-bis-2-mercaptoethyl isophthalamide, or a pharmaceutically- acceptable salt and / or derivative thereof, for the manufacture of a medicament for the treatment of pain.

3. A method for the treatment of pain, which method comprises the administration of an effective amount of N,N-bis-2-mercaptoethyl isophthalamide, or a pharmaceutically- acceptable salt and / or derivative thereof, to a patient in need thereof.

4. A pharmaceutical formulation comprising: (a) N,N-bis-2-mercaptoethyl isophthalamide, or a pharmaceutically-acceptable salt and / or derivative thereof; and (b) one or more other therapeutic agent that is useful in the treatment of pain, and optionally one or more pharmaceutically-acceptable excipients, for use in the treatment of pain.

5. A kit-of-parts comprising components: (A) a pharmaceutical formulation comprising N,N-bis-2-mercaptoethyl isophthalamide, or a pharmaceutically-acceptable salt and / or derivative thereof, and one or more pharmaceutically-acceptable excipients; and (B) a pharmaceutical formulation comprising one or more other therapeutic agent that is useful in the treatment of pain, and one or more pharmaceutically-acceptable excipients, which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other, for use in the treatment of pain.

6. A pharmaceutical formulation comprising: (a) N,N-bis-2-mercaptoethyl isophthalamide, or a pharmaceutically-acceptable salt and / or derivative thereof; and (b) one or more other therapeutic agent that is useful in the treatment of pain, provided that said other therapeutic agent is not paracetamol, and one or more pharmaceutically-acceptable excipients.

7. A kit-of-parts comprising components: (A) a pharmaceutical formulation comprising N,N-bis-2-mercaptoethyl isophthalamide, or a pharmaceutically-acceptable salt and / or derivative thereof, and one or more pharmaceutically-acceptable excipients; and (B) a pharmaceutical formulation comprising one or more other therapeutic agent that is useful in the treatment of pain, provided that said other therapeutic agent is not paracetamol, and one or more pharmaceutically-acceptable excipients, which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.

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