Patent Application
20130095194
This application claims the benefit of priority under 35 U.S.C. §119 (a) and (b) to French Application No. 1159296, filed Oct. 14, 2011, the entire contents of which are incorporated herein by reference.
The invention relates to a xenon-based or N2O-based gaseous inhalable composition or medicament for preventing, i.e. stopping the occurrence of, or treating, i.e. completely or partially curing, or for at least minimizing, neuropathic pain caused by a cancer chemotherapy substance administered to a patient suffering from cancer.
The development of chemotherapies for treating cancers has led to a notable improvement in patient survival and often to a return to normal or virtually normal life.
However, cancer chemotherapy is generally neurotoxic and often causes considerable complications.
More specifically, the neurotoxic side effects affect the peripheral nervous system by targeting the cell body of neurons, the axon, the myelin sheath and/or the glial cells. This usually results in peripheral neuropathy caused by the chemotherapy, as recalled by C. Sioka et al., Central and peripheral nervous system toxicity of common chemotherapeutic agents; Cancer Chemother. Pharmacol.; 2009; 63; p. 761-767).
More generally, the prevalence of chemo-induced sensory neuropathies varies from 10% to 80% depending on the medicament.
Cancer chemotherapeutic agents or cancer chemotherapy substances which cause this type of neurotoxicity are in particular platinum salts, such as cisplatin, oxaliplatin and carboplatin; taxanes, such as paclitaxel and docetaxel; and alkaloids, in particular vincristine, thalidomide and bortezomib.
Neuropathic pain is consequently an important side effect for many patients, which can occur at the beginning of treatment, but also as a late consequence of the treatment, and then result in chronic pain.
Thus, the document S. Couraud et al.; Hypersensibilité aux sels de platine [Hypersensitivity to platinum salts]; Revue de Pneumo. Clinique; Vol. 64, No. 1; p. 20-26; February 2008, recalls that hypersensitivity reactions to platinum salts are frequent and sometimes serious. These effects can occur after 4 to 8 cycles of treatment. Moreover, a long interval between two courses of treatment increases the risk of reaction. The medical treatment should then consist, in simple cases, of careful reintroduction of the active ingredient, i.e. of the platinum salt used, according to a desensitization protocol, or, in severe cases, of careful replacement of the salts used with another salt, when this is possible.
In any event, it is understood that these hypersensitivity reactions to platinum salts are a real problem and must not be taken lightly.
Sometimes, neuropathy can develop even after a single drug application, in particular in the case of a treatment with oxaliplatin, as shown by M. Stengel et al.; Oxaliplatin-induced painful neuropathy—Flicker of hope or hopeless pain?; Pain 2009; 144; p. 225-226).
Similarly, taxanes are known to produce unwanted side effects, in particular neuropathies which are reflected by feelings of numbness or tingling, mainly in the hands and feet in patients.
However, up until now, no medicament or product really effective for preventing and/or curing neuropathic pain caused by cancer chemotherapy treatment has been proposed.
Moreover, document FR-A-2944969 proposes using nitrous oxide at a content between 5 and 45% by volume for treating chronic pain in humans, in particular that of dysfunctional, inflammatory, neuropathic or iatrogenic origin, in particular neuropathic pain chosen from post-shingles pain, diabetic pain, central pain, post-stroke pain, multiple sclerosis-related pain, pain related to spinal cord injury, aids-related or cancer-related pain, chemotherapy-related pain or pain of post-operative origin.
However, this document is completely silent with regard to pain resulting from treatment with one or more platinum salts, taxanes or another analogous substance of the alkaloid, thalidomide or bortezomib type.
The problem which arises is consequently that of being able to provide an effective medicament capable of preventing and/or curing, completely or partially (i.e. attenuating), a neuropathic pain (or pains) caused by a cancer chemotherapy treatment to which a patient, typically a human patient, is subjected, in particular a treatment by administration of a substance containing one or more platinum salts, such as cisplatin, oxaliplatin and carboplatin, more particularly oxaliplatin, or taxanes, alkaloids, thalidomide or bortezomib.
The solution according to the invention relates to a gaseous inhalable medicament containing xenon (Xe) or nitrous oxide (N2O) as active ingredient for use by inhalation for preventing and/or for treating at least one neuropathic pain caused by at least one cancer chemotherapy substance administered to a patient suffering from cancer, said cancer chemotherapy substance containing one or more compounds chosen from platinum salts, taxanes, alkaloids, thalidomide and bortezomib.
In the context of the invention, it is specified that:
As appropriate, the inhalable medicament of the invention, i.e. the gaseous medicinal composition of the invention, may comprise one or more of the following technical characteristics:
In other words, according to the present invention, it is proposed to inhale nitrous oxide or xenon in order to prevent or treat in a long-lasting manner, i.e. for one or more days, weeks or months, the neuropathic pain that may be caused by one (or more) cancer chemotherapy substance, i.e. an anticancer agent, chosen from platinum salts, taxanes, alkaloids, thalidomide and bortezomib, in particular caused by a substance such as oxaliplatin.
The invention is therefore based on coadministration of the cancer chemotherapy substance chosen from platinum salts, taxanes, alkaloids, thalidomide and bortezomib, and of the gas mixture comprising nitrous oxide or xenon in order to prevent or treat chemo-induced neuropathic pain.
The concentration and/or the duration of administration most suitable for a given patient can be chosen empirically by the care staff, for example depending on the patient's state of health or physical condition, on the severity of the pain, on the patient's sex and age, on the type of cancer, on the type of anticancer agent coadministered, etc.
The gas mixture or medicament of the invention may be used in the context of a therapeutic treatment method, in which the gas mixture is administered by inhalation, for example by means of a breathing mask, either directly connected to a source of N2O or of xenon at the required concentration, for example a ready-to-use gas cylinder, or else to the outlet of a gas mixer supplied by several sources of gas (O2, N2O or Xe, etc.) so as to obtain the desired mixture; or connected to a respiratory ventilator supplied with the desired gas(es). In other words, the present invention is therefore based on the use of a therapeutic gas mixture containing N2O or xenon as active ingredient in an effective proportion, for producing an inhalable medicament with curative or preventive effects, intended for treating neuropathic pain caused by a substance used in the context of cancer chemotherapy and administered to a patient suffering from cancer, said substance being chosen from platinum salts, taxanes, alkaloids, thalidomide and bortezomib, in particular a substance of the oxaliplatin type.
The nitrous oxide (N2O) or the xenon are therefore, according to the invention, used in the context of a therapeutic treatment method in which the N2O or the xenon is administered to a mammal, in particular a human patient, by inhalation, for preventing or treating neuropathic pain caused by an anticancer substance used as cancer chemotherapy administered to said patient.
The present invention will now be understood more fully by means of the following description and the following examples, which are given purely by way of illustration and with reference to the appended figures, among which:
Oxaliplatin is commonly used for combating cancers, in particular cancers of the rectum and colon, since it allows inhibition of DNA synthesis and replication by formation of intra-strand bridges between adjacent guanines, which is a treatment of choice in combating cancers of this type. This molecule unfortunately has the drawback of inducing neuropathic pain in the cancer patients to whom it is administered.
As a result, in order to demonstrate the efficacy of the N2O-based or xenon-based gas according to the invention in combating this type of neuropathic pain caused by oxaliplatin, comparative trials were carried out under the following conditions.
A preclinical study in rats was carried out.
In order to mimic the clinical use as closely as possible, a series of 8 intraperitoneal injections of oxaliplatin were given every 3 to 4 days, as illustrated in
The pain thresholds were evaluated by means of a Randall-Selitto device by applying an increasing pressure to the paw of the rat until the animal lets out a cry. The corresponding weight in grams is then noted (the Y-axis in
In order to evaluate the effects of 50% nitrous oxide and of 50% xenon (% by volume) on the neuropathic pain caused by oxaliplatin, 4 groups of animals, in a proportion of 8 rats per group, were used (see
Following the administrations of oxaliplatin, the pain thresholds of group B (oxaliplatin+air) are significantly decreased, namely approximately 150 g compared with 200 g in group A, revealing hypersensitivity to pain or hyperalgesia in the rats of group B which did receive oxaliplatin. This confirms that this molecule has the drawback of inducing neuropathic pain.
The significance of the results is represented by the star close to the black diamonds in
Interestingly, it is noted that this hypersensitivity to pain persists well beyond the final administration of oxaliplatin. Indeed, as can be seen in
Conversely, groups C and D in which the rats inhaled N2O or xenon after administration of oxaliplatin exhibit no sign of hypersensitivity to pain.
Thus, the respective curves (grey square and grey circle) for groups C and D are not different from the curve of group A (white triangle) acting as a control group.
In other words, the administrations of gas mixture containing N2O or xenon made it possible, surprisingly, to prevent or treat the hypersensitivities to pain caused by the successive administrations of oxaliplatin.
This constitutes a notable advance from the medical point of view since, applied to human patients, these N2O or xenon inhalations would make it possible, finally, to relieve the pain experienced by cancer patients undergoing chemotherapies based on oxaliplatin or on other anticancer substances.
Moreover, even more surprisingly, the effect of the xenon or of the N2O lasts over time since, even following the final administration of oxaliplatin, the long-term hypersensitivity to pain is completely prevented. In fact, these trials show that the preventive effect of N2O or of xenon lasts more than 2 weeks.
These trials clearly demonstrate that xenon and N2O administered by inhalation make it possible to prevent or treat neuropathic pain caused by cancer chemotherapy substances, such as oxaliplatin.
Xenon and N2O gases mixed with oxygen or with air, for example, can consequently be used for treating, preventing, decreasing, minimizing, etc., neuropathic pain which is a negative side effect of the use of certain anticancer substances, such as platinum salts, taxanes, alkaloids, thalidomide and bortezomib, which can be administered alone or in the form of a “cocktail” of several substances.
While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the appended claims. The present invention may suitably comprise, consist or consist essentially of the elements disclosed and may be practiced in the absence of an element not disclosed. Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense. For example, it can be recognized by those skilled in the art that certain steps can be combined into a single step.
The singular forms “a”, “an” and “the” include plural referents, unless the context clearly dictates otherwise.
“Comprising” in a claim is an open transitional term which means the subsequently identified claim elements are a nonexclusive listing (i.e., anything else may be additionally included and remain within the scope of “comprising”). “Comprising” as used herein may be replaced by the more limited transitional terms “consisting essentially of” and “consisting of” unless otherwise indicated herein.
“Providing” in a claim is defined to mean furnishing, supplying, making available, or preparing something. The step may be performed by any actor in the absence of express language in the claim to the contrary.
Optional or optionally means that the subsequently described event or circumstances may or may not occur. The description includes instances where the event or circumstance occurs and instances where it does not occur.
Ranges may be expressed herein as from about one particular value, and/or to about another particular value. When such a range is expressed, it is to be understood that another embodiment is from the one particular value and/or to the other particular value, along with all combinations within said range.
All references identified herein are each hereby incorporated by reference into this application in their entireties, as well as for the specific information for which each is cited.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1159296 | Oct 2011 | FR | national |
