WO2008017000A2

WO2008017000A2 - Methods and pharmaceutical preparations for contributing to the treatment of chemotherapy-induced neuropathy

Info

Publication number: WO2008017000A2
Application number: PCT/US2007/075008
Authority: WO
Inventors: Guru Reddy; Dorla Mirejovsky; Luigi Lenaz
Original assignee: Spectrum Pharmaceuticals, Inc.
Priority date: 2006-08-01
Filing date: 2007-08-01
Publication date: 2008-02-07
Also published as: WO2008017000A8; CN101657199A; RU2009107123A; EP2046335A2; IL196824A0; KR20090047501A; ZA200900728B; JP2009545619A; CA2659477A1; WO2008017000A3; NO20090279L; MX2009001116A; BRPI0715504A2

Abstract

Methods and pharmaceutical preparations for using a leteprinim suspension to contribute to the treatment of chemotherapy-induced neuropathy.

Description

METHODS AND PHARMACEUTICAL PREPARATIONS FOR CONTRIBUTING TO THE TREATMENT OF CHEMOTHERAPY-INDUCED NEUROPATHY

FIELD OF THE INVENTION

[0001] The present invention relates to methods and pharmaceutical preparations for contributing to the treatment of chemotherapy-induced (e.g., cisplatin-induced) neuropathy.

BACKGROUND OF THE INVENTION

[0002] While chemotherapeutic agents are vital to cancer treatment, their use may be limited by side effects such as neuropathy, which may result in at least a partial loss of bodily sensation. An example of one such chemotherapy agent is cisplatin, which is used extensively in the treatment of several types of cancers including bladder, testicular and ovarian tumors (Williams et al., (1979) Br. Med. J. 1 : 1689-1691 ). While cisplatin can provide beneficial effects in the treatment of cancers, the total dose that can be administered is limited by its toxic effects in the peripheral nervous system (Mollman, (1990) N. Engl. J. Med 322: 126-127). Specifically, the pathological examination of cisplatin-treated patients reveals selective damage or loss of large sensory nerve fibers, which can result in the loss of sensation in various parts of the body (Thompson et a/., (1984) Cancer 54: 1269-1275). Recovery from this nerve damage is variable and many cisplatin-treated cancer survivors suffer from persistent nerve damage and sensory loss. (Cavaletti et a/., (1994) Anticancer Res 14: 1287- 1292).

[0003] A variety of agents have shown potential activity as nerve protectants against cisplatin-induced nerve damage in clinical trials. Some of these agents include an ACTH 4-9 fragment with growth factor activity (ORG2766) (Gerritsen et al., (1990) N. Engl. J. Med. 322: 89-94), and the thiols amifostine (Kemp et al., (1996) J. Clin. Oncol. 14: 2101-2112) and glutathione (Pirovano et al., (1992) Tumori 78: 253-257). In preclinical studies, compounds such as nerve growth factor (Apfel et at., (1992) Ann. Neurol. 31 : 76-80), neurotrophin-3 (Gao et al., (1995) Ann. Neurol. 38 (1 ): 30-37) and glutamate (Boyle et ai, (1999) J. NeuroOncol. 41 : 107-116) have shown an ability to help prevent nerve damage caused by cisplatin. While all of these agents have shown the potential to aid in the prevention of cisplatin-induced nerve damage, there remains a need for additional agents that can achieve this function. The present invention provides such an agent.

SUMMARY OF THE INVENTION

[0004] The present invention is directed to compositions that contain leteprinim (in any of its various forms including salts and acids of leteprinim) and their use to contribute to the prevention of chemotherapy-induced (e.g., cisplatin-induced) nerve damage in cancer patients. The present invention also provides methods of administering leteprinim and leteprinim formulations to help mitigate chemotherapy-induced neuropathy. Thus, the present invention encompasses methods and pharmaceutical preparations that can be used to contribute to the prevention of chemotherapy-induced (e.g., cisplatin-induced) nerve damage.

[0005] Specifically, one embodiment according the present invention includes a method comprising administering leteprinim (SPI-082) to a patient thereby contributing to the treatment of chemotherapy-induced neuropathy. Another one embodiment according the present invention includes a method comprising administering leteprinim (SPI-082) to a patient thereby contributing to the treatment of cisplatin-induced neuropathy. Another method according to the present invention comprises administering a chemotherapeutic (e.g., cisplatin) to contribute to the treatment of a cancer and administering leteprinim thereby contributing to the treatment of chemotherapeutic-induced (e.g., cisplatin-induced) neuropathy. Another method according to the present invention comprises administering cisplatin to contribute to the treatment of a cancer and administering leteprinim thereby contributing to the treatment of cisplatin-induced neuropathy.

[0006] In accordance with the present invention, leteprinim administration may precede the beginning of treatment with a chemotherapeutic (e.g., cisplatin) or leteprinim administration may begin after the beginning of treatment with a chemotherapeutic (e.g., cisplatin). In certain embodiments leteprinim may be administered, without limitation, less than once per day on a weekly basis (i.e., up to six times per seven day week), more preferably twice weekly (i.e., twice per seven day week). A chemotherapeutic may be administered, without limitation, from any effective amount up to its toxic amount. For example, cisplatin may be administered twice weekly. Leteprinim and chemotherapeutic (e.g., cisplatin) administration also may occur substantially simultaneously. When administration occurs substantially simultaneously, leteprinim and the chemotherapeutic (e.g., cisplatin) can be part of different or part of the same pharmaceutical preparations. Appropriate doses of leteprinim may include, without limitation, from about 25 mg/kg to about 100 mg/kg, e.g., about 50 mg/kg. In one embodiment, leteprinim and, optionally, another active agent(s) may be formulated as a suspension, optionally, a buffered suspension.

[0007] Embodiments of the present invention also include pharmaceutical preparations comprising leteprinim wherein the pharmaceutical preparation is sold with instructional information that directs the administration of the pharmaceutical preparation to contribute to the treatment of a chemotherapeutic-induced (e.g., cisplatin-induced) neuropathy. In certain embodiments, the instructional information will direct the administration of the leteprinim in a manner of one or more of the above-described methods. The pharmaceutical preparations accompanied by such instructional information can include leteprinim as the only active ingredient or can further comprise at least one other active agent (e.g., a chemotherapeutic like cisplatin). These pharmaceutical preparations also may include other active or inactive ingredients. [0008] Pharmaceutical preparations according to the present invention can also include those comprising chemotherapeutic (e.g., cisplatin) and leteprinim wherein the chemotherapeutic in the pharmaceutical preparation is intended to contribute to the treatment of a cancer and the leteprinim is intended to contribute to the treatment of cisplatin-induced neuropathy. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FiG. 1 shows the effect of leteprinim on cisplatin-induced changes in body weight.

[0001O]FIG. 2 shows the effect of leteprinim on cisplatin-induced changes in sensory perception as measured in a hot piate paradigm.

[00011]FIGS. 3 and 4 show the effect of leteprinim on cisplatin-induced changes in H- wave amplitude and latency respectively.

[00012JFIG. 5 shows the effect of leteprinim on cisplatin-induced changes in sensitive nerve conduction velocity (SNCV).

[00013] FIG. 6 shows the effect of leteprinim on cisplatin-induced changes in axon diameter.

[00014] FIG. 7 shows the effect of leteprinim on cispiatin-induced changes in g-ratio. [0001 S]FIG. 8 shows the effect of leteprinim on changes in the proportion of degenerated to non-degenerated fibers following cisplatin administration,

DETAILED DESCRIPTION I. Definitions

[00016] Instructional Information: As used herein, the term "instructional information" shall mean material accompanying a pharmaceutical preparation that provides a description of how to administer the pharmaceutical preparation. This instructional information generally is regarded as the "label" for a pharmaceutical preparation. Instructional information can come in many forms including, without limitation, a paper insert, c.d. rom or directions to a web site containing information relating to the pharmaceutical preparation.

[00017] Prodrug: As used herein, the term "prodrug" shall mean compounds that transform rapidly in vivo to a compound useful in the invention, for example, by hydrolysis. A thorough discussion of prodrugs is provided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, of the A.C.S.D. Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. [00018] Substantially Simultaneously: As used herein, the term "substantially simultaneously" shall mean that two pharmaceutical preparations (i.e. leteprinim and cisplatin) are administered at the same time. According to this definition, "same time" should be read to include exactly simultaneously as well as within about ten minutes. [00019] Treat, Treatment and Contributing to the Treatment Of: As used herein, the terms "treat", "treatment" and "contributing to the treatment of shall mean preventing, inhibiting, slowing, or partially or fully reversing the development of nerve damage following cisplatin administration. With regard to cancers the terms include preventing, retarding the progression or growth of, shrinking, or eliminating a cancer including a solid tumor. As such, these terms include both medical therapeutic and/or prophylactic administration, as appropriate.

[0002O]As used herein, the term "twice weekly" means that a pharmaceutical preparation is administered twice within a 7-day period. Generally, these administrations will be evenly spaced over the course of the 7-day period but this feature is not required and the two administrations can occur with any spacing between them over the course of the 7-day period.

[00021] As used herein, the term "leteprinim" refers to N-4-carboxyphenyl-3-(6- oxohydropurin-9-yl) propanamide and its various forms (e.g., leteprinim acid and salt forms). Leteprinim also variously is known as AIT-082, SPI-082, and SPl-205. [00022]The leteprinim compositions and methods of the present invention may be used to treat peripheral neuropathy associated at least in part with the administration of any chemotherapeutic agent(s). Exemplary chemotherapeutic classes include, but are not limited to, podophyllotoxins, terpenoids (e.g., taxanes and vinca alkaloids), antimetabolites, anthracyclines, alkylating agents (e.g., platins), and other anti-tumour agents. Vinca alkaloids include, among others, vincristine vinblastine, vinorelbine, and vindesine. Other exemplary chemotherapeutic agents include, but are not limited to, etoposide, teniposide, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, suramin, altretamine, chlorambucil, cytarabine, dacarbazine, docetaxel, etoposide, fludarabine, ifosfamide with mesna, tamoxifen, teniposide, and thioguanine. Peripheral neuropathy associated with the administration of oncolytic drugs is described in C. M. Haskell, "Cancer Treatment" (δ.sup.th Ed., W. B. Saunders, Philadelphia, 2001 ), Ch. 10, pp. 104- 214. In one embodiment, the present invention is directed to treating drug-induced peripheral neuropathy associated with the administration of vinca alkaloids (e.g., vincristine), taxanes (e.g., paclitaxel/Taxol^®), or alkylating agents (e.g., cisplatin). In another embodiment, the present invention is directed to treating drug-induced peripheral neuropathy associated with the administration of cisplatin. [00023]Cisplatin is an antitumor agent widely used in the treatment of many common and therapeutically refractory tumors. Cisplatin is useful as an anticancer agent due to its effects as a DNA synthesis inhibitor which hinders cell division. Currently, neuropathy (i.e. nerve damage) is recognized as a dose-limiting toxicity, with symptoms developing after a cumulative dose of more than about 300 mg/m². Cisplatin neuropathy affects predominantly large fibers sensory neurons and is generally associated with a reduction in the signal amplitude of the sensory nerves, resulting in a profound disabling sensory ataxia. This neuropathy can continue to progress after cessation of cisplatin treatment. The present invention shows that leteprinim can contribute to the treatment or prevention of cisplatin-induced nerve damage.

[00024] Depend ing upon the particular needs of the individual subject involved, the leteprinim compositions of the present invention may be administered in various doses and regimens to provide effective treatments. What constitutes an effective amount of the selected leteprinim composition will vary based upon factors including, but not limited to, the activity of the chemotherapeutic compound, the patient's physiology, the patient's disease or condition, and the method/frequency/mode of administration of the leteprinim and/or the chemotherapeutic agent(s). Initially, the dosage and dosing regimen may be modulated to determine the optimum dosage for a particular patient. [00025] Minimum leteprinim dosage concentrations (drug weight to patient weight) effective in mitigating chemotherapeutic-induced neuropathy are about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, or about 45 mg/kg. Maximum dosage concentrations effective in mitigating chemotherapeutic-induced neuropathy are about 100 mg/kg, 75 mg/kg, about 65 mg/kg, about 60 mg/kg, or about 55 mg/kg. One dosage concentration effective in mitigating chemotherapeutic-induced (e.g., cisplatin- induced) neuropathy is about 50 mg/kg. The leteprinim compositions may be administered less than once per day weekly based on a seven day week (e.g., three to six times per week), or twice per week. Regardless of the regimen, the time interval between administrations need not, but may, be equal.

[00026]The leteprinim compositions may be administered using a number of different routes including orally, topically, transdermal^, intraperitoneal^, subcutaneously, or intravenously. Effective amounts of the compounds also may be administered through injection into the cerebrospinal fluid or infusion directly into the brain. In one embodiment, the mode of administration is subcutaneous administration. [00027]The methods of the present invention may be affected using leteprinim administered to a patient (e.g., mamma! in need of treatment) either alone or as a pharmaceutical formulation. Further, the leteprinim may be combined with pharmaceutically acceptable excipients and carrier materials such as inert solid diluents, aqueous solutions or non-toxic organic solvents. If desired, these pharmaceutical formulations may also contain preservatives and stabilizing agents and the like, as well as minor amounts of auxiliary substances such as wetting or emulsifying agents, as well as pH buffering agents and the like which enhance the effectiveness of the active ingredient. The pharmaceutically acceptable carrier can be chosen from those generally known in the art, including, but not limited to, human serum albumin, ion exchangers, dextrose, alumina, lecithin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, propylene glycol, polyethylene glycol, and salts or electrolytes such as protamine sulfate, sodium chloride, or potassium chloride. Other carriers can be used. Liquid compositions may also contain liquid phases either in addition to or to the exclusion of water. Examples of such additional liquid phases are glycerin, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions. In one embodiment, the leteprinim formulation may be an optionally buffered hydrophobic suspension, In another embodiment, the leteprinim formulation may be an optionally buffered lipid suspension. The formulations may be buffered with conventional buffers (e.g., acids or salts). In another embodiment, the formulation is buffered with, for example, a salt or acid form of leteprinim (e.g., potassium salt form of leteprinim). In yet another embodiment, the leteprinim formulation is a lipid suspension buffered with the potassium salt form of leteprinim.

[00028] Materials & Methods

1. Animals

[00029]Ten week-old female Dark Agouti rats (Janvier, Le Genest-St-lsle, France) were randomly distributed in 5 experimental groups: (a) a control group (n = 17) receiving subcutaneous (s.c.) leteprinim acid suspension placebo treatment; (b) a control group (n = 17) receiving s.c. leteprinim salt (0.9% NaCI) placebo treatment; (c) a cisplatin alone treated group (n = 17) (d) a cispiatin-treated group (n = 17) receiving a 50 mg/kg/d s.c. leteprinim acid suspension treatment; and (e) a cispiatin-treated group (n = 17) receiving a 50 mg/kg/d s.c. leteprinim K salt solution treatment. Animals were housed 2 per cage and maintained in a room with controlled temperature (21-22°C) and a reversed light-dark cycle (12h/12h) with food and water available ad libitum. All experiments were carried out in accordance with institutional guidelines.

2. Induction of cisplatin neuropathy, pharmacological treatment & monitoring and testing schedule

[00030] Neuropathy was induced by intraperitoneal (i.p.) injection of a 0.1 mg/ml cisplatin solution (Sigma, L'lsle d'Abeau Chesnes, France) twice a week for 4 weeks at a dose of 2 mg/kg per injection. Leteprinim treatments were performed on a daily basis from the first day of cisplatin administration until the end of the study (week 7). Cisplatin and leteprinim K salt were dissolved in sterile solutions of 0.9% NaCI (saline). Leteprinim acid suspension and its placebo form were prepared in a 5% glucose solution. Leteprinim acid suspension and its placebo and leteprinim K salt solution were prepared freshly everyday. Body weight and survival rate were recorded daily. Hot plate and electromyography (EMG) testings were performed once a week. Sciatic nerves from 5 animals in each group were harvested at week 5 for histological analysis. 3. Sensory test: hot plate

[00031]Rats were individually placed inside a glass cylinder (height: 17 cm; diameter: 21 cm) on a heating-plate heated to 52°C (Medite OTS 40, Microm, Francheville, Rhone, France). Animal behavior was observed and recorded, particularly the licking of feet and the adjusted leap (leaping to escape the heat). The time needed to feel thermal pain (as evidenced by licking and leaping) is related to thermal sensitivity and tends to increase when thermal sensitivity is diminished.

4. Electromyography

[00032] Electrophysiological recordings were performed using a Neuromatic 2000M electromyograph (EMG) (Dantec, Les Ulis, France). Rats were anaesthetized by i.p. injection of 60 mg/kg ketamine chlorhydrate (Imalgene 500, Rhone Merieux, Lyon, France) and 4 mg/kg hyaline (Rompum 2%, Bayer Pharma, Kiel, Germany). Normal body temperature was maintained at 30⁰C with a heating lamp and controlled by a contact thermometer (Quick, Bioblock Scientific, lllkirch, France) placed on the tail surface.

[00033] H-wave reflex was recorded in the hind footpad muscle after stimulation of the sciatic nerve. A reference electrode and a ground needle were placed on the lower back of the rat. The sciatic nerve was stimulated with a single 0.2 ms pulse at supramaximal intensity. The amplitude (mV) and the latency of H waves were recorded. [00034] Sensitive nerve conduction velocity (SNCV) was also recorded. The tail skin electrodes were placed as follows: a reference needle inserted at the base of the tail and an anode needle placed 30 mm away from the reference needle towards the extremity of the tail, A ground needle electrode was inserted between the anode and reference needles. The caudal nerve was stimulated with a series of 20 pulses (for 0.2 ms) at an intensity of 12.8 mA. The velocity was expressed in m/s,

5. Morphometric analysis

[00035]At the end of the study, five animals per group were assigned for histological analysis in order to evaluate the effect of 50 mg/kg leteprinim on cisplatin-induced pathological changes. These animals were anesthetized with an i.p. injection of 100 mg/kg lmalgene 500. A 5 mm-segment of sciatic nerve was excised for histology. The tissue was fixed overnight with a 4% glutaraldehyde (Sigma, L¹IsIe d'Abeau-Chesnes, France) solution in phosphate buffered solution (pH = 7.4) and maintained in 30% sucrose at +4°C until use. The nerve samples were post-fixed in a 1 % osmium tetroxide (Sigma, L'lsle d'Abeau-Chesnes, France) solution in phosphate buffer solution for 2 h, dehydrated in serial alcohol solution, and embedded in Epon. Embedded tissues were then placed at +70⁰C during 3 days to allow the polymerization of tissue wax. Transverse sections of 1.5 μm were cut with a microtome, stained with a 1 % toluidine blue solution (Sigma, L'lsle d'Abeau-Chesnes, France) for 2 min, dehydrated and mounted in Eukitt.

[00036] One section from each sciatic nerve sample was examined using an optical microscope (Nikon, Tokyo, Japan). Analysis was performed on the entire surface of the section using a semi-automated digital image analysis software (Biocom, France). For each fiber, the axonal and myelin sizes were automatically calculated and reported in surface area (μm²). These two parameters were used to calculate the equivalent area of g-ratio (axonal diameter/fiber diameter) of each fiber (i.e., [A/(A+M)]0.5, A = axonal area, M = myelin area), indicative of the relative myelin sheath thickness. Myelin thickness is inversely proportional to the g-ratio.

[00037]The number of degenerated fibers was then counted manually by an operator. Myelinated fibers without axons, redundant myelin, and fibers showing sheaths with too large of a thickness compared to their axonal diameter were considered fibers undergoing degeneration processes.

6. Data analysis

[00038] Body weight was compared over the course of the experiment by two-way analysis of variance (ANOVA). Behavioral, electrophysiological and histological data were analyzed for each individual timepoint by ANOVA, followed by Fisher Protected Least Significant Difference as post-hoc tests (PLSD). The level of significance was set at p < 0.05. Results are expressed as mean ± standard error of the mean (s.e.m,). RESULTS 1. Body weight

[00039] In contrast to control rats showing a progressive weight gain throughout the study, all animals receiving cisplatin demonstrated marked weight loss as early as the day following cisplatin administration (p < 0.001 , two-way ANOVA) (See FIG. 1 ). The most severe weight loss was observed during the 3rd and 4th weeks of cisplatin administration. After the withdrawal of cisplatin treatment, rats showed progressive weight gain but remained below (about 20%) the level of controls. These results demonstrate that treatment with leteprinim acid or leteprinim K salt did not prevent the appearance of growth arrest but was associated with an improved growth profile as compared to the cisplatin alone treatment group (about 10% above the cisplatin alone treatment group).

2. Sensory test: hot plate

[00040] Figure 2 shows that from week 2 onwards, rats from the cisplatin alone treatment group demonstrated a significant increase in threshold latency scores as compared to the control groups (p < 0.05, Fisher's PLSD test). The most severe dysfunction was observed at week 4 (the last week of cisplatin administration) with a time score of about 30% above control groups. Even at the end of the study, animals from the cisplatin alone treatment group did not recover to the performance level of control animals.

[00041] As also seen in FIG. 2, treatment with leteprinim acid or with leteprinim K salt significantly improved the hot plate performance of cisplatin-treated rats (p < 0.05, Fisher's PLSD test). Significant effects were observed from week 3 up to week 7. At week 4, where the most severe cisplatin dysfunction was observed, cisplatin-rats treated with leteprinim acid or with leteprinim K salt showed a time score only about 15% above control values. At the end of the study (week 7), the performance of cisplatin-treated rats receiving leteprinim acid or with leteprinim K salt was comparable to that of control rats. These results demonstrate that leteprinim can contribute to the prevention of pathologies associated with cisplatin treatment. 3. Electrophysiological measurements a. Amplitude of H -wave

[00042]As shown in FIG. 3, a significant reduction in the amplitude of the H-wave was observed in the cisplatin alone treatment group as early as 1 week after the initiation of cisplatin administration. The most severe reduction in the H-wave amplitude occurred at week 4, where the loss exceeded 45% of control levels. Recovery began after the withdrawal of cisplatin treatment (post-cisplatin timepoints) and was complete at week 7 (end of study).

[00043] Cisplatin rats treated with leteprinim acid or with leteprinim K salt demonstrated improved H-wave performance when compared to the cisplatin alone treatment group. These differences were evident as early as week 2, At week 4 where the loss of H-wave amplitude was maximal in the cisplatin alone treatment group, cisplatin rats receiving leteprinim showed H-wave amplitudes about only 20% below the control values. By week 5, cisplatin rats treated with leteprinim recovered to the H-wave score of control rats. These results also demonstrate that leteprinim can help to prevent or alleviate physiological changes associated with cisplatin administration. b. Latency of H wave

[00044] Figure 4 shows a significant extension of H-wave latency in the cisplatin alone treatment group starting from week 2 as compared to that of control rats (p < 0.05, Fisher's test). The most severe alteration was observed at week 4 with a latency score extended by about 12%. Cisplatin alone-treated rats fully recovered on this measure by week 7.

[00045]Treatment with leteprinim acid or with leteprinim K salt significantly attenuated the cisplatin-induced H-wave latency alteration (p < 0.05, Fisher's test). At week 4 where the alteration was maximal in the cisplatin alone treatment group, only about 4% extension of the latency score (as compared to the control value) was observed in the cisplatin groups receiving leteprinim treatment. c. Sensory nerve conduction velocity

[00046] A progressive decrease in SNCV was observed in the cisplatin group starting as early as week 1 (p < 0.05, Fisher's test) (FIG. 5). The most severe dysfunction was observed at week 4 with a score of about 15% below control values. Recovery started by week 5 but performance did not return to control levels. [00047]Treatment with leteprinim significantly improved the SNCV performance of cisplatin-treated rats. At week 4 where SNCV dysfunction was maximal in the cisplatin alone treatment group, the dysfunction associated with cisplatin-rats receiving leteprinim was at most 7% below the control value. At week 7, the performance of cisplatin-rats treated with leteprinim was comparable with that of control rats. 4. Morphometric analysis a. Axon diameter

[00048]There was no statistical difference between groups (p > 0.05, ANOVA) (FIG. 6), although the axon diameters of nerve fibers harvested from cisplatin alone treated rats were slightly greater than those of the other groups. Treatment with leteprinim did not significantly modify axon size of cisplatin treated rats. b. Myelin thickness

[00049]There were no statistical differences between groups regarding the thickness of the myelin sheath of nerve fibers (p > 0.05, ANOVA) (FIG. 7). c. Percentage of degenerated fibers

[0005O]As shown in FIG. 8, the proportion of degenerated fibers in the sciatic nerves of the cisplatin alone treated group was significantly greater than that of control rats (p < 0.05, Fisher's test). Further, treatment with leteprinim significantly reduced the proportion of degenerated fibers in the sciatic nerves of cisplatin-treated rats. [00051 ]The described results show that chemotherapeutic (in this case, cisplatin) administration induces marked nerve dysfunction indicated by the alteration of both the H-wave signal (amplitude reduced and latency extended) and SNCV as well as by the delayed reactivity to heat. These signs of sensory neuropathy were supported by the histological results showing a significant increase in the proportion of sciatic nerve fibers showing characteristics of axonal degeneration, although the nature of these affected fibers (sensory or motor) was not identified.

[00052]The described results further demonstrated that treatment with leteprinim can markedly attenuate chemotherapeutic-induced (in this case, cisplatin-induced) nerve dysfunction and can accelerate recovery from this disorder. These improvements were evident in most of studied parameters (H-wave amplitude and latency, SNCV and axona! degeneration) and appeared to be in good correlation with improvements observed in the hot plate test.

[00053] Histological results showed that the axonai diameter of the cisplatin alone treated group was slightly increased. This might represent axonai degeneration, a phenomenon observed as a consequence of cisplatin administration in the developing rat brain (Rzeski et al., (2004) Ann. Neurol. 56 :351-360). Leteprinim treatment seemed to completely prevent this axonai swelling. In summary, the described results show that daily treatment with leteprinim can improve cisplatin-related sensory neuropathy. [00054] Pharmaceutical preparations containing the described active ingredients are suitable for administration to humans or other mammals. Typically, the pharmaceutical preparations are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered. Administration of the pharmaceutical preparation can be performed before, during, or after the onset of chemotherapeutic administration.

[00055] A method of the present invention can be accomplished using active ingredients as described above, or as a physiologically acceptable salt, derivative, prodrug, or solvate thereof. The active ingredients can be administered as the neat compound, or as a pharmaceutical preparation containing either or both entities. [00056] The pharmaceutical preparations include those wherein the active ingredients are administered in an effective amount to achieve their intended purpose. More specifically, a "therapeutically effective amount" means an amount effective to prevent development of, to eliminate, to retard the progression of, or to reduce the size of a solid tumor. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. [00057] A "therapeutically effective dose" refers to that amount of the active ingredients that results in achieving the desired effect. Toxicity and therapeutic efficacy of such active ingredients can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., determining the LD_5O (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD5₀ and ED₅0. A high therapeutic index is preferred. The data obtained can be used in formulating a range of dosage for use in humans. The dosage of the active ingredients preferably lies within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized.

[00058] The exact formulation and dosage is determined by an individual physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide levels of the active ingredients that are sufficient to maintain therapeutic or prophylactic effects.

[00059] The amount of pharmaceutical preparation administered can be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. [00060]The active ingredients can be administered alone, or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical preparations for use in accordance with the present invention thus can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active ingredients into preparations which can be used pharmaceutically.

[00061] When a therapeutically effective amount of the active ingredients is administered, the preparation can be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred preparation for intravenous injection typically will contain an isotonic vehicle although this characteristic is not required.

[00062] For veterinary use, the active ingredients are administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen that is most appropriate for a particular animal.

[00063] Various adaptations and modifications of the embodiments can be made and used without departing from the scope and spirit of the present invention which can be practiced other than as specifically described herein. The above description is intended to be illustrative, and not restrictive. The scope of the present invention is to be determined only by the claims.

[00064] The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding equivalents of the features shown and described, or portions thereof, it being recognized that various modifications are possible within the scope of the present invention claimed. Moreover, any one or more features of any embodiment of the present invention can be combined with any one or more other features of any other embodiment of the present invention, without departing from the scope of the present invention.

[00065] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. [00066] The terms "a" and "an" and "the" and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the present invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present invention. [00067] Groupings of alternative elements or embodiments of the present invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[00068] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these certain embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description, The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above- described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. [00069] Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety. [00070] In closing, it is to be understood that the embodiments of the present invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the present invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

What is claimed is:

1. A method comprising: administering a leteprinim suspension to a patient in need thereof thereby contributing to the treatment of chemotherapy-induced neuropathy.

2. A method according to claim 1 wherein said leteprinim administration precedes the beginning of treatment with a chemotherapeutic agent; said leteprinim administration begins after the beginning of treatment with said chemotherapeutic agent; or, said leteprinim administration and said chemotherapeutic agent administration occur substantially simultaneously.

3. A method according to claim 1 wherein said ieteprinim is administered six times or less per week.

4. A method according to claim 1 wherein said leteprinim is administered two times per week.

5. A method according to claim 2 wherein when said leteprinim administration and said chemotherapeutic agent administration occur substantially simultaneously.

6. A method according to claim 5 wherein said leteprinim and said chemotherapeutic agent are part of the same pharmaceutical preparation.

7. A method according to claim 1 wherein said leteprinim administration occurs in a dose of less than about 100 mg/kg.

8. A method according to claim 1 wherein said leteprinim administration occurs in a dose of about 50 mg/kg.

9. A method according to claim 2 wherein said chemotherapeutic agent is selected from podophyllotoxins, terpenoids, antimetabolites, anthracyclines, alkylating agents, other anti-tumour agents, and combinations thereof.

10. A method according to claim 2 wherein said chemotherapeutic agent is selected from vincristine vinblastine, vinorelbine, vindesine, etoposide, teniposide, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, suramin, altretamine, chlorambucil, cytarabine, dacarbazine, docetaxel, etoposide, fludarabine, ifosfamide with mesna, tamoxifen, teniposide, thioguanine, and combinations thereof.

11. A method according to claim 2 wherein said chemotherapeutic agent is selected from vinca alkaloids, taxanes, alkylating agents, and combinations thereof.

12. A method according to claim 2 wherein said chemotherapeutic agent is selected from vincristine, paclitaxel, cisplatin, and combinations thereof.

13. A method according to claim 2 wherein said chemotherapeutic agent is cisplatin.

14. A method according to claim 13 wherein said cisplatin is administered twice weekly.

15. A pharmaceutical preparation to contribute to the treatment of chemotherapy- induced neuropathy comprising a suspension of leteprinim.

16. The pharmaceutical preparation according to claim 15 wherein said leteprinim comprises a dose of less than about 100 mg/kg.

17. The pharmaceutical preparation according to claim 15 wherein said leteprinim comprises a dose of about 50 mg/kg.

18. The pharmaceutical preparation according to claim 15 in the form of a suspension.

19. A method comprising administering a leteprinim suspension to a patient in need thereof thereby contributing to the treatment of cisplatin-induced neuropathy.

20. A method comprising administering cisplatin to contribute to the treatment of a cancer and administering a leteprinim suspension to a patient in need thereof thereby contributing to the treatment of cisplatin-induced neuropathy.

21. A method according to claim 19 wherein said leteprinim administration precedes the beginning of treatment with cisplatin or said leteprinim administration begins after the beginning of treatment with cisplatin.

22. A method according to claim 20 wherein said leteprinim is administered daily.

23. A method according to claim 20 wherein said cisplatin is administered twice weekly.

24. A method according to claim 20 wherein said leteprinim is administered daily and said cisplatin is administered twice weekly.

25. A method according to claim 20 wherein when said leteprinim administration and said cisplatin administration occur substantially simultaneously.

26. A method according to claim 25 wherein said leteprinim and said cisplatin are part of the same pharmaceutical preparation.

27. A method according to claim 19 wherein said leteprinim administration occurs in a dose of less than about 100 mg/kg.

28. A method according to claim 27 wherein said leteprinim administration occurs in a dose of about 50 mg/kg.

29. A pharmaceutical preparation comprising a leteprinim suspension wherein said pharmaceutical preparation is sold with instructional information directing the administration of said pharmaceutical preparation to a patient in need thereof to contribute to the treatment of cisplatin-induced neuropathy.

30. A pharmaceutical preparation according to claim 29 wherein said instructional information directs that said pharmaceutical preparation administration precede the beginning of treatment with cisplatin or that said pharmaceutical preparation administration begin after the beginning of treatment with cisplatin.

31. A pharmaceutical preparation according to claim 29 wherein when cisplatin treatment and said pharmaceutical preparation administration have both begun, said instructional information directs that said pharmaceutical preparation be administered daily.

32. A pharmaceutical preparation according to claim 29 wherein when cisplatin treatment and said pharmaceutical preparation administration have both begun, said instructional information directs that said cisplatin be administered twice weekly.

33. A pharmaceutical preparation according to claim 29 wherein when cisplatin treatment and said pharmaceutical preparation administration have both begun, said instructional information directs that said pharmaceutical preparation be administered daily and that said cisplatin be administered twice weekly.

34. A pharmaceutical preparation according to claim 29 wherein when cisplatin treatment and said pharmaceutical preparation administration have both begun, said instructional information directs that said pharmaceutical preparation administration and said cisplatin treatment occur substantially simultaneously.

35. A pharmaceutical preparation according to claim 34 wherein said pharmaceutical preparation further comprises cisplatin.

36. A pharmaceutical preparation according to claim 29 wherein said instructional information directs that said pharmaceutical preparation administration occur in an amount to deliver a leteprinim dose of less than about 100 mg/kg.

37. A pharmaceutical preparation according to claim 29 wherein said instructional information directs that said pharmaceutical preparation administration occur in an amount to deliver a leteprinim dose of about 50 mg/kg.

38. A pharmaceutical preparation comprising cisplatin and leteprinim wherein said cisplatin in said pharmaceutical preparation is intended to contribute to the treatment of a cancer and said leteprinim is intended to contribute to the treatment of cisplatin- induced neuropathy.

39. A pharmaceutical preparation according to claim 15, wherein said preparation is administered subcutaneously.

40. A method according to any one of claims 1 , 19, or 20, wherein said leteprinim is administered subcutaneously.

41. A pharmaceutical preparation according to claim 15, wherein said leteprinim comprises leteprinim in acid form.

42. A method according to any one of claims 1 , 19, or 20, wherein said leteprinim comprises leteprinim in acid form.

43. A pharmaceutical preparation according to claim 15, wherein said leteprinim comprises leteprinim in salt form.

44. A method according to any one of claims 1 , 19, or 20, wherein said leteprinim comprises leteprinim in salt form.