BRPI0715504A2 - PHARMACEUTICAL METHODS AND PREPARATIONS TO CONTRIBUTE TO THE TREATMENT OF CHEMOTHERAPY-INDUCED NEUROPATHY. - Google Patents

Description

“PHARMACEUTICAL METHODS AND PREPARATIONS IN ORDER TO CONTRIBUTE TO THE TREATMENT OF CHEMOTHERAPY-INDUCED NEUROPATHY”

Field of the Invention

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

Background of the Invention

While chemotherapeutic agents are vital for cancer treatment, their use may be limited by side effects such as neuropathy, which may result in at least a partial loss of body sensation. An example of such a chemotherapy agent is cisplatin, which is used extensively in the treatment of various cancers including ovarian, testicular and bladder tumors (Williams et al., (1979) Br. Med. J. 1: 1689-1691). While cisplatin may have beneficial effects in the treatment of cancers, the total dose that can be administered is limited by its toxic effects on the peripheral nervous system (Mollman, (1990) N. Engl. J. Med 322: 126- 127). Specifically, pathological examination of cisplatin-treated patients reveals selective injury or loss of large sensory nerve fibers, which may result in loss of sensation in various parts of the body (Thompson et al., (1984) Cancer 54: 1269-1275). . Recovery from this nerve injury is variable and many cancer survivors treated with cisplatin suffer from sensory loss and persistent nerve injury. (CavaIetti et al. (1994) Anticancer Res 14: 12871292).

A variety of agents have shown potential activity as nerve protectors against cisplatin-induced nerve damage in clinical trials. Some of these agents include an ACTH 4-9 growth factor activity fragment (ORG2766) (Gerritsen et al., (1990) N. Engl. J. Med. 322: 89-94), and amifostine thiois (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 al., (1992) Ann. Neurol. 31: 76-80), neurotrophin-3 (Gao et al., (1995) Ann. Neurol. 38 (1): 30-37) and glutamate (Boyle et al. (1999) J. Neuro-Oncol. 41: 107-116) have shown an ability to help prevent nerve damage caused by cisplatin. While all these agents have shown the potential to assist in the prevention of cisplatin-induced nerve injury, at this point there is a need for additional agents that can achieve this function. The present invention will produce such an agent.

Summary of the Invention

The present invention is directed to compositions containing Ieteprinim (in any of its various forms including leteprinim salts and acids) and their use to contribute to the prevention of chemotherapy-induced (e.g. cisplatin-induced) nerve damage in Cancer patients. The present invention likewise produces leteprinim delivery methods and Ieteprinim formulations to help alleviate chemotherapy-induced neuropathy. Accordingly, the present invention encompasses methods and pharmaceutical preparations which may be employed to contribute to the prevention of chemotherapy-induced (e.g., cisplatin-induced) nerve injury.

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

According to the present invention, administration of leteprinim may precede initiation of treatment with a chemotherapeutic (e.g. cisplatin) or administration of leteprinim may begin after initiation of treatment with a therapeutic chemotherapeutic (eg cisplatin). ). In certain embodiments leteprinim may be administered without limitation less than once a day on a weekly basis (ie up to six times for seven days a week), more preferably twice a week (ie. twice for seven days a week). A chemotherapeutic may be administered, without limitation, by any effective amount to its toxic amount. For example, cisplatin may be administered twice a week. Leteprinim and chemotherapeutic administration (e.g. cisplatin) may likewise occur substantially simultaneously. When administration is substantially simultaneous, leteprinim and chemotherapeutic (eg cisplatin) may be part of different or part of the same pharmaceutical preparations. Suitable doses of leteprinim may include, without limitation, from about 25 mg / kg to about 100 mg / kg, for example about 50 mg / kg. In one embodiment, leteprinim and optionally another active agent (s) may be formulated as a suspension, optionally a buffered suspension.

Embodiments of the present invention likewise include pharmaceutical preparations comprising leteprinim in which the pharmaceutical preparation is sold with instructional information that directs the administration of the pharmaceutical preparation to contribute to the treatment of a chemotherapy-induced neuropathy. (eg cisplatin-induced). In certain embodiments, instructional information will direct the administration of leteprinim in some way to one or more of the methods described above. Pharmaceutical preparations accompanied by such instructional information may include leteprinim as only the active ingredient or may further comprise at least one other active agent (e.g., a cisplatin-type chemotherapeutic). These pharmaceutical preparations, likewise, may include other active or inactive ingredients.

Pharmaceutical preparations according to the present invention may also include those comprising chemotherapeutic (e.g. cisplatin) and leteprinim in which the chemotherapeutic in the pharmaceutical preparation is intended to contribute to the treatment of cancer and leteprinim is intended to contribute to for the treatment of cisplatin-induced neuropathy.

Brief Description of the Drawings

Figure 1 shows the effect of leteprinim on cisplatin-induced changes in body weight.

Figure 2 shows the effect of leteprinim on cisplatin-induced changes in sensory perception as measured in a hot plate model.

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

Figure 5 shows the effect of leteprinim on cisplatin-induced changes.

conduction velocity of the sensitive nerve (SNCV).

Figure 6 shows the effect of leteprinim on cisplatin-induced changes in axonal diameter.

Figure 7 shows the effect of leteprinim on cisplatin-induced changes in g-rate.

Figure 8 shows the effect of leteprinim on changes in the ratio of degenerate to non-degenerate fibers following administration of cisplatin.

Detailed Description

1. Definitions

Instructional Information: As used herein, the term "instructional information"

shall mean material accompanying a pharmaceutical preparation which gives a description of how to administer the pharmaceutical preparation. This instructional information is generally considered to be the "label" for a pharmaceutical preparation. Instructional information can come in many forms including, without limitation, a paper insert, c.d. guidelines or guidance for a place on the network containing information relating to pharmaceutical preparation.

Prodrug: As used herein, the term "prodrug" shall mean compounds that rapidly transform in vivo to a compound useful in the invention, for example by hydrolysis. A full discussion of prodrugs is provided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, Series A.C.S.D. Symposium, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

Substantially Concurrently: As used herein, the term "substantially concurrently" must mean that two pharmaceutical preparations (ie, leteprinim and cisplatin) being administered at the same time. According to this definition, "same time" should be interpreted to include exactly simultaneously as well as in about ten minutes.

Treating, Treating and Contributing to the Treatment of: As used herein, the terms "treating", "treating" and "contributing to the treatment of" shall mean preventing, inhibiting, reducing, or partially or completely reversing development. nerve injury following administration of cisplatin With reference to cancers the terms include preventing, slowing the progression or growth of, diminishing, or eliminating a cancer including a solid tumor.These terms include both prophylactic administration and / or medical therapy as appropriate.

As used herein, the term "twice a week" means that a pharmaceutical preparation is administered twice within a 7 day period. Generally, these administrations should be equally 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.

As used herein, the term "leteprinim" refers to N-4-carboxyphenyl-3- (6-oxoidropurin-9-yl) propanamide and its various forms (e.g., leteprinim salt and acid forms). Leteprinim is also variably known as AIT-082, SPI-082, and SPI-205.

The leteprinim methods and compositions of the present invention may be employed 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, alkylating agents, podophyllotoxins, terpenoids (e.g., taxanes and vinca alkaloids), anti-metabolites, anthracyclines (e.g. platinum), and other anti-tumor agents. Vinca alkaloids include, but are not limited to, vincristine, vinblastine, vinorelbine, and vindesine. Other examples of chemotherapeutic agents include, but are not limited to, etoposide, teniposide, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, suramine, altaramine, chlorambucil, cytarabine, dacarbazine, docetaxel, etoposide, fludarabine, ifoside. known as mesna, tamoxifen, teniposide, and thioguanine. Peripheral neuropathy associated with oncolytic drug administration is described in C. M. Haskell, "Cancer Treatment" (6th Ed., W.B. Saunders, Philadelphia, 2001), Ch. 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 antifungal agents. alkylation (e.g. cisplatin). In another embodiment, the present invention is directed to treating drug-induced peripheral neuropathy associated with cisplatin administration.

Cisplatin is an anti-tumor agent commonly employed in the treatment of

many therapeutically refractory and common tumors. Cisplatin is useful as an anti-cancer agent because of its effects as a DNA synthesis inhibitor that prevents cell division. Conversely, neuropathy (ie nerve damage) is recognized as a dose-limiting toxicity, with symptoms of development following a cumulative dose of more than about 300 mg / m2. Cisplatin neuropathy predominantly affects large sensory nerve fibers and is generally associated with a reduction in signal amplitude of the sensory nerves, resulting in profoundly incapacitating sensory ataxia. This neuropathy may continue to progress after cessation of cisplatin treatment. The present invention shows that leteprinim may contribute to the treatment or prevention of cisplatin-induced nerve damage.

Depending on the particular needs of the individual subject involved, the leteprinim compositions of the present invention may be administered in various doses and regimens to produce effective treatments. Which constitute an effective amount of the selected leteprinim composition that will vary based on factors including, but not limited to, the chemotherapeutic compound activity, the patient's physiology, the patient's condition or disease, and the method / frequency / mode. administration of the chemotherapeutic agent (s) and / or leteprinim. Initially, the dosage and dosage regimen may be modulated to determine the optimal dosage for a characteristic patient.

The minimum dosage concentrations of leteprinim (weight of drug to patient weight) effective in attenuating 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 effective dosage concentrations in attenuating chemotherapeutic-induced neuropathy are about 100 mg / kg, 75 mg / kg, about 65 mg / kg, about 60 mg / kg, or about 55 mg / kg . An attenuating chemotherapeutic-induced (e.g. cisplatin-induced) neuropathy dosage concentration attenuating is about 50 mg / kg. Leteprinim compositions may be administered less than once a day weekly based on seven days a week (e.g. three to six times a week), or twice a week. Regardless of the scheme, the time interval between administrations need not be, but may be the same.

Leteprinim compositions may be administered employing a number of different routines including orally, topically, transdermally, intraperitoneally, subcutaneously, or intravenously. Effective amounts of the compounds may likewise be administered by injection into the cerebrospinal fluid or infusion directly into the brain. In one embodiment, the mode of administration is subcutaneous administration.

The methods of the present invention may be affected by employing leteprinim administered to a patient (e.g., mammal in need of treatment) or alone or as a pharmaceutical formulation. In addition, 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 likewise contain stabilizing and preservative agents and the like, as well as minor amounts of auxiliary substances such as emulsifying or wetting agents, as well as pH buffering agents and the like. plus which enhance the effectiveness of the active ingredient. The pharmaceutically acceptable carrier may be chosen from those generally known in the art, including, but not limited to, human serum albumin, ion exchangers, dextrose, alumina, lecithin, buffering 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 may be employed. Liquid compositions may likewise contain liquid phases or in addition to or for the exclusion of water. Examples of such additional liquid phases are glycerine, 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 liquid 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 form of leteprinim acid or salt (e.g., potassium salt form of leteprinim). However in another embodiment, the leteprinim formulation is a buffered lipid suspension in the form of leteprinim potassium salt.

Materials and methods

1. Animals

Ten-week-old female Dark Agouti rats (Janvier, Le Genest-St-Isle, France) were randomly assigned to 5 experimental groups: (a) a control group (n = 17) receiving placebo suspension treatment subcutaneous leteprinim (sc) acid; (b) a control group (n = 17) receiving placebo treatment for leteprinim s.c. salt (0.9% NaCl); (c) a cisplatin-treated group only (n = 17) (d) a cisplatin-treated group (n = 17) receiving a leteprinim s.c. suspension treatment of 50 mg / kg / d; and (e) a cisplatin treated group (n = 17) receiving a leteprinim s.c. K salt treatment at 50 mg / kg / d. The animals were housed 2 per cage and kept in a temperature controlled environment (21-22 ° C) and a reverse light-dark cycle (12 hours / 12 hours) with food and water available ad libitum. All experiments were performed according to institutional norms.

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

The neuropathy was induced by intraperitoneal (ip) injection of 0.1 mg / ml cisplatin solution (Sigma, L1IsIe d'Abeau Chesnes, France) twice a week for 4 weeks at a dose of 2 mg / kg by injection. Leteprinim treatments were performed on a daily basis from the first day of cisplatin administration until the end of the study (7 weeks). Cisplatin and leteprinim K salt were dissolved in sterile 0.9% NaCl (saline) solutions. The leteprine acid suspension and its placebo form were prepared in a 5% glucose solution. The suspension of leteprinim acid and its placebo and leteprinim K salt solution were freshly prepared every day. Body weight and survival rate were recorded daily. Hot plate and EMG tests 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

The 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, Rhône, France). The animal's behavior was observed and recorded, in particular the licking of the feet and the adjusted heel (jumping to escape the heat). The time required to feel thermal pain (as evidenced by licking and bouncing) is related to thermal sensitivity and tends to increase when thermal sensitivity is decreased.

4. Electromyography

Electrophysiological recordings were performed using an electromyographic

2000M Neuromatic Cell (EMG) (Dantec, Les Ulis1 France). Rats were anesthetized by intraperitoneal injection of 60 mg / kg ketamine hydrochloride (Imalgene 500, Rhône Mérieux, Lyon, France) and 4 mg / kg hyaline (Rompum 2%, Bayer Pharma, Kiel, Germany. Normal body temperature was maintained at 30 ° C with a heating lamp and controlled by a contact thermometer (Quick, Bioblock Scientific, Illkirch, France) placed on the tail surface.

The H-wave reflex was recorded in the hind paw pad muscle after sciatic nerve stimulation. A reference electrode and a base needle were placed over the lower back of the mouse. The sciatic nerve was stimulated with a single pulse of 0.2 ms at supra-maximal intensity. Amplitude (mV) and latency of H waves were recorded.

Sensitive nerve conduction velocity (SNCV) was similarly recorded. The electrodes on the tail skin were placed as follows: a reference needle inserted into the base of the tail and an anode needle placed 30 mm away from the reference needle toward the tail end. A base needle electrode was inserted between the reference needles and the anode. The caudal nerve was stimulated with a series of pulses 20 (for 0.2 ms) at an intensity of 12.8 mA. Speed was expressed in m / s.

5. Morphometric Analysis

At the end of the study, five animals per group were assigned to

to evaluate the effect of 50 mg / kg leteprinim on cisplatin-induced pathological changes. These animals were anesthetized with an intraperitoneal injection of 100 mg / kg Imalgene 500. A 5 mm segment of the sciatic nerve was excised for histology. Tissue was fixed overnight with a 4% glutaraldehyde solution (Sigma, L1IsIe d'Abeau-Chesnes, France) in phosphate buffered solution (pH = 7.4) and maintained at 30% sucrose at + 4 ° C until use. Nerve samples were post-fixed in a 1% osmium tethoxide solution (Sigma, Lisle d'Abeau-Chesnes, France) in phosphate buffer solution for 2 hours, dehydrated in alcohol series, and embedded in Epon. The inlaid tissues were then placed at + 70 ° C for 3 days to allow for the wax polymerization of the tissue. The 1.5 μιτι cross sections were cut with a microtome, stained with a 1% toluidine blue solution (Sigma, L1IsIe d'Abeau-Chesnes, France) for 2 minutes, dehydrated and mounted on Eukitt. One section of each sciatic nerve sample was examined using an optical microscope (Nikon, Tokyo, Japan). The analysis was performed on the entire surface of the section using semi-automated digital analysis imaging software (Biocom, France). For each fiber, the myelin and axonal sizes were automatically calculated and reported on the surface area (μιτι2). These two parameters were used to calculate the equivalent g-rate area (axonal diameter / fiber diameter) of each fiber (ie, [A / (A + M)] 0.5, A = axonal area, M = myelin), indicative of the relative thickness of the myelin sheath. The thickness of myelin is inversely proportional to the rate g.

The number of degenerate fibers was then manually counted by an operator. Myelinated fibers without axons, redundant myelin, and very large fiber-appearance sheaths of a thickness compared to their axonal diameter were considered fibers supporting the degeneration processes.

6. Data Analysis

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 moment 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 (s.e.m.).

RESULTS

1. Body weight

Compared to control rats showing progressive weight gain from start to finish, all animals receiving cisplatin showed marked weight loss on the day following cisplatin administration (p <0.001, bidirectional ANOVA) (See, Figure 1). The most severe weight loss was observed during the third and fourth weeks of cisplatin administration. After abstaining from cisplatin treatment, the rats showed progressive weight gain but remained below (about 20%) the control level. These results demonstrate that treatment with leteprinim acid or leteprinim K salt did not prevent the onset of growth arrest, but was associated with an improved growth profile when compared to the cisplatin alone group (about 10% above group treated with cisplatin only).

2. Sensory Test: Hot Plate

Figure 2 shows that from 2 weeks onwards, rats in the cisplatin-only group demonstrated a significant increase in threshold acuity ratings when compared to control groups (p <0.05, Fysher PLSD test). ). The most severe dysfunction was observed at week 4 (the last week of cisplatin administration) with an assessment time of about 30% above the control groups. Until the end of the study, the animals in the cisplatin-treated group did not recover the performance level of the control animals.

As similarly seen in Figure 2, treatment with leteprinim acid or leteprinim K salt significantly improves the hot plate performance of cisplatin-treated rats (p <0.05, Fisher PLSD test). Significant effects were observed from week 3 to week 7. At week 4, when severe cisplatin dysfunction was observed, rats treated with cisplatin with leteprinim acid or K salt of leteprinim showed a time of evaluation of only about 15% above the control values. At the end of the study (week 7), the performance of cisplatin-treated rats receiving leteprinim acid or leteprinim K salt was comparable to those of control rats. These results demonstrate that leteprinim may contribute to the prevention of pathologies associated with cisplatin treatment.

3. Electrophysiological Evaluations

The. H wave amplitude

As shown in Figure 3, a significant reduction in H-wave amplitude was observed in the cisplatin-only group as early as 1 week after initiation of cisplatin administration. The most severe reduction in H wave amplitude occurred at week 4, when the loss exceeded 45% of control levels. Recovery begins after cessation of cisplatin treatment (post-cisplatin time points) and was complete at week 7 (study completion).

Cisplatin rats treated with leteprinim acid or leteprinim K salt demonstrated improved H wave performance when compared to the cisplatin alone group. These differences were evident as early as week 2. At week 4 when the loss of H wave amplitude was maximal in the cisplatin-treated group only, cisplatin-treated rats received leteprinim shown at wavelengths of only about 20 % below control values. During week 5, leteprinim-treated cisplatin rats recovered for wave evaluation of control rats. These results, similarly, demonstrate that leprinim may help prevent or alleviate physiological changes associated with cisplatin administration.

B. H wave latency

Figure 4 shows a significant extent of H wave latency in the cisplatin-only group starting from week 2 when compared to that of control rats (p <0.05, Fisher's test). The most severe change was observed at week 4 with an extended assessment of about 12%. Cisplatin-treated rats completely recover this measurement during week 7.

Treatment with leteprinim acid or leteprinim K salt significantly attenuated the cisplatin-induced H-wave latency change (p <0.05, Fisher's test). At week 4 when the change was maximal in the cisplatin-only group, only about 4% of the extent of latency assessment (compared to control value) was observed in cisplatin groups receiving leteprinim treatment.

ç. Sensitive nerve conduction velocity

A progressive increase in CNSV was observed in the cisplatin group starting at week 1 (p <0.05, Fisher's test) (Figure 5). The most severe dysfunction was observed at week 4 with an assessment of about 15% below control values. Recovery started at 5 weeks but performance did not control levels again.

Leteprinim treatment significantly improves the CNSV performance of cisplatin-treated rats. At week 4 when CNSV dysfunction was maximal in the cisplatin-only 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 to those of control rats.

4. Morphometric Analysis

The. Axonal diameter

There was no statistical difference between the groups (p> 0.05, ANOVA) (Figure 6), although the axonal diameters of nerve fibers harvested from cisplatin-treated rats were slightly larger than those of the other groups. Treatment with leteprinim did not significantly change the axonal size of cisplatin-treated rats.

B. Myelin thickness

There were no statistical differences between groups regarding nerve fiber myelin sheath thickness (p> 0.05, ANOVA) (Figure 7).

ç. Percentage of degenerate fibers

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

The results described also demonstrate that treatment with leteprinim can markedly attenuate chemotherapeutic-induced (in this case, cisplatin-induced) nerve dysfunction and may accelerate recovery from this disorder. These improvements were evident in many parameters studied (H-wave amplitude and latency, SNCV and axonal degeneration) and appeared to be in good correlation with improvements observed in the hot plate test.

Histological results showed that the axonal diameter of the cisplatin-only group was slightly increased. This could represent axonal degeneration, a phenomenon observed as a consequence of cisplatin administration in rat brain development (Rzeski et al., (2004) Ann. Neurol. 56: 351-360). Treatment with leteprinim appeared to completely prevent this axonal tumors. In summary, the results described show that daily treatment with leteprinim may improve cisplatin-related sensory neuropathy.

Pharmaceutical preparations containing the described active ingredients are suitable for administration to humans or other mammals. Typically, pharmaceutical preparations are sterile, and do not contain toxic, carcinogenic, or mutagenic compounds that should cause an adverse reaction when administered. The pharmaceutical preparation may be administered before, during, or after the initiation of chemotherapeutic administration.

A method of the present invention may be effected by employing the active ingredients as described above, or with a physiologically acceptable salt, derivative, prodrug, or solvate thereof. The active ingredients may be administered as the pure compound, or as a pharmaceutical preparation containing another or both entities.

Pharmaceutical preparations include those in which the active ingredients are administered in an amount effective to achieve their intended purpose. More specifically, a "therapeutically effective amount" means an amount effective to prevent the development of, to eliminate, to slow the progression of, or to reduce the size of a solid tumor. Determination of a therapeutically effective amount is well within the ability of those skilled in the art, especially in light of the detailed description produced herein. A "therapeutically effective dose" refers to that amount of active ingredients that results in obtaining the desired effect. The therapeutic efficacy and toxicity of such active ingredients may be determined by standard pharmaceutical procedures in experimental cell or animal cultures, for example by determining LD50 (the lethal dose for 50% of the population) and ED50 ( therapeutically effective in 50% of the population). The dose relationship between therapeutic and toxic effects is the therapeutic index, which is expressed as the relationship between LD50 and ED50. A mild therapeutic index is preferred. The data obtained can be employed by formulating a dosage range for use in humans. The dosage of active ingredients is preferably within a range of circulating concentrations that includes the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the administration routine employed.

The exact dosage and formulation is determined by a special physician regarding the patient's condition. The dosage range and amount may be individually adjusted to produce the levels of active ingredients that are sufficient to maintain therapeutic or prophylactic effects.

The amount of the pharmaceutical preparation administered may be dependent upon the subject being treated, the subject's weight, the severity of the affliction, the mode of administration, and the judgment in the physician's prescription.

The active ingredients may be administered alone, or in admixture with a selected pharmaceutical carrier with reference to the intended administration routine and standard pharmaceutical practice. Pharmaceutical preparations for use in accordance with the present invention, therefore, may conveniently be formulated employing one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate the processing of active ingredients into preparations which may be prepared. be employed pharmaceutically.

When a therapeutically effective amount of the active ingredients is administered, the preparation may be in the form of a parenterally acceptable aqueous solution without pyrogen. The preparation of such parenterally acceptable solutions, having due consideration to pH, isotonicity, stability, and the like, is within the practicability of the art. A preferred preparation for intravenous injection will typically contain an isotonic vehicle although this feature is not required.

For veterinary use, the active ingredients are administered as an appropriately acceptable formulation in accordance with normal veterinary practice. The veterinarian can easily determine the dosage regimen that is most suitable for a specific animal. Various adaptations and modifications of the embodiments may be prepared and employed without departing from the assessment and spirit of the present invention who may be practiced other than as specifically described herein. The above description is intended to be illustrative rather than restrictive. The scope of the present invention is to be

determined only by the claims.

The terms and expressions that have been used herein are used as terms of description and not limitation, and there is no intention in using such terms and expressing equivalents of the features shown and described, or portions thereof, being acknowledged that various modifications are possible without the scope of this claimed invention. Furthermore, any one or more features of any embodiment of the present invention may 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.

Unless otherwise indicated, all numbers express amounts of ingredients, properties such as molecular weight, reaction conditions, and so forth, employed in the specification and claims are to be understood to be modified in accordance with the present invention. in all cases by the term "about." Therefore, unless otherwise indicated, the numerical parameters set forth in the specification and the claims set forth are approximations which may vary depending on the desired properties sought to be obtained by the present invention. In 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 must at least be interpreted by the number of significant digits reported and by ordinary application rounding the techniques. Although the numerical ranges and parameters having the broad scope of the present invention are approximations, the numerical values given in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from standard deviation by meeting their respective evaluation tests.

The terms "one" and "one" and "o" and similar referents used in the context

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 contradicting the context. The recitation of the value ranges here is merely intended to serve as a shorthand method of 35 individually referring to each separate value being in the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually listed herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicting the context. The use of any and all examples, or language examples (e.g., "as") produced herein is intended to be further clarified in the invention and does not represent a limitation on the scope of the present invention, otherwise claimed. . No language in the specification is to be construed as indicated by any essential element not claimed for the practice of the present invention.

The groupings of alternative elements or embodiments of the present invention described herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members or other elements set forth herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for convenience and / or patentability. When any such inclusion or deletion occurs, the specification is herein considered to contain the group as modified, thereby fulfilling the written description of all Markush groups employed in the appended claims.

Certain embodiments of this invention are described herein, including the best known mode for the inventors to carry out the invention. Certainly, variations in certain embodiments should be apparent to those of ordinary skill in the art in reading the foregoing description. The inventor expects skilled technicians to employ such variations as appropriate, and the inventors intend for the invention to be practiced differently than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject of the individual listed in the appended claims relating to this subject matter as permitted by applicable law. Furthermore, any combination of the above described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicting the context.

In addition, numerous references have been prepared for patents and printed publications from beginning to end of this specification. Each of the above cited references and printed publications are incorporated herein by reference in their entirety.

In closing, it is to be understood that the embodiments of the present invention described 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 limitation, alternative embodiments of the present invention may be used in accordance with the teachings herein. Accordingly, the present invention is not limited to those precisely as shown and described.

Claims (44)

1. Method, characterized by the fact that it comprises: administering a suspension of Ieteprinim to a patient in need thereof, thereby contributing to the treatment of chemotherapy-induced neuropathy. Method according to claim 1, characterized in that said administration of Ieteprinim precedes initiation of treatment with a chemotherapeutic agent; said administration of Ieteprinim begins after initiation of treatment with said chemotherapeutic agent; or, said administration of Ieteprinim and said administration of the chemotherapeutic agent occurs substantially simultaneously. A method according to claim 1, characterized in that said Ieteprinim is administered six times or less per week. Method according to Claim 1, characterized in that said Ieteprinim is administered twice a week. A method according to claim 2, characterized in that said administration of Ieteprinim and said administration of the chemotherapeutic agent occur substantially simultaneously. A method according to claim 5, characterized in that said Ieteprinim and said chemotherapeutic agent are part of the same pharmaceutical preparation. A method according to claim 1, characterized in that said administration of Ieteprinim occurs at a dose of less than about 100 mg / kg. A method according to claim 1, characterized in that said administration of Ieteprinim occurs at a dose of about 50 mg / kg. A method according to claim 2, characterized in that said chemotherapeutic agent is selected from alkylating agents, podophyllotoxins, terpenoids, anti-metabolites, anthracyclines, other anti-tumor agents, and combinations thereof. A method according to claim 2 wherein said chemotherapeutic agent is selected from vincristine vinblastine, vinrelbine, 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. A method according to claim 2, characterized in that said chemotherapeutic agent is selected from alkylating agents, vinca alkaloids, taxanes, and combinations thereof. A method according to claim 2, characterized in that said chemotherapeutic agent is selected from vincristine, paclitaxel, cisplatin, and combinations thereof. A method according to claim 2, characterized in that said chemotherapeutic agent is cisplatin. A method according to claim 13, characterized in that said cisplatin is administered twice a week. 15. Pharmaceutical preparation, characterized by the fact that it contributes to the treatment of chemotherapy-induced neuropathy comprising a suspension of leteprinim. Pharmaceutical preparation according to claim 15, characterized in that said leteprinim comprises a dose of less than about 100 mg / kg. Pharmaceutical preparation according to claim 15, characterized in that said leteprinim comprises a dose of about 50 mg / kg. Pharmaceutical preparation according to claim 15, characterized in that it is in the form of a suspension. 19. Method, characterized by the fact that it comprises administering a leteprinim suspension to a patient with this need, thereby contributing to the treatment of cisplatin-induced neuropathy. 20. Method, characterized in that it comprises administering cisplatin to contribute to the treatment of cancer and administering a leteprinim suspension to a patient in need thereof, thereby contributing to the treatment of cisplatin-induced neuropathy. A method according to claim 19, wherein said administration of leteprinim precedes initiation of cisplatin treatment or said administration of leteprinim begins after initiation of treatment with cisplatin treatment. A method according to claim 20, characterized in that said leteprinim is administered daily. A method according to claim 20, characterized in that said cisplatin is administered twice a week. A method according to claim 20, characterized in that said leteprinim is administered daily and said cisplatin is administered twice a week. A method according to claim 20, characterized in that said administration of leteprinim and said administration of cisplatin occur substantially simultaneously. A method according to claim 25, characterized in that said leteprinim and said cisplatin are part of the same pharmaceutical preparation. Method according to claim 19, characterized in that said administration of leteprinim occurs at a dose of less than about 100 mg / kg. A method according to claim 27, characterized in that said administration of leteprinim occurs at a dose of about 50 mg / kg. 29. Pharmaceutical preparation, characterized in that it comprises a leteprinim suspension in which the 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. . Pharmaceutical preparation according to Claim 29, characterized in that said instructional information directs that said administration of the pharmaceutical preparation precedes initiation of cisplatin treatment or that said administration of the pharmaceutical preparation begins after initiation of the preparation. cisplatin treatment. Pharmaceutical preparation according to claim 29, characterized in that when the cisplatin treatment and said pharmaceutical preparation administration have both beginnings, said instructional information directs that said pharmaceutical preparation is to be administered on a daily basis. - seriously. Pharmaceutical preparation according to Claim 29, characterized in that when treatment of cisplatin and said administration of the pharmaceutical preparation have both beginnings, said instructional information directs that said cisplatin is administered twice. per week. Pharmaceutical preparation according to Claim 29, characterized in that when cisplatin treatment and said pharmaceutical preparation administration have both beginnings, the instructional information directs that said pharmaceutical preparation is administered. daily and for said cisplatin to be administered twice a week. Pharmaceutical preparation according to Claim 29, characterized in that when treatment of cisplatin and said administration of the pharmaceutical preparation have both beginnings, said instructional information directs that said administration of the pharmaceutical preparation and said treatment of cisplatin occurs substantially simultaneously. Pharmaceutical preparation according to claim 34, characterized in that said pharmaceutical preparation also comprises cisplatin. Pharmaceutical preparation according to Claim 29, characterized in that said instructional information directs said administration of the pharmaceutical preparation to occur in an amount to deliver a leteprinim dose of less than about 100 mg / kg. . Pharmaceutical preparation according to claim 29, characterized in that said instructional information directs said administration of the pharmaceutical preparation to occur in an amount to release a leteprinim dose of about 50 mg / kg. 38. Pharmaceutical preparation, characterized in that it comprises cisplatin and leteprinim in which said cisplatin in said pharmaceutical preparation is intended to contribute to the treatment of cancer and said leteprinim is intended to contribute to the treatment of neuropathy-induced cisplatin. Pharmaceutical preparation according to Claim 15, characterized in that said preparation is administered subcutaneously. A method according to any one of claims 1, 19, or 20, characterized in that said leteprinim is administered subcutaneously. Pharmaceutical preparation according to Claim 15, characterized in that said Ieteprininn comprises leteprinim in acid form. A method according to any one of claims 1, 19, or 20, characterized in that said leteprinim comprises leteprinim in the form of acid. Pharmaceutical preparation according to claim 15, characterized in that said leteprinim comprises leteprinim in salt form. A method according to any one of claims 1, 19, or 20, characterized in that said leteprinim comprises leteprinim in salt form.