U.S. patent application number 12/078991 was filed with the patent office on 2008-08-14 for medicament for preventing and/or treating peripheral neuropathies.
This patent application is currently assigned to SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A.. Invention is credited to Claudio Cavazza, Franco Mandelli, Claudio Pisano, Loredana Vesci.
Application Number | 20080194683 12/078991 |
Document ID | / |
Family ID | 26332128 |
Filed Date | 2008-08-14 |
United States Patent
Application |
20080194683 |
Kind Code |
A1 |
Cavazza; Claudio ; et
al. |
August 14, 2008 |
Medicament for preventing and/or treating peripheral
neuropathies
Abstract
This invention disclosed the use of acetyl L-carnitine or of a
pharmaceutically acceptable salt thereof for the preparation of a
medicament for preventing and/or treating peripheral neuropathies
induced by the administration of a peripheral neuropathy--inducing
anticancer agent. In particular said anticancer agent is selected
from the group consisting of the family of platin compounds,
taxanes, epothilone class and vinca alkaloids, farnesyl transferase
inhibitors, thalidomide, 5-fluorouracil, cryptophycin analogues,
proteasome inhibitors. Said medicament can be administered in a
co-ordinated manner to a subject suffering from said peripheral
neuropathies, or expected to suffer from said peripheral
neuropathies. Beneficial effects on the patient's quality of life
are achieved and an improvement of therapeutic index of the
anticancer agent is obtained.
Inventors: |
Cavazza; Claudio; (Rome,
IT) ; Pisano; Claudio; (Aprilia, IT) ; Vesci;
Loredana; (Rome, IT) ; Mandelli; Franco;
(Rome, IT) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
SIGMA-TAU INDUSTRIE FARMACEUTICHE
RIUNITE S.P.A.
Rome
IT
|
Family ID: |
26332128 |
Appl. No.: |
12/078991 |
Filed: |
April 9, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11407351 |
Apr 20, 2006 |
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12078991 |
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10292823 |
Nov 13, 2002 |
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11407351 |
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09769488 |
Jan 26, 2001 |
6610699 |
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10292823 |
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PCT/IT99/00242 |
Jul 27, 1999 |
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09769488 |
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Current U.S.
Class: |
514/556 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 25/00 20180101; A61K 31/28 20130101; A61K 38/14 20130101; A61K
31/475 20130101; A61P 39/00 20180101; A61K 31/221 20130101; A61P
43/00 20180101; A61K 31/555 20130101; A61K 33/24 20130101; A61K
31/221 20130101; A61P 35/04 20180101; A61K 31/475 20130101; A61K
31/205 20130101; A61K 31/28 20130101; A61K 2300/00 20130101; A61K
38/14 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/205 20130101; A61K 2300/00 20130101;
A61K 31/335 20130101; A61K 31/555 20130101; A61K 31/335 20130101;
A61K 45/06 20130101; A61K 33/24 20130101; A61P 25/02 20180101 |
Class at
Publication: |
514/556 |
International
Class: |
A61K 31/205 20060101
A61K031/205 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 7, 1999 |
IT |
RM99A000206 |
Jul 27, 1999 |
IT |
RM98A000571 |
Claims
1. A method of preventing and/or treating peripheral neuropathies
induced by the administration of a peripheral neuropathy-inducing
anticancer agent, with the proviso that said anticancer agent is
not taxol or cisplatin comprising administering to a subject acetyl
L-carnitine or of a pharmaceutically acceptable salt thereof and
said anticancer agent.
2. The method according to claim 1, wherein said anticancer agent
and said acetyl L-carnitine or of a pharmaceutically acceptable
salt thereof are administered in a co-ordinated manner.
3. The according to claim 1, wherein said peripheral
neuropathy-inducing anticancer agent is selected from the group
consisting of platin compounds, taxanes, epothilone class, vinca
alkaloids, farnesyl transferase inhibitors, thalidomide,
5-fluorouracil, cryptophycin analogues, and proteasome
inhibitors.
4. The method according to claim 3, wherein said anticancer agent
is selected from the group consisting of Carboplatin, Oxaliplatin,
Docetaxel, Epothilone, Vinorelbine, Vincristine, the farnesyl
transferase inhibitor R11577, thalidomide, the cryptophycin
analogue LY355703, and the proteasome inhibitor PS341.
5. The method according to claim 2, wherein said administration is
substantially simultaneous with the anticancer agent.
6. The method according to claim 2, wherein said administration of
said anticancer agent and said acetyl L-carnitine is
sequential.
7. The method according to claim 2, wherein said administration is
in the form of a composition comprising said acetyl L-carnitine or
a pharmaceutically acceptable salt thereof in combination and in a
mixture with said anticancer agent in addition to optional
pharmaceutically acceptable excipients and/or vehicles.
8. The method according to claim 1, wherein 0.1 to 3 g/day of
acetyl L-carnitine or of an equivalent amount of a pharmaceutically
acceptable salt thereof are administered.
9. The method according to claim 1, wherein said pharmacologically
acceptable salt of acetyl L-carnitine is selected from the group
consisting of chloride, bromide, orotate, acid aspartate, acid
citrate, acid phosphate, fumarate and acid fumarate, maleate and
acid maleate, acid oxalate, acid sulphate, glucose phosphate,
tartrate and acid tartrate.
10. The method according to claim 1, wherein said acetyl
L-carnitine is administered to a subject in view of the need of a
treatment with said anticancer agent.
11. The method according to claim 10, wherein said anticancer agent
and said acetyl L-carnitine are administered immediately before or
immediately after surgical removal of the tumor.
12. The method according to claim 10, wherein said anticancer agent
is alternative to surgical removal of the tumor.
13. The method according to claim 1, wherein a further carnitine or
a pharmaceutically acceptable salt thereof is administered.
14. The method according to claim 1, wherein a further anticancer
agent is administered.
15.-27. (canceled)
Description
[0001] This application is a continuation-in-part of application
Ser. No. 10/292,823, filed Nov. 13, 2002, which in turn is a
continuation-in-part of application Ser. No. 09/769,488 filed Jan.
26, 2001 (now U.S. Pat. No. 6,610,699) which is a continuation of
PCT/IT99/00242 filed Jul. 27, 1999, the entire content of which is
hereby incorporated by reference in this application.
[0002] The invention described herein relates to the use of
L-carnitine and alkanoyl L-carnitines in the preparation of
medicaments useful in the treatment of tumours, particularly in
combination with anticancer agents.
BACKGROUND TO THE INVENTION
[0003] It is well-known that the use of anticancer agents in human
therapy causes a large number of toxic or side effects which may be
life-threatening for the patients. These complications, in fact,
may lead to a reduction in the doses of the agents, and
occasionally to discontinuation of the therapy itself.
[0004] Reduction of the dose or discontinuation of the therapy in
many cases causes a deterioration of the individual's general
condition because it favours the development of relapses, with
consequences which are sometimes fatal for the patient.
[0005] Another very important and strongly felt aspect in the
hospital setting and among the families of oncological patients is
the concept of "improving the quality of life" of the patients
under treatment.
[0006] It is equally well known that patients undergoing regular
polychemo-therapy for cancer are subject to a substantial weight
loss.
[0007] The growing number and importance of the anticancer agents
used in human therapy, the main limitation of which continues to be
the occurrence of toxic or side effects, mean that this problem is
still a matter for considerable concern.
[0008] Thus, the discovery of new agents or new, appropriate
combinations of different agents capable of substantially reducing
the toxic or side effects caused by anticancer agents used in human
therapy is much to be desired.
[0009] Previous uses of L-carnitine in combination with anticancer
agents are already known.
[0010] In experimental animal models, it has been demonstrated that
rats treated with doxorubicin alone show a greater weight loss than
a group of rats treated with the same substance in combination with
L-carnitine (Senekowitsch R, Lohninger A, Kriegel H., Staniek H.,
Krieglsteiner H P., Kaiser E. Protective effects of carnitine on
adriamycin toxicity to heart. In: Kaiser E., Lohninger A., (eds.).
Carnitine: its role in lung and heart disorders: 126-137. Karger,
Basel-New York, 1987).
[0011] U.S. Pat. No. 4,713,370 describes the use of carnitine in
combination with cytostatic agents such as daunomycin,
N-acetyl-daunomycin and daunomycin oxime to reduce the cardiac
toxicity of these compounds. U.S. Pat. No. 4,267,163 describes the
use of carnitine in combination with cytostatic agents such as
adriamycin, adriamycin-14-octanoate, 4' -epi-adriamycin, adriamycin
beta-anomer and 4'-epi-adriamycin gamma-anomer to reduce the
cardiac toxicity of these compounds. U.S. Pat. No. 4,751,242
describes the use of acetyl L-carnitine for the therapeutic
treatment of peripheral neuropathies. In this latter patent,
peripheral neuropathies are defined as a group of persistent
disturbances of the motor neurons of the brain stem and spinal cord
and/or the primary sensory neurons and/or the peripheral autonomic
neurons, with involvement of the peripheral axons and their
attendant supporting structures. With regard to their etiology,
peripheral neuropathies constitute a heterogeneous class of
diseases because their etiology may be secondary to viral
infections (herpes zoster), ischaemia (arteriosclerosis), metabolic
unbalances (diabetes, renal and liver insufficiency), drug-induced
toxicity (adriamicine, isoniazide, nitrofurantoin), mechanical
stresses (compression, entrapment, fracture or dislocation of
bones), radiations, genetic factors and pathologies of the immune
system. However, no matter what the actual etiological cause of the
disease form is, it is always possible to detect an alteration in
the membrane fluidity resulting from an alteration of the cell
lipids, cholesterol and gangliosides. Lipids play a very important
role in defining the tertiary and quaternary protein structure and
in maintaining the stability of adenosin-triphosphatase structure.
In fact, their absence brings about the enzyme inactivity. In that
reference, it is postulated that acetyl L-carnitine is likely to
perform a "scavenger" effect on the free radicals (superoxide,
hydroperoxide) that form in conditions of irregular or insufficient
perfusion or during phlogistic processes because of the decreased
activity of cytochrome oxidase that controls the metabolic shift
between the tetravalent and the bivalent anaerobic route. Acetyl
L-carnitine, by increasing the levels of reduced glutathione, one
of the most important antioxidant metabolites, and probably the
levels of the cytochrome oxidases, might bring about the free
radicals scavenge and the restoration of the tetravalent
oxido-reductant respiratory mechanism in general and of the neurons
in particular. Moreover, acetyl L-carnitine would affect the
neurons by bringing about an increase in ATP-ase and AChE that are
indispensable for optimum neurotransmission.
[0012] Other studies have addressed the evaluation of the
protective effects of carnitines on anthracycline-induced cardiac
toxicity ((Neri B., Comparini T., Milani A., Torcia M., Clin. Trial
J. 20, 98-103, 1983; De Leonardis V., De Scalzi M., Neri B., et al.
Int. J. Clin. Pharm. Res. 70, 307-311, 1987).
[0013] The patent and bibliographical references cited above
demonstrate that many efforts have been made in an attempt to
reduce the toxic or side effects of anticancer agents, without,
however, solving this serious problem in a satisfactory manner.
[0014] Carboplatin is a structural analogue of Cisplatin and its
associated nephrotoxicity, though by no means negligible, is less
than that of Cisplatin. Peripheral neurotoxicity is the
dose-limiting side effect of the antineoplastic drug Cisplatin
(Cavaletti et al. Journal of the Peripheral Nervous System, Vol. 6,
Number 3; September 2001, 136-2001 Meeting of the Peripheral Nerve
Society).
[0015] Vincristine is a well-known anticancer agent which has toxic
effects, particularly at the level of the immune system.
[0016] Taxol is a natural extract, first isolated from the bark of
Taxus brevifolia, with anticancer properties and has proved
neurotoxic and myelotoxic in human subjects. It is used for the
treatment of tumours resistant to platinum therapy, but gives rise
to greater cumulative toxicity in the peripheral nervous system. It
has also been ascertained that Taxol induces neutropenia in the
subjects treated (Rowinsky e al.; Semin. Oncol. (1993), August 20
(4 suppl 3), 1-15; Onetto e al. J. Natl. Cancer Inst. Monogr.
(1993); (15):131-9).
[0017] Thalidomide is an oral immunomodulatory agent originally
developed as a treatment for insomnia and morning sickness in the
1950s.
[0018] The mechanism of action of thalidomide is not completely
understood. Thalidomide appears to have multiple actions, including
the ability to inhibit the growth and survival of myeloma cells in
various ways and to inhibit the angiogenesis (Micromedex, Inc.;
2002).
[0019] Recent Clinical Practice Guidelines for Multiple Myeloma
developed by the National Comprehensive Cancer Network (NCCN.RTM.,
2004) indicate that the use of thalidomide is an appropriate option
as salvage therapy for relapsed or refractory disease and in
combination with dexamethasone as initial therapy in patients with
advanced myeloma (Durie-Salmon Stage II or III).
[0020] A regulatory application for thalidomide is currently under
review by the Food and Drug Administration (FDA) to confirm its
efficacy and safety for use in myeloma. Thalidomide is approved in
the US for the treatment of the cutaneous manifestations of
moderate to severe erythema nodosum leprosum.
[0021] In addition to myeloma (Br. J. Haematol. 2003; 120:18-26),
thalidomide is being evaluated in clinical trials as a treatment
for a variety of solid tumors and hematologic maligancies.
[0022] Different classes of chemotherapeutic drugs induce
peripheral neurotoxicity, among which we mention: taxoids, platinum
compounds, vinca alkaloids, the epothilone class, farnesyl
transferase inhibitors, thalidomide, 5-fluorouracil, cryptophycin
analogues, proteasome inhibitors.
[0023] Severe peripheral neuropathy can induce therapy
modification, while mild or moderate cases still represent an
important tolerability problem limiting patient quality of
life.
[0024] Whereas the vinca alkaloids bind to tubulin and prevent the
polymerisation from soluble dimers into microtubules, the taxoids
promote the formation of microtubules and prevent their
depolymerisation, which results in an abundance of rigid
microtubules.
[0025] Microtubules are essential components for the maintenance of
cell shape, a variety of cellular actions and axoplasmic transport.
Defective function of microtubules in neurons and axons may be the
origin of the neurotoxicity of both families of chemotherapeutic
agents.
[0026] The taxoids induce primarily a symmetrically distributed
sensory distal neuropathy, which is related to both single and
cumulative doses of the drug and is possibly dependent on the
regimen. The neurotoxicity of Taxol is due to a unique mechanism of
action; it binds to tubulin and promotes microtubule assembly
(Schiff P. B. et al., Nature 1979; Parnass J. and Horowitz S. B.,
J. Cell. Biol. 1981). Microtubules formed in the presence of Taxol
are stable in conditions which ordinarily depolymerize them,
including the presence of calcium and cold. Paclitaxel also alters
the kinetics of microtubule assembly, eliminating the 3- to
4-minute lag time normally observed prior the initiation of
assembly (Horowitz S. B. et al., Ann. N.Y. Acad. Sci. 1986). This
mechanism contrasts with that of the vinca alkaloids which inhibit
microtubule assembly.
[0027] This contrasting mechanism makes difficult to find a drug
acting at the same time on the two differently induced
neuropathy.
[0028] With the use of hemopoietic growth factor rescue of
myelotoxicity, neurotoxicity becomes the dose-limiting factor
(Schiller et al., J. Clin. Oncol. 1994). Symptoms may begin as
early as 24 to 72 hours after treatment with high single doses
(>250 mg/m.sup.2), but the neurotoxicity is typically
cumulative, with symptoms progressing after each treatment at both
high and low doses.
[0029] The symptoms are generally tolerable (NCI grade 1 or 2). The
neurologic examination characteristically reveals an elevated
threshold and perception of vibration in a distal, symmetric,
glove-and-stocking pattern. In general, large-fiber modalities
(vibration, proprioception) are more frequently affected than loss
of small-fiber modalities (pain, temperature). Deep tendon reflexes
are also frequently affected, with the distal (ankle) reflex being
invariably absent or reduced.
[0030] Nerve conduction studies show reductions of sensory nerve
action potential amplitudes in a symmetric, distal,
length-dependent fashion. Sural sensory nerve action amplitude is
virtually always reduced or absent in symptomatic patients.
[0031] Mild sensory symptoms have usually improved or resolved
completely within several months after discontinuation of
Taxol.
[0032] Cisplatin induces a peripheral sensory axonal neuropathy,
affecting large-diameter and, to a lesser extent, small-diameter
sensory fibres. Paraesthesias and impaired propiocepsis are the
most common symptoms (Thompson S. W. et al., Cancer 1984).
Cisplatin accumulates in and damages the dorsal root ganglia,
axonal changes being secondary to neuronal damage (Warner E., Int.
J. Gynecol. Cancer 1995).
[0033] The incidence of Cisplatin-induced neuropathy depends
largely on the cumulative dose, the onset of symptoms being seen at
a total dose of Cisplatin 330 to 400 mg/m.sup.2. Cisplatin binds
tightly and irreversibly to nerve tissue, which explains the
deterioration of neurological condition which sometimes occurs
after cessation of Cisplatin therapy.
[0034] The vinca alkaloids induce a peripheral sensory-motor
polyneurophaty and autonomic neuropathy, which appears to be
partially reversible after some months (Potsma T. J. et al., J.
Neurooncol. 1993).
[0035] Thalidomide induces a peripheral sensory-motor
polyneurophaty. Thalidomide neurotoxicity occurs due to axonal
degeneration without demyelination and affects mainly the lower
limbs (Neurology 2004; 62:2291-2293). It can be quite painful and
is characterized by a stocking-glove distribution and begins in the
feet with paresthesias, progresses to the hands with a burning
sensation and muscle cramps. Motor disability does not usually
occur although may present late in the course of neuropathy and is
generally reversible.
[0036] The risk of developing thalidomide-induced sensory
peripheral neuropathy is highly variable and depends on the
cumulative dose of the drug. The incidence is .about.70% when 20 g
of thalidomide were given, and a progressive increase was evident
with dose escalation (Neurology 2004; 62:2291-2293). Moreover, the
severity of the sensory neuropathy is also dose related.
[0037] To date, the most effective approach to management of
thalidomide-induced sensory peripheral neuropathy is to discontinue
the treatment at appearance of symptoms. Sensory neuropathy may not
be reversible if thalidomide is continued with ongoing symptoms
(Br. J. Haematol. 2003; 120:18-26) There is therefore a perceived
need to identify a drug that be helpful in preventing and/or
treating thalidomide-induced sensory peripheral neuropathy.
[0038] The epothilone family has a toxicological profile similar to
the taxanes one (Lee F Y et al Proc Am Assoc Cancer Res, 2002,
792).
[0039] Several other compounds used in cancer treatment show mild
to severe neuropathy. Among others, particular mention is made for
the farnesyl transferase inhibitors, such as R11577 (Adjei, A. A.,
et al., J. Clin. Oncol., 2003, May, 1; 21 (9): 1760-6); Thalidomide
(Rajkumar, S. V., et al., Leukemia, 2003, April; 17 (4): 775-9);
5-fluorouracyl (van Laarhoven, H. W., et al., Anticancer Res.,
2003, January-February; 231 (1B): 647-8); Docetaxel (Thongprasert,
S., et al., J. Med. Assoc. Thai, 2002, December; 85 (12):
1296-300); cryptophycin analogues, such as LY355703 (Sessa, C., et
al., Eur. J. Cancer., 2002, December; 38 (18): 2388-96) and
proteasome inhibitors, such as PS431 (Aghajanian, C., et al., Clin.
Cancer Res., 2002, August; 8 (8): 2505-11).
[0040] One of the general problems of pharmacological therapy is
the therapeutic index of the agents, that is to say the ratio of
the therapeutically effective dose to the toxic dose, or, at any
rate, the dose that gives rise to the onset of side effects.
[0041] The medical community still perceives the need for
therapeutic regimens which allow the patient to face up to the
treatment, which, in the case of anticancer chemotherapy is
particularly hard to support, while at the same time conserving an
acceptable quality of life. These considerations also apply to the
therapeutic treatment of animals, for instance, so-called pets.
[0042] The natural tendency to reduce the doses, and thus the use
of pharmaceutical forms suitable for therapeutically useful
administrations without obliging the patient to take the agents too
often, contrasts with the minimum effective doses typical of each
anticancer agent.
[0043] International application WO 00/06134 discloses the use of
L-carnitine and its alkanoyl derivatives in the preparation of
medicaments with anticancer agents. In particular, the application
discloses the use of combinations of alkanoyl L-carnitine and
anticancer agents with an improvement in the therapeutic index and
a reduction of the side effects typical of anticancer chemotherapy.
In particular, the application discloses the effect of L-carnitine
on the general toxicity, expressed as survival time or weight loss
for an anticancer agent. More in detail, the cited application
provide a synergistic effect by propionyl L-carnitine on anticancer
activity, for example of taxol. As far as the specific toxicity of
the several anticancer agents is concerned, the cited application
provides examples of protective effect against pulmonary toxicity
of bleomycin, neutropenia induced by taxol, and taxol-induced
peripheral neuropathy.
[0044] This general disclosure on the carnitine family would not
have led the skilled person to foresee the specific activity of
acetyl L-carnitine in the prevention and/or treatment of peripheral
neuropathy induced by some anticancer agents.
[0045] The same reasoning can be applied in the case of the
description of the effects of acetyl L-carnitine in the prevention
and/or treatment of peripheral neuropathy induced by cisplatin
(Vitali, G. et al., Annals of Oncology, Vol. 13, 2002, Supplement
5: 179, 659P; Cavaletti, G. et al., Journal of Neurology, Vol. 249,
Suppl. 1, June 2002: 1/28, 78; Cavaletti, G. and Zanna, C.,
European Journal of Cancer, 38 (2002): 1832-7).
SUMMARY OF THE INVENTION
[0046] It has now been found that the co-ordinated use--this term
will be precisely defined below--of a peripheral
neuropathy-inducing anticancer agent and acetyl L-carnitine exerts
a preventive and/or treating effect on the neuropathy-inducing
activity of the anticancer agent.
[0047] In the context of the invention described herein, the
co-ordinated use of a therapeutically effective amount of a
peripheral neuropathy-inducing anticancer agent, in particular of
the family of platin compounds, taxanes, epothilone class and vinca
alkaloids, farnesyl transferase inhibitors, thalidomide,
5-fluorouracil, cryptophycin analogues, proteasome inhibitors and a
detoxifying amount of acetyl L-carnitine, or one of its
pharmacologically acceptable salts, affords a potent protective
effect against the peripheral nerve toxicity and side effects of
the anticancer agent, without impairing its efficacy, thus giving
rise, amongst other things, to a substantial improvement in the
quality of life and a prolonging of life itself in the subjects
treated, whether human subjects or animals.
[0048] It is an object of the present invention the use of acetyl
L-carnitine or of a pharmaceutically acceptable salt thereof for
the preparation of a medicament for preventing and/or treating
peripheral neuropathies induced by the administration of a
peripheral neuropathy-inducing anticancer drug, said medicament to
be administered in a coordinated manner to a subject suffering from
said peripheral neuropathies, or expected to suffer from said
peripheral neuropathies, with the proviso that said anticancer
agent is not taxol or cisplatin.
[0049] Another object of the invention described herein are
combinations of acetyl L-carnitine or a pharmaceutically acceptable
salt thereof with peripheral neuropathy-inducing anticancer agents
and the related pharmaceutical compositions.
[0050] The well known lack of toxic or side effects of acetyl
L-carnitine makes the use of this compound particularly safe even
for long periods of administration.
[0051] The implementation of the invention described herein also
contributes to improving the quality of life of the patients
treated; one need only think of the physical suffering caused by
peripheral neuropathy.
[0052] These and other objects of the invention described herein
will be described in detail in the embodiment forms of the
invention, also by means of examples.
[0053] In the context of the invention described herein, the terms
"antineoplastic", "anticancer" and "antiproliferative" are to be
understood as being essentially synonymous.
DETAILED DESCRIPTION OF THE INVENTION
[0054] In the context of the invention described herein, what is
meant by "co-ordinated use" of the aforesaid compounds is,
indifferently, either (i) co-administration, i.e. the substantially
simultaneous or sequential administration of acetyl L-carnitine or
one of its pharmacologically acceptable salts and of an anticancer
agent, or (ii) the administration of a composition comprising the
aforesaid active ingredients in combination and in a mixture, in
addition to optional pharmaceutically acceptable excipients and/or
vehicles.
[0055] The invention described herein thus covers both the
co-administration of acetyl L-carnitine or one of its
pharmacologically acceptable salts and of the anticancer agent, and
pharmaceutical compositions, which can be administered orally,
parenterally or nasally, including controlled-release forms,
comprising the two active ingredients in a mixture.
[0056] The intended use of the co-administration in the context of
the present invention means the possibility to perform a preventive
treatment (intended also as prevention) for the possible adverse
effect, i.e. peripheral neuropathy, of the anticancer agent. In
another embodiment, by the intended use of co-administration, the
present invention means the therapeutic treatment (intended also as
treatment or therapy) of the adverse effect of the anticancer
agent. In the case of preventive treatment, acetyl L-carnitine,
shall be administered in view of the need of a treatment with an
anticancer agent, known to imply peripheral neuropathy. The start
of the administration, the subsequent schedule (namely, the
posology) and the decision upon continuing the administration even
after the start of the treatment with the anticancer agent shall be
within the knowledge of the clinical expert, depending also on the
kind of anticancer agent, the type and severity of the foreseen
adverse effect, the conditions of the patient. Just for sake of
example, the administration of acetyl L-carnitine can be started
immediately before or immediately after surgical removal of the
tumor, but in any case before the start of the administration of
the anticancer agent, also in the case the agent be administered
before surgery. In case the administration of the anticancer agent
is foreseen before, or alternatively to, surgery, both prevention
and treatment may apply, whenever the case.
[0057] Co-administration also means a package, or manufactured
article, comprising distinct administration forms of acetyl
L-carnitine or one of its pharmacologically acceptable salts and of
an anticancer agent, accompanied by instructions for the
co-ordinated simultaneous or time-scheduled intake of the active
ingredients according to a dosage regimen established by the
primary care physician, on the basis of the patient's condition.
This package is suitable both for prevention and treatment. In a
different embodiment of the present invention, the package or
manufactured article comprises a unit dosage containing both the
anticancer agent and acetyl L-carnitine.
[0058] What is meant by a pharmacologically acceptable salt of
acetyl L-carnitine is any salt of the latter with an acid that does
not give rise to toxic or side effects. These acids are well known
to pharmacologists and to experts in pharmaceutical technology.
[0059] Examples of pharmacologically acceptable salts of
L-carnitine or of the alkanoyl L-carnitines, though not exclusively
these, are chloride; bromide; iodide; aspartate; acid aspartate;
citrate; acid citrate; tartrate; acid tartrate; phosphate; acid
phosphate; fumarate; acid fumarate; glycerophosphate; glucose
phosphate; lactate; maleate; acid maleate; mucate; orotate,
oxalate; acid oxalate; sulphate; acid sulphate; trichloroacetate;
trifluoroacetate; methane sulphonate; pamoate and acid pamoate.
Said salts are disclosed in several patents in the name of the
applicant.
[0060] One preferred form of daily dosing of acetyl L-carnitine for
clinical use is a composition comprising an amount of acetyl
L-carnitine from 0.1 to 3 g, and preferably 0.5 to 3 g, or an
equivalent amount of a pharmaceutically acceptable salt.
[0061] The invention described herein is advantageous in the
prevention or treatment of peripheral neuropathy.
[0062] What is meant by substantially protective effect is the
prevention, reduction or elimination or anyway treatment of the
side effect to a statistically significant extent.
[0063] The embodiment of the invention described herein also
contributes to healing and to prolonging the lives of the patients
thanks to the increase in therapeutic success due to the
possibility of maintaining the scheduled treatment protocols or of
increasing the doses of the chemotherapeutic agent, without having
to discontinue the treatment due to contraindications.
[0064] A further benefit which is obtained with the invention
described herein is related to the quality of life of the subjects
treated; in fact, as already mentioned, the elimination or
reduction of the physical suffering caused by a peripheral
neuropathy favours the patient's ability to be self-sufficient.
From the economic standpoint, there are obvious savings in terms of
the costs borne by hospital facilities or by the families for the
patient's care.
[0065] In a first preferred embodiment of the invention described
herein, acetyl L-carnitine is administered in a co-ordinated manner
with an anticancer agent selected from the group consisting of the
family of platin compounds, taxanes, epothilone class and vinca
alkaloids, farnesyl transferase inhibitors, thalidomide,
5-fluorouracil, cryptophycin analogues, proteasome inhibitors.
[0066] In a second preferred embodiment of the invention described
herein, acetyl L-carnitine has shown an unexpected degree of
protective activity against peripheral neuropathy induced by an
anticancer agent selected from the group consisting of Carboplatin,
Oxaliplatin, Docetaxel, Epothilone, Vinorelbine, Vincristine, the
farnesyl transferase inhibitor R11577, thalidomide, the
cryptophycin analogue LY355703, the proteasome inhibitor PS341.
This protective effect shall be understood both as prevention of
said side effect and as treatment of said protective effect.
[0067] Although the present inventors do not wish to be bound to
theoretical speculations, it shall be underlined how the said
protective activity (both preventive and therapeutic) by acetyl
L-carnitine appeared totally unexpected on the basis of the
knowledge in the art. As discussed in the Background section, it is
postulated that acetyl L-carnitine is likely to perform a
"scavenger" effect on the free radicals by increasing the levels of
reduced glutathione. In that section there are also explained the
mechanisms by which the anticancer drug of interest in the present
invention damage the peripheral nerve. In the case of platin
family, it is also well-known that radical scavenger agents are
likely to affect drug activity, since it acts through a radicalic
mechanism, so the use of a radical scavenger is not advisable.
[0068] Acetyl L-carnitine (ALC) exerts its protective effect
against peripheral neuropathy induced by the anticancer drugs of
interest herein by potentiating the effect of Nerve Growth Factor
(NGF) (Cavaletti, G. et al., Journal of Neurology, Vol. 249, Suppl.
1, June 2002: 1/28, 78). NGF is extensively studied in the art as a
neuroprotective agent in relation to Cisplatin and Taxol
neurotoxicity. Acetyl L-carnitine is able to potentiate the effect
of NGF on PC12 cells by enhancing expression of different genes, as
assessed by microarray analysis, and a relationship between NGF and
acetyl L-carnitine in promoting PC12 neuritis outgrowth was also
reported. Another definite relationship between acetyl L-carnitine
and NGF was found even in the animal model of chronic
Cisplatin-induced sensory neuropathy. In this model, a close
relationship has already been previously demonstrated between the
onset of a sensory neuropathy and the decrease in NGF circulating
levels.
[0069] A significantly reduced severity of neuropathy was also
observed in the in vivo model of Taxol neurotoxicity in the
Taxol-acetyl L-carnitine treated group. In addition to the effect
in reducing the NGF fall in Cisplatin treated animals, acetyl
L-carnitine seems to increase the cells response to NGF. Concerning
the molecular mechanisms at the basis of the protective effect of
acetyl L-carnitine, the studies performed in the present invention
showed the ability of the protective agent to enhance neuronal NGF
response via histone acetylation, which is involved in regulation
of gene expression. The acetyl group of acetyl L-carnitine is
transferred to histones in NGF-differentiated PC12 cells. The
presence of acetyl L-carnitine increased NGF-induced histone
acetylation. Moreover, the addition of acetyl L-carnitine to PC12
cells significantly stimulates the expression of NGFI-A, a gene
coding for a transcription factor with tumor suppressor effects. In
addition, NGFI-A protein is implicated in several physiological
processes and it was suggested to have an important role in tissue
repair. In conclusion, the present invention indicates that acetyl
L-carnitine is a specific protective agent for chemotherapy-induced
neuropathy following treatment with the anti-cancer agents of
interest in the present invention. Relevant to this point is the
lack of any interference with the antitumor activity of the drugs.
Finally, acetyl L-carnitine can enhance the supportive effect of
physiological NGF during chemotherapy-induced neuropathy, thus
avoiding the problem of the local and general side effects of the
exogenous administration of NGF which are a major problem of this
neuroprotective strategy.
[0070] When ALC is used according to the invention described
herein, no adverse effects on the anticancer action of the drug are
found.
[0071] ALC can be conveniently administered orally, without, for
that reason, excluding other administration routes which an expert
in the field may deem it advisable to adopt, particularly, by
injection, to be administered concomitantly, for example, in the
same infusion vial, with the anticancer agent, or in sequence, as
established by the expert in the field.
[0072] Since L-carnitine and other alkanoyl L-carnitines (herein
collectively named as "a carnitine), in particular propionyl
L-carnitine (PLC), showed beneficial effect with the therapeutic
activity of anticancer agents, as disclosed in the aforementioned
WO 00/06134, it can be advantageous to provide a combination, also
in separate dosage forms, or in some way combined, of acetyl
L-carnitine as a protective agent and one or more "carnitine"
together with the anticancer agent according to the present
invention. This combination can also comprise other anticancer
agents which induce substantially reduced side effects, much
particularly peripheral neuropathy, as a result of the combination
according to the invention described herein. This latter embodiment
is advantageous in case of polychemotherapy. It may also be
advantageous to add L-carnitine to the above-mentioned
combination.
[0073] It is therefore further evidently advantageous to provide a
ternary combination, also in separate dosage forms, or in some way
combined, of acetyl L-carnitine as a protective agent, propionyl
L-carnitine as a synergistic agent and one of the anticancer agents
according to the present invention. This combination also comprises
other anticancer agents which show a synergistic effect or induce
substantially reduced side effects as a result of the combination
according to the invention described herein. This latter embodiment
is advantageous in case of polychemotherapy. It may also be
advantageous to add L-carnitine to the above-mentioned
combination.
[0074] One specific object of the invention described herein is a
pharmaceutical composition comprising a therapeutically effective
amount of one of the anticancer agents according to the present
invention together with a protective amount of acetyl L-carnitine
and a synergistic amount of propionyl L-carnitine, in a mixture
with pharmaceutically acceptable vehicles and/or excipients.
[0075] As regards those aspects relating to industrial
applicability, the invention described herein also provides, in one
of its possible embodiments, for a kit containing a) a
pharmaceutical composition comprising a therapeutically effective
amount of an anticancer agent; b) a pharmaceutical composition
comprising acetyl L-carnitine or a pharmaceutically acceptable salt
thereof in an amount suitable for producing a substantially
protective action against the side effects on peripheral nervous
system of said anticancer agent. The kit according to the invention
described herein may also be presented in the form of a) a
pharmaceutical composition comprising a therapeutically effective
amount of an anticancer agent; b) a pharmaceutical composition
comprising acetyl L-carnitine in an amount suitable for producing a
substantially protective action against the side effects of said
anticancer agent.
[0076] A guideline for the kits is found in the above mentioned WO
00/6134 in particular for the cases of combination with other
carnitines.
[0077] We shall now disclose the ways of implementing the invention
described herein with reference to the preferred embodiments, using
Oxaliplatin or Epothilone or Vinorelbine as the anticancer
agent.
[0078] It remains understood that the expert in the field may
complete the experimental protocols with his or her own general
knowledge of the field in which he or she operates, possibly
resorting to neighbouring sectors in case of need.
[0079] We report here below the results of the most significant
experiments suitable for demonstrating the unexpected and
surprising protective effect obtained by the combination of
L-carnitine or its derivatives with the above-mentioned anticancer
agents. For experimental details, reference can be made to WO
00/6134 and the literature cited in this application.
EXAMPLE 1
[0080] Protective Effect of Acetyl L-carnitine on an Experimental
Model of Oxaliplatin-induced Peripheral Neuropathy--Prevention
Treatment.
[0081] The purpose of this study is to demonstrate and evaluate the
protective properties, by way of prevention, of acetyl L-carnitine
administered one day prior to Oxaliplatin treatment for 4
weeks.
[0082] Peripheral neuropathy was induced by intraperitoneally
administration of Oxaliplatin (2.7 mg/kg/1.5 ml) dissolved in
distilled sterilized water, twice a week for 4 weeks (for a total
of 8 administrations).
[0083] Acetyl L-carnitine was dissolved in distilled water and
administered subcutaneously. The dose of 100 mg/1.5 ml/Kg/day was
administered on the basis of individual body weight. ALC treatment
occurred daily, starting a day before Oxaliplatin treatment, for 4
weeks. Control and Oxaliplatin groups were treated s.c. with
vehicle.
[0084] Nerve conduction velocity (NCV) was measured in each animal
under halotane anaesthesia, prior to start of treatment (basal),
and the day after the last administration of Oxaliplatin
(final).
[0085] NCV was determined with the following method: the animals
were anaesthetised with a gaseous mixture composed of 0.45
halothane, nitrogen protoxide and oxygen. Nerve conduction velocity
was measured in the tail, by placing stimulating electrodes at the
base of the tail and a couple of recording ring electrodes distally
in the tail 5 and 10 cm with respect to the stimulating
electrodes.
[0086] The latencies of the potentials recorded at the two sites
after nerve stimulation were determined (peak to peak) and the
nerve conduction velocity was calculated accordingly.
[0087] The site of stimulations and recording were kept fixed on
repeated examinations performed in each animal by marking the tail
with permanent ink.
[0088] The recordings and stimulations of the tail nerve were done
using an Ote Biomedica Phasis II electromyograph using a
stimulation intensity equal to the threshold value with a duration
of 100 microseconds. In view of reports in the literature of nerve
conduction velocity depending on the animal body temperature, it
was necessary to keep the latter constant throughout the
experiment, measuring it with a rectal probe, with the aid of a BM
70002-type thermoregulator for animals (Biomedica Mangoni).
[0089] The velocity was measured in all groups of animals both in
basal conditions and after 5 weeks of treatment.
[0090] The results were expressed as means.+-.standard deviation;
significance was assessed using the "t"-test, for both independent
and paired data, with a statistical significance cut-off of
p<0.05.
[0091] The sensory nerve conduction velocity data measured on the
caudal nerve are given in the Table 1 here below.
TABLE-US-00001 TABLE 1 Oxaliplatin-induced neuropathy: sensory
nerve conduction velocity (m/s) measured on the animals' tails in
basal conditions and after treatment with acetyl L-carnitine.
TREATMENT Oxaliplatin 8.sup.th GROUP BASAL treatment Control 31.0
.+-. 1.4 35.8 .+-. 1.7 Oxaliplatin 31.3 .+-. 1.7 30.8 .+-. 1.2*
Acetyl L-carnitine + 31.4 .+-. 1.5 33.6 .+-. 2.6.sctn. Oxaliplatin
Values are means .+-. standard deviation. t-test (independent data)
*= p < 0.001 vs Control .sctn.= p < 0.001 vs Oxaliplatin
EXAMPLE 2
[0092] Protective Effect of Acetyl L-carnitine on an Experimental
Model of Oxaliplatin-induced Peripheral Neuropathy--Therapeutic
Treatment.
[0093] The purpose of this study is to demonstrate and evaluate the
protective properties, by way of therapy, of acetyl L-carnitine
administered at the end of Oxaliplatin treatments, during a
follow-up period of 3 weeks.
[0094] Peripheral neuropathy was induced by intraperitoneal
administration of Oxaliplatin (3 mg/kg/1.5 ml) dissolved in
distilled sterilized water, twice a week for 4 weeks (for a total
of 8 administrations).
[0095] Acetyl L-carnitine was dissolved in distilled water and
administered subcutaneously during the follow-up period. The dose
of 100 mg/1.5 ml/Kg/day was administered on the basis of individual
body weight. ALC treatment started the day after the last
Oxaliplatin administration.
[0096] Control and Oxaliplatin groups were treated s.c. with
vehicle.
[0097] Nerve conduction velocity (NCV) was measured in each animal
under halotane anaesthesia, prior to start of treatment (baseline),
the day after the last administration of Oxaliplatin (final) and
weekly after a follow-up period of 3 weeks (recovery).
[0098] NCV was determined as in Example 1.
[0099] The sensory nerve conduction velocity data measured on the
caudal nerve are given in the Table 2 here below.
TABLE-US-00002 TABLE 2 Oxaliplatin-induced neuropathy: sensory
nerve conduction velocity (m/s) measured on the animals' tails in
basal conditions and after treatment with acetyl L-carnitine.
TREATMENT RECOVERY 8th Oxaliplatin 2nd 3rd GROUP BASAL Treatment
1st week week week Control 31.0 .+-. 1.4 35.8 .+-. 1.7*** 37.8 .+-.
2.3*** 38.2 .+-. 1.5*** 39.3 .+-. 1.2*** Oxaliplatin 31.6 .+-. 2.0
30.8 .+-. 0.6*** 31.6 .+-. 2.7*** 32.0 .+-. 1.9** 35.9 .+-. 1.8*
Acetyl L- 31.0 .+-. 1.7 30.6 .+-. 1.5 34.1 .+-. 2.6.sctn. 35.1 .+-.
1.9.sctn..sctn. 36.6 .+-. 2.0 carnitine + Oxaliplatin Values are
means .+-. standard deviation. t-test (independent data) *= p <
0.01 vs Control; **= p < 0.005 vs Control; ***= p < 0.0001 vs
Control .sctn.= p < 0.05 vs Oxaliplatin; .sctn..sctn.= p <
0.01 vs Oxaliplatin
EXAMPLE 3
[0100] Protective Effect of Acetyl L-carnitine on Peripheral Nerve
from Oxaliplatin-induced Damage--Therapeutic and Preventive
Treatment.
[0101] The paw-withdrawal test (Randall-Sellitto) was used to
address mechanical hyperalgesia. Nociceptive threshold was measured
using an Ugo Basile analgesimeter by applying an increasing
pressure to the left and right hind paws. The nocicpetive threshold
is defined as the pressure (grams) at which the rat withdraws its
paw. Lower thresholds correspond to an increased sensitivity to
algesia. This behavioural test is conducted at different times
(days) from drug or vehicle administration. Rats are made familiar
with the testing procedure and with handling by investigators
during the week prior to the experiments.
[0102] Wistar female rats (Charles River) about 10 weeks of age
were used. Oxaliplatin (3 mg/kg i.p.) in saline was administered
three times a week. For the first two weeks, then two times a week
for two weeks and then once a week.
[0103] The preventive treatment was conducted as follows:
Oxaliplatin 3 mg/kg i.p.+ALC 100 mg/Kg s.c., daily from 1st day of
the Oxaliplatin treatment.
[0104] The therapeutic treatment was conducted as follows:
Oxaliplatin 3 mg/kg i.p.+ALC 100 mg/Kg s.c., daily from 24th day of
the Oxaliplatin treatment.
[0105] The nociceptive threshold data (Randall-Sellitto) are given
in the Table 3 here below.
TABLE-US-00003 TABLE 3 Oxaliplatin-induced neuropathy: nociceptive
threshold (g) measured on the animals' hind paws (mean .+-. S.D.)
Days GROUP N 0 9 16 23 30 37 40 44 51 Saline 9 235 245 214 204 234
215 234 204 209 48.6 83.8 38.4 41.5 59.5 37.2 65.3 39.4 46.0 d a d
d d Saline + 9 210 244 232 234 250 260 216 199 216 ALC 37.4 99.1
65.5 77.9 96.9 100.0 79.6 81.8 82.7 d d d d a a Oxaliplatin 15 217
129 133 121 114 151 143 147 136 41.2 35.7 41.2 42.2 59.1 94.3 46.4
107.1 60.8 ALC + Oxaliplatin 12 242 206 207 238 247 276 241 283 291
Preventive 34.0 104.5 110.8 46.0 115.7 114.0 87.5 129.4 95.2 a d d
d d d d ALC + Oxaliplatin 14 221 181 136 116 182 179 191 186 196
Therapeutic 32.3 92.2 44.0 42.1 76.9 50.2 46.3 68.5 98.1 ANOVA:
Dunnett's multiple comparison test vs Oxaliplatin. a = p < 0.05,
d = p < 0.001.
[0106] The statistical analysis is given in Table 4 herein
below.
TABLE-US-00004 TABLE 4 D.F. F P< Saline vs Oxaliplatin (0-51
days) Treatment 1-22 28.16 0.001 Interaction 8-176 2.03 0.045
Oxaliplatin + ALC - Preventive Vs Oxaliplatin (0-51-days) Treatment
1-25 21.98 0.001 Interaction 8-200 3.06 0.003 Saline vs Oxaliplatin
(23-51 days) Treatment 1-22 17.95 0.001 Interaction 5-110 1.10 NS
Oxaliplatin + ALC - Therapy Vs Oxaliplatin (23-51-days) Treatment
1-27 6.03 0.021 Interaction 5-135 1.41 NS
EXAMPLE 4
[0107] Protective Effect of Acetyl L-carnitine on Peripheral Nerve
from Vinorelbine-induced Damage--Therapeutic and Preventive
Treatment.
[0108] The paw-withdrawal test (Randall-Sellitto) was used as in
Example 3.
[0109] Sprague Dawley male rats (Harlan) about 3 months of age
(about 350 g) were used. Vinorelbine (0.200 mg/kg i.p.) in saline
was administered three times a week until the end of the
experiment.
[0110] The preventive treatment was conducted as follows:
Vinorelbine 3 mg/kg i.p.+ALC 100 mg/Kg s.c., daily (6 days a week)
from 1.sup.st day of the Vinorelbine treatment. Treatment with ALC
went until day 25.
[0111] The therapeutic treatment was conducted as follows:
Oxaliplatin 3 mg/kg i.p.+ALC 100 mg/Kg s.c., daily (6 days a week)
from 9.sup.th day of the Vinorelbine treatment. Treatment with ALC
went until day 25.
[0112] The test was done twice a week.
[0113] The nociceptive threshold data (Randall-Sellitto) are given
in the Table 5 here below.
TABLE-US-00005 TABLE 5 Vinorelbine-induced neuropathy: nociceptive
threshold (g) measured on the animals' hind paws (mean .+-. S.D.)
Days GROUP N 0 4 9 11 16 18 23 25 Saline 10 228.5 214.6 229.8 242.9
220.7 205.0 196.8 214.8 44.1 59.2 54.1 35.5 38.6 38.9 46.9 54.5 c d
d d c d Vinorelbine 12 211.4 173.5 168.8 156.8 135.8 127.7 136.2
122.7 32.9 51.6 45.6 50.5 36.0 38.2 45.4 40.9 ALC + Vinorelbine 10
222.0 197.4 234.0 211.2 235.4 204.6 202.6 201.2 Preventive - 1 day
23.8 39.6 74.5 41.4 44.4 35.6 41.8 36.1 a b d d c d ALC +
Vinorelbine 12 216.5 167.5 160.2 190.6 196.2 227.2 209.0 206.7
Therapeutic - 9 days 44.3 41.6 60.6 70.2 49.5 72.6 56.9 59.8 b d c
d Student's "t" test vs Vinorelbine a = p .ltoreq. 0.05, b = p
.ltoreq. 0.02, c = p .ltoreq. 0.01 d = p .ltoreq. 0.001.
EXAMPLE 5
[0114] Protective Effect of Acetyl L-carnitine on Peripheral Nerve
from Vincristine-induced Damage--Therapeutic and Preventive
Treatment.
[0115] The paw-withdrawal test (Randall-Sellitto) was used as in
Example 3.
[0116] Sprague Dawley male rats (Harlan) about 3 months of age
(about 350 g) were used. Vincristine (0.150 mg/kg i.p.) in saline
was administered three times a week until the end of the
experiment.
[0117] The preventive treatment was conducted as follows:
Vincristine 0.150 mg/kg i.p. three times a week+ALC 100 mg/Kg s.c.,
daily (6 days a week).
[0118] The therapeutic treatment was conducted as follows:
Vincristine 0.150 mg/kg i.p.+ALC 100 mg/Kg s.c., daily (6 days a
week) from 15th day of the Vincristine treatment.
[0119] The test was done twice a week.
[0120] The nociceptive threshold data (Randall-Sellitto) are given
in the Table 6 and Table 7 here below.
TABLE-US-00006 TABLE 6 Vincristine-induced neuropathy: nociceptive
threshold (g) measured on the animals' hind paws (mean .+-. S.D.) -
preventive treatment Days GROUP N.sup.o 0 3 8 10 15 17 22 Saline 30
212.7 220.0 202.0 221.3 213.3 213.3 222.0 50.4 67.4 59.2 63.5 60.2
72.3 73.9 d d d d d d Vincristine 30 222.0 137.3 114.7 117.3 126.7
94.7 133.0 43.8 52.6 53.1 43.8 69.6 80.5 73.9 ALC + 30 210.7 206.7
209.3 213.3 213.3 202.7 215.0 Vincristine 41.1 66.8 81.1 83.8 59.2
64.6 72.8 d d d d d d Student's "t" test vs Vincristine d = p <
0.001.
TABLE-US-00007 TABLE 7 Vincristine-induced neuropathy: nociceptive
threshold (g) measured on the animals' hind paws (mean .+-. S.D.) -
therapeutic treatment Days GROUP N.sup.o 0 4 8 10 15 22 24 29 31 36
38 Saline 10 197.2 233.5 201.5 209.4 224.8 231.0 223.5 215.9 222.2
250.4 248.6 24.0 60.7 55.7 47.4 59.5 47.4 62.6 44.9 46.2 86.3 62.0
a d d d c c d c c Vincristine 10 199.4 173.6 145.6 131.4 127.4
120.6 133.0 128.0 129.2 137.8 154.2 25.0 64.8 71.8 31.9 50.9 40.2
74.6 56.9 46.2 52.8 64.2 ALC + 10 216.2 212.8 186.8 152.6 128.0
188.6 230.5 248.4 282.0 265.0 281.6 Vincristine 38.9 62.9 87.3 59.5
39.8 72.4 68.9 100.2 76.8 71.5 97.1 b c c d d c Student's "t" test
vs Vincristine b = p .ltoreq. 0.02, c = p .ltoreq. 0.01 d = p
.ltoreq. 0.001.
EXAMPLE 6
[0121] Protective Effect of Acetyl L-carnitine on Peripheral Nerve
from Thalidomide-induced Damage.
[0122] Two patients, a men and a female, aged 52 and 78 years,
respectively, received thalidomide in combination with
dexamethasone. The reason for thalidomide treatment was multiple
myeloma. Both patients showed a bone marrow plasmacytosis
.gtoreq.60% and received a total dose of thalidomide >20 g. The
treatment was structured over a period of 85 and 105 days,
respectively.
[0123] An oral dose of ALC (3 g die) was given as concomitant
treatment in order to prevent thalidomide-induced sensory
peripheral neuropathy. Total doses of ALC were 243 g and 306 g,
respectively. Both patients were regularly examined.
[0124] No clinical signs of sensory peripheral neuropathy were
observed in these two patients during the treatment with
thalidomide. No side effects related to the ALC treatment were
reported.
* * * * *