Evaluation of antidepressant activity of clitoris ternatea in animals
Neurotoxicity
1. Neurotoxicity, a common side
effect of cytotoxic therapy –
how to protect the patient
Irena Netikova
General Teaching Hospital Prague
the Czech Republic
2. Neurotoxicity - side effect of
cancer therapy
second in frequency to hematological
toxicity
5. Ifosfamide induced encephalopathy
Symptoms:
disorientation, hallucination, catatonia, seizures and
gradually worsening sensorium lapsing into coma
circulatory collapse and death
The risk of development
advanced age, hepatic dysfunction, impaired renal
function, oral use of ifosfamide and concomitant use
of other central nervous systems depressants
Jain S, 2001
x very active metabolism (young sportsman)
6. Mechanism of toxicity
development
Ifosfamide undergoes a secondary ‘‘deactivation’’
→ dechloroethylated metabolites and
chloroacetaldehyde
Chloroacetaldehyde - nephrotoxicity and
neurotoxicity
(a) direct neurotoxic damage
(b) depletion of central nervous system glutathione level
(c) inhibition of mitochondrial oxidative phosphorylation
resulting in impaired fatty acid metabolism
7. Methylene blue
restores and maintains mitochondrial respiration and
therefore can be used to correct or prevent acute
neurotoxic effects
moderate to severe cases of ifosfamide neurotoxicity
prophylactically to prevent encephalopathy in high-risk
conditions
useful in the treatment of grade III or IV neurotoxicity
( i.v.)
prophylactic or concurrent administration of methylene
blue with ifosfamide requires further clinical evaluation
Sarah Donegan, 2001, Klener 2000
8. Pharmacy of GTH Prague
Rp.
Methylenii Caeruleum 0,2
Aquae destil. ad 20,0
M.f.sol.
D.S. 3 – 4x daily 5 ml (1 teespoon)
stability 1 month
protect against light
i. v. administration :
50 mg methylen blue at 10 % water solution
slow administration
9. Case report I
patient L.N., 31 years
dg.: 10/07 - PNET upper lip tumor without meta TNM klasifikace:
T3N0M0, St.III
OA: trombosis, Leyden mutation, acné vulgaris
80kg, 187cm
BSA: 2,02
BMI: 22,88
FT: Vessel Due 1-0-1, Doxybene 100mg 1-0-0, Retin A 0,05%crm.
smoker
after 3. CHT cycle:
numbness and tingling in his fingers
change of mood ( agresivity)
10. CHT: 6 cycles VAI + RT
Scheme VAI:
Kytril, Dexona á 1amp./ 100ml FR day 1-5
2 g Uromitexan/ 100ml FR day 1-5
4 g ifosfamid / 1000ml G5 day 1-5
40 mg doxorubicin / 250ml FR day 1-4
800 mg Uromitexan 4 times daily after infusion, day 1-5
2 mg vincristin, day 1
Zofran Zydis 1tbl.
methylen blue: 3 x 5 ml, p.o. 5 days
after the 3. cycle 2 days more at home
11. Chemotherapy-induced
peripheral neuropathy (CIPN)
neuropathies cannot be treated easily
protective treatment strategies have not
been effective enough
a consequence of antineoplastic
pharmacotherapy, cancers themselves, or
other diseases and medications
12. Peripheral neuropathy
symptoms
sensory nerves :
pain, numbness and tingling, burning,
prickling, pinching or a loss of feeling
motoric nerves:
weakness or paralysis of the muscles that
control those nerves
autonomic neuropathy:
dizziness, constipation, difficulty urinating,
impotence, vision changes, hearing loss
13. What patients feel
symptoms may begin gradually
glove-and-stocking distribution of sensory
loss
nerve hyperexcitability
the skin is so sensitive that the slightest touch is
agonizing
heaviness or weakness in the arms and legs,
an unsteady gait and can have difficulty feeling
the floor beneath them
14. These symptoms may be
disabling, adversely affecting
activities of daily living and
thereby quality of life
15. It is paradoxical that nondividing
neurons and supporting cells of
the peripheral nervous system are
susceptible
16. Vulnerability reasons of
peripheral nervous system
sensory and autonomic neurons are contained
in ganglia
→ lie outside the blood-brain barrier
are supplied by capillaries
long peripheral nerve axons are susceptible to
agents, which interfere with
→ energy metabolism
→ axonal transport (microtubule–based,
stuctural-based, high mitochondrial activity
needed)
17. CIPN
Neurotoxicity may develop as a consequence of treatment with :
platinum analogues (cisplatin, oxaliplatin,
carboplatin)
taxanes (paclitaxel, docetaxel)
vinca alkaloids (vincristine, vinorelbin)
more recently thalidomide and bortezomib
new molecularly targeted, biological agents
promise to significantly reduce injury to normal
tissue
peripheral neurotoxicity is dose limiting
18. Incidence of CIPN
related to:
cumulative dose
infusion duration
individual risk factors may also
influence the development and
severity of neurotoxicity
19. What we know about risk
factors
As more effective multiple drug combinations are
used, patients are treated with several neurotoxic
drugs.
Synergistic neurotoxicity
has not been extensively investigated
pre-existent neuropathy may influence the
development of a CIPN
underlying inherited or inflammatory neuropathies
may predispose patients to developing very severe
symptoms
other factors such as focal radiotherapy or
intrathecal administration may enhance PN
20. Mechanisms of CIPN
damage to neuronal cell bodies in the dorsal root
ganglion
axonal toxicity via transport deficits or energy failure
axonal membrane ion channel dysfunction
patients treated with oxaliplatin have revealed
alterations in axonal Na(+) channels
prophylactic pharmacological therapies aimed at
modulating ion channel activity may prove useful in
reducing neurotoxicity
21. Development of CIPN
prospective studies demonstrate that
maximum symptoms and deficit may occur up
to a month after discontinuation of treatment
(Verstappen et al., 2005)
symptoms reach a plateau at or soon after
the end of treatment and improve after
treatment is discontinued
22. The notable exceptions -
platinum compounds
Oxaliplatin
often produces acute, reversible
symptoms during the first courses of
treatment
all the platinum compounds
produce ‘‘coasting’’ where
neuropathy progresses for weeks to
several months after drug treatment
ends
23. The diagnosis of a CIPN
based on:
the case history
the clinical and electrophysiological
findings
knowledge of the pattern of
neuropathy associated with specific
agents
24. Platinum compounds
CIPN is closely related to total cumulative drug dose
cDDP ≥ 400–500 mg/m2 of cisplatin; typically 3–6 months into treatment
(Walsh et al., 1982; Thompson et al., 1984; Ozols et al., 1985)
sensory CIPN with initial complaints of paresthesias in
the distal extremities
all sensory modalities are involved, but loss of large fiber
sensory function is often prominent.
→ this may progress to severe sensory ataxia
the neuropathy may continue to progress for
several months after cessation of cisplatin and
symptoms may develop as long as 3–6 weeks after the
last dose of chemotherapy (Mollman et al., 1988)
25. autonomic neuropathy is infrequent and
can cause dizziness, palpitations, or
impotence (Hansen, 1990; 1992)
oxaliplatin - 60–80% of patients develop a
stereotyped cold-induced acute toxicity
that involves reversible paresthesias in the
throat, mouth, face, and hands occurring
within 30–60 min
26. Pt compounds mechanism of
action
similar to alkylating agents that bind to DNA
DNA damage causes aberrant re-entry into
the cell cycle and apoptosis (Gill and Windebank, 1998a).
concentrations in peripheral nervous tissue
are similar to tumor tissue compared with
much lower concentrations in brain ( Gregg et al.,
1992; Screnci et al., 2000).
binding of platinum to mitochondrial DNA is a
potential mechanism underlying delayed
neuronal death (Podratz et al., 2007)
27. Other alkylating agents
- mild peripheral neuropathy:
Cyclophosphamide, Procarbazine, Thiotepa has
little or no peripheral toxicity
HD Ifosfamide- CIPN occurred in about 8% of
patients and central neurotoxicity is common too
paresthesias and pain in the feet and pan-modal
sensory loss
slow and incomplete recovery occurred over years after
drug withdrawal (Patel et al., 1997).
Cranial nerves can be affected by intra-arterial infusion
or concomitant radiation (Shingleton et al., 1982; Wilson et al., 1987).
28. Mitotic spindle inhibitors
vinca alkaloids, taxanes, and podophyllin analogs
(etoposide and tenoposide)
interfere with microtubule assembly and
mitotic spindle formation
slows mitosis
results in disordered cell division and
apoptosis
disruption of microtubule function in axons
inhibits axonal transport
→ length-dependent axonal damage
29. neuropathy is distally predominant, symptoms
begin in the lower limbs and appear later in the
upper limbs
sensory, motoric and autonomic fibers are all
affected
because the cell body is usually spared, good
recovery of function can occur, especially in
children and young adults
peripheral rather than central neurotoxicity
31. Therapy of CIPN
neuropathies cannot be treated easily
protective treatment strategies have
not been enough effective yet
32. Therapy of CIPN pain
Pain relievers
aspirin, ibuprofen - mild symptoms
more severe symptoms - NSAID (nimesulid, COX II inhibitors) and
opioids (tramadol, oxycodon, morfin)
Antidepressant medications - mild to moderate
symptoms.
amitriptyline, nortriptyline, imipramine,
citalopram, venlafaxin, paroxetin and bupropion
Antiseizure medications - jabbing, shooting pain
carbamazepine, gabapentin, pregabalin, lamotrigin
Mexiletine, a drug normally used to treat irregular heart rythmus,
may help to relieve burning pain
33. Proposed prophylactic strategies
amifostin ( Ethyol)
Ndubisi, Boniface U., et al. "A Phase II Open-Label Study to Evaluate the Use of
Amifostine in Reversing Chemotherapy-Induced Peripheral Neuropathy in Cancer
Patients—Preliminary Findings." American Society of Clinical Oncology 1999 Annual
Meeting Abstract: 2326.
vitamin E
glutathione
A recent Cochrane review (Albers et al., 2007)
concluded that there was insufficient evidence to
recommend the use of any therapies for the
prevention of the neuropathy caused by platin
compounds
34. Experimental Therapeutics
Acetyl-L-carnitine (ALC)
the acetyl ester of L-carnitine, plays an essential role
in intermediary metabolism
neuroprotective and neurotrophic actions,
antioxidant activity, positive actions on
mitochondrial metabolism, and stabilisation of
intracellular membranes
ALC has demonstrated efficacy and high tolerability in
the treatment of neuropathies of various aetiologies,
including CIPN Maestri A et al. 2003
Claudio Pisano et al 2003
35. Glutamate
animals experiment
Glutamate significantly protected
against both sensory and motor
neuropathy.
no intrinsic neurotoxicity with glutamate
was observed and no interference with
the cytotoxic efficacy of vincristine
Boyle FM et al, 1996, Boyle FM et al.,1999.
36. Glutamine
Glutamine as a neuroprotective agent in high-dose
paclitaxel-induced peripheral neuropathy
Stubblefield MD et al.,2005
to chemotherapy oral glutamine significantly
reduces the incidence and severity of peripheral
neuropathy of patients receiving oxaliplatin without
affecting response and survival
Florian Strassera, 2008
37. Glutamic
acid/glutamine/glutamate
The synaptically released glutamate is taken up into
glial cells, where it is converted into glutamine by the
glia-specific enzyme glutamine synthetase;
Glutamine reenters the neurons and is hydrolyzed
by glutaminase to form glutamate, thus replenishing
the neurotransmitter pool
In the brain, glutamine is a substrate for the
production of both excitatory and inhibitory
neurotransmitters (glutamate and gamma-
aminobutyric acid)
Glutamine is also an important source of energy for
the nervous system
Glutamate" is the term used interchangeably with
"glutamic acid," though strictly speaking glutamate
is an anionic amino acid.
38. Pharmacy of GTH Prague
Sol. acidi glutamici 10%
Rp.
Acidum glutamicum 15,0
Sirupus plantaginis 45,0
Aqua purificata ad 150,0
D.S: 10 ml 3 times a day
by CIPN symptoms after taxanes and
oxaliplatin
39. Effectivity of 10% glutamic
acid solution in CIPN treatment
100
40
number of
50 15
pacients
23
0
mild reduction of CIPN effective reduction of CIPN
no reduction of CIPN
