[e-farmacos] Informacion sobre rivastigmina

["Tassoni, Silvia" <hoteo0@rosario.gov.ar>]

E-farmacos: Informacion sobre rivastigmina
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Estimado Jorge,

Espero te resulte util. Este articulo compara las
diferentes drogas para la enfermedad de  Alzheimer.

Saludos,

Dra. Silvia Tassoni
Comision Municipal de Medicamentos
Rosario
(Argentina)

DRUG CONSULTS

ALZHEIMER'S DISEASE - INVESTIGATIONAL DRUGS RESPONSE:
Finding effective drug therapy for Alzheimer's Disease
(AD) has been frustrating, and the possibility for
both alpha and beta error in interpreting drug
response is high. Limitations of prior research 
include both diagnostic imprecision in patient
selection and the lack of an effective marker of AD
which would allow earlier diagnosis. The high
percentage of patients enrolled in studies who do not
in fact have AD (perhaps as many as 20%) along with
the relatively late stage of  neuronal loss already
present in these patients might make any response to 
palliative treatment unreasonable. Drugs currently in
use often have poor kinetic profiles (short
half-lives, poor blood-brain barrier penetration, 
narrow 
therapeutic windows, lack of receptor selectivity).
The multiple neurotransmitter deficits which likely
exist probably require  combination drug therapy
approaches rather than monotherapy (Lamy, 1994;
Davidson & Stern, 1991).

Measuring outcomes for the drug therapy has also been
difficult. The  U.S. Food and Drug Administration
would like to see a dual-outcome criteria  with
both a cognitive performance scale used and a global-
function scale  for the evaluation of these drugs
(Jann, 1998). The most commonly used scales  in
current clinical research include the Alzheimer's
Disease Assessment Scale (ADAS) for 
cognitive/neuropsychological change along with the
Clinician's Interview-Based Impression of Change with
Caregiver Input (CIBIC-Plus) Or the Clinical Global
Impression of Change (CGIC). The Mini-Mental State
Examination is a common secondary measure (Schneider &
Tariot, 1994; Speight, 1991).

While cholinergic deficit remains a primary premise as
a cause for much of the cognitive deterioration
associated with AD, a number of different
neurotransmitter systems are likely involved in the
pathogenesis. As a result, in addition to
"cholinergic-enhancing" strategies for drug treatment,
other systems such as monoaminergic and
neuropeptidergic
enhancing treatment strategies are also being applied
or investigated  for potential beneficial effects in
reversing or slowing cognitive decline (Whitehouse &
Geldmacher, 1994; Schneider & Tariot, 1994; Davidson &
Stern, 1991).

The following is a brief summary of some of the
various pharmacologic approaches under study in AD
with an aim towards preserving or enhancing cognitive
function (Lamy, 1994; Schneider & Tariot, 1994;
Davidson &  Stern, 1994; Cooper, 1991).

CHOLINERGIC AGONISTS
Cholinergic agonists have failed to produce
significant cognitive improvement in AD patients.
These include ARECOLINE (Soncrant et al,  1993),
BETHANECHOL (Schneider & Tariot, 1994), NICOTINE
BITARTRATE (Newhouse et al, 1988), and OXOTREMORINE
(Schneider & Tariot, 1994). The major drawback to such
agents is a high prevalence of both peripheral and
central  cholinergic side effects which either mask or
counter any potential therapeutic  benefit. The
identification of at least 5 different muscarinic
receptor subtypes  may allow future development of
more selective agents with a greater  therapeutic
index (Davidson & Stern, 1991).

ACETYLCHOLINESTERASE (AChE) INHIBITORS
AChE inhibitors, while not producing dramatic
improvements, are  currently the only drugs available
which have been associated with symptomatic benefit.
An "ideal" AChE inhibitor would include 5
characteristics: be a pseudoreversible or irreversible
inhibitor; produce selective  inhibition within the
brain; produce long-lasting 40% to 60% inhibition of
AChE;  double the concentration of acetylcholine (Ach)
in AD patients; and have low toxicity (Szeto, 1994).

METRIFONATE is metabolized to the active component
DICHLORVOS (DDVP),  an irreversible AChE inhibitor
which can produce 40% to 60% suppression of  ACh
activity for 24 hours following oral dosing (Szeto,
1994). Toxicity isobserved at doses above 10
milligrams/kilogram (mg/kg) (Davidson &  Stern, 1991).
Reports of muscle weakness have slowed the U.S. Food
and Drug Administration's approval process.
RIVASTIGMINE is reported to have greater effects in
the cortex and hippocampus (the main targets for
symptomatic treatment) than the  striatum, with 80%
AChE inhibition maintained for 10 hours after oral
dosing in animals. It has shown efficacy in a large
trial (n=699); however, more information is needed to
rule out any causal association between high  dose
rivastigmine and potential increased death (Steinberg,
1999). 
PHYSOSTIGMINE's toxicity and short half-life are
drawbacks; however, it has shown some benefit in 9 of
11 trials in at least a subpopulation of patients.
Dosing regimens have ranged from 6 to 16 mg given in
four to nine divided doses; a sustained-release dosage
form holds promise (Schneider  & Tariot, 1994;
Davidson & Stern, 1991; Davidson et al, 1986). 
Unfortunately the manufacturer received a "not
approvable" letter from the U.S. Food  and Drug
Administration in November of 1998 (Steinberg, 1999).

EPTISTIGMINE (MF-201) is a physostigmine derivative
with potentially  less toxicity, longer half-live, and
greater blood brain barrier penetration (Parnetti et
al, 1997; Davidson & Stern, 1991). Doses of 20 mg 2 to
3  times daily achieved a 23% to 54% suppression of
AChE activity, with about one-third of patients
showing improved CGIC scores (Szeto, 1994). Doses  up
to 120 mg/day have revealed a reversible neutropenia
(Parnetti et al,  1997).

GALANTHAMINE (GAL 9301) is an AChE inhibitor that is
also reported to modulate nicotine cholinergic
receptors (Steinberg, 1999). It was  previously used
in Europe for over 30 years (post-polio paralysis,
myasthenia  gravis; curare antagonist post-op). Unlike
tacrine, galanthamine is a  reversible, highly
specific inhibitor of neurogenic AChE  compared to
plasma butylcholinesterase) and is not protein bound.
Bioavailability is 90% to 100% compared to 5% to 30%
for tacrine (MacPherson, 1995; Szeto, 1995).  It
has been safe without apparent liver toxicity in doses
of 15 to 55 mg  daily in 2 or 3 doses for up to 1 year
in Eastern European studies (Davidson  & Stern, 1991).
Clinical response rate (improved functional ability)
in preliminary studies is 50% to 60% in selected
patients with mild to  moderate AD, with delay in
deterioration for up to 1 year. Nausea (19%), 
vomiting (16%), and diarrhea (4%) are usually
transient over the first 2 to 3  weeks of treatment;
clinical benefits become apparent at 6 to 8 weeks,
while response can be fully appreciated after 8 to 10
weeks (MacPherson,  1995; Szeto, 1994). Currently
extracted from daffodils (Galanthus nivalis),
synthetic production will be necessary to meet
expected worldwide patient needs (MacPherson, 1995;
Szeto, 1994).

MUSCARINIC AGONISTS
XANOMELINE is a selective M(1) agonist which may
provide another  approach to cholinergic enhancement
of AD (Shadlen & Larson, 1999; Peskind, 1998).  It
demonstrates cognitive enhancement similar to the AChE
inhibitors and reduced noncognitive behavior problems,
unfortunately with significant  side effects.

NOOTROPICS
Nootropics are derivatives of GABA, although devoid of
GABA-like  effects. They are thought to be
neuroprotective against hypoxia, enhance
microcirculation secondary to platelet effects, and
may augment neurotransmitter release. Dopamine and
acetylcholine release may be increased (Flynn, 1999).
They are used to improve memory and learning. 
Among the agents in this class are PIRACETAM,
OXIRACETAM, PRAMIRACETAM, ANIRACETAM, ROLZIRACETAM,
ETIRACETAM, TENILSETAM, and  LORACETAM  (Schneider &
Tariot, 1994; Speight, 1991). Piracetam, tenilsetam,
and oxiracetam  have demonstrated modest effects on
cognition when given for several weeks or months
(Speight, 1991). Other studies have claimed slowing of
 deterioration of memory and attention, but no
significant effects on cognition or  behavior compared
to placebo when given over a year (Croisile et al,
1993).

NERVE GROWTH FACTOR ENHANCERS
IDEBENONE increases brain nerve growth factor and may
have antioxidant activity (Knopman, 1998). European
trials have reported success with good tolerability.
PROPENTOPHYLLINE is another agent with nerve growth
factor enhancing properties (Knopman, 1998). It is
studied in Europe for AD and vascular dementia (Wimo
et al, 1998). 

CONCLUSION:
Effective treatment strategies for AD continue to
emerge as the various neurotransmitter defects become
better characterized. To date no single  drug or
combination drug regimen has been associated with
dramatic, sustained, or predictable benefit for
cognitive dysfunction, although combination  therapy
will probably be the most likely strategy for future
success. 

REFERENCES:
1. Croisile B, Trillet, M, Fondarai J et al: Long-term
and high-dose piracetam treatment of Alzheimer's


[NOTA: Mensaje sin acentos ni caracteres especiales.]
























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