Current Pharmaceutical Design, Volume 10, No. 3, 2004
Contents
Current
Pharmacotherapeutic Approaches to the Treatment of Cognitive Impairment in
Alzheimer’s Disease and Related Disorders
Executive
Editor : Bernd Ibach
Targets of Antidementive Therapy: Drugs with
a Specific Pharmacological Mechanism of Action Pp.223-229
Lutz
Frolich, Johannes Fox, Frank Padberg, Konrad Maurer, Hans-Jurgen Moller and Harald Hampel
Acetylcholinesterase Inhibition in
Alzheimer's Disease
Pp.231-251
Bernd
Ibach and Ekkehard Haen
NMDA-antagonism (Memantine): An Alternative
Pharmacological Therapeutic Principle in Alzheimer's and Vascular Dementia Pp.253-259
Horst
J. Koch, Alexander Szecsey and Ekkehard Haen
Review About Ginkgo Biloba Special Extract
EGb 761 (Ginkgo) Pp.261-264
Gertz, H.-J. and Kiefer, M.
Functional Neurochemistry of Alzheimer´s
Disease Pp.265-293
Wieland Gsell, Gerd Jungkunz and Peter Riederer
Economic Aspects on Drug Therapy of Dementia Pp.295-301
Wimo,
A. and Winblad, B.
Cholecystokinin Antagonists A New Way to Improve
the Analgesia from Old Analgesics? Pp.303-314
Gary
McCleane
Clinical Development of Microbicides for the
Prevention of HIV Infection
Pp.315-336
Osmond
J. D’Cruz and Fatih M. Uckun
Abstracts
[Back to top] Targets of Antidementive Therapy: Drugs with
a Specific Pharmacological Mechanism of Action
Lutz
Frolich, Johannes Fox, Frank Padberg, Konrad Maurer, Hans-Jurgen Moller and Harald Hampel
Diagnosis and therapy of dementia have made considerable progress in
recent years. Drugs have been developed which improve cognitive performance,
delay the loss of abilities of daily living and prevent early nursing home
placement in a considerable number of patients. With the various
pharmacological and non-pharmacological approaches, effective treatment options
of AD are available at present and the therapeutic potential will even increase
in future. Thus, the treatment of dementia should more focused and explicit in
its goals for the doctor, the patient and the relatives. Therapeutic targets
must be defined on the basis of the individual needs and deficits and with
regard to different levels of the disease process. Ideally, treatment should
always aim at an etiological and/or a pathophysiological level. At present,
however, aiming at the neurotransmitter level, the core syndrome of cognitive
deficits can be approached by treatment options. Further therapeutic targets
can be defined on the level of activities of daily living, following a resource
focused approach, as well as on the level of behavioral disturbances.
Additional therapeutic targets should be seen under a humanitarian or
palliative perspective. And finally, family members are also targets for
therapy in dementia, even if such therapy is not directed towards the demented
patient. All these treatment targets have to be evaluated and adapted under the
perspective of time because prominent symptoms in AD change considerably with
disease progression. Selection and adaptation of medication becomes easier if
such targets are considered and if therapeutic effects are monitored target-specifically.
[Back to top] Acetylcholinesterase Inhibition in
Alzheimer's Disease
Bernd
Ibach and Ekkehard Haen
Alzheimer's Disease (AD) is the most common cause for dementia in our
ageing population, which leads to a slowly progressive, irretrievable ruination
of mental function. The destructive, primarily degenerative condition is
neuropathologically characterized by the formation of amyloid plaques,
neurofibrillary tangles and loss of neurons and synapses as well. Research
during the past twenty years revealed early in the disease course a
degeneration of cholinergic nuclei localised in the basal forebrain. Impairment
of this cholinergic system, which projects into large areas of the limbic
system and the neocortex is followed by disturbance of attentional processes
and cognitive decline. The link between the cholinergic dysfunction and
cognitive impairment has focused large scientific efforts to understand the
neurobiology of cognition and to develop therapeutic tools for the fight
against Alzheimer's Disease. Acetylcholinesterase inhibitors are currently the
best established treatment for this devastating disease.
This review describes historical aspects and the vast range of use of
cholinesterase inhibitors in traditional societies and industrial nations.
Second, the rational basis will be outlined for their development as
medication, the so-called cholinergic hypotheses of AD. Third,
acetylcholinesterase inhibitors currently available for the treatment of AD
will be reviewed. This includes donepezil, galanthamine and rivastigmine.
Tacrine, the first acetylcholinesterase inhibitor who became available in 1993
as a treatment for AD, does not play an essential role anymore besides his
historical value, because of its hepatotoxicity.
Although acetylcholinesterase inhibitors are no cure, these drugs can
delay the progress of mental deterioration, reduce neuropsychiatric symptoms
and therefore represent a rational therapeutic approach to the treatment of
Alzheimer's Disease.
[Back to top] NMDA-antagonism (Memantine): An Alternative
Pharmacological Therapeutic Principle in Alzheimer's and Vascular Dementia
Horst
J. Koch, Alexander Szecsey and Ekkehard Haen
Memantine, a non-competitive NMDA antagonist, has been clinically used
in the treatment of dementia in
of dementia, particularly Alzheimer´s disease, in controlled clinical
trials. Provided that the dose is slowly increased it is generally well
tolerated and safe up to 20 and 30 mg per day, with intake preferably in the
morning. The compound is completely absorbed after oral intake with Cmax values
after 6 hours, undergoes little metabolism and has a terminal elimination half
life between 60 and 100 hours. Due to its low potential of interaction,
memantine can be combined with acetylcholinesterase inhibitors, the mainstay of
current symptomatic treatment of Alzheimer's disease and it is suited in
elderly patients receiving multiple drug therapy.
[Back to top] Review About Ginkgo Biloba Special Extract
EGb 761 (Ginkgo)
Gertz, H.-J. and
Kiefer, M.
Ginkgo biloba extracts (EGb) are well-defined plant extracts. It has
several indications as dementia, macula degeneration, tinnitus and winter
depression. A review of the current and past literature about older people with
Alzheimer's dementia or vascular dementia or age-associated memory impairment
treated with Ginkgo biloba extract, reveals that EGb has reproducible effects
on cognitive functions in Alzheimer's disease. The drug is well tolerated.
[Back to top] Functional Neurochemistry of Alzheimer´s
Disease
Wieland Gsell, Gerd Jungkunz and Peter Riederer
A review of neurochemical research on classical neurotransmitters, i.e.
acetylcholine, serotonin, noradrenaline, dopamine, glutamate, and GABA in
Alzheimer´s disease is presented. Findings are linked to the information
processing system of the human brain to establish a more functional
neurochemistry. On this basis, different pharmacotherapeutic strategies are
discussed. Our conclusion is that current symptomatic therapy of Alzheimer´s
disease is insufficient. Besides therapy with acetylcholineesterase inhibitors,
comedication to act on imbalances between serotonin and noradrenaline on the
one site, and dopamine, glutamate and GABA on the other site should should be
considered.
[Back to top] Economic Aspects on Drug Therapy of Dementia
Wimo, A. and Winblad, B.
The great number of people suffering from dementia present a great
challenge for the health care and social support systems. In a situation where
resources are scarce, health economical aspects of dementia care are of great
importance in order to identify cost-effective care. However, the literature in
this field is limited. There are also aspects where there methodological
development is necessary (e.g. informal care, quality of life, long term
effects). In the absence of proepctive long term data, it is necessary to use
pharmacoeconomical models. It is also important to have population based data
for the description of how resources and costs are allocated between the
different care sectors. Current data show that there is a strong relationship
between cognitive functioning and costs. The number of pharmacoeconomical
evaluations of drugs influencing on the symptomatology of dementia is low.
Available data show that there is support for a view that treatment is
cost-neutral or perhaps cost saving which in combination with positive effects
in terms of efficacy may indicte cost-effectiveness.
[Back to top] Cholecystokinin Antagonists A New Way to Improve the Analgesia from Old
Analgesics?
Gary McCleane
Cholecystokinin, originally thought to be confined only to the
gastrointestinal tract, is now known to be co-localised in both the
gastrointestinal tract and central nervous system.
In animal models levels are increased after neural injury and with
opioid administration. This peptide acts as an anti-opioid, and as levels
increase, the extent of opioid derived antinociception decreases.
Co-administration of a CCK antagonist along with an opioid is associated with
an improved level of antinociception. Furthermore CCK antagonists may prevent
antinociceptive tolerance with opioids and even reverse established tolerance
Human studies have now confirmed the pro-analgesic effect of some CCK
antagonists. Human investigation of the effect of CCK antagonists on analgesic
tolerance has yet to be performed.
This review examines the available evidence that suggests a role for
CCK antagonists in human pain management.
[Back to top] Clinical Development of Microbicides for the Prevention of HIV
Infection
Osmond J. D’Cruz
and Fatih M. Uckun
The HIV/AIDS pandemic continues its spread at a rate of over 15,000 new
infections every day. Sexual transmission of HIV-1 is the dominant mode of this
pandemic spread. For the first time since the disease emerged in the early
1980s, about half the 42 million people now living with HIV/AIDS worldwide are
women. Worldwide, more than 90 percent of all adolescent and adult HIV
infections have resulted from heterosexual intercourse. The “feminization” of
the pandemic largely driven by the social, economic, and biological factors
warrants urgent attention particularly for the adolescent female population. In
the absence of an effective prophylactic anti-HIV therapy or vaccine, current
efforts are aimed at developing intravaginal/intrarectal topical formulations
of anti-HIV agents or microbicides to curb the mucosal and perinatal HIV
transmission. Microbicides would provide protection by directly inactivating
HIV or preventing HIV from attaching, entering or replicating in susceptible
target cells as well as dissemination from target cells present in semen or the
host cells that line the vaginal/rectal wall. Thus, ideally, anti-HIV
microbicides should be capable of attacking HIV from different angles. In
addition, a contraceptive microbicide could help prevent unintended pregnancies
worldwide. To be a microbicide, these agents must be safe, effective following
vaginal or rectal administration, and should cause minimal or no genital
symptoms following long-term repeated usage. A safe and efficacious anti-HIV
microbicide is not yet available despite the fact that more than 60 candidate
agents have been identified to have in vitro activity against HIV, 18 of which
have advanced to clinical testing. Targeting HIV entry has been a favored
approach because it is the first step in the process of infection and several
readily available anionic polymeric products seem to variably interfere with
these processes are the primary candidates for potential microbicides.
Formulations of some anionic polymeric antiviral agents have been tested at
various doses and various durations for safety, tolerability, and acceptability
in Phase I/II clinical trials (vaginal, rectal, or penile studies) in
HIV-uninfected and/or HIV–infected populations. Current multicenter Phase I/II
safety and Phase II/III efficacy studies that are being conducted or planned in
different geographical locations by various special interest groups are
designed for rapid clinical development of candidate products. The currently
marketed detergent-type spermicide, nonoxynol-9 (N-9), has failed in Phase III
clinical trials, due to the drug-induced formation of localized genital lesions
that might in fact actually promote virus transmission. Alternative
“first-generation” microbicides that have undergone Phase I/II safety and tolerability
studies in HIV-uninfected and/or HIV-infected volunteers include polymeric
viral fusion inhibitors (dextrin sulfate/Emmelle™, carrageenans [PC-213,
PC-503, PC-515/Carraguard™], cellulose sulfate/Ushercell™, polystyrene
sulfonate, naphthalene sulfonate [PIC 024-4/PRO 2000/5], acidifying gel
[Carbomer 974P/BufferGel™], Lactobacillus (L. crispatus) suppository/CTV-05,
detergent-type dual-function barriers [ACIDFORM™, GEDA Plus™, SURETE™,
Glyminox™/C31G/Savvy™, Invisible Condom], herbal extracts [Praneem™], and viral
replication inhibitors [PMPA/Tenofovir™]. For majority of these products, no
information is available regarding their long-term mucosal safety,
carcinogenicity potential, bioavailability, or efficacy following their
extended vaginal or rectal exposure. The irritative genitourinary symptoms
reported for a number of these first-generation products in Phase I clinical
trials implies that the “soft” preclinical endpoints for mucosal safety
established for the use and development of vaginal spermicides may not be
rigorous enough for vaginal and rectal microbicides because of the efficient
sexual transmission of virus, virus diversity, and genetic environment. It is
now apparent that sexually transmitted R5 HIV-1 viruses have less positive charge
on their surface compared with the R4 HIV-1 viruses, which may limit the
anionic polymers as topical microbicides despite extensive clinical trials.
Nevertheless, their ongoing clinical trials, reviewed here, using optimized
formulations, and special populations in various geographic locations are
paving the way for future rigorous clinical testing of “mechanism-based”
broad-spectrum anti-HIV microbicides that are currently under intense
development. It is anticipated that future microbicide trials will focus on
combination of products capable of attacking HIV life cycle at multiple steps
intended to increase efficacy, limit cross-resistance as well as minimize
microbicide-induced host toxicity.