Current Pharmaceutical Design - Volume 10, Issue 3, 2004

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 targetspecifically.

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.

Memantine, a non-competitive NMDA antagonist, has been clinically used in the treatment of dementia in Germany for over ten years. The rationale for this indication is strongly related to the physiological and to the pathological role of glutamate in neurotransmission. Physiolgically, NMDA receptors mediate synaptic plasticity by acting as a coincidence detector. Only those synapses that show temporally and spatially discrete activation of NMDA receptors undergo plastic changes secondary to Ca++ influx after rapid unblocking of Mg++, thus crucially contributing to memory and learning processes. The voltage-dependency of Mg++ is so pronounced that under pathological conditions it leaves the NMDA channel upon moderate depolarisation, thus interrupting memory and learning. Its pharmacological properties allow memantine to rapidly leave the NMDA channel upon transient physiological activation by synaptic glutamate (restoring significant signal transmission), but to block the sustained activation of low glutamate concentration under pathological conditions, i. e. to protect against excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent in various animal models based on both neurodegnerative and vascular processes as it ameliorates cognitive and memory deficits. Memantine has shown to be effective and safe in the treatment 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.

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.

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.

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.

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.

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 HIVuninfected 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.