Indication:
Alzhemeiers disease
Summary-
Venacrine appears to be promising agent for the treatment of Alzhemeirs disease .
Additional trials are needed to identify subsetsf patients most likely to respond,
demonstrate sustained efficacy and assess its place in combination therapy
An NDA was filed by Hoeschst -Roussel in early 1992 for venacrine (Mentane) .
FDA was considering a treatment IND for velnacrine, however, due to concerns over
safety and efficacy, the FDAs Peripheral and Central Nervous System Drugs Advisory
Committee unanimously decided not to recommend approval of the drug, even treatment
IND status
Adverse Reaction:
Side effects-
The side effects profile of velnacrine is similar to other cholinomimetic drugs.
Nausea, diarrhea, flushing and headache, dizziness and abdominal cramping are
reported most frequently and occur most commonly at the higher dosage ranges
(150 to 300mg).
In the largest protocol group reported to date, 75% of th patients discontinuing the drug
due to adverse event did so because of elevated liver enzymes. The hepatotoxicity
of velnacraine appears to be dose related , mild and revesible, usually within 4 weeks
of discontinuation.
Clinical features of the enzyme elevation were consistent with a biochemical insult (70%),
hypersensitivity (10%) or a mixture of both.
Pharmacology/ Pharmacokinetics:
Pharmacology-
Alzeheimers disease is associated with alertation in the number of neurotransmitters,
including norephinephrine, serotonin, somastatin, corticotrophin releasing factor and
acetycholine. Of these, a disturbance in cholinergic function mediated by a defecit
of neutronal choline acetyltransferase ( an enzmye responsible forb the formation of
acetylcholine) plays a central role in the etiologyof cognitive symptomsin Alzeimheirs
disease patients.
As a result of this assoiation,cholinometric compounds such as physiostigmine
(Antilrium) and the invetigational agent tacrine (tetrahydroaminocridine, THA Cognex)
have been evaluated with encoraging premilinary results.
Valinacrine (HP 029) is the maleate of an alcohol derivative of tacrine. It produces
cholinergic-mediated physiological effectsand inhibits true and pseudocholinesterase.
The cholinometric efects are not due to release of acetylcholine or to a direct
muscrainic agonist effect.
Pharmacokinetics-
Valenacrine is rapidly and extensively absorbed after oral administration .
Peak plasma concentrations are acheived in approximately 1 hour, are lineraly
proportional to the dose and tend tob slightly higher in elderly( 0.9 to 1.7 hours)
There appears to be no correlation between plasma levels and therapeutic or
adverse effect in individual patients.
The drug undergoes conjugation the liver and the fate and the activity of these metabolites
are unknown. Appromitely 11% to 30% of the administred drug is excreted unchanged
in the urine. Renal clearance ismarkedly reduced in the elderly, however, accumulation
has not been detected.
The half-life is about 2 hours in younger volunteers and is slightly longer in elderly
volunteers. Food appears to delay delay the rate but not extend of absorption
Clinical trials-
Cholinometric agents are most efective at improving memory ( a core feature of
Alzeheimrts disease and reversing scopolamine -induced dementia in animal models.
Liited publisheddata suggest that velnacrine 150 to 225mg/day in divided doses
produces most benefit in cognitive funtion in upto two-thirds of patients as judged by
performance based measures.
Improvement tends to be greater during dose titration , suggesting the potential for
tolerance or the use of inadequate performance measures
Current evident seem to suggest that the predominent neurotransmitter defecit may vary
fro one patient to other.Attempts to idenitfy subsets of patients most likely to benefit
may require combination therapy with different classes of drugs. Until markers are
identified that will predict response singlr drug efficacy trials in Alzehemiers disease
patients are likely to show only moderate results.
Manufacturer Details