Tirlizad- Antioxidoxant - Investigational Drug
Drug Name:Tirlizad- Antioxidoxant - Investigational Drug
List Of Brands:
Indication Type Description:
Indication
Adverse Reaction
Pharmacology/ Pharmacokinetics
Indication:
Antioxidant
Summary-
Tirilazad is a potent antioxidant similar in structure to other steroids, but without the
glucocorticoid activity. Due to its ability to prevent oxygen radical-mediated lipid
peroxidation, it may b be useful in preventing progressive neuronal degeneration
and associated complications following brain and spinal injury, SAH and stroke
Upjohn submitted a new drug application in June 1994 for tirilazad with the indication
of SAH. Due to lack of serious side effects that have been documented thus far,in
areas greatly in need of new treatment modalities, approval is anticipated.
However, in on September 26, 1994, the FDAs Peripheral and Central Nervous
System Drugs Advisory Committee decided that the studies for tililazad did not
confirm efficacy and that further studies would be necessary. A treatment IND
program was discussed as a possibility.
Adverse Reaction:
Side effects-
Tirilazad has been shown to be safe in elderly patients (average age 66 years) with
acute ischemic stroke at doses upto 6mg/kg/day for 3 days.. In healthy volunteers ,
tirilazad had no effect on cerebral blood flow or cerebral oxygen metabolism.
Studies have failed to show any significant glucocorticoid effect to be caused by
the serum alanine transaminase. Thus far the most noted side effect has been mild
to moderate pain at the injection site, occuring in 60% to 80% of patients.
Studies invloving tirilazad and both nimodine (Nimotop) and cimetidine (eg Tagamet)
have failed to identify a clinically significant drug interaction with either of those
drugs.
Pharmacology/ Pharmacokinetics:
Pharmacology-
Tirilazad mesylate is a 21-aminosteroid ( also referred to as lazaroids) with distinct
antioxidant properties. It does not manifest glucocorticoid activity.
Trilazad acts as cytoprotrotective agent that oxidizes peroxyl radicals and stabilizes
cell membranes. It also helps to preserve the membrane content of Vitamin E
(alphatocopherol) another important antioxidant. as a result of its ability to prevent
lipid peroxidationin cell membranes , trilizad promotes tissue survival in the vicinity
of CNS injury
Due to high content of polyunsaturated lipids in neuronal membranes,the CNS is
particularly susceptible to the destructive effects of oxygen radicals. Tissue injury
occuring during CNS trauma or a stroke increases oxygen radical production,
which in turns leads to damaging lipid peroxidation reactions. Such oxygen-mediated
processes appear to be involved in posttraumatic brain edema, spinal axonal
degeneration and microvacular damage. The progressive secondary tissue destruction
which follows the precipitating event may be amenable to therapy with antooxidants.
Pharmacokinetics-
Tirlizad is administered in a citrate solution as an IV infusion over not more than 30
minutes. It is lipophilic substance that distributes extensively in the tissue, with a
volume of distribution of about 1.7 L/kg. The drug appears to follow a multicompartment
elimination pattern. Following a single dose, a terminal elimination half-life of 35 hours
has been observed. Elimination occurs via hepatic metabolism. The clerance of tirilazad
is roughly equal to hepatic flow.
Clinical Studies-
In numeroous neurological studies of animal models, tirilazad has shown distinct promise
as useful therapeutic agent for the brain and spinal injury, aneurysmal subarchnoid
haemorrhage (SAH ) and stroke. Phase III clinical trials are currently being conducted
in each of these areas.
The second National Acute Spinal Cord Injury Study (NASCIS) demonstrated that
patients treated wth high dose of methylprednisolone (eg. Solu-Medrol 8 to 9g/day)
with 8 hours of injury , experienced significantly greater neurological improvement
than those treated with placebo. The efficacy of methylprednisolone in slowing the
progression of CNS damage is believed to be due to its antioxidant properties rather
than its glucocorticoid activity. For this reason in NASCIS ( an ongoing follow-up study)
one of the three treatment involves 2g methylprednisolone bolus, followed by
2.kmg/kg trilizad infusion every 6 hours for 48 hours.
Today most of the clinical efficacy trials conducted by tirilazad have studied its use
in SAH. Upjohn have submitted three double blind, randomized , placebo controlled
study to the FDA in support of an NDA for tirilazad in the treatment of SAH. However,
an FDA committee determined that these studies did not confirm efficacy, one study
showed an improvement in males, but this was not replicated in another study, and
there were no differences in females.
Tirilazad and newer , more potent antioxidants may also be studied in other
neurological conditions in which perioxidative mechanisms have been implicated,
These include Alzheimers disease, Parkinsons disease and multiple sclerosis
