To all,
After we clear confusion, let me refresh memory on Cerestat clinical data : PI and PII
Because, Cerestat will be hot issue in this tread for next +six months, any additional data on PII will be appreciate.
Miljenko
bdw, where is sec PO?
(PI)
Title
Systemic and cerebral hemodynamic responses to the noncompetitive N-methyl-D-aspartate (NMDA) antagonist CNS
1102.
Author
Grosset DG; Muir KW; Lees KR
Address
University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, U.K.
Source
J Cardiovasc Pharmacol, 25: 5, 1995 May, 705-9
Abstract
The excitatory amino acid antagonists are being developed as neuroprotective drugs aimed at limiting ischemic neuronal
damage. Their hemodynamic and neurologic side effects are important in assessing safety and tolerability. We studied
CNS 1102, a high-affinity noncompetitive N-methyl-D-aspartate (NMDA) receptor-channel antagonist, in normal
volunteers. The effects of 2 mg CNS 1102 were assessed in a single-blind, placebo-controlled, fixed-dose, cross-over
trial comparing administration by intravenous infusion for 15 min or bolus for 2 min in 8 healthy male subjects. Cerebral
hemodynamics were studied with carotid and vertebral duplex ultrasound imaging, common carotid artery walltracking,
and middle cerebral artery velocity readings. CNS 1102 administration was associated with light-headedness, mild
disorientation, perioral and peripheral paresthesias, and flushing. Mean arterial blood pressure (MAP) increased
significantly from baseline 1 h after CNS 1102 administration, with a maximal increase of 17 mm Hg over placebo.
Pulse rate was unchanged. Common carotid artery pulsatility decreased by 38.4% [8.3-64.5, 95% confidence interval
(CI)] and vertebral pulsatility by 43.8% [11.5-74.1], both p < 0.02. No significant differences were detected for other
velocity and flow parameters. Middle cerebral artery mean velocity increased by 4.6 cm/s (1.6-7.8 cm/s) and diastolic
velocity by 4.6 cm/s (2.4-7.3 cm/s) (both p < 0.01), but systolic velocity was unchanged. The middle cerebral pulsatility
index decreased by 11% (3.8-16.1), p < 0.001. CNS 1102 is well tolerated at a fixed dose of 2 mg in normal
volunteers. Cerebral arteriolar constriction is inferred from the ultrasound results.(ABSTRACT TRUNCATED AT 250
WORDS)
RECENT DEVELOPMENTS (PII)
NEWS RELEASE
March 28, 1996 -- Cambridge NeuroScience CERESTATr Data In Stroke Patients Reported At American Academy Of
Neurology --- Pivotal Trial in Stroke to Begin Later This Year -- San Francisco, California and Cambridge, Massachusetts --
A Southwestern Vermont Medical Center researcher presented preliminary results of a Phase II trial of CERESTATr in
patients with acute ischemic stroke. The study results were reported today by Keith Edwards, M.D., at the American
Academy of Neurology meeting in San Francisco. CERESTATr is Cambridge NeuroScience's NMDA ion-channel blocker,
currently in Phase III trials for traumatic brain injury, being jointly developed with Boehringer Ingelheim.
In this dose response study, CERESTATr was well tolerated at all doses, and there was evidence of clinical benefit and
neurological improvement in patients treated with the higher doses of CERESTATr at 90 days following the stroke. A pivotal
trial of CERESTATr in stroke is scheduled to begin later this year, with doses higher than those which produced improvement
in this Phase II study, which have been shown to be safe in a prior study reported in January 1996.
"I am extremely encouraged by the strong indication of activity that these results provide, particularly in light of the absence of
alternative therapies for stroke," said Keith Edwards, M.D., a neurologist at the Southwestern Vermont Medical Center, and a
principal investigator in the study. "This drug clearly warrants further assessment in a large-scale trial."
The double-blind, placebo-controlled study involved 132 patients enrolled at 30 centers in the United States and Europe. The
primary measure of outcome was the National Institutes of Health Stroke (NIHS) Scale, a measure of the severity of
neurological impairment. Secondary measures included assessments of function, such as the Rankin Scale and the Barthel
Index of Activities of Daily Living. Patients were randomized to either placebo, or one of three dose regimens: 30, 70 or 110
æg/kg of CERESTATr by bolus and infusion over a four-hour period.
Among the findings were:
At Day 30, patients in the top two CERESTATr dose groups improved on average by 5.2 and 4.3 points on the
NIHS Scale, in contrast to control patients whose average improvement was 3.6 points. This effect did not reach
statistical significance.
At Day 90, patients in the top two CERESTATr dose groups had improved on average by 5.2 and 6.3 points on the
NIHS scale, in contrast to control patients whose average improvement was 4.7 points. The degree of improvement
compared to placebo for the highest dose group was statistically significant at p < 0.04.
At Day 90, of the patients who had entered the study with more severe impairments, 32 to 40% of those who received
the highest dose of CERESTATr had no, or minor disabilities, in contrast to only 19% of such patients who received
placebo. These responses were measured on the Rankin and Barthel functional scales respectively.
Dr. Edwards commented that even before the treatment groups were identified in the double-blind trial, some patients
appeared to have a superior course of recovery. "My impression, before the blind was broken, was that some patients had a
course of recovery that was much better than I would have expected without treatment, and that impression has been
confirmed by subsequent analysis."
Dr. Edwards added that the placebo group had more mild strokes than the treated groups, so that despite the trend towards
greater improvement on the NIHS Scale at day 30 in the two higher dose groups, the effect was not statistically significant.
"The positive results of this trial, along with the data from two other trials in stroke patients, have led Cambridge NeuroScience
and our partner Boehringer Ingelheim to initiate a 900-patient clinical trial," said Elkan R. Gamzu, Ph.D., President and Chief
Executive Officer, Cambridge NeuroScience. "We expect this pivotal trial to begin later this year at l00 sites in the United
States and internationally."
To date, over 400 patients and volunteers have participated in CERESTATr clinical trials over the last three years, including
more than 300 treated with CERESTATr. The drug acts to prevent nerve cell death and brain damage following head injury
or stroke by preventing excessive entry of calcium into nerve cells. It is known that nerve cell death following a serious head
injury or stroke is triggered by excessive glutamate released from damaged nerve terminals, which stimulates the massive entry
of calcium into nerve cells. There are approximately 500,000 victims of stroke in the United States annually. No effective drug
therapy is available to treat these patients, or to prevent the nerve cell damage that occurs subsequent to a stroke or traumatic
brain injury.
This press release contains forward-looking statements based on the current expectations of management. There are certain
important factors that could cause results to differ from those anticipated by the statements made above, including, but not
limited to, the continued funding of the Company's development program for CERESTATr from BI under the BI
collaborative agreement, the rate of enrollment of patients in the Company's current and future clinical trials, and the
acceptance by regulatory authorities of the Company's clinical trial outcomes as a basis for marketing approval.
Southwestern Vermont Medical Center is a dynamic community hospital with a longstanding commitment to clinical research.
Through its departments of Neurology, Oncology, and Endocrinology, it is linked with research teams at the University of
Vermont, Dana-Farber Cancer Institute, and the Joslin Clinic. 20% of its affiliated physicians hold teaching positions at area
medical schools, further contributing to the hospital's culture of academic inquiry. |
