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Biotech / Medical : Neurobiological Tech (NTII) -- Ignore unavailable to you. Want to Upgrade?

To: John McCarthy who wrote (742)	1/5/2000 8:27:00 AM
From: Dr. John M. de Castro	Respond to of 1494

Pharmacologic rationale for memantine in chronic cerebral hypoperfusion, especially vascular dementia. Mobius HJ, Merz and Co., Frankfurt, Germany. Alzheimer Dis Assoc Disord 1999 Oct-Dec;13 Suppl 3:S172-8 Memantine is a moderate-affinity, voltage-dependent, uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. In contrast to competitive NMDA antagonists, Memantine is well tolerated in humans and is being developed for the treatment of dementia. The pathogenesis of vascular dementia (VaD) is largely unknown, and is likely multifactorial, but it involves the impairment of blood circulation as a common denominator. There is broad evidence for the efficacy of Memantine in several animal models of ischemia. Memantine also acts on several secondary, potentially contributing factors in VaD such as neuronal depolarization, removal of magnesium block of NMDA receptors, chronic overstimulation of these receptors, and, possibly, mitochondrial dysfunction. Among others, it also has additional positive effects on long-term potentiation and cognition in standard animal models of impaired synaptic plasticity. Recently, clinical efficacy of Memantine has been shown in an etiologically mixed population of severely demented patients, including those with VaD. Given the difficulties of diagnosing VaD in clinical practice, an optimal antidementive drug should be beneficial in both Alzheimer disease and VaD. Preclinical data presented in this paper indicate that such benefits can be achieved with Memantine. In addition, phase II clinical data in dementia are summarized, and two ongoing pivotal trials in VaD are described. Suggestions for VaD guideline development are made regarding clinical instruments, and etiologies and severity stages are considered.

To: John McCarthy who wrote (742)	1/5/2000 8:30:00 AM
From: Dr. John M. de Castro	Respond to of 1494

Clinically available NMDA antagonist, memantine, attenuates tolerance to analgesic effects of morphine in a mouse tail flick test. Pol J Pharmacol 1999 May-Jun;51(3):223-31 Popik P, Kozela E, Department of Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland. Converging lines of evidence indicate that N-methyl-D-aspartate (NMDA) receptor antagonists attenuate the development of morphine tolerance tested in antinociception assays in rodents. The present study extends these findings to the effects of clinically available NMDA receptor antagonist, memantine. Male Albino Swiss mice were tested for analgesia using the tail-flick apparatus. Preliminary experiment was designed to find out the optimal dose of morphine and the number of injections that would produce tolerance to its analgesic effects. In the main experiment, during the development of tolerance period (6 days), mice received 10 mg/kg sc b.i.d. morphine injections in the animal room (non-associative tolerance). This treatment resulted in 5.8 fold rightward shift of morphine cumulative dose-response effect from 3.39 mg/kg on day 1 to 16.19 mg/kg on day 8 of the experiment. Memantine pretreatment (5 and 10 mg/kg, but not 2.5 mg/kg), given 30 min prior to each morphine dose during the development of tolerance period, inhibited the rightward shift of morphine cumulative dose-response curve. Thus, pretreatment with memantine at doses of 2.5, 5 and 10 mg/kg resulted in ED50 values of 12.13, 4.74 and 1.95 mg/kg, respectively, corresponding to 3.35, 1.02 and 0.94 fold changes. These data indicate that low affinity, clinically available NMDA receptor antagonist, memantine, may be used to inhibit the development of morphine tolerance.

To: John McCarthy who wrote (742)	1/5/2000 8:37:00 AM
From: Dr. John M. de Castro	Read Replies (1) \| Respond to of 1494

The results of the Phase II trial of memantine for Neuropathic pain should be out within the next two weeks. The data are almost ready for analysis and the blind should be broken early next week. This is major. If the results are positive and the early indications are that they are, then, NTII becomes a very valuable company. If they are not positive, I will be very disappointed, but, the company will still have viable AIDS Dementia Complex and senile dementia indications for memantine. Best regards John de C

To: John McCarthy who wrote (742)	1/5/2000 8:41:00 AM
From: Dr. John M. de Castro	Respond to of 1494

Dopamine release in the prefrontal cortex in response to memantine following sub-chronic NMDA receptor blockade with memantine: a microdialysis study in rats. J Neural Transm 1999;106(9-10):803-18 Hesselink MB, De Boer AG, Breimer DD, Danysz W, Department of Pharmacological Research, Merz + Co., Frankfurt/Main, Federal Republic of Germany. Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist which blocks the NMDA receptor with moderate-affinity in a use- and voltage dependent manner. In clinical practice it is used chronically in the treatment of dementia and does not induce psychotomimetic effects as, high affinity, uncompetitive antagonists. Thus, it was of interest to determine dopamine (DA) and metabolite (DOPAC - dihydroxyphenylacetic acid and HVA - homovanillic acid) concentrations in the prefrontal cortex (PFC) in response to 14 days administration of memantine (20 mg/kg/day). It was previously determined that in rats this treatment induces sensitization to the locomotor effect and tolerance to the learning impairing properties of high doses of memantine. Acute administration of memantine (20 mg/kg, i.p.) did not affect dopamine levels in the PFC. It did however increase DA metabolite (DOPAC and HVA) concentrations. Administration of memantine (20 mg/kg/day) for 14 days before the acute challenge only slightly changed memantine's effect on PFC neurochemistry even though pharmacokinetic tolerance was observed. When memantine was administered to the sham group, which had been repeatedly treated with Hypnorm (including neuroleptic), an increase in PFC dopamine and metabolite content was seen. In accordance with the fact that memantine does not possess psychotomimetic activity at therapeutically relevant doses, these experiments showed that it does not affect the prefrontal cortex dopamine levels.