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To: LLCF who wrote (580)	2/18/1999 1:27:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 1073

Jim and David: Please keep posting this great stuff. Thanks, Rick

To: LLCF who wrote (580)	2/18/1999 5:55:00 PM
From: limit	Read Replies (1) \| Respond to of 1073

Thanks for the heads-up. I hope it was an "insider" Long and patient <<If anyone cares 1500 CEPH May 10 calls traded today on a pretty high volatility... I'm hearing Morgan Stanley sold and the "crowd" (MM's) bought. This is positive because it means Morgan has a client willing to take down 150K at this price >>

To: LLCF who wrote (580)	2/18/1999 8:07:00 PM
From: scaram(o)uche	Read Replies (3) \| Respond to of 1073

David: CEPH is not off-topic in the least. Low MC:book (3) with an approved product. I am particularly interested in hearing more about the "signal transduction modulator" (prostate CA, oral, phase I, TAP Holdings and Kyowa Hakko) and the Alzheimer's stuff. Given what Baldino did with myo, I am less than impressed. In fact, I am antagonized. However, they've always seemed to have plenty of science........ J Pharmacol Exp Ther 1999 Feb;288(2):421-7 CEP-1347/KT-7515, an inhibitor of c-jun N-terminal kinase activation, attenuates the 1-methyl-4-phenyl tetrahydropyridine-mediated loss of nigrostriatal dopaminergic neurons In vivo. Saporito MS, Brown EM, Miller MS, Carswell S Cephalon Inc., West Chester, Pennsylvania. [Medline record in process] We have identified a bis-ethylthiomethyl analog of K-252a, CEP-1347/KT-7515, that promotes neuronal survival in culture and in vivo. The neuronal survival properties of CEP-1347/KT-7515 may be related to its ability to inhibit the activation of c-jun N-terminal kinase, a key kinase in some forms of stress-induced neuronal death and perhaps apoptosis. There is evidence that the selective nigrostriatal dopaminergic neurotoxin, MPTP, produces neuronal apoptosis in culture and in adult mice. Thus, our studies were designed to determine if CEP-1347/KT-7515 could protect dopaminergic neurons from MPTP-mediated neurotoxicity. CEP-1347/KT-7515 was assessed for neuroprotective activity in a low dose MPTP model (20 mg/kg) where there was a 50% loss of striatal dopaminergic terminals in the absence of substantia nigra neuronal loss, and a high dose (40 mg/kg) MPTP model where there was a complete loss of dopaminergic terminals and 80% loss of dopaminergic cell bodies. In the low dose MPTP model, CEP-1347/KT-7515 (0.3 mg/kg/day) attenuated the MPTP-mediated loss of striatal dopaminergic terminals by 50%. In the high dose model, CEP-1347/KT-7515 ameliorated the loss of dopaminergic cell bodies by 50% and partially preserved striatal dopaminergic terminals. CEP-1347/KT-7515 did not inhibit monoamine oxidase B or the dopamine transporter, suggesting that the neuroprotective effects of CEP-1347/KT-7515 occur downstream of the metabolic conversion of MPTP to MPP+ and accumulation of MPP+ into dopaminergic neurons. These data implicate a c-jun N-terminal kinase signaling system in MPTP-mediated dopaminergic degeneration and suggest that CEP-1347/KT-7515 may have potential as a treatment for Parkinson's disease. Brain Res 1999 Jan 23;816(2):446-56 4-Aminopyridine enhances motor evoked potentials following graded spinal cord compression injury in rats. Gruner JA, Yee AK Cephalon, Department of Experimental Pharmacology, 145 Brandywine Pkwy., West Chester, PA 19380-4245, USA. [Medline record in process] Although several experimental and clinical studies have demonstrated the ability of 4-aminopyridine (4-AP) to restore electrophysiological and/or behavioral function following chronic spinal cord injury, the mechanism by which this occurs remains unclear. Demonstration of efficacy in rat spinal cord injury has not been reported, evidently because even relatively mild spinal cord contusions that produce only minor permanent locomotor disturbances abolish hind limb myoelectric motor evoked potentials (mMEPs). In this study, mMEPs were recorded acutely 25 days following graded thoracic spinal cord compression in rats. mMEP amplitudes were significantly enhanced by a single, 2 mg/kg i.v. dose of 4-AP. mMEPs were increased in all rats showing some evoked responses initially, and also in some animals which had no responses prior to treatment. 4-AP was further found to increase the maximum following frequency of mMEPs in both normal and injured rats from about 0.1 Hz to between 1 and 10 Hz. These data suggest that 4-AP might act by enhancing synaptic efficacy, as well as enhancing conduction in spinal axons whose myelination has been rendered dysfunctional by trauma. Copyright 1999 Elsevier Science B.V.