Fujihara K, Nakashima I, Itoyama Y
J Neural Transm Suppl 2000;(58):205-14
Tohoku Univ, School of Medicine, Dept of Neurology, Sendai, Japan
PMID# 11128610; UI# 21011156
Optic-Spinal form of Multiple Sclerosis (OS-MS) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) are two Immune-mediated Myelopathy relatively common in Japan.
Transverse Myelitis, once seen in 60% of MS, mostly OS-MS, 30 years ago, drastically decreased (5%) recently in Japan.
In contrast, frequency of conventional form of MS (C-MS) increased during this period of time. But unlike C-MS in white patients, Cerebellar Hemispheric lesions are uncommon in Japanese C-MS.
These findings emphasize influence of changes in exogenous factors on manifestations of MS and distinct Genetic factors related to MS in Japanese and white patients.
To clarify the reason of high HTLV-I proviral load in HAM/TSP, we studied Cellular Immune surveillance against HTLV-I.
And found that significant CytoToxic T-Lymphocyte activity, suppressed Natural Killer activity, and AntiBody-dependent Cell-mediated CytoToxicity in the patients.
These altered Immune surveillance may be associated with the spread of HTLV-1 infection and the PathoGenesis of HAM/TSP.
Identification And Characterization Of A Potent, Selective And Orally Active Antagonist Of The CC Chemokine Receptor-1
Liang M, Mallari C, Rosser m, Ng HP, May K, Monahan S, Bauman JG, Islam I, Ghannam A, Buckman B, Shaw K, Wei GP, Xu W, Zhao Z, Ho E, Shen J, Oanh H, Subramanyam B, Vergona R, Taub D, Dunning L, Harvey S, Snider RM, Hesselgesser J, Morrissey MM, Perez HD, Horuk R
J Biol Chem 2000 Mar 29
Berlex Biosciences, Dept of Molecular Pharmacology, Richmond, CA 94804
The CC Chemokine Receptor-1 (CCR1) is a prime therapeutic target for treating AutoImmune Diseases.
Through high capacity screening followed by chemical optimization, we identified a novel non-Peptide CCR1 antagonist, R-N-[5-Chloro-2-[2-[4-[(4-fluorophenyl)methyl] -2-methyl-1-piperazinyl]-2-oxoethoxy]phenyl] Urea Hydrochloric Acid Salt (BX 471).
Competition binding studies revealed that BX 471 was able to displace the CCR1 Ligands, MIP-1, RANTES and MCP-3, with high affinity (Ki ranged from 1 nM to 5.5 nM).
BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca2+ mobilization, increase in ExtraCellular acidification rate, CD11b expression and Leukocyte migration.
BX 471 demonstrated a greater than 10,000 fold selectivity for CCR1 compared with 28 G-protein coupled Receptors. Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs.
Furthermore, BX 471 effectively reduces disease in a rat Experimental Allergic EncephaloMyelitis model of Multiple Sclerosis.
This study is the first to demonstrate that a non-Peptide Chemokine Receptor antagonist is efficacious in an animal model of an AutoImmune Disease.
In summary, we have identified a potent, selective and orally available CCR1 antagonist which may be useful in the treatment of Chronic Inflammatory Diseases.
A Comparison Of NeuroPsychological Deficits In Primary And Secondary/Progressive Multiple Sclerosis
Foong J, Rozewicz L, Chong WK, Thompson AJ, Miller DH, Ron MA
J Neurol 2000 Feb;247(2):97-101
Institute of Neurology, London, UK
PMID# 10751110; UI# 20213162
NeuroPsychological deficits and the relationship to Brain Pathology were examined in 13 Primary/Progressive (PP) and 12 Secondary/Progressive (SP) Multiple Sclerosis patients with a similar duration of the Progressive phase and comparable physical Disability.
A battery of NeuroPsychological tests to assess Attention, Short-Term and Working Memory was administered to the patients, and their performance was compared to that of 20 healthy controls matched for age and premorbid IQ.
Total Cerebral lesion load on T2-weighted Magnetic Resonance Imaging was measured in the patients. Both PP and SP patients performed significantly worse than controls in most of the NeuroPsychological tests.
There were only subtle differences between SP and PP on the Working Memory task although Magnetic Resonance Imaging Lesion Load was significantly higher in SP than in PP patients.
In this exploratory study only subtle differences in Cognitive Impairment were detected between SP and PP patients matched for physical Disability and relevant illness features.
The results also suggest that the severity of Cognitive Impairment cannot be fully explained by the extent of abnormalities detected on conventional T2-weighted Magnetic Resonance Images.
And that other Pathological abnormalities such as in Normal-Appearing White Matter are likely to be involved.