We assessed the clinicopathological features of 28 patients with peripheral neuropathy associated with Churg-Strauss syndrome. Initial symptoms attributable to neuropathy were acute painful dysaesthesiae and oedema in the dysaesthetic portion of the distal limbs. Sensory and motor involvement mostly showed a pattern of mononeuritis multiplex in the initial phase, progressing into asymmetrical polyneuropathy, restricted to the limbs. Parallel loss of myelinated and unmyelinated fibres due to axonal degeneration was evident as decreased or absent amplitudes of sensory nerve action potentials and compound muscle action potentials, indicating acute massive axonal loss. Epineurial necrotizing vasculitis was seen in 54% of cases; infiltrates consisted mainly of CD8-positive suppressor/cytotoxic and CD4-positive helper T lymphocytes. Eosinophils were present in infiltrates, but in smaller numbers than lymphocytes. CD20-positive B lymphocytes were seen only occasionally. Deposits of IgG, C3d, IgE and major basic protein were scarce. The mean follow-up period was 4.2 years, with a range of 8 months to 10 years. Fatal outcome was seen only in a single patient, indicating a good survival rate. The patients who responded well to the initial corticosteroid therapy within 4 weeks regained self-controlled functional status in longterm follow-up (modified Rankin score was < or = 2), while those not responding well to the initial corticosteroid therapy led a dependent existence (P < 0.01). In addition the patients with poor functional outcomes had significantly more systemic organ damage caused by vasculitis (P < 0.05). Necrotizing vasculitis mediated by cytotoxic T cells, leading to ischaemic changes, appears to be a major cause of Churg-Strauss syndrome-associated neuropathy. The initial clinical course and the extent of systemic vasculitic lesions may influence the long-term functional prognosis.

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A new series of 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives were found to show potent and selective inhibition of platelet-dervied growth factor (PDGF) receptor phosphorylation. In this exploration of the structure-activity relationships (SARs) of the prototype inhibitor KN1022, the 4-nitrophenylurea moiety was probed. We found that 4-substitution on the phenyl ring was optimal and the introduction of more than two substituents on the phenyl ring decreased activities. Bulky substituents on the phenyl ring enhanced activities. Thiourea analogues were also prepared, and the SARs were found to be slightly different from those of the urea derivatives. Through this research, we obtained some potent KN1022 derivatives such as 4-(4-methylphenoxy)phenyl (36, IC(50) 0.02 micromol/L), 4-tert-butylphenyl (16, IC(50) 0.03 micromol/L), and 4-phenoxyphenyl (21, IC(50) 0.08 micromol/L) analogues, which had almost a 10-fold increase in activity against KN1022. These potent compounds retained their high selectivity against the PDGF receptor family similar to KN1022. We also observed that these compounds could inhibit the PDGF-BB-induced proliferation of porcine vascular smooth muscle cells without cell toxicity almost at the same IC(50) values observed for PDGF receptor phosphorylation. To evaluate the biological effects in vivo, we selected some analogues on the basis of the measurement of the plasma drug concentration after oral administration to rats. Oral administration of the 4-chlorophenyl (6), 4-bromophenyl (9), or 4-isopropoxyphenyl (20) analogue to Sprague-Dawley rats (30 mg/kg, twice daily) resulted in significant inhibition (24-38%) of neointima formation in the carotid artery of the balloon catheter deendothelialized vessel in the rats. Therefore, 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives, which are potent inhibitors of PDGFR phosphorylation, may be expected to represent a new therapeutic approach for the treatment of various aspects of atherosclerosis and other cellular proliferative disorders.

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