1 We have previously shown that manganese enhances L-dihydroxyphenylanine (L-DOPA) toxicity to PC12 cells in vitro. The supposed mechanism of manganese enhancing eect [an increase in L-DOPA and dopamine (DA) auto-oxidation] was studied using microdialysis in the striatum of freely moving rats. 2 Systemic L-DOPA [25 mg kg 71 intraperitoneally (i.p.) twice in a 12 h interval] signi®cantly increased baseline dialysate concentrations of L-DOPA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and uric acid, compared to controls. Conversely, DA and ascorbic acid concentrations were signi®cantly decreased. 3 A L-DOPA oxidation product, presumptively identi®ed as L-DOPA semiquinone, was detected in the dialysate. The L-DOPA semiquinone was detected also following intrastriatal infusion of L-DOPA. 4 In rats given L-DOPA i.p., intrastriatal infusion of N-acetylcysteine (NAC) signi®cantly increased DA and L-DOPA dialysate concentrations and lowered those of L-DOPA semiquinone; in addition, NAC decreased DOPAC+HVA and uric acid dialysate concentrations. 5 In rats given L-DOPA either systemically or intrastriatally, intrastriatal infusion of manganese decreased L-DOPA dialysate concentrations and greatly increased those of L-DOPA semiquinone. These changes were inhibited by NAC infusion. 6 These ®ndings demonstrate that auto-oxidation of exogenous L-DOPA occurs in vivo in the rat striatum. The consequent reactive oxygen species generation may account for the decrease in dialysate DA and ascorbic acid concentrations and increase in enzymatic oxidation of xanthine and DA. L-DOPA auto-oxidation is inhibited by NAC and enhanced by manganese. These results may be of relevance to the L-DOPA long-term therapy of Parkinson's disease. British Journal of Pharmacology (2000) 130, 937 ± 945

In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m 2 /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m 2 ; cycles 4-8, 500 mg/ m 2 ). Responders were randomized to 12 8-week doses of R (375 mg/m 2 ) or observation. As per intention-totreat analysis, 82.4% (95% CI, 74.25-90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60-64 years, 92.3%; 65-69, 85.2%; 70-74, 75.0%; 75, 81.0%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients.

1 The e ects of systemic, intrastriatal or intranigral administration of d-amphetamine on glutamate, aspartate, ascorbic acid (AA), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in dialysates from the striatum of freely-moving rats were evaluated using microdialysis. 2 d-Amphetamine (2 mg kg 71 ) given subcutaneously (s.c.) increased DA, AA and uric acid and decreased DOPAC+HVA, glutamate and aspartate dialysate concentrations over a 3 h period after d-amphetamine. 5-HIAA concentrations were una ected. Individual changes in glutamate and AA dialysate concentrations were negatively correlated. 3 d-Amphetamine (0.2 mM), given intrastriatally, increased DA and decreased DOPAC+HVA and aspartate dialysate concentrations, but failed to change those of glutamate, AA uric acid or 5-HIAA, over a 2 h period after d-amphetamine. Haloperidol (0.1 mM), given intrastriatally, increased aspartate concentrations without a ecting those of glutamate or AA. 4 d-Amphetamine (0.2 mM), given intranigrally, increased AA and uric acid dialysate concentrations and decreased those of glutamate, aspartate and DA; DOPAC+HVA and 5-HIAA concentrations were una ected. 5 These results suggest that d-amphetamine-induced increases in AA and uric acid and decreases in glutamate concentrations are triggered at nigral sites. The changes in aspartate levels may be evoked by at least two mechanisms: striatal (mediated by inhibitory dopaminergic receptors) and nigral (activation of amino acid carrier-mediated uptake).

No abstract

No abstract