ABSTRACT
Reduced serotonergic tone may be a compensatory adaptation to reduced dopaminergic activity in Parkinson's disease (PD) and may result in vulnerability to depression. To test this hypothesis this study examined the effects of serotonin depletion, using the technique of acute tryptophan depletion (ATD) in PD. The effects of ATD were investigated in a double-blind, placebo-controlled, counterbalanced, cross-over, randomised design, in 20 patients with PD and 32 healthy controls matched for age, gender and pre-morbid IQ. The primary outcome was change in scores on a modified Montgomery-Asberg Depression Rating Scale (MADRS). ATD resulted in a small but statistically significant increase in score on the MADRS, but there was no effect specific to the PD group. The results do not support the hypothesis that low serotonergic tone results in vulnerability to depression in PD and are in accord with an earlier study using the same technique in PD.
Subject(s)
Affect , Depression/etiology , Parkinson Disease/psychology , Tryptophan/deficiency , Age Factors , Aged , Antiparkinson Agents/therapeutic use , Cross-Over Studies , Depression/diagnosis , Depression/metabolism , Depression/psychology , Double-Blind Method , Humans , Middle Aged , Parkinson Disease/complications , Parkinson Disease/diagnosis , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Placebo Effect , Psychiatric Status Rating Scales , Serotonin/metabolism , Severity of Illness IndexABSTRACT
Interactions between the 5-HT system and the dopaminergic system and cholinergic system may be important in determining cognitive function and motor function in Parkinson's disease (PD). Previous studies have shown effects of reducing serotonin function, by acute tryptophan depletion (ATD), on neuropsychological function. In particular, an adverse effect on verbal memory has been demonstrated. This study compared with the effects of ATD on cognitive and motor function in PD and healthy control subjects. The effects of ATD were investigated in a double-blind, placebo-controlled, counterbalanced, cross-over, randomised design in 20 patients with PD and 35 healthy controls matched for age, gender and premorbid IQ. There was a differential group effect of ATD on global cognitive function whereby the mean score on the modified mini mental state examination during ATD was lower than placebo in PD but higher in controls. There was a similar pattern of effects on verbal recognition. In a visual recognition task, ATD improved performance in the PD but not in the control group. In terms of psychomotor speed, there was also a group-specific effect with reduced latency of response during ATD in the PD group but increased latency in the control group. ATD has subtle neuropsychological effects, which differ significantly between PD and healthy control subjects. This suggests that the dopaminergic and cholinergic deficit of PD significantly modulates the effects of serotonin depletion, resulting in positive effects in some domains. Further investigation on the effects of specific serotonin antagonists may be merited in PD.
Subject(s)
Cognition/physiology , Deficiency Diseases/physiopathology , Movement Disorders/physiopathology , Parkinson Disease/physiopathology , Tryptophan/deficiency , Aged , Aged, 80 and over , Cross-Over Studies , Deficiency Diseases/blood , Deficiency Diseases/complications , Double-Blind Method , Female , Humans , Male , Memory, Short-Term , Middle Aged , Neuropsychological Tests , Parkinson Disease/blood , Parkinson Disease/complications , Psychomotor Performance , Reaction Time , Serotonin/physiology , Severity of Illness Index , Tryptophan/administration & dosage , Tryptophan/bloodABSTRACT
Alminoprofen is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylpropionic acid class. It has anti-inflammatory properties different from the classical NSAID. Using both in vitro systems of cells in culture and in vivo models of inflammation, we report here that alminoprofen possesses both antiphospholipase A2 (PLA2) activity and anti-cycloxygenase (COX) activity. The PLA2 targeted by alminoprofen is likely the secretory phospholipase A2 (sPLA2) while the COX targeted is the COX-2.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Phospholipases A/antagonists & inhibitors , Phospholipids/metabolism , Propionates/pharmacology , Animals , Cell Line , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Dinoprostone/analysis , Edema/chemically induced , Edema/drug therapy , Flurbiprofen/pharmacology , Group II Phospholipases A2 , Humans , Indans/pharmacology , Indomethacin/pharmacology , Isoenzymes/metabolism , Melitten , Membrane Proteins , Phospholipases A/toxicity , Phospholipases A2 , Propionates/therapeutic use , Prostaglandin-Endoperoxide Synthases/metabolism , Prostaglandins F/analysis , Rats , Rats, WistarABSTRACT
The influx of eosinophils in tissues plays a central role in the pathophysiology of allergic diseases such as allergic rhinitis, allergic asthma or atopic dermatitis. The death of eosinophils by apoptosis is an important factor for the resolution of hypereosinophilia. In the present study, we have shown that Uriage spring water induced in vitro the apoptosis of IL-5-primed eosinophils. This effect was dose-dependent and was statistically significant at Uriage water concentrations above 20%. The induction of apoptosis was related to the Ca2+ content of Uriage water. Indeed, Ca2+ at the same concentration as in Uriage water mimicked the apoptotic effect of the spring water. Furthermore, EGTA reversed the apoptotic effect of Uriage water. These results suggest that topically applied, Uriage water could contribute to the resolution of eosinophilic inflammation.
Subject(s)
Apoptosis , Eosinophils/drug effects , Hypersensitivity/pathology , Water/pharmacology , Calcium/metabolism , Cells, Cultured , Eosinophils/metabolism , Eosinophils/pathology , Humans , Interleukin-5/metabolismABSTRACT
The pharmacokinetics of alminoprofen in plasma and synovial fluid (SF) at steady state (300 mg t.i.d.) was studied in 45 patients with knee effusion. Plasma and SF samples, one each per patient, were obtained. Six groups were made according to the time of sampling after ingestion of the 13th dose: 1 h (n = 7), 2 h (n = 7), 4 h (n = 7), 6 h (n = 10), 8 h (n = 6), 12 h (n = 8). A three-compartment model was used to describe alminoprofen kinetics in plasma and SF, with two parameterizations, a 'classical' and a 'physiological' one. The non-linear mixed effect model approach was used to estimate the mean and variance of the pharmacokinetic parameters. The mean +/- SE of the estimates (coefficient of variation of interindividual variability as a percentage) were volume of distribution, 11.0 +/- 1.711 (12%); elimination rate constant, 0.236 +/- 0.025 h-1 (18%); absorption rate constant 2.80 +/- 0.31 h-1 (464%), clearance of influx into SF, 0.29 +/- 0.14 mL min-1; clearance of efflux into plasma, 0.56 +/- 0.25 mL min-1. These two clearances were not significantly different, which indicates that passive diffusion occurs in both directions. The mean +/- SD alminoprofen concentration versus time curve in plasma and SF at steady state was simulated and showed that the mean +/- SD maximal concentration in SF was 8.1 +/- 6.3 mg L-1 and was obtained 4 h after dose administration.
