A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain: 3-(p-trifluoromethylphenoxy). N-methyl-3-phenylpropylamine.

3-(p-Trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140) competitively inhibited the uptake of serotonin (5-HT), norepinephrine (NE) and dopamine into synaptosomes of rat brain with Ki values of 5.5 x 10-minus8, 9.5 x 10-minus6 and 1.3 x 10-minus5 M, respectively. Aiming for a more effective inhibitor of 5-HT uptake, we found the trifluoromethyl group in the phenoxy ring was most favorable at the para-position and was better than other substituting groups including fluoro, chloro, methyl and methoxy groups. The N-demethylated (primary amine) and the N.N-diemthylated (tertiary amine) derivatives inhibited the uptake of monoamines with the same effectiveness as Lilly 110140 (a secondary amine). The uptake of 5-HT into synaptosomes was significantly inhibited 15 minutes after an intraperitoneal administration of Lilly 110140. The inhibition persisted for a 24-hour period. NE uptake in vitro maintained a normal rate during the entire time course. Lilly 110140 likewise had no effect on the in vitro and in vivo accumulation of 3-H-tryptophan in the brain. The effect of Lilly 110140 and the tricyclic drug, chlorimipramine, was compared. Although chlorimipramine inhibited the uptake of 5-HT into synaptosomes with same effectiveness as Lilly 110140 in vitro, it reduced the uptake of both 5-HT and NE in vivo. Chlorimipramine exerted its greatest inhibition on the two uptake processes in the 1st hour and none by the 4th hour. Unlike the tricyclic drugs, imipramine, chlorimipramine, desipramine and chlordesipramine, Lilly 110140 and its primary amine derivative did not block the in vivo uptake of NE into rat heart. The present study suggests that Lilly 110140 is a potent and selective inhibitor for uptake of 5-HT into synaptosomes of rat brain.     

EFFECT OF CAFFEINE-DEXTROSE ON FlXATlONAL AND READING EFFICIENCY

Fourteen male optometry students were tested under control conditions (taking neither stimulant nor placebo) on reading comprehension, duration (speed), total number of fixations, and span of fixation. They then were divided randomly into two equal groups. One group ingested two tablets, each containing 200 mg caffeine alkaloid and 150 mg of dextrose; the other, two placebo tablets containing sugar and pepper. Results showed no difference between the two control groups, indicating about equal base for initiating the experimental procedure, and no difference between control and placebo, reflecting the ineffectiveness of this placebo as a stimulant. Significant difference between control and caffeine-dextrose appeared in three of the four efficiency measures, implying a need for still higher dosage to bring out significant improvement in duration. Significant difference between the two experimental mean-percent improvements indicated that caffeine-dextrose, at the present composition and dosage, does enhance the fixational and reading efficiency.     

Longitudinal change in 99mTcHMPAO cerebral perfusion SPECT in Parkinson's disease over one year

BACKGROUND: Brain perfusion deficits have been reported previously in subjects with Parkinson's disease in comparison with healthy controls. OBJECTIVE: To carry out a longitudinal study of perfusion in patients with Parkinson's disease and controls to find areas showing a reduction in perfusion over one year. METHODS: Two HMPAO cerebral perfusion scans were acquired one year apart in 30 subjects with Parkinson's disease (mean (SD) age, 76 (5) years) and 34 healthy comparison subjects (76 (7) years). Scans were normalised to the mean intensity in the cerebellum. RESULTS: Using SPM99 within groups to investigate regions that showed a decrease in perfusion between scans, it was found that in Parkinson's disease subjects but not controls there was a significant cluster in the frontal lobe (Brodmann area 10) where perfusion decreased over the year. CONCLUSIONS: The progressive frontal perfusion deficits in Parkinson's disease are consistent with results from previous structural and neuropsychological studies suggesting frontal lobe involvement and executive dysfunction even in early Parkinson's disease.     

The role of levodopa in the management of dementia with Lewy bodies

BACKGROUND: One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for Parkinson's disease (PD), but its use in DLB has been tempered by concerns of exacerbating neuropsychiatric symptoms. AIM: To assess the efficacy and tolerability of L-dopa in managing EPS in DLB and to compare the motor response with that seen in PD and PD with dementia (PDD). METHOD: EPS assessment consisted of the Unified Parkinson's Disease Rating Scale, motor subsection (UPDRS III), and finger tapping and walking tests. Patients with DLB were commenced on L-dopa. After 6 months, patients were examined in the "off" state, given L-dopa and assessed for motor responses. Identical assessments were performed in patients with PD and PDD also receiving L-dopa. RESULTS: Acute L-dopa challenge in 14 DLB patients yielded a mean 13.8% (p = 0.02) improvement in UPDRS III score, compared with 20.5% in PD (n = 28, p < 0.0001) and 23% in PDD (n = 30, p<0.0001) respectively. Finger tapping scores increased (12.3% v 20% and 23%), while walking test scores decreased (32% v 41% and 67%). Of the DLB patients, 36% were classified as "responders" on L-dopa challenge, compared with 70% of the PDD and 57% of the PD patients. Nineteen DLB patients were treated for 6 months with L-dopa (mean daily dose 323 mg). Two withdrew prematurely with gastrointestinal symptoms and two with worsening confusion. CONCLUSION: L-dopa was generally well tolerated in DLB but produced a significant motor response in only about one third of patients. Younger DLB cases were more likely to respond to dopaminergic treatment.     

Sensory abnormalities in unaffected relatives in familial adult-onset dystonia

Somatosensory abnormalities are found in adult-onset primary torsion dystonia (PTD). Therefore we assessed spatial discrimination thresholds (SDT), a measure of spatial acuity, in four multiplex families with adult-onset PTD. In family members aged 20 to 45 years vs controls (mean + 2.5 SD), abnormal SDTs were found in four of five affected with adult-onset PTD and in 12 of 49 unaffected relatives. Sensory abnormalities may be an endophenotype, possibly expressed later as adult-onset PTD.