Ondansetron, a 5-HT3 antagonist, improves tardive dyskinesia

P4 Degenemtiue

Cognitive performances were assessed by the Alzheimer’s Disease Assessment Scale, global functions by the Clinician’s Interview-Based Impression of Change. Patients were treated with 5 mg/die of donepezil for the first one or two months, then with 10 mg/die for more than 9 months. Cytokine assays were carried out by using immunoenzimatic techniques before and during treatment (at 1, 3, 6, 9, 12 months). We found that DAT patients had significantly higher TNF-a, IL-6 and IL-12 levels (but lower IL-10 levels) than sex- and age-matched healthy controls. Treatment with donepezil was linked to a reduction of IL-12 and TNF-a levels; serum IL-6 amounts did not change significantly; IL- 10 levels increased (but inconstantly). Our research work demonstrates that, although in DAT there is a CNS-localized immune response, immune abnormalities are also found peripherally: our data stand for a systemic T-cell activation in DAT, partially counteracted by donepezil. In particular, anticholinesterase treatment might act on T-helper cells modulating their function through some effects on cholinergic tone, given the presence of specific nicotininc and muscarinic receptors on human lymphocytes. References

[I] K&via,R.N. (1993) The immunopathology of Alzheimer’s disease and some related disorders. Brain Pathol. 3, 333-347. [2] Bongioanni, P, Romano, M.R., Sposito, R., Castagna, M., Boccardi, B., Borgna, M. and Favilli, B. (1997) T-cell tumor necrosis factor-a receptor binding in demented patients. J. Neural. 244,418-425. [3] Bongioanni, F!, Boccardi, B., Borgna, M. and Rossi, B. (1998) T-lymphocyte interleukin-6 receptor binding in patients with Dementia of Alzheimer type. Arch. Neural. 55, 1305-1308.

[p.4.0241

T-cell cytokine

binding

in myasthenia

S321

and neurological disorders

gravis

I? Bongioanni, R. Ricciardi, D. Lucchesi, B. Boccardi, S. Nuti, C. Baldini, C. Chisari, B. Rossi. Department of Neurosciences, University of Piss. Italy

Myasthenia gmvis (MG) is a T-cell-dependent and antibody-mediated autoimmune disease manifested by weakness and fatigability of vohmtary muscles. Cytokines play an important role in MG pathogenesis and pathophysiology, by regulating autoantibody production and interfering with cell-mediated immunity. TM-type cytokines interleukin (IL)-4, IL-6 and IL-10 exert remarkable effects on anti-acetylcholine receptor (AChR) antibody production; among Tst-type cytokines, interferon (IFN)-y is involved in inducing B-cell maturation and helping anti-AChR antibody synthesis [I], and tumor necrosis factor (TNF)-a modulates the immune response in MG by acting within the cytokine network [2]. Specific IFNy, TNFa and IL-6 receptors have been found on human lymphocytes, as well as on other cell types, even in the CNS. The aim of our study was to assay such cytokine binding on peripheral blood T cells from MG patients, as compared with healthy subjects. Using radioiodinated hgands, we studied T-cell cytokine binding in 38 MG patients, consecutively selected according to the Osserman’s criteria, and assigned to I (n = 7), II A (n = 13), and II B (n = 18) groups. Disease severity was scored by a quantitative clinical scale. Single-fiber electromyography and response to intravenous edrophonium were positive in all patients tested. Nine of 38 patients were negative for antibodies against human AChR by conventional radioimmunoassay. At the time of blood sampling, 20 patients were receiving pyridostigmine and corticosteroids, with or without immunosuppressive drugs; and 10 pyridostigmine alone. There were 8 “de nova” subjects. We found that T cells from MG patients had significantly fewer IFN-y receptors and more TNF-a and IL-6 receptors than those from controls (Bmax: 483 f 14 vs 734 & 13, 654 f 12 vs 133 * 4 and 334 i 6 vs 251 i 4 (mean & SEM) receptors/cell, for IFN-y, TNF-a and IL-6, respectively). Such cytokine binding sites were of the same type in patients and healthy subjects. Changes in cytokine T-cell binding were due to related changes in cytokine receptor numbers on T-helper lymphocytes. Our data point out an “in vivo” T-cell activation in MG. These results are discussed in terms of MG immunopatbogenesis, since it has

been reported that activated T cells have decreased amounts of IFN-y receptors, and an enhanced number of TNF-a and IL-6 receptors. References [1] Zhang, G.X., Navikas, V and Link, H. (1997) Cytokines and the pathogenesis of myasthenia gravis. Muscle Nerve 20, 543-551. [2] Matusevicius, D., Navikas, V., Palasik, W., Pirskanen, R., Fredrikson, S. and Link, H. (1996) Tumor necrosis factor-a, lymphotoxin, interleukin (IL)-6, IL10, IL-12 and pert&in mRNA expression in mononuclear cells in response to acetylcholine receptor is augmented in myasthenia gravis. J. Newoimmunol. 71, 191-198.

1-1

Ondansetron, dyskinesia

a 5-HT3 antagonist,

improves tardive

P. Sirotalt3, T. Mosheva’n’, H. Shabtay2*3,N. Giladi2a3,A.D. Korcyn2*3. ‘Abarbanel Mental Health Centec Bat-Yam; 2Sieratzki Chair of Neumlogy, Tel-Auiu Uniuersity; ‘Sackler Faculty of Medicine, Tel-Aviv Vniversity, Tel-Aviv, Israel Background: The mechanism of development of tardive dyskinesia (TD) remains unclear. Serotonin may modulate dopaminergic activity and thus be involved in TD. Ondansetron is a selective 5-HTs receptor antagonist that is successfully used to prevent nausea and vomiting in cancer patients treated with chemotherapy. Objectives: The authors conducted a preliminary open-label study to examine the efficacy, tolerability and safety of ondansetron in patients with tardive dyskinesia. Methods: We studied 20 patients (5 males had 15 females), 4281 years old (mean f SD: 69.8 Ifr lo.]), who met Research Diagnostic Criteria for at least mild tardive dyskinesia. They had stable psychopathology and had been on a stable psychotropic drug regimen for at least six months. All patients met DSM4 criteria for schizophrenia and provided signed informed consent. Their disease duration was l30 years. Ondansetron 8-12 mgiday was administered for 12 weeks. All patients were assessed by four independent investigators who used video tapes of the patients’ movements. The scales used for the clinical evaluations were: 1) Positive and Negative Syndrome Scale (PAN%); 2) Abnormal Involuntary Movement Scale (ALMS); 3) Clinical Global Impression Scale (CGI). Evaluations were performed at baseline and every 4 weeks thereafter until the completion of the study. Results: Ondansetron caused a statistically significant improvement of TD as measured by AIMS scores (p = 0.000). PANSS scores also improved significantly (p = 0.0002). At the completion of the study a statistically significant correlation was found between the PANSS and AIMS scores (p < 0.02). Age and sex did not influence the AIMS scores at all four evaluations. There were no hematological or chemical laboratory impairments before or after the treatment with Ondansetron. Conclusions: Ondansetron may be an effective and safe therapy to control tardive dyskinesia and psychotic symptoms in schizophrenic patients. Such a pharmacalogical strategy may improve patients mobility and quality of life.

lp.4.0261

Donepezil in the treatment of Alzheimer’s disease: results from the first year of a study in clinical practice in the UK

HP Matthews, J. Korbey, D.G. Wilkinson, .I. Rowden. Western Community Hospital, Southampton,

UK

Introduction: This open-label study assessed the efficacy of donepezil in patients with mild to moderately severe Alzheimer’s disease in clinical practice. Method: Patients were referred over 1 year to an elderly mental health clinic in Southampton, UK. Eighty-two patients received 5 mg/day donepezil for 4 weeks, after which, if tolerated, the dose was increased to 10 mgday. The efficacy measures were the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State