Three-year observation of mesulergine (CU 32-085) in advanced and newly treated parkinsonism.

In 15 patients (8 men, 7 women), aged 44-81 years, with idiopathic parkinsonism, the effects of mesulergine (CU 32-085) were observed for up to 3 years. Of these patients, four had been without previous levodopa treatment, five had been on levodopa/decarboxylase inhibitor for 6.4 years and six patients had been on levodopa/decarboxylase inhibitor and bromocriptine for a period of 7.5 years. Mesulergine proved to be effective in all three groups of patients and for each main symptom of the disease. Rigidity and tremor showed a better response than akinesia. A decline in efficacy could be observed after 18 months of treatment. By increasing the levodopa dosage, the worsening of the symptomatology could be reduced again and after 3 years patients were slightly better off than before the introduction of mesulergine. Fine motor performance showed a longer-lasting improvement than walking, which was affected by an increase of freezing. Mesulergine was not fully sufficient when given in monotherapy and the levodopa saving effect was only temporary. Parallel with the decline in the therapeutic response as assessed by the rating scales, there was a worsening in the on/off symptomatology. The on/off symptoms, evaluated by patients themselves, had shown very small or no improvement at the beginning of mesulergine administration, contrasting with the findings reflected in the assessment scales. The most frequent side-effects were hallucinations and dyskinesias. Orthostatic hypotension did not prove a problem. Dyskinesias were not seen during monotherapy with mesulergine in de novo patients.

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Low interleukin-10 production is associated with higher disability and MRI lesion load in secondary progressive multiple sclerosis.

Abnormalities in T-cell-derived cytokine production are a well-known phenomenon in multiple sclerosis (MS). An association between disability and the production of interferon gamma has been demonstrated recently. The present study investigated associations between disability, cytokine production in stimulated blood lymphocytes and magnetic resonance imaging data in 37 patients with the secondary progressive course in the stable phase of the disease. Patients with high interleukin-10 (IL-10) production had significantly lower disability scores (p=0.009) and lower T2 lesion load (p=0.03). Interleukin-10 might not only play a role in the pathological process of multiple sclerosis but has an impact on disease outcome as well.

No effect of intravenous immunoglobulins on cytokine-producing lymphocytes in secondary progressive multiple sclerosis.

Intravenous immunoglobulins (IVIG) have been effective in reducing multiple sclerosis (MS) disease activity and improving disability scores. However, the mechanism by which this beneficial effect is achieved remains unclear. An effect of IVIG on pro- and anti-inflammatory cytokines which are thought to play a role in the disease process - has been postulated in a number of animal and ex vivo studies. Hence, we performed a study on 34 patients with secondary progressive (SP) MS being treated with monthly IVIG or placebo for two years according to the protocol of the ESIMS study. Clinical outcome measures and cytokine production (interferon gamma, tumour necrosis factor alpha, interleukin-4 and -10) were recorded in all patients and compared with respect to the treatment group. Against our expectations, IVIG did not reduce the relapse rate or the progression of disability or cytokine production. Our data argue against an enduring immunomodulating effect of IVIG, at least in SPMS.

Mesulergine and bromocriptine in long-term treatment of advanced parkinsonism.

24 levodopa pretreated patients with advanced parkinsonism were split into two equal groups receiving mesulergine or bromocriptine respectively as an adjuvant therapy. The trial was carried out under double blind conditions the first three months and then continued as an open trial for one year. Clinical benefit was similar in both groups with minor differences in regard to single symptoms. While bromocriptine showed a beginning decline in efficacy after one year, mesulergine showed no decline. The mean mesulergine-dose, necessary to achieve good clinical improvement, was about half of bromocriptine. Side-effects were similar, except orthostatic hypotension requiring vasopressor medication, which was less frequent in mesulergine treated patients. This advantage of mesulergine might be explained by its special pharmacological pattern with biphasic action on dopaminergic receptors.