American Academy of Neurology: Interferon Beta-1b and Azathioprine Combination for Multiple Sclerosis

Speaker: Peter A. Calabresi, MD, Associate Professor of Neurology, Department of Neurology, The Johns Hopkins University School of Medicine, and Director of the Johns Hopkins Multiple Sclerosis Center, Johns Hopkins Hospital, Baltimore, Maryland.

Combination therapy with interferon beta-1b (Betaseron®, Berlex/Schering AG) and azathioprine (Prometheus) is safe and effective at reducing inflammatory disease activity in most patients who have multiple sclerosis (MS) with “breakthrough activity” who are receiving interferon beta monotherapy.

Several previous studies have documented the potential benefit of interferon beta plus azathioprine, but because results have been variable, an attempt was made to determine the parameters that might guide optimal dosing.

In an open-label, baseline-versus-treatment study, 15 MS patients with breakthrough activity on relapse received, added in a dose-titrated manner to 325 mcg of interferon beta-1b subcutaneously every other day for up to six months. ADEs, blood counts, and serum chemistry profiles were used to assess the safety of therapy.

The primary endpoint was a decrease in inflammatory disease activity, as measured by a reduction in contrast-enhanced lesions. Secondary measures of safety and efficacy included:

  • the number of relapses.
  • scores on the Kurtzke Expanded Disability Status Scale (EDSS).
  • MS Functional Composite (MSFC) scores.
  • gadolinium-enhanced lesion counts: three at two months, at one month, and at baseline with monotherapy, and three at four months, at five months, and at six months with combination therapy.

Optimization of dosing was evaluated according to the white blood cell (WBC) count nadir and per 6-mercaptopurine levels, an active metabolite of azathioprine, from red blood cell (RBC) “pellets.”

Three of the 15 patients who received combination therapy discontinued treatment prematurely because of ADEs or noncompliance. Of the 12 patients who completed six months of therapy, gastrointestinal toxicity was the most common clinical ADE. Liver function test abnormalities occurred in five of the 12 patients, but this ADE was resolved in all patients with a reduced dose of azathioprine canadian.

There was a statistically significant 63% reduction in contrast-enhancing lesions after combination therapy compared with monotherapy. From the baseline evaluation to the sixth month, EDSS and MSFC scores remained stable in the group as a whole. As predicted, neither active metabolite levels of azathioprine nor WBC levels were correlated with doses of azathioprine. However, WBC and lymphocyte counts were strongly correlated with the reduction in the number of gadolinium-positive lesions, as detected with magnetic resonance imaging.

It should be noted that careful monitoring of liver function tests and WBC counts is necessary to prevent toxicity. Azathioprine should be titrated upward to the highest tolerated dose, and the WBC count should be used to help guide dosing.

Pramipexole for Restless Legs Syndrome

Speaker: Markku Partinen, MD, Associate Professor of Neurology, Department of Neurology, University of Helsinki,

Helsinki, Finland, and Director of Rinnekoti Research Centre, Espoo, Finland.

Pramipexole (Mirapex®, Pfizer/Boehringer Ingelheim), a dopamine agonist indicated for the treatment of Parkinson’s disease, offers rapid relief of restless legs syndrome (RLS). Typical symptoms include motor restlessness, nocturnal worsening of RLS, and sleep disturbances. Apcalis Oral Jelly

To determine the optimal dose of pramipexole in patients with idiopathic RLS, researchers enrolled 109 patients with RLS in a double-blind, placebo-controlled, single-center, comprehensive polysomnographic study. The patients were randomly assigned to receive pramipexole 0.125 mg/day, 0.25 mg/day, 0.5 mg/day, or 0.75 mg/day or placebo. All of the pramipex-ole groups were started at 0.125 mg/day, and the doses were increased stepwise for the higher levels of drugs administered.

For patients receiving 0.25 mg, the final dose was reached on the fifth day; for patients receiving 0.5 mg, the final dose was reached on the ninth day; and for patients receiving 0.75 mg, the final dose was reached on the 13th day. The total study period was three weeks at each dose.

The primary endpoint was a reduction in limb movements, as assessed by the Periodic Limb Movement Index (PLMI) during time in bed. Secondary endpoints included changes on (1) the Restless Legs Symptom Rating Scale (RLSRS) and (2) the CGI-I. The mean age of the patients was 57 years, and 74% were women. The mean duration of RLS was 4.74 years.

Pramipexole showed excellent efficacy over the entire dose range of 0.125 to 0.75 mg/day within three weeks of therapy. A statistically significant difference in the reduction of periodic limb movements during time in bed was observed with pramipexole compared with placebo (P < .0001).

The responder rate, defined as greater than a 50% reduction on the RLSRS, increased from more than a 60% reduction with pramipexole 0.125 mg to approximately 78% with 0.5 mg, and to 75% with 0.75 mg. At three weeks, CGI-I scores showed “very much” to “much” improvement in 60% of patients taking 0.125 mg, up to approximately 85% with 0.5 mg, and 83% with 0.75 mg.

From the results of the high responder rates and high scores on the CGI-I, it is obvious that the severity of the RLS symptoms was significantly reduced by pramipexole treatment. Clinical efficacy was most prominent in the patients receiving 0.5 and 0.75 mg/day. Furthermore, safety and tolerability were favorable at all dose levels, with no serious ADEs occurring during the study.

Fluphenazine for Tourette Syndrome

Speaker: Yavuz S. Silay, MD, Research Coordinator, Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas.

Fluphenazine (e.g., fluphenazine, Geneva; Proloxin®, Novar-tis) appears to be safe and effective in the long-term treatment of tics in patients with Tourette syndrome (TS).

To provide data on the long-term safety and efficacy of fluphenazine, investigators enrolled 1,348 patients with a diagnosis of TS, as defined by criteria formulated by the Tourette Syndrome Classification Study Group, between December 14, 1981, and March 24, 2004. A total of 272 patients were randomly selected for further analysis and were grouped into one of three categories:

  • patients who had never been treated with fluphenazine
  • patients who had tried fluphenazine but discontinued it within the first year
  • patients who had taken fluphenazine for at least one year during the past 23 years

Responses to fluphenazine, the main outcome measure, were rated on a clinical rating scale of 1 to 5, with 1 representing a marked reduction in tics and improved function and 5 representing a worsening of tics or a deterioration in function.
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The investigators assessed 63 patients; the mean age of those with TS symptoms was 8.3 + 7.2 years (range, 1.2-60 years). The mean age at initiation of fluphenazine therapy was 15.6 + 9.9 years (range, 5.7-60 years). These patients received fluphenazine for a mean of 3.9 + 3.3 years, and their response was rated as 1 or 2 ( i.e., marked to moderate improvement) in 84.1% of patients. The mean daily dose of fluphenazine was 3.9 + 2.7 mg/day.

Although tardive dyskinesia did not affect any patients, 23 patients discontinued the study because of (1) the study medication’s lack of efficacy, (2) the occurrence of side effects, (3) the achievement of better results with botulinum toxin, or (4) other reasons.

While acknowledging the limitations of a retrospective analysis, these findings represent the long-term clinical experience in a large number of patients. On the basis of these longitudinal findings of a high degree of efficacy and a relatively low frequency of ADEs, fluphenazine is now considered to be the first-line pharmacotherapy for treating tics at the Movement Disorders Clinic at Baylor College. Although other neuro-leptic agents have been reported to cause tardive syndromes in patients with TS, tardive dyskinesia was not encountered in this study. This is a major consideration because tardive dys-kinesia is one of the most feared side effects of chronic neuro-leptic therapy. It still is prudent for patients to be monitored carefully so that any potentially serious side effects might be detected as early as possible.


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