Introduction

More than 8,000 neurologists, neuroscientists, and other healthcare professionals from around the world gathered at the 54th Annual Meeting of the American Academy of Neurology, held in Denver, Colorado, on April 13–20, 2002, to hear the latest developments in the control and treatment of neurological diseases. Of particular interest at this year’s meeting were a number of new therapeutic options being recommended for well known, established agents already approved for use in the treatment of a variety of neurological diseases. Listed below are highlights of some of these presentations.

Donepezil Offers Effective Treatment for Vascular Dementia

Recent findings from a landmark study demonstrated that the acetylcholinesterase inhibitor donepezil (Aricept^®, Pfizer/Eisai), indicated for the treatment of Alzheimer’s disease (AD), significantly improves cognition and enhances overall global function in patients with vascular dementia. This strongly suggests that donepezil may also have an important role to play in individuals with vascular dementia, according to Raymond D. Pratt, MD, Senior Director and Therapeutic Head, CNS & Internal Medicine, Clinical Research & Development at Eisai.¹

These conclusions were reached from a 24-week, randomized, double-blind, placebo-controlled study in which 603 men and women with vascular dementia (according to NINDS-AIREN [National Institute of Neurological Diseases and Stroke—Association International pour la Recherche et l’Enseigment en Neurosciences] criteria and no prior diagnosis of AD). Participants were randomly assigned to daily doses of placebo, donepezil 5 mg, or donepezil 10 mg, and followed for 24 weeks. Patients were evaluated using The Alzheimer’s Disease Assessment Scale—cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), the Clinician’s Interview-Based Impression of Change with caregiver input (CIPIC-plus), the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), and the Clinical Dementia Rating—sum of the boxes (CDR-SB).

At Week 24, both the patients on donepezil 5 mg and those on donepezil 10 mg demonstrated significant improvement in cognitive function compared to placebo, as measured by ADAS-cog and significant improvement in cognitive function compared to baseline scores as measured by the MMSE. In contrast to AD patients treated with placebo, patients in this study who received placebo showed no change in cognitive function as measured by either ADAS-cog or MMSE. Significant improvements in global function were observed in patients on donepezil 5 mg, as measured by the CIBIC-plus and in patients on donepezil 10 mg, as measured by CDR-SB. In addition, functional deterioration was significantly slowed in patients given either of the two doses of donepezil, compared with placebo, as measured by ADFACS. Donepezil was relatively well tolerated, with adverse events not differing substantially in frequency between the two donepezil groups and the placebo groups. Cardiovascular (CV) event rates also were similar among all the study participants, a most important factor since these patients, unlike those with AD, have multiple CV comorbidities.

Rivastigmine Relieves Parkinsonian Hallucinosis

The cholinesterase inhibitor rivastigmine (Exelon^®, Novartis) has been shown to have a positive effect on the neuropsychiatric symptoms of hallucinations and sleep disturbances common among patients with advanced Parkinson’s disease and to improve cognitive impairment without a worsening of motor control, reported Paul Reading, PhD, Clinical Neurologist, Regional Neuroscience Centre of Newcastle General Hospital, New Castle-Upon-Tyne, UK.²

In an open exploratory study, 12 patients with established Parkinson’s disease, persistent hallucinations, and moderate cognitive impairment were given rivastigmine for six weeks at the maximum tolerated doses, followed by drug withdrawal. Measures used to assess cognitive ability included the MMSE and the CDRC (Cognitive Drug Research computerized battery). The NPI (Neuropsychiatric Inventory) was used to assess neuropsychiatric symptoms and their effects on the caregiver. Finally, the motor subscale of the UPDRS (Unified Parkinson’s Disease Rating Scale) was used as a measure of motor disability.

Patients who received high-dose rivastigmine for six weeks demonstrated highly significant improvements in both MMSE (20.8 to 25.4—the higher score indicating better cortical functioning) and total NPI (39.6 to 15.2) scores Notably, particular improvements were seen in NPI scores for hallucinations and sleep disturbance. Caregiver distress also was significantly improved. On the CDR battery, all indices of performance were enhanced and reaction times were significantly faster with rivastigmine treatment. Improvements in attentional tasks measuring numerical working memory and vigilance were particularly affected positively. The UPDRS scores showed no significant changes. After rivastigmine therapy was withdrawn, all aspects of performance and levels of symptoms deteriorated. The drug was generally well tolerated.

Addition of Mitoxantrone to Interferon Beta-1b Enhances Therapeutic Efficacy in MS

The combination of therapy with interferon beta-1b (INF-1b; Betaseron^®; Berlex) and mitoxantrone (Novantrone^®; Immunex) has been shown to be effective and well tolerated in patients with worsening multiple sclerosis (MS) and a suboptimal response to INF-1b, according to Luca Durelli, MD, Associate Professor of Neurology, Department of Neurosciences, University of Turin Medical School, Torino, Italy.³

Despite the demonstrated efficacy of immunotherapeutic agents in the treatment of MS, many patients have a less than optimal response with continued progression of disability and frequent relapse. Since mitoxantrone has been demonstrated to decrease relapse rates and reduce new gadolinium-enhancing lesions in both relapse-remitting and secondary progression MS, a trial was designed to examine the efficacy and safety of combined treatment with INF-1b and mitoxantrone in patients with MS not controlled with INF-1b alone.

Ten patients with relapse-remitting or secondary progressive MS, all of whom had been on INF-1b for at least six months before entry into the study and were neutralizing antibody negative, underwent monthly MRI scans using triple dose contrast for three months to obtain baseline numbers of new enhancing lesions (NEL). Following this period, mitoxantrone was administered at 12 mg/m² in the first month, and 5 mg/m² at Month 2 and Month 3, with dosing continued at 5 mg/m² every third month. Monthly MRI scanning was continued for the duration of the study. The primary outcome measures was the number of NELS. Secondary endpoints were relapse rates, EDSS (Expanded Disability Status Scale) scores, and changes in T2 and T1 lesion volume.

The mean number of Nels per month at baseline was 2.92 ± 2.46. Following the addition of mitoxantrone to INF-1b therapy, the median NEL number decreased by 81%, with both clinical and MRI measures of the disease activity responding well to the combination. Relapse rates decreased by 74% and, at the time of the last scan (six months), only two patients had new enhancing lesions, and volumes were very small. The addition of mitoxantrone to INF-1b proved to be well tolerated and there were no serious adverse events.

Early Treatment of Migraine Improves Therapeutic Efficacy

While earlier studies recommended that migraine sufferers wait until moderate to severe pain to take medication, new data point out that taking sumatriptan (Imitrex^®; GlaxoSmithKline) while the pain is still mild results in a high degree of pain-free efficacy, declared Paul Winner, co-director of the Palm Beach Headache Center, West Palm Beach, Florida.⁴

To reach this conclusion, two prospective, single-attack studies were carried out at 15 sites to determine whether or not sumatriptan would be effective in providing pain-free relief when taken early in a migraine headache when the pain still was mild. A total of 691 individuals were randomized to sumatriptan 50 mg, (233 pts), sumatriptan 100 mg (222 pts) or placebo (236 pts) within two hours of onset of pain. Study endpoints included the percentage of patients pain-free at two and four hours post-dose in the sumatriptan groups versus placebo and the percentage of patients that worsened from mild to moderate or severe at two and four hours in the sumatriptan groups versus placebo. Side effects also were evaluated.

In a combination of data from the two studies, pain-free rates at two hours were 29%, 50%, and 57% for persons on placebo, sumatriptan 50 mg, and sumatriptan 100 mg, respectively. Pain-free rates at four hours were 30%, 61%, and 68% for individuals receiving placebo, sumatriptan 50 mg, and sumatriptan 100 mg, respectively. The percentage of persons that worsened (mild pain to moderate, severe pain) at four hours post-dose was 56% on placebo, 27% on sumatriptan 50 mg, and 16% on sumatriptan 100 mg. In addition, at four hours post-dose, the percentage of individuals who were migraine-free (no pain, no photophobia, no phonophobia) was 28% in the placebo group, 54% in those treated with sumatriptan 50 mg, and 63% in those on sumatriptan 100 mg. The study also confirmed that rates of adverse events, both general and drug-related, were lower when migraine was treated with sumatriptan at the first sign of pain.

References

1.      Pratt, R.D., et al. 54th Annual Meeting Program of the AAN. Supplement to Neurology 558:7 (Suppl. 3), pg. A167:S20:005.

2.      Reading, R.J., et al. 54th Annual Meeting Program of the AAN. Supplement to Neurology 58:7 (Suppl. 3), pg. A38:P05.110.

3.      Jeffrey, D.R., et al. 54th Annual Meeting Program of the AAN. Supplement to Neurology 58:7 (Suppl. 3), pg. A167:S23:004.

4.      Winner, P, et al. 54th Annual Meeting Program of the AAN. Supplement to Neurology 58:7 (Suppl. 3), pg. A415:S55.003.

This article was written by Larry M. Prescott, PhD, a frequent contributor to D&MD Newsletter.

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