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Mitoxantrone Therapy
In Multiple Sclerosis

Dear New MS Patient:

When you are first diagnosed with MS, Doctors are likely to tell you there is nothing they can do for you - or they will prescribe Avonex, Copaxone, or Betaseron, none of which can help slow deterioration due to MS.

There is no treatment approved by the FDA which will make you better, or prevent deterioration.

However there is a lot known and you must take responsibility for your life. Read about Mitoxantrone. Very Good results!

Multiple Sclerosis Information: updated 1-06-2000

What follows is the latest - as of 10-10-97- abstracts on Mitoxantrone and MS:

In particular read the last article, By Kornhuber. You will learn that the dose is crucial, and they have figured it out. A smaller dose makes for less effectivity.

http://home.earthlink.net/~robert016/


Randomized placebo-controlled trial of Mitoxantrone in Relapsing/Remitting Multiple Sclerosis: 24-month clinical and MRI outcome

Millefiorini E, Gasperini C, Pozzilli C, D'Andrea F, Bastianello S, Trojano M, Morino S, Morra VB, Bozzao A, Calo A, Bernini ML, Gambi D, Prencipe M
J Neurol 1997 Mar;244(3):153-159
Dept. of Neurological Science,
Universita' La Sapienza, Rome, Italy

We designed a randomized, placebo-controlled, multicenter trial involving 51 Relapsing/Remitting Multiple Sclerosis patients to determine the clinical efficacy of Mitoxantrone treatment over 2 years.

Patients were allocated either to the Mitoxantrone group (27 patients receiving I.V. infusion of Mitoxantrone every month for 1 year at the dosage of 8 mg/m2) or to the placebo group (24 patients, receiving I.V. infusion of saline every month for 1 year) using a centralized randomization system.

Disability at entry and at 12-24 months was evaluated by four blinded Neurologists trained in the application of the Kurtzke Expanded Disability Status Scale (EDSS).

In addition, the number and clinical characteristics of the exacerbations over the 24 months were recorded by the local investigators.

MRI, at 0, 12 and 24 months, was performed with a 0.2 T permanent unit. MRI data were analyzed by two blinded NeuroRadiologists. All patients underwent a clinical evaluation.

A statistically significant difference in the mean number of exacerbations was observed between the Mitoxantrone group and placebo group both during the 1st and the 2nd year.

Although there was no statistically significant benefit in terms of mean EDSS progression over 2 years, the proportion of patients with confirmed progression of the disease, as measured by a one point increase on the EDSS scale, was significantly reduced at the 2nd year evaluation in the Mitoxantrone group.

Forty-two (23 Mitoxantrone, 19 placebo) patients underwent all MRI examinations during the 24-month period. We observed a trend towards a reduction in the number of new lesions on T2-weighted images in the Mitoxantrone group.

Our study suggests that Mitoxantrone might be effective in reducing disease activity, both by decreasing the mean number of exacerbations and by slowing the clinical progression sustained by most patients after 1 year from the end of treatment.


Therapeutic effect of Mitoxantrone combined with MethylPrednisolone in Multiple Sclerosis: a randomized multicenter study of active disease using MRI and clinical criteria

Edan G, Miller D, Clanet M, Confavreux C, Lyon-Caen O, Lubetzki C, Brochet B, Berry I, Rolland Y, Froment JC, Cabanis E, Iba-Zizen MT, Gandon JM, Lai HM, Moseley I, Sabouraud O
J Neurol NeuroSurg Psychiatry 1997 Feb;62(2):112-118
Dept of Neurology, Centre Hospitalier Universitaire, Rennes, France

Objective
To evaluate the efficiency of Mitoxantrone in Multiple Sclerosis.

Methods
Forty two patients with confirmed Multiple Sclerosis, selected as having a very active disease on clinical and MRI criteria were randomized to receive either Mitoxantrone (20 mg intravenously (IV) monthly) and MethylPrednisolone (1 g iv monthly) or MethylPrednisolone alone over six months.

In the Steroid alone group five patients dropped out due to severe exacerbation.

Results
Blinded analysis of MRI data showed significantly more patients with no new enhancing lesions in the Mitoxantrone group compared with the Steroid alone group, (90% v 31%, P < 0.001).

In the Mitoxantrone group there was a month by month decrease almost to zero in the number of new enhancing lesions, and in the total number of enhancing lesions, whereas both remained high in the Steroid alone group.

The differences were significant for both indices at all months from 1-6.

Unblinded clinical assessments showed a significant improvement in change in EDSS at months 2-6 in the Mitoxantrone group, with a final mean improvement of more than one point (-1.1 v + 0.3; P < 0.001).

There was a significant reduction in the number of relapses (7 v 31; P < 0.01), and an increase in the number of patients free of exacerbation (14 v 7; P < 0.05).

Conclusion:
In this selected group of patients with Multiple Sclerosis with very active disease, Mitoxantrone combined with MethylPrednisolone was effective in improving both clinical and MRI indices of disease activity over a period of six months whereas MethylPrednisolone alone was not.

Further double blinded long term studies are needed to properly evaluate the effect of Mitoxantrone on progression in disability.


Noninvasive assessment of Mitoxantrone CardioToxicity in Relapsing/Remitting Multiple Sclerosis

De Castro S, Cartoni D, Millefiorini E, Funaro S, Gasperini C, Morino S, Tallarico D, Beni S
J Clin Pharmacol 1995 Jun;35(6):627-632
Dept of Clinical Medicine, La Sapienza Univ of Rome, Italy

Multiple Sclerosis is the most common cause of Neurologic Disability in young adults. Recent reports have suggested that Mitoxantrone might be a candidate for clinical trials in Multiple Sclerosis patients.

The authors studied 20 patients with Relapsing/Remitting Multiple Sclerosis to evaluate cardiac toxicity during a one-year follow-up period. Patients were divided into 2 groups: group A, Mitoxantrone treated patients (cumulative dose of 96 mg/m2); group B, placebo patients.

The clinical course of Multiple Sclerosis was assessed using the Expanded Disability Status Scale and the number of relapses during the follow-up.

Each patient had an ElectroCardiogram and a Spectral and color flow Doppler EchoCardiographic examination at enrollment, and 6 and 12 months later, to investigate cardiac toxicity. The mean exacerbation rate was reduced significantly in group A patients.

No significant differences in the ElectroCardiograms or the EchoCardiographic parameters of systolic and diastolic function were noted between the two groups or in group A during the follow-up.

Mitoxantrone treatment seems able to improve the clinical course of Relapsing/Remitting Multiple Sclerosis patients. It does not show any Cardiac Toxicity in selected patients at this dosage.


Serial Gadolinium-enhanced MRI in patients with Multiple Sclerosis treated with Mitoxantrone

Krapf H, Mauch E, Fetzer U, Laufen H, Kornhuber HH
NeuroRadiology 1995 Feb;37(2):113-119
Dept of Neurology,
Univ of Ulm, Germany

Serial Gadolinium (Gd)-enhanced Magnetic Resonance Imaging (MRI) was used to monitor the effect of Mitoxantrone in ten patients with rapidly deteriorating Multiple Sclerosis (MS).

MRI was performed as a baseline and thereafter at 1, 3, 6, 9, 12 and 24 months. The total number of Gd-enhancing lesions diminished from 169 at baseline to 10 after 1 year and to 5 after 2 years.

This reduction and the percentage of follow-up MRI studies showing no Gd enhancement were more pronounced than in other MRI studies of the natural course of MS.

Measured with quantitative Neurological Scales, only one patient showed deterioration after 2 years; nevertheless, the changes in MRI were much more marked than those observed clinically.

Serial Gd-MRI therefore, seems necessary for documenting efficacy in future therapeutic trials.


A controlled trial of Mitoxantrone in Multiple Sclerosis: serial MRI evaluation at one year

Bastianello S, Pozzilli C, D'Andrea F, Millefiorini E, Trojano M, Morino S, Gasperini C, Bozzao A, Gallucci M, Andreula C, et al
Can J Neurol Sci 1994 Aug;21(3):266-270
Chair of NeuroRadiology,
Univ of Rome La Sapienza, Italy

We present the results of a randomized double-blinded placebo controlled, multicenter trial, of low-dose Mitoxantrone (MX), after one year, in 25 patients with Relapsing/Remitting Multiple Sclerosis, who had serial enhanced Magnetic Resonance Imaging (MRI).

Treatment groups were balanced for age, gender, duration of illness and Neurological disability. Five of the 13 MX patients and 10 of the 12 placebo patients had exacerbations during treatment (p < 0.02).

The mean change in the Expanded Disability Status Scale was not significantly different between the MX and placebo treatment groups.

Serial Gadolinium-DTPA enhanced MRI detected no significant difference between the MX treated and placebo groups in the mean total number of new, enlarging, or Gadolinium-DTPA enhancing lesions; there was a trend toward a reduction of new, enlarging and Gadolinium-DTPA enhancing lesions in MX patients.

Despite this ameliorating effect, the results indicate that serial Gadolinium-DTPA enhanced MRI, performed over one year in a limited number of patients, could not provide conclusive evidence for a role of MX therapy in Relapsing/Remitting Multiple Sclerosis.


ImmunoSuppressive therapy of Multiple Sclerosis with Mitoxantrone

Mauch E, Kornhuber HH Fortschr Neurol Psychiatr 1993 Dec;61(12):410-417
Abteilung Neurologie,
Universitat Ulm

Preliminary clinical results indicate that the cytostatic agent Mitoxantrone is an effective and very tolerable substance for treating Multiple Sclerosis (MS).

Our own experience, added to the findings of other pilot studies, seems to indicate that disease progression can be slowed in a majority of patients with rapidly Progressive MS.

Mitoxantrone is mainly excreted by the Hepato-Biliary Pathways and therefore it can be used in patients with Renal Insufficiency or chronic Cystopyelitis, a frequently occurring condition in MS.

The side effects observed in our therapeutic scheme which could be attributed to Mitoxantrone were tolerable.

Mild GastroIntestinal complaints were occasionally reported and vomiting was very rare. A CarcinoGenic effect from Mitoxantrone has not been reported.

A decrease in the Leucocyte count is to be expected 6-15 days following treatment administration. Potential CardioToxicity represents the primary long term adverse reaction and thus patients with CardioVascular risk factors should not be treated with Mitoxantrone.

Once a cumulative dosage of 140 mg/m2 is reached Cardiac Function Tests, including EchoCardiography with measurement of the Left Ventricular ejection fraction, should be routinely carried out preceding each treatment administration in all patients.

Mitoxantrone is currently not licensed for use in patients with MS and therefore should be restricted to patients with rapid disease progression where other generally accepted treatment modalities have failed.


An open-trial evaluation of Mitoxantrone in the treatment of Progressive MS

Noseworthy JH, Hopkins MB, Vandervoort MK, Karlik SJ, Lee DH, Penman M, Rice GP, Grinwich KD, Cauvier H, Harris BJ, et al
Neurology 1993 Jul;43(7):1401-1406
Dept of Clinical Neurological Sciences,
Univ of Western Ontario, London, Canada

We treated 13 patients with Progressive MS with Mitoxantrone. All patients received a standard IV dose of Mitoxantrone (8 mg/m2) every 3 weeks for a total of seven infusions, with dosage adjustments depending on the Hematologic profile at the nadir.

The treatment was well tolerated, with the most common side effect being mild Nausea. Four of seven women developed transient secondary Amenorrhea.

The postenrollment clinical behavior of these patients was generally more favorable than during the 18 months prior to enrollment (only three of 13 patients developed an increase in the Expanded Disability Status Scale of more than 0.5 points).

Suggesting a possible treatment effect, but comparison with two historical control groups (both the active and placebo groups from the Canadian Cooperative Trial of Cyclophosphamide and Plasma Exchange) does not suggest that Mitoxantrone was efficacious.

Eight of 12 patients had evidence of MRI activity on 13 of 29 follow-up visits. This small, open-labeled pilot study did not provide strong support for proceeding with a randomized, controlled trial of this dosage regimen of Mitoxantrone in patients with Progressive MS.


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***Below is the most important article ***


Treatment of Multiple Sclerosis
with Mitoxantrone


Mauch E, Kornhuber HH, Krapf H, Fetzer U, Laufen H
Eur Arch Psychiatry Clin NeuroSci 1992;242(2-3):96-102
Dept of Neurology, Ulm University, Dietenbronn/Schwend, Federal Republic of Germany

Ten Multiple Sclerosis patients, all with a rapid deteriorating disease profile, were treated with 12 mg/m2 of the cytostatic agent Mitoxantrone, administered every 3 months.

This dosage is only 25% of what a patient with a solid tumour would normally receive during the same time period.

In all treated patients the deterioration was stopped following the initial dosage; in four out of ten patients there was even an immediate improvement of the Neurological status.

Eight out of nine patients showed an improvement after 1 year as compared with their enrollment status; the other one remained stable.

In correlation with the clinical improvement, the mean P100 latencies of visual evoked potentials showed a reduction after 1 year.

However, the changes identified through Magnetic Resonance Imaging were even clearer than those seen clinically.

At admission, this group of patients presented with a total of 169 gadolinium (Gd)-enhancing lesions. Only 10 lesions were enhancing in nine patients 12 months after the initiation of treatment.

It appears that Mitoxantrone accelerates the disappearance of Gd-enhancing lesions and prevents the development of new ones.

Minimal side effects such as mild nausea and a slight faintness were evident in six patients and then for only 1-2 days.


Currently there are multicenter Trials in Germany, Belgium, and France, using Mitoxantrone. The German tests are due to be completed in 1997.

The medicine is being given at 12 mg/ m sq or 5 mg/m sq, or placebo. Dr. B. Storch, at Heidelberg U. is leading the German effort.

Dr. Roy Swank,( who has treated over 3000 MS patients) in his book, " the Multiple Sclerosis Diet Book", concludes that a low fat diet, supplemented by the Essential Fatty Acids, is essential for slowing progress of the disease.

He also recommends avoiding heat (like Jacuzzi's, hot baths and sunbathing), resting in a flat position every day to let the body cool, avoiding and eliminating stress, and getting exercise.

Swimming and pool exercises are best because your body will not overheat while exercising.


Additional Articles

Summary of Monoclonal Antibody Research

Some additional important article abstracts follow


Monoclonal AntiBodies

Multiple Sclerosis and Vitamin B12 Metabolism
A Preliminary Report on B-F5 in 21 Patients

Treatment of Multiple Sclerosis with AntiCD4 MonoClonal Antibody

Rumbach.L, Battailard D.M, Galmiche, J,Henlin,JL,et al
Journal of AutoImmunity, 1993 Dec, 6(6):771-86

Twenty one patients with definite active Multiple Sclerosis (MS) were treated with a MonoClonal anti - CD4/B-F5 (murine IgG1) AntiBody for 10 days.

Side effects were observed in 11 patients during the first infusion. These side effects were accompanied by and probably related to a transient increase in IL6 and TNF-alpha Serum levels. This problem led to treatment interruption in one patient.

Neither clinical improvement nor deterioration was observed in the course of treatment. EDSS improvement (> 1 point) occurred in six patients one month post-treatment.

One month after the end of treatment total Lymphocytes and CD3+ and CD4+ Cells were significantly decreased.

Cytokine analysis performed in Serum and in CSF before and after treatment showed no induced modifications. Ten patients developed XenoGenic AntiBodies. It is of interest that the patients with Relapsing/Remitting forms were relapse free at the 6th month post therapy.


Causes Of MS

The British Isles survey of Multiple Sclerosis in twins

Mumford CJ; Wood NW; Kellar─Wood H; Thorpe JW; MillerDH; Compston DA
Neurology, 1994 Jan, 44(1):11-5

Abstract: During a 27-month recruitment period, we identified 146 individuals with Multiple Sclerosis (MS) who have a twin.

A single clinician interviewed and examined 105 pairs of twins, and we confirmed zygosity using minisatellite probes.

Including two suspected cases, 11 of 44 (25%) monozygotic twin pairs were concordant compared with two of 61 (3%) dizygotic twin pairs - two of 33 (6%) like-sexed and zero of 28 (0%) opposite-sexed.

MRI was performed in 64 of 105 co-twins, and showed abnormalities consistent with DeMyelination in 13% of monozygotic and 9% of dizygotic co-twins who were clinically unaffected.

These findings are similar to the results of most previous studies of MS in twins in which zygosity was not unequivocally established and where the majority of clinically unaffected co─twins were not studied by MRI; the difference in concordance rates in monozygotic and dizygotic twins indicates a significant Genetic component in the etiology of MS.


On the Causes of Multiple Sclerosis

Hutter C.
Medical Hypotheses, 1993 Aug, 41(2):93-6

Abstract: Evidence on Aetiology in Multiple Sclerosis suggests that the prevalence depends on the interaction of two factors, Diet and exposure to visible Sunlight.

The dietary features which may be beneficial include supplementation with Fish Oils, avoidance of saturated fats, and the associated intake of AntiOxidants with unsaturated fatty acids.

Inhibition, by AntiOxidants, of the Enzyme Lipoxygenase inhibits Leukotriene synthesis, and the presence of Fish Oils leads to the production of Leukotrienes with less inflammatory properties.

This is of particular importance in the Retina where Leukotrienes might be the underlying cause of Retrobulbar Neuritis. The AntiOxidant properties of Vitamin A may also lead to inhibition of Leukotriene synthesis.

Visible solar radiation could be of benefit therefore by releasing Vitamin A from visual pigment rhodopsin. The interaction of these two factors may explain the Epidemiological observations on the prevalence of Multiple Sclerosis.


Prepared by Robert Miller, an MS patient.
robert016@earthlink.net
Updated 9-20-98





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