multiple sclerosis research update

robert miller aj746 at LAFN.ORG
Wed Mar 22 15:52:45 EST 1995





MS MEDICAL RESEARCH HIGHLIGHTS







   



Myelin Basic Protein-attempts to reduce cd4+ T-cell population with

oral medicine,mbp.Very successful in men in double blind trial.Now

in multicenter trials 8-94.Dr Weiner.



Vitamin B12-long known as necessary for brain, known to be

necessary for myelin growth.Also,there appears to be  some

correlation with low b12 and ms,although there is no cause -effect

established.Supplement with b12 shots reported widely to be

helpful;anecdotal.No trials,but much research by Dr. Reynolds.





Mitoxantrone-a medicine already approved for cancer,thus available.

Novantrone is its name.This medicine ,given by infusion,in

hospital,has produced dramatic,quick,and long lasting

improvement.Tested on 200+people at Ulm U. In Germany.There is a

max lifetime dose after which much care for myocardiopathy must be

given.No multicenter trials are underway.there is a new article to

review*************



Cladribine_approved for hairy cell leukemia as Leustatin,was tested

by scripps on 51 people,double blind.Three monthly infusions were

given,with generally positively results.Scripps,dr j.Sipe.They

think subcutaneous injections will be used in future.future plans

include a multicenter trial under leadership of scripps.Info

available @ 1-800-998-6098.



4 Aminopyridine_an existing chemical,manufactured by Regis.Acts by

improving nerve conduction even in presence of myelin damage.Some

spectacular results,in motor  vision were observed.There is a

problem of seizures as a possibility if blood level of 4ap gets too

high.Must manage its use.Results are spectacular in giving

temporary relief.This is not a cure.Van diemen,polman are main

researchers.Now in multicenter trials.Some 100 people already

tested.a new report is available.



Cop-I  add report****************



Monoclonal antibody_functions by making long term reduction of cd4+

population after 10 days of treatment.Bf5 is the name.21 People

were treated.Patients were relapse free six months post treatment.



Monoclonal antibody cmt412,an anti cd4 antibody was tested on 29

people with ms.They got a prompt and long lasting reduction in cd4

cells three hours after treatment.Edss was stable for an extended

time,and the medicine was well tolerated.Dr lindsey.











Azothioprene-has apparently had the effect of slowing disease

progression in a test group of forty patients,reducing relapse rate

as well.Its use in ms is recommended.Dr Milanese.





Methotrexate- developed at cleveland Clinic,Mellen center,Dr.Donald

Goodkin.They conducted a double blind trial with chronic

progressive patients.no publication has yet been released.the

Mellen letter very crudely describes the results,in semi scientific

terms.Whatever benefits there were  were minor.No mode of action

was described.patients received weekly treatment over two years.No

toxicity was found.This drug is used for Rheumatoid Arthritis.It

was successful in Preventing EAE in animals.53% showed progression

while on medicine vs 83% of placebo patients.best results were seen

on upper extremity function.methotrexate is widely available,has

been used for years in leukemia.



We see the possibility that just by reducing the cd4+population in

the csf we minimize the tendency for continuing worsening.If we add

b12 simultaneously we improve conditions for healing whether

naturally or by some new agent.

We need a mechanism of action for each medicine,but it is clear

that the immune system,and in particular the cd4+ t-cells are the

main target of much of the new research and human trials.

                               updated 082994

               Technical Articles Summary

Recent articles about multiple sclerosis are presented.  The

citation for each article is given so that you may acquire the

article in full.

HIGHLIGHTS****************

1.   Double blind pilot trial of oral tolerization with myelin

antigens in multiple sclerosis (Harvard/Brigham and Womens

Hospital)

Science, 26 feb, 1993: 1321-1324; Howard l. Weiner M.D. And others.

It is thought that ms is an autoimmune disease wherein certain 

cells recognize and attack the central nervous system.It is known

that, in rats,eae, an ms-like disease, could be ameliorated by

injecting myelin basic protein(mbp).Human trials were conducted

earlier which proved the safety of the oral mbp (bovine myelin).The

present trial was carried out on a group of 30

people,doubleblind,for

a period of one year. Only exacerbating-remitting patients were

selected.The results were that the use of oral mbp caused a

reduction of cd4 t cells-the cells believed responsible for

attacking the myelin sheath. More important,on a statistical basis

there was improvement in the patients.This was determined by

measuring the frequency of attacks and changes on the disability

scale(edss) rankings. Although it was not known why, all of the

male

patients were exacerbation free during the one year period, while

females continued to suffer exacerbations.All males who were on mbp

were stable or improved one full point or more on the six point



edss scale.One female improved,the rest were stable or worse. There

werE no toxicities associated with this treatment.All male patients

in this study have remained on mbp for 2 1/2 years with continued

stabilization of the disease. This treatment would appear to hold

good prospects for causing improvement in ms patients.Multicenter

trials started in mid 1994.



2.   Interferon Beta in multiple sclerosis.

Three articles in neurology, april, 1993. 641-643, 662-667,655-661.

Authors are :Barry g.W. Arnason,M.D.:D.W.Paty,m.D.:Ifnb multiple

sclerosis study group. 

The essence of this project was a multicenter,  placebo controlled,

double blind trial over a span of three years with 372 ambulatory

patients.Two  different  amounts  of  IB  were administered,  by

subcutaneous injection, every second day.  Thus there were three

groups in the trial. The precise mode of action of interferon  

beta(ib) is  not  presently known.However,it is not presented as a

possible cure.  The main results  were that:patients on the ib

experienced,statistically, some improvement in mri scores. 66%  Of 

patients on maximum dose of IB showed more than 10% reduction in

mri placque area over the three years.Most notable was a reduction 

in  exacerbations from  1.21 Per year (average) for the placebo

group to 0.84 Per year for the group on maximum dose of IB.In

addition the severity of attacks  was reduced for those on IB.  The

effect of the treatment on Edss disability status at the end of the

three year trial was that,on average,both placebo and IBb patients

worsened.Placebo group edss(disability scale) status was a

worsening from 2.8  To  3.2 Versus 3.0  To  3.1 For the IB

group.Interferon beta(ib) has been approved by the FDA,and is now

in wide use.



3 Multiple sclerosis and vitamin B12 metabolism (england).

E.H.Reynolds frcp. 

A review of newly  admitted  kings  college  hospital  patients 

showed  that patients with definite ms had mild but significantly

enlarged red blood cells(macrocytosis)  compared  with  an  age 

and sex matched neurological control group admitted to the  same 

ward.This  effect  is  typical  of  vitamin  b12 deficiency.  In 

a  study  of  patients with ms,dr.Reynolds found significant

lowering of serum vitamin b12.Using a new and very sensitive

technique,  they found  a  significant  lowering of cerebrospinal

fluid (csf) b12 levels.  In some cases,  even though serum  b12 was

normal.  Reynolds  states that it is very unlikely that this

association is coincidental.He asks "at the very least  it  may  be

asked  whether  the associated   vitamin  b12  deficiency from  any

cause  is  aggravating  the underlying ms or hindering the process 

of  remyelination ?"   He  closes  by calling for more research in

this area. new work by dr Kari of Japan seems to have found the

reason for r-binder problems and b12 deficiency. 

*****************************************************************





                      Abstracts Of Articles

VITAMIN B12************************

Reynolds EH. Multiple sclerosis and vitamin b12 metabolism.

Journal of neuroimmunology, 1992 oct, 40(2-3):225-30.     

Abstract: Multiple sclerosis (ms) is occasionally associated with

vitamin b12    deficiency. Recent studies have shown an increased

risk of macrocytosis, low    serum and/or csf vitamin b12 levels,

raised plasma homocysteine and raised    unsaturated r-binder

capacity in ms. The aetiology of the vitamin b12    deficiency in

ms is often uncertain and a disorder of vitamin b12 binding or   

transport is suspected. The nature of the association of vitamin

b12    deficiency and ms is unclear but is likely to be more than

coincidental. There is a remarkable similarity in the

epidemiology of ms and pernicious anaemia. Vitamin b12

deficiency should always be looked for in ms. The deficiency may

aggravate ms or impair recovery. There is evidence that vitamin b12

is important for myelin synthesis and integrity but further   

basic studies are required.



Reynolds E.H.,Bottiglieri T; Laundy M; Crellin RF; Kirker SG.

Title: Vitamin B12 metabolism in Multiple Sclerosis.

Archives of Neurology, 1992 Jun, 49(6):649-52.    

Abstract: We have previously described 10 patients with multiple

sclerosis (ms)    and unusual vitamin b12 deficiency. We have

therefore studied vitamin b12 metabolism in 29 consecutive cases

of ms, 17 neurological controls,and 31 normal subjects. Patients

with ms had significantly lower serum vitamin b12    levels and

significantly higher unsaturated r-binder capacities than   

neurological and normal controls, and they were significantly

macrocytic compared with normal controls. Nine patients with ms

had serum vitamin b12 levels less than 147 pmol/l and, in the

absence of anemia, this subgroup was    significantly macrocytic

and had significantly lower red blood cell folate    levels than

neurological and normal controls. Nine patients with ms had   

raised plasma unsaturated r-binder capacities, including three

patients with very high values. There is a significant

association between ms and disturbed vitamin b12 metabolism.

Vitamin b12 deficiency should always be looked for in patients with

ms. The cause of the vitamin b12 disorder and the nature of the

overlap with ms deserve further investigation. Coexisting  vitamin

b12 deficiency might aggravate ms or impair recovery from ms.





Sandyk R; Auerbuch GI.

Vitamin B12 and its relationship to age of onset of multiple

sclerosis.

International Journal of Neuroscience, 1993 Jul-Aug, 71(1-4):93-9.

Abstract: Attention has been focused recently on the association

between vitamin B12 metabolism and the pathogenesis of multiple

sclerosis (MS). Several recent reports have documented vitamin B12

deficiency in patients with MS. The etiology of this deficiency in

MS is unknown. The majority of these patients do not have

pernicious anemia and serum levels of the vitamin are unrelated to

the course or chronicity of the disease. Moreover,vitamin B12

does not reverse the associated macrocytic anemia nor are the   

neurological deficits of MS improved following supplementation with

vitamin B12. It has been suggested that vitamin B12 deficiency

may render the patient more vulnerable to the putative viral

and/or immunologic mechanisms widely suspected in MS. In the

present communication, we report that serum vitamin B12 levels  in

MS patients are related to the age of onset of the disease.

Specifically, we found in 45 MS patients that vitamin B12 levels  

 were significantly lower in those who experienced the onset of

first    neurological symptoms prior to age 18 years (N = 10)

compared to patients in whom the disease first manifested after age

18 (N = 35). In contrast,serum folate levels were unrelated to age

of onset of the disease. As vitamin B12 levels were statistically

unrelated to chronicity of illness, these findings suggest a

specific association between the timing of onset of first

neurological symptoms of MS and vitamin B12 metabolism. In   

addition, since vitamin B12 is required for the formation of myelin

and for immune mechanisms, we propose that its deficiency in MS is

of critical pathogenetic significance.



Reynolds E.H.

Multiple Sclerosis and Vitamin B12 Metabolism [editorial].

Journal of Neurology, Neurosurgery and Psychiatry, 1992 may,

55(5):339-40.

Abstract: Multiple Sclerosis (ms) is a human disease characterized

by chronic demyelination in the brain caused by immunological

mechanisms involving t-lymphocytes and macrophages. Recently

developed models of chronic relapsing  forms of experimental

allergic encephalomyelitis, sharing many of the   clinical and

pathological features of ms, and new discoveries of efficient   

autoregulatory mechanisms intrinsic to the immune system, have

suggested new possibilities for therapeutic intervention in ms.

Moreover, recent data support the concept that the immune system

is exposed to a broad framework of regulation, including

neuroendocrine control. In particular, interfering with secretion

of the lactogenic hormone prolactin and of glucocorticoids has

consistently resulted in a reduction of clinical and pathological 

manifestations of the disease. In this review, frank berkenbosch

and colleagues highlight several of the possible therapeutic

opportunities for the treatment of ms.There is now more info on b12

and ms in the literature.





Frequin ST; Wevers RA; Braam M; Barkhof F; Hommes OR.

Decreased vitamin B12 and folate levels in cerebrospinal fluid and

serum of multiple sclerosis patients after high-dose intravenous 

methylprednisolone.  

Journal of Neurology, 1993 May, 240(5):305-8.

Abstract: Twenty-one patients (15 women, 6 men) with definite

multiple sclerosis (MS) were treated with 1000 mg intravenous   

methylprednisolone-succinate (MP) daily for 10 days. Before MP

treatment there was a negative correlation (r = 0.59, P = 0.0084)

between serum vitamin B12 and progression rate, defined as the

ratio of the score on Kurtzke's Expanded Disability Status Scale

and disease duration. A significant decrease was demonstrated in

the cerebrospinal fluid (CSF) and serum levels of folate and in the

CSF level of vitamin B12 after MP treatment. The decrease in serum

B12 was not statistically significant. After MP treatment all

median levels of vitamin B12 and folate were below the reference

medians. We hypothesize that low or reduced vitamin B12/folate

levels found in MS patients may be related to previous

corticosteroid treatments. Otherwise a more causal relationship

between low vitamin B12/folate and MS cannot be excluded.Further

studies may be required to clarify the vitamin B12 and folate

metabolism in patients with MS.



MITOXANTRONE*********************************

Spuler,S

Current therapy of multiple sclerosis:Mitoxantrone.

Language :german

Nervenarzt,1994 Feb 65 (2) 136-138



Authors: E.Mauch,H.H.Kornhuber, et.Al(Ulm university,germany)

title:the course of multiple sclerosis under cyclophosphamide or

mitoxantrone as compared with the spontaneous course or

cortisone/acth.

Journal: neurology,psychiatry and brain research (1993)1:220-227

Abstract: The course of ms under cyclophosphamide (cp) or

mitoxantrone (mx) treatment has been compared with the spontaneous

course of ms in 241 patients with definite ms.Use of cortisone or

acth showed no difference from spontaneous groups.While the state

of the patients deteriorated(kurtzke scale) in the control group by

about 1/2 point per year,there was a significant improvement in the

cp and mx groups.Thus both the cp and mx were effective in

stabilizing the patients over three years.The main acute side

effect ofcp and mx was nausea,which may be taken care of by

drugs.The main risk of mx in the long term is myocardiopathy.If one

treats patients with mx every three months,one can treat ms

effectively for three to four years.  The anti tumor drugs in this

paper should be given only by hospitals competent in the

symptomatic management of ms,especially in management of the

neurogenic bladder by training methods. Mitoxantrone is an existing

approved cancer medicine known as Novantrone.



Noseworthy JH; Hopkins MB; Vandervoort MK; Karlik SJ; Lee DH;

Penman M; Rice GP; Grinwich KD; Cauvier H; Harris BJ; et al.

An open-trial evaluation of mitoxantrone in the treatment of

progressive MS. Neurology, 1993 Jul, 43(7):1401-6.

Abstract: 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.



CLADRIBINE*********************************

Cladribine (2-cda) in treatment of chronic progressive ms

authors:j.Sipe,j.S.Romine,j.A.Koziol,r.Mcmillian,j.Zyroff,e.Beutler

journal:lancet 1994:344:9-13

abstract:51 patients received four monthly courses of 0.7 Mg/kg of

cladribine or placebo,double blind.Cerebrospinal fluid (csf) and

brain mri were evaluated at six and 12 months.Average neurological

scores,demyelinated volumes on mri,and concentrations of

oligoclonal bands in csf were stable or improved in patients

receiving cladribine but continued to deteriorate in patients

receiving placebo.We conclude that cladribine influences favorably

the course of chronic ms. Cladribine is now an approved medicine

for hairy cell leukemia,known as leustatin.They conclude that in

future the medicine may be given subcutaneously.Multicenter trials

are planned.



4-AMINOPYRIDINE*****************************

Bever CY,JR

The current status of studies of aminopyridines in patients with

ms.

Annals of Neurology,1994,36 suppl :s118-121**************



Bever CT,JR

The effects of 4-aminopyridine in ms patients.Results of a

randomized,placebo controlled,double blind,concentration

controlled,crossover trial.

Neurology 1994 june,44 (6) 1054-9**********************



van Diemen HA; Polman CH; vn Dongen MM; Nauta JJ; Strijers RL; van

Loenen AC; Bertelsmann FW; Koetsier JC.

4-Aminopyridine induces functional improvement in multiple

sclerosis patients: a neurophysiological study.

Journal of the Neurological Sciences, 1993 Jun, 116(2):220-6.   

Abstract: This study reports on the neurophysiological measurements

that were    performed in the context of a randomized,

double-blind, placebo-controlled,    cross-over study with

intravenously administered 4-aminopyridine (4-AP) in    70 patients

with definite multiple sclerosis (MS). A beneficial effect of   

4-AP was found for both visual evoked response and eye movement   

registration parameters.This study extends the experimental data

obtained on animal nerve fibers, showing that 4-AP can improve

impulse conduction in demyelinated nerve, to clinical data which

indicate that 4-AP induces an objective improvement in the central

nervous system function in MS-patients. It thereby also provides a

theoretical basis for clinical efficacy of 4-AP in MS.





Van Diemen HA; Polman CH; Koetsier JC; Van Loenen AC; Nauta JJ;

Bertelsmann FW.

4-Aminopyridine in patients with multiple sclerosis: dosage and

serum level related to efficacy and safety.

Clinical Neuropharmacology, 1993 Jun, 16(3):195-204.

Abstract: In a recent randomized, double-blind, placebo-controlled

crossover trial, we demonstrated efficacy of 4-aminopyridine

(4-AP) in improving disability of patients with multiple

sclerosis (MS). Here we describe the relationship between

dosage, serum level, efficacy, and safety of intravenously and

orally administered 4-AP in the same group of 70 MS patients.

After both intravenous and oral administration there was a

significant relationship between serum levels and 4-AP doses used

(p < 0.001 and p < 0.01, respectively). The use of 4-AP in oral

doses three times a day showed a large variation and fluctuation

in serum levels. After 12 weeks of oral treatment (maximum daily

dosage 0.5 mg/kg body weight), a  statistically significant

improvement was found for the smooth pursuit gain of the eye

movements (estimated effect 0.14, 95% confidence interval

0.06-0.23, p < 0.001). The amount of improvement was significantly

related to 4-AP serum levels (p = 0.0013). Side effects after

intravenous 4-AP occurred frequently and were very troublesome

(pain in infusion arm, dizziness). Side effects during oral

treatment (dizziness, paresthesias)were very mild and occurred

30-45 min after intake of the medication and  could be related to

high serum levels.



Author: Polman CH; Bertelsmann FW; van Loenen AC; Koetsier

JC.Title:4-aminopyridine in the treatment of patients with multiple

sclerosis. Long-term efficacy and safety.

Journal:Archives of Neurology, 1994 Mar, 51(3):292-6.

Abstract: OBJECTIVE: To study the long-term efficacy and safety of 

4-aminopyridine in patients with multiple sclerosis. DESIGN: Case

series,    follow-up varying from 6 to 32 months. SETTING:

University referral center.    PATIENTS: Thirty-one patients with

definite MS, 23 of them being exposed to    long-term

administration (6 to 32 months) of 4-aminopyridine, since they   

showed a favorable initial response to the drug. INTERVENTIONS:

Long-term    oral treatment with 4-aminopyridine in daily doses of

up to 0.5 mg/kg of body weight. MAIN OUTCOME MEASURES:

Neurologic functions and symptoms as reported by the patients;

side effects. RESULTS: Twenty of 23 patients who showed a

favorable initial response benefited from long-term   

administration. Ambulation and fatigue (each in 13 patients) and

visual function (in five patients) were most frequently reported

to be improved. Three major side effects did occur during a

follow-up of 406 patient    months: a generalized epileptic seizure

in two patients and hepatitis in one. CONCLUSIONS: Although a

substantial proportion of patients with multiple sclerosis seem

to benefit from long-term administration of 4-aminopyridine,

additional studies are needed to clarify the exact value    of the

drug.   (  ELAN IS DOING THESE STUDIES,MULTICENTER,IN 1994 )





MYELIN BASIC PROTEIN*******************************

Weiner HL;Mackin GA;Matsui M;Orav EJ;KhourySJ;DawsonDM;HaflerDA.

Double-blind pilot trial of oral tolerization with myelin antigens

in multiple sclerosis [see comments].

Science, 1993 Feb 26, 259(5099):1321-4.       

Abstract: Multiple sclerosis (MS) is thought to be an autoimmune

disease mediated by T lymphocytes that recognize myelin

components of the central nervous system. In a 1-year

double-blind study, 30 individuals with relapsing-remitting MS

received daily capsules of bovine myelin or a control protein to

determine the effect of oral tolerization to myelin antigens on the

disease. Six of 15 individuals in the myelin-treated group had at

least one major exacerbation; 12 or 15 had an attack in the

control group. T cells reactive with myelin basic protein were

reduced in the myelin-treated group. No toxicity or side effects

were noted. Although conclusions about efficacy cannot be drawn

from these data, they open an area of investigation for MS and

other autoimmune diseases.(multicenter trials started in mid 1994)





FATIGUE**********************************

Author: Duffy JD; Campbell J.

Title:Bupropion for the treatment of fatigue associated with

multiple  sclerosis [letter].

Journal:Psychosomatics, 1994 Mar-Apr, 35(2):170-1.

Unique ID:    94225039.**************************



Author:  Fisk JD; Pontefract A; Ritvo PG; Archibald CJ; Murray TJ.

Title:The impact of fatigue on patients with multiple sclerosis.

Journal:Canadian Journal of Neurological Sciences, 1994 Feb,

21(1):9-14.

Abstract: Although fatigue is recognized as a symptom of MS, there

have been insufficient methods for evaluating this symptom. We

administered the Fatigue Impact Scale to 85 MS patients and 20

hypertensive patients. Neurologic impairment, mental health, and

general health status were also assessed. MS patients reported

significantly higher fatigue impact than hypertensive patients.

Most MS patients reported fatigue as either  their worst (14%), or

one of their worst (55%) symptoms. Disease  classification and

neurologic impairment had little bearing on Fatigue Impact Scale

scores in the MS sample. The best predictive models for mental

health and general health status in the MS sample both included the

Fatigue Impact Scale as a significant factor. This study

demonstrates that: 1) fatigue is a very prevalent and severe

problem in MS, 2) fatigue impact cannot be predicted by clinical

measures of neurologic impairment, 3) fatigue has a significant   

effect on the mental health and general health status of MS

patients.



MONOCLONAL ANTIBODIES***************************



AUTHOR:  RUMBACH,L,BATTAILARD D.M.GALMICHE,J,HENLIN,JL,ET AL

Title:Treatment of multiple sclerosis with anti-CD4

monoclonal  antibody. A preliminary report on B-F5 in 21 patients.

Journal:Journal of Autoimmunity, 1993 Dec, 6(6):771-86.

Twenty-one patients with definite active multiple sclerosis (MS)

were treated with a monoclonal anti-T 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.





Author: Lindsey JW; Hodgkinson S; Mehta R; Siegel RC;

Mitchell DJ; Lim M;Piercy C; Tram T; Dorfman L; Enzmann D; et al.

Title:Phase 1 clinical trial of chimeric monoclonal anti-CD4

antibody.in multiple sclerosis.

Journal: Neurology, 1994 Mar, 44(3 Pt 1):413-9.

Abstract: We conducted an open trial of cM-T412, a chimeric

monoclonal anti-CD4 antibody, in 29 patients with MS. This

antibody caused a prompt and long-lasting depletion of circulating

CD4 (helper/inducer) lymphocytes. The mean (+/- SE)CD4 count for

the group decreased from 870 (+/- 66) cells/mm3 at baseline to 76

(+/- 11) 3 hours after treatment, and then increased to 425 (+/-

38) at 1 month after treatment and 475 (+/- 39) at 6 months after 

treatment. Numbers of CD8 (cytotoxic/suppressor) lymphocytes,

B-lymphocytes, granulocytes, and monocytes changed transiently but

showed no significant long-term effects. The most common side

effects were headache,nausea, myalgia, fever and tachycardia

occurring in the first few hours after treatment. No serious 

effects occurred. Kurtzke EDSS scores remained  stable,and MRI

scans showed less contrast enhancement 1 week after treatment. We

concluded that treatment of MS patients with cM-T412 chimeric

anti-CD4 antibody  is well tolerated at the doses tested and

produces a long-lasting, selective  depletion of CD lymphocytes.



COPOLYMER I*************************************

Johnson,KP

Experimental therapy of relapsing remitting multiple sclerosis with

copolymer I

ANNNALS OF NEUROLOGY,1994 36 SUPPL:S115-117.********************



CAUSES OF MS***********************************

Author: Mumford CJ; Wood NW; Kellar-Wood H; Thorpe JW; MillerDH;

Compston DA.

Title:The British Isles survey of multiple sclerosis in twins.

Journal: 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.





Silberud EL

Evidence that mercury from silver dental fillings may be an

etiological factor in multiple sclerosis.

Science of the Total Environment 1994 march 15,142 (3): 191-205***



Hutter C.

On the Causes of Multiple Sclerosis.

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.



MERCURY AND MS*********************************

Eley BM; Cox SW.

The release, absorption and possible health effects of mercury from

dental amalgam: a review of recent findings.

British Dental Journal, 1993 Sep 11, 175(5):161-8.      

Abstract: Recently many articles have appeared on the subject of

mercury from dental amalgam and some of these have questioned its

safety as a dental material. This article reviews critically

the evidence on mercury release from dental amalgam restorations,

its absorption, accumulation and excretion by the body, and its

possible relationship to ill-effects.Finally, brief recommendations

are given for the handling and usage of dental amalgam.



Clausen J.

Mercury and multiple sclerosis.

Acta Neurologica Scandinavica, 1993 Jun, 87(6):461-4

Abstract: It has occasionally been claimed that multiple sclerosis

(MS) may be due to a chronic mercury intoxication, e.g. from

mercury liberated from dental fillings. Therefore, the present

communication compares the mercury content assayed by neutron

activation in 8 macroscopically normal areas (frontal lobe) of

MS autopsy brains with those of 8 control samples. No significant

differences could be traced between the two groups concerning total

mercury. However, the lipid-soluble mercury (preferably methyl

mercury) expressed per cell unit (DNA) was found significantly

decreased in MS. These data may be explained either by a wash-out

of lipid soluble mercury due to break-down of the blood-brain

barrier in MS or to abnormalities in methylation processes probably

related to the vitamin B12  metabolism in MS.



AZOTHIOPRENE****************************

Milanese C; La Mantia L; Salmaggi A; Eoli M.

A double blind study on azathioprine efficacy in multiple

sclerosis:final report.

Journal of Neurology, 1993 May, 240(5):295-8.       

Abstract: Forty patients, affected by multiple sclerosis with

remitting-relapsing or progressive course, were included in a

double blind study of treatment with azathioprine (2 mg/kg/day)

lasting 3 years. The  mean changes on the Expanded Disability

Status Scale and in the survival analysis show a trend in favor of

azathioprine both in slowing disease progression and reducing

relapse frequency.These findings, repeatedly observed in similar

trials, indicate that azathioprine should be used in the treatment

of multiple sclerosis.



GEOGRAPHICAL DISTRIBUTION OF MS*****************************

Ebers GC; Sadovnick AD.

The geographic distribution of multiple sclerosis:

review[editorial].

Neuroepidemiology, 1993, 12(1):1-5.      

Abstract: The decisive conclusions to be drawn from the geography

and prevalence of MS are: (1) a north-south (as well as

west-east in the United States) gradient exists independent from

genetic/racial factors; (2) major differences in prevalence

occur in the absence of difference in latitude; (3) individuals

from the same ethnic derivation have either the similar prevalence

or have very different prevalence rates in widely separated   

geographical areas, and (4) specific resistance isolates are shown

to exist regardless of latitude. Existing prevalence information

leads to the almost inescapable conclusion that the geography of MS

cannot be explained by any single known environmental or genetic

factor(s) in isolation. A combination  and distribution of both

genetic and environmental factors  appears to be required to

explain the available data on MS and geography.



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