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Nancy Shlaes wrote:
>
> I would be very grateful to receive the text file of the COM inhibitors article
> (UPF)/
>
> Many thanks
>
> Nancy Shlaes (60/4)
>
> Charles T. Meyer wrote:
>
> > I have scanned the UPF Article that Nancy mentioned regarding the COMT
> > inhibitors.  I will forward a text file to anyone that is interested.  Just
> > E-mail me directly.  It is long and I didn't want to clutter the mailboxes of
> > people who aren't interested.
> >
> > Charlie
> > --
> >
> > CHARLES T. MEYER, M.D.
> > Middleton, WI
> > [log in to unmask]

--

CHARLES T. MEYER, M.D.
Middleton, WI
[log in to unmask]
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UNITED PARKINSON FOUN DAT ION
833 West Washington Boulevard Chicago, Illinois 60607 312/733-1893 SUPPLE=
MENT, January, 1998

    INHIBITORS OF CATECHOL-O-METHYLTRANSFERASE (COMT):
A NEW THERAPEUTIC STRATEGY FOR PARKINSON'S DISEASE PATIENTS


  by PeterA. LeWitt, M.D.
Sinai Clinical Neuroscience Center   West Bloomfield, Michigan

 Levodopa treatment and COMT inhibitors

      Among new medications developed in recent years for the symptomatic=
 treatment of Parkinson's Disease are two drugs with a property described=
 as COMT inhibition.  COMT is an abbreviation for catechol-O-methyltransf=
erase, an enzyme present throughout the body. COMT converts levodopa to a=
nother substance called 3-O-methyldopa. Levodopa is the active ingredient=
 of Sinemet, the most widely-used medication for relief of parkinsonian s=
ymptoms.

When levodopa reaches the brain, this drug is rapidly converted to an imp=
ortant brain chemical called dopamine. A deficiency of dopamine in the br=
ain is responsible for most of the symptoms of Parkinson's Disease. Treat=
ment with levodopa serves to restore the functioning of this important ne=
urotransmitter. Only a small amount of levodopa actually reaches the brai=
n after ingestion. A large fraction of each dose is diverted by COMT to 3=
-O-methyldopa, an inactive by-product that cannot be converted to provide=
 relief of symptoms. However, the quantity of levodopa that does arrive i=
n the brain is usually adequate to produce major improvements in parkinso=
nian signs and symptoms.

 Levodopa and decarboxvlase inhibitors

Levodopa is generally prescribed in the United States as a combination pr=
oduct with carbidopa (or in other countries, with a similar drug called b=
enserazide). Carbidopa and benserazide are classified as decarboxylase in=
hibitors. These drugs inhibit another enzyme that acts on levodopa called=
 L-aromatic amino acid decarboxylase. If decarboxylase inhibitors were no=
t given with each dose of levodopa, dopamine would be produced throughout=
 the body instead of just within the brain. Dopamine produced outside of =
the brain can cause a number of side effects such as nausea and low blood=
 pressure. The use of decarboxylase inhibitors avoids these and other sid=
e effects. These drugs also result in more levodopa gaining entrance into=
 the brain. The combination of the two classes of inhibitors (COMT and de=
carboxylase) offers a new strategy for increasing the fraction of each le=
vodopa dose that reaches the brain.

In some respects, the increased levodopa entrance to the brain with COMT =
and decarboxylase inhibitors could also be achieved by more daily levodop=
a intake. However, COMT inhibition gives a clinical effect different from=
 the results of larger oral doses of levodopa. As described below, the ke=
y difference is extending levodopa action without augmenting its peak eff=
ects. The peak effects of levodopa occur typically one to two hours after=
 each dose and can be associated with involuntary movements (dyskinesias)=
 or side effects on the mind such as hallucinations. COMT inhibitors offe=
r the promise of fewer side effects with levodopa and more constancy in c=
ontrol of symptoms.


Variability in levodopa effect: "motor fluctuations"

When levodopa is first started for treating Parkinson's Disease symptoms,=
 the drug usually provides a uniform effect over the course of a day. In =
this situation, a patient could be described as a "non-fluctuator" in tha=
t there is no variation in control of symptoms (slowed walking, stiffness=
, tremor and so on).  The rise and fall of levodopa concentration in the =
bloodstream occurs in a cycle lasting only a few hours. This oscillation =
in levodopa concentrations occurs whether this drug is administered in ei=
ther the immediate-release or sustained-release (Sinemet CR) forms. Despi=
te the variability of levodopa blood concentrations, many patients never =
lose the consistency of beneficial response to this medication. After sev=
eral years, though, patients can start to experience variable degrees of =
relief offered by levodopa against their symptoms. At best, there can be =
the same extent of improvements as previously experienced. However, patie=
nts with motor fluctuations experience a wearing-off of benefits after ea=
ch dose, either gradually or abruptly (over a few minutes). The likelihoo=
d of several hours of improvement from each dose of levodopa may also bec=
ome less reliable. Maintaining the consistency of medication effect can b=
ecome a continuing challenge for patients experiencing motor fluctuations=
=2E

Several strategies can be attempted for controlling motor fluctuations. T=
hese include dividing a levodopa regimen into smaller doses taken at more=
 frequent intervals (as brief as one to three hours between doses). A swi=
tch to the sustained-release preparation of levodopa, Sinemet CR, can hel=
p. Other approaches include combining levodopa with adjunctive drugs that=
 can extend its effects. Extenders of levodopa effects include selegiline=
 (Eldepryl) and amantadine (Symmetrel). Drugs that can block COMT provide=
 another option for increasing the duration of action of levodopa. As des=
cribed below, two COMT inhibitors will soon be available for this purpose=
=2E


Inhibitors of COMT: tolcapone and entacapone

Tolcapone and entacapone are likely to be released shortly in the U.S. A =
product of Roche Laboratories (Basel, Switzerland), tolcapone is currentl=
y marketed in the United Kingdom, Canada and South America. Its world-wid=
e brand name is Tasmar". Entacapone was developed by Orion Pharma (Espoo,=
 Finland) and will be marketed in the United States by Novartis Pharmaceu=
ticals with the brand name of Comtan.. Tolcapone will be available in 100=
 and 200 mg tablets, while entacapone will likely be marketed only as a 2=
00 mg tablet.

Studies with tolcapone and entacapone have shown that these drugs reliabl=
y increase the duration of effect from each dose of levodopa. A COMT inhi=
bitor causes the blood concentrations of levodopa to remain higher for a =
longer period of time. The result is improved control of motor fluctuatio=
ns. COMT inhibition offers advantages to patients who are experiencing th=
e regular wearingoff of levodopa action at three hours or less after the =
last dose of immediate-release levodopa. Clinical trials with each of the=
se drugs have validated the potential offered by COMT inhibitors. A numbe=
r of studies have been published of results of trials with tolcapone and =
entacapone that have been carried out in patients with typical problems o=
f wearing-off levodopa responses. These studies have shown that tolcapone=
 and entacapone produce improvements such as less abrupt "ofP' states and=
 more daily "on" time (from one to three hours per day). In some of the c=
linical trial patients, the duration or severity of dyskinesias was incre=
ased, but usually this problem could be managed by lowering the dose of l=
evodopa.

Wearing-off of levodopa effect is the most common reason Parkinson's Dise=
ase patients experience variability in medication benefits. Other pattern=
s of fluctuations can occur, however. It is important to distinguish the =
regular, predictable cycle of levodopa actions from the others, because C=
OMT inhibitors and other extenders of levodopa action work only for this =
particular problem. Besides the "wearing-off' response, patients can beco=
me suddenly immobile for periods lasting for ten minutes or more. This co=
ndition, "on-off' syndrome, is named after the abrupt transitions between=
 good mobility and prolonged states of being "frozen" in place unable to =
move. The "on-off' syndrome can be difficult to control. Even an extra do=
se of levodopa tends not to restore mobility.

Some patients have momentary "freezing" in place. Start hesitancy is char=
acterized by sudden immobility when beginning to walk. "Freezing" can als=
o occur when turning or in other specific situations, such as upon reachi=
ng a doorway or entering a confined space. Like the "on-off' syndrome, th=
ese momentary "off' states are not related to falls in the blood concentr=
ation of levodopa, nor are they avoided by an increased intake of levodop=
a.

An important reason for differentiating these patterns of fluctuations in=
 control of symptoms is that the medication approaches to these problems =
are different. Start-hesitancy and "on-off' can be responsive, in some in=
stances, to the use of dopaminergic agonists (medications such as pergoli=
de (Permax), bromocriptine (Parlodel), ropinerole (Requip) and pramipexol=
e (Mirapex)). The "wearing-off' problem has the most logical solution in =
that the clinical state can be improved by extending the duration of elev=
ation of levodopa's bloodstream concentrations. Hence, the use of COMT in=
hibitors in motor fluctuations should be targeted at lessening "wearing-o=
ff" responses. Sometimes a patient can have a combination off fluctuation=
 patterns, and so fluctuations need careful analyses to choose the best t=
reatments.


Comparisons between tolcapone and entacapone

Both tolcapone and entacapone are highly selective, reversible inhibitors=
 of COMT. Each is designed for multiple daily dosing. Though both drugs a=
ct in a similar fashion, their recommended daily schedules for dosing are=
 different. Tolcapone is the longer acting of the two. Consequently, tolc=
apone can be taken at six-hour intervals. In contrast, the briefer action=
s of entacapone require that this drug be administered with each dose of =
levodopa. The recommended dosing of tolcapone is for three daily doses, a=
lthough its six-hour duration of action means that some patients could ge=
t by with two doses per day. Tolcapone will be marketed in 100 and 200 mg=
 tablets. Clinical studies have suggested that the lower dose is sufficie=
nt to produce the same degree of COMT inhibition as does the 200 mg dose,=
 and so the need for the larger tablet is not clear at this time. Entacap=
one, too, is likely to be almost as effective in 100 mg doses as in its p=
rojected marketing tablet size of 200 mg.

The desired action of the COMT inhibitors is inhibiting a reaction which =
diverts levodopa to 3-O-methyldopa before levodopa reaches the brain. Bot=
h drugs are similar in this regard. Tolcapone also has some ability to in=
hibit COMT activity in the brain. Studies of this central inhibitory effe=
ct in animals have not shown any advantage or drawback to COMT inhibition=
 in the brain, although it is possible that this property might be the ba=
sis for a difference in the clinical effectiveness of one of the COMT inh=
ibitors. Both tolcapone and entacapone have undergone extensive clinical =
trials. Priorto human testing, these drugs were studied in several animal=
 species for safety and definition of their actions on levodopa. Human te=
sting has shown them to be very safe. The most common side effects from t=
he COMT inhibitors are effects resulting from increased actions oflevodop=
a. These include enhanced involuntary movements (dyskinesias), nausea, vi=
vid dreams or hallucinations. Such side effects can be lessened by loweri=
ng the dosage of levodopa. Other side effects seem specific to tolcapone.=
 Up to ten percent of patients taking this drug experienced diarrhea. Thi=
s can be a mild problem of brief duration, and discontinuing tolcapone gi=
ves prompt recovery from diarrhea. Some patients have been unable to cont=
inue with tolcapone because of this side effect. The best means for contr=
olling this side effect is not currently known. Rarely, the use of tolcap=
one has also led to increased blood concentrations of enzymes derived fro=
m the liver. This test result suggests that tolcapone very rarely can hav=
e some toxicity against the liver. Many doctors prescribing tolcapone wil=
l perform a blood test to exclude this possibility several weeks after th=
e start of tolcapone. It is possible that entacapone might have similar s=
ide effects, since it is a closely related substance. However, results to=
 date suggest that diarrhea has occurred commonly and abnormalities of li=
verfunction tests have not been reported.

Other possible applications for COMT inhibitors

The rationale for using COMT inhibitors is clear in the context of patien=
ts affected with "wearing-off" responses. However, another application ha=
s been under consideration, namely, the patient who has not yet experienc=
ed fluctuations in response to levodopa. There has been speculation for m=
any years that a regimen yielding less variation in delivery of levodopa =
to the brain might lead to a lower incidence of dyskinesias or motor fluc=
tuations. This hypothesis led to a five-year study with sustained-release=
 levodopa (Sinemet CR), which did not show any benefit overthe immediate-=
release form of this drug with respect to occurrence of motor fluctuation=
s at the end of the trial. The same question will be explored in an ongoi=
ng multi-center study over the next five years. This study will contrast =
outcomes from combining tolcapone with levodopa with the results of using=
 levodopa alone. A similar study is planned to be undertaken with entacap=
one. If the more constant blood levels of levodopa with the use of COMT i=
nhibitors are effective at preventing dyskinesias and motor fluctuations,=
 then these drugs might become important options even from the start of l=
evodopa therapy. At present, however, there is no evidence in support of =
combination therapy for long-term outcomes. A six-month study with supple=
mental tolcapone has shown improvements in clinical and disability rating=
s as compared to a levodopa-alone treatment group. The significance of th=
e findings in the latter study is not clear but may indicate extra benefi=
ts even for the non-fluctuating patient.

The bottom line:
the roles of tolcapone and entacapone in Parkinson's Disease symptomatic =
treatment

Tolcapone and entacapone offeran important new option for treating proble=
ms that can develop after chronic use of levodopa. Though COMT inhibitors=
 are not the only means of extending the effects of levodopa, these drugs=
 have great promise for improving the reliability of continuous levodopa =
action. Sustained-release levodopa (Sinemet CRaP) is also available for h=
elping to improve the consistency of levodopa effect. Clinical experience=
 to date strongly suggests that the COMT inhibitors offer more effectiven=
ess. The combination of Sinemet CRQ with a COMT inhibitor could conceivab=
ly be a better solution for "wearing-oft" than either of these strategies=
 alone. However, the effectiveness of COMT inhibitors might make such a c=
ombination unnecessary.

Levodopa is, by itself, an expensive therapy and strategies to extend its=
 duration of action can substantially add to the cost of therapy. The pri=
c ing of the two COMT inhibitors has not been announced. However, the use=
 of tolcapone or entacapone may permit the elimination of Sinemet CR (who=
se cost is substantially greater than the price of the same amount of lev=
odopa in a generic, immediate-release preparation of levodopa/ carbidopa)=
=2E COMT inhibitors increase the magnitude of clinical effect from each d=
ose of levodopa. Consequently, it may be possible to reduce the daily dos=
age of levodopa by up to fifty percent. For example, if a patient needs 6=
00 mg of levodopa per day for optimal effect, the concomitant use of tolc=
apone or entacapone might permit a reduction of levodopa to 300-400 mg/ d=
ay with no loss of benefit. It may be that the increment of levodopa/carb=
idopa intake "saved" by use of a COMT inhibitor would not be a cost-effec=
tive alternative to the addition of a new drug. However, a COMT inhibitor=
 can improve clinical effects beyond the best results that adjustment of =
levodopa/carbidopa, by itself, can offer.

COMT inhibitors have a major role to play in treating "wearing-off' respo=
nses to levodopa. Likely, they will become widely promoted and extensivel=
y prescribed. It is important to recognize their limitations in the manag=
ement of Parkinson's Disease. For some patients, addition of a COMT inhib=
itor will offer benefits no different from a thirty-to-fifty percent incr=
ease of daily levodopa intake. The problems of start hesitance, prolonged=
 "freezing" or sub-optimal response to levodopa even in high dosage are s=
ituations in which a dopaminergic agonist often can help. A COMT inhibito=
r is unlikely to improve these problems.


(Editor's note: This supplement to the UPF Quarterly Newsletter has been =
funded by a generous unrestricted educational grant from Hoffmann-LaRoche=
, Inc. We suggest that patients who are being followed by a family practi=
tioner or an internist might want to make copies of the supplement for th=
eir physicians, since we are aware that many clinicians are hesitant abou=
t combining medications. In fact, because of the completeness of the supp=
lement, patients being followed by neurologists, even movement disorders =
specialists, might want to provide them with copies as well. No other rep=
roduction is hereby authorized. And finally, UPF members who wish to cons=
ult such a specialist are encouraged to contact the UPF staff for the nam=
es and numbers of the referrals nearest them.)






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