The recently concluded PAN Conference in Washington DC, Sunday included a 
session Moderated by Morton Kondrake of the PAN Board of Directors. The 
panel included Ulf Rosen, CEO of NeoPharma which is a pharmaceutical company 
located in Sweden.

What NeoParma hopes will be a new treatment for advanced Parkinson's is 
included in this press release:

Parkinson’s Disease Treated By Drug and Delivery System Combination

NeoPharma has developed the Duodopa system for
treating Parkinson’s disease. Their approach focuses
on how known components, used in a new way, add
value to the patient, physician and society. This article
is a summary of a session held during the recent
MedEdge™ International Conference hosted by Medical
Alley. Featured speakers from Uppsalla Sweden
included Ulf Rosen, CEO of NeoPharma, and Bjorn
Berg, Director, Business Development, Animech AB.

Business Concept

NeoPharma’s business concept is to develop, manufacture
and market unique patent-protected pharmaceutical
formulations and systems, primarily for the
treatment of Parkinson’s disease. The company’s first
product is used to treat advanced Parkinson’s disease,
where the desired outcome is no longer being obtained
with current treatment. Two well known substances,
levodopa and carbidopa, are the active ingredients in
Duodopa. Duodopa is delivered by an ambulatory
pump via a tube directly into the duodenum, ensuring
even supply and therefore even uptake of active substances.
The patient’s mobility is improved and their
quality of life is significantly increased.

Parkinson’s Disease

In most cases the first symptoms of Parkinson’s disease
appear when a person is between 50 and 70 years
old, but there are cases where the age of onset is
around 30.

There are several transmitter systems in the brain,
including the cholinergic and dopaminergic nervous
systems. These systems act in collaboration to regulate
a number of the body’s various functions and
rely on transmitter substances to function. What happens
in Parkinson’s disease is that the cholinergic
system continues to function as usual, while the dysfunctional
dopaminergic system is unable to keep up,
which is manifested as Parkinson’s disease.

Complications Phase

The complications phase usually comes 5-10 years
after the onset of the disease. The dopaminergic brain
cells have then become so depleted that there is not
enough dopamine available for release. The effect of
the medication on mobility and other symptoms is
shortened, and it is very common with conventional
treatment to end up either below or above the therapeutic
window, resulting in immobility or involuntary
movements. Over time, more and more dopaminergic
brain cells die and symptoms worsen. Fluctuations
in efficacy appear suddenly, like turning a
switch on or off. These problems may be experienced
as severely disabling, as the patient finds it difficult
to know when the drugs will be effective. Since the
brain does not store enough dopamine for release in
the complications phase, an even supply is required
for the medication to be effective.

Lack of Treatment

One reason why fluctuations in efficacy occur is that
almost all drugs are given orally. Emptying of the
stomach is an irregular bodily mechanism. A common
problem in the complication phase is that the
patient takes a tablet to obtain relief from the immobility,
this fails to have an effect and the patient therefore
takes a second tablet. Both tablets end up in the
stomach, and when the stomach empties into the intestine
and the drugs are absorbed, the patient suffers
severe involuntary movements due to overdose.
The time a patient spends close to normality may be
very short and difficult to control. Duodopa reduces
this problem. The dose of levodopa/carbidopa administered
can be adjusted in very small steps, suited
to the individual’s need, and as a result the period of
time with normal mobility is increased.

Market Potential for Duodopa

The primary target group for Duodopa consists of
patients with Parkinson’s disease in the complications
phase. Today these patients are severely disabled
by their disease and require a great deal of care.
Traditional treatment no longer provides sufficient
alleviation of symptoms for this group. These patients
account for some 10-20 percent of the total
number of individuals with Parkinson’s disease.

Article by Kevin McArdle for Medical Alley

End Article

Many of us remember the concept of the Sinemet Cocktail and Alan Bonander's 
participation in a study being conducted by Dr. Mathias Kurth  in 1991 described 
by Alan.
http://tinyurl.com/6egub

The era has changed but much has happened in the meantime.

NeoPharma realized that the composition of the carbidopa/levodopa must be 
changed into form that was more consistent than the solution that Alan 
concocted out of crushed Sinemet tablets and vitamin C crystals.

NeoParma has developed a gel form of carbidopa/levodopa that comes in  a 2 
gram cartridge used by the computerized pump for infusion directly into the 
small intestine. What the pumps and patient controls look like are here:
http://www.msdistributors.com/biomed/meh/CADD.HTM

The name of the new formulation is Duodopa and approval has been requested 
from the EU and according to Ulf Rosen, CEO of NeoPharma hopes for FDA 
approval in 2007.

There are presently 3 patients in the US using the new formulation, although 
several centers are conducting Clinical Trials.

Several recent papers by Dr. D. Nyholm have appeared in the Journals.

10-20 mg doses which compares to 10 times the tablet
E-MOVE - Research News in Movement Disorders
Subject: PD Treatment Update from Movement Disorders Congress 2004
Date: 7/19/2004
E-MOVE reports from the Eight International Congress of Parkinson’s Disease 
and Movement Disorders, Rome June 14-17, 2004. Page (S) and poster (P) 
numbers are from Movement Disorders 2004;19 (supplement 9) 

Duodopa: Duodenal Infusion of Levodopa 
Two studies report on the use of Duodopa, an intraduodenal infusion of 
levodopa/carbidopa in a gel suspension for PD patients with motor 
complications. In a randomized cross-over study, Duodopa was superior to 
conventional pharmacologic therapy in reduction of UPDRS and quality of 
life. Long-term follow-up indicated a low rate of device complications. 

1. Enteral levodopa infusion as monotherapy is superior to conventional oral 
treatment of advanced Parkinson’s disease 
D Nyholm, N Dizdar, IN Remahl, R Constantinescu, B Holmberg, R Jansson, SM 
Aquilonius, H Askmark 

Twenty-four patients with motor complications were randomized to receive 
either conventional medical treatment (optimized individually for each 
patient) or Duodopa by intraduodenal infusion for three weeks, followed by 
crossover to the other treatment. Patients were videotaped every 30 minutes 
for 8 hours during treatment, and videos were rated by blinded investigators 
for “on” vs. “off” with or without dyskinesias. UPDRS and two 
quality-of-life scales were also administered. 

Number of ratings in the on state without significant dyskinesias was 82% 
for conventional treatment vs. 100% for Duodopa (p<0.01). Finger tapping, 
hand movements, rising from a chair, gait, and bradykinesia were also 
improved. Median UPDRS was 53 on conventional treatment vs. 35 on Duodopa, 
and both QoL scores were more improved for Duodopa as well. Adverse events 
were similar between treatments. 


2. Intraduodenal infusion of a gel suspension of levodopa/carbidopa, 
Duodopa®, in advanced Parkinson’s disease: Safety, tolerability, efficacy, 
dosage 
D Nyholm, T Lewander, A Johansson, P LeWitt, C Lundqvist, SM Aquilonius 
P496, S177 

Fifty-two patients received Duodopa, primarily as monotherapy, for one year 
or more (average 4.1 years). Device complications occurred at a rate of 1.8 
times per patient per year. These were primarily tube occlusions and 
dislocations. Side effect frequency and severity was similar to oral 
levodopa. Eighty-four percent of patients had “improved” or “much improved” 
motor fluctuations, and 50% had improved or much improved dyskinesias. No 
patients reported worsening as a result of therapy. 

E-MOVE - Research News in Movement Disorders
Subject: Alternative Levodopa Administration Strategies (WCN 2001)
Date: 6/22/2001
E-MOVE reports from the 17th World Congress of Neurology, London, June 
17-22. Poster and Platform session numbers refer to those in the abstract 
book, published in Journal of the Neurological Sciences 2001;187 (supplement 
1). 

1. Continuous intestinal infusion of Duodopa--the optimal delivery of 
levodopa in advanced Parkinson's disease? 
D Nyholm, H Askmark, T Knutson, C Gomes-Trolin, C Nystrom, SM Aquilonius 
P0676 

Intestinal infusion of levodopa stabilizes plasma levels of levodopa and 
reduces motor complications, according to this study. Twelve patients were 
randomized to receive levodopa, administered either orally or by a 
computer-controlled minipump via nasoduodenal tube, followed by crossover to 
the other administration method. 

Over 3 weeks of treatment, intraindividual variation of plasma levodopa 
averaged 34% for oral delivery, and 14% for infusion delivery. On time 
without dyskinesias increased from 61% to 80% with infusion, and off time 
decreased from 25% to 12%. The authors note that the nasoduodenal tube is 
replaced by percutaneous gastrostomy tube in clinical practice. 

Duodenal levodopa infusion in Parkinson's disease--long-term experience.

Nilsson D, Nyholm D, Aquilonius SM.

Department of Neuroscience, Neurology, Uppsala University, Sweden.

Motor fluctuations in parkinsonian patients can be reduced by intraduodenal 
infusion of levodopa. Between 1991 and 1998 continuous daytime 
administration of levodopa through a transabdominal port has been used in 28 
very advanced patients over a total period of 1045 months. A stable 
suspension of levodopa and carbidopa (Duodopa) has been developed. Patients 
were characterized by early onset, long history of disease and levodopa 
therapy. The reason for infusion was in all cases related to on-off 
fluctuations. All patients experienced a general improvement after the 
introduction of continuous treatment. There have been no severe 
complications. Six patients have taken the decision to curtail their 
treatment. The mean daily levodopa consumption has been slightly reduced on 
infusion as compared to oral therapy. Nine of the first group of patients 
participating in the new therapy have been regularly evaluated by means of 
rating scales and movement analyses. Short-term results have already been 
published and a follow-up showing continued positive effect after 4-7 years 
of continuous duodenal infusion is presented.

PMID: 11903087 [PubMed - indexed for MEDLINE] 

MDS: Enteral Carbidopa/Levodopa (Duodopa) Alleviates Motor Symptoms, "Off" 
Times in Parkinson's Disease

By Paula Moyer
ROME, ITALY -- June 21, 2004 -- An enterally infused gel formulation of 
carbidopa/levodopa (Duodopa) is more effective as monotherapy than a 
cocktail of oral therapies for patients with Parkinson's disease who have 
motor fluctuations and dyskinesias, according to findings presented here 
June 15th at the 8th International Congress of the Movement Disorder Society.
"The enteral infusion offers an important alternative for patients with 
advanced Parkinson's disease," said Dag Nyholm, MD, consultant neurologist, 
Uppsala University Hospital, Uppsala, Sweden. He noted that patients in the 
study reported a higher quality of life and greater satisfaction with their 
motor functioning when treated with the enteral formulation.
The researchers wanted to compare enteral levodopa monotherapy, infused over 
a 16-hour period during the day, to individually optimized conventional 
combination therapies that are often used to treat patients with advanced 
Parkinson's disease. They conducted a randomized crossover study in 24 
patients with Parkinson's disease and motor fluctuations treated with 
individual conventional treatment or the investigative formulation for 3 
weeks each.
They were interested in an enteral formulation because the conventional oral 
therapies are often inadequate to control the motor fluctuations of advanced 
Parkinson's disease. Since the enteral formulation offered a nearly constant 
plasma levodopa concentration, the investigators wanted to see if it 
therefore provided continuous dopaminergic stimulation and therefore better 
control of motor fluctuations.
Video recordings of each patient were made every 30 minutes for 8 hours on 2 
days in each treatment arm. A blinded observer assessed each video for motor 
function and gave a score on a Treatment Response Scale (-3 for severe 
parkinsonism, 0 for normal function, and +3 for severe dyskinesia). Patients 
used an electronic diary to record real-time self-assessment of motor 
function and quality of life.
Median time in a near normal motor state, scores of -1 to +1, increased from 
81% to 100% with infusion therapy (P <.01). Patients also had a significant 
decrease in median score on the Unified Parkinson's Disease Rating Scale, 
from 53 (range 14 to 80) on conventional therapy to 35 with enteral therapy 
(range 19 to 63) (P <.05).
The investigators obtained quality-of-life data from the Physicians' Data 
Query-39, the Measure of Health Related Quality of Life 15D questionnaire 
(15D), and the patients' electronic diaries. These instruments showed higher 
quality-of-life assessments when patients were on enteral therapy, Dr. 
Nyholm said.
The study was funded by NeoPharma, the manufacturers of Duodopa.
[Presentation title: Enteral Levodopa Infusion as Monotherapy is Superior to 
Conventional Oral Treatment of Advanced Parkinson's Disease. Abstract P500]

John Cottingham

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