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Good morning, Bob.
Thanks for the summary. It helps with the patience.
Likewise, all the best to you.
Bart
> [Original Message]
> From: Robert A. Fink, M. D. <[log in to unmask]>
> To: <[log in to unmask]>
> Date: 8/11/2004 2:00:10 AM
> Subject: Proceedings of 8th International Congress, Rome
>
> Conference Report
> Highlights of the 8th International Congress of Parkinson's Disease and
> Movement Disorders
> June 13-17, 2004; Rome, Italy
> Posted 07/08/2004
>
> Robert A. Hauser, MD, MBA
>
> The 8th International Congress of Parkinson's Disease and Movement
> Disorders was held in Rome, Italy, from June 13 to 17, 2004. Herewith are
> highlights from this premiere scientific meeting.
>
> Parkinson's Disease
>
>
> Etiopathogenesis
>
> At the first plenary session, McNaught[1] reviewed information suggesting
> that Parkinson's disease (PD) might be caused by dysfunction of the
> ubiquitin-proteasome system (UPS) and discussed a rat model of PD induced
> by proteasome inhibitors.[2] The UPS is responsible for degradation and
> clearance of unwanted proteins. Mutations in parkin and ubiquitin
C-terminal
> hydrolase L1, components of the UPS, cause rare familial forms of PD.
Other
> genetic causes of PD, such as mutations or triplications of the
alpha-synuclein
> gene, might also inhibit the UPS, although direct neuronal toxicity of
alpha-
> synuclein due to misfolding has also been hypothesized.
>
> On the basis of these observations, it is possible that exposure to
> environmental proteasome inhibitors could cause or contribute to the
> development of PD. To test this concept, rats were administered proteasome
> inhibitors (either epoxomicin or PSI) 6 times over a period of 2 weeks.
> Several weeks later, the animals developed progressive parkinsonism that
> improved with levodopa or apomorphine. Positron emission tomography
> (PET) demonstrated the loss of dopaminergic neurons, and autopsy findings
> were similar to those seen in humans with PD, including the presence of
> Lewy body-like inclusions. The UPS dysfunction hypothesis represents an
> important alternative (or addition) to the synuclein-toxicity hypothesis
and
> suggests that at least some forms of PD may be caused by environmental
> proteasome inhibitors. Possible neuroprotective agents, including those
that
> help restore the UPS, can be tested in this rat model.
>
>
> Current Medications
>
> Entacapone
>
> Marin and colleagues[3] reported that levodopa plus entacapone* causes
less
> dyskinesia than levodopa alone in the 6-hydroxydopamine hemiparkinsonian
> rat model of PD. Four weeks after lesioning, rats were treated with
levodopa
> twice daily, levodopa plus entacapone twice daily, or placebo. Compared
> with treatment with levodopa alone, levodopa plus entacapone caused less
> dyskinesia. This study confirms similar findings from the MPTP monkey
> model of PD and supports the notion that more continuous dopaminergic
> stimulation causes less dyskinesia. It raises the issue as to whether
catechol-
> O-methyltransferase (COMT) inhibitors, such as entacapone, should be
> administered from the initial introduction of levodopa in the management
of
> patients. A study to evaluate the potential of entacapone to delay the
onset of
> dyskinesia in PD patients is currently in the planning stages.
>
> *Agent not currently approved for the indication discussed
>
> Pergolide
> Agarwal and associates[4] presented 2 cases of pergolide-induced fibrosis
> and reviewed the literature on this subject. They identified 21 cases in
the
> literature, with patients having been treated for 1-8 years at a dose of
1-8 mg
> of pergolide per day. The most common presenting sign of fibrosis was
> dyspnea (13 of 23, including the presenters' cases), and most patients
with
> pulmonary fibrosis had abnormal chest x-rays. Four patients received
> substantial benefit from steroid treatment. Fibrosis should be considered
a
> possible complication of ergot dopamine agonists (bromocriptine and
> pergolide) in patients with new dyspnea, chest pain, weight gain, or
dysuria.
> Work-up should include electrocardiogram (ECG) and computed
> tomographic (CT) scans of the chest, abdomen, and pelvis.
>
> Apomorphine
> Trosch and colleagues[5] presented the results of a 6-month study of
> intermittent subcutaneous apomorphine for patients with advanced PD.
> Patients were premedicated with trimethobenzamide for 3 days to help
reduce
> nausea and then underwent inpatient dosing of apomorphine. Dosing began at
> 2 mg and increased in 2-mg increments to a maximum of 10 mg (mean, 5 mg)
> to achieve an optimal response. Patients then continued their optimal
dose of
> apomorphine on an as-needed basis and were evaluated at 1 and 2 weeks as
> well as 1, 4, and 6 months. In all, 32 of 56 patients completed 6 months
of
> treatment. At the 6-month evaluation, benefit in the Unified Parkinson's
> Disease Rating Scale (UPDRS) motor scores was observed at 20, 40, and 90
> minutes post dose, similar to what had been seen at the beginning of the
> study. Adverse events were mild to moderate and included nausea, vomiting,
> and injection-site reactions; 17 of 56 patients discontinued treatment
because
> of adverse events.
>
> This study demonstrates that the benefit of apomorphine injections is
> sustained through at least 6 months of treatment, although almost a third
of
> patients discontinued because of side effects. Apomorphine subcutaneous
> injections are now approved in the United States as rescue therapy for
> patients with motor fluctuations. It has a relatively rapid onset of
action (10-
> 15 minutes in other studies) and lasts approximately 90 minutes.
>
>
>
>
> Future Medications
>
> Rasagiline
> Rascol and colleagues[6] presented the results of a comparative randomized
> study of rasagiline* vs placebo or entacapone as an adjunct to levodopa in
> patients with motor fluctuations (the LARGO study). Rasagiline is an
> irreversible monoamine oxidase type B (MAO-B) inhibitor that is expected
to
> be approved as once-daily monotherapy for patients with early PD and as an
> adjunct to levodopa in those with advanced PD. In this study, both
rasagiline
> 1 mg once daily and entacapone 200 mg, with each levodopa dose, reduced
> daily OFF time by approximately 1.2 hours as compared with placebo, which
> reduced daily OFF time by 0.4 hours (P < .0001). In clinical practice,
> rasagiline and entacapone can be administered concurrently, and it is
> anticipated that their benefits together should be greater than either
alone
> because they have different mechanisms of action.
>
> *Agent not currently approved for the indication discussed
>
> Rotigotine
> Watts and coworkers[7] reported the results of a prospective, randomized,
> placebo-controlled trial of rotigotine* transdermal patch for patients
with
> early PD (n = 277). Patients were started at a dose of 4.5 mg/day and
titrated
> to as much as 13.5 mg/day. They were then followed through a 6-month
> maintenance phase. Approximately 80% of patients completed the
> maintenance phase, and rotigotine was associated with an improvement in
> UPDRS activities of daily living (ADL) plus motor score of approximately
> 5.3 points as compared with placebo (P < .0001). The most common side
> effects (rotigotine vs placebo) were application-site reaction (43% vs
12%),
> nausea (41% vs 17%), somnolence (33% vs 19%), and vomiting (95 vs 1%).
> The rotigotine transdermal patch is now in phase 3 evaluation as
monotherapy
> in early disease and as an adjunct to levodopa in advanced disease.
>
> *Agent not currently approved for the indication discussed
>
> Istradefylline
> LeWitt and colleagues[8] presented the results of 2 prospective,
randomized,
> multicenter studies of istradefylline (KW-6002)* as an adjunct to levodopa
> for patients with motor fluctuations. Istradefylline is an adenosine A2A
> receptor antagonist that improves parkinsonian signs in animal models
> without increasing dyskinesia. In 1 of the current studies, 40 mg/day of
> istradefylline reduced OFF time by 1.2 hours as compared with placebo (P =
> .0006). In the second study, there was a strong trend for a reduction of
the
> percentage of daily OFF time with 20 mg/day or 60 mg/day of istradefylline
> as compared with placebo. When the baseline percentage OFF time was
> included as a covariate, these differences were significant (P = .026 and
P =
> .024, respectively). Istradefylline is now in phase 3 clinical trials as
an
> adjunct to levodopa. No results are yet available regarding its use as
> monotherapy in early disease.
>
> *Agent not currently approved for the indication discussed
>
> --------------------------------------------------------------------
>
>
> PD -- Interventional Techniques
>
> Subthalamic Nucleus Stimulation
> Chronic subthalamic nucleus stimulation is now a widely used treatment for
> patients with major disability caused by motor fluctuations. However, some
> patients experience inadequate improvement following surgery. Batir and
> colleagues[9] evaluated whether reimplantation of electrodes closer to the
> target would provide benefit in such patients. They reimplanted
electrodes in
> 6 patients who experienced an inadequate response and found that 5 had
> improved substantially. OFF motor scores and Schwab and England activities
> of daily living scores improved; levodopa doses were reduced; and major
> improvements in dyskinesia and motor fluctuations were observed. The
> distance from the electrical contact to the theoretical subthalamic
nucleus
> target was reduced from 5.7 to 1.7 mm. This experience indicates that
> patients with an inadequate response should be evaluated for
reimplantation
> to move the electrodes closer to the target.
>
> Glial Cell Line-Derived Neurotrophic Factor Infusion
> Patel and coworkers[10] presented the 2-year results of their phase 1
> evaluation of glial cell line-derived neurotrophic factor * in 5 patients
with
> advanced PD. They identified no serious side effects. OFF UPDRS motor
> scores improved by 57% and ADL scores improved by 63%. PET scans
> demonstrated a 60% increase in fluorodopa uptake in the posterior putamen.
> Thus, the results of this initial open-label safety study remain very
> encouraging through 2 years. A double-blind study is now underway.
>
> *Agent not currently approved for the indication discussed
>
>
>
> =============================================
>
> Best,
>
> Bob
>
>
>
>
>
----------------------------------------------------------------------------
----
>
>
> **********************************************
> Robert A. Fink, M. D., F.A.C.S., P. C.
> 2500 Milvia Street Suite 222
> Berkeley, California 94704-2636
> Telephone: 510-849-2555 FAX: 510-849-2557
> WWW: http://www.rafink.com/
>
> mailto:[log in to unmask]
>
> "Ex Tristitia Virtus"
>
> *********************************************
>
> ----------------------------------------------------------------------
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August 2003, Week 5 August 2003, Week 4 August 2003, Week 3 August 2003, Week 2 August 2003, Week 1 July 2003, Week 5 July 2003, Week 4 July 2003, Week 3 July 2003, Week 2 July 2003, Week 1 June 2003, Week 5 June 2003, Week 4 June 2003, Week 3 June 2003, Week 2 June 2003, Week 1 May 2003, Week 5 May 2003, Week 4 May 2003, Week 3 May 2003, Week 2 May 2003, Week 1 April 2003, Week 5 April 2003, Week 4 April 2003, Week 3 April 2003, Week 2 April 2003, Week 1 March 2003, Week 5 March 2003, Week 4 March 2003, Week 3 March 2003, Week 2 March 2003, Week 1 February 2003, Week 4 February 2003, Week 3 February 2003, Week 2 February 2003, Week 1 January 2003, Week 5 January 2003, Week 4 January 2003, Week 3 January 2003, Week 2 January 2003, Week 1 December 2002, Week 5 December 2002, Week 4 December 2002, Week 3 December 2002, Week 2 December 2002, Week 1 November 2002, Week 5 November 2002, Week 4 November 2002, Week 3 November 2002, Week 2 November 2002, Week 1 October 2002, Week 5 October 2002, Week 4 October 2002, Week 3 October 2002, Week 2 October 2002, Week 1 September 2002, Week 5 September 2002, Week 4 September 2002, Week 3 September 2002, Week 2 September 2002, Week 1 August 2002, Week 5 August 2002, Week 4 August 2002, Week 3 August 2002, Week 2 August 2002, Week 1 July 2002, Week 5 July 2002, Week 4 July 2002, Week 3 July 2002, Week 2 July 2002, Week 1 June 2002, Week 5 June 2002, Week 4 June 2002, Week 3 June 2002, Week 2 June 2002, Week 1 May 2002, Week 5 May 2002, Week 4 May 2002, Week 3 May 2002, Week 2 May 2002, Week 1 April 2002, Week 5 April 2002, Week 4 April 2002, Week 3 April 2002, Week 2 April 2002, Week 1 March 2002, Week 5 March 2002, Week 4 March 2002, Week 3 March 2002, Week 2 March 2002, Week 1 February 2002, Week 4 February 2002, Week 3 February 2002, Week 2 February 2002, Week 1 January 2002, Week 5 January 2002, Week 4 January 2002, Week 3 January 2002, Week 2 January 2002, Week 1 December 2001, Week 5 December 2001, Week 4 December 2001, Week 3 December 2001, Week 2 December 2001, Week 1 November 2001, Week 5 November 2001, Week 4 November 2001, Week 3 November 2001, Week 2 November 2001, Week 1 October 2001, Week 5 October 2001, Week 4 October 2001, Week 3 October 2001, Week 2 October 2001, Week 1 September 2001, Week 5 September 2001, Week 4 September 2001, Week 3 September 2001, Week 2 September 2001, Week 1 August 2001, Week 5 August 2001, Week 4 August 2001, Week 3 August 2001, Week 2 August 2001, Week 1 July 2001, Week 5 July 2001, Week 4 July 2001, Week 3 July 2001, Week 2 July 2001, Week 1 June 2001, Week 5 June 2001, Week 4 June 2001, Week 3 June 2001, Week 2 June 2001, Week 1 May 2001, Week 5 May 2001, Week 4 May 2001, Week 3 May 2001, Week 2 May 2001, Week 1 April 2001, Week 5 April 2001, Week 4 April 2001, Week 3 April 2001, Week 2 April 2001, Week 1 March 2001, Week 5 March 2001, Week 4 March 2001, Week 3 March 2001, Week 2 March 2001, Week 1 February 2001, Week 4 February 2001, Week 3 February 2001, Week 2 February 2001, Week 1 January 2001, Week 5 January 2001, Week 4 January 2001, Week 3 January 2001, Week 2 January 2001, Week 1 December 2000, Week 5 December 2000, Week 4 December 2000, Week 3 December 2000, Week 2 December 2000, Week 1 November 2000, Week 5 November 2000, Week 4 November 2000, Week 3 November 2000, Week 2 November 2000, Week 1 October 2000, Week 5 October 2000, Week 4 October 2000, Week 3 October 2000, Week 2 October 2000, Week 1 September 2000, Week 5 September 2000, Week 4 September 2000, Week 3 September 2000, Week 2 September 2000, Week 1 August 2000, Week 5 August 2000, Week 4 August 2000, Week 3 August 2000, Week 2 August 2000, Week 1 July 2000, Week 5 July 2000, Week 4 July 2000, Week 3 July 2000, Week 2 July 2000, Week 1 June 2000, Week 5 June 2000, Week 4 June 2000, Week 3 June 2000, Week 2 June 2000, Week 1 May 2000, Week 5 May 2000, Week 4 May 2000, Week 3 May 2000, Week 2 May 2000, Week 1 April 2000, Week 5 April 2000, Week 4 April 2000, Week 3 April 2000, Week 2 April 2000, Week 1 March 2000, Week 5 March 2000, Week 4 March 2000, Week 3 March 2000, Week 2 March 2000, Week 1 February 2000, Week 5 February 2000, Week 4 February 2000, Week 3 February 2000, Week 2 February 2000, Week 1 January 2000, Week 5 January 2000, Week 4 January 2000, Week 3 January 2000, Week 2 January 2000, Week 1 December 1999, Week 5 December 1999, Week 4 December 1999, Week 3 December 1999, Week 2 December 1999, Week 1 November 1999, Week 5 November 1999, Week 4 November 1999, Week 3 November 1999, Week 2 November 1999, Week 1 October 1999, Week 5 October 1999, Week 4 October 1999, Week 3 October 1999, Week 2 October 1999, Week 1 September 1999, Week 5 September 1999, Week 4 September 1999, Week 3 September 1999, Week 2 September 1999, Week 1 August 1999, Week 5 August 1999, Week 4 August 1999, Week 3 August 1999, Week 2 August 1999, Week 1 July 1999, Week 5 July 1999, Week 4 July 1999, Week 3 July 1999, Week 2 July 1999, Week 1 June 1999, Week 5 June 1999, Week 4 June 1999, Week 3 June 1999, Week 2 June 1999, Week 1 May 1999, Week 5 May 1999, Week 4 May 1999, Week 3 May 1999, Week 2 May 1999, Week 1 April 1999, Week 5 April 1999, Week 4 April 1999, Week 3 April 1999, Week 2 April 1999, Week 1 March 1999, Week 5 March 1999, Week 4 March 1999, Week 3 March 1999, Week 2 March 1999, Week 1 February 1999, Week 4 February 1999, Week 3 February 1999, Week 2 February 1999, Week 1 January 1999, Week 5 January 1999, Week 4 January 1999, Week 3 January 1999, Week 2 January 1999, Week 1 December 1998, Week 5 December 1998, Week 4 December 1998, Week 3 December 1998, Week 2 December 1998, Week 1 November 1998, Week 5 November 1998, Week 4 November 1998, Week 3 November 1998, Week 2 November 1998, Week 1 October 1998, Week 5 October 1998, Week 4 October 1998, Week 3 October 1998, Week 2 October 1998, Week 1 September 1998, Week 5 September 1998, Week 4 September 1998, Week 3 September 1998, Week 2 September 1998, Week 1 August 1998, Week 5 August 1998, Week 4 August 1998, Week 3 August 1998, Week 2 August 1998, Week 1 July 1998, Week 5 July 1998, Week 4 July 1998, Week 3 July 1998, Week 2 July 1998, Week 1 June 1998, Week 5 June 1998, Week 4 June 1998, Week 3 June 1998, Week 2 June 1998, Week 1 May 1998, Week 5 May 1998, Week 4 May 1998, Week 3 May 1998, Week 2 May 1998, Week 1 April 1998, Week 5 April 1998, Week 4 April 1998, Week 3 April 1998, Week 2 April 1998, Week 1 March 1998, Week 5 March 1998, Week 4 March 1998, Week 3 March 1998, Week 2 March 1998, Week 1 February 1998, Week 5 February 1998, Week 4 February 1998, Week 3 February 1998, Week 2 February 1998, Week 1 January 1998, Week 5 January 1998, Week 4 January 1998, Week 3 January 1998, Week 2 January 1998, Week 1 December 1997, Week 5 December 1997, Week 4 December 1997, Week 3 December 1997, Week 2 December 1997, Week 1 November 1997, Week 5 November 1997, Week 4 November 1997, Week 3 November 1997, Week 2 November 1997, Week 1 October 1997, Week 5 October 1997, Week 4 October 1997, Week 3 October 1997, Week 2 October 1997, Week 1 September 1997, Week 5 September 1997, Week 4 September 1997, Week 3 September 1997, Week 2 September 1997, Week 1 August 1997, Week 5 August 1997, Week 4 August 1997, Week 3 August 1997, Week 2 August 1997, Week 1 July 1997, Week 5 July 1997, Week 4 July 1997, Week 3 July 1997, Week 2 July 1997, Week 1 June 1997, Week 5 June 1997, Week 4 June 1997, Week 3 June 1997, Week 2 June 1997, Week 1 May 1997, Week 5 May 1997, Week 4 May 1997, Week 3 May 1997, Week 2 May 1997, Week 1 April 1997, Week 5 April 1997, Week 4 April 1997, Week 3 April 1997, Week 2 April 1997, Week 1 March 1997, Week 5 March 1997, Week 4 March 1997, Week 3 March 1997, Week 2 March 1997, Week 1 February 1997, Week 5 February 1997, Week 4 February 1997, Week 3 February 1997, Week 2 February 1997, Week 1 January 1997, Week 5 January 1997, Week 4 January 1997, Week 3 January 1997, Week 2 January 1997, Week 1 December 1996, Week 5 December 1996, Week 4 December 1996, Week 3 December 1996, Week 2 December 1996, Week 1 November 1996, Week 5 November 1996, Week 4 November 1996, Week 3 November 1996, Week 2 November 1996, Week 1 October 1996, Week 5 October 1996, Week 4 October 1996, Week 3 October 1996, Week 2 October 1996, Week 1 September 1996, Week 5 September 1996, Week 4 September 1996, Week 3 September 1996, Week 2 September 1996, Week 1 August 1996, Week 5 August 1996, Week 4 August 1996, Week 3 August 1996, Week 2 August 1996, Week 1 July 1996, Week 5 July 1996, Week 4 July 1996, Week 3 July 1996, Week 2 July 1996, Week 1 June 1996, Week 5 June 1996, Week 4 June 1996, Week 3 June 1996, Week 2 June 1996, Week 1 May 1996, Week 5 May 1996, Week 4 May 1996, Week 3 May 1996, Week 2 May 1996, Week 1 April 1996, Week 5 April 1996, Week 4 April 1996, Week 3 April 1996, Week 2 April 1996, Week 1 March 1996, Week 5 March 1996, Week 4 March 1996, Week 3 March 1996, Week 2 March 1996, Week 1 February 1996, Week 5 February 1996, Week 4 February 1996, Week 3 February 1996, Week 2 February 1996, Week 1 January 1996, Week 5 January 1996, Week 4 January 1996, Week 3 January 1996, Week 2 January 1996, Week 1 December 1995, Week 5 December 1995, Week 4 December 1995, Week 3 December 1995, Week 2 December 1995, Week 1 November 1995, Week 5 November 1995, Week 4 November 1995, Week 3 November 1995, Week 2 November 1995, Week 1 October 1995, Week 5 October 1995, Week 4 October 1995, Week 3 October 1995, Week 2 October 1995, Week 1 September 1995, Week 5 September 1995, Week 4 September 1995, Week 3 September 1995, Week 2 September 1995, Week 1 August 1995, Week 5 August 1995, Week 4 August 1995, Week 3 August 1995, Week 2 August 1995, Week 1 July 1995, Week 5 July 1995, Week 4 July 1995, Week 3 July 1995, Week 2 July 1995, Week 1 June 1995, Week 5 June 1995, Week 4 June 1995, Week 3 June 1995, Week 2 June 1995, Week 1 May 1995, Week 5 May 1995, Week 4 May 1995, Week 3 May 1995, Week 2 May 1995, Week 1 April 1995, Week 5 April 1995, Week 4 April 1995, Week 3 April 1995, Week 2 April 1995, Week 1 March 1995, Week 5 March 1995, Week 4 March 1995, Week 3 March 1995, Week 2 March 1995, Week 1 February 1995, Week 4 February 1995, Week 3 February 1995, Week 2 February 1995, Week 1 January 1995, Week 5 January 1995, Week 4 January 1995, Week 3 January 1995, Week 2 January 1995, Week 1 December 1994, Week 5 December 1994, Week 4 December 1994, Week 3 December 1994, Week 2 December 1994, Week 1 November 1994, Week 5 November 1994, Week 4 November 1994, Week 3 November 1994, Week 2 November 1994, Week 1 October 1994, Week 5 October 1994, Week 4 October 1994, Week 3 October 1994, Week 2 October 1994, Week 1 September 1994, Week 5 September 1994, Week 4 September 1994, Week 3 September 1994, Week 2 September 1994, Week 1 August 1994, Week 5 August 1994, Week 4 August 1994, Week 3 August 1994, Week 2 August 1994, Week 1 July 1994, Week 5 July 1994, Week 4 July 1994, Week 3 July 1994, Week 2 July 1994, Week 1 June 1994, Week 5 June 1994, Week 4 June 1994, Week 3 June 1994, Week 2 June 1994, Week 1 May 1994, Week 5 May 1994, Week 4 May 1994, Week 3 May 1994, Week 2 May 1994, Week 1 April 1994, Week 5 April 1994, Week 4 April 1994, Week 3 April 1994, Week 2 April 1994, Week 1 March 1994, Week 5 March 1994, Week 4 March 1994, Week 3 March 1994, Week 2 March 1994, Week 1 February 1994, Week 4 February 1994, Week 3 February 1994, Week 2 February 1994, Week 1 February 1994 January 1994 December 1993 November 1993
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