|
PARKINSN Archives
|
PARKINSN@LISTSERV.UTORONTO.CA
|
|
|
|
Really out-of-the-box thinking, Greg! Hope someone out there is listening
and will take action..
Moneesha
On 07/07/2008, Greg Wasson <[log in to unmask]> wrote:
>
> Hi All,
>
> Has it occurred to anyone else that there may be an important pattern in
> the
> seemingly unbroken string of failures of very promising new PD therapies to
> make it past stage 2 clinical trials? In the GDNF trials, in the recently
> discontinued trials of Spheramine, in the Neuroimmunophilin Ligand trials a
> few
> years back, in fact in the forty years since the development of the gold
> standard of carbidopa/levodopa, there have been a remarkable number of
> trials
> that appeared to have dramatic results on patients in early clinical stages
> but
> subsequently failed to meet statistical endpoints in placebo-controlled
> double-blind phase 2 trials.
>
> Could anyone who had seen PWP Peggy Willocks in 2000 before her Spheramine
> surgery doubt in any way that her surgery had a dramatic and lasting
> positive
> effect on her ability to function. Does anyone doubt that the film of some
> of
> the GDNF clinical trial participants before and after receiving that
> biologic
> showed clearly that some of them responded in a way that could not be
> attributable to a placebo response?
>
> Could it possibly be that some patients are legitimately responding in a
> dramatic fashion to these experimental therapies, while others are not,
> regardless of the presence of placebo controls? Is it possible that the
> reason
> for these apparently topsy-turvy, now-you-see-it-now-you-don't results are
> themselves the result of clinical trials which are fundamentally flawed in
> their design. That is, if "idiopathic Parkinson's disease" is in fact a
> bundle
> of related diseases as has been increasingly discussed, and may well be a
> disease, or diseases, which affects many more parts of the brain than had
> traditionally been assumed, it may well be that it's not the data that is
> wrong
> in recent clinical trials, it is the square peg of data which scientists
> are
> trying to fit the into what they refuse to recognize as the round hole of
> current clinical trial design.
>
> A child can see that the symptoms from patient to patient very so
> dramatically
> that one would intuitively assume that he or she was looking at different
> diseases. How do we make the leap to the assumption that despite the
> evidence
> of our eyes, we all have (with rare exceptions) "idiopathic Parkinson's
> disease"? It is rather ironic that this so-called "designer disease" can
> only
> be diagnosed through clinical observation. Clinical observation alone would
> lead the average person to assume that more than one disease, or form of
> the
> disease, is present in the population. But since the discovery that
> carbidopa/levodopa dramatically ameliorates the symptoms of PD in almost
> all
> patients regardless of their presenting symptoms, and because we can detect
> a
> dramatic loss of dopaminergic cells in "PD" patients through brain scans
> and at
> autopsy, we leap to the conclusion that we all suffer from the exact same
> malady.
>
> It seems to me that the existence of several variants on what we call one
> disease would explain the varying results or effects on patients with
> regard to
> new experimental therapies. We know so little about the disease in the
> larger
> sense that we even call it "idiopathic," meaning of unknown origin.
> Remember,
> only a few short years ago, even a movement disorder specialist would have
> told
> you that Parkinson's, in an oft-repeated comparison, was the disease that
> left
> your mind clear while trapping you in a body that would eventually lave you
> completely immobilized, while Alzheimer's was the disease that destroyed
> your
> mind while leaving your body intact. I don't think that any movement
> disorder
> specialist worth his or her credentials would make that same statement
> today
> about Parkinson's disease. We know that it affects frontal cortex to some
> degree in almost every patient. And it appears to affect other areas of the
> brain as well. Could it be that we have been so mesmerized for the last 190
> years by the massive and dramatically observable destruction that
> Parkinson's
> does to the portion of the brain devoted to movement that we failed to
> recognize what in hindsight should have been obvious secondary symptoms of
> the
> disease or a set of related diseases?
>
> We all know that a new paradigm of Parkinson's disease is emerging that in
> some
> ways is consistent with the view of Parkinson's I have described above.
> What we
> will finally learn about Parkinson's and its causes, and the dramatic
> variance
> of symptom constellations among individual patients, remains to be seen.
> But I
> think that it's time to take a good hard look at clinical trials and their
> results in light of this emerging new view of what we had assumed was a
> single
> disease. If Parkinson's is indeed a cluster of related diseases it would
> make
> sense that some therapeutic applications would work for all or nearly all
> of
> the patient population, such as carbidopa/levodopa. It would also make
> sense
> that certain dopamine agonists would work among a large portion of the
> population, but leave a significant minority of patients unaffected or with
> a
> negative response to the therapy.
>
> Perhaps most importantly, it would explain why year after year, decade
> after
> decade, we have been getting to large phase 2 trials and winding up with
> statistical endpoints that may in fact be unachievable for most therapeutic
> applications because only certain patients with certain variants of the
> disease
> are going to respond. It may be that bad trial management in some cases
> (disconnected catheters and poor infusion techniques in the GDNF trials)
> and
> placebo effect itself are "noise" that interferes with a proper
> interpretation
> of what these drugs are doing to patients. A proper interpretation of this
> pattern of clinical trial failures may mean having to conclude that the
> trial
> design itself is based on the false premise that we all have the same
> variant
> of the same disease.
>
> As PWP and Intel founder Andy Grove has asked, why aren't we learning from
> our
> failures? Why do we keep coming at the same problem from the same position
> with
> the same set of assumptions? Why don't we at least entertain the notion
> that
> the way we test new therapies is inconsistent with the disease, or
> diseases,
> that we are trying to cure. In fact, one would almost think that the
> refusal to
> budge from the current thinking about Parkinson's clinical trials reflects
> some
> of the cognitive damage that Parkinson's does in the tendency of patients
> to
> exhibit a stubborn inability to move from one approach to another. All the
> while, we may be throwing away the baby with the bathwater, as therapy
> after
> therapy that may in fact address major problems for some of the patient
> population, are deemed to be failures and tossed aside. If so, it is a
> mistake
> of gigantic proportions, and one which has tremendous significance for us
> all.
>
> I hope I haven't stated the obvious, or shown my ignorance of clinical
> trial
> design and biomedical science, but when I advanced this idea at a PD
> meeting
> two weeks ago, I looked across the room at a top British neuroscientist who
> nodded his head "yes" the entire time I was speaking. Interestingly,
> however,
> he remained silent.
>
> Just thinking out loud,
>
> Greg
>
> ----------------------------------------------------------------------
> To sign-off Parkinsn send a message to: mailto:
> [log in to unmask]
> In the body of the message put: signoff parkinsn
>
----------------------------------------------------------------------
To sign-off Parkinsn send a message to: mailto:[log in to unmask]
In the body of the message put: signoff parkinsn
|
|
|
|
|
Archives |
March 2024, Week 4 January 2022, Week 4 November 2021, Week 4 February 2021, Week 2 December 2020, Week 2 October 2020, Week 4 June 2020, Week 4 May 2020, Week 2 May 2020, Week 1 April 2020, Week 5 April 2020, Week 1 March 2020, Week 5 March 2020, Week 4 March 2020, Week 2 March 2020, Week 1 February 2020, Week 4 February 2020, Week 3 February 2020, Week 1 January 2020, Week 5 January 2020, Week 2 October 2019, Week 1 September 2019, Week 5 September 2019, Week 3 July 2019, Week 1 June 2019, Week 5 June 2019, Week 4 June 2019, Week 3 June 2019, Week 1 April 2019, Week 5 April 2019, Week 4 April 2019, Week 2 March 2019, Week 5 March 2019, Week 3 March 2019, Week 2 March 2019, Week 1 February 2019, Week 4 January 2019, Week 3 January 2019, Week 2 January 2019, Week 1 December 2018, Week 5 December 2018, Week 4 December 2018, Week 2 November 2018, Week 3 November 2018, Week 2 November 2018, Week 1 October 2018, Week 4 October 2018, Week 3 October 2018, Week 1 September 2018, Week 4 September 2018, Week 3 August 2018, Week 4 August 2018, Week 3 August 2018, Week 1 July 2018, Week 4 July 2018, Week 3 July 2018, Week 2 July 2018, Week 1 June 2018, Week 5 June 2018, Week 3 June 2018, Week 1 May 2018, Week 5 May 2018, Week 4 May 2018, Week 3 May 2018, Week 2 May 2018, Week 1 April 2018, Week 4 April 2018, Week 3 April 2018, Week 2 February 2018, Week 3 January 2018, Week 5 January 2018, Week 2 January 2018, Week 1 December 2017, Week 4 December 2017, Week 3 December 2017, Week 1 November 2017, Week 5 November 2017, Week 4 November 2017, Week 3 November 2017, Week 2 November 2017, Week 1 October 2017, Week 4 October 2017, Week 2 October 2017, Week 1 September 2017, Week 5 September 2017, Week 4 September 2017, Week 3 September 2017, Week 2 September 2017, Week 1 August 2017, Week 4 August 2017, Week 2 August 2017, Week 1 July 2017, Week 5 July 2017, Week 4 July 2017, Week 3 July 2017, Week 2 July 2017, Week 1 June 2017, Week 5 June 2017, Week 4 June 2017, Week 3 June 2017, Week 2 June 2017, Week 1 May 2017, Week 5 May 2017, Week 4 May 2017, Week 3 May 2017, Week 2 May 2017, Week 1 April 2017, Week 3 April 2017, Week 2 April 2017, Week 1 March 2017, Week 4 March 2017, Week 3 March 2017, Week 2 March 2017, Week 1 February 2017, Week 3 February 2017, Week 2 February 2017, Week 1 January 2017, Week 4 January 2017, Week 2 January 2017, Week 1 December 2016, Week 5 December 2016, Week 4 December 2016, Week 2 December 2016, Week 1 November 2016, Week 4 November 2016, Week 3 November 2016, Week 2 November 2016, Week 1 October 2016, Week 4 October 2016, Week 3 October 2016, Week 1 September 2016, Week 3 September 2016, Week 2 September 2016, Week 1 August 2016, Week 4 July 2016, Week 5 July 2016, Week 4 July 2016, Week 3 July 2016, Week 2 July 2016, Week 1 June 2016, Week 5 June 2016, Week 3 June 2016, Week 2 June 2016, Week 1 May 2016, Week 5 May 2016, Week 4 May 2016, Week 3 May 2016, Week 2 May 2016, Week 1 April 2016, Week 5 April 2016, Week 4 April 2016, Week 3 April 2016, Week 2 April 2016, Week 1 March 2016, Week 5 March 2016, Week 4 March 2016, Week 3 March 2016, Week 2 March 2016, Week 1 February 2016, Week 5 February 2016, Week 4 February 2016, Week 3 February 2016, Week 2 February 2016, Week 1 January 2016, Week 5 January 2016, Week 4 January 2016, Week 3 January 2016, Week 2 January 2016, Week 1 December 2015, Week 5 December 2015, Week 4 December 2015, Week 3 December 2015, Week 2 December 2015, Week 1 November 2015, Week 5 November 2015, Week 3 November 2015, Week 2 November 2015, Week 1 October 2015, Week 5 October 2015, Week 4 October 2015, Week 3 October 2015, Week 2 October 2015, Week 1 September 2015, Week 5 September 2015, Week 4 September 2015, Week 3 September 2015, Week 2 September 2015, Week 1 August 2015, Week 5 August 2015, Week 4 August 2015, Week 3 August 2015, Week 2 August 2015, Week 1 July 2015, Week 5 July 2015, Week 4 July 2015, Week 3 July 2015, Week 2 July 2015, Week 1 June 2015, Week 5 June 2015, Week 4 June 2015, Week 3 June 2015, Week 2 June 2015, Week 1 May 2015, Week 5 May 2015, Week 4 May 2015, Week 3 May 2015, Week 2 May 2015, Week 1 April 2015, Week 4 April 2015, Week 3 April 2015, Week 2 April 2015, Week 1 March 2015, Week 5 March 2015, Week 4 March 2015, Week 3 March 2015, Week 2 March 2015, Week 1 February 2015, Week 4 February 2015, Week 3 February 2015, Week 2 February 2015, Week 1 January 2015, Week 5 January 2015, Week 4 January 2015, Week 3 January 2015, Week 2 December 2014, Week 5 December 2014, Week 4 December 2014, Week 3 December 2014, Week 2 December 2014, Week 1 November 2014, Week 5 November 2014, Week 4 November 2014, Week 3 November 2014, Week 2 November 2014, Week 1 October 2014, Week 5 October 2014, Week 4 October 2014, Week 3 October 2014, Week 2 October 2014, Week 1 September 2014, Week 5 September 2014, Week 4 September 2014, Week 3 September 2014, Week 2 September 2014, Week 1 August 2014, Week 5 August 2014, Week 4 August 2014, Week 3 August 2014, Week 2 August 2014, Week 1 July 2014, Week 5 July 2014, Week 4 July 2014, Week 3 July 2014, Week 2 July 2014, Week 1 June 2014, Week 5 June 2014, Week 4 June 2014, Week 3 June 2014, Week 2 June 2014, Week 1 May 2014, Week 4 May 2014, Week 3 May 2014, Week 2 May 2014, Week 1 April 2014, Week 5 April 2014, Week 4 April 2014, Week 3 April 2014, Week 2 April 2014, Week 1 March 2014, Week 5 March 2014, Week 4 March 2014, Week 3 March 2014, Week 2 March 2014, Week 1 February 2014, Week 4 February 2014, Week 3 February 2014, Week 2 February 2014, Week 1 January 2014, Week 5 January 2014, Week 4 January 2014, Week 3 January 2014, Week 2 January 2014, Week 1 December 2013, Week 5 December 2013, Week 4 December 2013, Week 3 December 2013, Week 2 December 2013, Week 1 November 2013, Week 4 November 2013, Week 3 November 2013, Week 2 November 2013, Week 1 October 2013, Week 5 October 2013, Week 4 October 2013, Week 3 October 2013, Week 2 October 2013, Week 1 September 2013, Week 5 September 2013, Week 4 September 2013, Week 3 September 2013, Week 2 September 2013, Week 1 August 2013, Week 5 August 2013, Week 4 August 2013, Week 3 August 2013, Week 2 August 2013, Week 1 July 2013, Week 5 July 2013, Week 4 July 2013, Week 3 July 2013, Week 2 July 2013, Week 1 June 2013, Week 5 June 2013, Week 4 June 2013, Week 3 June 2013, Week 2 June 2013, Week 1 May 2013, Week 5 May 2013, Week 4 May 2013, Week 3 May 2013, Week 2 May 2013, Week 1 April 2013, Week 5 April 2013, Week 4 April 2013, Week 3 April 2013, Week 2 April 2013, Week 1 March 2013, Week 5 March 2013, Week 4 March 2013, Week 3 March 2013, Week 2 March 2013, Week 1 February 2013, Week 4 February 2013, Week 3 February 2013, Week 2 February 2013, Week 1 January 2013, Week 5 January 2013, Week 3 January 2013, Week 2 January 2013, Week 1 December 2012, Week 5 December 2012, Week 4 December 2012, Week 3 December 2012, Week 2 December 2012, Week 1 November 2012, Week 5 November 2012, Week 3 November 2012, Week 2 November 2012, Week 1 October 2012, Week 5 October 2012, Week 4 October 2012, Week 3 October 2012, Week 2 October 2012, Week 1 September 2012, Week 5 September 2012, Week 4 September 2012, Week 3 September 2012, Week 2 September 2012, Week 1 August 2012, Week 5 August 2012, Week 4 August 2012, Week 3 August 2012, Week 2 August 2012, Week 1 July 2012, Week 5 July 2012, Week 4 July 2012, Week 3 July 2012, Week 2 July 2012, Week 1 June 2012, Week 5 June 2012, Week 4 June 2012, Week 3 June 2012, Week 2 June 2012, Week 1 May 2012, Week 5 May 2012, Week 4 May 2012, Week 3 May 2012, Week 2 May 2012, Week 1 April 2012, Week 5 April 2012, Week 4 April 2012, Week 3 April 2012, Week 2 April 2012, Week 1 March 2012, Week 5 March 2012, Week 4 March 2012, Week 3 March 2012, Week 2 March 2012, Week 1 February 2012, Week 5 February 2012, Week 4 February 2012, Week 3 February 2012, Week 2 February 2012, Week 1 January 2012, Week 5 January 2012, Week 4 January 2012, Week 3 January 2012, Week 2 January 2012, Week 1 December 2011, Week 5 December 2011, Week 4 December 2011, Week 3 December 2011, Week 2 December 2011, Week 1 November 2011, Week 5 November 2011, Week 4 November 2011, Week 3 November 2011, Week 2 November 2011, Week 1 October 2011, Week 5 October 2011, Week 4 October 2011, Week 3 October 2011, Week 2 October 2011, Week 1 September 2011, Week 5 September 2011, Week 4 September 2011, Week 3 September 2011, Week 2 September 2011, Week 1 August 2011, Week 5 August 2011, Week 4 August 2011, Week 3 August 2011, Week 2 August 2011, Week 1 July 2011, Week 5 July 2011, Week 4 July 2011, Week 3 July 2011, Week 2 July 2011, Week 1 June 2011, Week 5 June 2011, Week 4 June 2011, Week 3 June 2011, Week 2 June 2011, Week 1 May 2011, Week 5 May 2011, Week 4 May 2011, Week 3 May 2011, Week 2 May 2011, Week 1 April 2011, Week 5 April 2011, Week 4 April 2011, Week 3 April 2011, Week 2 April 2011, Week 1 March 2011, Week 5 March 2011, Week 4 March 2011, Week 3 March 2011, Week 2 March 2011, Week 1 February 2011, Week 4 February 2011, Week 3 February 2011, Week 2 February 2011, Week 1 January 2011, Week 5 January 2011, Week 4 January 2011, Week 3 January 2011, Week 2 January 2011, Week 1 December 2010, Week 5 December 2010, Week 4 December 2010, Week 3 December 2010, Week 2 December 2010, Week 1 November 2010, Week 5 November 2010, Week 4 November 2010, Week 3 November 2010, Week 2 November 2010, Week 1 October 2010, Week 5 October 2010, Week 4 October 2010, Week 3 October 2010, Week 2 October 2010, Week 1 September 2010, Week 5 September 2010, Week 4 September 2010, Week 3 September 2010, Week 2 September 2010, Week 1 August 2010, Week 5 August 2010, Week 4 August 2010, Week 3 August 2010, Week 2 August 2010, Week 1 July 2010, Week 5 July 2010, Week 4 July 2010, Week 3 July 2010, Week 2 July 2010, Week 1 June 2010, Week 5 June 2010, Week 4 June 2010, Week 3 June 2010, Week 2 June 2010, Week 1 May 2010, Week 5 May 2010, Week 4 May 2010, Week 3 May 2010, Week 2 May 2010, Week 1 April 2010, Week 5 April 2010, Week 4 April 2010, Week 3 April 2010, Week 2 April 2010, Week 1 March 2010, Week 5 March 2010, Week 4 March 2010, Week 3 March 2010, Week 2 March 2010, Week 1 February 2010, Week 4 February 2010, Week 3 February 2010, Week 2 February 2010, Week 1 January 2010, Week 5 January 2010, Week 4 January 2010, Week 3 January 2010, Week 2 January 2010, Week 1 December 2009, Week 5 December 2009, Week 4 December 2009, Week 3 December 2009, Week 2 December 2009, Week 1 November 2009, Week 5 November 2009, Week 4 November 2009, Week 3 November 2009, Week 2 November 2009, Week 1 October 2009, Week 5 October 2009, Week 4 October 2009, Week 3 October 2009, Week 2 October 2009, Week 1 September 2009, Week 5 September 2009, Week 4 September 2009, Week 3 September 2009, Week 2 September 2009, Week 1 August 2009, Week 5 August 2009, Week 4 August 2009, Week 3 August 2009, Week 2 August 2009, Week 1 July 2009, Week 5 July 2009, Week 4 July 2009, Week 3 July 2009, Week 2 July 2009, Week 1 June 2009, Week 5 June 2009, Week 4 June 2009, Week 3 June 2009, Week 2 June 2009, Week 1 May 2009, Week 5 May 2009, Week 4 May 2009, Week 3 May 2009, Week 2 May 2009, Week 1 April 2009, Week 5 April 2009, Week 4 April 2009, Week 3 April 2009, Week 2 April 2009, Week 1 March 2009, Week 5 March 2009, Week 4 March 2009, Week 3 March 2009, Week 2 March 2009, Week 1 February 2009, Week 4 February 2009, Week 3 February 2009, Week 2 February 2009, Week 1 January 2009, Week 5 January 2009, Week 4 January 2009, Week 3 January 2009, Week 2 January 2009, Week 1 December 2008, Week 5 December 2008, Week 4 December 2008, Week 3 December 2008, Week 2 December 2008, Week 1 November 2008, Week 5 November 2008, Week 4 November 2008, Week 3 November 2008, Week 2 November 2008, Week 1 October 2008, Week 5 October 2008, Week 4 October 2008, Week 3 October 2008, Week 2 October 2008, Week 1 September 2008, Week 5 September 2008, Week 4 September 2008, Week 3 September 2008, Week 2 September 2008, Week 1 August 2008, Week 5 August 2008, Week 4 August 2008, Week 3 August 2008, Week 2 August 2008, Week 1 July 2008, Week 5 July 2008, Week 4 July 2008, Week 3 July 2008, Week 2 July 2008, Week 1 June 2008, Week 5 June 2008, Week 4 June 2008, Week 3 June 2008, Week 2 June 2008, Week 1 May 2008, Week 5 May 2008, Week 4 May 2008, Week 3 May 2008, Week 2 May 2008, Week 1 April 2008, Week 5 April 2008, Week 4 April 2008, Week 3 April 2008, Week 2 April 2008, Week 1 March 2008, Week 5 March 2008, Week 4 March 2008, Week 3 March 2008, Week 2 March 2008, Week 1 February 2008, Week 5 February 2008, Week 4 February 2008, Week 3 February 2008, Week 2 February 2008, Week 1 January 2008, Week 5 January 2008, Week 4 January 2008, Week 3 January 2008, Week 2 January 2008, Week 1 December 2007, Week 5 December 2007, Week 4 December 2007, Week 3 December 2007, Week 2 December 2007, Week 1 November 2007, Week 5 November 2007, Week 4 November 2007, Week 3 November 2007, Week 2 November 2007, Week 1 October 2007, Week 5 October 2007, Week 4 October 2007, Week 3 October 2007, Week 2 October 2007, Week 1 September 2007, Week 5 September 2007, Week 4 September 2007, Week 3 September 2007, Week 2 September 2007, Week 1 August 2007, Week 5 August 2007, Week 4 August 2007, Week 3 August 2007, Week 2 August 2007, Week 1 July 2007, Week 5 July 2007, Week 4 July 2007, Week 3 July 2007, Week 2 July 2007, Week 1 June 2007, Week 5 June 2007, Week 4 June 2007, Week 3 June 2007, Week 2 June 2007, Week 1 May 2007, Week 5 May 2007, Week 4 May 2007, Week 3 May 2007, Week 2 May 2007, Week 1 April 2007, Week 5 April 2007, Week 4 April 2007, Week 3 April 2007, Week 2 April 2007, Week 1 March 2007, Week 5 March 2007, Week 4 March 2007, Week 3 March 2007, Week 2 March 2007, Week 1 February 2007, Week 4 February 2007, Week 3 February 2007, Week 2 February 2007, Week 1 January 2007, Week 5 January 2007, Week 4 January 2007, Week 3 January 2007, Week 2 January 2007, Week 1 December 2006, Week 5 December 2006, Week 4 December 2006, Week 3 December 2006, Week 2 December 2006, Week 1 November 2006, Week 5 November 2006, Week 4 November 2006, Week 3 November 2006, Week 2 November 2006, Week 1 October 2006, Week 5 October 2006, Week 4 October 2006, Week 3 October 2006, Week 2 October 2006, Week 1 September 2006, Week 5 September 2006, Week 4 September 2006, Week 3 September 2006, Week 2 September 2006, Week 1 August 2006, Week 5 August 2006, Week 4 August 2006, Week 3 August 2006, Week 2 August 2006, Week 1 July 2006, Week 5 July 2006, Week 4 July 2006, Week 3 July 2006, Week 2 July 2006, Week 1 June 2006, Week 5 June 2006, Week 4 June 2006, Week 3 June 2006, Week 2 June 2006, Week 1 May 2006, Week 5 May 2006, Week 4 May 2006, Week 3 May 2006, Week 2 May 2006, Week 1 April 2006, Week 5 April 2006, Week 4 April 2006, Week 3 April 2006, Week 2 April 2006, Week 1 March 2006, Week 5 March 2006, Week 4 March 2006, Week 3 March 2006, Week 2 March 2006, Week 1 February 2006, Week 4 February 2006, Week 3 February 2006, Week 2 February 2006, Week 1 January 2006, Week 5 January 2006, Week 4 January 2006, Week 3 January 2006, Week 2 January 2006, Week 1 December 2005, Week 5 December 2005, Week 4 December 2005, Week 3 December 2005, Week 2 December 2005, Week 1 November 2005, Week 5 November 2005, Week 4 November 2005, Week 3 November 2005, Week 2 November 2005, Week 1 October 2005, Week 5 October 2005, Week 4 October 2005, Week 3 October 2005, Week 2 October 2005, Week 1 September 2005, Week 5 September 2005, Week 4 September 2005, Week 3 September 2005, Week 2 September 2005, Week 1 August 2005, Week 5 August 2005, Week 4 August 2005, Week 3 August 2005, Week 2 August 2005, Week 1 July 2005, Week 5 July 2005, Week 4 July 2005, Week 3 July 2005, Week 2 July 2005, Week 1 June 2005, Week 5 June 2005, Week 4 June 2005, Week 3 June 2005, Week 2 June 2005, Week 1 May 2005, Week 5 May 2005, Week 4 May 2005, Week 3 May 2005, Week 2 May 2005, Week 1 April 2005, Week 5 April 2005, Week 4 April 2005, Week 3 April 2005, Week 2 April 2005, Week 1 March 2005, Week 5 March 2005, Week 4 March 2005, Week 3 March 2005, Week 2 March 2005, Week 1 February 2005, Week 4 February 2005, Week 3 February 2005, Week 2 February 2005, Week 1 January 2005, Week 5 January 2005, Week 4 January 2005, Week 3 January 2005, Week 2 January 2005, Week 1 December 2004, Week 5 December 2004, Week 4 December 2004, Week 3 December 2004, Week 2 December 2004, Week 1 November 2004, Week 5 November 2004, Week 4 November 2004, Week 3 November 2004, Week 2 November 2004, Week 1 October 2004, Week 5 October 2004, Week 4 October 2004, Week 3 October 2004, Week 2 October 2004, Week 1 September 2004, Week 5 September 2004, Week 4 September 2004, Week 3 September 2004, Week 2 September 2004, Week 1 August 2004, Week 5 August 2004, Week 4 August 2004, Week 3 August 2004, Week 2 August 2004, Week 1 July 2004, Week 5 July 2004, Week 4 July 2004, Week 3 July 2004, Week 2 July 2004, Week 1 June 2004, Week 5 June 2004, Week 4 June 2004, Week 3 June 2004, Week 2 June 2004, Week 1 May 2004, Week 5 May 2004, Week 4 May 2004, Week 3 May 2004, Week 2 May 2004, Week 1 April 2004, Week 5 April 2004, Week 4 April 2004, Week 3 April 2004, Week 2 April 2004, Week 1 March 2004, Week 5 March 2004, Week 4 March 2004, Week 3 March 2004, Week 2 March 2004, Week 1 February 2004, Week 5 February 2004, Week 4 February 2004, Week 3 February 2004, Week 2 February 2004, Week 1 January 2004, Week 5 January 2004, Week 4 January 2004, Week 3 January 2004, Week 2 January 2004, Week 1 December 2003, Week 5 December 2003, Week 4 December 2003, Week 3 December 2003, Week 2 December 2003, Week 1 November 2003, Week 5 November 2003, Week 4 November 2003, Week 3 November 2003, Week 2 November 2003, Week 1 October 2003, Week 5 October 2003, Week 4 October 2003, Week 3 October 2003, Week 2 October 2003, Week 1 September 2003, Week 5 September 2003, Week 4 September 2003, Week 3 September 2003, Week 2 September 2003, Week 1 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
|
|
|
|