10 October 2006
I WON'T BE BEATEN BY PARKINSON'S
EX-CHAMPION BODYBUILDER IS LIFTING WEIGHTS AGAIN AFTER 15 YEARS THANKS TO REVOLUTIONARY COMPUTERISED DRUG BELT
By Samantha Booth

A FORMER champion body builder, who was crippled by Parkinson's disease for 15 years, has had his life transformed by pioneering treatment.

Fitness fanatic Michael Thompson, 59, won Mr Inverclyde and Mr East of Scotland titles until he was struck down by Parkinson's at the age of 44.

Crippled and confined to a wheelchair by the age of 57, Michael's once active life was destroyed by the disease.

But now, after receiving the groundbreaking drug Apomorphine, Michael is back lifting weights again.

He hopes his experience can help lead to a major breakthrough for thousands of other sufferers.

Parkinson's disease, which affects one in 500 people across Britain, had left the former champion bodybuilder suffering from uncontrollable tremors.

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But after becoming only one of a handful of people across the UK to try a pioneering treatment, Michael is walking - and even lifting weights.

Michael, of Greenock, has a special pump on a belt around his waist which gradually releases a drug into his stomach to control his tremors.

Parkinson's has been had a high profile in recent years with celebrities such as Muhammad Ali and Michael J. Fox among the four million sufferers.

After an agonising 13 years of suffering, Michael's doctor recommended Apomorphine two years ago.

Parkinson's is a progressive neurological condition caused by the death of nerve cells in the base of the brain, called neurons.

These nerves usually produce a chemical called dopamine that is used by the movement centres of the brain to maintain smooth and fluid movement, and as Parkinson's disease progresses, they slowly degenerate or die off.

The brain loses its ability to produce dopamine, causing sufferers to lose control of their body and muscle movement.

They experience uncontrollable shaking, stiffness in the limbs and slowness of movement.

Apomorphine is often given to sufferers who have had Parkinson's for 10 to 15 years, when tablets no longer work.

The drug does not cure the disease but controls the shaking and stiffness by imitating the action of dopamine and helping the brain transmit signals to control body movements.

It can be used either as an intermittent injection to manage temporary lapses in control of the condition, or, as in Michael's case, by continuous infusion through a computerised pump.

The drug was discovered in the Fifties, but it was not until the Eighties that it was used both in the diagnosis and treatment of Parkinson's. It has only been used for continuous infusion in recent years using the computerised pump.

After initially getting a specialist nurse to fit the pump every morning, Michael's wife Elizabeth, 60, now does it herself.

She gives Michael a four mg dose of the drug every morning through a syringe which is fitted to the pump. The pump is connected to a line which is inserted into the skin on his stomach.

The computerised device, tied around Michael's waist, gradually releases the drug into his body over the next 12 hours.

Dr Roger Barker, an expert on Parkinson's disease from Cambridge University, said the drug was only used when other treatments were no longer controlling the condition.

But he stressed Apomorphine was not a cure, simply a way of managing the symptoms. "The disease will carry on progressing, and most people will find several years into the treatment that they will start to break down again," he said.

"They will usually get a few good years and then move on to whatever drug is available next. They will stay on it until the drug is not working any longer, or they start getting side effects."

Potential side effects include confusion, skin irritation or feeling sick or faint.

Elizabeth said: "I don't want people to think Michael has been cured because he hasn't. He still has Parkinson's disease. This is just a way of managing it.

"Every morning, he can hardly move at all until I give him the drug. Once I have put it into the pump, it takes half an hour to an hour for it to kick in, and then he is much better for the rest of the day.

"At night, he can lie in bed hardly able to move at all."

But Michael is delighted at the improvement. Before he received the treatment, people often thought he was drunk when he fell down in the street.

One day, when he was out with his four-year-old granddaughter, Michael was shocked to be accused of being drunk.

He said: "One guy said to me: 'That is ridiculous. You in charge of a little girl when you are drunk'.

"I replied: 'You're wrong. I suffer from Parkinson's'. It is amazing how many people can be cruel and think that you are drunk."

Elizabeth struggled to look after Michael as his symptoms became worse. She said: "Since he started on the pump, I have noticed a great difference in Michael.

"The nurses wish they had taken a video of Michael before he got this pump to compare it to how he is now. I hope other people will get to know about this drug and it can help them too."

Although he will never be cured, the drug has given Michael a new lease of life.

"Now I am able to go back to the gym to train, but I am only allowed to go with a carer," he said. "They won't let me go back in on my own.

"When I get the pump put in each the morning it takes 30 minutes to an hour for it to work. After that, I don't even notice it for the rest of the day. Now I don't fall down in the street anymore."

Is the delivery system approved in the US? It took the drug longer - I think the delivery would have to be appro0ved too. Sounds very promising delivered that way.

thanks zf.
paula

Can't answer your question yet, Paula. But this is interesting:

J Neurol Neurosurg Psychiatry 1998;64:573-576 ( May )

Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson's disease
A Colzi, K Turner, A J Lees

Received 24 July 1997 and in revised form 22 October 1997; Accepted 23 October 1997

OBJECTIVES---To determine whether continous waking day dopaminergic stimulation with the dopamine agonist apomorphine can reduce levodopa induced dyskinesias in Parkinson's disease
METHODS---19 patients with severe unpredictable refractory motor fluctuations and functionally disabling levodopa induced dyskinesias were treated with continuous subcutaneoius apomorphine monotherapy for a minimum duration of 2.7 years


RESULTS---A mean 65% reduction in dyskinetic severity and a mean 85% reduction in frequency and duration occurred. On discontinuing levodopa a concomitant reduction in off period time was also seen (35% of waking day "off" reduced to 10%)


CONCLUSION---Continuous waking day dopaminergic stimulation with apomorphine reset the threshold for dyskinesias and led to a pronounced reduction in their frequency.

Apomorphine should be considered as a less invasive alternative to pallidotomy or deep cerebral stimulation in controlling levodopa induced interdose dose dyskinesias.

Apomorphine: An underutilized therapy for Parkinson's disease
Werner Poewe, MD *, Gregor K. Wenning, MD, PhD
Department of Neurology, University Hospital Innsbruck, Innsbruck, Austria

Abstract

Apomorphine was the first dopaminergic drug ever used to treat symptoms of Parkinson's disease. While powerful antiparkinsonian effects had been observed as early as 1951, the potential of treating fluctuating Parkinson's disease by subcutaneous administration of apomorphine has only recently become the subject of systematic study.

A number of small scale clinical trials have unequivocally shown that intermittent subcutaneous apomorphine injections produce antiparkinsonian benefit close if not identical to that seen with levodopa and that apomorphine rescue injections can reliably revert off-periods even in patients with complex on-off motor swings.

Continuous subcutaneous apomorphine infusions can reduce daily off-time by more than 50% in this group of patients, which appears to be a stronger effect than that generally seen with add-on therapy with oral dopamine agonists or COMT inhibitors. Extended follow-up studies of up to 8 years have demonstrated long-term persistence of apomorphine efficacy.

In addition, there is convincing clinical evidence that monotherapy with continuous subcutaneous apomorphine infusions is associated with marked reductions of preexisting levodopa-induced dyskinesias.

The main side effects of subcutaneous apomorphine treatment are related to cutaneous tolerability problems, whereas sedation and psychiatric complications play a lesser role. Given the marked degree of efficacy of subcutaneous apomorphine treatment in fluctuating Parkinson's disease, this approach seems to deserve more widespread clinical use.

Received: 7 January 2000; Accepted: 29 March 2000

Research Article
Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: A prospective study using single-dose challenges
Regina Katzenschlager, MD 1 2 3, Andrew Hughes,

Abstract

Continuous subcutaneous (SC) infusion of the dopamine agonist apomorphine was shown in retrospective studies to improve drug-induced dyskinesias in Parkinson's disease (PD).

We prospectively assessed the antidyskinetic effect of continuous SC apomorphine therapy using subjective and objective measures, and sought to determine whether any observed dyskinesia reduction could be corroborated using single-dose dopaminergic challenges.

Twelve PD patients with on-off fluctuations and disabling dyskinesias who were scheduled to start apomorphine pump treatment underwent acute levodopa and apomorphine challenges at baseline and 6 months later.

Video recordings involving motor tasks were rated blindly by two independent raters using modified AIMS and Goetz dyskinesia scales. At 6 months, mean apomorphine dose was 75.2 mg per day and the mean l-dopa dose had been reduced by 55%. Daily off time in patients' diaries was reduced by 38% (2.4 hours).

The l-dopa challenges showed a reduction of 44% in AIMS and 40% in Goetz scores (both P < 0.01). Apomorphine challenges showed a reduction of 39% in AIMS and 36% in Goetz scores (both P < 0.01).

Patients' self-assessment scores reflected these significant changes. Dyskinesia improvement correlated with reduction in oral medication and with the final apomorphine dose (P < 0.05).

This prospective study confirms marked dyskinesia reduction on continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests.

Our findings support the concept that replacement of short-acting oral antiparkinsonian medication with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesias in PD. © 2004 Movement Disorder Society
Received: 5 January 2003; Revised: 7 April 2004; Accepted: 25 April 2004

Magnetic Resonance Imaging
Volume 24, Issue 4 , May 2006, Pages 419-424

Research article

A cluster-based quantitative procedure in an fMRI study of Parkinson's disease

Maria Antonietta Macrìa, b, c, Girolamo Garreffab, c, d, Federico Gioveb, c, e, Marta Moraschib, c, e, Giovanni Giuliettib, c, e, Nicola Modugnod, Claudio Colonnesed and Bruno Maravigliab, c, e,


Received 2 December 2005; accepted 2 December 2005. Available online 13 March 2006.


Abstract

Parkinson's disease is a neurological disorder associated with disfunction of dopaminergic pathways of the basal ganglia. In this study, we report the effects of decreasing plasma concentrations of the dopamine-agonist apomorphine on the size and extents of activity clusters observed with functional magnetic resonance imaging during a simple motor task.

Eight patients at advanced disease stage and six healthy volunteers were studied during four consecutive sessions. We observed consistent activations in the primary sensorimotor area of the contralateral side and in the supplementary motor area of both patients and controls during the first session.

During subsequent sessions, while the drug concentration gradually decreased in patients, they showed a fragmentation of the activity areas, with an overall decrease of involved volume and a decline of activity in the supplementary motor area.

The appearing of activity in the ipsilateral motor area matched a partial recovery of supplementary motor area activation. During the last session, when patients showed severe dyskinesia, a widespread region of positive and negative correlations between signal and task was observed.

We conclude that the lack of subcortical circuitry is partially reversible by apomorphine and that when the drug effects are reduced, there is a possible mechanism recruitment of alternate subcortical pathways.

FULL ARTICLE:

http://www.sciencedirect.com/science...53f612477695b2

DISCUSSION from the article above:

Discussion

Our findings clearly show that during the first session, when the patients are still under the effects of apomorphine and have their best performances, the activation patterns are similar to the patterns of normal subjects; however, the total volume of the activated regions is more than doubled if compared to the healthy subjects. Apparently, the drug can restore, at least partially, the subcortical circuitry, thus resulting in particular in SMA activity, but the cooperation of neuronal populations larger than in healthy subjects is required. On the other hand, when the apomorphine effects decrease, the total activated volume also tends to decrease, but the activity spreads in an increasing number of little clusters also present in the ipsilateral region.

These findings and, in particular, the fact that the declining of the drug effects induces a reduction of activated volume, but an increase of involved regions, strongly suggest that the pharmacological effect of apomorphine is at least partially related to its vasodilatory properties.

While the same data from literature agree on the positive effects of the dopaminergic treatment on patients performances [5], [6], [7], [13], [14], [15] and [16], they diverge as regards the interpretation of the pharmacological mechanism and, in particular, about the effects on regional brain activity.

An increase of activity in the SMA induced by dopaminergic treatment was often reported in patients affected by PD in advanced [13], [14] and [15] and early stages [5]. Our results confirm this finding, which can be related to a restoration of efficiency of subcortical loops induced by the drug. However, we observed also a partial recovery of SMA activity during the third session, while activation spots appear in other regions and, specifically, in the ipsilateral M1. On the basis of these results, a switch of circuitry can be hypothesized: as the pharmacological effects decline, a kind of neuronal recruitment seems to occur as the brain copes with the reduction of efficiency of the normal subcortical loops that the drug can typically sustain only at the price of a very large volume of activated brain. However, this hypothesis requires a stronger evidence to be proven.

In fact, the observed clusterization could be ascribed to the expected variation of physiological parameters due to the decreasing vasodilatory effect of the infused drug. This variation has a well-known clinical effect, which is headache related to a CO2 backlog, due to increased blood pressure. But this alternative interpretation does not explain the reappearing of SMA activity, coupled with the development of little activity spots, in particular, in the ipsilateral region. However, an interaction between the hand involved in the task and the extension of the activated regions cannot be ruled out.

A treatment-related increase of activity in the primary sensorimotor cortex of the contralateral side was reported in PET and single photon emission computed tomography studies [13], [14] and [15]. Also, in our results, the activity in contralateral M1 declines when subjects are out of the apomorphine effect, but the overall decrease of activity is comparatively less pronounced due to the corresponding increase of small activated clusters. Activity in the ipsilateral sensorimotor cortex in levodopa-treated PD patients was also reported [15] and ascribed to drug-related involuntary movements of the corresponding hand. In our study, we did not observe significant ipsilateral activity during the first session.

Buhmann et al. [6] tested the levodopa effects on early-stage idiopathic hemiparkinsonian syndrome patients using fMRI. In PD patients, the authors found that bilateral SMA and contralateral M1 showed less activation when the task was performed with the affected side and that levodopa administration lead to an increase of these activations. These areas overlapped with those in which healthy volunteers had stronger activation than PD patients, suggesting a normalization (increase) effect on underactivation of SMA and M1 by levodopa. These results on early stage, hemiparkinsonian subjects are hardly comparable to our findings; however, our data are in good agreement with their results during the first two sessions, confirming the reduced input to the motor cortex coming from the subcortical motor loop in untreated PD subjects, which is reversible by dopaminergic treatment.

Also, Peters et al. [7] studied the effects of apomorphine on activation patterns during a finger-tapping fMRI experiment in PD patients, all of whom were symptomatic on the right side only. An overall decrease of activation areas after apomorphine application was reported: activations were restricted in the contralateral gyrus of both sides (affected and unaffected), while prior to drug injection, a significant extent of ipsilateral and cerebellar activity was observed. The ipsilateral and cerebellar activations were interpreted as indication of coactivation aimed to compensate for the lack of subcortical motor loops. However, rather surprisingly, also when the unaffected side was stimulated, the activation patterns spread in the ipsilateral side, and the injection of apomorphine induced a reduction and focusing of activated patterns. The contradiction between these and other results can be partially explained by taking into account the heterogeneity of the sample, but probably, it is also related to the complex interaction between dispersion and extent of activation areas that we attempted to address with our quantitative approach.

The increase of total volume of regions with task-correlated signal variations during the last session and the corresponding general odd aspect of BOLD maps and quantitative parameters are probably related to different events not easily interpretable basing on these data. Actually, the performances of subjects that in these conditions were very poor (Table 1) and the collapse of BOLD intensity (Fig. 6) suggests a disorganized activity, probably related to the almost complete lacking of the required subcortical loops.

In this work, we reported results that suggest a dynamic change of used subcortical loops corresponding to the decrease of apomorphine plasma concentration in PD-affected patients at advanced state. Our data suggest that the normal circuitry (but with comparatively large activated areas) is maintained by apomorphine and that the brain attempts to deal with reduced apomorphine effects with alternative circuitry, evidenced by spot-like activations located in particular in the ipsilateral motor primary cortex. In advanced-state PD patients, this mechanism cannot indefinitely sustain the motor performances, and the activation patterns evolve to disorganized widespread shapes where BOLD signal changes without clear sign.

In conclusion, the main objective of our study was to point out, by a cluster-based approach, the usefulness of quantitative assessment in evaluating the degree of activation in those subjects when a spread activation is present, causing a possible ambiguity in the interpretation of the results.

Outstanding references and offering real hope........!!

Paula

Apokyn®

Apokyn® is the only therapy available in the US for the acute, intermittent treatment of immobilising “off” episodes associated with advanced Parkinson’s disease. It is administered by means of an injector pen, as needed, to treat periods of immobility in people with advanced disease.

In April 2004, Apokyn® received FDA approval with Orphan Drug designation to treat approximately 112,000 Parkinson's patients who experience the severe “on/off” motor fluctuations unresponsive to other therapies. It was launched in the US in July 2004 and acquired by Vernalis from Mylan Bertek in November 2005. Mylan Bertek originally licensed the product from Britannia Pharmaceuticals Limited in 1999. Apokyn® is now marketed by Vernalis’ newly established neurology sales force, which is focusing its promotional efforts on the high-prescribing neurologists who treat Parkinson’s disease in key US metropolitan areas.

Apokyn® is indicated for the acute, intermittent treatment of hypomobility, or ‘‘off'' episodes (end-of-dose wearing off and unpredictable “on/off” episodes) associated with advanced Parkinson's disease. "Off" episodes are debilitating periods of partial loss of movement or total immobility experienced by patients. As Parkinson's disease progresses, patients may begin to experience immobilising "off" episodes despite treatment with drugs used to increase or replace dopamine, an important brain chemical that is lost in Parkinson's disease leading to poor control of movement and muscle rigidity. Apokyn® is not used to prevent "off" episodes and it does not replace other Parkinson's disease medications, but rather is used as short-term rescue from an "off" episode when it occurs. Patients with Parkinson's disease lose motor control during "off" episodes, making routine tasks such as walking and even speaking extremely difficult. Apokyn® injections can improve function within minutes in Parkinson's disease patients, permitting them to walk, talk and perform normal activities more easily. The intensity, duration and frequency of "off" episodes vary for each sufferer. Patients with Parkinson's or their caregivers administer Apokyn® via injection under the skin.

Since Apokyn® may cause a decrease in blood pressure when first administered, initial treatment is usually conducted under medical supervision. Initial administration of Apokyn® is also associated with nausea and vomiting, so it is usual for patients to take an anti-emetic drug prior to initiating treatment. Evidence suggests, however, that these side effects diminish over time.....

Regulatory Status

Apokyn® was approved through the FDA's Orphan Drug route in April 2004 and was launched in the US in July 2004. It was marketed by Mylan Pharmaceuticals until November 2005 when it was acquired by Vernalis. For full prescribing information, please visit: www.apokyn.com .

In November 2005, Vernalis entered into a collaboration with Britannia Pharmaceuticals to explore the development of new formulations of apomorphine for the US market. Vernalis has exclusive rights to Britannia's technology to develop a continuous sub-cutaneous infusion using a small portable pump for patients with frequent fluctuations or who require multiple injections in a day and to negotiate terms for a nasal powder formulation of apomorphine, which is currently in clinical development in Europe.

http://www.vernalis.com/ver/rdc2/neurology/apokyn/

the olfactory research was just mentioned today in a meeting ..she must have been referring to that. Very interesting so that's moving right along - good!

paula