monocytes, if stimulated directly with an injec-

tion of hormones, might mature into dendritic

cells in their own bodies.

Early resultsPreliminary results with 21 patients with ad-

vanced cancers have shown promise. The trial

demonstrated that GM-CSF alone had no im-

pact on dendritic cells, but that the two hor-

mones together, especially at higher doses of

IL-4, triggered monocyte maturation into den-

dritic cells; dendritic cell-counts increased by

100-fold. Several patients showed a positive

tumour response with some loss of tumour

mass or reduction in growth rate, although

only one patient showed ‘clinically significant

and sustained tumour regression’, according to

the researchers.

There is a long way to go before this therapy

becomes optimized, although the benefits

to patients are obvious if it proves to be

efficacious, ideally with injections that can be

carried out at home and with minimal side ef-

fects. The researchers hope to begin further

testing of their hormone combination later in

2000 and are likely to focus on prostate cancer.

References1 Roth, M.D. et al. (2000) Granulocyte

macrophage colony-stimulating factor and

interleukin-4 enhance the number and

antigen-presenting activity of circulating

CD141 and CD831 cells in cancer patients.

Cancer Res. 60, 1934–1942

2 Belldegrun, A. (1999) Presentation of renal

tumor antigens by human dendritic cells

activates tumor-infiltrating lymphocytes

against autologous tumors: implications for

live kidney cancer vaccines. Clin. Cancer Res. 5,

445–454

3 Kiertscher, S.M. and Roth, M.D. (1996) Human

CD141 leukocytes acquire the phenotype and

function of antigen-presenting dendritic cells

when cultured in GM-CSF and IL-4. J. Leukocyte

Biol. 59, 208–218

PSTT Vol. 3, No. 6 June 2000 update news

1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00271-6 191

At the end of March this year, the Neurological

Device Panel Advisory Committee (NDPAC) of

the Food and Drug Administration (FDA)

granted marketing clearance to Activa

Parkinson’s Control Therapy, an electronic sys-

tem developed by Medtronic (Minneapolis, MN,

USA) to reduce the disabling motor symptoms

seen in advanced Parkinson’s disease. The vote

of the nine members of the committee was

unanimous, which makes FDA approval likely.

The NDPAC recommendation is, however, con-

tingent on certain conditions; a three-year,

long-term clinical follow-up must be planned,

and the product will require better instructions

for its use by physicians, as well as some label

changes. Despite this, Joseph McGrath of

Medtronic is optimistic. ‘After a recom-

mendation like this, we would normally expect

to receive full FDA approval within 3–6 months,’

he says.

Bilateral deep brain stimulationActiva aims to treat all four major motor symp-

toms associated with the disease, and the side

effects caused by drug therapy. Jerrold Vitek

(Emory University School of Medicine, Atlanta,

GA, USA), one of the clinical neurologists cur-

rently testing Activa and who attended the

NDPAC meeting, says that the device is a big

step forward. ‘Most Parkinson’s patients’ re-

sponse to drug therapy becomes erratic and

they develop complications of excessive and

uncontrolled movement within 5–10 years.

Until recently, the only treatment option avail-

able at that stage was lesioning surgery,’ he ex-

plains. It has been known for a long time that

lesions in the subthalamic nucleus and the in-

ternal segment of the globus pallidus can re-

lieve symptoms such as stiffness, slowness or

lack of movement, shaking and poor balance.

However, lesioning surgery was only performed

on one side of the brain because lesions made

on both sides produced an increased incidence

of side effects and its benefits for symptoms

such as gait and balance were unpredictable.

‘Although gait and balance could be improved

more consistently with bilateral lesions, the

associated side effects are irreversible, and this

became a major disincentive to performing this

procedure,’ says Vitek.

The deep brain stimulation provided by

Activa mimics the effects of surgery; in addi-

tion, it has the advantage of being not only

reversible but also adjustable. The device is

implanted after administration of local anaes-

thetic and patients are fully conscious through-

out. Electrodes are inserted in the brain and

positioned in either the subthalamic nucleus or

the internal segment of the globus pallidus, and

then connected to a small signal generator. The

pulses are adjusted to achieve the greatest re-

duction in unwanted motor symptoms. The

generator, which is a similar size to a cardiac

pacemaker, can then be implanted under the

skin at the collarbone (Fig. 1). ‘Further, non-

invasive adjustment is then possible, and the

maximum effect is usually achieved within a

month after implantation,’ says Vitek.

Evaluation will continueEven if the FDA approves Activa this year, some

important questions about its use remain.

Bilateral brain stimulation for advancedParkinson’s diseaseKathryn Senior, tel: 144 118 942 1639, e-mail: ksenior@dircon.co.uk

Previous trials were not randomized and the

choice of brain site for the electrode was

biased. It was thought that implanting in the

globus pallidus was more effective for involun-

tary movement, whereas implanting in the sub-

thalamic nucleus was better for gait and bal-

ance-related problems. ‘The observations

suggested that both sites worked for a variety

of symptoms,’ says Vitek. Vitek and colleagues

are currently in the middle of a randomized,

double-blinded study to try to resolve this

question. Although the trial will not finish until

the year 2004, Vitek hopes that the statisticians

working with the data will be able to reveal

some interim findings within the next year.

Ryan Uitti (Mayo Clinic, Jacksonville, FL, USA)

says that the device should have a significant

impact on some of the most disabling problems

seen in advanced-stage Parkinson’s disease.

However, he warns that ‘deciding which pa-

tients are most likely to benefit from Activa will

also be a challenge’. It is still unclear whether or

not the device can slow the progression of

motor symptoms if implanted at an earlier

stage of the disease. ‘It is something that

should be investigated, but this may be diffi-

cult to do,’ adds Uitti. Vitek agrees and reports

that a recent survey revealed that approxi-

mately 30% of patients who suffer from

Parkinson’s disease, and whose drug therapy

was still effective, would be prepared to take

the risk of trialing Activa. ‘They were aware that

there were no promises that the treatment

would change the natural history of their dis-

ease, but they were prepared to take the

chance,’ he says.

Uitti also points out that the cost of the

treatment could pose a problem. ‘There is

significant cost for each device (US$12 000);

the cost of implanting two devices and follow-

up care must be added to that for the final

treatment bill, so this can be substantial,’ he

says. McGrath says that the device has been

priced in consultation with Medicare and other

independent healthcare funders in the USA.

‘There is a significant unmet need for Activa

and, so far, indications are that the cost will not

be a problem in this country,’ he adds. McGrath

cites the example of a precursor device to

Activa, which was granted FDA approval three

years ago for essential tremor and tremor in

Parkinson’s. ‘This device was priced at a similar

level but had been accepted by healthcare pay-

ers in all 50 states in the USA within 18 months.

There is no reason to expect less for Activa,’ he

concludes.

update news PSTT Vol. 3, No. 6 June 2000

192

Figure 1. The Activa system providesbilateral deep brain stimulation via twoimplanted electrodes. The signal generatoris implanted under the skin in the patient’schest and can be adjusted non-invasively.

In the July issue of Drug Discovery Today…

Editorial – Navigating the technology mazeby Jon Miller

Update – latest news and views

Strategies for discovering drugs from previously unexplored natural productsAlan Harvey

Drug discovery and vaccine development using mixture-based synthetic combinatorial librariesRichard A. Houghten, Darcy B. Wilson and Clemencia Pinilla

Diversity screening versus focussed screening in drug discoveryMartin J. Valler and Darren Green

Monitor – new bioactive molecules, combinatorial chemistry, invited profile