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Published on 8 April 2011

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Innovations and challenges

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Laurence A Goldberg FRPharmS
Editorial Consultant

Update on stroke management
Effective treatment of stroke depends on rapid recanalisation of cerebral vessels, and given that approximately 2 x 106 neurones are lost every minute in an evolving stroke, “time is brain”, Norbert Nighoghossian (Professor of Neurology, Hôpital Neurologique Pierre Wertheimer, Lyon, France) told the audience.

Some 80% of strokes are due to arterial ischaemia whilst 15–10% are vascular in origin. Stroke is the second most common cause of death in the west and it accounts for 3–5% of public health expenditure in Europe. Strokes also contribute to the development of dementia.

Mortality from stroke can be reduced by prompt treatment but this depends on early recognition. Educating the population about stroke is essential. In Lyon 70% of patients are admitted to the SAMU (Service d’Aide Médicale Urgente) within six hours of the onset of stroke symptoms.

As soon as a cerebral artery is blocked necrosis of cells begins. Around the dead area there is an ischaemic penumbra – poorly perfused cells that could be saved if perfusion is restored quickly. After 100–120 minutes about 50% of brain parenchyma is necrosed and after 400 minutes the symptoms are no longer reversible, explained Professor Nighoghossian.

Thrombolytic therapy is effective in the management of stroke and the earlier the treatment is started the more function is preserved. A study in 1995 showed that in order for one patient to become self-reliant, the number needed to treat (NNT) was between eight and nine. However, intravenous treatment is better for distal arterial occlusion and less effective for proximal (large) arteries, said Prof Nighoghossian. In Germany 6% of patients are eligible for such treatment, in France 1% and in the UK 0.1%. The differences arise because of lower numbers of stroke centres in France and the UK. Haemorrhage – seen in 4–6% of patients – is the main risk with thrombolytic therapy. About two thirds of such haemorrhages are fatal.

Improved recanalisation can be achieved by combining intravenous thrombolytic therapy with intra-arterial thrombectomy, he said. Clinical outcomes can be further improved by using MRI scanning to identify the patients who will benefit from treatment.

There are relatively few pivotal studies that support the use of thrombectomy devices in stroke, according to Xavier Armoiry (departments of innovation and pharmacy, Lyon hospitals, France). The available devices include the ‘fish-type’ e.g. Catch®, the ‘corkscrew-type’ e.g. MERCI retriever®, the aspirator-type e.g. Penumbra® and the ‘stent-like’ e.g. Solitaire®. The Solitaire passes through the clot and is then inflated and withdrawn, achieving perfect retrieval of the clot. The MERCI retriever, which is made of a titanium-based alloy and has a ‘memory’, can retrieve large clots of the type found in patients with atrial fibrillation, noted Dr Armoiry.

At present evidence of efficacy for such devices is based on single-arm studies. Each device costs about €3,000 and they are not reimbursable. Two trials are now in progress in France and in the USA to compare combined thrombolysis and thrombectomy with thrombolysis alone.  In the French study both clinical and economic endpoints will be used.

Flow diversion prostheses are used to prevent rupture of cerebral aneurysms. The traditional approach – surgical clipping of the aneurysm – is invasive. Newer approaches include ‘endovascular coiling’ – implantation of small metallic coils that cause the aneurysmal sac to thrombose and flow diversion stents. The devices cost €10,000–€12,000 and, as yet, there are limited efficacy data and no direct comparisons. However, three trials are planned.

Work in this field is a good example of clinical pharmacy at the leading edge of innovation, concluded Dr Armoiry.

Greater clinical pharmacy expertise and input into the management of stoke patients is needed according to explained Carina Hohmann (clinical pharmacist, Fulda Clinic, Germany).

Key interventions for stroke prevention include reduction of blood pressure, anticoagulation for those with atrial fibrillation and treatment with statins. A study in the USA had shown that 19% of patients hospitalised for acute stroke experienced medication errors – commonly over-rapid antihypertensive treatment putting them at risk of further infarcts and unnecessary antiplatelet treatment putting them at risk of bleeding.

Long-term adherence is also a problem according to a Swedish study of more than 21,000 stroke patients. The study showed that after two years, adherence to antihypertensive treatment was 74%, statins 56%, antiplatelet agents 63% and warfarin 45%.

At the Fulda Clinic a study is now under way in which clinical pharmacists provide detailed information about medication changes and plans in the physician’s discharge letter. This should ensure that patients’ general practitioners have complete, up-to-date information for prescribing.

Treatment options in multiple sclerosis
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterised by demyelinating lesions in the brain and spinal cord, explained David Laplaud (Department of Neurology, Nantes University Hospital, France). It affects one to two people per 1,000 and is three times more common in women. It usually follows relapsing and remitting course.

Recent research suggests that activated CD4 and CD8 lymphocytes are able to cross the blood brain barrier and gain access to brain parenchyma. As there is peripheral activation of the immune system, immunomodulators such as beta-interferon are used as first line treatment. Copaxone is used second line and this appears to act on antigen presenting cells (APCs) to switch cytokine production to a Th2 (anti-inflammatory) pattern. It also has a direct effect on macrophages.  Copaxone reduces the risk of relapse by 30%. Immunosuppressant agents such as mitoxantrone (azathioprine, myfenolate) are limited by their toxicity and only used when nothing else is available, explained Dr Laplaud.

Monoclonal antibodies such as natalizumab have the advantage of specificity. Natalizumab targets VLA4 on endothelial cells; it inhibits migration of cells to the CNS but it also reduces immunosurveillance and carries the risk of progressive multifocal leukoencephalopathy (PML), due to infection with Polyomavirus JC. Alemtuzamab, rituximab and daclizumab target different points in the immune pathway and are also used for treatment of MS.

Cladribine causes apoptosis of lymphocytes and monocytes but can increase risk of infections and cancers.

Fingolimod is a sphingosine-like molecule that induces down-regulation of the sphingosine-1-phosphate (S1P) receptor. It acts on trafficking of T-cells so that naïve T-cells and memory T-cells are trapped in lymph nodes, leading to loss of circulating lymphocytes. Fingolimod is the only product known to cross the blood brain barrier and down-regulate S1P receptors in lesional cells in the CNS.

The FREEDOMS and TRANSFORMS trials demonstrate the efficacy of fingolimod. Both were multicentre, randomised, double-blind trials involved more than 1,200 patients with relapsing MS, explained Sandra Vukusic (professor of neurology, Hôpital Neurologique Pierre Wertheimer, Lyon, France). FREEDOMS compared two different doses of oral fingolimod (0.5mg and 1.25mg) with placebo and TRANSFORMS compared two different doses of oral fingolimod (0.5mg and 1.25mg) with intramuscular interferon beta1a.

The results showed that in both trials the relapse rate was more than halved with fingolimod treatment. In the FREEDOMS trial there was significantly less progression of disability with active treatment.

Serious adverse effects were similar in both studies and included infections and skin cancers. Cardiovascular events such as bradycardia and atrio-ventricular (AV) block were dose-related and thought to arise because of the role of S1P in AV conduction. Macular oedema was also dose-related, added Professor Vukusic.

Fingolimod (Gilenia®, 0.5mg capsules, Novartis) has now been approved by the FDA but has yet to receive approval in Europe.
Biomarkers
Understanding differences at chromosomal, DNA and protein levels provides us with news ways to treat cancer, Jean-Paul Borg (professor of cell biology, University of the Mediterranean, Marseille, France) told the audience. Better biomarkers and better targets for drug treatment are needed, he explained

One area of interest is the large family of kinases. There are more than 500 kinases – some of which are membrane bound and some cytoplasmic. Both dasatinib and imatinib were designed on the basis of what was known about kinases, noted Professor Borg. Tyrosine kinases all have extracellular, tranmural and intracellular regions. The FLT3 mutation, associated with very aggressive acute myeloid leukaemia, was identified recently. This confers high resistance to any tyrosine kinase inhibitor. It can therefore be used to predict resistance to treatment.

About 10% of kinases are pseudokinases that have no catalytic activity (usually because of missing residues in the kinase domain) but are important in tumour growth. For example, HER3 is a pseudokinase that is important in tumour genesis because it can dimerise with HER2 and convert it to its active form.

Recently, PTK7, an ‘orphan pseudokinase receptor’, has been identified in a number of tumours. It is expressed in breast tumours and also in colon cancers where it is linked to a poor prognosis. Studies have shown that PTK7 confers the capacity to migrate and appears to be implicated in the Wnt signalling pathway. The Wnt pathway is deregulated in colon cancer, said Professor Borg. PTK7 is also expressed in a small subset of progenitor cells in the bone marrow. It was found in 72% of cases of acute myeloid leukaemia in one study.  Here, the expression of PTK7 correlates with poor overall survival. PTK7 promotes resistance to anthracycline-induced apoptosis. If expression of the receptor is reduced then sensitivity to anthracycline-induced apoptosis increases. These observations establish that PTK7 is a biomarker – the next question is whether it can also be target. Recent studies have shown that the receptor can be blocked using recombinant soluble PTK7-Fc protein and this partially resensitises the leukaemic cells to anthracycline-induced apoptosis.

Update on colorectal cancer
Colorectal cancer is the third most common cancer worldwide and accounts for 530,000 deaths per year, according to Johannes Kosterink (clinical pharmacist, University Medical Centre, Groningen, The Netherlands). Recent advances in the understanding of tumour biology, such as the roles of KRAS and BRAF mutations, have underpinned the use biological agents in this condition, he continued.

Tumour growth is very dependent on new vascularisation. Activation of vascular endothelial growth factor (VEGF) leads to increased endothelial survival, cell proliferation and migration. Over-expression of VEGF is associated with rapid tumour growth and a poor prognosis. Bevacizumab binds to VEGF preventing activation of the signalling pathway, thereby decreasing angiogenesis and increasing apoptosis. So far, small studies in first line treatment of CRC show that bevacizumab is associated with a small but significant increase in survival.

The endothelial growth factor receptor (EGFR) signalling pathway is important for cell proliferation, migration, angiogenesis and apoptosis. Many signal adaptors and enzymes are involved in this pathway, added Dr Kosterink. Cetuximab targets EGFR with a high affinity, however its effects can be blunted by the presence of KRAS mutations. In patients with the wild-type KRAS gene, when the EGFR receptor is blocked all downstream processes are also blocked. However, the mutated KRAS gene is permanently ‘turned on’ and so EGFR-blocking drugs have no effect. Thus, the benefits of cetuximab and panitumumab treatment are limited to patients with the wild-type gene.

Pharmaceutical care in paediatric cancer
Julie Mycroft (Royal Marsden Hospital, London, UK) emphasised that paediatric cancer is very different from adult cancer. In the UK there are about 1,500 new cases each year but this accounts for only 0.5% of the total cancer burden.

Paediatric cancer treatment is intense, complex and curative. It represents a high-risk governance area where there is little margin for error and therefore pharmacists play a vital role.

Fear of needles is common and therefore most patients have central venous catheters. Children continue to grow during treatment and need adequate nutritional support. Fluid balance can be critical in children because small children in particular can dehydrate quickly and can require hyperhydration – up to 3L/m2day.

Estimation of renal function is important when high doses of nephrotoxic drugs such as methotrexate, cisplatin, carboplatin or ifosfamide are used. Ms Mycroft stressed that when carboplatin is used in children the Calvert formula is not suitable for dosage calculations. Alternative formulae using uncorrected glomerular filtration rate (GFR) should be used.  Furthermore, GFR should be calculated using the Schwartz formula and not the Cockcroft and Gault formula, which is only suitable for over-18s.

Chemotherapy dosing for very small children should be on a mg/kg basis; dosing by body surface area is suitable for children of 10kg–12kg.

Unlicensed and off-label use of medicines is common. A recent survey in a paediatric oncology unit showed that 19% of doses were unlicensed, 26% off-label and 40% of cytotoxic medicines were unlicensed. This causes some practical problems – accurate and reproducible doses are critical but most chemotherapy doses have been developed for adults and few liquid preparations are available. Although ‘specials’ can be made they usually have short expiry dates. Recently a 6-mercaptopurine 10mg tablet has been developed through cooperation between the UK and Germany. A liquid 6-mercaptopurine preparation is also being developed, she added.

Symptom management is also important and an up-to-date understanding of the management of pain, febrile neutropaenia and nausea and vomiting is essential.

Finally, given that cure rates are approximately 75%, long-term follow up for issues such as fertility is also important for this group of patients.



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