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Microsoft word - pace bulletin vol 6 no 4 pacef january 2012.doc
Volume 6; Number 4
What’s new this month?
Both tapentadol immediate release tablets (Palexia) and tapentadol prolonged
release tablets (Palexia SR) have been designated RED-RED (see page 3).
Atorvastatin chewable tablets (Lipitor) are designated RED-RED, although it is
recognized that there are exceptional circumstances where they may have a
limited role (i.e. hypercholesterolaemia in children over 10 years and patients
with swallowing difficulties unable to cope with lower cost alternatives)(see
In view of the supply problems with ketoprofen 2.5% gel, alternative topical
NSAIDs are reviewed and lower cost alternatives identified. These include:
generic ibuprofen 5% gel (100g £4.95), ibuprofen 5% gel (Ibugel) (100g £4.87),
ibuprofen 5% gel (Fenbid) (100g £1.50), ibuprofen gel 10% (Fenbid) (100g £4.00)
and piroxicam gel 0.5% (112g £3.40). Of these, ibuprofen 5% gel (Fenbid)
emerges as the lowest cost, but only if supplied in the 100g tube (i.e. not 2 x
50g) (see page 4).
Key patent expiries for 2012/13 are reviewed (see page 6). The impact of the
atorvastatin patent expiry and the need for associated review of rosuvastatin
prescribing is considered in detail (see page 8)
Safety concerns with dabigatran (Pradaxa) are reviewed (see page 10).
New Drug Assessment: Tapentadol immediate release tablets (Palexia)
and tapentadol prolonged release tablets (Palexia SR)
New Formulation Assessment: Atorvastatin chewable tablets (Lipitor)
Review: Topical Non-Steroidal Anti-Inflammatory Drugs
NICE Technology Appraisal 237: Ranibizumab for the treatment of
diabetic macular oedema (November 2011)
NICE Technology Appraisal 240: Panitumumab in combination with
chemotherapy for the treatment of metastatic colorectal cancer
Key Patent Expiries 2012/13
Atorvastatin patent expiry and the future role of rosuvastatin
MHRA: Drug Safety Update (2011): Dabigatran (Pradaxa): risk of serious
haemorrhage; Angiotensin II receptor antagonists; evidence does not
suggest any link with cancer
This bulletin has been created specifically to convey details of decisions taken at the Prescribing and ClinicalEffectiveness Forum (PACEF) to all stakeholders across the Lincolnshire Healthcare Community in both primary andsecondary care. Back issues of the PACE Bulletin
and other PACEF publications are available through the NHSLincolnshire website (www.lincolnshire.nhs.uk). Click on ‘Commissioning’ and follow the links to PACEF.
SUMMARY OF PACEF DECISIONS: FEBRUARY 2012 UPDATE
Traffic Light Status
dyslipidaemia when response to dietand other non-pharmacological
measures is inadequate. As anadjunct to diet in homozygousfamilial hypercholesterolaemia.
Primary prevention of cardiovascularevents in high-risk patients as anadjunct to the correction of other riskfactors.
with non-valvular atrial fibrillation and
previous stroke, transientischaemic attack or systemicembolism.
symptomatic heart failure (>NYHA class II).
> 65 years with diabetes,coronary artery disease orhypertension (110mg and150mg capsules only).
expressing metastatic colorectalcarcinoma, with non-mutated KRASafter failure of fluoropyrimidine,oxaliplatin and irinotecan containingregimens
impairment due to diabetic macularoedema or macular oedemasecondary to retinal vein occlusion.
RED-RED: This signifies that a product is not recommended
for prescribing in either
primary or secondary care. All
new products are classified as RED-RED pending assessment by PACEF.
RED: This signifies that a product has been approved for use within secondary care, tertiary care or a primary care
hosted specialist service only and should not be routinely prescribed in primary care
. RED drugs may be used
within ULHT or LPFT subject to approval for use within each Trust. ULHT and LPFT reserve the right to determine
whether or not RED drugs will be used within their Trusts. RED classification does not automatically signify that a
drug will be available within secondary/tertiary care.
AMBER: This signifies that a drug has been approved for use in primary care subject to specialist initiation; a
shared care guideline (SCG) may also be required
. The main purpose of the SCG will be to clearly define both
specialist and GP responsibilities. Not all AMBER drugs that require SCGs are currently covered by formal
documents; PACEF are working to rectify this.
GREEN: This signifies a product that is approved for initiation in either primary or secondary care.
REPORTING INCIDENTS TO THE NATIONAL PATIENT SAFETY AGENCY (NPSA)
The NPSA are keen to encourage the anonymous reporting of patient safety errors and systems failures both from
healthcare professionals and patients. The National Reporting and Learning System (NRLS) has been set up to
facilitate this process. Healthcare professionals can either report patient safety incidents through their local risk
management scheme or directly into the NRLS using the eForm on the NPSA website. Please access
www.npsa.nhs.uk for more information. All healthcare professionals are encouraged to report incidents, errors
and systems failures; the aim is to help the NHS to learn from things that go wrong.
NEW DRUG ASSESSMENT: TAPENTADOL IMMEDIATE RELEASE TABLETS
(PALEXIA) AND TAPENTADOL PROLONGED RELEASE TABLETS (PALEXIA
Tapentadol is an opioid analgesic combining two mechanisms of action: mu-opioidreceptor agonism and noradrenaline reuptake inhibition. The prolonged-releasetablets (Palexia SR) are licensed for the management of severe chronic pain inadults, which can be adequately managed only with opioid analgesics. Theimmediate-release tablets (Palexia) are licensed for the relief of moderate to severeacute pain in adults.
The efficacy of tapentadol prolonged-release has been assessed in osteoarthritis,low-back and diabetic neuropathic pain. Tapentadol is significantly more effectivethan placebo in reducing average pain intensity, and non-inferior to oxycodonecontrolled-release. Tapentadol has not been compared with opioid analgesics otherthan oxycodone and it has not been studied in cancer pain. The incidence of gastro-intestinal adverse effects is less common with tapentadol than with oxycodone.
The efficacy of tapentadol immediate-release has been assessed in the managementof acute pain associated with bunionectomy and end-stage joint disease. Tapentadolis significantly more effective than placebo in reducing average pain intensity and 50and 75mg doses are non-inferior to oxycodone 10mg.
Tapentadol prolonged-release is the same cost as oxycodone controlled-release inprimary care; immediate-release is slightly more expensive than oxycodone.
PACEF were concerned about the lack of comparative data between tapentadol
and lower cost opioid alternatives such as modified release morphine. It was
acknowledged that the drug emerged as non-inferior to oxycodone in trials,
better tolerated and at a similar cost, but oxycodone is a high-cost intervention
in comparison to alternatives. As a result of this both tapentadol immediate
release tablets (Palexia) and prolonged release tablets (Palexia SR) were
NEW FORMULATION ASSESSMENT: ATORVASTATIN CHEWABLE TABLETS
Pfizer have recently launched a chewable atorvastatin tablet licensed identically tothe established standard atorvastatin tablet. PACEF evaluated this product both interms of its paediatric role and as an alternative for patients who experiencedifficulties taking statins in tablet form due to swallowing difficulties. Atorvastatin islicensed for the treatment of hypercholesterolaemia in children over 10 years,although this role is extremely limited and largely subject to advice from specialisttertiary centres. Similarly, the prescribing of licensed and unlicensed statin liquidformulations in Lincolnshire is low, although high-cost liquid specials remain aproblem and can result in disproportionately high statin prescribing costs aroundindividual patients. Currently, chewable atorvastatin is priced slightly higher than thestandard atorvastatin tablet formulation:
Daily dose range
Cost (£) (28 days)
In view of the forthcoming atorvastatin (Lipitor) patent expiry in May 2012,
PACEF are reluctant to endorse the use of this new chewable formulation
which will reduce potential generic savings if it becomes significantly
established. The paediatric role in children over 10 is extremely limited and
likely to be led by specialist advice. With adult patients genuinely experiencing
swallowing difficulties, standard advice published in PACE Bulletin, Vol 4 No
17 (November 2010) applies. Standard atorvastatin tablets can be crushed or
dispersed slowly in 10mls of water; alternatively, simvastatin tablets can be
dispersed in water or crushed. Atorvastatin liquid specials are available, but
are not licensed for purpose and are prohibitively expensive. In accordance
with MHRA advice, use of a licensed product (i.e. simvastatin or atorvastatin
tablets) in an unlicensed way (i.e. dispersed in water or crushed) is always
preferable to use of an unlicensed product. Atorvastatin chewable tablets
(Lipitor) are designated RED-RED, although it is recognized that there are
exceptional circumstances where they may have a limited role (i.e.
hypercholesterolaemia in children over 10 years and patients with swallowing
difficulties unable to cope with lower cost alternatives).
REVIEW: TOPICAL NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
In NICE Clinical Guideline 59: Osteoarthritis – the care and management ofosteoarthritis in adults
(February 2008), NICE recommend that the pharmaceuticaltreatment of OA should commence with relatively safe options such as paracetamoland/or topical non-steroidal anti-inflammatory drugs (NSAIDs). Topical NSAIDs areparticularly recommended in knee or hand OA (see PACE Bulletin
Vol 2 No 7 (May2008)).
Long standing supply problems affecting the availability of generic ketoprofen 2.5%gel (a preferred first line option) have necessitated a review of the comparative costsof alternative topical NSAIDs. Preferred lower-cost first line options are highlighted inbold.
Pack size (g)
Ketoprofen Gel 2.5% (supply difficulties)
Ibuprofen Gel 5% (generic)
Fenbid Gel 5%
Fenbid Gel 10%
Piroxicam Gel 0.5%
Topical NSAIDs of low acquisition cost should be prescribed first line. Lower
cost topical NSAIDs currently available include: generic ibuprofen 5% gel (100g
£4.95), ibuprofen 5% gel (Ibugel) (100g £4.87), ibuprofen 5% gel (Fenbid) (100g
£1.50), ibuprofen gel 10% (Fenbid) (100g £4.00) and piroxicam gel 0.5% (112g
£3.40). Of these, ibuprofen 5% gel (Fenbid) emerges as the lowest cost, but
only if supplied in the 100g tube (i.e. not 2 x 50g).
The use of premium price products such as ketoprofen gel 2.5% (Oruvail/
Powergel), ibuprofen gel 10% (Ibugel Forte), piroxicam gel 0.5% (Feldene),
felbinac gel 3% and foam 3.17% (Traxam) and diclofenac gel (Voltarol Emulgel)
should be avoided where possible. PACEF are currently working with ULH
Drug and Therapeutics Committee to reduce the initiation of diclofenac gel
(Voltarol Emulgel) within United Lincolnshire Hospitals.
NICE TECHNOLOGY APPRAISAL 237: RANIBIZUMAB FOR THE TREATMENT
OF DIABETIC MACULAR OEDEMA (NOVEMBER 2011)
Ranibizumab is not recommended for the treatment of visual impairment due todiabetic macular oedema. People currently receiving ranibizumab for the treatment ofvisual impairment due to diabetic macular oedema should have the option tocontinue treatment until they and their clinicians consider it appropriate to stop.
Ranibizumab intravitreal injection (Lucentis) has already been approved by
NICE for the treatment of wet age related macular degeneration subject to
criteria and has been designated RED for this indication by PACEF. Following
the publication of NICE TA237, ranibizumab is designated RED-RED for the
treatment of diabetic macular oedema.
NICE TECHNOLOGY APPRAISAL 240: PANITUMUMAB IN COMBINATION WITH
CHEMOTHERAPY FOR THE TREATMENT OF METASTATIC COLORECTAL
CANCER (DECEMBER 2011)
NICE is unable to recommend the use in the NHS of panitumumab in combinationwith chemotherapy for the treatment of metastatic colorectal cancer because no
evidence submission was received from the manufacturer or sponsor of thetechnology. This appraisal relates to the treatment of wild-type KRAS metastaticcolorectal cancer for first-line treatment in combination with FOLFOX, and forsecond-line treatment in combination with FOLFIRI for patients who have receivedfirst-line fluoropyrimidine-based chemotherapy (excluding irinotecan).
Panitumumab intravenous infusion (Vectibix) in combination with
chemotherapy is designated RED-RED for the treatment of metastatic
KEY PATENT EXPIRIES 2012/13
Many prominent brand name pharmaceuticals are due to go off-patent within the next12 months. The most widely anticipated of these is atorvastatin (Lipitor) in May 2012(discussed in some detail later in the Bulletin
). The table below highlights the mostimportant patent expiries and their implications for primary care.
available, but the NHSreimbursement price is yet to fallsignificantly. Prescribers shouldensure that all scripts aregenericized and that the use of lineextensions such as olanzapineorodispersible tablets (ZyprexaVelotab) is reviewed.
patent life A2RAs (olmesartan andtelmisartan) are in process in manypractices. Many of the remainingA2RAs are likely to becomeavailable as low cost generics in thecoming 12 months. NICE nowrecommend an ACEI or a low costA2RA as first line treatment ofchoice in people under 55 withhypertension (see PACE Bulletin
Vol6 No 1 (January 2012). At present,losartan is the only low cost A2RAavailable but this is set to change inthe coming months. Prescribers whowere reluctant to support therapeuticswitching to losartan will be asked toreconsider once a wider range ofgeneric A2RAs becomes available.
glaucoma will be reviewed in early2012 to address the implications fortherapy of low cost latanoprost eyepreparations in comparison to highercost branded preparations(bimatoprost, tafluprost andtravoprost). Genericlatanoprost/timolol eye preparationsare also likely to become availablelater in 2012.
acetylcholinesterase (AChE)inhibitors, donepezil, galantamineand rivastigmine, as options for themanagement of mild to moderate
Alzheimer’s disease. However, theyemphasise the importance of startingtherapy with the AChE inhibitor oflowest acquisition cost. At present,all three medicines are broadlycomparable in price; patent expiryand generic availability may changethis and will be kept under review.
range of products containingmometasone in relation toalternatives remains to be seen.
line treatment choices for migraine.
PACEF will review later in the yearonce the implications of genericprice reductions become fullyapparent.
patent expiry that should contributeto significant reductions inprescribing costs in mental health in2012/13. Guidance around the useof Seroquel XL will be reviewed byPACEF in preparation.
practices in Lincolnshire favourcandesartan and will makesignificant savings from this patentexpiry. Therapeutic switching fromtelmisartan/olmesartan tocandesartan is likely to be an optionin some practices.
should result in low cost genericatorvastatin by October 2012.
Simvastatin 40mg will remain thefirst line drug of choice, but practicesshould ensure that atorvastatinbecomes the preferred second linestatin of choice (where simvastatinand pravastatin are eitherinsufficiently effective or poorlytolerated). Practices currentlyprescribing rosuvastatin in this rolewill need to review their practice.
Product switching away fromrosuvastatin will remain a priority in2012/13 in preparation for this patentexpiry. New initiations ofrosuvastatin will be stronglydiscouraged (see below).
to significantly reduce treatmentcosts in the area of urinaryincontinence. Guidance on thetreatment of over active bladder isunder review with urologists. Therole of tolterodine will be clarifiedand the future of line extensionssuch as Detrusitol XL considered.
The place of higher cost alternativessuch as fesoterodine (Toviaz)(currently RED-RED) is also part ofthis review.
practices are already usinggenerically available lower costalternatives.
glaucoma will be reviewed in early2012.
ATORVASTATIN PATENT EXPIRY AND THE FUTURE ROLE OF
The atorvastatin (Lipitor) patent is due to expire in May 2012 with generic versionsexpected to be available from wholesalers from the outset. It will take some time forthe generic reimbursement price of atorvastatin to fall, but the interest from genericmanufacturers and the likelihood of strong competition between different genericatorvastatin products is likely to drive prices down relatively quickly. As a result, it isexpected that generic atorvastatin will move into Category M of the Drug Tariff
veryquickly with NHS reimbursement prices expected to begin to fall by October 2012. Inpreparation for this, PACEF have already endorsed atorvastatin as our preferredhigh-cost high-potency statin where lower cost generic statins are either insufficientlyeffective or poorly tolerated. In a best case scenario where atorvastatin prices fall toa level comparable with the current simvastatin 40mg generic price, the likely annualsavings across Lincolnshire are £3.88M pa broken down between the ClinicalCommissioning Groups as follows:
Potential Annual Saving
The speed and extent to which generic atorvastatin prices will fall remains to beseen; while the financial impact of the atorvastatin patent expiry will be significant, itis likely to be 2013/14 before the full impact is felt. Nonetheless, Lincolnshire CCGssupported by the Prescribing and Medicines Management Team will need to takeaction in the coming months to ensure that Lincolnshire maximises the potentialimpact of the savings linked to this patent expiry.
Practices should continue to follow existing PACEF lipid modification
guidance (see PACE Bulletin Vol 4 No 13 (August 2010). Simvastatin 40mg
remains the first line drug of choice in both primary and secondary prevention
of CVD. In secondary prevention of CVD where treatment to target is advocated
(5mmol/l Total Cholesterol; 3mmlol/l LDL-C), atorvastatin is the second line
statin of choice (where simvastatin and pravastatin are either insufficiently
effective or poorly tolerated). In primary prevention of CVD a standard ‘fire-
and-forget’ dose of simvastatin 40mg (or pravastatin 40mg if not tolerated)
should be sufficient for most patients.
What about rosuvastatin (Crestor)?
Licensed indications, outcomes data and safety concerns
Rosuvastatin (Crestor) has a narrower range of licensed indications than most of theother statins. It is licensed for the treatment of hypercholesterolaemia (including
familial hypercholesterolemia) and for the prevention of cardiovascular events inpatients at high risk of first cardiovascular event (primary prevention).It is not licensedfor the secondary prevention of CVD, despite its widespread use for this indication.
Until the publication of the JUPITER trial there was no published outcomes dataavailable. The recently published SATURN study compared treatment withatorvastatin 80mg or rosuvastatin 40mg in people with CHD. Both groups saw aregression in atherosclerosis from baseline in about two-thirds of patients but therewas no statistically significant difference between the two groups.
Rosuvastatin (Crestor) is not licensed for the secondary prevention of CVD
despite the fact that the majority of prescriptions written for rosuvastatin each
year are for this indication. Safety concerns remain around the risk of muscle
disorders and rhabdomyolysis at the higher doses and have been recently
reiterated by the MHRA (see PACE Bulletin, Vol 6 No 3 (January 2012)). As a
result of this, the prescribing of rosuvastatin is only justified if a patient with
raised cholesterol does not respond adequately to maximal doses of other
statins or if a patient cannot tolerate alternatives. Advice from local cardiologists
is that a low dose of rosuvastatin (5mg) may be tolerated where intolerance to
other statins has been proven to be a problem. Rosuvastatin should always be
considered prior to introducing ezetimibe as it is comparable in cost,
substantially more effective at lowering TC and LDL-C and has published
outcomes data. Rosuvastatin (Crestor) remains under patent until 2018 and will
become the only remaining high-cost, high-potency branded statin after May
2012. Prescribers are urged to review all patients currently taking rosuvastatin
to ensure that: (1) rosuvastatin is not being inadvertently prescribed for
primary prevention of CVD where simvastatin 40mg or pravastatin 40mg
should be the dominant products; (2) the majority of patients prescribed
rosuvastatin for secondary prevention of CVD are switched to simvastatin
40mg where this has never been tried or an equivalent dose of atorvastatin
where a high-potency agent is clinically necessary. Patients who are intolerant
to alternatives or who have failed to respond sufficiently to alternative statins
can remain on rosuvastatin therapy, although this is envisaged to be far fewer
patients than are currently treated with the drug.
We currently spend £1.9Mpa on rosuvastatin in Lincolnshire and £4.5Mpa in EastMidlands as a whole. Almost half of the rosuvastatin prescribed in the whole of theEast Midlands is in our county. The quarterly expenditure on rosuvastatin in each ofthe Lincolnshire CCGs is detailed below (September 2011 Qtr):
Following atorvastatin patent expiry, rosuvastatin to atorvastatin switches are likely torelease an additional annual saving in Lincolnshire of £1.45Mpa (assuming that theprice of generic atorvastatin will fall to a level comparable with generic simvastatinand that 80% of rosuvastatin scripts are appropriate to switch to genericatorvastatin). The potential annual savings at CCG level from pursuing such astrategy are detailed below:
Potential Annual Saving
The atorvastatin (Lipitor) patent expiry alone will potentially save £3.88Mpa
across Lincolnshire. However, the full impact of this patent expiry is unlikely to
be felt until 2013/14. Lincolnshire has high residual use of rosuvastatin and
must tackle this problem to avoid continued investment in a high-cost long
patent life statin until 2018. Rosuvastatin to atorvastatin switches are
encouraged in 2012/13 in order to maximise the financial impact of the
atorvastatin patent expiry as far as possible. Additional savings of £1.45Mpa
across Lincolnshire could be achieved if rosuvastatin to atorvastatin switch
programmes are implemented. The Prescribing and Medicines Management
Team are developing resources for use in 2012/13 to support the
implementation of this switch.
MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY: DRUG
SAFETY UPDATE (DECEMBER 2011)
Dabigatran (Pradaxa): risk of serious haemorrhage – need for renal function
A number of cases of serious and fatal haemorrhage have been reported in
elderly patients with renal impairment who were receiving dabigatran.
Renal function should be assessed in all patients before starting dabigatran and
at least once a year in patients older than 75 years or those with suspecteddecline in renal function,
Dabigatran has a rapid onset of action and does not require therapeutic
monitoring. It is eliminated unchanged in urine. Exposure to dabigatran issubstantially increased in patients with renal insufficiency.
To minimise the risk of bleeding, dabigatran is contraindicated in patients with
severe renal impairment (creatinine clearance <30mL/min).
In moderate renal impairment (creatinine clearance 30 - 50mL/min), a dose
reduction and close clinical surveillance should be considered, particularly inthose at increased risk of bleeding. Similar precautions are advocated in thoseover 75.
There is no specific antidote to dabigatran.
There are a number of case reports of fatal haemorrhage with dabigatran for the
prevention of systemic embolism in patients over 75 who had renal impairmentand additional risk factors for bleeding (including concomitant medication). Half ofthe cases had severe renal impairment (a contra-indication for dabigatran).
It is important to remember that haemorrhage is a well recognised adverse
outcome of any anticoagulant; all patients at increased risk of bleeding requireclose monitoring.
For warfarin, a dose reduction in elderly people should be considered and
increased frequency of INR monitoring in patients at high risk of bleeding,including those with renal insufficiency.
For rivaroxaban (Xarelto), caution is required in patients with severe renal
impairment (creatinine clearance < 30mL/min) or moderate hepatic impairment. Itis not recommended in patients with a creatinine clearance of less than15mL/min.
Do not start dabigatran in any patient with severe renal impairment (creatinine
Assess renal function: (1) in all patients before starting dabigatran; (2) when a
decline in renal function is suspected during treatment (e.g. hypovolaemia,dehydration or with some co-medications); (3) at least annually in patients over75; (4) at least annually in patients with renal impairment.
Check for signs of bleeding or anaemia and stop treatment if severe bleeding
There is still no approved role for the use of dabigatran in Lincolnshire primary
care. NICE have approved dabigatran for the prevention of venous
thromboembolism after hip or knee replacement surgery in adults, although
ULH prefer to use rivaroxaban for this indication (also approved by NICE). Both
drugs are designated RED, with ULH providing the patient with the complete
course. As discussed in PACE Bulletin Vol 5 No 17 (October 2011), dabigatran
for the prevention of stroke and systemic embolism in patients with non-
valvular atrial fibrillation remains RED-RED pending publication of the relevant
NICE Technology Appraisal.
Angiotensin II receptor antagonists: evidence does not suggest any link with
The European Medicines Agency’s Committee for Medicinal Products for Human
Use (CHMP) has reviewed a possible link between ARBs and the occurrence ofnew cancers and has concluded that the evidence does not support anyincreased risk.
Many thanks to Cathy Johnson, Interface Lead Pharmacist, NHSL, Gill Kaylor,Prescribing Adviser, NHSL and Robyn Thompson, Senior Pharmacist, ULH for theircontributions to this Bulletin
Stephen GibsonHead of Prescribing and Medicines ManagementNHS Lincolnshire
Sandra Wood – copyright Respecting, navigating and negotiating the delicate interplay between the aspirations of carers and care-recipients Introduction • Thank you to our Hong Kong hosts, thank you for your welcome. I’m here to talk about respite. I’m speaking particularly about the respite program I work in, Southern Respite Service, in Victoria, Australia, and I want t
European Journal of Human Genetics (2009) 17, 793 – 801& 2009 Macmillan Publishers Limited All rights reserved 1018-4813/09 $32.00Variable number of tandem repeat polymorphismsof DRD4: re-evaluation of selection hypothesis andanalysis of association with schizophreniaEiji Hattori1,4, Mizuho Nakajima1,4, Kazuo Yamada1, Yoshimi Iwayama1, Tomoko Toyota1,Naruya Saitou2 and Takeo Yoshikawa*,1